All Topics Are Updated As New Evidence Becomes Available and Our Peer Review Process Is Complete

Direccin Provincial de Salud de Cotopaxi
Hospital Provincial General de Latacunga
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2013. | This topic last updated: jul 19, 2013.
INTRODUCTION Rheumatoid arthritis (RA) is a symmetric, inflammatory, peripheral polyarthritis of
unknown etiology. It typically leads to deformity through the stretching of tendons and ligaments and
destruction of joints through the erosion of cartilage and bone. If it is untreated or unresponsive to
therapy, inflammation and joint destruction lead to loss of physical function, inability to carry out daily
tasks of living, and maintenance of employment.
Early recognition and treatment with disease-modifying antirheumatic drugs is important in achieving
control of disease and prevention of joint injury and disability. However, in patients with early disease,
the joint manifestations are often difficult to distinguish from other forms of inflammatory polyarthritis.
The more distinctive signs of RA, such as joint erosions, rheumatoid nodules, and other extraarticular
manifestations, are seen primarily in patients with longstanding, poorly-controlled disease but are
frequently absent on initial presentation.
This topic will review the approach to the diagnosis and differential diagnosis of RA. The clinical
features of this disorder, its extraarticular manifestations, and laboratory markers that are clinically
useful in the diagnosis of RA are discussed in detail separately. (See "Clinical features of rheumatoid
arthritis" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis" and
"Clinically useful biologic markers in the diagnosis and assessment of outcome in rheumatoid
arthritis".)
EVALUATION FOR SUSPECTED RA RA should be suspected in the adult patient who presents
with inflammatory polyarthritis. The initial evaluation of such patients requires a careful history and
physical examination, along with selected laboratory testing to identify features that are characteristic
of RA or that suggest an alternative diagnosis. (See "Clinical features of rheumatoid arthritis" and
'Differential diagnosis' below.)
We focus especially on the following for the purposes of diagnosis:
We perform a thorough medical history, with particular attention to joint pain, reported
swelling, and the presence, location (peripheral joints rather than low back), and duration
(at least 30 minutes) of morning stiffness. The absence of other conditions or symptoms
suggesting an alternative diagnosis, such as psoriasis, inflammatory bowel disease, or a
systemic rheumatic disease such as systemic lupus erythematosus (SLE), helps to
exclude other disorders.
Symptoms of arthritis that have been present for a short time (for example, less than six
weeks) may well be due to an acute viral polyarthritis rather than to RA. The longer
symptoms persist, the more likely the diagnosis of RA becomes. Thus, in patients
presenting very early, close observation with frequent follow-up appointments is required,
with repeated serologic analysis for anti-cyclic citrullinated peptide (CCP) antibodies,
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rheumatoid factor, and acute-phase reactants. In a minority of patients, several such

visits are required before the differential diagnosis between RA and viral arthritis
becomes established. (See "Clinical features of rheumatoid arthritis", section on 'Typical
"classic" RA' and 'Differential diagnosis' below.)
A complete physical examination is indicated to assess for synovitis, including the
presence and distribution of swollen or tender joints and limited joint motion;
extraarticular disease manifestations, such as rheumatoid nodules; and signs of
diseases, such as systemic lupus erythematosus or psoriasis, included in the differential
diagnosis. (See "Clinical features of rheumatoid arthritis", section on 'Physical findings'
and "Rheumatoid nodules" and 'Differential diagnosis' below.)
We perform the following laboratory tests, which support the diagnosis if positive and/or
elevated:
Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies We

perform both RF and anti-CCP antibody testing when initially evaluating a patient
with suspected RA. The results of both tests are informative, since a positive result
for either test increases overall diagnostic sensitivity, while the specificity is increased
when both tests are positive. Despite this, both tests are negative on presentation in
up to 50 percent of patients and remain negative during follow-up in 20 percent of
patients with RA. (See "Clinically useful biologic markers in the diagnosis and
assessment of outcome in rheumatoid arthritis", section on 'Rheumatoid factors' and
"Clinically useful biologic markers in the diagnosis and assessment of outcome in
rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies'.)
Erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) levels
Both the ESR and CRP are typically elevated in RA. (See "Clinically useful biologic
markers in the diagnosis and assessment of outcome in rheumatoid arthritis", section
on 'Erythrocyte sedimentation rate' and "Clinically useful biologic markers in the
diagnosis and assessment of outcome in rheumatoid arthritis", section on 'C-reactive
protein'.)
We perform the following testing in all patients, which may be helpful in the differential
diagnosis of RA and as baseline testing for monitoring of disease activity or progression
and medication safety:
Antinuclear antibody (ANA) testing A negative ANA helps exclude SLE and other
systemic rheumatic diseases; the ANA may be positive in up to one-third of patients
with RA. In patients with a positive ANA, anti-double stranded DNA and anti-Smith
antibody testing should also be performed; these antibodies have high specificity for
SLE. (See "Measurement and clinical significance of antinuclear antibodies".)

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Complete blood count (CBC) with differential and platelet count, tests of liver and
kidney function, serum uric acid, and a urinalysis The CBC is often abnormal in
RA, with anemia and thrombocytosis consistent with chronic inflammation. Liver and
kidney testing abnormalities indicate a disorder other than RA; if caused by comorbid
conditions, they may affect therapeutic choices or drug dosing. Hyperuricemia may
prompt additional efforts, including arthrocentesis and crystal search, to exclude
gout; polyarticular gout can infrequently be mistaken for RA. (See "Hematologic
manifestations of rheumatoid arthritis", section on 'Anemia of chronic disease' and
"Hematologic manifestations of rheumatoid arthritis", section on 'Platelet
abnormalities' and 'Differential diagnosis' below.)
Radiographs of the hands, wrists, and feet We obtain radiographs during the initial
evaluation primarily as a baseline for monitoring disease progression. However,
characteristic joint erosions may be observed in patients presenting with symptoms
for the first time and, hence, aid in diagnosis. Additionally, in patients with other
disorders, such as psoriatic arthritis, spondyloarthropathy, gout, or chondrocalcinosis,
radiographic changes more characteristic of these conditions may point to an
alternative diagnosis. (See '2010 ACR/EULAR criteria' below and 'Differential
diagnosis' below and "Clinical features of rheumatoid arthritis", section on 'Imaging'.)
We perform the following studies in selected patients:
Serologic studies for infection In patients with a very short history (for example,
less than six weeks) particularly those who are seronegative for anti-CCP and
rheumatoid factor, we perform serologic testing for human parvovirus B19, hepatitis
B virus (HBV), and hepatitis C virus (HCV). In areas endemic for Lyme disease, we
perform serologic studies for Borrelia as well. (See 'Acute viral polyarthritis' below
and "Specific viruses that cause arthritis" and "Diagnosis of Lyme disease", section
on 'Indications for serologic testing'.)
Synovial fluid analysis We perform arthrocentesis and synovial fluid analysis for
the diagnosis or exclusion of gout, pseudogout, or an infectious arthritis if a joint
effusion is present and if there is uncertainty regarding the diagnosis, particularly in
the setting a monoarthritis, oligoarthritis, or asymmetric joint inflammation. Synovial
fluid testing should include a cell count and differential, crystal search, as well as
Gram stain and culture. Synovial fluid analysis should also be obtained to exclude
infection or crystalline arthropathy in patients who undergo glucocorticoid injections
for symptomatic relief. (See "Clinical features of rheumatoid arthritis", section on
'Laboratory findings' and "Synovial fluid analysis and the diagnosis of septic
arthritis".)
MRI and ultrasound Magnetic resonance imaging (MRI) studies and
ultrasonography do not have an established role in the routine evaluation of patients
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with polyarthritis. However, MRI and ultrasound are more sensitive than radiography
at detecting changes resulting from synovitis and may be helpful in establishing the
presence of synovitis in patients with normal radiographs and uncertainty regarding
either the diagnosis or the presence of inflammatory changes, such as patients with
obesity or subtle findings on examination. (See "Clinical features of rheumatoid
arthritis", section on 'Imaging'.)
DIAGNOSIS
Our diagnostic criteria The diagnosis of RA can be made when the following clinical features are
all present:
Inflammatory arthritis involving three or more joints (see "Clinical features of rheumatoid
arthritis", section on 'Physical findings')
Positive rheumatoid factor (RF) and/or anti-citrullinated peptide/protein antibody (such as
anti-CCP) testing (see "Clinically useful biologic markers in the diagnosis and
assessment of outcome in rheumatoid arthritis", section on 'Anti-citrullinated peptide
antibodies')
Elevated levels of C-reactive protein (CRP) or the erythrocyte sedimentation rate (ESR)
(see "Clinically useful biologic markers in the diagnosis and assessment of outcome in
rheumatoid arthritis", section on 'Erythrocyte sedimentation rate')
Diseases with similar clinical features have been excluded, particularly psoriatic arthritis,
acute viral polyarthritis, polyarticular gout or calcium pyrophosphate deposition disease,
and systemic lupus erythematosus. (See 'Differential diagnosis' below.)
The duration of symptoms is more than six weeks.
These criteria are consistent with the 2010 ACR/EULAR classification criteria for RA. (See '2010
ACR/EULAR criteria' below.)
The diagnosis of RA may also be made in some patients who do not meet all of our criteria. (See
'Patients not meeting above criteria' below.)
Inflammatory arthritis Arthritis is typically present in the metacarpophalangeal (MCP) and

proximal interphalangeal (PIP) joints of the hands. The wrists are also commonly involved, as are the
metatarsophalangeal (MTP) joints in the feet, but any upper or lower extremity joint may be affected.
Symmetric polyarthritis, particularly of the MCP, MTP, and/or PIP joints, strongly suggests RA.
Although distal interphalangeal (DIP) joint disease can occur in patients with RA, DIP involvement
strongly suggests a diagnosis of osteoarthritis or psoriatic arthritis. (See "Clinical features of
rheumatoid arthritis", section on 'Physical findings' and 'Osteoarthritis' below and 'Psoriatic arthritis'
below.)
Serology Rheumatoid factors (RF) occur in 70 to 80 percent of patients with RA. Their diagnostic
utility is limited by their relatively poor specificity since they are found in 5 to 10 percent of healthy

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individuals, in 20 to 30 percent of people with SLE, in virtually all patients with mixed cryoglobulinemia
(usually caused by hepatitis C virus infections), and in those with many other inflammatory conditions.
Higher titers of RF (at least three times the upper limit of normal) have somewhat greater specificity for
RA. The prevalence of RF positivity in healthy individuals rises with age. (See "Origin and utility of
measurement of rheumatoid factors" and "Clinically useful biologic markers in the diagnosis and
assessment of outcome in rheumatoid arthritis", section on 'Rheumatoid factors'.)
Antibodies to citrullinated peptides/proteins are usually measured by enzyme linked immunosorbent

assays using cyclic citrullinated peptides (CCP) as antigen. Anti-CCP antibodies have a similar
sensitivity to RF for RA but have a much higher specificity (95 to 98 percent) [1-4]. The specificity is
greater in patients with higher titers of anti-CCP antibodies (at least three times the upper limit of
normal). Another test, anti-mutated citrullinated vimentin, gives similar results to anti-CCP and is used
as an alternative in some laboratories [5]. (See "Clinically useful biologic markers in the diagnosis and
assessment of outcome in rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies'.)
Acute phase reactants Elevations of the ESR and/or CRP level are consistent with the presence
of an inflammatory state, such as RA. Normal acute phase reactants may occur in untreated patients
with RA, but such findings are very infrequent. The degree of elevation of these acute phase reactants
varies with the severity of inflammation. As an example, an ESR of 50 to 80 is not uncommon in
patients with severely active RA. By comparison, an ESR of 20 to 30 can be observed with only a few
mildly to moderately active joints. Although increased levels of acute phase reactants are not specific
for RA, they are often useful for distinguishing inflammatory conditions from noninflammatory disorders
that present with musculoskeletal symptoms (eg, osteoarthritis or fibromyalgia). (See "Acute phase
reactants" and "Clinically useful biologic markers in the diagnosis and assessment of outcome in
rheumatoid arthritis", section on 'Erythrocyte sedimentation rate' and "Clinically useful biologic markers
in the diagnosis and assessment of outcome in rheumatoid arthritis", section on 'C-reactive protein'.)
Patients not meeting above criteria The diagnosis of RA may also be made in patients without all
the criteria described in the previous section. Examples include the following:
Seronegative RA Patients who lack both rheumatoid factor and anti-CCP antibodies
may be diagnosed with RA based upon findings otherwise characteristic of RA if
appropriate exclusions have been met. Such patients with seronegative RA differ from
anti-CCP-positive patients genetically and in their environmental risks, disease severity,
and clinical responsiveness to some medications [6]. Additional research is needed to
better characterize this population.
Recent onset RA Patients with disease for less than six weeks may be diagnosed
with RA based upon findings otherwise characteristic of RA, including anti-CCP
antibodies, if testing for viral serologies is negative and if other appropriate exclusions
have been met. (See 'Evaluation for suspected RA' above and 'Acute viral polyarthritis'
below.)

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Inactive RA Patients without active arthritis or elevated acute phase reactants (eg,
due to treatment of recent onset disease or with longstanding disease) may be
diagnosed with RA based upon well-documented past findings characteristic of RA,
especially in the presence of positive testing for RF and anti-CCP, or of typical bone
erosions on radiography, and in the absence of an alternative more likely diagnosis.
Patients in the several categories above, and other patients who should be diagnosed with RA but do
not meet our standard criteria, will generally have findings that are consistent with the 2010 American
College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification
criteria for RA [7,8]. These criteria were developed for the classification of patients with RA for the
purpose of epidemiologic studies and clinical trials, not primarily for clinical diagnosis. Nevertheless,
the same features that are of value in classification tend to be useful for the purpose of diagnosis in
clinical practice. Further study is required to establish their utility as diagnostic criteria in general
practice. (See 'Classification criteria' below.)
CLASSIFICATION CRITERIA The 2010 American College of Rheumatology (ACR) and European
League Against Rheumatism (EULAR) classification criteria focus on features that would identify
patients at an earlier stage of disease than would the previously used criteria that had been last
revised in 1987 [7-10]. The 1987 ACR criteria were formulated to distinguish patients with established
RA from patients with other defined rheumatic diseases; the 2010 ACR/EULAR criteria for RA focused
on identifying the factors, among patients newly presenting with undifferentiated inflammatory
synovitis, which could allow for the identification of patients for whom the risk of symptom persistence
or structural damage is sufficient to be considered for intervention with disease-modifying
antirheumatic drugs [7,8]. (See below.)
2010 ACR/EULAR criteria Using the 2010 ACR/EULAR criteria (table of 2010 ACR/EULAR criteria
shown at: www.rheumatology.org/practice/clinical/classification/ra/ra_2010.asp [accessed September
21, 2010]), classification as definite RA is based upon the presence of synovitis in at least one joint,
the absence of an alternative diagnosis that better explains the synovitis, and the achievement of a
total score of at least 6 (of a possible 10) from the individual scores in four domains. The highest score
achieved in a given domain is used for this calculation. These domains and their values are:
Number and site of involved joints
2 to 10 large joints (from among shoulders, elbows, hips, knees, and ankles) = 1
point
1 to 3 small joints (from among the metacarpophalangeal joints, proximal
interphalangeal joints, second through fifth metatarsophalangeal joints, thumb
interphalangeal joints, and wrists) = 2 points
4 to 10 small joints = 3 points
Greater than 10 joints (including at least 1 small joint) = 5 points
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Serological abnormality (rheumatoid factor or anti-citrullinated peptide/protein antibody)
Low positive (above the upper limit of normal, ULN) = 2 points

High positive (greater than three times the ULN) = 3 points
Elevated acute phase response (erythrocyte sedimentation rate or C-reactive protein)

above the ULN = 1 point
Symptom duration at least six weeks = 1 point
In addition to those with the criteria above, which are best suited to patients with newly presenting
disease, the following patients are classified as having RA:
Patients with erosive disease typical of RA with a history compatible with prior fulfillment
of the criteria above
Patients with longstanding disease, including those whose disease is inactive (with or
without treatment) who have previously fulfilled the criteria above based upon
retrospectively available data
1987 ACR criteria It is important to recognize that RA has been defined in virtually all clinical trials
of drugs for RA initiated from 1987 through 2010 based upon the criteria developed and validated by
the American College of Rheumatology (previously the American Rheumatism Association) in 1987
(table 1) [9,10]. A patient was classified as having RA if at least four of these seven criteria were
satisfied; four of the criteria must have been present for at least six weeks: morning stiffness, arthritis
of three or more joint areas, arthritis of the hands, and symmetric arthritis. Rheumatoid factor was
included as a criterion, but anti-CCP antibody testing was not available at that time. The other two
criteria were rheumatoid nodules and radiographic erosive changes typical of RA, but these are
generally not present in the early stages of disease.
Thus, while these criteria were very good at separating inflammatory from noninflammatory arthritis,
the major drawback of the 1987 criteria has been their insensitivity in identifying some patients with
early disease who subsequently develop typical established RA [10]. On the other hand, the criteria
did not require any exclusions, and patients could initially fulfill the diagnostic criteria but occasionally
evolve into other diagnoses, particularly systemic lupus erythematosus (SLE), Sjgren's syndrome,
scleroderma, mixed connective tissue disease, psoriatic arthritis, and crystalline arthritis.
DIFFERENTIAL DIAGNOSIS A variety of conditions must be considered in the differential

diagnosis of RA. Features of some disorders that are included in the differential diagnosis of RA are
shown in the table (table 2). (See "Evaluation of the adult with polyarticular pain".)
Acute viral polyarthritis A number of viral infections may cause an acute viral polyarthritis.

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Viral infections such as rubella [11], parvovirus B19 [12], and HBV can cause an acute
polyarthritis syndrome that may be mistaken for the inflammatory polyarthritis of RA.
However, the syndrome is usually short-lived, lasting only from a few days to several
weeks, and rarely beyond six weeks. HCV can cause a polyarthritis or oligoarthritis in a
minority of patients but is more commonly associated with arthralgias.
Serologic testing can help identify patients with HBV, HCV, or human parvovirus B19 in
some individuals with early disease, but a viral etiology cannot always be excluded until
after symptoms are present for at least six to eight weeks in the absence of diagnostic
serologic testing for a specific virus. (See "Specific viruses that cause arthritis".) Unlike
rheumatoid factor (which may occur in patients with a variety of infections, including HCV
infection), anti-CCP antibodies are usually negative in patients with HCV infection who do
not have RA. (See "Clinically useful biologic markers in the diagnosis and assessment of
outcome in rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies'.)
Increasingly reported in travelers, alphaviruses are globally distributed mosquito-borne
RNA viruses that cause epidemics of polyarthritis/arthralgia [13,14]. Among all of the
viruses that can cause arthritis, the alphaviruses are unusual because nearly all
symptomatic infections in adults result in joint symptoms. The incubation period lasts
from several days to three weeks; infection is typically associated with triad of fever,
arthritis, and rash [13]. However, all aspects of the triad may not be present, thereby
making the diagnosis difficult. One such alphavirus, Chikungunya, has become a global
disease with increasing world travel and has caused large outbreaks in Italy, India, and
Indian Ocean islands [15,16].
Alphavirus infections generally resolve over three to six months. The diagnosis of
alphavirus infection can be made by appropriate serologic testing in travelers from
endemic areas with persistent arthritic symptoms. (See "Specific viruses that cause
arthritis", section on 'Alphaviruses' and "Chikungunya fever".)
A large joint arthritis has been reported in association with human T lymphotropic virus
type 1 (HTLV-I) [17]. These infections are sometimes associated with the presence of
RFs (usually in low titer), antinuclear antibodies, and elevated acute phase reactants.
HTLV-I infections can generally be distinguished from RA by the finding of specific
antiviral antibodies and the typically self-limited nature of arthritis associated with HTLV-I.
Systemic rheumatic diseases Early RA may be difficult to distinguish from the arthritis of systemic
lupus erythematosus (SLE), Sjgren's syndrome, dermatomyositis, or overlap syndromes, such as
mixed connective tissue disease. In contrast with RA, these disorders are generally characterized by
the presence of other systemic features, such as rashes, dry mouth and dry eyes, myositis, or
nephritis, and by various autoantibodies not seen in RA. Additionally, the relative responses of the
erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can be less well-correlated with
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each other in other diseases, particularly SLE, than in RA. Whereas both are commonly raised in RA,
the CRP is often normal or only minimally elevated in patients with active SLE even when the ESR is
elevated.
Taken together, the pattern of long-standing disease, morning stiffness, symmetric arthritis,
subcutaneous nodules, and the deformities characteristic of RA does not develop in these other
disorders. There are several exceptions to this observation:
Morning stiffness is common in all inflammatory arthritides. Symmetric arthritis is seen in

patients with SLE and can be present in other disorders. Infrequently, nodules similar to
those seen in RA may occur in patients with SLE, and other nodular lesions may mimic
rheumatoid nodules. (See "Rheumatoid nodules", section on 'Subcutaneous nodules'
and "Rheumatoid nodules", section on 'Differential diagnosis'.)
An erosive arthritis has been described in some overlap syndromes, particularly those
associated with anti-tRNA synthetases and anti-U1 RNP antibodies [18]. (See "Clinical
manifestations of mixed connective tissue disease".)
Jaccoud's arthropathy occurs in up to 5 to 10 percent of patients with Sjgren's
syndrome or SLE and can also occur in sarcoidosis [19]. (See "Musculoskeletal
manifestations of systemic lupus erythematosus" and "Sarcoid arthropathy".)
The joint deformities of Jaccoud's arthropathy are not caused by destruction of joints but
by loosening and lengthening of periarticular structures and tendons. The ulnar drift or
swan neck deformities caused by this disorder resemble RA superficially but can be
distinguished by the fact that they are "correctable" on physical examination: fingers with
these deformities can be moved manually back into normal alignment. In addition,
radiographs in Jaccoud's arthropathy rarely reveal the cartilage loss, erosions, or cysts
that are typical of longstanding RA.
Palindromic rheumatism Palindromic rheumatism is characterized by episodes of joint

inflammation sequentially affecting one to several joint areas for hours to days, with symptom-free
periods that may last from days to months. Some patients presenting with this syndrome eventually
develop a well-defined rheumatic disease, the most common being RA (ranging from 28 to 67
percent); some of the remaining patients develop SLE and other systemic disorders [20,21]. Patients
with anti-CCP antibodies appear more likely to progress to definite RA [22,23]. Close follow-up and
specific serologic evaluation can help distinguish among these disorders. (See "Clinical features of
rheumatoid arthritis", section on 'Palindromic rheumatism'.)
Hypermobility syndrome and fibromyalgia Pain, rather than stiffness or swelling, is the dominant
symptom of the two common disorders, hypermobility syndrome and fibromyalgia [24,25]. Although
the hypermobility syndrome and fibromyalgia can both bear superficial resemblances to RA due to the
presence of polyarthralgia, there are important distinguishing features:
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The hypermobility syndrome is associated with hyperextensible joints, and patients lack
signs of synovitis. (See "Clinical manifestations and treatment of the hypermobility
syndrome".)
Fibromyalgia is associated with tender points at nonarticular sites such as at the medial
portions of the elbows, across the trapezius muscle, and down the spine; there is no
evidence of synovitis on examination, such as swelling, warmth, or diminished joint range
of motion, although patients may exhibit joint line tenderness on exam. (See "Clinical
manifestations and diagnosis of fibromyalgia in adults".)
Neither the hypermobility syndrome nor fibromyalgia is associated with significant titers
of rheumatoid factor or anti-cyclic citrullinated peptide antibodies or with elevated levels
of acute phase reactants.
Although RA is normally not difficult to distinguish from fibromyalgia, a significant minority of patients
with RA also develop fibromyalgia. The source of complaints in such patients needs to be carefully
assessed to distinguish heightened pain sensitivity from pain related to inflammatory joint disease.
Reactive arthritis and arthritis of IBD Reactive arthritis often presents as a monoarthritis or
oligoarthritis in large joints, such as the knees, and RA may occasionally present in this fashion as well
[26]. The physical signs of both reactive arthritis and RA can be identical in the knees. (See "Reactive
arthritis (formerly Reiter syndrome)".)
The following findings on history, physical examination, or other assessments are more consistent with
reactive arthritis than RA:
History of recent urethritis or enteric infection

Asymmetric pattern of joint involvement
Symptoms or signs of enthesopathy (inflammation at the site where a tendon inserts into
a bone, eg, the insertion point of the Achilles tendon into the heel)
Keratoderma blenorrhagica or circinate balanitis (see "Reactive arthritis (formerly Reiter
syndrome)" and "Reactive arthritis (formerly Reiter syndrome)", section on 'Extraarticular
signs and symptoms')
Radiologic evidence of sacroiliitis and/or spondylitis
The presence of HLA-B27
Involvement of the hands in reactive arthritis does not pose as great a diagnostic dilemma as that of
the knees. Hand arthritis is more commonly asymmetric than in RA. Furthermore, reactive arthritis will
often involve not only the joint but also the tenosynovium, entheses, and surrounding tissues of the
digit, giving rise to a characteristic "sausage" swelling of the fingers (or toes if the feet are involved)
(picture 1).
The arthritis associated with inflammatory bowel disease (IBD) or other gastrointestinal disorders is
also part of the differential diagnosis. Patients with IBD may develop a peripheral polyarthritis with
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prominent involvement of the metacarpophalangeal joints that can be mistaken for RA; other
presentations include predominantly large joint oligoarticular involvement or a spondyloarthropathy
with sacroiliitis. This disorder may be missed if abdominal symptoms or symptoms of diarrhea and/or
blood or mucus in the stool are not prominent or are not specifically sought in the history. (See
"Arthritis associated with gastrointestinal disease".)
Lyme arthritis Lyme arthritis, a late manifestation of Lyme disease, occurs primarily in individuals
who live in or travel to Lyme disease endemic areas. Lyme arthritis is characterized by intermittent or
persistent inflammatory arthritis in a few large joints, especially the knee. The most commonly involved
joints, after the knee, are the shoulder, ankle, elbow, temporomandibular joint, and wrist. Migratory
arthralgias without frank arthritis may occur during early localized or early disseminated Lyme disease.
(See "Musculoskeletal manifestations of Lyme disease".)
The diagnosis of Lyme arthritis can usually be made by serologic testing, which should be performed
in patients presenting with undiagnosed inflammatory arthritis in endemic areas. In addition, several
clinical features help distinguish Lyme arthritis from RA. Unlike RA, for example, involvement of the
small joints of the hands and feet is uncommon in patients with Lyme arthritis. Furthermore, many, but
not all, patients with Lyme arthritis will describe an antecedent history of erythema migrans or other
early disease manifestations. (See "Musculoskeletal manifestations of Lyme disease", section on
'Laboratory testing'.)
Psoriatic arthritis Psoriatic arthritis can be difficult to distinguish from RA because a symmetric
polyarthritis can be observed in both disorders [27]. We generally make the diagnosis of psoriatic
arthritis in such patients who also have psoriasis and are seronegative for RF and anti-CCP. However,
we diagnose RA in those with a symmetric polyarthritis who are seropositive for at least one of these
antibodies since skin psoriasis is so common. However, serologic testing and skin findings may not be
informative, since patients with RA may not have RF or CCP antibodies (eg, seronegative RA) and the
joint symptoms of psoriatic arthritis may precede the onset of skin disease by many years. Such
patients should be evaluated and monitored for other signs more characteristic of psoriatic arthritis,
such as nail changes or enthesitis; occasional patients exhibit overlapping features of both disorders.
In some patients with a symmetric inflammatory polyarthritis, the only clue to the diagnosis of psoriatic
arthritis is a family history of psoriasis. However, in the majority, the findings of skin psoriasis, nail
changes (onychodystrophy), sausage toes or fingers, oligoarticular asymmetric large joint or spinal
involvement, and/or arthritis mutilans help distinguish the two entities. (See "Clinical manifestations
and diagnosis of psoriatic arthritis".)
Polymyalgia rheumatica Polymyalgia rheumatica (PMR) can sometimes be mistaken for RA in

patients presenting with more limited arthritis over the age of 50 who are seronegative or only have a
low RF titer. Unlike RA, PMR is usually associated with marked myalgias in the shoulders and hips,
and joint involvement tends to be milder, more limited, and more often asymmetric.

