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44 Rheumatoid Arthritis
Steven W. Chen, Rory E. O’Callaghan, and Alison M. Reta

C O R E P R I N C I P L E S
CHAPTER CASES

RHEUMATOID ARTHRITIS

1 Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder characterized Case 44-1 (Questions 1, 2)
by potentially deforming polyarthritis and a wide spectrum of extra-articular
manifestations. Diagnosis of RA is based on joint involvement, serology, acute-phase
reactants, and symptom duration.

2 Treatments for RA include nonpharmacologic (heat or cold therapy, range-of-motion Case 44-1 (Questions 3–5),
exercises, physical therapy, occupational therapy) and pharmacologic options Case 44-2 (Question 1),
(nonsteroidal anti-inflammatory drugs [NSAIDs], traditional and biologic Case 44-3 (Questions 1, 2),
disease-modifying antirheumatic drugs [DMARDs], corticosteroids). NSAIDs are for Case 44-4 (Question 1),
symptom management only and must be used cautiously, if at all, because of serious Case 44-5 (Questions 1–3)
health risks, including gastrointestinal complications and thromboembolic
cardiovascular events.

3 Owing to the destructive nature of the disease, DMARDs should be initiated shortly Case 44-5 (Questions 4–7),
after a diagnosis has been established. Methotrexate is the most common selection Case 44-6 (Questions 1–9),
because of efficacy, safety, rapid onset, and cost-effectiveness. Other traditional Case 44-7 (Questions 1–8)
DMARDs and combinations of traditional DMARDs are selected based on disease
severity, disease duration, and the presence of poor prognostic indicators.
Several traditional DMARDs are no longer used as a result of poor efficacy or
intolerable adverse effects. Regardless of the DMARD chosen, all require diligent
monitoring.

4 Patients with RA who experience an inadequate response to traditional DMARDs, Case 44-7 (Questions 9–13),
either alone or in combination, or intolerable adverse effects should consider the Case 44-8 (Question 1)
addition of or switching to a biologic DMARD. Diligent monitoring is also critical with
biologic agents owing to the risk of serious adverse effects such as infections and
lymphoma.

5 Corticosteroids, when used judiciously at the lowest effective doses and for limited Case 44-9 (Questions 1–4)
durations, are very effective at quickly controlling inflammation while awaiting onset
of DMARD therapy. In rare instances when long-term corticosteroid therapy is
prescribed, appropriate therapy must be used to help prevent steroid-induced
osteoporosis.

6 Although systemic corticosteroids can be prescribed for short-term flares of RA Case 44-9 (Question 5)
disease activity, intra-articular corticosteroid injections are very effective at managing
flares that are limited to a few joints and are not associated with the adverse effects
of systemic therapy.

continued

1002
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1003
CHAPTER CASES

JUVENILE IDIOPATHIC ARTHRITIS

1 Juvenile idiopathic arthritis (JIA) describes an assortment of arthritis conditions Case 44-10 (Questions 1, 2)
affecting adolescents. Symptoms of JIA such as joint inflammation and
range-of-motion limitation present before 16 years of age. As in RA, the diagnosis
of JIA is based on clinical manifestations, and all infectious, traumatic, and other
etiologies must be ruled out.

2 Pharmacologic treatment options for JIA include NSAIDs, traditional and biologic Case 44-10
DMARDs, and corticosteroids. (Questions 3, 4),
Case 44-11 (Questions
1, 2),
Case 44-12 (Question 1),
Case 44-13 (Questions 1, 2),
Case 44-14 (Question 1)

3 Many nonpharmacologic treatment options are also available to supplement JIA Case 44-14 (Question 2)
pharmacologic therapy, including exercise, massage, and physical and
occupational therapy.