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Stiffness is thus more axial in PMR and more likely to be described as difficulty getting out of bed,
while stiffness in the small joints of the hands and other involved joints predominates in RA, in which
difficulty buttoning clothing is more likely to be reported. However, similar complaints to RA may be
present in patients with PMR with synovitis affecting the small joints in the hands.
The arthritis in PMR tends to respond strikingly to modest doses of glucocorticoids used to control
other symptoms [28]. In patients initially diagnosed with PMR, persistent or recurrent small joint
arthritis with tapering of glucocorticoids and the absence of other findings suggestive of PMR may lead
to a change in the diagnosis to RA after several months or even years of treatment. (See "Clinical
manifestations and diagnosis of polymyalgia rheumatica".)
Crystalline arthritis Crystalline arthritis (gout and pseudogout) can become chronic and even
assume a polyarticular distribution. The diagnosis is established by the finding of urate or calcium
pyrophosphate crystals, respectively, in synovial fluids. The presence of tophi on physical
examination, the detection of serological markers of RA, and the characteristic appearance of gouty
erosions are also useful in distinguishing RA from polyarticular gout. (See "Clinical manifestations and
diagnosis of gout" and "Clinical manifestations and diagnosis of calcium pyrophosphate crystal
deposition disease".)
Infectious arthritis Infectious arthritis is usually monoarticular, but polyarthritis can occur. The
diagnosis is established by culturing the pathogen from the synovial fluid or from the blood. Patients
with septic arthritis may or may not appear toxic on examination, depending upon the stage of their
infection, the presence of medications that can mask infection (eg, glucocorticoids), and other clinical
variables. Peripheral blood leukocytosis with a left shift is common but not invariably present.
A low threshold for suspecting infection is required, particularly in compromised hosts. Patients with
RA are at increased risk for joint infections because a damaged joint can serve as a nidus of infection.
Synovial fluid changes, including marked granulocytosis and low glucose levels, are similar to those
seen in RA. (See "Septic arthritis in adults".)
Osteoarthritis Osteoarthritis (OA) can be confused with RA in the middle aged or older patient
when the small joints of the hands are involved. However, different patterns of clinical involvement
usually permit the correct diagnosis (table 3). The following are examples (see "Clinical manifestations
of osteoarthritis"):
OA of the fingers typically affects the distal interphalangeal joints and is frequently
associated with Heberden's nodes in this area. In contrast, RA typically affects the MCP
and PIP joints and is not associated with Heberden's nodes.
The carpometacarpal joint of the thumb is typically involved in OA.
Swelling of the joints is hard and bony in OA. In contrast, soft, warm, boggy, and tender
joints are typical of RA.

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Stiffness of the joint is a very common feature of RA but is relatively uncommon in OA.
Furthermore, the stiffness of RA is characteristically worse after resting the joint (eg,
morning stiffness), while the stiffness of OA, if present, is typically worse after any effort
and is often described as evening stiffness. Morning stiffness in OA, when present, is
usually transient or lasts no more than a few minutes, unlike the more sustained stiffness
typical of RA.
Radiographs also help distinguish RA from OA. OA is characterized by narrowing of the
joint space due to cartilage loss and osteophytes due to bone remodeling, but not
erosions or cysts.
OA is classically associated with the absence of RFs and normal levels of acute phase
reactants. However, RFs may be present, usually in low titer, consistent with the patient's
(older) age.
Paraneoplastic disease Joint pain or frank polyarthritis can occur in association with cancer. The
following are some examples:
Myelodysplasia Patients with myelodysplastic syndrome sometimes develop

polyarthritis that mimics seronegative RA. In a cohort study of 87 patients with
myelodysplastic syndrome, 5 had inflammatory arthritis that resembled RA [29].
Hypertrophic pulmonary osteoarthropathy Patients with hypertrophic pulmonary
osteoarthropathy typically demonstrate clubbing of the digits, joint pain, and periosteal
new bone formation. Additionally, they give a characteristic history suggestive of bone
pain and often describe the pain as deep and achy; nocturnal pain is common. Joint
effusions may occur. (See "Malignancy and rheumatic disorders", section on
'Hypertrophic osteoarthropathy'.)
Multicentric reticulohistiocytosis Multicentric reticulohistiocytosis is a rare but highly destructive

form of arthritis. The rapid joint destruction of multicentric reticulohistiocytosis resembles the arthritis
mutilans occasionally observed in RA. Multiple smooth, shiny, erythematous nodules located in the
periungual region suggest multicentric reticulohistiocytosis. Binucleated or multinucleated foreign body
type giant cells are present on skin or synovial biopsies in multicentric reticulohistiocytosis [30,31]. In a
minority of patients, an underlying malignancy may be present. (See "Cutaneous manifestations of
internal malignancy", section on 'Multicentric reticulohistiocytosis'.)
Multicentric reticulohistiocytosis is relatively resistant to glucocorticoids and to disease-modifying

antirheumatic drugs such as methotrexate and hydroxychloroquine. However, there are case reports
of response to tumor necrosis factor-alpha inhibition [32,33] and to parenteral administration of an
aminobisphosphonate [34,35].
Sarcoid arthropathy Chronic arthritis in sarcoidosis may be oligoarticular or polyarticular and can
appear similar to RA in some patients. It most frequently affects the ankles, knees, hands, wrist, and

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metacarpophalangeal and proximal interphalangeal joints, and it is frequently associated with

parenchymal pulmonary disease.
This disorder is distinguished from RA by the following findings:
Elevated serum concentrations of angiotensin converting enzyme (ACE) are found in up

to 50 percent of patients.
A chest radiograph may reveal characteristic findings of sarcoidosis.
The pattern of acute arthritis with Lofgrens syndrome in patients with sarcoidosis is not
observed in those with RA.
(See "Sarcoid arthropathy".)
Fibroblastic rheumatism Fibroblastic rheumatism, a rare disease of unknown etiology, shares the
features of arthralgia, arthritis, and nodules with RA [36-38]. Flexion contractures of the fingers occur
in most patients, while thickened palmar fascia is noted in about one-half of reported cases. Biopsy of
a nodule or thickened skin typically reveals increased thickness of collagen fibers and fibroblastic
proliferation. Decreased elastic fibers and the presence of myofibroblasts are noted in approximately
50 percent. Radiographic findings are variable, but periarticular osteopenia and erosions may be
noted.
Due to the rarity of fibroblastic rheumatism, there is no well-established treatment. Progressive

disease may lead to sclerodactyly and ankylosis of affected joints.
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The
Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at
th th
the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview and who
prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
th th
sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and
are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on patient info and the keyword(s) of interest.)
Basics topics (see "Patient information: Rheumatoid arthritis (The Basics)")

Beyond the Basics topics (see "Patient information: Rheumatoid arthritis symptoms and
diagnosis (Beyond the Basics)" and "Patient information: Rheumatoid arthritis treatment
(Beyond the Basics)" and "Patient information: Complementary therapies for rheumatoid
arthritis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS

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RA should be suspected in the adult patient who presents with inflammatory polyarthritis.
The initial evaluation of such patients requires a careful history and physical examination,
along with selected laboratory testing to identify features that are characteristic of RA or
that suggest an alternative diagnosis. (See 'Evaluation for suspected RA' above and
'Differential diagnosis' above.)
The following components of the medical evaluation are helpful in making a clinical
diagnosis of RA, both for the identification of characteristic findings and for the exclusion
of other diagnoses (see 'Evaluation for suspected RA' above):
A thorough medical history, with particular attention to joint pain, stiffness, and
associated functional difficulties
A complete physical examination to assess for synovitis, limited joint motion,
extraarticular disease manifestations, and signs of diseases included in differential
diagnosis
Basic and selected laboratory testing, including assays for acute phase reactants
(erythrocyte sedimentation rate and C-reactive protein), rheumatoid factor, anti-cyclic
citrullinated peptide (CCP) antibodies, and antinuclear antibodies
Selected imaging studies, including bilateral radiographs of the hands, wrists, and
feet
Arthrocentesis, if there is diagnostic uncertainty.
The diagnosis of RA can be made in a patient with inflammatory arthritis involving three
or more joints, positive rheumatoid factor and/or anti-citrullinated peptide/protein
antibody, disease duration of more than six weeks, and elevated CRP or ESR, but
without evidence of diseases with similar clinical features. (See 'Our diagnostic criteria'
above.)
RA may also be diagnosed in patients without all of the classic findings of disease. This
includes patients with seronegative RA, those with clinically quiescent disease, and those
with recent onset RA. Such patients have findings/clinical features that are generally
consistent with those described as meeting the ACR/EULAR classification criteria for RA.
(See 'Patients not meeting above criteria' above.)
The 2010 classification criteria for RA were developed primarily for the identification for
research purposes of patients with RA who are at high risk of persistent symptoms and
joint injury unless treated with DMARDs. These criteria have replaced the 1987 criteria,
which were based only upon patients with established disease. (See 'Classification
criteria' above.)
The differential diagnosis of RA includes multiple disorders that can generally be
distinguished clinically or by limited laboratory testing, based upon a combination of the
following features (see 'Differential diagnosis' above):

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Limited duration (eg, in viral arthropathy)

The presence of other diseases (eg, in psoriatic arthritis or arthritis of inflammatory
bowel disease)
The pattern of joint involvement and other symptoms (eg, in psoriatic arthritis,
spondyloarthropathy, or polymyalgia rheumatica)
The presence of systemic features (eg, in systemic lupus or dermatomyositis)
Diagnostic laboratory tests associated with other conditions (eg, specific
autoantibodies in SLE, synovial fluid crystals in gout or calcium pyrophosphate
disease)
Relatively high specificity of anti-CCP antibodies for RA
INTRODUCTION Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disorder of

unknown etiology that primarily involves joints. The arthritis is symmetrical and may be remitting, but, if
uncontrolled, it may lead to destruction of joints due to erosion of cartilage and bone which leads to
deformity. The disease usually progresses from the periphery to more proximal joints and, in patients
who do not fully respond to treatment, results in significant locomotor disability within 10 to 20 years.
Many of the clinical features that are discussed in this topic review are used in the clinical diagnosis of
RA and also serve as classification criteria for RA. The latter are used to define patient populations
with RA for clinical or other research purposes. The diagnosis and classification of RA are presented
separately. (See "Diagnosis and differential diagnosis of rheumatoid arthritis".)
The following is a summary of characteristic clinical features, some of which are also useful for
diagnostic and/or classification purposes:
Morning stiffness for at least one hour and present for at least six weeks
Swelling of three or more joints for at least six weeks
Swelling of wrist, metacarpophalangeal, or proximal interphalangeal joints for at least six
weeks
Symmetric joint swelling
Hand x-ray changes typical of RA that include erosions or bony decalcification
Rheumatoid subcutaneous nodules
Rheumatoid factors or anti-citrullinated peptide/protein antibodies
Elevated acute phase reactants (erythrocyte sedimentation rate or C-reactive protein)
CLINICAL PRESENTATIONS Polyarticular disease with a gradual onset, intermittent or migratory

joint involvement, and a monoarticular onset are different types of clinical presentations of RA. In
addition, extraarticular manifestations may be present.

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Patients need to be questioned regarding how the arthritis has affected their capacity to perform the
activities of daily living (eg, walking, stairs, dressing, use of a toilet, getting up from a chair, opening
jars, doors, typing), the type of job they have, and their ability to do their job.
Typical "classic" RA The disease onset is usually insidious, with the predominant symptoms
being pain, stiffness, and swelling of many joints [1]. Typically, the metacarpophalangeal and proximal
interphalangeal joints of the fingers, interphalangeal joints of the thumbs, the wrists, and
metatarsophalangeal joints of the toes are sites of arthritis early in the disease. Other joints of the
upper and lower limbs, such as the elbows, shoulders, ankles, and knees are also commonly affected
[2,3].
Morning stiffness is a common feature of those with active RA; it has been defined as the following:
"slowness or difficulty moving the joints when getting out of bed or after staying in one position too
long, which involves both sides of the body and gets better with movement" [4].
Morning stiffness, or stiffness after any prolonged period of inactivity, is also seen in virtually all
inflammatory arthropathies and myopathies [5]. However, morning stiffness lasting more than one
hour reflects a severity of joint inflammation that rarely occurs in diseases other than RA.
Up to one-third of patients have the acute onset of polyarthritis associated with prominent myalgia,
fatigue, low grade fever, weight loss, and depression.
Occasionally, the syndrome of polymyalgia rheumatica may be present. When this occurs in the
absence of clinically detectable synovitis, the distinctive clinical features of RA may not develop until
months or even years later. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica".)
Palindromic rheumatism The onset of RA is episodic in a few patients, with one to several joint
areas being affected sequentially for hours to days, with symptom free periods that may last from days
to months; an episodic pattern referred to as "palindromic rheumatism." Patients with palindromic
rheumatism have similar predisposing genetic risk factors and exhibit a dose effect of carriage of
certain HLA alleles, as do patients with a more typical persistent presentation of RA [6]. (See
"Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis", section on 'Genetic
susceptibility'.)
The proportion of patients presenting with palindromic rheumatism who progress to develop RA or
another well defined disease varies between studies. In one study of 60 patients with palindromic
rheumatism followed over 20 years, 40 (67 percent) developed RA [7]. In another study, among 147
such patients seen in a tertiary referral center, 41 were eventually diagnosed with RA (28 percent) and
4 with other disorders (3 with systemic lupus erythematosus and 1 with Behets disease) [6].
In one study, a majority of those with palindromic rheumatism also had anti-citrullinated
peptide/protein antibodies (ACPA), a serologic finding that is common in RA [8]. In another study,
ACPA were positive in 83 percent of patients who progressed to definite RA [9]. (See "Clinically useful

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biologic markers in the diagnosis and assessment of outcome in rheumatoid arthritis", section on 'Anti-
citrullinated peptide antibodies'.)
Use of antimalarial drugs may reduce the risk of progression to RA. One retrospective study of 113
such patients found that those who received antimalarials were 20 percent less likely to develop a
chronic rheumatic disease [10].
Monoarthritis Persistent single joint arthritis (monoarthritis), frequently of a large joint such as the
knee, shoulder, hip, wrist, or ankle, may be the sole manifestation or may herald the onset of
polyarticular disease. There may be a history of joint trauma as an apparent initiating event. The
interval between monoarthritis and polyarthritis may extend from days to several weeks in patients
whose disease progresses. Until polyarthritis develops, the approach to such patients is that for any
patient with monoarticular arthritis. (See "Evaluation of the adult with monoarticular pain".)
Extraarticular involvement Extraarticular features of RA, including anemia, fatigue, subcutaneous

("rheumatoid") nodules, pleuropericarditis, neuropathy, episcleritis, scleritis, splenomegaly, Sjgren's
syndrome, vasculitis, and renal disease, may occur during the course of the disease These and other
systemic and extraarticular manifestations are presented in more detail separately. (See "Overview of
the systemic and nonarticular manifestations of rheumatoid arthritis".)
Most patients with extraarticular manifestations also have the classic joint symptoms of RA. Rarely,
patients present with extraarticular disease in the absence of clinical arthritis. (See "Overview of the
systemic and nonarticular manifestations of rheumatoid arthritis".)
In addition, a proportion of patients complain of persistent nonarticular symptoms, such as generalized

aching, stiffness, bilateral carpal tunnel syndrome, loss of weight, depression, and fatigue (the last
simulating chronic fatigue syndrome). This constellation of symptoms may antedate the onset of
polyarthritis by many months.
DISTRIBUTION OF JOINT INVOLVEMENT RA eventually affects the peripheral joints in almost all
patients. Involvement of axial and central joints, such as the interfacetal and atlantoaxial joints of the
neck, acromioclavicular [11], sternoclavicular, temporomandibular, cricoarytenoid joints, and shoulders
and hips is less common, occurring in 20 to 50 percent of patients.
Symmetrical involvement of joints is a characteristic feature, although this may be less apparent early
in the disease. The severity of joint disease and consequent deformity is sometimes notably
asymmetrical, an observation that may be attributed to increased structural damage to joints related to
unilateral overuse of a dominant limb, or joint protection of a limb resulting from neurologic disease.
The pattern of joint involvement may also be diagnostically useful. As an example, involvement limited
to the distal interphalangeal joints is usually due to osteoarthritis, whereas proximal interphalangeal
involvement can reflect either RA or osteoarthritis. Squeeze tenderness at the MCP and MTP joints
and palpable synovial thickening at these joints are characteristic of RA.

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CLINICAL COURSE RA shows a marked variation of clinical expression in individual patients (table
1). This difference may be apparent in the number and pattern of joint involvement. As an example,
some patients may have mainly small joints or large joints affected. A given patient may also have
only a few or almost all joints involved. Finally, extraarticular disease may be prominent in a subset of
patients.
Patterns of progression Variation is also seen in the course of disease activity and the rapidity of
structural damage to joints [12].
Most patients show fluctuation of disease activity over periods lasting weeks to months.
This corresponds to an increase or decrease in symptoms of arthritis, a pattern which
may recur throughout the course of the disease.
Disease activity may not abate in about 10 to 20 percent of cases.
Remission has been reported in a small proportion of patients with a well established
diagnosis of RA [13]. In our experience, however, this is very rare without disease
modifying antirheumatic drugs (DMARDs). As an example, among 191 patients treated
with such drugs beginning within a year of disease onset, 48 (25 percent) met criteria for
remission after three years of treatment, and 38 (20 percent) after five years of DMARD
therapy [14].
Some clinical features that can be assessed early in the course of RA may be predictive of the
likelihood of achieving a remission with DMARD treatment. Patients with less initial disease activity,
less disability, lower levels of acute phase reactants, absence of RF and antibodies to citrullinated
peptides (ACPA), and less radiographic joint damage when initially evaluated, are more likely to
achieve a remission when treated with DMARDs within the first year of disease [14].
Disease activity versus structural damage The concept of disease activity is based upon the
state of the underlying inflammatory response and may be distinguished from the destructive process
that leads to irreversible damage of the joint (table 2):
Disease activity can (and does) vary. This variation in part reflects the endogenous
rhythms of the disease process but is mainly the result of therapeutic interventions. Thus,
periods of spontaneous exacerbations and quiescence, characterized by an increase (a
"flare") or decrease in symptoms, are modulated by both the beneficial effects of drug
therapy and withdrawal of therapy due to loss of efficacy or side effects.
In contrast, structural damage is cumulative and irreversible. The degree of damage is
closely linked to inflammation and hence to disease activity, but is also associated with
degeneration and repair [15]. As structural damage progresses, the detection of variation
in disease activity by clinical examination becomes increasingly difficult. At these later
stages, symptoms and signs of inflammation, such as pain, stiffness, tenderness,

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swelling, and joint effusions, may be caused either by continuing rheumatoid disease or
as a secondary result of mechanical and degenerative change.
Remission Rarely, disease activity is absent; in this circumstance, the disease is said to be in
remission. Attempts to define clinical remission for clinical trials and in clinical practice, in order to
understand better the natural history of RA and the effects of therapy, have resulted in provisional
definitions of remission by a joint effort of the American College of Rheumatology (ACR) and the
European League Against Rheumatism (EULAR) [16,17]. A complete lack of joint pain, swelling, and
tenderness may be impossible to achieve in patients who have developed structural damage of the
joints, despite actual remission in the rheumatoid disease process, and is not required by the
ACR/EULAR criteria. (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical
practice", section on 'Remission'.)
The current ACR/EULAR definitions of remission include use of either the Simplified Disease Activity
Index (for clinical trials) or the Clinical Disease Activity Index (in clinical practice). Alternatively, the
definition of remission for clinical trials can be met in patients with scores on the tender joint count,
swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) all 1. The CRP can
be excluded in clinical practice.
Achieving a clinical remission does not preclude the development of further erosive changes. This was
illustrated in a retrospective study of 187 patients who were in remission for six months and whose
clinical course and radiographic findings were subsequently followed [18]. A majority (52 percent)
remained in remission during two years of follow-up. Despite inapparent clinically active disease, one
new erosion in a previously unaffected joint appeared in 14 percent of these patients.
Because the past remission criteria of the ACR included measures of fatigue and required at least two
months of sustained response, they had not been applied widely in clinical trials [13]. Measures using
the Disease Activity Score (DAS <1.6 or DAS28 <2.4 or 2.6) to define remission were previously also
proposed [19-21].
PHYSICAL FINDINGS The key features of early rheumatoid inflammation are pain and swelling of
the affected joints. Painful inflammation is demonstrated either by local tenderness from pressure
applied on the joint or by pain on moving the joint. Swelling may be due to synovial hypertrophy or
effusion. Synovial thickening is detected by a "boggy" feel to a swollen joint, and effusion by
demonstrating fluctuation. Heat and redness (the other signs of Celsus) are not prominent features of
RA, although an involved joint is often perceptibly warmer on careful examination. The characteristic
joint deformities are late manifestations of disease that result from the physical stresses and local
anatomy of involved joints.
The hands The main signs of disease can often be found in the hands early in the course of RA
[22]. Symmetrical effusions and soft tissue swelling around the metacarpophalangeal joints and
proximal interphalangeal joints typically occur, although distal interphalangeal involvement can be

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seen later in the disease [23]. These joints are tender to the touch and exhibit a restricted range of
movement. Palmar erythema may be present (as with any peripheral arthritis).
Occasionally, thickening of the flexor tendons can be detected by palpation of the palm; this finding is
due to synovitis of the tendon sheaths ("tenosynovitis"). Nodules may form along the palmar tendon
sheaths, resulting in the tendon sheath catching (or triggering) and in an inability to fully extend the
finger. The nodules may cause tendon rupture, especially of the extensor pollicis longus (extensor of
the DIP joint of the thumb).
Other physical signs include the following:
Reduced grip strength can be a surprisingly sensitive indicator of early disease, as well
as a useful parameter in the evaluation of disease activity and progression. However, the
multiplicity of factors (joint pain, tendon involvement, nerve compression, and muscle
wasting) that contribute to a weak grip makes this assessment rather nonspecific.
The whole hand may be swollen in very acute RA, with pitting edema over the dorsum
giving rise to the "boxing glove" appearance. The range of movement of involved joints is
restricted, and loss of active flexion may be so severe that the patient is unable to
oppose the finger tips to the palm.
Between 1 and 5 percent of patients present with carpal tunnel syndrome. Affected
patients develop dysesthesia and muscle weakness of the first three fingers and the
radial side of the fourth finger. A positive Tinel's or Phalen's sign is usually present. (See
"Clinical manifestations and diagnosis of carpal tunnel syndrome".)
The characteristic joint deformities appear in more established chronic RA. These findings include
ulnar deviation or "ulnar drift" swan neck or Boutonniere deformities of the fingers (picture 1A-B), or
the "bow string" sign (prominence of the tendons in the extensor compartment of the hand).
Occasional patients present with extensor tendon rupture, most commonly affecting the thumb, little or
ring fingers of either hand. The nails and fingertips should also be examined in every patient for
evidence of digital infarcts.
The upper limb All of the upper extremity joints may be involved in RA. The wrist is probably the
most common to be involved. Early in the disease there is a loss of extension. Late changes due to
erosive damage lead to volar subluxation and radial drift of the carpus, resulting in increasing
prominence of the ulnar styloid and lateral deviation [24]. Tendon rupture can also occur at the wrist.
The elbow is frequently affected, with loss of extension (fixed flexion) both in early and late disease
(image 1). An effusion or synovitis may be detected as a bulge between the head of the radius and the
olecranon. A compressive neuropathy of the ulnar nerve, with dysesthesias of the fourth and fifth
fingers, can result from elbow synovitis. Olecranon bursitis is also common. Destruction of the joint
may occur due to erosion of cartilage and bone.

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The elbow is the most common site for subcutaneous rheumatoid nodules. These should always be
looked and felt for in view of their diagnostic and prognostic importance.
The shoulder, being more proximal, tends to be involved later in the disease. As an example, one
prospective study assessed shoulder involvement over time in 74 patients with RA [25]. At 15 years,
55 percent had developed radiographic evidence of erosive glenohumeral joint disease [25]. The most
common site for erosions was the superolateral aspect of the humerus.
Disease in the glenohumeral joint leads to painful restriction of movement resembling a capsulitis, and
can result in the development of a "frozen" shoulder. This will typically cause pain at night, when the
patient lies on the affected shoulder. Rotator cuff injury is common. Effusions are relatively rare, but
when they occur they may be detected in the anterior glenohumeral joint as a filling of the depression
under the clavicle anterior to the head of the humerus.
The lower limb Foot involvement is common in early disease, with a pattern which mirrors that
occurring in the hand.
Tenderness of the metatarsophalangeal joints may be marked, resulting in the tendency

to bear weight on the heels and hyperextend the toes.
Erosive damage results in lateral drift of the toes, and plantar subluxation of the
metatarsal heads, resulting in "cock-up" deformities. The latter may be palpable as bony
lumps on the sole with associated callosities.
Involvement of the tarsus and the associated tendon sheaths is also common, leading to
pain on inversion or eversion of the foot and diffuse edema and erythema over the
dorsum of the foot.
Heel pain may be associated with retrocalcaneal bursitis tarsal tunnel syndrome, caused
by impingement of the posterior tibial nerve. Tarsal tunnel syndrome is also associated
with paresthesiae of the toes and is important because it is readily diagnosed by
ultrasound and treated by local injection or surgical release. Two rare but easily missed
causes of heel pain are Achilles tendon rupture or calcaneal stress fracture [26,27].
Arthritis of the ankle can lead to a diffuse swelling around the tibiotalar joints which may
be red and edematous. These findings may be wrongly attributed to fluid retention or an
infective cellulitis of the skin.
The knee manifests many changes in RA. Synovial thickening is easily detected at the knee, often
extending around the patella. Effusion is a common feature of knee involvement and can be elicited by
patellar tap. Restriction of movement, particularly flexion, is also a common physical finding. In
addition, ligamentous laxity leading to deformities and quadriceps atrophy is frequently observed.
The popliteal fossa should always be palpated for evidence of a popliteal (Baker's) cyst [28]. Ruptured
Baker's cysts extending down the calf are of clinical importance because they can resemble a deep
vein thrombosis or acute thrombophlebitis [29]. A history of arthritis, morning stiffness, lack of a

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palpable occluded venous cord, and edema below the posterior of the knee all suggest a Baker's cyst.
Traditionally, a ruptured Baker's cyst is demonstrated by arthrography, though it can now be reliably
demonstrated by ultrasonography or magnetic resonance imaging [30]. (See "Popliteal (Baker's)
cyst".)
Erosion of the femoral condyles and tibial plateau can result in either genu varus or genu valgus.
Involvement of the hips typically occurs only in well established disease. Hip disease is most
frequently manifested as pain in the groin, thigh, low back, or referred to the knee on standing or
movement. Restriction of movement, detected by "log rolling the leg" or rotation of the hip, also may
be seen. Pain in the lateral thigh suggests trochanteric bursitis.
The axial skeleton Cervical spine joints are the most clinically important joints in the axial skeleton
in RA and may cause pain and stiffness of the neck. Long standing disease may lead to instability and
cause symptoms such as neck pain, stiffness, radicular pain, related to subluxation. If the subluxation
is causing spinal cord compression, there may be signs of long tract involvement such as
hyperreflexia or up going toes on Babinski testing. The clinical manifestations of cervical spine
subluxation and the approach to diagnosis and management are discussed in detail separately. (See
"Cervical subluxation in rheumatoid arthritis".)
Cricoarytenoid joint Nearly 30 percent of patients with RA have involvement of the cricoarytenoid
joint; symptoms may include hoarseness and an inspiratory stridor.
LABORATORY FINDINGS A number of abnormalities are present in the blood and synovial fluid of
patients with RA. These include changes reflecting systemic and intraarticular inflammation, and the
autoimmune features of the disorder, including the presence of rheumatoid factors and anti-
citrullinated peptide antibodies.
Synovial fluid examination typically reveals an inflammatory effusion, with a leukocyte count typically
between 1500 and 25,000/cubic mm characterized by a predominance of polymorphonuclear cells
[31]. Cell counts in excess of 25,000 may occur in very active disease, but levels over 25,000 should
alert the clinician to the increased possibility of coexisting infection [32,33]. Additional findings in RA
synovial fluid are low glucose, low C3 and C4 complement levels, and protein levels approaching
those in serum, but these tests are generally not obtained in clinical practice. (See "Synovial fluid
analysis and the diagnosis of septic arthritis" and "Diagnosis and differential diagnosis of rheumatoid
arthritis", section on 'Evaluation for suspected RA'.)
Other laboratory features of RA are reviewed in detail elsewhere. (See "Hematologic manifestations of
rheumatoid arthritis" and "Clinically useful biologic markers in the diagnosis and assessment of
outcome in rheumatoid arthritis".)
IMAGING Patients with RA develop joint space narrowing and bony erosions, which are best
observed in radiographs of the hands and feet. These may already be present when first seen by a
clinician but more usually become evident over time with ongoing synovitis beyond the first few
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months of disease. Erosions of cartilage and bone are among the cardinal features of RA. However,
they can also occur in some other forms of inflammatory and gouty arthropathy and are, therefore, not
diagnostic of RA in and of themselves. (See "Diagnosis and differential diagnosis of rheumatoid
arthritis", section on 'Differential diagnosis'.)
Magnetic resonance imaging (MRI) studies and ultrasonography are more sensitive than radiography
for the detection of changes resulting from synovitis, but additional research is ongoing to determine
the prognostic importance of changes observed with these studies that are not evident
radiographically.
With extreme destruction, the severity of erosions may reach a level beyond which further progression
cannot be assessed radiographically, despite the presence of ongoing joint damage [34].
Plain film radiography Plain radiographs are often normal early in disease, and the early changes
evident on plain films may include only soft tissue swelling and periarticular osteopenia (image 2A-C).
To be detected by plain radiography, erosions must have eroded through the cortex of the bone
around the margins of the joint. Erosions in the metacarpophalangeal (image 3A-B) and proximal
interphalangeal joints (image 4A-B) can be identified by plain radiography in 15 to 30 percent of
patients in the first year of the disease. By the end of the second year of disease in patients who do
not respond to therapy, the cumulative incidence of erosions is 90 percent [35,36]. In some patients,
erosions occur first in the ulnar styloid (image 5A-B) or MTP joints (image 6A-B). Joint space
narrowing may also be present.
MR imaging Magnetic resonance imaging (MRI) is a more sensitive technique than plain
radiography for identifying bone erosions. When radiography and MRI were compared in a group of 55
patients with early arthritis, MRI identified seven times as many erosions in the metacarpophalangeal
and proximal interphalangeal joints than plain radiographs [37]. However, the clinical significance of
erosions only detected by MRI awaits elucidation.
MRI also may detect bone erosions earlier in the course of the disease than is possible with plain films
[38]. As an example, approximately 45 percent of patients with symptoms for only four months were
found to have erosions detected by this method [39]. Decreased signal from the bone marrow on T1-
weighted images and enhancement of the marrow with gadolinium administration is interpreted as
bone marrow edema. The presence of marrow edema on MRI is predictive of later development of
erosive disease [40]. A similarly increased sensitivity of MRI has also been noted for early RA of the
forefoot [41].
It is also possible to identify and estimate the quantity of hypertrophic synovial tissue using MRI. The
presence of MRI-detected synovial proliferation correlates with the later development of bone erosions
[42]. Use of this imaging technique outside of research settings may be hastened by the development
of MRI scanners that are designed specifically for imaging the extremities [43,44].

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Ultrasonography Ultrasonography is another alternative for estimating the degree of inflammation

and the volume of inflamed tissue. Direct comparison of color Doppler ultrasonography and contrast
enhanced MRI in one study of 29 patients demonstrated agreement regarding the presence or
absence of inflammation between the two techniques in 75 percent of the joints of the hands and
wrists [45]. Both imaging modalities found features of inflammation in joints that were neither tender
nor swollen on physical examination. The clinical importance of these findings remains to be
determined. Ultrasonography can also be used to assess the MTP joints, which may become affected
early in the course of disease [46].
th th
th th
Basics topics (see "Patient information: Rheumatoid arthritis (The Basics)" and "Patient
information: Hand pain (The Basics)")
The onset of rheumatoid arthritis (RA) is usually insidious, with the predominant
symptoms being pain, stiffness, and swelling of many joints. Onset may occasionally be
intermittent or with migratory joint involvement, or onset may be monoarticular. RA may
adversely affect a patients capacity to perform the activities of daily living. (See 'Clinical
presentations' above and 'Typical "classic" RA' above and 'Palindromic rheumatism'
above and 'Monoarthritis' above.)
Extraarticular features of RA, including anemia, fatigue, subcutaneous ("rheumatoid")
nodules, pleuropericarditis, neuropathy, episcleritis, scleritis, splenomegaly, Sjgren's
syndrome, vasculitis, and renal disease, may occur during the course of the disease.
(See 'Extraarticular involvement' above and "Overview of the systemic and nonarticular
manifestations of rheumatoid arthritis".)

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RA eventually affects the peripheral joints in almost all patients. Involvement of axial and
central joints is less common, occurring in 20 to 50 percent of patients. Symmetrical joint
involvement is characteristic, although this may be less apparent early in the disease.
The pattern of joint involvement may also be diagnostically useful. Squeeze tenderness
at the MCP and MTP joints and palpable synovial thickening at these joints are
characteristic of RA. (See 'Distribution of joint involvement' above.)
RA shows a marked variation of clinical expression in individual patients (table 1). This
difference may be apparent in the number and pattern of joint involvement and whether
extraarticular disease is prominent. Variation is also seen in the course of disease activity
and the rapidity of structural damage to joints. (See 'Clinical course' above and 'Patterns
of progression' above.)
The concept of disease activity is based upon the state of the underlying inflammatory
response, and may be distinguished from the destructive process that leads to
irreversible damage of the joint (table 2). Rarely, disease activity is absent; in this
circumstance, the disease is said to be in remission. (See 'Disease activity versus
structural damage' above and 'Remission' above.)
The key features of early rheumatoid inflammation are pain and swelling of the affected
joints. Painful inflammation is demonstrated either by local tenderness from pressure
applied on the joint or by pain on moving the joint. Swelling may be due to synovial
hypertrophy or effusion. Synovial thickening is detected by a "boggy" feel to a swollen
joint, and effusion by demonstrating fluctuation. (See 'Physical findings' above and 'The
hands' above and 'The lower limb' above and 'The axial skeleton' above and
'Cricoarytenoid joint' above.)
A number of abnormalities are present in the blood and synovial fluid of patients with RA.
These include changes reflecting systemic and intraarticular inflammation, and the
autoimmune features of the disorder, including the presence of rheumatoid factors and
anti-citrullinated peptide antibodies. (See 'Laboratory findings' above.)
Patients with RA develop joint space narrowing and bony erosions, which are best
observed in radiographs of the hands and feet. These may already be present when first
seen by a physician but more usually become evident over time with ongoing synovitis
beyond the first few months of disease. (See 'Imaging' above.)

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INTRODUCTION The treatment of rheumatoid arthritis (RA) is directed toward the control of
synovitis and the prevention of joint injury. The choice of therapies depends upon several factors,
including the severity of disease activity when therapy is initiated and the response of the patient to
prior therapeutic interventions.
Common principles that guide management strategies and the choice of agents have been derived
from an increased understanding of the disease and from evidence from clinical trials and other
studies. These strategies include approaches directed at achieving remission or low disease activity
by more rapid and sustained control of inflammation and by the institution of disease-modifying
antirheumatic drug (DMARD) therapy early in the disease course.
The general principles and treatment strategies that should be applied to the management of RA are
reviewed here. The initial therapy of RA and the treatment of patients resistant to initial disease-
modifying antirheumatic drugs are discussed in greater detail elsewhere. (See "Nonpharmacologic
and preventive therapies of rheumatoid arthritis" and "Initial treatment of mildly active rheumatoid
arthritis in adults" and "Initial treatment of moderately to severely active rheumatoid arthritis in adults"
and "Treatment of rheumatoid arthritis resistant to initial DMARD therapy in adults".)
GENERAL PRINCIPLES Our overall approach to the treatment of patients with rheumatoid arthritis
(RA) depends upon the timely and judicious use of several types of therapeutic interventions. The
appropriate use of these therapies is based upon an understanding of a group of general principles
that have been widely accepted by major working groups and by professional organizations of
rheumatologists [1-4]. (See 'Recommendations by major groups' below.)
These principles include:
Early recognition and diagnosis (see 'Early recognition and diagnosis' below)
Care by an expert in the treatment of rheumatic diseases, such as a rheumatologist (see
'Care by a rheumatologist' below)
Early use of disease-modifying antirheumatic drugs (DMARDs) for all patients diagnosed
with RA (see 'Early use of DMARDs' below)
Importance of tight control with target of remission or low disease activity (see 'Tight
control' below)
Use of antiinflammatory agents, including nonsteroidal antiinflammatory drugs (NSAIDs)
and glucocorticoids, only as adjuncts to therapy (see 'Adjunctive role of antiinflammatory
agents' below)
The application of these principles has resulted in significant improvement in the outcomes of
treatment, although the etiology and pathogenesis of RA are complex and are not fully understood [5-
7]. Such improvements may owe even more to the therapeutic strategies that have been adopted than
to the development and use of newer and more potent drugs [8].

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RA is characterized by acute and chronic inflammation in the synovium, which is associated with a
proliferative and destructive process in joint tissues [7,9,10]. Many elements of innate and adaptive
immunity are involved in this process, and evidence of significant and irreversible joint injury may
occur as early as during the first two years of disease if inflammation persists. Measures aimed at
identifying early active disease and at markedly reducing inflammation are, therefore, essential for
modifying disease outcome [6,8,11,12]. (See "Pathogenesis of rheumatoid arthritis" and 'Tight control'
below.)
Early recognition and diagnosis Achieving the benefits of early intervention with disease-
modifying antirheumatic drugs (DMARDs) depends upon making the diagnosis of RA as early as
possible. The recognition of RA early in the course of inflammatory arthritis, before irreversible injury
has occurred, is thus an important element of effective management. (See 'Early use of DMARDs'
below.)
International collaborative efforts led in 2010 to the development of new classification criteria for RA,
which have identified factors that support the early diagnosis of RA among patients presenting with
inflammatory arthritis [13]. These criteria are directed at the recognition of patients with early arthritis
who are most likely to develop progressive and erosive disease. The diagnosis and differential
diagnosis of RA are reviewed in detail elsewhere. (See "Diagnosis and differential diagnosis of
rheumatoid arthritis" and "Assessing the probability of developing rheumatoid arthritis in patients with
undifferentiated inflammatory arthritis" and "Clinical features of rheumatoid arthritis".)
Care by a rheumatologist An expert in the treatment of rheumatic diseases, such as a

rheumatologist, should participate in the care of patients with inflammatory arthritis who are suspected
of having RA and in the ongoing care of patients diagnosed with this condition [4,14]. The early and
ongoing care of patients with RA by a rheumatologist is associated with better disease outcomes
compared with care rendered primarily by other clinicians [15-19].
As an example, in one study of 598 patients from an early arthritis cohort (symptoms for less than two
years), those in whom assessment by a rheumatologist had been delayed at least 12 weeks from
symptom onset, compared with those evaluated within less than 12 weeks, were significantly more
likely not to achieve DMARD-free remission (hazard ratio 1.87, 95% CI 1.18-2.99) and had a
significantly higher rate of joint destruction (calculated as 1.34-fold greater) over six years of follow-up
[20].
The initial rheumatology consultation allows the diagnosis to be made or reassessed, the severity of
disease to be estimated, and a plan of care to be developed and initiated. The frequency of
subsequent specialist care depends upon the severity of symptoms and joint inflammation, upon the
patients response to treatment, upon the complexity and risks associated with the therapy, and upon
the preferences of the patient and primary care physician.
NONPHARMACOLOGIC AND PREVENTIVE THERAPIES A number of nonpharmacologic

measures and other medical interventions are important in the comprehensive management of
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rheumatoid arthritis (RA) in all stages of disease, in addition to antiinflammatory and antirheumatic
drug therapies. Patient education that addresses issues related to the disease and its management is
indicated for all patients with RA. Attention to health promotion and specific strategies aimed at
minimizing the adverse effects of RA and of agents used to treat it are also appropriate. These
therapies are discussed in detail elsewhere. (See "Nonpharmacologic and preventive therapies of
rheumatoid arthritis".)
Briefly, these measures include:
Patient education
Psychosocial interventions
Rest, exercise, and physical and occupational therapy
Nutritional and dietary counseling
Interventions to reduce risks of cardiovascular disease, including smoking cessation, and
of osteoporosis
Immunizations to decrease risk of infectious complications of immunosuppressive
therapies
PHARMACOLOGIC THERAPY
Pretreatment evaluation Prior to starting, resuming, or significantly increasing therapy with

nonbiologic or biologic disease-modifying antirheumatic drugs (DMARDs), we do the following
baseline studies [1]:
General testing for all patients We obtain a baseline complete blood count, serum
creatinine, aminotransferases, erythrocyte sedimentation rate (ESR), and C-reactive
protein (CRP) in all patients.
Serologic testing for hepatitis prior to methotrexate, leflunomide, or biologic DMARDs
All patients at increased risk of hepatitis, such as those who have a history of intravenous
drug abuse, those who have had multiple sex partners in the previous six months, and
those who are healthcare workers, should be screened for hepatitis B and C before
starting these medications [1]. Some experts, including the authors, prefer to screen for
hepatitis B and C in all patients without a known history of hepatitis before initiating
therapy with these medications. (See "Hepatitis B virus reactivation associated with
immunosuppression".)
Ophthalmologic screening for hydroxychloroquine use A complete baseline
ophthalmologic examination should be performed within the first year of treatment,
including examination of the retina through a dilated pupil and automated visual field
testing. (See "Antimalarial drugs in the treatment of rheumatic disease", section on
'Monitoring for toxicity'.)

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Testing for latent tuberculosis We screen for latent tuberculosis (TB), consistent with
the US Centers for Disease Control (CDC) and 2008 American College of Rheumatology
(ACR) guidelines, with skin testing or an interferon-gamma release assay prior to all
biologic DMARDs and prior to use of the Janus kinase inhibitor, tofacitinib; such
screening is based upon evidence that these medications, including the tumor necrosis
factor (TNF) inhibitors, other biologics, and tofacitinib, may increase the risk of
mycobacterial infection [1,21,22].
We also screen for latent TB in patients about to receive methotrexate (MTX), but some
experts do not perform testing in such patients, given the lack of sufficient evidence to
document the benefit of this approach. A possible exception is rituximab, since there is
no clear evidence of an increased risk of TB with this agent [23]. We obtain a chest
radiograph in patients with a history of other risk factors for latent TB, even if screening
tests are negative, given the risks of false-negative testing. Additionally, skin testing
should be repeated in patients with new TB exposures. Glucocorticoids and other factors
may cause false-negative results. Screening for latent TB is discussed in detail
separately. (See "Tumor necrosis factor-alpha inhibitors and mycobacterial infections"
and "Diagnosis of latent tuberculosis infection in HIV-negative adults".)
Interferon-gamma release assays can be used in place of tuberculin skin testing in the
United States, according to CDC recommendations, and may be preferred in patients
who have previously received vaccination with Bacillus Calmette-Guerin (BCG).
However, in some countries, tuberculin skin testing is preferred. (See "Interferon-gamma
release assays for diagnosis of latent tuberculosis infection".)
Choice of therapy Choices between treatment options are based upon multiple factors, including:
Level of disease activity (eg, mild versus moderate to severe)

Stage of therapy (eg, initial versus subsequent therapy in patients resistant to a given
intervention)
Regulatory restrictions (eg, governmental or health insurance company coverage
limitations)
Patient preferences (eg, route and frequency of drug administration, monitoring
requirements, personal cost)
A combination of the following types of therapies may be used:
Rapidly acting antiinflammatory medications, including nonsteroidal antiinflammatory

drugs (NSAIDs) and systemic and intraarticular glucocorticoids (see 'Adjunctive role of
antiinflammatory agents' below)

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Disease-modifying antirheumatic drugs (DMARDs), including nonbiologic (traditional

small molecule or synthetic) and biologic DMARDs, and an orally-administered small
molecule kinase inhibitor, which all have the potential to reduce or prevent joint damage
and to preserve joint integrity and function (see "Overview of the use of
immunosuppressive and disease-modifying drugs in the rheumatic diseases")
The nonbiologic DMARDs most frequently used include hydroxychloroquine,

sulfasalazine, methotrexate, and leflunomide. (See "Overview of the use of
immunosuppressive and disease-modifying drugs in the rheumatic diseases", section on
'Disease-modifying antirheumatic drugs' and "Antimalarial drugs in the treatment of
rheumatic disease" and "Sulfasalazine in the treatment of rheumatoid arthritis" and "Use
of methotrexate in the treatment of rheumatoid arthritis" and "Leflunomide in the
treatment of rheumatoid arthritis".)
Biologic DMARDs, produced by recombinant DNA technology, generally target cytokines

or their receptors or are directed against other cell surface molecules. These include
anticytokine therapies, such as the tumor necrosis factor (TNF)-alpha inhibitors,
etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol; the interleukin
(IL)-1 receptor antagonist, anakinra; and the IL-6 receptor antagonist, tocilizumab. They
also include other biologic response modifiers such as the T-cell costimulation blocker,
abatacept (CTLA4-Ig), and the anti-CD20 B-cell depleting monoclonal antibody,
rituximab. (See "Overview of biologic agents in the rheumatic diseases" and "T cell
targeted therapies for rheumatoid arthritis", section on 'Abatacept' and "Rituximab and
other B cell targeted therapies for rheumatoid arthritis", section on 'Rituximab' and
"Randomized clinical trials in rheumatoid arthritis of biologic agents that inhibit IL-1, IL-6,
and RANKL", section on 'Tocilizumab'.)
Several kinase inhibitors are in development for use in rheumatoid arthritis (RA), and one
of these, tofacitinib, is available for such clinical use in the United States and is under
review for potential approval in Europe. Tofacitinib is an orally-administered small
molecule DMARD that inhibits cytokine and growth factor signalling through interference
with Janus kinases. (See "Cytokine networks in rheumatic diseases: Implications for
therapy", section on 'JAK inhibition'.)
Early use of DMARDs We recommend that all patients diagnosed with RA be started on disease-
modifying antirheumatic drug (DMARD) therapy as soon as possible. The choice of initial drug therapy
depends in large part upon the degree of disease activity. We distinguish between those patients with
mildly active disease and the majority of patients with more active disease. Our choice of drug
therapies in patients with RA and the evidence supporting these choices is described in detail
separately. Briefly, we take the following approach (see 'Assessment of disease activity' below):
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In patients with mildly active RA, we initiate antiinflammatory therapy with a NSAID for
rapid symptomatic relief and begin DMARD treatment with either hydroxychloroquine
(HCQ) or sulfasalazine (SSZ). (See "Initial treatment of mildly active rheumatoid arthritis
in adults".)
In patients with moderately to severely active RA, we initiate antiinflammatory therapy
with either a NSAID or glucocorticoid, depending upon the degree of disease activity, and
generally start DMARD therapy with methotrexate (MTX). (See "Initial treatment of
moderately to severely active rheumatoid arthritis in adults".)
In patients resistant to initial DMARD therapy (eg, MTX), we treat with a combination of
DMARDs (eg, MTX plus either a TNF inhibitor or SSZ and HCQ) or, alternatively, we
switch the patient to a different DMARD of potentially comparable efficacy (eg,
leflunomide or a TNF inhibitor), while also treating the active inflammation with
antiinflammatory drug therapy. (See "Treatment of rheumatoid arthritis resistant to initial
DMARD therapy in adults".)
Much of the joint damage that ultimately results in disability begins early in the course of the disease
[24,25]. As an example, more than 80 percent of patients with RA of less than two years duration had
joint space narrowing on plain radiographs of the hands and wrists, while two-thirds had erosions [25].
The use of more sensitive imaging techniques, such as magnetic resonance imaging (MRI) and high
resolution ultrasonography, can identify even earlier damage than that which is recognized by
radiography, although the prognostic implications of such findings are unknown [26-28].
Better outcomes are achieved by early compared with delayed intervention with DMARDs in patients
with RA [11,29-33]. As examples:
An observational study of 1435 patients involved in 14 trials, primarily of MTX or other

nonbiologic DMARDs, found a progressive decrease over time in the likelihood of a
significant response to DMARD therapy. Response rates were higher in patients with no
more than one year of disease than in those with one to two years of disease, and
response rates were lowest in the group with greater than 10 years of disease (53 versus
43 versus 35 percent) [29].
A further observational study comparing very early (median disease duration of three
months) with late early (median disease duration of 12 months) initiation of nonbiologic
(traditional) DMARD therapy showed significantly greater improvement in disease activity
in the very early group within three months after starting DMARDs; the greater degree of
improvement in the very early treatment group remained statistically and clinically
significant after 36 weeks of DMARD therapy (Disease Activity Score for 28 joints
[DAS28] improvement of 2.8 versus 1.7) [31].
Another study found that the combination of MTX with etanercept was more effective
upon evaluation after one year of treatment in patients begun on therapy less than four

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months after diagnosis compared with those begun on therapy from four months to two
years after diagnosis (DAS28 remission rates of 70 versus 48 percent) [33].
ASSESSMENT AND MONITORING Patients should be seen on a regular basis for clinical
evaluation and monitoring of clinical and laboratory assessment of disease activity and for screening
for drug toxicities. The initial evaluation and subsequent monitoring should also include periodic
assessment of disease activity using a quantitative composite measure of disease activity. (See
'Assessment of disease activity' below.)
Additionally, the ongoing evaluation and monitoring of patients with rheumatoid arthritis (RA) following
the initiation of therapy also involves:
Patient and clinician assessment of symptoms and functional status (see 'Symptoms and
functional status' below)
Evaluation of joint involvement and extraarticular manifestations (see 'Physical
examination' below)
Laboratory markers (see 'Laboratory monitoring of disease activity' below and 'Monitoring
and prevention of drug toxicity' below)
Imaging (see 'Imaging' below)
Assessment of disease activity Disease activity should be evaluated initially and at all
subsequent visits. We recommend that a structured assessment of disease activity using a composite
measure, such as those described here, should be performed initially, and most patients should be
seen at least every three months to monitor the response to therapy using the same measure.
Adjustments to treatment regimens should be made to quickly achieve and maintain control of disease
activity if targeted treatment goals (remission or low disease activity), rather than an undefined degree
of improvement, have not been achieved. (See "Assessment of rheumatoid arthritis activity in clinical
trials and clinical practice", section on 'Composite indices for disease activity assessment' and 'Tight
control' below.)
The initial assessment, made once the diagnosis is established, helps to distinguish the smaller group
of patients who present with mild disease from the majority of patients who present with moderately to
severely active disease and who are usually treated initially with methotrexate. (See "Initial treatment
of mildly active rheumatoid arthritis in adults" and "Initial treatment of moderately to severely active
rheumatoid arthritis in adults".)
The use of periodic structured assessments of disease activity is complementary to ongoing regular
monitoring of disease manifestations, disease progression, joint injury, disability, and complications of
the disease and to monitoring for adverse effects of medications. (See 'Assessment and monitoring'
above.)

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Multiple composite measures employing different combinations and weighting of these variables have
been developed for use in clinical research and practice. Among the greater than 60 activity measures
available for evaluation of patients with RA, the six measures noted below have been identified by the
American College of Rheumatology (ACR) as having the greatest utility in clinical practice because
they accurately reflect disease activity; are sensitive to change; discriminate well between low,
moderate, and high disease activity; have remission criteria; and are feasible to perform in clinical
settings [34]. The choice of measure is based upon clinician preference; some measures require both
patient and clinician input, while others are based only upon patient-reported data. (See "Assessment
of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'Composite indices for
disease activity assessment'.)
Measures that require both patient and clinician input, as well as calculators for these measures,
include the following:
The Disease Activity Score derivative for 28 joints (DAS28) (calculator 1)

The Simplified Disease Activity Index (SDAI) (calculator 2)
The Clinical Disease Activity Index (CDAI) (calculator 3)
The patient-reported outcome measures include:
The Routine Assessment of Patient Index Data 3 (RAPID3) [35]

The Patient Activity Scale (PAS) and PAS-II [36]
The RAPID3 correlates well with the results obtained by use of the DAS28 or CDAI [35]. (See
"Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'RAPID3
score'.)
Symptoms and functional status The clinical assessment of disease activity should include
questions concerning the degree of joint pain, the duration of morning stiffness, and the severity of
fatigue [1,37]. In addition, evidence for and changes in extraarticular manifestations of RA should be
actively sought, including systemic signs such as fever, anorexia, malaise, weight loss, and symptoms
of cardiovascular disease. (See "Clinical features of rheumatoid arthritis".)
Fever is not a common feature of RA in adults. Infection must be excluded before ascribing fever to
RA.
Patients should be queried regarding their functional capacity, including the performance of activities
of daily living, of vocational activities, and of avocational activities, such as hobbies or participation in
sports. A self-report questionnaire that measures function can also be often helpful for this purpose.
The Stanford Health Assessment Questionnaire (HAQ) is one of the best known and tested of these
questionnaires [38,39]; others include the Functional Independence Measure [40], the Arthritis Impact
Measurement Scale (AIMS), the Short Form 36 (SF36), and the Modified Health Assessment

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Questionnaire (MHAQ) [41]. (See "Disease outcome and functional capacity in rheumatoid arthritis",
section on 'Functional capacity'.)
We use the evaluation of functional capacity to identify which of a variety of interventions may be
required in addition to pharmacologic therapy, especially in patients with diminished functional
capacity, such as counseling, exercise, and occupational therapy. (See "Nonpharmacologic and
preventive therapies of rheumatoid arthritis".)
Physical examination A physical examination should be performed at regular intervals that vary
with disease activity and severity. As an example, patients with severely active disease may be seen
at four-week intervals, while those with mildly active or well-controlled disease could be seen every
two to four months. At these visits, an examination should be performed to assess changes in
previously affected joints or the appearance of inflammation in previously uninvolved joints.
A 28 joint examination is appropriate if the hands but not the feet are involved [42]. Examined joints
include the wrists, elbows, shoulders, and knees, as well as the metacarpophalangeal and proximal
interphalangeal joints of the hands. If the feet are involved, the metatarsophalangeal joints and
proximal interphalangeal (PIP) joints of the feet should also be assessed. The joints should be
evaluated for the presence of swelling, tenderness, loss of motion, and deformity.
In addition to the articular examination, a periodic general physical examination should be performed,
with particular attention to the skin for rheumatoid nodules or other dermal manifestations of RA and to
the lungs for signs of pleural or interstitial disease, to detect evidence of systemic or extraarticular
involvement. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)
Laboratory monitoring of disease activity The acute phase reactants, such as C-reactive protein
(CRP) or erythrocyte sedimentation rate (ESR), are useful for assessment of disease activity and are
components of several of the formal composite measures used for evaluating the level of disease
activity. In addition to these studies, we obtain other tests primarily for medication monitoring that may
also reflect changes or levels of disease activity. Examples of the latter include serum hemoglobin,
decreases in which may reflect anemia of chronic inflammation, and serum albumin, which may also
be reduced in association with increased disease activity. Additionally, platelet counts may be mildly
elevated (typically up to 400,000 to 450,000/microL) in patients with ongoing inflammation. (See
'Pretreatment evaluation' above and "Assessment of rheumatoid arthritis activity in clinical trials and
clinical practice", section on 'Acute phase reactants' and "Acute phase reactants" and "Clinically useful
biologic markers in the diagnosis and assessment of outcome in rheumatoid arthritis" and "Anemia of
chronic disease (anemia of chronic inflammation)" and "Hematologic manifestations of rheumatoid
arthritis".)
Monitoring and prevention of drug toxicity Because of the potential risks of serious adverse
effects and the frequency of common side effects of antirheumatic drugs, a careful balance must be
struck between the risks and potential benefits of these agents [43,44]. We generally follow the
recommendations of the American College of Rheumatology (ACR) for drug monitoring in the
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treatment of RA (table 1) [1,37,45]. Additional precautions, warnings, and the manufacturers

recommendations for clinical and laboratory monitoring are provided in the individual UpToDate drug
information topics for each medication. (See appropriate topic reviews.)
Monitoring for adverse effects, such as osteoporosis, diabetes, and hypertension, should be
performed in patients on glucocorticoids, and appropriate preventive measures should be undertaken.
RA is considered an independent risk factor for osteoporotic fracture, and a fracture risk assessment
should be performed to help guide treatment decisions. (See "Prevention and treatment of
glucocorticoid-induced osteoporosis" and "Osteoporotic fracture risk assessment", section on
'Assessment of fracture risk' and "Major side effects of systemic glucocorticoids" and "Antimalarial
drugs in the treatment of rheumatic disease", section on 'Monitoring for toxicity' and "Leflunomide in
the treatment of rheumatoid arthritis", section on 'Liver'.)
Imaging Early in the course of RA, it is appropriate to obtain plain radiographs of the hands and
wrists (one film, postero-anterior [PA] view), as well as at least one anterio-posterior (AP) view of both
forefeet to include the metatarsophalangeal joints. These radiographs serve as a baseline for
evaluating change in the joints during treatment. Radiographs should be repeated every two years in
patients in remission or with low disease activity. We view the therapy in use by the patient as
insufficient if radiologic evidence of disease progression, such as periarticular osteopenia, joint space
narrowing, or bone erosions, appears or worsens during this interval, despite good control of disease
activity by other measures. In such patients, based upon our clinical experience, we may intensify or
modify the treatment regimen. The clinician must be aware that, in hand radiographs of older patients,
coexistent osteoarthritis may account, in part, for joint space narrowing noted near the joints involved
with RA [46].
Computerized tomographic (CT) scanning, ultrasonography, computerized image analysis, and

magnetic resonance imaging (MRI) are more sensitive for the detection of cartilage and bone
abnormalities, and their role in the process of making therapeutic decisions is under investigation
[26,47,48]. We do not use these techniques for routine clinical assessment.
TIGHT CONTROL We recommend the use of tight control treatment strategies to quickly minimize
inflammation and disease progression; our therapeutic target is remission or a state of minimal
disease activity, without compromising safety. In patients resistant to initial disease-modifying
antirheumatic drug (DMARD) therapy, we either add additional DMARDs to the ongoing regimen or
switch the patient to a different DMARD, while also treating the active inflammation with
antiinflammatory drug therapy. A description of our treatment approach and the evidence supporting
use of particular medications in patients with active disease despite initial DMARD therapy are
discussed in detail separately. (See 'Drug therapy for flares' below and "Treatment of rheumatoid
arthritis resistant to initial DMARD therapy in adults".)