Epidemiology chemical or laboratory finding is specific for this disease.2 The

prevalence of RA is estimated to be 1% worldwide, but varies
The term arthritis refers to more than 100 diseases causing pain, greatly between geographic regions.3,4 In the United States, RA
swelling, and damage to joints and connective tissue.1 Rheuma- afflicts approximately 1.5 million individuals, occurring nearly
toid arthritis (RA) is a chronic systemic inflammatory disorder twice as often in women as in men.4 The onset of RA typically
characterized by potentially deforming polyarthritis and a wide occurs between the third and fourth decades of life, and preva-
spectrum of extra-articular manifestations. The diagnosis of RA is lence increases with advancing age up to the seventh decade.1,3
based primarily on clinical criteria (Table 44-1) because no single The prevalence of RA increased from 0.62% to 0.72% between
1995 and 2005, and the average age of RA prevalence increased
from 63.3 years in 1965 to 66.8 years in 1995.5 RA-related morbid-
TA B L E 4 4 - 1 ity, mortality, and disability are expected to increase substantially
Criteria for Diagnosis of Rheumatoid Arthritis in future years as the US boomer population ages.5
The cause of RA seems to be an interplay among multiple
Criteria Scorea factors (e.g., genetic susceptibility, environmental influences, the
effects of advancing age on somatic changes in the musculoskele-
Joint Involvement
tal and immune systems).3 It is suspected that genetics con-
1 large joint 0 tribute to 50% or 60% of the risk of developing RA.6 The genes
2–10 large joints 1 with the strongest implication include the HLA-DRB1 gene of
1–3 small joints 2 the major histocompatibility complex (MHC), and chromosome
4–10 small joints 3 1’s PTPN22 gene. Epidemiologic associations between cigarette
>10 small joints 5 smoking and RA have now been clearly established; cigarette
Serology smoking increases the production of rheumatoid factor (RF) and
anti-cyclic citrullinated peptide antibody (anti-CCP, another clin-
Negative RF and negative anti-CCP 0 ical marker for RA).6 It appears that female sex hormones may
Low-positive RF or low-positive anti-CCP 2
play a role in RA development. In women, peak incidence occurs
High-positive RF or high-positive anti-CCP 3
at the fifth decade, a time when many enter menopause or peri-
Acute-Phase Reactants menopause. Estrogen is known to stimulate the immune system;
Normal CRP and normal ESR 0 pregnant patients often experience a remission of RA symptoms,
Chapter 44

Abnormal CRP or abnormal ESR 1 and women who take oral contraceptives appear to be protected
Duration of Symptoms
somewhat against the development of RA.4,6 Diets rich in fish,
olive oil, and other omega-3 fatty acid sources are associated with
<6 weeks 0 a lower risk of developing RA.6 A deficiency of vitamin D is also
≥6 weeks 1 associated with RA.4
The course of RA is variable and can be categorized as poly-
a
Rheumatoid Arthritis

Score-based algorithm: add score of all categories; score of ≥6/10 needed to
classify patient as having definite RA.
anti-CCP, anti–cyclic citrullinated peptide; CRP, C-reactive protein; ESR,
erythrocyte sedimentation rate; RA, rheumatoid arthritis; RF, rheumatoid factor.
Source: Aletaha D et al. 2010 rheumatoid arthritis classification criteria: an
American College of Rheumatology/European League Against Rheumatism
collaborative initiative [published correction appears in Ann Rheum Dis.
2010;69:1892]. Ann Rheum Dis. 2010;69:1580.
cyclic, monocyclic, or progressive.7 The polycyclic course occurs
in approximately 70% of patients, who initially experience mild
intermittent symptoms that resolve over the course of several
weeks to months. The patient can be symptomfree for several
weeks to months and then experience symptoms that can be
more severe than those experienced initially. Monocyclic patients
(∼20% of patients) experience a relatively sudden onset of
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1004 symptoms followed by a prolonged clinical remission of disease
activity. Patients with the progressive form (∼10% of patients)
experience advancing disease that usually evolves uninterrupted
over the course of a few months, but the rate of disease progres-
sion in this group can be rapid or slow. Patients within this group
can be subdivided further into those who respond to “aggressive”
therapy and those who do not. Patients with more aggressive dis-
ease (multiple joint involvement, positive RF) have a greater than
70% probability of developing joint damage or erosions within
2 years of disease onset.8
The rate of RA disease remission was low before medica-
tions capable of halting or slowing disease progression became
more available and commonly used in clinical practice. American
College of Rheumatology (ACR) criteria for RA remission were
established in 19819 ; however, the criteria did not incorporate
some common RA symptoms and were so stringent that very
few patients were able to meet remission criteria. As a result,
the majority of RA clinical trials use modified remission criteria,
often removing one or more of the ACR criteria and making
meaningful comparisons between trials very difficult. This vari-
ance in remission criteria is highlighted in a systematic review
of literature that evaluated RA remission rates.10 Among 17
observational trials involving RA patients treated with traditional
and biologic disease-modifying antirheumatic drugs (DMARDs),
27% of patients were reported to experience disease remission;
however, rates differed when using ACR criteria (17%) versus
Disease Activity Score (DAS) criteria (33%). Importantly, many
patients deemed to be in remission continued to experience radi-
ological progression of disease, although less progression was
noted with combination DMARD therapy versus monotherapy.
In response to the need for stringent yet achievable criteria for RA
remission that would be more uniformly accepted, updated cri-
teria were recently released jointly by the ACR and the European
League Against Rheumatism (EULAR) (Table 44-2).11 These cri-
TA B L E 4 4 - 2
Provisional Criteria for Rheumatoid Arthritis Remission in
Clinical Trials From the American College of
Rheumatology/European League Against Rheumatism
A patient with rheumatoid arthritis is considered to be “in remission” if
either of the following applies:
1. Boolean-based definition:
At any time, patient must satisfy ALL of the following:
Tender joint count ≤1a
Swollen joint count ≤1a
C-reactive protein ≤1 mg/dL
Patient global assessment ≤1 (on a 0–10 scale)b
2. Index-based definition:
At any time, patient must have a Simplified Disease Activity Index
score of ≤3.3c
a
For tender and swollen joint counts, use of a 28-joint count may miss actively
involved joints, especially in the feet and ankles, and it is preferable to include
Section 9
feet and ankles also when evaluating remission.
b
For the assessment of remission, the following format and wording is suggested
for the global assessment questions. Format: a horizontal 10-cm visual analog or
Likert scale with the best anchor and lowest score on the left side and the worst
anchor and highest score on the right side. Wording of question and anchors: For
patient global assessment, “Considering all of the ways your arthritis has affected
you, how do you feel your arthritis is today?” (anchors: very well–very poor). For
Arthritic Disorders
physician or assessor global assessment, “What is your assessment of the
patient’s current disease activity?” (anchors: none–extremely active).
c
Defined as the simple sum of the tender joint count (using 28 joints), swollen
joint count (using 28 joints), patient global assessment (0–10 scale), physician
global assessment (0–10 scale), and C-reactive protein level (mg/dL).
Source: Felson DT et al. American College of Rheumatology/European League
Against Rheumatism provisional definition of remission in rheumatoid arthritis
for clinical trials. Arthritis Rheum. 2011;63:573.
November 19, 2011 2:2
teria state that patients with RA in clinical trials will be considered
“in remission” if either of the following occurs: (1) tender joint
count, swollen joint count (of 28 joints), C-reactive protein in
mg/dL, and patient global assessment scores (scale of 0 to 10)
are all 1 or less, or (2) Simplified Disease Activity Index is 3.3
or less.
During the first 10 years of the disease, survival rates of
patients with RA appear to be no different from those of the
general population.12,13 However, more recent data indicate that
patients with RA have an overall lower life expectancy (median
age at death is 3 to 10 years less than non-RA populations),6 with
lower life expectancy associated with more severe disease.14 The
excess mortality has been attributed primarily to accelerated
cardiovascular disease, which in turn might be related to RA-
induced vascular inflammation, hyperhomocysteinemia, dys-
lipidemia, or elevations in tumor necrosis factor-alpha (TNF-α).15
About one-third to one-half of deaths among adults with RA are
attributable to cardiovascular disease, compared with one-fourth
to one-fifth of deaths among adults without RA. RA is associ-
ated with a twofold to threefold increased rate of myocardial
infarction (MI), as well as lower MI survival. An evidence-rated
guideline for reducing cardiovascular disease risk in patients with
RA was recently published by EULAR (Table 44-3).16 Core rec-
ommendations from the guideline include annual cardiovascular
risk evaluations for all patients, multiplying risk scores by 1.5 for
patients with more than one marker of severe disease activity,
use of statins and cardiovascular medications known to reduce
cardiovascular risk, caution when prescribing nonsteroidal anti-
inflammatory drugs (NSAIDs) owing to associated cardiovascu-
lar risk, and smoking cessation.16
Pathophysiology
RA-induced joint destruction begins with inflammation of the
synovial lining that surrounds the joint space.17 This normally
thin membrane proliferates and transforms into the synovial pan-
nus. The pannus, a highly erosive enzyme-laden inflammatory
exudate, invades articular cartilage (leading to narrowing of joint
spaces), erodes bone (resulting in osteoporosis), and destroys
periarticular structures (ligaments, tendons), resulting in joint
deformities (Fig. 44-1).
Familiarity with the basic cellular processes involved in tis-
sue destruction and sustained inflammation in rheumatoid syn-
ovium is essential to understanding pharmacologic therapies for
RA.17,18 Under normal circumstances, the body can distinguish
between self (i.e., proteins found within the body) and nonself
(i.e., foreign substances such as bacteria and viruses). On occa-
sion, immune cells (T or B lymphocytes) can react to a self-protein
while developing in the thymus or bone marrow. These develop-
ing cells are usually killed or inactivated before release from their
place of formation; sometimes, however, a self-targeted immune
cell can escape destruction and become activated years later to
initiate an autoimmune response. Some experts believe the acti-
vation of RA is initiated by bacteria (possibly Streptococcus) or a
virus containing a protein with an amino acid sequence similar
to tissue protein, but this assertion remains disputable.6 When
the activation source (i.e., the self-targeted immune cell) reaches
the joint, complex cell–cell interactions take place, leading to the
pathology associated with RA.
The initiating interaction for an autoimmune response takes
place between antigen-presenting cells (APC), which display
complexes of class II MHC molecules, and CD4-lineage T-cell
lymphocytes (Fig. 44-2). In addition, B cells (previously thought
to have little to do with the inflammatory response) can become
activated, leading to antibody formation (including RF and anti-
CCP), proinflammatory cytokine production, and accumulation
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1005
TA B L E 4 4 - 3
Recommendations for Reducing Cardiovascular Riska in Patients With Rheumatoid Arthritis (Evidence/Strength Rating)b