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In patients with disease exacerbations despite a preceding period of better control of disease activity
(a disease flare), a temporary increase in antiinflammatory therapies, including the use of
glucocorticoids, may be required. (See 'Drug therapy for flares' below.)
The use of strategies for tight control involves frequent periodic reassessment of disease activity,
usually at least every three months; adjustment of DMARD regimens every three to six months, if
needed, as the primary tool to achieve treatment goals; and administration of antiinflammatory
therapies (eg, nonsteroidal antiinflammatory drugs [NSAIDs] and oral and intraarticular
glucocorticoids) as an adjunct to DMARDs to maintain control of disease activity until DMARD
therapies are sufficiently effective to discontinue glucocorticoids or to reduce their use to an
acceptably low level. Treatment protocols based upon this general approach are associated with
improved radiographic and functional outcomes compared with less aggressive approaches [6,49-57].
The periodic reevaluation of disease activity using a quantitative composite measure and the use of
antiinflammatory drugs, including nonsteroidal antiinflammatory drugs and glucocorticoids, as bridging
therapies are both important elements in the strategy of tight control. Glucocorticoids can rapidly
achieve control of inflammation until disease-modifying antirheumatic drugs (DMARDs) are sufficiently
effective. (See 'Assessment of disease activity' above and "Assessment of rheumatoid arthritis activity
in clinical trials and clinical practice" and 'Adjunctive role of antiinflammatory agents' below.)
Taken together, studies that have compared tight control with less aggressive approaches support the
following observations:
Most patients should receive a DMARD as soon as possible after diagnosis. Achieving
and maintaining low disease activity using a DMARD or DMARD combinations as quickly
as possible improve long-term outcomes and are cost-effective compared with older,
more gradual approaches to initiating DMARD therapy. (See 'Early use of DMARDs'
above.)
Excellent treatment responses can be achieved with a wide variety of nonbiologic and
biologic DMARDs and with regimens that combine either nonbiologic DMARDs alone or
nonbiologic DMARDs with a biologic agent, as described below.
Escalation in the treatment regimen is needed for patients resistant to initial treatment;
both intraarticular glucocorticoids and oral or intramuscular glucocorticoids help minimize
disease activity until DMARDs are sufficient. (See 'Adjunctive role of antiinflammatory
agents' below.)
Regular assessment with composite measures of disease activity is critical to optimize
clinical decision-making. (See 'Assessment of disease activity' above.)
These observations are reflected in the 2008 and 2012 American College of Rheumatology (ACR) and
2010 European League Against Rheumatism (EULAR) treatment recommendations and in the
recommendations of a 2010 international task force [1-4,6,58].

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The benefits of tight control have been shown in a meta-analysis of six heterogeneous trials that
evaluated tight control strategies in comparison with usual care for rheumatoid arthritis (RA) [59].
Significantly greater improvement from baseline to one year in the DAS28 composite measure of
disease activity was seen in the patients randomly allocated to tight control strategies compared with
usual care (mean difference in reduction in DAS28 of 0.59, 95% CI 0.22-0.97). A statistically
significantly greater reduction compared with usual care was observed in the trials in which tight
control was achieved with protocolized treatment adjustments compared with trials without such
protocols (mean difference in DAS28 of 0.91, 95% CI 0.72-1.11, versus 0.25, 95% CI 0.03-0.46). Four
of the six studies analyzed compared functional ability in the two treatment arms using the Health
Assessment Questionnaire (HAQ). Greater improvement in HAQ scores in the tight control groups that
were statistically significant were seen in two of these trials, while improvements in the HAQ scores
did not differ significantly between the treatment arms in the other two trials. (See "Assessment of
rheumatoid arthritis activity in clinical trials and clinical practice", section on 'Health Assessment
Questionnaire (HAQ)'.)
The following trials and related studies best illustrate the range of medications and approaches that
support these conclusions [49-55,60]:
BeSt trial In the Behandel-Strategien voor Reumatoide Artritis (Dutch for treatment
strategies for rheumatoid arthritis or BeSt) trial, 508 patients with early active RA were
randomly assigned to sequential monotherapy (group one), to initial monotherapy with
step-up combination therapy as required (group two), to combination therapy plus high-
dose prednisone (group three), or to combination therapy including infliximab (group four)
[49,50]. Regimens in this trial were adjusted in all groups based upon assessment of
disease activity every three months. The next intervention in the defined sequence was
assigned if the DAS44 score was >2.4. The treatment sequence in each group was:
Group one (sequential monotherapy) Initially methotrexate (MTX) 15 mg weekly,

followed, if needed, by switching sequentially to MTX 25 to 30 mg weekly,
sulfasalazine (SSZ), leflunomide (LEF), MTX plus infliximab, gold plus
methylprednisolone, and MTX plus cyclosporine A (CSA) and prednisone.
Group two (step-up combination therapy) Initially MTX 15 mg weekly, followed, if
needed, by increasing MTX to 25 to 30 mg weekly, adding SSZ, adding
hydroxychloroquine (HCQ), adding prednisone, and switching to MTX plus infliximab,
to MTX plus CSA and prednisone, and to LEF.
Group three (initial combination therapy with prednisone) Combination of MTX 7.5
mg weekly plus SSZ and prednisone (60 mg daily tapered gradually to 7.5 mg daily),
then MTX 25 to 30 mg weekly plus SSZ and prednisone, MTX plus CSA and
prednisone, MTX plus infliximab, LEF, gold plus methylprednisolone, and
azathioprine plus prednisone.

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Group four (initial combination therapy) MTX 25 to 30 mg weekly plus infliximab (3

mg/kg per infusion), MTX plus infliximab (6 mg/kg), MTX plus infliximab (7.5 mg/kg),
MTX plus infliximab (10 mg/kg), then SSZ monotherapy, LEF monotherapy, MTX
plus CSA and prednisone, gold plus methylprednisolone, and azathioprine plus
prednisone.
At 3 and 12 months, functional improvement was significantly better in those who
received initial combination therapy (groups three and four). Significantly less
radiographic progression was observed at two and four years in the combination
groups compared with the initial monotherapy groups [50,56]. Remission at four
years was achieved in 43 percent of all patients, and drug-free remission was seen in
13 percent.
FIN-RACo trial The Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial evaluated
the outcomes of 199 patients randomly assigned for at least two years to monotherapy (initially SSZ 2
g daily) and then sequentially switched every three months, if criteria for an inadequate response were
met, to SSZ (3 g daily), MTX (7.5 to 15 mg weekly), azathioprine, auranofin, hydroxychloroquine,
injectable gold, penicillamine, or podophyllotoxin (which could be used alternatively after azathioprine),
respectively, or to combination therapy (SSZ, MTX, hydroxychloroquine, and prednisolone, with dose
adjustment at three months based upon criteria for active disease and with subsequent dose
adjustments as needed within defined limits) [52-54].
The treatment target after the first two years remained remission, but medication choices were not
restricted. At follow-up at 11 years following the initial randomization, a significantly greater proportion
of patients in the initial combination group had achieved minimal disease activity (63 versus 43
percent) and remission by ACR criteria (37 versus 19 percent) [54]. Additionally, radiographic
progression at 11 years was significantly less in the group receiving initial combination therapy
compared with the group on monotherapy for at least two years (increase in Larsen score of 17, 95%
CI 22-33, versus 27, 95% CI 22-33) [60].
TICORA trial In the Tight Control of Rheumatoid Arthritis (TICORA) trial, 111 patients
were randomly assigned to intensive or routine management [55]. Intensively-managed
patients in this trial had monthly visits, with calculation of disease activity scores (a
validated composite score based upon the erythrocyte sedimentation rate, Ritchie
articular index, joint swelling count, and patients global assessment of disease activity
defining high, moderate, and low disease activity levels of 3.6, of 2.4 to <3.6, and of
1.6 to <2.4, respectively); glucocorticoid injections of swollen joints; and, every three
months, adjustment of their treatment regimen by a predefined protocol if moderate or
highly active disease was present. Routinely managed patients were seen every three
months, with no formal measurement of disease activity performed, and glucocorticoid
injections and other treatment adjustments were made at the discretion of the

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rheumatologist.
After 18 months, the patients receiving intensive management demonstrated a

significantly greater decrease in their disease activity scores compared with the routine
management group (-3.5 versus -1.9), and a higher proportion achieved a good response
by European League Against Rheumatism criteria (82 versus 44 percent). Additionally,
physical function assessed by the HAQ was improved to a statistically and clinically
significantly greater degree in the patients receiving intensive management (change in
HAQ of -0.97 versus -0.47).
Adjunctive role of antiinflammatory agents We use antiinflammatory therapies, including

systemic and intraarticular glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs),
primarily as adjuncts for temporary control of disease activity in patients in whom treatment is being
started with disease-modifying antirheumatic drugs (DMARDs), in patients in whom the DMARD
regimen requires modification, or in patients who are experiencing disease flares. Although NSAIDs
and/or glucocorticoids act rapidly to control inflammation, they do not provide adequate benefit on their
own for longer-term control of disease or for prevention of joint injury. More detailed discussions of
NSAID and glucocorticoids in RA are presented elsewhere. (See "Use of glucocorticoids in the
treatment of rheumatoid arthritis" and "Initial treatment of mildly active rheumatoid arthritis in adults",
section on 'Symptomatic treatment'.)
In patients who receive glucocorticoids, we taper the medication as rapidly as tolerated once disease
control is achieved and can be maintained, with the ideal goal of discontinuing systemic glucocorticoid
therapy.
Intraarticular injections of long-acting glucocorticoids (eg, triamcinolone hexacetonide) are used to

reduce synovitis in particular joints that are more inflamed than others. Occasional patients benefit
from intramuscular rather than oral administration. (See "Intraarticular and soft tissue injections: What
agent(s) to inject and how frequently?".)
There is strong evidence that glucocorticoids retard radiographic progression in patients with RA in the
short to medium term (ie, up to two years of therapy) [61-63]. However, these agents should not be
used alone for an extended period. We avoid long-term use, if possible, because chronic use for
inflammatory disease is often associated with adverse effects [64]. However, patients with severe RA
sometimes require sustained therapy with low doses of glucocorticoids (less than 10 mg/day); such
doses in RA are generally well-tolerated and may have some benefit in retarding disease progression
[63,65]. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis", section on 'Efficacy of
chronic use'.)
Drug therapy for flares RA has natural exacerbations (also known as flares) and reductions of
continuing disease activity. It is important to distinguish a disease flare, characterized by symptoms
and by physical and laboratory findings of increased inflammatory synovitis, from noninflammatory
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causes of local or generalized increased pain. Patients with recurrent flares may require adjustment in
the background DMARD therapy. (See "Clinical features of rheumatoid arthritis" and 'Assessment of
disease activity' above.)
The severity of the flare and background drug therapy influence the choice of therapies. The following
is a brief summary of glucocorticoid therapy, which is discussed in detail separately. (See "Use of
glucocorticoids in the treatment of rheumatoid arthritis".)
With respect to the severity of the flare:
In patients with a single or few affected joints, intraarticular glucocorticoid injections may
be effective and avoid the need for additional or prolonged systemic therapy.
More widespread flares may be treated by initiating glucocorticoid therapy or by
increasing the dose of oral glucocorticoid, with the intention of reducing the dose once
the flare is under control. The magnitude of dose increase varies with the baseline dose
and with the severity of the flare. An alternative to an increase in the oral dose is a single
intramuscular injection of depot methylprednisolone acetate, which is available in the
United Kingdom (UK) and most other European countries in a dose of 120 mg.
Pulse intravenous methylprednisolone therapy, usually consisting of three daily infusions
of up to 1000 mg, is generally limited to severe flares, particularly those associated with
systemic manifestations, such as rheumatoid vasculitis.
With respect to background drug therapy, an escalation in dose or a modification in drugs is warranted
if the patient is flaring frequently or severely. The strategy depends upon the background DMARDs
being used:
Patients on methotrexate (MTX) who will tolerate a slower resolution of their flare may
respond to an increase in the dose of MTX or to a switch from oral to subcutaneous
therapy [66].
Patients initially controlled with a regimen that includes infliximab may benefit from a
decrease in the interval of infliximab dosing or from higher doses [67,68]. However,
increasing the dose from 3 to 5 mg/kg was not beneficial in one well-designed trial
[69,70].
Increases in doses of etanercept (greater than 50 mg weekly) or adalimumab (weekly
rather than every two weeks), with or without MTX, do not appear to increase efficacy
[71,72].
Patients who require multiple treatment courses with glucocorticoids for recurrent disease flares and
whose medication doses have been increased to the maximally tolerated or acceptable level should
be treated as patients with sustained disease activity. (See "Treatment of rheumatoid arthritis resistant
to initial DMARD therapy in adults".)

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OTHER CONSIDERATIONS IN RA MANAGEMENT The focus of therapeutic decision-making is

control of disease activity, as described above, but additional factors, such as the degree of joint injury
or disability, may influence the choice of specific therapies in individual patients [3,7]. Additionally, the
efficacy of particular medications may be affected by the presence or absence of some of these
factors, which are associated with an adverse prognosis. (See 'Prognosis' below.)
The relative importance of these factors depends upon the individual treatment choice; these are
discussed in more detail in the appropriate individual treatment topics. We consider the following
factors, depending upon the specific treatment decision:
Disability and function General scales that measure disability may not identify specific
limitations of greater impact on an individual patient. As an example, specific vocational
requirements, family responsibilities, or recreational interests may affect a patients
willingness to accept the risks of a given intervention that would help to achieve a greater
degree of disease control than low disease activity. We therefore incorporate patient-
specific needs in our assessment of the severity of disease-related disability.
Joint injury Good control of disease activity may not result in complete elimination of
progressive joint injury in all patients. In patients with low disease activity but with
worsening findings on imaging studies, either changes in medications or increased
dosing may be of benefit. However, there is insufficient evidence to determine whether
treating to targets that are based upon imaging findings provides additional benefit for
long-term outcomes, compared with targets based upon measures of disease activity
alone.
Comorbidities The presence of comorbidities, such as renal or hepatic disease, may
affect medication choices and may influence the degree of risk inherent in attempting to
reach a goal of remission or of low disease activity in a given patient.
Comorbidities A number of medical conditions that often coexist with or result from rheumatoid
arthritis (RA) may influence the choice of medications [1,2,73]. (See appropriate treatment and drug
information topics.)
Pregnancy RA often improves or remits completely during pregnancy. Issues related to the
pregnant woman with RA, including the use of immunosuppressive drugs, are discussed separately.
(See "Rheumatoid arthritis and pregnancy" and "Use of antiinflammatory and immunosuppressive
drugs in rheumatic diseases during pregnancy and lactation".)
Lung disease Comorbid pulmonary disease is common in patients with RA and may also be a
complication of therapy or of the disease [73]. Therapeutic agents with potential for causing adverse
pulmonary effects include methotrexate, leflunomide, tumor necrosis factor (TNF) inhibitors,
sulfasalazine, parenteral gold, abatacept, and rituximab. (See "Overview of lung disease associated
with rheumatoid arthritis".)

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Cardiovascular disease Comorbid cardiovascular disease can occur in patients with RA and may
also be a complication of therapy [73]. Both glucocorticoids and nonsteroidal antiinflammatory drugs
(NSAIDs) may increase cardiovascular risk. TNF inhibitors should be avoided in patients with
moderate or severe heart failure (HF), as they can worsen HF. Active RA is associated with an
increased risk of cardiovascular disease, but good control of disease activity has been associated with
reduced cardiovascular complications. (See "Coronary artery disease in rheumatoid arthritis:
Epidemiology, pathogenesis, and risk factors" and "Coronary artery disease in rheumatoid arthritis:
Diagnostic and therapeutic implications" and "Major side effects of systemic glucocorticoids", section
on 'Cardiovascular disease' and "Nonselective NSAIDs: Overview of adverse effects", section on
'Cardiovascular effects' and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects",
section on 'Heart failure'.)
Neurologic manifestations Neurologic manifestations of RA and the presence of coexistent

neurologic disease are generally uncommon, other than the occurrence of impingement neuropathies
such as carpal tunnel syndrome. However, TNF inhibitors should be avoided in those with a history of
or with an ongoing demyelinating disorder because of case reports of such disorders in patients being
treated for RA and because of increased risk of disease worsening in trials of TNF blockade in
patients with multiple sclerosis (MS). Some RA experts are also cautious about using TNF-alpha
inhibitors in patients with family histories of MS [73]. (See "Neurologic manifestations of rheumatoid
arthritis" and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on
'Demyelinating disease'.)
Diabetes The risk of diabetes mellitus is not increased in patients with RA. However, in patients
with both diabetes and RA, glucocorticoids should be used with particular caution because they may
worsen control of the diabetes [73]. In contrast, patients being treated with hydroxychloroquine or with
TNF inhibitors for RA have a lower risk of diabetes [74], and sulfasalazine may have glucose-lowering
effects [75]. (See "Major side effects of systemic glucocorticoids", section on 'Glucose metabolism' and
"Antimalarial drugs in the treatment of rheumatic disease", section on 'Reduction of diabetes risk'.)
Renal disease RA infrequently affects the kidney, but, if renal disease coexists, it increases
mortality risk [73]. In addition to NSAIDs, the use of some medications occasionally or only historically
used in the treatment of patients with RA may adversely affect renal function, including gold,
penicillamine, and cyclosporine. Some nonbiologic disease-modifying antirheumatic drugs (DMARDs),
particularly methotrexate and cyclosporine, should be avoided or used with particular caution in
patients with significantly decreased renal function. (See "Renal disease in patients with rheumatoid
arthritis".)
Extraarticular disease Rheumatoid arthritis has many extraarticular manifestations. The treatment
of these specific features, such as vasculitis, interstitial lung disease, and others, is reviewed in detail
elsewhere. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis"
and "Treatment of rheumatoid vasculitis".)

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Use of analgesics Drugs that primarily or only provide analgesia, including topical medications (eg,
capsaicin) and oral agents, such as acetaminophen (paracetamol), tramadol, and more potent opioids
(eg, oxycodone, hydrocodone), have a limited role in most patients with active disease but may be
helpful in patients with end-stage disease and, occasionally, in patients with more severe involvement
or during disease flares for added temporary benefit. These medications should not be used as the
sole or primary therapy in patients with active inflammatory disease. Apparent need for additional
analgesic medications when inflammatory disease is well-controlled (other than acetaminophen or
occasional NSAIDs) should prompt a search for alternative comorbid diagnoses, such as fibromyalgia,
to explain the patients symptoms. (See "Clinical manifestations and diagnosis of fibromyalgia in
adults" and "Clinical manifestations and diagnosis of fibromyalgia in adults", section on 'Inflammatory
rheumatic diseases'.)
THERAPY OF END-STAGE DISEASE Despite therapeutic intervention, some patients progress to

disabling, destructive joint disease. Symptoms in such patients may be present in the absence of
active inflammatory joint disease and may be due to the secondary degenerative changes alone. The
accurate evaluation of such patients is essential since deterioration associated with mechanical
problems of the muscle or joint is treated much differently from ongoing inflammation or systemic
manifestations of rheumatoid arthritis (RA). Disease exacerbations and their systemic effects are
usually easily recognized by the presence of many inflamed joints, fever, anemia, an elevated
erythrocyte sedimentation rate (ESR), or an elevated serum C-reactive protein (CRP) concentration.
The goals of therapy in the patient with end-stage disease are:
Pain relief
Protection of remaining articular structures
Maintenance of function
Relief from fatigue and weakness
In the absence of inflammation, which requires antiinflammatory medications and disease-modifying

antirheumatic drugs (DMARDs), treatments other than medications may be particularly important in
management. These include nonpharmacologic interventions, such as physical and occupational
therapy, use of adaptive devices, and surgery. (See "Evaluation and medical management of end-
stage rheumatoid arthritis".)
The indications for surgical intervention in patients with RA include intractable pain or severe
functional disability due to joint destruction, as well as impending tendon rupture. The timing of surgery
is often critical. If one waits too long, there may be so much muscle atrophy from disuse that
postoperative rehabilitation is unsuccessful. On the other hand, a decision about joint replacement
should take into account the average life of the artificial joint. (See "Total joint replacement for severe

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RECOMMENDATIONS BY MAJOR GROUPS Recommendations for the management of patients

with rheumatoid arthritis (RA) have been developed by major professional organizations, including the
American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR)
[1,2,4]. In addition, an international task force has developed recommendations for treating RA to
targeted goals [3,6]. Our approach to treatment is generally consistent with these recommendations.
The 2008 ACR recommendations and 2012 update can be accessed online.
The EULAR recommendations for the management of RA represent a European consensus on the
management of RA with disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids and on
the strategies to reach optimal outcomes, based upon evidence and expert opinion [4]. The evidence
used was detailed in a series of systematic literature reviews [5,76-79]. The recommendations include
three overarching principles for the care of patients with RA and a set of 15 recommendations
covering major issues in disease management. The EULAR recommendations can be accessed
online.
PROGNOSIS Rheumatoid arthritis (RA) was associated with a high degree of economic loss,
morbidity, and early mortality prior to the widespread use of methotrexate that began in the 1980s, to
more aggressive treatment of early disease, and to the availability of targeted biologic agents since
the later part of the 1990s. As an example, almost 80 percent of patients in one center were severely
disabled after 20 years of follow-up (from 1967 to 1987); an additional one-third had died [80]. Patients
with RA that required hospital care had at least a twofold increased mortality when compared with
those without disease [81], and more severe RA was associated with higher mortality rates due to
higher rates of myocardial infarction, infection, and certain malignancies, comparable to three vessel
coronary artery disease or to stage IV Hodgkin lymphoma [82].
Clinical outcomes have improved significantly with changes in drug therapy and in the approach to
treatment. The average level of disability in RA was found in a longitudinal study of over 3000 patients
to have declined by about 40 percent from 1977 to 1998, even prior to the introduction of the biologic
disease-modifying antirheumatic drugs (DMARDs) [83]. Similarly, patients with RA seen in a single
university clinic from 1984 through 1986 had significantly more disability and greater radiographic
evidence of joint injury compared with a cohort from the same clinic seen from 1999 through 2001
(modified Health Assessment Questionnaire disability score on a 0 to 3 scale of 0.4 versus 1,
respectively, and Larsen radiographic score on a 0 to 100 scale of 3 versus 20, respectively) [12].
Patients able to achieve remission with combination therapy had significantly less work disability over
five years of follow-up compared with patients with incomplete responses to treatment [84]. (See
"Disease outcome and functional capacity in rheumatoid arthritis".)
A number of factors have been associated with poorer outcomes in patients with RA. The following
four markers of adverse prognosis can be used to identify patients who may require more aggressive
pharmacotherapy, especially in early stages of disease [1]:
Functional limitation
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Extraarticular disease
Rheumatoid factor positivity or presence of anticyclic citrullinated peptide (CCP)
antibodies
Bony erosions documented radiographically
Other factors associated with a worse prognosis include concurrent medical disorders, cigarette
smoking, lack of formal education, and lower socioeconomic status [85]. Older age, female sex, and
the presence of the shared epitope have also been associated with a poorer prognosis [1]. Some
studies have derived models to estimate prognosis, such as persistent erosive disease [86]. However,
these models have not been validated in other cohorts. The individual factors associated with a poor
prognosis are discussed in detail separately. (See "Epidemiology of, risk factors for, and possible
causes of rheumatoid arthritis" and "Disease outcome and functional capacity in rheumatoid arthritis"
and "Clinically useful biologic markers in the diagnosis and assessment of outcome in rheumatoid
arthritis" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis" and
"HLA and other susceptibility genes in rheumatoid arthritis".)
th th
th th
(Beyond the Basics)" and "Patient information: Disease-modifying antirheumatic drugs
(DMARDs) (Beyond the Basics)" and "Patient information: Complementary therapies for
rheumatoid arthritis (Beyond the Basics)")
In patients with rheumatoid arthritis (RA), affected areas may be irreversibly damaged or
destroyed if inflammation persists. Thus, prompt diagnosis, early recognition of active
disease, and measures to quickly achieve and maintain control of inflammation and the
underlying disease process, with the goal of remission or low disease activity, are central
to modifying disease outcome. The application of these principles in the management of

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patients with RA, together with the development and use of newer and more potent
drugs, has resulted in significant improvement in the outcomes of treatment. (See
'General principles' above and 'Early recognition and diagnosis' above.)
An expert in the care of rheumatic disease, such as a rheumatologist, should participate
in the care of patients suspected of having RA and in the ongoing care of patients
diagnosed with this condition. The treatment of patients with RA by a rheumatologist is
associated with better disease outcomes compared with care rendered primarily by other
clinicians. (See 'Care by a rheumatologist' above.)
Nonpharmacologic measures, such as patient education, psychosocial interventions, and
physical and occupational therapy, should be used in addition to drug therapy. Other
medical interventions that are important in the comprehensive management of RA in all
stages of disease include cardiovascular risk reduction and immunizations to decrease
the risk of complications of drug therapies. (See 'Nonpharmacologic and preventive
therapies' above.)
We recommend that all patients diagnosed with RA be started on disease-modifying
antirheumatic drug (DMARD) therapy as soon as possible following diagnosis, rather
than using antiinflammatory drugs alone, such as nonsteroidal antiinflammatory drugs
(NSAIDs) and glucocorticoids (Grade 1B). Better outcomes are achieved by early
compared with delayed intervention with DMARDs. (See 'Early use of DMARDs' above.)
We recommend the use of tight control treatment strategies to guide adjustments in the
treatment regimen, rather than less aggressive approaches (Grade 1B). Tight control
involves reassessment of disease activity on a regularly planned basis with the use of
quantitative composite measures and adjustment of treatment regimens to quickly
achieve and maintain control of disease activity if targeted treatment goals (remission or
low disease activity), rather than an undefined degree of improvement, have not been
achieved. Such tight control treatment strategies are associated with improved
radiographic and functional outcomes compared with less aggressive approaches. (See
'Tight control' above and 'Assessment of disease activity' above.)
Laboratory testing prior to therapy should include a complete blood count, erythrocyte
sedimentation rate, C-reactive protein, aminotransferases, blood urea nitrogen, and
creatinine. Patients receiving hydroxychloroquine should have a baseline ophthalmologic
examination, and most patients who will receive a biologic agent should be tested for
latent tuberculosis infection. Screening for hepatitis B and C should be performed in all
patients at increased risk of hepatitis. (See 'Pretreatment evaluation' above.)
We use antiinflammatory drugs, including nonsteroidal antiinflammatory drugs and
glucocorticoids, as bridging therapies to rapidly achieve control of inflammation until
disease-modifying antirheumatic drugs are sufficiently effective. Some patients may
benefit from longer-term therapy with low doses of glucocorticoids. (See 'Adjunctive role
of antiinflammatory agents' above.)