1. Rheumatoid arthritis should be considered as a disease in which cardiovascular risk is elevated, because of both an increased prevalence of
traditional cardiovascular risk factors and the inflammatory burden. Although the evidence base is less, this may also apply to ankylosing
spondylitis and psoriatic arthritis (2b–3/B).
2. To lower cardiovascular risk, adequate control of arthritis disease activity is necessary (2b–3/B).
3. All patients with rheumatoid arthritis should undergo annual cardiovascular risk evaluation with use of national guidelines. This should also be
considered for all patients with ankylosing spondylitis and psoriatic arthritis. When antirheumatic treatment has been changed, risk assessments
should be repeated (3–4/C).
4. For patients with rheumatoid arthritis, risk score models should be adapted by introducing a 1.5 multiplication factor when the patient meets two
of the following three criteria: disease duration of more than 10 years, rheumatoid factor or anti–cyclic citrullinated peptide positivity, and the
presence of certain extra-articular manifestations (3–4/C).
5. When using the Systematic Coronary Risk Evaluation model for determination of cardiovascular risk, triglyceride to high-density lipoprotein
cholesterol ratio should be used (3/C).
6. Intervention for cardiovascular risk factor management should be performed according to national guidelines (3/C).
7. Preferred treatment options are statins, angiotensin-converting enzyme inhibitors, or angiotensin II blockers (2a–3/C–D).
8. The effect of cyclo-oxygenase-2 inhibitors and most nonsteroidal anti-inflammatory drugs on cardiovascular risk is not completely determined and
should be studied further. Clinicians should therefore be very cautious in prescribing these drugs, especially to patients with cardiovascular risk
factors or with documented cardiovascular disease (2a–3/C).
9. When corticosteroids are prescribed, this should be at the lowest possible dose (3/C).
10. Patients should be actively encouraged to stop smoking (3/C).
a
Cardioprotective treatment is recommended when 10-year cardiovascular risk is above the threshold of “moderate” that is established for each country (i.e., either 10% or
20%).
b
Level of Evidence: Category 1A, from meta-analysis of randomized, controlled trials; 1B, from at least one randomized, controlled trial; 2A, from at least one controlled
study without randomization; 2B, from at least one type of quasi-experimental study; 3, from descriptive studies, such as comparative studies, correlation studies, or
case-control studies; 4, from expert committee reports or opinions or from clinical experience of respected authorities; strength of recommendation directly based on: A,
category 1 evidence; B, category 2 evidence or extrapolated recommendations from category 1 evidence; C, category 3 evidence or extrapolated recommendations from
category 1 or 2 evidence; D, category 4 evidence or extrapolated recommendations from category 2 or 3 evidence.
Source: Peters MJ et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of
inflammatory arthritis. Ann Rheum Dis. 2010;69:325.

of polymorphonuclear leukocytes that release cytotoxins and
other substances destructive to the synovium and joint struc-
tures. B cells also act as APCs, leading to T-cell activation and
acceleration of the inflammatory process.18 T-cell activation
requires two signals: (a) an antigen-specific signal occurring when
a class II MHC antigen molecule on an APC binds to a T-cell
receptor; and (b) binding of CD39 on the T cell to either CD80
or CD86 on the APC. T-cell activation leads to activation of
macrophages and secretion of cytokines, polypeptides that serve
as important mediators of inflammation, and cytotoxins, which
can directly destroy cells and tissues. Proinflammatory cytokines
such as interleukin (IL)-1 and TNF-α stimulate both synovial
fibroblasts and chondrocytes in neighboring articular cartilage
to secrete enzymes that cause degradation of proteoglycan and
collagen tissues. In healthy individuals, the inflammatory process
is regulated by balancing the ratios of proinflammatory cytokines
(e.g., IL-1, IL-6, TNF-α) with anti-inflammatory cytokines—for
example, IL-1 receptor antagonist (IL-1Ra), IL-4, IL-10, and IL-
11. In the synovium of patients with RA, however, this balance is
heavily weighted toward the proinflammatory cytokines, which
results in sustained inflammation and tissue destruction.
Treatment
The treatment of RA involves a combination of interventions,
which include rest, exercise (physical therapy), emotional sup-
port, occupational therapy, and drugs.8 Specific treatment should
be individualized based on joint function, degree of disease activ-
ity, patient age, sex, occupation, family responsibilities, drug
costs, and results of previous therapy. The ultimate goal of RA
treatment is disease remission; however, because sustained remis-
sion is uncommon, minimizing disease activity to provide pain

Normal Rheumatoid Arthritis

Normal, thin
synovium Intact tendons Loosening of
and ligaments tendon sheath and
Chapter 44

surrounding
joint space other periarticular
structures, leading
to joint
deformities

Well-defined Joint space

Rheumatoid Arthritis

joint space narrowing

Erosion of Synovial
Smooth, intact articular thickening,
cartilage surfaces surfaces, leading leading to
providing to bone erosion pannus FIGURE 44-1 Overview of joint
protection to bone and osteoporosis formation changes in rheumatoid arthritis.
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1006 Synovial tissue Blood Endothelial

cells
T cell Monocyte

Adhesion
molecules

IL-12 CD80
CD28
TLR TCR
APC T cell
MHC II
Auto (?) antigen
CD40
CD40L
IFN- IL-2 CD4
IFN-

IL-17
T cell help

FcR Costimulation

IL-15 Th1 B cell

Macrophage

IL-18
IC

TNF, IL-1

AutoAb
(RF and others)
RANKL Plasma cell

Synovial
fibroblast

MMPs
Chondrocyte
RANK

Cartilage

Osteoclast
Bone
Section 9

FIGURE 44-2 Schematic representation of events occurring in rheumatoid arthritis. T cells invading the synovial membrane are primarily
CD4+ memory cells, which produce interleukin-2 (IL-2) and interferon-γ (IFN-γ ) to a similar extent as antigen-triggered T cells, and which are
either already preactivated or become (further) activated by antigen-presenting cells (APCs) in conjunction with arthrogenic (auto)antigen(s) and
appropriate major histocompatibility complex (MHC) class II molecules, costimulation (mainly through CD80, CD81, and CD28) and certain
cytokines (IL-1, IL-15, IL-18). Through cell–cell contact (e.g., through CD11- and CD69-mediation) and through different cytokines, such as
IFN-γ , tumor necrosis factor-α (TNF-α), and IL-17, these T cells activate monocytes, macrophages, and synovial fibroblasts. The latter then
Arthritic Disorders