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RA has natural exacerbations (also known as flares) and reductions of continuing

disease activity. The severity of the flare and background drug therapy influence the
choice of therapies. Patients who require multiple treatment courses with glucocorticoids
for recurrent disease flares and whose medication doses have been increased to the
maximally tolerated or acceptable level should be treated as patients with sustained
disease activity. Such patients require modifications of their baseline drug therapies.
(See 'Drug therapy for flares' above.)
The monitoring that we perform on a regular basis includes testing that is specific to
evaluation of the safety of the drugs being used; periodic assessments of disease activity
with composite measures; monitoring for extraarticular manifestations of RA, other
disease complications, and joint injury; and functional assessment. (See 'Assessment
and monitoring' above.)
Other factors in RA management that may influence the target or choice of therapy
include the disabilities or functional limitations important to a given patient, progressive
joint injury, comorbidities, and the presence of adverse prognostic factors. (See 'Other
considerations in RA management' above and 'Prognosis' above.)
INTRODUCTION Although rheumatoid arthritis (RA) develops its central pathology within the
synovium of diarthrodial joints, many nonarticular organs become involved, particularly in patients with
severe joint disease. Despite the differences between the normal form and function of joints and, for
example, the bone marrow, it is becoming clearer that the same cytokines that drive synovial
pathology are also responsible for generating pathology in extraarticular tissues. (See "Pathogenesis
of rheumatoid arthritis".)
Involvement of the musculoskeletal system other than joints (eg, bone and muscle) and of organs not
considered part of the musculoskeletal system (eg, skin, eye, lung, heart, kidney, blood vessels,
salivary glands, central and peripheral nervous systems, and bone marrow) occurs in about 40
percent of patients with RA over a lifetime of disease [1,2]. These manifestations are reviewed here.
Articular manifestations are discussed in detail separately. (See "Clinical features of rheumatoid
arthritis".)
Risk factors for systemic, extraarticular disease include the presence of rheumatoid factor (RF) and
smoking [3]. Patients with severe extraarticular RA often have high levels of RF at presentation of
systemic manifestations and are more likely to have circulating antibodies against citrullinated proteins
than are patients with RA but without extraarticular disease [4].
Extraarticular involvement in rheumatoid arthritis is a marker of disease severity and is associated with
increased overall morbidity and premature mortality [5,6]. Successful management of systemic
manifestations of RA is predicated upon control of the underlying joint disease and often includes
glucocorticoid and immunosuppressive treatments [7].
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OSTEOPENIA Osteopenia in RA may be generalized, resulting from immobility, the inflammatory

process, and treatment effects with glucocorticoids; it also includes periarticular demineralization
typical of RA. It is due to the combined actions of prostaglandins and cytokines in association with
normal amounts of parathyroid hormone. In the absence of antiresorptive therapy, all patients with RA
can be expected to lose bone mineral [8]. The decrease in bone secondary to the disease itself is
separate from glucocorticoid-induced osteopenia; in some patients, however, the disease and
glucocorticoid treatment are additive, producing substantial morbidity. These individuals are those who
are particularly prone to loss of height, to symptomatic vertebral compression fractures, and to stress
fractures of metatarsals or long bones in the leg. Patients who develop fractures often are immobilized
for significant periods, and this deficiency of normal weightbearing amplifies bone loss by diminishing
new bone formation while bone resorption continues at an accelerated pace.
Periodontal bone loss may be associated with joint destruction at the wrist, and both were associated
with the possession of the shared epitope [9]. The presence of a lymphocytic infiltration of the
salivary glands and the sicca syndrome were also associated with periodontal bone resorption in this
study [9]. (See 'Sjgren's syndrome' below.)
Bone formation is decreased in rheumatoid patients not treated with glucocorticoids, compared with
controls [10]. An inverse association has been found between measurements of acute phase
reactants and bone mineral density [11], although, in this same cohort, no correlation could be found
between bone mineral density and joint counts, swollen joints, or degree of general health.
Prevalence Osteoporosis of the hip or lumbar spine is common in adults with RA. This was
illustrated in one study of 287 Norwegian patients among whom the prevalence of osteoporosis, as
indicated by a bone mineral density of more than 2.5 standard deviations below the average for
healthy young people at one or both sites, was 22 percent [12].
There are conflicting data on the frequency of glucocorticoid-associated osteopenia in rheumatoid

patients taking low-dose (<7.5 mg/day) prednisone. This issue and the mechanism of glucocorticoid-
induced osteoporosis are discussed in detail elsewhere. (See "Pathogenesis, clinical features, and
evaluation of glucocorticoid-induced osteoporosis", section on 'Effect of low-dose glucocorticoid
therapy'.)
All else being equal, it is likely that net bone loss in a patient with RA who is taking low-dose daily
prednisone would exceed that in a patient not treated with glucocorticoids. However, it is possible that,
in those patients who gain greater mobility and exercise tolerance, with the use of 5 to 7.5 mg of
prednisone each day, the increase in bone loss from the therapy would be offset by an increase in
new bone formation associated with an increase in muscle contraction and weightbearing [13]. In a
multivariable analysis of several risk factors for vertebral compression fracture in 925 women with RA,
a one point increase in disability (as measured by the health assessment questionnaire) was
associated with more fracture risk than a 1 gram cumulative dose of prednisone [14].

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In addition, there may be factors other than the disease process itself and glucocorticoid therapy that
are associated with an increased risk of osteoporosis. These include:
Postmenopausal state
A previous diagnosis of osteoporosis
Disability
Increased age
Inadequate physical activity
Female sex
Family history of osteoporosis
Disease duration
Impaired grip strength
Low body mass
Fair complexion
Cigarette smoking
Although most studies of osteopenia in patients with RA have included a preponderance of women,
men with the disorder also appear to have lower bone mass. In one study of 94 males with RA
compared with population controls, there was a twofold increase in osteopenia among patients (bone
mineral density [BMD] decreased by more than one standard deviation [SD]) [15]. Multiple regression
analysis found advancing age and lower body weight to be associated with lower BMD at the femoral
neck and total hip. However, disease-related factors, including concurrent glucocorticoid use,
rheumatoid factor status, and self-reported disability, were not associated with osteopenia in the hip or
spine.
There is a high incidence of stress fracture of long bones in patients with RA, particularly in those
treated with glucocorticoids [16]. Synovitis and glucocorticoid use are both risk factors for thinning of
cortical bone [17]. The fibula is the most common fracture site and, in older patients, often manifests
as acute and debilitating pain in the lateral leg with no history of trauma. Other fractures can be
facilitated by geodes, the subchondral cysts that develop when high intraarticular pressures force
synovial fluid through breaks in the subchondral plate in patients who have particularly aggressive,
proliferative synovitis [18]. Vertebral compression deformities are also more common among those
with RA than among age- and gender-matched controls [19]. The higher prevalence is not fully
explained by their lower BMD or by the use of glucocorticoids.
Diagnosis It should be assumed that every patient with RA is at risk for osteoporosis. Those
patients with added risk factors outlined above should be considered for baseline determinations of
bone mineral density before the disease becomes well-entrenched and before glucocorticoid therapy
is started. Dual energy x-ray absorptiometry, if available, is a precise and popular method for
measuring bone density; quantitative computerized tomography is another option. (See "Diagnosis
and evaluation of osteoporosis in postmenopausal women".)
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Management The generalized and periarticular osteopenia that affects all patients with RA should
lead to a low threshold for therapy to prevent bone loss. Interventions that are used to prevent or
minimize RA and glucocorticoid-induced bone loss are presented elsewhere. Rheumatologists and
primary care clinicians should have a low threshold for initiating bisphosphonate therapy in patients,
particularly postmenopausal women, with RA. (See "Nonpharmacologic and preventive therapies of
rheumatoid arthritis", section on 'Bone protection' and "Prevention and treatment of glucocorticoid-
induced osteoporosis".)
MUSCLE WEAKNESS Muscle weakness is a common symptom in rheumatoid arthritis. It may

have several, often additive, causes.
Synovial inflammation Synovial inflammation is usually associated with diminished motion of

joints, which rapidly results in atrophy of muscle serving these joints. This effect is most obvious in the
knee, in which synovitis quickly leads to quadriceps weakness. This weakness results in greater
mechanical stress on the affected joints. As an example, when quadriceps weaken, more force is
applied directly through the patella than when quadriceps strength is normal. Exercise can help
prevent muscle weakness or can help restore muscle strength when due to synovitis. (See
"Nonpharmacologic and preventive therapies of rheumatoid arthritis", section on 'Exercise'.)
Myositis In autopsy series, focal accumulation of lymphocytes and plasma cells contiguous with
foci of muscle necrosis are found in almost all patients with RA. These lesions have been called
nodular myositis. They are particularly common in a small but interesting subset of patients who have
mild synovitis and a disproportionately elevated erythrocyte sedimentation rate [20]. Some foci of
muscle lymphocytes have been shown to synthesize immunoglobulin M (IgM) rheumatoid factor [20].
Rarely, a patient with RA develops a true polymyositis, with elevated levels of serum creatine kinase
and with typical findings on electromyography and muscle biopsy. These patients should be managed
as are those with polymyositis, by using prednisone in moderately high doses (60 to 80 mg/day) and
by having a plan of moving quickly to methotrexate (25 mg intramuscular/week) or azathioprine (up to
2.5 mg/kg per day). (See "Initial treatment of dermatomyositis and polymyositis in adults".)
Most rheumatoid patients have generalized atrophy of type II fibers. This is probably due to disuse as
described above.
Vasculitis Patients with RA may occasionally develop vasculitis. Risk factors include high titers of
rheumatoid factor and active extraarticular disease elsewhere, such as nodulosis or scleritis.
Involvement of skeletal muscle vessels can cause acute pain in muscle bundles associated with an
acute flare of disease, while a vasculitic neuropathy can cause muscle weakness and a mononeuritis
multiplex. With the use of aggressive and effective disease-modifying antirheumatic drug (DMARD)
therapies for RA, this manifestation has become less common, occurring in less than 1 percent of
patients. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis".)

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Drug-induced myopathy Superimposed on active RA, with or without muscle involvement, a drug-
induced myopathy can gradually weaken a patient and can confuse the clinician who may assume that
there is an inflammatory cause for the weakness. Glucocorticoids, antimalarial drugs, and statin drugs
are among the drugs that can cause myopathy.
Glucocorticoids There is wide variation in the glucocorticoid dose and duration of treatment prior
to the onset of muscle weakness. Some patients become weak after a low dose of glucocorticoids for
a few weeks, while others never develop myopathy despite receiving large doses for months or years.
Despite this variability, there is a general dose relationship for systemic glucocorticoid therapy. (See
"Glucocorticoid-induced myopathy".)
Glucocorticoid myopathy is unusual in patients treated with less than 10 mg/day of

prednisone or its equivalent.
The higher the dose of glucocorticoid, the greater is the likelihood of developing
myopathy, and the more rapid is the onset of weakness. Daily doses in excess of 40 to
60 mg/day can induce clinically important weakness within two weeks and almost always
result in some degree of muscle weakness when continued for more than one month.
Other features of glucocorticoid excess such as moon facies, diabetes, mood alteration, skin fragility,
and osteoporosis are often, but not always, present in patients with myopathy. (See "Major side effects
of systemic glucocorticoids" and "Epidemiology and clinical manifestations of Cushing's syndrome".)
Glucocorticoid-induced myopathy is a diagnosis of exclusion, being based upon the history and timing
of glucocorticoid exposure and upon the absence of other causes of myopathy. The diagnosis should
be strongly suspected if weakness develops at a time when the other signs of RA have become
quiescent, and it is generally established by demonstrating improved strength within three to four
weeks after appropriate dose reduction.
Antimalarial drugs Antimalarial drugs used to treat RA (eg, hydroxychloroquine and chloroquine)
rarely cause muscle weakness as a symptom of drug-induced myopathy. Antimalarial drug-induced
myopathy is discussed elsewhere. (See "Drug-induced myopathies", section on 'Antimalarial drugs'.)
Lipid-lowering drugs Recognition of the increased incidence of cardiovascular disease in patients

with RA and of the increased prevalence of traditional risk factors for coronary artery and other
atherosclerotic disease has lead to more vigorous use of lipid-lowering agents, especially statins, in
many adults with RA. Statins and other lipid-lowering drugs may cause muscle injury, typically with
muscle pain. Thus, treatment with a statin or, rarely, with other lipid-lowering drugs should be
considered as a cause of myalgia or weakness in a patient with RA who is being treated for
dyslipidemia. (See "Statin myopathy".)
SKIN DISEASE The most common of the cutaneous manifestations of RA is the rheumatoid nodule
[21]. Other cutaneous manifestations may arise when rheumatoid vasculitis is present (see

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'Noncardiac vascular disease' below), or such manifestations may arise due to dermal infiltration of
neutrophils. Atrophic skin over involved joints is sometime present.
Rheumatoid nodules Palpable nodules are present in 20 to 35 percent of patients with RA.
Rheumatoid factor is almost always present in patients with nodules. Nodules are common on
pressure points such as the olecranon but can form anywhere within or upon the body (eg, in the
lungs). (See 'Lung disease' below.) Most skin nodules need no specific treatment. For painful nodules
or for those that interfere with joint motion or that impinge upon nerves, local injection with a mixture of
a potent glucocorticoid and local anesthetic may cause regression. Surgical excision of skin nodules is
rarely indicated. A more detailed discussion of rheumatoid nodules in the skin and subcutaneous
tissues is presented separately. (See "Rheumatoid nodules", section on 'Subcutaneous nodules'.)
Skin ulcers Ulcerative lesions may result from venous stasis, arterial insufficiency, neutrophilic
infiltration, and/or vasculitis (picture 1) [22]. Chronic ulcers in patients with RA are often multifactorial
and may require aggressive immunosuppression for healing. (See 'Neutrophilic dermatoses' below
and 'Noncardiac vascular disease' below.)
Neutrophilic dermatoses Dermal manifestations associated with sterile infiltration of neutrophils

are uncommon; these include Sweet syndrome (picture 2), pyoderma gangrenosum (picture 3), and
rheumatoid neutrophilic dermatitis (picture 4). (See "Neutrophilic dermatoses".)
Medication-induced skin changes Medications used to treat RA can cause skin changes. These
include skin atrophy and ecchymoses from glucocorticoids, as well as petechiae from medications that
cause thrombocytopenia. (See "Major side effects of systemic glucocorticoids" and "Hematologic
Other Rare cutaneous manifestations include erythema elevatum diutinum, linear bands or annular
lesions, urticarial eruptions, and dermal papules which may have various histologic appearances,
ranging from edema, vasculitis, or palisading granulomatous inflammation [23]. The Raynaud
phenomenon is relatively common in patients with RA, affecting nearly one-quarter of patients in one
study [24]. (See "Clinical manifestations and diagnosis of the Raynaud phenomenon", section on
'Prevalence'.)
EYE INVOLVEMENT Episcleritis and scleritis occur in less than 5 percent of patients. Uveitis,
including iritis, may also occur in RA. Scleritis and peripheral ulcerative keratitis with corneal melt can
be devastating consequences of RA. This is discussed in detail elsewhere. (See "Ocular
In episcleritis, the eye becomes acutely red and painful without a discharge (picture 5).
(See "Episcleritis".)
In scleritis, there is a deep ocular pain. In addition, dark red discoloration can appear as
metalloproteases generated by activated scleral cells degrade scleral collagen (picture

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6), in rare cases down to the uveal layer (called scleromalacia perforans) (picture 7).
(See "Clinical manifestations and diagnosis of scleritis".)
Keratoconjunctivitis sicca, or dry eyes, occurs in 10 to 20 percent of patients as part of the sicca
complex (picture 8). (See "Clinical manifestations of Sjgren's syndrome: Exocrine gland disease".)
LUNG DISEASE The clinical manifestations, diagnosis, and management of pleural (eg, pleuritis
and pleural effusion) and parenchymal lung diseases (eg, interstitial fibrosis, pulmonary nodules,
bronchiolitis obliterans, and organizing pneumonia) that are associated with RA are presented
separately. (See "Overview of lung disease associated with rheumatoid arthritis".)
Lung disease caused by drugs or other agents used to treat RA may occur as a result of direct
pulmonary toxicity (eg, rarely methotrexate and gold salts) or as a result of infectious complications
resulting from immunosuppression (eg, glucocorticoids, antimetabolites, and anticytokine therapies).
(See "Drug-induced lung disease in rheumatoid arthritis" and "Approach to the immunocompromised
patient with fever and pulmonary infiltrates".)
CARDIAC DISEASE Clinically apparent pericarditis and myocarditis are uncommon disorders in
patients with RA. There is an increased risk of coronary artery disease in patients with RA, and there
may be an increased risk of heart failure and of atrial fibrillation [25,26]. These issues and cardiac
involvement by rheumatoid nodulosis are discussed in the following sections.
Pericarditis During the course of disease, less than 10 percent of patients have a clinical episode
of pericarditis, although up to 30 percent have echocardiographic evidence of pericardial effusions that
are of no clinical significance. The prevalence of pericardial involvement at a single point in time in a
group of 30 patients with RA when assessed using transesophageal echocardiography was 13
percent [27]. Other patients have asymptomatic pericardial involvement detected at autopsy.
Restrictive pericarditis with tamponade physiology is uncommon and may present a diagnostic
challenge.
Most patients with symptomatic pericarditis have a positive test for rheumatoid factor in sera.
Pericarditis occurs most frequently in patients with active rheumatoid disease and other extraarticular
manifestations. As a result, management should be linked to control of the RA.
Treatment As in other nonbacterial causes of pericarditis, glucocorticoids are preferred if maximal

doses of nonsteroidal antiinflammatory drugs (NSAIDs) are not effective. High-dose prednisone (1
mg/kg per day) may be required in patients with RA and severe, exudative pericarditis. Surgery may
be necessary in some patients with severe constrictive pericarditis and with associated heart failure.
(See "Diagnosis and treatment of pericardial effusion".)
Myocarditis Myocarditis, which can be either granulomatous or interstitial, is rare in RA and is

usually associated with active articular disease and with other nonarticular manifestations [28].
Granulomatous myocarditis has higher specificity for RA, while the interstitial form is much less

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frequent in RA than in SLE. Direct granulomatous involvement of the endocardium can produce mitral
insufficiency, while involvement of the conduction system can induce atrioventricular block.
Diagnosis Echocardiography can be used to assess left ventricular function. Right ventricular
biopsy at time of cardiac catheterization may be helpful diagnostically if myocarditis or chronic
constrictive pericarditis is considered as a possible cause of heart failure [29]. (See "Clinical
manifestations and diagnosis of myocarditis in adults".)
Differential diagnosis The major differential diagnostic entities to consider in a patient with RA
who develops heart failure are:
Ischemic cardiomyopathy The risk of coronary artery disease is significantly increased

among patients with RA. Previously unrecognized myocardial infarction or severe
ischemia may be a cause of heart failure. Rarely, widespread myocardial dysfunction can
be the result of rheumatoid vasculitis [30]. (See 'Coronary artery disease' below.)
Drug-induced myopathy Antimalarial drugs used to treat RA can sometimes cause
myopathy. Skeletal muscle and myocardium may be affected. (See "Antimalarial drugs in
the treatment of rheumatic disease", section on 'Neuromuscular and cardiac toxicity'.)
NSAID-exacerbated heart failure Use of nonselective NSAIDs and selective
cyclooxygenase (COX) -2 inhibitors may unmask subclinical heart failure due to effects
on blood pressure and renal function. (See "Nonselective NSAIDs: Adverse
cardiovascular effects", section on 'Patients with heart failure' and "COX-2 selective
inhibitors: Adverse cardiovascular effects".)
Rheumatoid nodules Valvular insufficiency and heart block may be manifestations of
rheumatoid nodules. (See 'Rheumatoid nodules' above.)
Amyloidosis Deposition of AA amyloid (secondary amyloidosis) may occur, causing an
infiltrative cardiomyopathy. Patients with longstanding active RA are at increased risk for
this complication. Concomitant renal involvement with proteinuria or nephrotic syndrome
is often present. (See "Clinical manifestations and diagnosis of amyloid
cardiomyopathy".)
Treatment Because of the rarity of rheumatoid myocarditis, optimal treatment is uncertain. In one
reported case of heart failure due to rheumatoid vasculitis with myocardial involvement that was
detected by right ventricular biopsy, a favorable response to glucocorticoid therapy was noted [29]. We
suggest use of high-dose methylprednisolone (pulse therapy 500 to 1000 mg/day for three days or 80
mg daily) as initial therapy.
Use of an anti-tumor necrosis factor (TNF)-alpha agent could be considered for a patient with mild
heart failure or with other manifestations of myocarditis. However, high doses of infliximab have been
associated with increased severity and mortality when used in patients with severe heart failure of
other etiologies, and their use in patients with moderate to severe heart failure should be avoided.
Immunosuppressive therapies such as azathioprine and cyclophosphamide, as used for the treatment
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of systemic rheumatoid vasculitis, are other options for patients who do not respond to glucocorticoids.
The role of biologic therapies in the management of rheumatoid myocarditis is uncertain. (See "Heart
failure and left ventricular dysfunction in rheumatoid arthritis" and "Treatment of rheumatoid
vasculitis".)
Coronary artery disease The risks of sudden death and myocardial infarction appear to be
increased in patients with RA. Although a higher prevalence of traditional cardiac risk factors may be
present in patients with RA than in the general population, epidemiologic data suggest that RA is an
independent risk factor for coronary artery disease. Among patients with RA, those with systemic
involvement are at a higher risk of coronary events [31]. These data and other issues related to
coronary heart disease in patients with RA are presented elsewhere. (See "Coronary artery disease in
rheumatoid arthritis: Epidemiology, pathogenesis, and risk factors".)
Cardiovascular disease is a major contributor to increased mortality among patients with RA. The
effect of atherosclerotic coronary artery disease on long-term patient outcomes is discussed
separately. (See "Disease outcome and functional capacity in rheumatoid arthritis", section on
'Mortality'.)
Heart failure The incidence of heart failure in patients with RA is increased about twofold higher
than in people without RA. As is the case with coronary heart disease, the increased risk of heart
failure is not fully explained by other, traditional risk factors. A discussion of the evidence for an
association between RA and heart failure, as well as left ventricular dysfunction, is presented
separately. (See "Heart failure and left ventricular dysfunction in rheumatoid arthritis".)
Atrial fibrillation Risk factors for atrial fibrillation (AF), including heart failure, ischemic heart
disease, and cigarette smoking, are increased in patients with RA, although the incidence of AF in
patients with RA has received little attention. A nationwide cohort study in Denmark involving 18,247
patients with RA followed for a median of 4.8 years found a significant increase in the risk of atrial
fibrillation in patients with RA, compared with age- and sex-matched controls from the general
population (event rates of 8.2 versus 6 per 1000 person-years) [26]. This represented a greater than
40 percent increase in the incidence of atrial fibrillation in RA (adjusted incidence rate ratio 1.41, 95%
CI 1.31-1.51).
The incidence of stroke was also increased in this cohort of patients with RA. The relative risks of both
AF and stroke were increased to a greater extent in younger patients, while the absolute differences in
risk were higher in older patients. (See 'Stroke' below.)
Nodules Rheumatoid nodules may develop in the pericardium, myocardium, and valvular
structures [32]. They may be noted echocardiographically [33]. Symptoms related to the presence of
nodules are rare, but syncope or death due to heart block from a lesion situated in the conduction
system can occur [34]. Stroke or other manifestations of arterial embolization, as well as valvular
insufficiency, may result from nodules on a heart valve [35-37]. The histopathology of rheumatoid
nodules in the heart is similar to that of nodules at other sites. (See 'Rheumatoid nodules' above.)
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NONCARDIAC VASCULAR DISEASE Vascular disease can take several forms in patients with
RA. Vasculitis of small to medium blood vessels can occur, and higher than expected rates of
coronary artery, peripheral vascular, and cerebrovascular disease are also seen.
Vasculitis The manifestations of rheumatoid vasculitis range from a relatively limited condition, with
focal digital involvement alone, to a severe, systemic condition which may resemble polyarteritis
nodosa. Both small- and medium-sized vessels can be involved. Rheumatoid vasculitis is discussed in
detail separately. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis".)
The following is a brief summary of some of the varied manifestations that rheumatoid vasculitis can
cause:
Distal arteritis that can range from nailfold infarcts (common) to gangrene of finger tips
(rare)
Cutaneous ulceration, which can resemble pyoderma gangrenosum in severe cases
Neurovascular disease, which can lead to a mild distal sensory neuropathy or to a severe
sensorimotor neuropathy (eg, mononeuritis multiplex). Neuropathic pain may be a major
problem, but this often responds to immunosuppressive treatment in patients with
vasculitis-related neuropathy. Other symptoms, such as numbness or local weakness,
are more likely to persist.
Visceral arteritis, which is identical to necrotizing polyarteritis and which can involve
peripheral nerves, as well as the bowel, lungs, heart, spleen, and other organs. Intestinal
involvement can begin as minor abdominal pain that can progress to severe pain, a quiet
tender belly on examination, bowel infarction, and gastrointestinal bleeding.
Palpable purpura, which is rarely found in untreated RA and which, when present, is
usually linked to antirheumatic therapy
Digital gangrene, the presence of intestinal involvement, cardiac involvement, and
mononeuritis multiplex, which are associated with a very poor prognosis (see 'Nervous
system involvement' below)
Peripheral vascular disease The prevalence of atherosclerotic peripheral artery disease appears
to be greater in patients with RA than in otherwise healthy individuals. This was illustrated in a study
that compared 234 non-smoking North American patients with RA to 102 healthy non-smoking
controls [38]. Peripheral arterial abnormalities (an abnormal ankle or brachial index and/or evidence of
occlusion of a peripheral artery) were present in a significantly greater proportion of those with RA (19
versus 5 percent). These differences were not explained by traditional markers of cardiovascular risk
such as hypertension, diabetes, and hyperlipidemia. However, markers of inflammation (eg, C reactive
protein or erythrocyte sedimentation rate) and glucocorticoid use accounted for some of the excess
risk seen in those with RA.
The presence of other systemic and nonarticular manifestations of RA appears to be an independent

risk factor for the development of peripheral vascular disease. This was illustrated in a retrospective
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study of 609 patients [39]. After adjustment for other risk factors, the incidence of peripheral vascular
events was significantly greater in those with severe extraarticular features of RA than in those without
these features (hazard ratio 2.29, 95% CI 1.20-4.34).
In particular, patients with RA appear to have an up to twofold higher occurrence of venous

thromboembolism [40,41]. In one population-based study in the US, the risk appeared somewhat
higher in patients exposed to anti-TNF agents, although it was unknown whether this was a drug effect
or whether anti-TNF exposure was a surrogate for more severe disease which may itself be related to
this increased risk [40]. In another population-based study, conducted in Sweden, the increase in risk
among patients with RA compared with the general population could be detected within the year
following diagnosis and did not increase further during the first decade of disease [41]. The risk was
further increased among patients who required hospitalization, although the increase in such patients
with RA was comparable to that in the general population.
Stroke Patients with RA may be at increased risk for stroke, although the supporting data are not
as conclusive as those reporting an increased risk of coronary artery disease. This is discussed in
more detail separately. (See "Neurologic manifestations of rheumatoid arthritis", section on 'Stroke'.)
Lymphatic obstruction Impaired lymphatic drainage leading to lymphedema is an unusual

extraarticular manifestation of RA. In some cases involving unilateral extremity swelling,
lymphoscintigraphy confirmed lymphatic obstruction [42-44]. Upper and lower limbs may be affected,
and cases of symmetrical swelling have been reported [43]. Other causes of lymphedema should be
considered before attributing lymphatic obstruction to RA. (See "Clinical manifestations and diagnosis
of lymphedema", section on 'Inflammatory arthritis'.)
KIDNEY DISEASE Direct effects of RA on the kidney are rare and include a focal
glomerulonephritis, usually of the mesangioproliferative type without rapid progression of renal
dysfunction; possible membranous nephropathy; and rheumatoid vasculitis. Much more common is
drug toxicity, since many of the drugs used in RA, including nonsteroidal antiinflammatory drugs, gold,
penicillamine, and cyclosporine, can cause renal disease. In addition, patients with longstanding
inflammatory disease may develop AA (secondary) amyloidosis. (See "Renal disease in patients with
SJGREN'S SYNDROME Sjgrens syndrome has both a primary form, in which it is apparently
the sole systemic disease, and a secondary form, in which it is associated with RA or another
rheumatic disease. Symptoms of ocular and/or oral dryness are the hallmarks of this disorder. The
clinical manifestations, classification criteria, and diagnosis of Sjgrens syndrome are discussed in
detail separately. (See "Clinical manifestations of Sjgren's syndrome: Exocrine gland disease" and
"Clinical manifestations of Sjgren's syndrome: Extraglandular disease" and "Classification and
diagnosis of Sjgren's syndrome".)
NERVOUS SYSTEM INVOLVEMENT A range of neurologic abnormalities may be associated with

RA, which can involve the peripheral or central nervous systems and which can result from local or
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systemic factors. Carpal tunnel syndrome is the most common neurologic manifestation, and a
compressive myelopathy or radiculopathy can also occur. Patients with instability of the cervical spine,
most commonly at the articulation of C1 and C2, are at increased risk for myelopathy and require
particular attention. The neurologic manifestations are discussed in detail elsewhere. (See "Neurologic
manifestations of rheumatoid arthritis" and "Cervical subluxation in rheumatoid arthritis".)
Patients with rheumatoid vasculitis may experience subtle or more severe neurologic disease, such as
mononeuritis multiplex or a symmetric polyneuropathy. Central nervous system involvement is
uncommon. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis".)
HEMATOLOGIC ABNORMALITIES Anemia is commonly present in patients with active RA.