overproduce proinflammatory cytokines, mainly TNF-α, IL-1, and IL-6, which seems to constitute the pivotal event leading to chronic
inflammation. Through complex signal transduction cascades, these cytokines activate a variety of genes characteristic of inflammatory
responses, including genes coding for various cytokines and matrix metalloproteinases (MMPs) involved in tissue degradation. Tumor necrosis
factor-α and IL-1 also induce RANK expression on macrophages, which when interfering with RANKL on stromal cells or T cells, differentiate into
osteoclasts that resorb and destroy bone. In addition, chondrocytes also become activated, leading to the release of MMPs. Initial events might
also involve activation of APCs through Toll-like receptors (TLRs) before T-cell engagement. RANK, receptor activator of nuclear factor-κB;
RANKL, RANK ligand; RF, rheumatoid factor; TCR, T-cell receptor. (Reprinted with permission from Smolen JS, Steiner G. Therapeutic strategies
for rheumatoid arthritis. Nat Rev Drug Discov. 2003;2:473.)
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relief, help patients maintain activities of daily living, maximize
their quality of life, and slow joint damage is also a goal.
Although symptoms of RA generally can be controlled by con-
servative management, more aggressive therapy is needed to pre-
vent disease progression and disability. Although NSAIDs provide
rapid anti-inflammatory and analgesic effects, they do not prevent
or slow joint destruction. Therefore, DMARD therapy should
be initiated for all patients diagnosed with RA.19 Traditional
DMARDs (e.g., hydroxychloroquine [HCQ], sulfasalazine [SSZ],
methotrexate [MTX], leflunomide [LEF], minocycline [MIN],
gold, azathioprine [AZA], d-penicillamine) have demonstrated
the ability to slow disease progression; however, d-penicillamine
is seldom used because of a very slow onset of action and numer-
ous toxicities.19,20 These agents, alone or in combination, should
be considered as initial therapy for most patients. The newest
class of DMARDs is the biologic agents (also referred to as anticy-
tokines, biologics, biologic modifiers, or biologic response mod-
ifiers). These agents target the physiological proinflammatory
and joint-damaging effects of inflammatory mediators includ-
ing TNF-α, IL-1, IL-6, T cells, and B cells. This class of bio-
logic DMARDs include the TNF-α inhibitors (infliximab, etan-
ercept, adalimumab, certolizumab pegol [CZP], and golimumab
[GLM]), anti-IL-1 receptor antagonist (anakinra), anti-B cell ther-
apy (rituximab [RXB]), IL-6 receptor antagonist (tocilizumab
[TZB]), and the T-cell modulator (abatacept).
Despite recent advances in RA treatment, MTX remains the
initial treatment of choice for most patients with RA owing to its
strong efficacy and favorable safety profile.8,19,20 TNF-α biologics
are recommended for patients who fail to achieve an adequate
response either with MTX alone or MTX in combination with
other traditional DMARDs, or for patients intolerant to MTX.
RXB, abatacept, and TZB each have novel mechanisms of
action for the treatment of RA. They are recommended for
patients with high levels of disease activity and features of poor
prognosis despite treatment with at least one traditional DMARD
(abatacept) or for patients who have failed treatment with at least
one TNF-alpha inhibitor. Abatacept, RXB, and TZB, however, are
expensive, are associated with serious side effects, and have less
data detailing their long-term effects. As a result, these newer
agents warrant cautious and judicious use.
Corticosteroids are also potent anti-inflammatory agents that
slow the progression of joint damage in RA; however, they
are reserved for brief periods of active disease (low-dose oral
therapy), or for isolated joints experiencing disease flares (local
intraarticular injection) because of serious adverse effects asso-
ciated with long-term systemic use. New modified-release corti-
costeroids target nocturnal increases in inflammatory mediators,
IL-6 and cortisol, demonstrating a reduction in morning stiff-
ness compared with older agents.21 Alkylating cytotoxic drugs,
although effective, are highly toxic and normally reserved for
severe disease uncontrolled by other drug therapies.20
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
Aspirin, an acetylated salicylate, has a long history of established
efficacy and continues to be the standard against which the effec-
tiveness of all other NSAIDs is measured. However, aspirin (par-
ticularly non–enteric-coated versions) is associated with a higher
incidence of gastrointestinal (GI) bleeding than other NSAIDs
and is no longer commonly used for the treatment of RA.20,22
A variety of other NSAIDs are available, including nonacetylated
salicylates (e.g., salsalate, choline salicylate, and magnesium sali-
cylate) and nonsalicylate NSAIDs (e.g., ibuprofen, naproxen, and