Neutropenia, present in Feltys syndrome and in the large granular lymphocyte syndrome, may require
therapeutic interventions, while reactive thrombocytosis and eosinophilia generally parallel disease
activity and do not themselves require treatment [45].
Anemia Most patients with RA have a mild normocytic hypochromic anemia which correlates with
the erythrocyte sedimentation rate and general disease activity. The anemia is that of chronic
inflammation, in which there is an inability of the marrow to incorporate stored iron into red blood cells
and in which the hemoglobin concentration is rarely less than 10 g/dL. (See "Anemia of chronic
disease (anemia of chronic inflammation)" and "Hematologic manifestations of rheumatoid arthritis",
section on 'Anemia of chronic disease'.)
Felty's syndrome Patients with Feltys syndrome have seropositive rheumatoid arthritis and
neutropenia. Many have an associated anemia or thrombocytopenia, an enlarged spleen, and, rarely,
leg ulcers. More detailed discussions of the clinical manifestations, the drug treatment, and the role of
splenectomy in Feltys syndrome are presented separately. (See "Clinical manifestations and
diagnosis of Felty's syndrome" and "Drug therapy in Felty's syndrome" and "Indications for
splenectomy in Felty's syndrome".)
Large granular lymphocyte syndrome The large granular lymphocyte (LGL) syndrome in RA, or
pseudo-Feltys syndrome, must be distinguished from Feltys syndrome. Patients with LGL syndrome
have many circulating LGLs, neutropenia, splenomegaly, and frequent infections. The LGL syndrome
is discussed in detail elsewhere. (See "Large granular lymphocyte leukemia in rheumatoid arthritis".)
Lymphoproliferative disease As has already been noted, large granular lymphocyte proliferation
may be present in some patients with RA, and, in a minority, it will progress to LGL leukemia. (See
"Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte
leukemia", section on 'Autoimmune disorders'.)
In addition, the risk of lymphoma is increased in patients with RA, both in those treated with
methotrexate and in those with active disease who have not been exposed to methotrexate or to other
immunosuppressive agents. Longstanding, active disease is the major risk factor for lymphoma in

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patients with RA. (See "Major side effects of low-dose methotrexate" and "Disease outcome and
functional capacity in rheumatoid arthritis", section on 'Lymphoproliferative disorders'.)
th th
th th
Basics topics (see "Patient information: Anemia of chronic disease (The Basics)")
SUMMARY
Involvement of the musculoskeletal system other than joints (eg, bone and muscle) and
of nonarticular organs (eg, skin, eye, lungs, heart, and others) occurs in about 40 percent
of patients with rheumatoid arthritis (RA). Risk factors for systemic, extraarticular disease
include the presence of rheumatoid factor (RF), anti-citrullinated peptide antibodies
(ACPA), and smoking. Extraarticular involvement in RA is associated with increased
severity of disease, with overall morbidity, and with premature mortality. Successful
management depends upon control of the underlying joint disease and upon additional
strategies. (See 'Introduction' above.)
Bone loss in RA is common. It may be generalized, resulting from immobility, the
inflammatory process, and treatment effects with glucocorticoids; it also includes
periarticular demineralization typical of RA. It is due to the combined actions of
prostaglandins and cytokines in association with normal amounts of parathyroid
hormone. In the absence of antiresorptive therapy, all patients with RA can be expected
to lose bone mineral. The generalized and periarticular osteopenia that affects all
patients with RA should lead to a low threshold for therapy to prevent bone loss. (See
'Osteopenia' above.)
Muscle weakness is a common symptom in rheumatoid arthritis. It may have several,
often additive, causes, including synovial inflammation, myositis, vasculitis, and drug-

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induced myopathy (eg, from glucocorticoids, hydroxychloroquine, or statins). (See

'Muscle weakness' above.)
The most common of the cutaneous manifestations of RA is the rheumatoid nodule.
Other cutaneous manifestations may arise when rheumatoid vasculitis is present or may
be due to dermal infiltration of neutrophils. Atrophic skin over involved joints is
sometimes present. (See 'Skin disease' above.)
Symptoms of ocular and/or oral dryness are the hallmarks of Sjgrens syndrome, which
may occur in association with RA. Eye involvement in RA also may include episcleritis,
scleritis, peripheral ulcerative keratitis, and, less frequently, uveitis. (See "Clinical
manifestations of Sjgren's syndrome: Exocrine gland disease" and "Clinical
manifestations of Sjgren's syndrome: Extraglandular disease" and 'Eye involvement'
above.)
Pulmonary involvement in RA may include pleurisy and parenchymal lung diseases (eg,
interstitial fibrosis, pulmonary nodules, bronchiolitis obliterans, and organizing
pneumonia), as well as lung disease caused by drugs or other agents used to treat RA or
as a result of infectious complications resulting from immunosuppression. (See 'Lung
disease' above and "Drug-induced lung disease in rheumatoid arthritis" and "Overview of
lung disease associated with rheumatoid arthritis".)
Cardiac involvement, such as clinically apparent pericarditis and myocarditis, and the
presence of rheumatoid nodules in the pericardium, myocardium, or valvular structures
are uncommon in patients with RA, although there is an increased risk of coronary artery
disease, heart failure, and atrial fibrillation. Vascular disease can take several forms in
patients with RA. Vasculitis of small to medium blood vessels can occur, and higher than
expected rates of coronary artery, peripheral vascular, and cerebrovascular disease are
also seen. (See 'Cardiac disease' above and 'Noncardiac vascular disease' above and
"Clinical manifestations and diagnosis of rheumatoid vasculitis".)
Direct effects of RA on the kidney are rare and include a focal glomerulonephritis,
possible membranous nephropathy, and rheumatoid vasculitis. Drug toxicity is much
more common. A range of neurologic abnormalities may be associated with RA, which
can involve the peripheral or central nervous systems and which can result from local or
systemic factors. Carpal tunnel syndrome is the most common neurologic manifestation,
and a compressive myelopathy or radiculopathy can also occur. Patients with rheumatoid
vasculitis may experience subtle or more severe neurologic disease. (See 'Kidney
disease' above and 'Nervous system involvement' above and "Neurologic manifestations
of rheumatoid arthritis" and "Cervical subluxation in rheumatoid arthritis" and "Clinical
manifestations and diagnosis of rheumatoid vasculitis".)
Anemia is commonly present in patients with active RA. Neutropenia, present in Feltys
syndrome and in the large granular lymphocyte syndrome, may require therapeutic
interventions, while reactive thrombocytosis and eosinophilia generally parallel disease

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activity and do not themselves require treatment. (See 'Hematologic abnormalities'

above.)
INTRODUCTION The treatment of rheumatoid arthritis (RA) is directed toward the control of
synovitis and the prevention of joint injury. In patients whose condition is resistant to an initial course
of treatment with disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, timely
adjustments in the treatment regimens are required to achieve effective disease control and to prevent
damage to the joints. (See "General principles of management of rheumatoid arthritis in adults",
section on 'Tight control' and "General principles of management of rheumatoid arthritis in adults",
section on 'Early use of DMARDs'.)
Support for an early aggressive approach to treatment is based upon the observations that joint
damage, which may ultimately result in disability, begins early in the course of disease and that the
longer that disease activity persists, the less likely the patient is to respond to therapy [1]. Improved
outcomes have resulted from the use of potent and well-tolerated nonbiologic (traditional) and biologic
DMARDs used alone and in combination to induce and maintain tight control of disease [2-10]. These
medications and strategies have the potential to control synovitis and to slow or even stop
radiographic progression [2,9,11,12].
The treatment of active RA resistant to initial DMARD therapies in adults will be reviewed here. The
details of many of the clinical trials upon which this approach is based, the general principles of the
management of RA, the initial treatment of RA, and the approach to RA patients with severe structural
damage are presented separately. (See "Clinical trials of combination therapy in persistently active
rheumatoid arthritis in adults" and "General principles of management of rheumatoid arthritis in adults"
and "Initial treatment of mildly active rheumatoid arthritis in adults" and "Initial treatment of moderately
to severely active rheumatoid arthritis in adults", section on 'Monitoring and reevaluation' and
"Evaluation and medical management of end-stage rheumatoid arthritis" and "Total joint replacement
for severe rheumatoid arthritis".)
GENERAL PRINCIPLES AND APPROACH
Principles of management There are several general principles that are important in the
management of all patients with RA. Briefly, these include:
Achievement and maintenance of tight control of disease activity, defined as remission or

a state of low disease activity, without compromising safety
Treatment of all patients diagnosed with RA with DMARD therapy

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Use of antiinflammatory therapies, including nonsteroidal antiinflammatory drugs

(NSAIDs) and glucocorticoids, to help control symptoms until DMARDs take effect
Evaluation and ongoing care by an expert in the treatment of RA, typically a
rheumatologist
These principles are discussed in detail elsewhere. (See "General principles of management of
It is important to determine whether joint symptoms in patients with persistently symptomatic RA are
due to active inflammatory arthritis or are the result of structural damage that is unlikely to respond to
antiinflammatory drugs and to nonbiologic or biologic DMARDs. (See "Assessment of rheumatoid
arthritis activity in clinical trials and clinical practice" and "General principles of management of
rheumatoid arthritis in adults", section on 'Assessment of disease activity'.)
Definition of resistance to initial DMARDs Resistance to initial DMARD therapy is defined as one
of the following:
Failure to achieve remission or low disease activity within three to six months of initiating
methotrexate (MTX) or other DMARD therapy in maximally tolerated doses within the
usual therapeutic range (see "Assessment of rheumatoid arthritis activity in clinical trials
and clinical practice", section on 'Remission' and "Initial treatment of moderately to
severely active rheumatoid arthritis in adults")
A requirement, in addition to DMARDs, for chronic glucocorticoid therapy in a dose of
greater than about 5 to 7.5 mg/day of prednisone or equivalent to achieve or maintain
remission or low disease activity after three to six months of treatment with DMARDs
A requirement for multiple courses with glucocorticoids, in excess of doses used for
chronic therapy, for the treatment of recurrent disease flares in patients whose
medication doses have been increased to the maximally tolerated or acceptable level
Resistance or an inadequate response to subsequent DMARD therapy may be defined similarly,

depending upon the treatment goals in an individual patient. (See "General principles of management
of rheumatoid arthritis in adults", section on 'Tight control' and "General principles of management of
rheumatoid arthritis in adults", section on 'Other considerations in RA management'.)
Nonpharmacologic and preventive therapies A number of nonpharmacologic measures and

other medical interventions are important in the comprehensive management of RA, in addition to
antiinflammatory and antirheumatic drug therapies. These interventions, including patient education,
vaccinations, and others, are discussed in detail elsewhere. (See "Nonpharmacologic and preventive
therapies of rheumatoid arthritis".)
Approach to drug therapy In patients resistant to initial therapy with DMARDs, we either add
additional DMARDs or switch the patient to a different DMARD or DMARD combination, while also

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treating the active inflammation with antiinflammatory drug therapy. The choice of DMARD therapy in
patients resistant to initial DMARD treatment depends largely upon the responses to the specific
medications that have been used previously. It is also influenced by patient preferences, especially for
oral versus parenteral administration; by regulatory or insurance limitations on drug choice; by
comorbidities; and by cost to the patient. A choice among these agents is dependent upon the initial
DMARD therapy and upon disease activity. (See 'Resistant to initial DMARD' below and 'Resistant to
TNF inhibitor' below and 'Symptomatic drug therapy' below.)
Briefly, we generally take the following approach:
In patients treated for mildly active disease who have not responded adequately to initial
therapy with hydroxychloroquine (HCQ) or sulfasalazine (SSZ) within three to six months,
we add an alternative DMARD, usually methotrexate (MTX), or we administer triple
therapy with HCQ, SSZ, and MTX. (See 'Resistant to HCQ and/or SSZ' below.)
In patients who have not achieved treatment goals after three to six months of MTX, we
generally treat with MTX plus a tumor necrosis factor (TNF) inhibitor, particularly in
patients with high levels of disease activity or with adverse prognostic features.
Abatacept may be used as an alternative to a TNF inhibitor. (See 'Resistant to MTX'
below and 'Choice of therapy' below and 'MTX plus TNF inhibitor' below.)
Triple therapy is an acceptable alternative to MTX plus a TNF inhibitor. In patients who
do not achieve a satisfactory response with this combination within three to six months,
we discontinue SSZ and HCQ and continue to administer MTX while adding a TNF
inhibitor. (See 'Resistant to MTX' below and 'Choice of therapy' below and 'DMARD triple
therapy' below.)
In patients who do not respond adequately to therapy with MTX plus an initial TNF
inhibitor within three to six months, we generally switch to a different TNF inhibitor and
continue therapy with MTX. An alternative approach is switching to another biologic
agent with a different mechanism of action in this setting rather than a second TNF
inhibitor, particularly in patients who discontinue the initial TNF inhibitor due to an
adverse reaction. (See 'Resistant to one TNF inhibitor' below.)
In patients who do not respond adequately to the therapies above, including MTX and
trials of one or two TNF inhibitors, we use abatacept, tocilizumab, rituximab, or the
kinase inhibitor tofacitinib in place of the TNF inhibitor. (See 'Resistant to two TNF
inhibitors' below.)
Importantly, we do NOT recommend combinations of biologic DMARDs, such as anakinra and a TNF
inhibitor, or the combination of abatacept with either a TNF inhibitor or anakinra. Similarly, a biologic
agent should not be combined with tofacitinib. These regimens are associated with an increased
frequency of severe adverse effects, particularly serious infections, compared with combinations of a

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nonbiologic and biologic DMARD. (See "General principles of management of rheumatoid arthritis in
adults".)
PRETREATMENT INTERVENTIONS A number of important precautions should be taken before

using DMARDs, including laboratory assessment (complete blood count, serum creatinine,
aminotransferases, and other studies as indicated), evaluation of comorbidities, vaccinations, and
screening for hepatitis C, hepatitis B, and latent tuberculosis infection. Precautions relevant to the use
of each new agent being prescribed should be reviewed before initiating such therapy to confirm that
all appropriate measures have been performed. A chest radiograph should be obtained prior to
initiating treatment with methotrexate. These issues are discussed in detail elsewhere. (See
"Nonpharmacologic and preventive therapies of rheumatoid arthritis", section on 'Vaccinations' and
"Hepatitis B virus reactivation associated with immunosuppression" and "Tumor necrosis factor-alpha
inhibitors and mycobacterial infections" and "Diagnosis of latent tuberculosis infection in HIV-negative
adults" and "Major side effects of low-dose methotrexate", section on 'Pulmonary toxicity' and "General
principles of management of rheumatoid arthritis in adults", section on 'Pretreatment evaluation'.)
RESISTANT TO INITIAL DMARD The approach to patients resistant to initial DMARD therapy
depends upon the treatment the patient has already been given. In patients with only mildly active
disease when DMARDs were initiated, hydroxychloroquine (HCQ) or sulfasalazine (SSZ) may have
been started, and the patient may not have received methotrexate (MTX). The next step at this point is
starting MTX, either in place of or in addition to these agents. In patients who have already been
treated with MTX, combination therapy of MTX with a biologic DMARD or additional nonbiologic
DMARDs is the next step. (See 'Resistant to HCQ and/or SSZ' below and 'Resistant to MTX' below
and 'Choice of therapy' below.)
Resistant to HCQ and/or SSZ In patients resistant to three to six months of therapy with
hydroxychloroquine (HCQ) or sulfasalazine (SSZ)for initially mildly active disease, we suggest adding
an alternative DMARD, usually methotrexate (MTX); the approach in these patients is generally similar
to that for patients with moderately to severely active disease presenting for initial DMARD therapy. An
acceptable alternative would be treatment with a combination of HCQ, SSZ, and MTX, termed triple
therapy. A therapeutic trial of greater than three months is generally used in patients with partial
responses showing progressive improvement, particularly in those in this group with low levels of
disease activity and with limited functional impairment. (See "Initial treatment of mildly active
rheumatoid arthritis in adults", section on 'Monitoring and reevaluation' and "Initial treatment of
moderately to severely active rheumatoid arthritis in adults", section on 'Initial therapy with
methotrexate'.)
We prefer MTX over alternative nonbiologic and biologic DMARDs in such patients for several
reasons. MTX typically serves as the anchor drug for the most commonly used DMARD
combinations [13-15]. Randomized head-to-head trials have found that MTX has a faster onset of
action, has comparable or greater efficacy, has better long-term tolerance, and improves survival,
compared with other nonbiologic DMARD monotherapy [16,17]. Direct comparisons of MTX with TNF
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inhibitor monotherapy have also shown comparable benefit [18,19]. Additionally, those patients with
an inadequate response to MTX can be quickly identified and subsequently treated prior to the
development of irreversible injury [18-23]. There is also some evidence that risk may be greater with
biologic agents, and, frequently, there are regulatory or cost barriers to the use of biologic therapies in
patients who have not been treated with MTX. Treatment with MTX is reviewed in detail separately,
and the efficacy of such triple therapy with this DMARD combination is discussed in further detail
below. (See "Initial treatment of moderately to severely active rheumatoid arthritis in adults", section
on 'Initial therapy with methotrexate' and "Initial treatment of moderately to severely active rheumatoid
arthritis in adults", section on 'MTX versus other DMARDs' and "Initial treatment of moderately to
severely active rheumatoid arthritis in adults", section on 'MTX versus initial combination therapy' and
'Efficacy of MTX/TNF inhibitor versus triple therapy' below.)
Resistant to MTX In patients resistant to MTX after three to six months of treatment at optimal
doses, we suggest either the combination of continued MTX plus a tumor necrosis factor (TNF)
inhibitor or the use of DMARD triple therapy with MTX plus sulfasalazine (SSZ) and
hydroxychloroquine (HCQ), rather than monotherapy with another nonbiologic or biologic DMARD. In
patients with partial responses showing progressive improvement, we may continue therapy with MTX
for greater than three months before switching to one of these approaches, particularly in those with
low to moderate levels of disease activity and with limited functional impairment. (See 'Choice of
therapy' below and 'MTX plus TNF inhibitor' below and 'DMARD triple therapy' below.)
Abatacept, the T-cell costimulation blocker, is an alternative to TNF inhibitors for use in combination
with MTX in patients with an inadequate response to MTX, but its use in this setting is supported by a
smaller body of evidence than that for TNF inhibitor use. It can be administered intravenously or
subcutaneously. Usual practice since TNF inhibitors came into clinical use beginning in the late 1990s
has been to add a TNF inhibitor to MTX in patients with an inadequate response to MTX.
Abatacept and tocilizumab have each generally been used in practice only following inadequate
responses to both MTX and TNF inhibitors. However, both of these biologic agents are available for
use in the US for patients who have not responded adequately to MTX alone. Their respective efficacy
in such patients is supported by evidence from randomized trials, including trials in which each were
compared with a TNF inhibitor, which are described separately. (See 'MTX plus abatacept' below and
"Randomized clinical trials in rheumatoid arthritis of biologic agents that inhibit IL-1, IL-6, and RANKL",
section on 'Tocilizumab' and 'Abatacept' below and 'Tocilizumab' below.)
A further alternative for patients resistant to or unable to take MTX is leflunomide (LEF), an orally
administered immunosuppressive agent, which may be used as monotherapy or in combination with
either MTX or a TNF inhibitor. (See 'Choice of therapy' below and 'Leflunomide' below and "Initial
treatment of moderately to severely active rheumatoid arthritis in adults", section on 'Alternatives to
MTX'.)

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Choice of therapy A number of treatment options are reasonable in patients with an inadequate
response to methotrexate (MTX) therapy. The choice of drug combinations in such patients depends
upon a combination of factors, including the level of disease activity, patient preference for route of
administration, the presence of adverse prognostic features, and regulatory and cost barriers to drug
access. (See "General principles of management of rheumatoid arthritis in adults", section on
'Prognosis'.)
We prefer combination therapy with MTX plus a TNF inhibitor (eg, adalimumab,
etanercept, or infliximab), particularly in patients with high levels of disease activity or
with adverse prognostic features. It may have a faster onset of action compared with
DMARD triple therapy. However, it requires subcutaneous injections or intravenous
infusions, and regulatory or cost considerations may limit access. (See 'MTX plus TNF
inhibitor' below.)
We prefer triple therapy with MTX, sulfasalazine (SSZ), and hydroxychloroquine (HCQ)
in patients for whom drug cost, regulatory restrictions on the use of biologic DMARDs, or
preference for an oral agent that is not a biologic is an important factor. In addition,
concern regarding the risk of serious infections, the uncertain long-term increased risk of
malignancy, and other possible adverse effects may influence clinician or patient
preference for nonbiologic agents [24-26]. In those who do not achieve a satisfactory
response with nonbiologic triple therapy within three to six months, we discontinue SSZ
and HCQ and administer a TNF inhibitor with MTX. Some experts continue one or both
of these medications, usually HCQ, when adding a TNF inhibitor, but this practice has
not been formally evaluated or compared with other approaches. (See 'DMARD triple
therapy' below and "Tumor necrosis factor-alpha inhibitors: An overview of adverse
effects".)
Abatacept may be used as an alternative to a TNF inhibitor in patients in whom MTX plus
a TNF inhibitor would otherwise be appropriate, particularly in patients unable to use a
TNF inhibitor and in patients with a high level of disease activity. It may have a faster
onset of action than triple therapy or leflunomide (LEF). We generally prefer a TNF
inhibitor over abatacept because the data supporting the use of abatacept are more
limited than those available for the TNF inhibitors, although they suggest comparable
benefit. (See 'MTX plus abatacept' below.)
LEF may be of particular benefit for patients in whom regulatory or cost considerations
preclude use of a biologic agent, despite failure of MTX to adequately control disease
activity. It can be used in place of MTX in those patients who do not tolerate MTX, or it
can be used in combination with MTX instead of adding a biologic agent, with appropriate
monitoring of liver function tests. It is also an option for patients who prefer not to use a
parenterally administered drug. (See 'Leflunomide' below.)

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MTX plus TNF inhibitor In patients resistant to MTX, particularly those with high levels of disease
activity or with adverse prognostic features, we prefer combination therapy with MTX plus a TNF
inhibitor. We usually use etanercept (50 mg administered subcutaneously once weekly) or
adalimumab (40 mg administered subcutaneously every two weeks) as the initial TNF inhibitor in
combination with continued MTX therapy, after appropriate pretreatment measures have been
performed. An alternative TNF inhibitor in patients who prefer therapy by intravenous infusions is
infliximab (usually 3 to 5 mg/kg every eight weeks after an initial loading schedule at zero, two, and six
weeks). Other alternative TNF inhibitors include golimumab and certolizumab pegol. (See
'Nonpharmacologic and preventive therapies' above and 'Pretreatment interventions' above.)
In patients with an inadequate response to MTX, the use of combination therapy with the addition of a
TNF inhibitor is supported by multiple randomized trials and meta-analyses that demonstrate the
superiority of this approach compared with adding placebo while continuing the MTX [24,27-30]. The
American College of Rheumatology (ACR) 20 percent response (ACR20), ACR50, and ACR70 are
composite measures reflecting at least 20, 50, and 70 percent improvement in several defined
measurements of disease activity [31]. Trials of MTX plus a TNF inhibitor in patients who have not
responded adequately to MTX alone typically result in ACR20, ACR50, and ACR70 response rates of
about 60, 40, and 20 percent, respectively [28]. Indirect comparisons of the biologic agents in meta-
analyses of randomized trials involving patients with an inadequate response to MTX have shown a
statistically nonsignificant trend suggesting that TNF inhibitors may be more likely to result in an
ACR50 response compared with other biologic agents (odds ratio [OR] 1.30, 95% CI 0.91-1.86) [32].
(See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'ACR
response criteria'.)
Meta-analyses and randomized trials have also shown that combination therapy of MTX with a
biologic agent, such as a TNF inhibitor, is superior to biologic or traditional DMARD monotherapy in
patients who are nave to DMARDs [19,24,29,33,34]. However, in patients who have had an
inadequate response to MTX, most randomized trials have continued MTX while adding either a
biologic or a placebo. A small number of randomized trials and retrospective studies have evaluated
the relative benefits of adding a biologic agent to MTX compared with biologic monotherapy; results
range from showing small, statistically nonsignificant advantages for combination therapy to
demonstrating substantial added benefit that is both statistically and clinically significant [35-42]. Trials
of biologic DMARDs and data supporting their use in patients with active RA are described in detail
separately. (See "Clinical trials of combination therapy in persistently active rheumatoid arthritis in
adults" and "Randomized clinical trials of tumor necrosis factor inhibitors in rheumatoid arthritis".)
The evidence comparing the efficacy and safety of MTX plus a TNF inhibitor in this setting with those
of nonbiologic DMARD triple therapy and with those of MTX plus abatacept are described in detail
below. (See 'Efficacy of MTX/TNF inhibitor versus triple therapy' below and 'Efficacy of MTX/TNF
inhibitor versus MTX/abatacept' below.)

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There is no convincing evidence that any one of the TNF inhibitors has greater efficacy than the others
[43]. The choice of TNF inhibitor depends upon regulatory or insurance restrictions on drug choice,
upon safety issues, and upon patient preference for route and/or frequency of injection. Etanercept
and adalimumab might be safer than infliximab [25,27,44]. However, comparisons between these
agents are largely indirect [25,27]; additionally, a case control study suggesting greater safety with
etanercept, compared with infliximab or adalimumab, only addressed the risk of reactivation of latent
tuberculosis in patients who had not received adequate chemoprophylaxis prior to therapy [44].
Indirect comparisons of randomized trial results in a network meta-analysis suggested that patients
receiving etanercept, adalimumab, or golimumab had statistically significantly lower rates of
withdrawal from trials due to adverse effects compared with infliximab (OR 0.63, 95% CI 0.41-0.95;
OR 0.50, 95% CI 0.32-0.78; and OR 0.55, 95% CI 0.30-0.99) [25].
TNF inhibitor therapy is generally well-tolerated, but these medications pose increased risk of
reactivation of latent tuberculosis and of new infection with other granulomatous diseases (eg,
histoplasmosis and coccidiomycosis) or with varicella zoster. Adverse effects include injection-site
reactions, infusion reactions, mildly reduced neutrophil counts and cytopenias, serious common and
opportunistic infections, reactivation of hepatitis B, autoimmune phenomena including multiple
sclerosis, and hepatotoxicity. There is no proof of increased risk of malignancy with these agents in
analyses of short-term randomized trial data, and results of a large population-based long-term study
of patients with RA are encouraging [45,46]. However, further long-term studies are required. TNF
inhibitors should not be administered to patients with active infections, and they are relatively
contraindicated in patients with multiple sclerosis or congestive heart failure. The adverse effects of
TNF inhibitor therapy are discussed in detail elsewhere. (See "Tumor necrosis factor-alpha inhibitors:
An overview of adverse effects" and "Tumor necrosis factor-alpha inhibitors: Risk of bacterial, viral,
and fungal infections" and "Tumor necrosis factor-alpha inhibitors and mycobacterial infections" and
"Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)
Efficacy of MTX/TNF inhibitor versus triple therapy Three randomized trials have compared the
combination of MTX plus a TNF inhibitor with DMARD triple therapy combining MTX plus sulfasalazine
(SSZ) and hydroxychloroquine (HCQ) [47-50]; two of the trials found no significant differences in
clinical efficacy using composite measures of disease activity (eg, ACR20 responses of approximately
35 to 60 percent after one or two years) [49,50], while one of the trials showed a significant difference
at 12 months but not at 6, 9, or 24 months [47,48]. Radiographic outcomes only slightly favored TNF
inhibitor use, but these differences did achieve statistical significance in some of the trials. Limitations
in trial design and the use of different TNF inhibitors in the published reports preclude adequate direct
comparisons of the regimens in the two trials of patients with early disease [47-49]; both trials included
a step-up design for at least a portion of the patients, in which patients were randomly assigned (either
before or after initial treatment with MTX) to receive one of the two treatment options following an
inadequate response to MTX. The third trial had a double-blind design and enrolled patients with more
longstanding disease (mean duration since diagnosis of 4.9 to 5.5 years) who had also had
inadequate responses to MTX [50]:
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Swefot trial The Swedish Pharmacotherapy (Swefot) trial compared the efficacy of
MTX plus infliximab with that of triple therapy using MTX, SSZ, and HCQ [47,48]. This
randomized but non-blinded trial involved 258 patients with RA of less than one year in
duration who had not achieved low disease activity within three to four months of starting
treatment with MTX alone (20 mg once weekly). Differences between the groups were
not significant at six or nine months, but, by one year (nine months after randomization
and one year after initiating DMARD therapy with MTX alone), there was a significantly
higher proportion of good responders (by the European League Against Rheumatism
[EULAR] response criteria) among the group receiving infliximab (39 versus 25 percent,
risk ratio [RR] 1.59, 95% CI 1.10-2.30). However, by two years, this difference was
reduced, and the trend toward a higher frequency of good responders in the infliximab
group was no longer statistically significant (38 versus 31 percent, RR 1.31, 95% CI 0.93-
1.85). A similar proportion of each group achieved an ACR20 response at two years (40
versus 33 percent). Interpretation of these results is hampered by the open design of this
trial and by the switching of some patients to alternate therapies within the trial,
particularly since the initial switch in the triple therapy group was to cyclosporine, while
the initial switch in the infliximab group was to etanercept.
Radiographic outcomes at two years favored the infliximab group, but the treatment
differences were of uncertain clinical significance [48]. At 24 months, the mean increases
in the van der Heijde-modified Sharp score (score range 0 to 448, reflecting radiographic
detection of joint damage) were statistically significantly lower in the patients receiving
infliximab compared with those receiving conventional DMARD triple therapy (4 versus
7.23, for a treatment difference of 3.23, 95% CI 0.14-6.32). However, this difference
between treatments was less than 5, which is considered the minimum clinically
important difference using this scoring system [51]. Moreover, despite these radiographic
differences, at 21 months after randomization both the infliximab and the triple therapy
groups experienced similar reductions in time lost from work due to sick leave and
disability compared with baseline (-4.9 and -6.2 days per month, adjusted mean
difference 1.6 days per month, 95% CI -1.2 to 4.4) [52].
TEAR trial The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial, which
included 755 patients with poor prognosis early RA, compared the efficacy of therapy for
active RA in four groups over two years [49]. Previous receipt of a biologic agent was an
exclusion criterion; patients were randomly assigned in this double-blind trial to receive
one of the following: immediate treatment with MTX plus etanercept; immediate
treatment with DMARD triple therapy (MTX plus SSZ and HCQ); step-up from MTX to
MTX plus etanercept at week 24, if the Disease Activity Score 28 using erythrocyte
sedimentation rate (DAS28-ESR) was 3.2 (moderate or greater disease activity); and
step-up from MTX to triple therapy at week 24, if the DAS28-ESR was 3.2.

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Clinical outcomes (DAS28 scores) were comparable at 24 weeks in the two immediate
combination therapy groups, which together showed a significantly greater reduction in
disease activity compared with the two step-up groups (DAS28-ESR decrease of 4.2
versus 3.6) at this time point (prior to stepping up to combination therapy). Patients on
MTX alone who had not reached the target of low disease activity at 24 weeks stepped
up either to MTX plus etanercept or to triple therapy at that time. Clinical outcomes,
measured by the DAS28-ESR scores, were comparable during weeks 48 to 102 in
patients receiving MTX plus etanercept or receiving triple therapy, regardless of whether
they were initially assigned to immediate or step-up therapy. Similar proportions of all
four groups achieved an ACR20 at two years (approximately 45 to 50 percent). At two
years, the immediate combination groups did not differ clinically or radiographically from
the step-up combination groups. However, radiographic outcomes at week 102 slightly
but statistically significantly favored those who received MTX plus etanercept (increased
van der Heijde-modified Sharp score of 0.64 versus 1.69 on a scale of 0 to 448). There
was no difference in the frequency of overall adverse effects or of serious adverse effects
between the treatment groups.
RA comparison of active therapies trial (RACAT) Comparable benefit was achieved
in a blinded 48-week trial involving 353 patients with moderate to severely active RA
(despite use of MTX), who were randomly assigned to next receive triple therapy (MTX
plus SSZ plus HCQ) or the combination of MTX and etanercept [50]. An equal proportion
of patients in each group (27 percent) failed to meet predefined criteria for continuing the
initially assigned therapy at week 24 (a reduction in the DAS28 of at least 1.2) and were
switched to the alternate therapy. The strategy of initial assignment to triple therapy was
clinically and statistically non-inferior to initial assignment to MTX plus etanercept with
respect to the degree of improvement in disease activity at week 48 (change in DAS28 of
-2.12 and -2.29).
At week 24, a lower proportion of patients receiving triple therapy had achieved an
ACR70 response (5 versus 16 percent), consistent with a trend suggesting more rapid
responses to MTX plus etanercept. However, by week 48, differences between the triple
therapy group and the MTX plus etanercept group in the proportion of patients reaching
ACR20, ACR50, and ACR70 were not statistically significant (57, 36, and 18 percent
versus 66, 43, and 27 percent). Importantly, the majority of the improvement obtained in
the second 24 weeks was among the patients who did not switch. Differences in the
radiographic worsening in the van der Heijde-modified Sharp score (0.54 and 0.29, on a
scale of 0 to 380) and in the level of functional improvement (reductions in Health
Assessment Questionnaire scores of -0.46 and -0.64) were also not significant. There
were four serious infections in patients receiving triple therapy and 12 serious infections
in those receiving MTX plus etanercept. Gastrointestinal symptoms were the most
common cause of discontinuation in patients receiving triple therapy (7 of 12), while
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infections were the most common cause in patients receiving MTX plus etanercept (four
of five).
Efficacy of MTX/TNF inhibitor versus MTX/abatacept Two randomized trials have compared
abatacept with a TNF inhibitor for use in combination with continued MTX therapy in patients with an
inadequate response to MTX, suggesting comparable benefit and safety of the two regimens, with 60
to 70 percent of patients achieving an ACR20 response [53,54]:
ATTEST trial In the Abatacept or infliximab versus placebo, a Trial for Tolerability,
Efficacy, and Safety in Treating rheumatoid arthritis (ATTEST) trial, 431 patients with
active RA and with an inadequate response to MTX were randomly assigned to receive
abatacept (500, 750, or 1000 mg in patients weighing <60 kg, 60 to 100 kg, or >100 kg,
respectively, by intravenous infusion on days 1, 15, and 29, then every four weeks),
infliximab (3 mg/kg by intravenous infusion on days 1, 15, 43, and 85, then every eight
weeks), or placebo infusions, while continuing background MTX [53]. After six months,
use of either abatacept or infliximab resulted in significantly greater benefit compared
with placebo (ACR20 responses of 67 and 59 percent versus 42 percent, respectively).
After one year of treatment, the frequency of ACR20 responses with abatacept plus MTX
was statistically significantly greater than with infliximab plus MTX (72 versus 56
percent). An increase in the dose or frequency of infliximab, which may occur in clinical
practice in infliximab-inadequate responders, was not allowed in the trial, but the patients
receiving abatacept had numerically fewer serious adverse events (10 versus 18
percent) and serious infections (2 versus 9 percent), compared with those receiving the
trial dose of infliximab.
AMPLE trial A preliminary report of the Abatacept versus Adalimumab Comparison in
Biologic-Nave RA Subjects with Background Methotrexate (AMPLE) trial, involving 646
patients with active RA and with an inadequate response to MTX, found comparable
clinical and radiographic responses to MTX plus abatacept (125 mg administered
subcutaneously weekly) and to MTX plus adalimumab (40 mg administered
subcutaneously every two weeks) at one year (ACR20 of 65 and 63 percent,
respectively, and increased modified total Sharp scores of 0.58 and 0.38 on a scale of 0
to 448, respectively) [54]. Rates of adverse effects, including infections, were similar
between the two groups. (See 'Efficacy of MTX/TNF inhibitor versus triple therapy'
above.)
DMARD triple therapy In patients resistant to MTX as the sole DMARD, for whom drug cost,
regulatory restrictions on the use of biologic DMARDs, or preference for an oral agent that is not a
biologic is an important factor, we prefer triple therapy with MTX, sulfasalazine (SSZ), and
hydroxychloroquine (HCQ). (See 'Choice of therapy' above.) Drug dosing is as follows:

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MTX is continued at the maximum tolerated dose achieved with initial therapy up to 25
mg once weekly. The use of MTX in RA and the adverse effects of MTX are described in
detail separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and
"Major side effects of low-dose methotrexate" and "Initial treatment of moderately to
severely active rheumatoid arthritis in adults".)
SSZ is gradually increased from 500 mg twice daily to 1000 mg twice daily. The use of
SSZ in RA and the adverse effects of SSZ are described in detail separately. (See
"Sulfasalazine in the treatment of rheumatoid arthritis" and "Initial treatment of mildly
active rheumatoid arthritis in adults", section on 'Patients with mild activity and poor
prognostic signs'.)
HCQ is used at a dose of 400 mg daily in most patients but does not exceed 6.5
mg/kg/day calculated on the basis of lean body weight. The use of HCQ in rheumatic
disease, including RA, as well as the dosing, adverse effects, and monitoring of HCQ, is
discussed in detail separately. (See "Antimalarial drugs in the treatment of rheumatic
disease" and "Initial treatment of mildly active rheumatoid arthritis in adults" and "Initial
treatment of mildly active rheumatoid arthritis in adults", section on 'Patients who lack
poor prognostic features'.)
Treatment with the triple therapy regimen is usually well-tolerated, with adverse effects comparable to
MTX alone, and the available evidence indicates that switching to a regimen containing a biologic
agent in patients who do not first respond adequately to a three- to six-month trial of triple therapy
results in similar patient outcomes compared with having started a biologic agent sooner. The
evidence describing the efficacy of triple therapy in patients who have had an inadequate response to
MTX and comparing triple therapy with the combination of MTX plus a TNF inhibitor are described
above; the efficacy and safety of DMARD triple therapy compared with other nonbiologic DMARDs
used singly or in combination are described separately. (See "Randomized clinical trials of
combinations of nonbiologic DMARDs in rheumatoid arthritis" and "Clinical trials of combination
therapy in persistently active rheumatoid arthritis in adults" and 'Efficacy of MTX/TNF inhibitor versus
triple therapy' above.)
Alternatives to MTX/TNF inhibitor and to triple therapy In some patients resistant to initial
DMARD therapy with MTX, the use of abatacept as an alternative biologic to a TNF inhibitor or the use
of leflunomide, an orally administered nonbiologic DMARD, in place of or in addition to MTX may be
appropriate. We suggest the combination of MTX plus abatacept in patients in whom MTX plus a TNF
inhibitor would otherwise be appropriate, particularly in patients who are unable to use a TNF inhibitor
and who have a high level of disease activity. We suggest either switching to leflunomide (LEF) or
adding LEF to ongoing MTX as therapeutic options for patients in whom regulatory or cost
considerations preclude use of a biologic agent, despite failure of MTX to adequately control disease
activity. (See 'Choice of therapy' above and 'MTX plus abatacept' below and 'Leflunomide' below.)

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MTX plus abatacept Abatacept may be used as an alternative to a TNF inhibitor. In patients for
whom MTX plus abatacept is the choice of therapy following an inadequate response to MTX,
abatacept can be administered intravenously (IV) every four weeks (750 mg per dose for patients 60
to 100 kg, adjusted for lower or higher weight to 500 or 1000 mg, respectively) after the three initial
doses given at two-week intervals, or it can be administered subcutaneously (SC) (125 mg once
weekly, with or without an intravenous loading dose given on the first week before starting SC dosing
the following week). The decision regarding route of administration can be based upon patient
preference. We generally use abatacept in combination with continued MTX therapy, after appropriate
pretreatment measures have been performed, but it may also be administered as monotherapy or in
combination with other nonbiologic DMARDs. It should not be used in combination with other biologic
DMARDs, such as TNF inhibitors or anakinra. (See "T cell targeted therapies for rheumatoid arthritis",
section on 'Abatacept'.)
Meta-analyses of multiple randomized trials have documented the benefits of abatacept compared
with placebo for use either alone or in combination with nonbiologic DMARDs [25,55,56]. In a
systematic review and in indirect comparisons of randomized trial results from a network meta-
analysis of biologic agents in patients with an inadequate response to MTX, the combination of
abatacept with MTX was significantly more effective compared with MTX alone (ACR50 at 24 weeks of
32 versus 12 percent) [55]. Abatacept was comparable to other biologic agents, including several TNF
inhibitors, rituximab, and tocilizumab. Evidence describing the benefits of abatacept compared with
placebo in patients who have had an inadequate response to a TNF inhibitor is further reviewed
below. (See 'Resistant to two TNF inhibitors' below and 'Dosing and efficacy' below.)
Only a few trials have directly compared abatacept with another active DMARD. These include two
randomized trials described above, which have suggested comparable benefit of abatacept to TNF
inhibitor therapy when either is used in combination with continued MTX in patients with an inadequate
response to MTX therapy [53,54]. (See 'Efficacy of MTX/TNF inhibitor versus MTX/abatacept' above.)
The efficacy and safety of subcutaneous and intravenous administration of abatacept were
comparable in a randomized trial involving 1457 patients with a previously inadequate response to
methotrexate [57]. The efficacy of abatacept SC (125 mg SC on days one and eight, then weekly, plus
an IV loading dose on day one of approximately 10 mg/kg) was comparable to abatacept IV
(approximately 10 mg/kg IV on days 1, 15, and 29, then every four weeks) in achieving an ACR20
response after six months of treatment (both 76 percent). The onset and magnitude of the responses,
disease activity, improvements in physical function, and adverse effects were also comparable.
Injection site reactions were mostly mild and were as frequent in patients receiving the active SC drug
as in those receiving SC placebo (2.5 to 2.6 percent).
Potential adverse effects of abatacept include infusion reactions, which may occur within an hour after
beginning the intravenous administration of the drug and which may be characterized by headache,
dizziness, and hypertension; anaphylactoid reactions are rare. Abatacept also appears to increase the
risk of serious infections, including pneumonia, pyelonephritis, cellulitis, and diverticulitis. A definite
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association with tuberculosis has not been shown. The overall safety of abatacept appears
comparable to or, possibly, slightly better than that of the TNF inhibitors, although there are few direct
comparisons. An indirect comparison of biologic agents in data from a 2011 meta-analysis of
randomized trials and extension studies showed a statistically nonsignificant trend for abatacept
compared with the other agents toward fewer serious adverse events (OR 0.65, 95% CI 0.42-1.01)
and serious infections (OR 0.57, 95% CI 0.30-1.08), while other biologics generally showed similar
risks compared with each other [25]. Additional evidence supporting the use and safety of abatacept in
RA is reviewed in detail separately. (See "T cell targeted therapies for rheumatoid arthritis", section on
'Abatacept'.)
Leflunomide In patients with an inadequate response to MTX, some, but not all, experts advocate
either switching to leflunomide (LEF) or adding LEF to ongoing MTX therapy. The use of LEF alone,
without MTX, is preferred in the absence of clinical improvement from prior treatment with the
maximally tolerated dose of MTX within the usual therapeutic range, as well as in patients in whom
there is a greater degree of concern for the possible increased risk of side effects with the combination
of LEF and MTX. Although both drugs are potentially hepatotoxic, the rationale for combined therapy
is based upon their differing mechanisms of action. (See "Leflunomide in the treatment of rheumatoid
arthritis" and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Mechanism of
action'.)
In patients in whom LEF is used in place of MTX, the usual dose is 20 mg daily. Reduced dosing with
either LEF (10 instead of 20 mg daily) or MTX (eg, 15 mg instead of 20 to 25 mg weekly) should be
used initially if the drugs are used in combination; the dose is then increased incrementally no more
frequently than monthly to usual maximal doses if it is required clinically and if there is no evidence of
toxicity. Some experts continue to use a loading dose of LEF (100 mg daily for the first three days of
therapy) in patients given LEF monotherapy, but other experts avoid the use of a loading dose
because of increased risk of frequent bowel movements and of diarrhea with this approach. The use
of LEF in patients with RA is discussed in detail separately. (See "Leflunomide in the treatment of
The efficacy of LEF was superior to placebo and was comparable to MTX in a systematic review of six
randomized trials including comparisons of LEF with placebo and/or MTX, suggesting approximately
twice the likelihood compared with placebo of achieving an ACR20 response at 6 or 12 months for
either LEF or MTX [58]. In one trial involving 482 patients, for example, an ACR20 at one year was
achieved in a similar proportion of patients on LEF or on MTX, and this rate was significantly higher
than that seen with placebo (52 and 46 percent versus 26 percent) [59]. However, these trials have
been criticized for using lower maximum doses of MTX (up to 15 mg/week) than those that have
subsequently been commonly employed (up to 25 mg/week) [58-60]. LEF had comparable efficacy to
cyclosporine at 12 months of therapy in patients with an inadequate response to MTX (ACR50 of 40
versus 42 percent) [61]; however, LEF has not been compared directly with other agents in such
patients. LEF has not been directly compared with the TNF inhibitors, but the superiority of TNF

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inhibitors is suggested by the comparability of LEF to sometimes suboptimal doses of MTX and to
SSZ; by the more rapid effects and greater overall benefit of TNF inhibitors when they have been
directly compared with MTX or SSZ; and by clinical experience. The trial data that support the efficacy
of LEF in the treatment of RA, including its use together with MTX, and the adverse effects of LEF are
reviewed in detail separately. (See "Initial treatment of moderately to severely active rheumatoid
arthritis in adults", section on 'MTX versus other DMARDs' and "Clinical trials of combination therapy
in persistently active rheumatoid arthritis in adults", section on 'MTX-leflunomide' and "Leflunomide in
the treatment of rheumatoid arthritis".)
The combination of leflunomide and MTX is effective in patients who have not responded adequately
to MTX alone. As an example, in a randomized trial of 263 patients, LEF or placebo was added to
existing MTX therapy [62]. At 24 weeks, the proportion of patients who met ACR20 criteria for
improvement was significantly higher with LEF compared with placebo (46 versus 20 percent). The
combination was well-tolerated. The rate of discontinuation and the incidence of adverse events,
which were predominantly mild or moderate, were similar in the two groups. Diarrhea and elevation of
serum aminotransferases were the only adverse effects seen significantly more often with LEF plus
MTX than with placebo plus MTX. (See "Randomized clinical trials of combinations of nonbiologic
DMARDs in rheumatoid arthritis", section on 'Leflunomide and MTX'.)
Patients on both LEF and MTX may require closer monitoring (eg, monthly aminotransferase testing)
for hepatotoxicity, given the increased risk of hepatotoxicity in some but not most studies, including
reports of fatal liver failure [63-65]. Other adverse effects of LEF include diarrhea, alopecia,
myelosuppression, hypertension, and rash.
In patients with an inadequate response to initial treatment with LEF alone, a TNF inhibitor may be
added to LEF. An analysis of patients with RA in a large population database from Switzerland
indicated that the addition of a TNF inhibitor was beneficial in patients with persistent disease activity
on LEF alone [66]. However, randomized trials to prospectively evaluate the efficacy and safety of LEF
used together with a biologic DMARD have not been performed. (See "Clinical trials of combination
therapy in persistently active rheumatoid arthritis in adults", section on 'Leflunomide-TNF inhibitors'.)
REEVALUATION AND MONITORING Disease activity and the response to therapy should be
regularly reassessed, along with monitoring for drug toxicities, every four to eight weeks following a
change in the treatment regimen until the patient is stable and until disease is under control [9,67-69].
Subsequently, assessments should not be less frequent than every three months. More frequent
laboratory monitoring may be required depending upon the medications being used and following
increases in dosing; more frequent clinical assessments may be required in patients experiencing a
flare of disease or in those undergoing changes in therapy. Well-controlled patients who are seen less
frequently may require laboratory monitoring beyond that performed at scheduled visits and should be
counseled, as should all patients, to contact their treating clinician if the arthritis flares. Laboratory
testing for the monitoring of disease activity and for the monitoring and prevention of drug toxicity is
discussed separately. (See "General principles of management of rheumatoid arthritis in adults",
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section on 'Pretreatment evaluation' and "General principles of management of rheumatoid arthritis in

adults", section on 'Assessment and monitoring'.)
We periodically reevaluate disease activity using a quantitative composite measure at each

assessment (eg, the Clinical Disease Activity Index [CDAI] or the Disease Activity Score [DAS] with 28
joint count [DAS28]). (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical
practice" and "General principles of management of rheumatoid arthritis in adults", section on 'Tight
control' and "General principles of management of rheumatoid arthritis in adults", section on
'Assessment of disease activity'.)
Patients who fail to achieve remission or low disease activity within three to six months of initiating
therapy or who require more than 5 mg/day of prednisone or equivalent glucocorticoid to maintain a
state of remission should generally receive a more potent DMARD or combination of DMARDs. A
therapeutic trial of greater than three months is generally used in patients with partial responses
showing progressive improvement, particularly in those with low to moderate levels of disease activity
and with limited functional impairment.
RESISTANT TO TNF INHIBITOR
Resistant to one TNF inhibitor In patients who do not respond adequately to therapy with an
initial TNF inhibitor within three months, we suggest switching to a different TNF inhibitor and
continuing therapy with MTX. In such patients, we usually use one of the three more established TNF
inhibitors (adalimumab, etanercept, or infliximab), rather than one of the newer agents with which
there is less experience (golimumab or certolizumab pegol). An inadequate response to one anti-TNF
agent does not predict resistance to other agents in this class, although inefficacy and discontinuation
rates increase with successive switches. (See 'Definition of resistance to initial DMARDs' above.)
Some experts advocate switching to another class of biologic in patients who have experienced a
serious adverse event (as defined by the US Food and Drug Administration [FDA]) with an initial TNF
inhibitor [70]. The FDA definition of a serious adverse event includes an adverse event associated with
the use of a medical product that resulted in a life-threatening event, in hospitalization, prolongation of
a hospitalization, in disability or permanent damage, in a congenital anomaly or birth defect in a child
of a parent using the medication, or in an adverse event requiring intervention to prevent permanent
impairment or damage.
Limited randomized trials, several large registry-based studies, and case series have demonstrated
the benefit of switching from one biologic DMARD to another, if inefficacy or toxicity limits the use of a
given agent [71-81].
The best data illustrating that switching to a second TNF inhibitor after discontinuation of a first is
effective are from a randomized trial of golimumab as the second agent [72]. There is more limited
clinical experience with golimumab than with several of the other TNF inhibitors, and its role relative to
other TNF inhibitors in RA treatment remains to be better defined. In this trial, 461 patients with active

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RA despite prior use of at least one TNF inhibitor were randomly assigned to golimumab or placebo
while continuing stable doses of baseline nonbiologic DMARDs (MTX, SSZ, and/or HCQ),
glucocorticoids, and nonsteroidal antiinflammatory drugs. The prior TNF inhibitor could have been
discontinued due either to ineffectiveness (58 percent) or to other factors unrelated to effectiveness,
including intolerance or inaccessibility (53 percent); some discontinued the first TNF inhibitor for
multiple reasons. Among those who had discontinued the first TNF inhibitor due to lack of
effectiveness, patients in the combined golimumab group (who received either 50 or 100 mg every
four weeks) were significantly more likely to achieve an ACR20 or higher response at week 14 (39
versus 18 percent). Patients who discontinued the first drug for reasons other than ineffectiveness
were also more likely to achieve at least an ACR20 response with golimumab (34 versus 20 percent).
There was no increase in serious adverse events in patients on golimumab compared with those on
placebo. The results of this trial are consistent with findings from observational studies of other TNF
inhibitors.
The relative benefits of switching to a second or a third TNF inhibitor (etanercept, infliximab, or
adalimumab) were examined in a prospective observational study of 373 patients in the South
Swedish Arthritis Treatment Group register [75]. After three months of treatment, patients receiving
their first compared with their second anti-TNF agent and patients receiving their second compared
with their third anti-TNF agent were more likely to achieve an ACR20 (61 versus 51 versus 35 percent,
respectively) or ACR50 response (37 versus 27 versus 18 percent, respectively). European League
Against Rheumatism (EULAR) overall response rates in the three groups were 76 versus 71 versus 58
percent.
No direct comparisons have been performed of different biologic agents in patients who have had an
inadequate response to a TNF inhibitor; indirect comparisons based upon data from the small number
of available trials have not shown significant differences in benefit between golimumab and biologic
DMARDs from other classes with which there are much less experience in this setting, including
rituximab, tocilizumab, and abatacept [32,82].
Resistant to two TNF inhibitors In patients who do not respond adequately to three- to six-month
trials of the therapies above, including trials of MTX and trials of two TNF inhibitors, or who are unable
to take a TNF inhibitor, we suggest the use of abatacept, tocilizumab, or rituximab, biologic agents
which may all be effective in patients who have not responded adequately to MTX plus a TNF
inhibitor. Tofacitinib, the orally administered kinase inhibitor available for use in the US, is also an
alternative in this setting, although there is very limited experience with this agent, and its role will be
better defined over time with wider use and further study.
Because the likelihood of a response decreases with second switches of TNF inhibitors, a change to a
biologic DMARD other than a TNF inhibitor is suggested after the failure of two such agents. There are
no randomized trials that have evaluated this hypothesis. (See 'Resistant to one TNF inhibitor' above.)

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In patients who discontinue the second TNF inhibitor, analyses of data from a large national patient
registry in Great Britain suggested that discontinuation was primarily due to the same reason for which
the first drug was stopped (inefficacy or toxicity) [74].
Choice of therapy The choice between abatacept, tocilizumab, rituximab, and tofacitinib depends
upon several factors, which vary in importance in different patients. These factors include patient
preference; regulatory, insurance, and cost limitations; comorbidities; and clinician experience. They
have not been directly compared, but abatacept, tocilizumab, and rituximab appear comparable in
indirect comparisons of randomized trial data in a meta-analysis [82]. We generally take the following
approach:
We usually use abatacept, rituximab, or tocilizumab as the first choice in this group of
patients in the seropositive subset. In seronegative patients, we prefer abatacept or
tocilizumab. In patients who experience adverse effects from these agents, the
immunosuppressive or immunomodulatory actions of abatacept or tocilizumab are more
rapidly reversed than those of rituximab, whose effects may last for several months or
longer. Additionally, rituximab use may be very rarely associated with devastating illness
due to reactivation of the polyomavirus JC (JC virus), progressive multifocal
leukoencephalopathy (PML). (See "Rituximab and other B cell targeted therapies for
rheumatoid arthritis", section on 'Rituximab' and "Progressive multifocal
leukoencephalopathy: Epidemiology, clinical manifestations, and diagnosis".)
In older patients with more comorbidities, we prefer abatacept over tocilizumab or
rituximab. There is more limited experience with tocilizumab than with abatacept or
rituximab, and some concerns remain regarding potential toxicity. Indirect comparisons
suggest that abatacept may have fewer adverse effects than the other biologic agents
used in RA [25].
Rituximab may be preferred in patients in whom monthly drug administration may be
problematic, as a treatment course of two IV infusions is administered no more frequently
than every six months. Patients with rheumatoid factor or with anti-citrullinated peptide
antibodies may have a greater response to the drug than seronegative patients [83,84].
Otherwise, the efficacy and safety of rituximab in patients with RA appear similar to those
of other biologic agents [25,85].
The relative role of tofacitinib in patients who have had an inadequate response to other
DMARDs is unclear. A potential advantage of this medication is that it is administered
orally, but data regarding the risk of adverse events and outcomes with this drug
compared with other antirheumatic medications are more limited compared with what is
known regarding other available agents.
We prefer these agents over anakinra, as they all appear more effective than anakinra,
based upon their comparability to biologic DMARDs that have been shown superior to
anakinra in indirect comparisons [27]. (See 'Resistant to standard therapies' below.)

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Dosing and efficacy The dosing, efficacy, and safety of abatacept, tocilizumab, rituximab, and
tofacitinib are described below:
Abatacept The dosing and administration of abatacept in patients with RA are described elsewhere
in this topic review, and the use of abatacept in patients with RA in general, evidence supporting such
use, and the adverse effects of abatacept are also reviewed in detail separately. (See 'MTX plus
abatacept' above and 'Efficacy of MTX/TNF inhibitor versus MTX/abatacept' above and "T cell
targeted therapies for rheumatoid arthritis", section on 'Abatacept'.)
A randomized trial and larger open-label study have described the benefits of abatacept compared
with placebo in patients who have had an inadequate response to a TNF inhibitor [77,86]. In the
randomized trial, involving 391 patients, patients receiving abatacept were significantly more likely
compared with placebo-treated patients to achieve at least 20 percent improvement in the level of
disease activity after 24 weeks of therapy (ACR20 of 50 versus 20 percent) [77]. The rate of serious
infections was the same in both groups (2.3 percent).
Tocilizumab Tocilizumab, a humanized anti-human interleukin (IL)-6 receptor antibody, is

administered intravenously every four weeks (at an initial dose of 4 mg/kg per infusion, which may be
increased to 8 mg/kg per infusion, based upon the clinical response, to a maximum of 800
mg/infusion). The efficacy and safety of tocilizumab in RA have been characterized in meta-analyses
of randomized trials of the drug as monotherapy or together with MTX compared with placebo. This
evidence is reviewed in detail separately. (See "Randomized clinical trials in rheumatoid arthritis of
biologic agents that inhibit IL-1, IL-6, and RANKL", section on 'Tocilizumab'.)
Tocilizumab has been effective in patients with RA who have not responded adequately to TNF
inhibitors. In a randomized trial involving 499 patients with an inadequate response to TNF inhibitor
therapy, the use of tocilizumab (8 mg/kg and 4 mg/kg administered intravenously every four weeks,
respectively), together with continued treatment with MTX, significantly improved treatment outcomes
at six months compared with placebo plus MTX (ACR20 of 50 and 30 percent versus 10 percent) [79].
Substantial improvement was noted within four weeks and may be maintained for at least several
years in long-term follow-up [81]. The rates of serious adverse events, serious infections, and adverse
events leading to drug discontinuation were similar in all three groups; adverse events that were
numerically more common in patients on tocilizumab included infections (49 and 47 percent versus 41
percent), gastrointestinal symptoms (37 and 33 percent versus 19 percent), and rash (22 and 31
percent versus 14 percent).
Tocilizumab was compared directly with adalimumab as monotherapy for patients with active RA who
were intolerant to MTX or who were considered inappropriate candidates for continued treatment with
MTX [87]. In this randomized 24-week trial involving 326 patients, tocilizumab (8 mg/kg administered
intravenously every four weeks plus subcutaneous placebo every two weeks) was compared with
adalimumab (40 mg administered subcutaneously every two weeks plus intravenous placebo every
four weeks). Tocilizumab use resulted in a significantly greater reduction in the disease activity score

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using 28 joints and the erythrocyte sedimentation rate (DAS28-ESR decrease of -3.3 versus -1.8,
difference of -1.5, 95% CI -1.8 to -1.1). A proportionately smaller but statistically significant difference
in the degree of improvement was noted using the Clinical Disease Activity Index (CDAI decrease of -
23.8 versus -18.9, difference of -4.9, 95% CI -8.3 to -1.5), which is independent of the reduced levels
of acute phase reactants that may occur disproportionately with tocilizumab, unlike the DAS28-ESR. A
trend toward greater improvement in the Health Assessment Questionnaire (HAQ) score did not
achieve statistical significance. Only the higher dose of tocilizumab was used in this trial; there was no
comparison with the more standard 4 mg/kg dose. Serious adverse effects did not differ between the
groups, but laboratory abnormalities were more common with tocilizumab.
A dose adjustment or drug discontinuation may be required in patients with significant liver enzyme
(aminotransferase) elevations, neutropenia, or thrombocytopenia. Other adverse effects include
serious infections, including mycobacterial and other opportunistic infections. The risk of adverse
effects is greater in patients on concomitant immunosuppressive therapy. Hyperlipidemia may occur
and should be managed according to available guidelines. Intestinal perforations have been reported,
especially in older patients and in those with a history of diverticulitis, which is a contraindication to the
use of tocilizumab. (See "Treatment of lipids (including hypercholesterolemia) in primary prevention"
and "Treatment of lipids (including hypercholesterolemia) in secondary prevention".)
Rituximab Rituximab is a monoclonal anti-CD20 antibody that depletes B cells. It is administered

intravenously (1000 mg/dose) on days 1 and 15 of therapy, usually 30 minutes following intravenous
administration of methylprednisolone (100 mg), which can reduce the incidence and severity of
infusion reactions. Subsequent courses are usually given every 6 to 12 months if clinically indicated,
based upon disease activity. Similarly, we generally wait six months after administration of rituximab
before switching to an alternative medication for lack of efficacy or for adverse effects because of the
duration of its biologic effects. Rituximab is given in combination with ongoing MTX treatment.
The efficacy of rituximab plus continued therapy with MTX in patients with an inadequate response to
a TNF inhibitor was shown in comparison with placebo plus continued MTX in a randomized trial
involving 520 patients [78]. At six months, significantly more patients receiving rituximab showed at
least 20 percent improvement in clinical activity compared with placebo treated patients (ACR20 of 51
versus 18 percent). Additional evidence suggests benefit with retreatment six months after an initial
course [88]. Additionally, a registry-based study suggested that, when the reason for stopping a TNF
inhibitor was lack of effect rather than an adverse event, rituximab resulted in a greater decrease in
disease activity compared with treatment with another TNF inhibitor (DAS28 decrease of -1.34 versus
-0.93) [76]. The use of rituximab in the treatment of RA, additional evidence supporting such use, and
the adverse effects of rituximab are reviewed in detail separately. (See "Rituximab and other B cell
targeted therapies for rheumatoid arthritis", section on 'Rituximab'.)
Tofacitinib Tofacitinib is an orally administered Janus kinase (JAK kinase) inhibitor that decreases
signalling by a number of cytokine and growth factor receptors. It is taken in a dose of 5 mg twice
daily. Tofacitinib can be used as monotherapy or combined with MTX or other nonbiologic DMARDs in
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patients with moderately to severely active RA who have had an inadequate response or intolerance
to MTX, but it should not be taken in combination with biologic agents or with other potent
immunosuppressants, such as azathioprine or cyclosporine. The evidence supporting the use of
tofacitinib in patients with RA is reviewed here briefly and is discussed in more detail separately. (See
"Cytokine networks in rheumatic diseases: Implications for therapy", section on 'JAK inhibition'.)
The efficacy and safety of tofacitinib in rheumatoid arthritis have been evaluated in a series of trials in
patients with an inadequate response to MTX or another traditional or biologic DMARD [89-92]. As
examples:
Tofacitinib can be effective as monotherapy in patients with an inadequate response to

MTX. In a randomized trial involving 611 patients with an inadequate response to at least
one nonbiologic or biologic DMARD (usually MTX), tofacitinib monotherapy (5 mg twice
daily) resulted significantly more often in reductions in signs and symptoms of active RA
after three months of treatment, compared with placebo (ACR20 of 60 versus 27 percent)
[89].
Tofacitinib has also shown benefit as cotherapy with MTX in patients who have not had
an adequate response to MTX alone and was comparably effective to a TNF inhibitor in
this setting. A trial involving 797 patients with active RA and inadequate responses to
MTX showed significantly greater benefit at six months for continued MTX plus 5 or 10
mg twice daily of tofacitinib compared with MTX plus placebo (ACR20 of 52 and 62
percent versus 25 percent) [91]. At six months, those treated with tofacitinib
demonstrated improved Health Assessment Questionnaire Disability indices (HAQ-DI
0.4 and -0.54 versus -0.15) and smaller increases in the degree of radiographic injury
(changes in modified Sharp/van der Heijde scores of 0.12 and 0.06 versus 0.47). The
reduction in radiographic change seen using the dose recommended for clinical use by
the manufacturer (5 mg twice daily) did not reach statistical significance.
In a randomized trial involving 717 patients, tofacitinib (5 mg twice daily) and adalimumab
(40 mg administered subcutaneously every two weeks) showed similarly significant
benefit compared with placebo after six months in patients with active RA who had had
an inadequate response to MTX and who continued MTX cotherapy (ACR20 of 52 and
47 percent versus 28 percent, respectively) [90].
Tofacitinib has also been shown to have efficacy in patients who have not responded
adequately to TNF inhibitor therapy. In a randomized trial involving 399 patients with an
inadequate response to MTX plus a TNF inhibitor, the addition of tofacitinib (5 or 10 mg
twice daily) to MTX, compared with placebo plus MTX, resulted at three months in a
significantly greater response rate (ACR20 of 42 and 48 percent versus 24 percent) and
in significantly greater reductions in the degree of disability (HAQ-DI -0.43 and -0.46
versus -0.18) [92].

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The relative safety of tofacitinib appeared similar to that of biologic DMARDs, including increased risk
of infections (eg, herpes zoster) and liver function test abnormalities; additional concerns that require
attention in clinical use include neutropenia, hyperlipidemia, and, possibly, increased serum creatinine
[89,90,93-95]. Gastrointestinal perforations have also been reported. The need for concurrent MTX
therapy with use of tofacitinib is uncertain and requires further study.
Resistant to standard therapies There are several options in patients who are unable to take or
who have an inadequate response to TNF inhibitors, abatacept, tocilizumab, rituximab, and tofacitinib.
The choice between these further options depends upon patient preferences regarding route of
administration, patient comorbidities, and clinician preference based upon degree of experience with a
given agent. There have been no head-to-head comparisons of these therapies.
Nonbiologic (traditional) DMARDs Treatment options in this setting should include

the use of nonbiologic DMARDs, such as leflunomide, or DMARD combinations, such as
triple therapy, which were not used in the original sequence of drug regimens in a given
patient. These agents may be tried before less effective biologic agents, such as
anakinra, or before the other nonbiologic DMARDs used infrequently in practice, such as
those mentioned below. (See 'Leflunomide' above and 'DMARD triple therapy' above.)
Anakinra The interleukin-1 receptor antagonist, anakinra, can be used in combination
with MTX but appears less effective than other biologic DMARDs in RA [27]. Its
effectiveness in patients who have failed to respond to MTX plus a TNF inhibitor has not
been evaluated. (See "Randomized clinical trials in rheumatoid arthritis of biologic agents
that inhibit IL-1, IL-6, and RANKL", section on 'Anakinra'.)
Other nonbiologic traditional DMARDs Nonbiologic DMARDs that have less efficacy,
greater toxicity, or both, compared with other available medications, but that may be of
use in patients without other treatment options include:
Azathioprine (see "Pharmacology and side effects of azathioprine when used in

rheumatic diseases", section on 'Use in rheumatic diseases')
Gold (see "Use of gold compounds in rheumatic diseases")
Cyclosporine (see "Randomized clinical trials of combinations of nonbiologic
DMARDs in rheumatoid arthritis", section on 'Cyclosporine and MTX')
Minocycline or doxycycline (See "Initial treatment of mildly active rheumatoid arthritis
in adults", section on 'Other therapies'.)
SYMPTOMATIC DRUG THERAPY Antiinflammatory drugs are used as a supplement to DMARDs
under several conditions, including as bridging therapies until newly instituted DMARD regimens
become effective, as adjuncts to DMARDs on a chronic basis, and for the management of disease
exacerbations (flares). Analgesic effects of nonsteroidal antiinflammatory drugs (NSAIDs) or
acetaminophen may also give additional relief.

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Antiinflammatory therapy We use NSAIDs or systemic and/or intraarticular glucocorticoids when

needed for ongoing control of inflammation, while awaiting the response to modifications in DMARD
therapy. Glucocorticoids can help to rapidly control inflammation and to improve symptoms. However,
they should be used in the lowest dose required once such control is achieved, and they should be
tapered and discontinued as soon as feasible. Some patients require ongoing therapy with low doses
of glucocorticoids to maintain remission or a low level of disease activity. (See "Initial treatment of
moderately to severely active rheumatoid arthritis in adults", section on 'NSAIDs' and "Initial treatment
of moderately to severely active rheumatoid arthritis in adults", section on 'Glucocorticoids' and "Use of
glucocorticoids in the treatment of rheumatoid arthritis".)
Drug therapy for flares RA has natural exacerbations (also known as flares) and reductions of
continuing disease activity. It is important to distinguish a disease flare, characterized by symptoms
and by physical and laboratory findings of increased inflammatory synovitis, from noninflammatory
causes of local or generalized increased pain. The severity of the flare and background drug therapy
influence the choice of therapies. The treatment of such flares is described in detail elsewhere. (See
"Clinical features of rheumatoid arthritis" and "Use of glucocorticoids in the treatment of rheumatoid
arthritis" and "General principles of management of rheumatoid arthritis in adults", section on
'Assessment of disease activity' and "General principles of management of rheumatoid arthritis in
adults", section on 'Drug therapy for flares'.)
Analgesics In addition to the medications noted above, including NSAIDs, which also have
analgesic effects, we use other analgesic medications, such as acetaminophen and/or tramadol, for
additional pain relief, if required. We generally avoid the use of potent opioids because pain can be
controlled in most patients with RA by effective use of antiinflammatories and DMARDs that control the
disease process. Patients without evidence of very significant joint injury who appear to require
opioids for adequate pain relief should be evaluated for fibromyalgia or other comorbid causes of pain
(eg, fracture, tumor, spinal disorders, neuropathy, or others).
DURATION OF THERAPY Most patients with early, severely active RA require sustained therapy
and adjustments in their treatment regimen over months to years to achieve treatment goals. In the
minority of patients who achieve a sustained clinical remission of greater than one year, we cautiously
try to reduce nonbiologic and biologic DMARD doses while maintaining close monitoring to facilitate
recognition of any recurrence of disease activity. However, we generally avoid discontinuing all
DMARD treatment. Although some patients may tolerate a reduced dose of medications, the decision
to discontinue DMARDs in patients in remission remains controversial, and there is limited evidence
regarding tapering of DMARDs in patients who are started on DMARDs early in their disease course
or who have been treated with biologic DMARDs [96-104]. One randomized trial involving 604 patients
evaluated the consequences of discontinuation of etanercept in patients who had previously achieved
a reduction from moderate to (at most) low disease activity at week 36 after the addition of etanercept
(50 mg weekly) to ongoing use of methotrexate (MTX) [102]. Patients with low disease activity
randomly assigned to continue etanercept (50 or 25 mg weekly) plus MTX were significantly more

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likely to maintain low disease activity after one additional year of therapy compared with patients
assigned to MTX plus placebo injections (83 and 79 percent versus 43 percent). Our approach is
based upon the available data and upon our clinical experience. (See "Initial treatment of moderately
to severely active rheumatoid arthritis in adults", section on 'Duration of therapy' and "Assessment of
rheumatoid arthritis activity in clinical trials and clinical practice", section on 'Remission'.)
As an example of our approach, in a patient in clinical remission being treated with prednisone (7
mg/day), MTX (20 mg/week), and etanercept (50 mg/week), we would first try to reduce prednisone
because of the risk of long-term adverse effects with glucocorticoids. In such a patient, we would lower
the glucocorticoid dose slowly (no faster than 1 mg every two to four weeks), as long as there was no
recurrence of disease activity.
If prednisone can be discontinued or if it cannot be completely eliminated but can be lowered to a

dose no greater than 5 mg/day, we would then reduce the dosing of the TNF inhibitor, based upon our
clinical experience. We try to reduce etanercept by slowly decreasing the dosing frequency (eg, to
every 10 to 14 days, then gradually to every three to four weeks if dose reduction is tolerated). In
patients on infliximab, in whom dose adjustment is more feasible compared with etanercept or
adalimumab, we would try to incrementally reduce the dose to as low as 3 mg/kg and to increase the
interval between infusions to every eight weeks.
In patients who are able to discontinue a biologic and who then remain in remission for at least a year,
we next decrease MTX. We reduce the MTX dose in 2.5 mg increments every two to three months as
tolerated but generally to no lower than 10 mg/week. In patients who are tolerating methotrexate more
poorly, reduction in the methotrexate dose can be implemented before reduction in the dose of the
TNF antagonist.
Continued close monitoring is required in patients who discontinue or reduce any of their medications.
The risk of disease recurrence in such patients is high, and flares of disease may occur even several
years after stopping therapy [97-101]. Additionally, clinical remission can be difficult to achieve upon
resumption of DMARD therapy in patients who have discontinued all DMARDs. The best candidates
for achieving a drug-free remission appear to be patients who have a short duration of symptoms
when treatment is started, patients who are of the male sex, patients who have an absence of
autoantibodies, and patients who receive early intensive therapy [99,105-107]. The effects on the
progression of joint injury of less frequent dosing (eg, based upon symptomatic need only) have not
been evaluated.
PREGNANCY Considerations relevant to the management of RA during pregnancy are reviewed

separately. (See "Rheumatoid arthritis and pregnancy" and "Use of antiinflammatory and
immunosuppressive drugs in rheumatic diseases during pregnancy and lactation".)
th th
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th th
Basics topics (see "Patient information: Rheumatoid arthritis (The Basics)" and "Patient
information: Disease modifying antirheumatic drugs (DMARDs) (The Basics)")
Beyond the Basics topics (see "Patient information: Rheumatoid arthritis treatment
(Beyond the Basics)" and "Patient information: Rheumatoid arthritis symptoms and
diagnosis (Beyond the Basics)")
Patients with rheumatoid arthritis (RA) benefit from the achievement and maintenance of
tight control of disease activity, with the ideal goal of remission. Whenever possible,
antiinflammatory agents, including glucocorticoids, should be used only as adjunctive
agents. Patient education and other nonpharmacologic and preventive therapies,
including appropriate immunizations, are needed for all patients with RA. (See 'General
principles and approach' above.)
In patients with RA, resistance to initial therapy with disease-modifying antirheumatic
drugs (DMARDs) is defined as failure to achieve remission or low disease activity within
three to six months despite the use of maximally tolerated doses within the usual
therapeutic range; as a requirement, in addition to DMARDs, for excessively high doses
of glucocorticoids; or as recurrent flares of disease requiring multiple courses of
glucocorticoids with doses in excess of those acceptable for chronic therapy, despite
maximally tolerated or acceptable doses of the DMARDs being used. (See 'Definition of
resistance to initial DMARDs' above.)
In patients with active RA resistant to initial therapy after three to six months of treatment,
we recommend treatment with a different or additional DMARD or with DMARD
combinations to achieve control of signs and symptoms of disease, rather than
continuing the initial DMARD regimen (Grade 1B). The choice of drug combinations in
such patients depends upon prior therapy, upon the level of disease activity, upon patient
preference for route of administration, upon the presence of adverse prognostic features,
and upon regulatory and cost barriers to drug access. (See 'Resistant to initial DMARD'
above and 'Choice of therapy' above.)

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In patients resistant to initial therapy with hydroxychloroquine (HCQ) or sulfasalazine

(SSZ), we suggest adding methotrexate (MTX) or treating with a combination of
HCQ, SSZ, and MTX, rather than switching to a TNF inhibitor or to a TNF inhibitor
plus MTX (Grade 2B). Usual doses of these medications are MTX (up to 25 mg once
weekly administered orally or parenterally), HCQ (400 mg daily taken orally), and
SSZ (1000 mg twice daily taken orally). (See 'Resistant to HCQ and/or SSZ' above
and "Initial treatment of mildly active rheumatoid arthritis in adults", section on
'Monitoring and reevaluation' and "Initial treatment of moderately to severely active
In patients who have not achieved treatment goals after three to six months of MTX
at optimal doses, we suggest either the combination of continued MTX plus a tumor
necrosis factor (TNF) inhibitor (eg, etanercept or adalimumab) or the use of DMARD
triple therapy with MTX plus SSZ and HCQ, rather than monotherapy with another
nonbiologic or biologic DMARD (Grade 2A). Usual doses of these TNF inhibitors are
etanercept (50 mg subcutaneously once weekly) and adalimumab (40 mg
subcutaneously every two weeks). We use triple therapy in patients for whom drug
cost and preference for an oral agent are important factors. (See 'Resistant to MTX'
above and 'Choice of therapy' above and 'MTX plus TNF inhibitor' above and
'DMARD triple therapy' above.)
In patients in whom MTX plus a TNF inhibitor would otherwise be appropriate but
who are unable to use a TNF inhibitor, we suggest the combination of MTX plus
abatacept, rather than biologic monotherapy or another DMARD combination (Grade
2B). Abatacept may be administered either intravenously (usually 750 mg once every
four weeks) or subcutaneously (125 mg once weekly). (See 'Alternatives to MTX/TNF
inhibitor and to triple therapy' above and 'MTX plus abatacept' above.)
In patients in whom regulatory or cost considerations preclude use of a biologic agent
despite failure of MTX or DMARD triple therapy to adequately control disease
activity, we suggest the use of leflunomide (LEF) rather than alternative nonbiologic
DMARDs (eg, gold, azathioprine, or cyclosporine) (Grade 2B). (See 'Alternatives to
MTX/TNF inhibitor and to triple therapy' above and 'Leflunomide' above.)
In patients whose treatment regimen has changed, reevaluation may be required up to

every four weeks for the effectiveness of therapy and for the monitoring of possible drug
toxicity. We assess and monitor disease activity using a quantitative composite measure
at each assessment. Further management is dependent upon disease response. (See
'Reevaluation and monitoring' above.)
In patients who do not respond adequately to therapy with an initial TNF inhibitor
within three to six months, we suggest switching to a different TNF inhibitor, rather
than to another class of biologic (Grade 2C). We prefer one of the agents with which
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there is more experience, such as etanercept, adalimumab, or infliximab (which is

administered intravenously, usually in a dose of 3 to 5 mg/kg every eight weeks). An
alternative approach is switching to another biologic agent with a different
mechanism of action in this setting rather than to a second TNF inhibitor, particularly
in patients who discontinue the initial TNF inhibitor due to an adverse reaction. (See
'Resistant to one TNF inhibitor' above.)
In patients who do not respond adequately to the therapies above, including trials of
MTX and trials of two TNF inhibitors, we suggest the use of abatacept, tocilizumab,
or rituximab, rather than the administration of a third TNF inhibitor (Grade 2B).
Tofacitinib is an alternative agent in such patients. Choice between these agents
depends primarily upon patient preference; upon regulatory, insurance, and cost
limitations; upon comorbidities; and upon clinician experience. (See 'Resistant to two
TNF inhibitors' above and 'Choice of therapy' above and 'Dosing and efficacy'
above.)
We continue nonbiologic and biologic DMARD therapy at reduced doses, if possible,
for patients in remission, rather than discontinuing treatment with DMARDs. (See
'Duration of therapy' above.)
In patients experiencing a disease flare that is not controlled with NSAIDs, we suggest
treatment with intraarticular or oral glucocorticoids rather than switching or continuing
NSAIDs as the only additional agent (Grade 2A). We use antiinflammatory drug therapy,
including nonsteroidal antiinflammatory drugs (NSAIDs) or glucocorticoids, on a
temporary basis to quickly achieve control of signs and symptoms of disease, and we
then taper and withdraw these medications once a new DMARD regimen has taken
effect. Some patients benefit from chronic low-dose glucocorticoid therapy (eg,
prednisone to 5 to 7.5 mg daily). (See 'Symptomatic drug therapy' above and
'Antiinflammatory therapy' above and 'Drug therapy for flares' above and "General
principles of management of rheumatoid arthritis in adults", section on 'Drug therapy for
flares'.)

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Direccin Provincial de Salud de Cotopaxi

Hospital Provincial General de Latacunga

We focus especially on the following for the purposes of diagnosis:

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rheumatoid factor, and acute-phase reactants. In a minority of patients, several such

Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies We

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We perform the following studies in selected patients:

Inflammatory arthritis Arthritis is typically present in the metacarpophalangeal (MCP) and

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Antibodies to citrullinated peptides/proteins are usually measured by enzyme linked immunosorbent

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Number and site of involved joints

Serological abnormality (rheumatoid factor or anti-citrullinated peptide/protein antibody)

Low positive (above the upper limit of normal, ULN) = 2 points

Elevated acute phase response (erythrocyte sedimentation rate or C-reactive protein)

DIFFERENTIAL DIAGNOSIS A variety of conditions must be considered in the differential

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Morning stiffness is common in all inflammatory arthritides. Symmetric arthritis is seen in

Palindromic rheumatism Palindromic rheumatism is characterized by episodes of joint

History of recent urethritis or enteric infection

Polymyalgia rheumatica Polymyalgia rheumatica (PMR) can sometimes be mistaken for RA in

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Myelodysplasia Patients with myelodysplastic syndrome sometimes develop

Multicentric reticulohistiocytosis Multicentric reticulohistiocytosis is a rare but highly destructive

Multicentric reticulohistiocytosis is relatively resistant to glucocorticoids and to disease-modifying

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metacarpophalangeal and proximal interphalangeal joints, and it is frequently associated with

This disorder is distinguished from RA by the following findings:

Elevated serum concentrations of angiotensin converting enzyme (ACE) are found in up

(See "Sarcoid arthropathy".)

Due to the rarity of fibroblastic rheumatism, there is no well-established treatment. Progressive

Basics topics (see "Patient information: Rheumatoid arthritis (The Basics)")

SUMMARY AND RECOMMENDATIONS

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Limited duration (eg, in viral arthropathy)

INTRODUCTION Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disorder of

CLINICAL PRESENTATIONS Polyarticular disease with a gradual onset, intermittent or migratory

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Extraarticular involvement Extraarticular features of RA, including anemia, fatigue, subcutaneous

In addition, a proportion of patients complain of persistent nonarticular symptoms, such as generalized

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Other physical signs include the following:

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Tenderness of the metatarsophalangeal joints may be marked, resulting in the tendency

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Ultrasonography Ultrasonography is another alternative for estimating the degree of inflammation

SUMMARY AND RECOMMENDATIONS

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These principles include:

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Care by a rheumatologist An expert in the treatment of rheumatic diseases, such as a

NONPHARMACOLOGIC AND PREVENTIVE THERAPIES A number of nonpharmacologic

Briefly, these measures include:

Pretreatment evaluation Prior to starting, resuming, or significantly increasing therapy with

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Level of disease activity (eg, mild versus moderate to severe)