cyclo-oxygenase [COX] inhibitors).
Although NSAIDs differ in chemical structure, they generally
have similar pharmacologic properties (e.g., antipyresis, analge-
sia, anti-inflammatory activity, inhibition of prostaglandin syn-
November 19, 2011 2:2
thesis), mechanisms of action (i.e., inhibition of COX activity), 1007
harmful side effects largely attributable to COX inhibition (GI
intolerance, nephrotoxicity, increased risk of bleeding, cardio-
vascular events), and pharmacokinetic properties (e.g., highly
protein bound, extensively metabolized to renally cleared inac-
tive metabolites).20
For a multimedia slide set describing the
cardiovascular risks of COX-2 agents, go to
http://thepoint.lww.com/AT10e.
The nonacetylated salicylates have virtually no effect on COX,
suggesting that they might be associated with less GI and renal
toxicity; however, both the GI and renal toxicities of nonacety-
lated salicylates appear to be no different than those of nonse-
lective NSAIDs.20,23 (Note: For simplicity and clarity, the term
NSAID is used henceforth to describe NSAIDs other than acety-
lated [i.e., aspirin] and nonacetylated salicylates.)
NSAIDs are usually better tolerated than aspirin. Because of
interpatient variability in response to a given NSAID, selection
has traditionally been based on cost, duration of action, and
patient preference. Courses of several different NSAIDs, even
those within the same chemical class, may be necessary to deter-
mine the best choice for an individual patient. The greatest con-
cern of NSAID therapy is the risk of serious GI bleeding, although
cardiovascular (hypertension, heart failure) and renal toxicity are
also important considerations.24
TRADITIONAL DISEASE-MODIFYING
ANTIRHEUMATIC DRUGS
With rare exception, every patient should receive DMARD ther-
apy soon after diagnosis to minimize loss of joint integrity and
function and risk of cardiovascular disease related to RA.19 This
contrasts with previous guidelines,8 which suggested that use of
NSAIDs for up to 3 months may be reasonable for some patients.
Corticosteroid therapy (i.e., injections into isolated joints or low
oral doses for multiple joint involvement) and NSAIDs can be
used initially and intermittently as needed to control symptoms
of pain and swelling. Although DMARDs have the potential to
cause serious toxicity, they can substantially reduce joint inflam-
mation, reduce or prevent joint damage, maintain joint function
and integrity, and ultimately reduce health care costs and allow
patients to remain productive.8,19
The onset of action of most traditional DMARDs is slow
(about 3 to 6 months); however, SSZ, MTX, LEF, and cyclosporine
can be beneficial within 1 to 2 months, and biologic agents can be
beneficial within days to weeks.19,20 Several factors must be con-
sidered when selecting a traditional DMARD, including conve-
nience of administration, monitoring requirements, medication
and monitoring costs, time to therapeutic onset, and frequency
and severity of adverse reactions.
Chapter 44
MTX, a folate antimetabolite with immunosuppressive and
anti-inflammatory properties, remains the most prescribed
DMARD because of its relatively rapid onset of action and an
excellent history of efficacy and safety.19 The primary metabolite
of LEF, A77 1726 (M1), is responsible for nearly all of its pharma-
cologic activity. Although the exact mechanism of M1 is not com-
Rheumatoid Arthritis
pletely understood, it is known that M1 inhibits dihydro-orotate
dehydrogenase, an enzyme in cell mitochondria responsible for
catalyzing an important step in de novo pyrimidine synthesis;
this is believed to be its main mechanism of action.25 LEF has
now established a record of safety and efficacy similar to MTX,
and is recommended along with MTX as first-line therapy for all
levels of RA.19
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1008 HCQ, MIN, or SSZ are recommended for relatively mild cases
of RA.19 The mechanism of anti-inflammatory effect of HCQ
may be attributable to inhibition of migration of neutrophils and
eosinophils, histamine and serotonin blockade, or inhibition of
prostaglandin synthesis.25 MIN appears to improve RA by inhibit-
ing collagenase activity in synovial tissue.26 It may also inhibit
protein synthesis in rapidly proliferating cells or inhibit leukocyte
activity. SSZ appears to induce anti-inflammatory effects through
one of its active metabolites, mesalamine, which is believed to
inhibit both COX and lipoxygenase.25
SELDOM-USED DISEASE-MODIFYING
ANTIRHEUMATIC DRUGS
Several DMARDs were not included in the current treatment
guideline because of infrequent use (e.g., anakinra), high inci-
dence of adverse events (e.g., cyclophosphamide), or being not
considered a reasonable selection for most patients by the expert
committee in light of other available drugs (e.g., AZA, gold,
cyclosporine).19 Injectable gold is a very effective DMARD, but
can be inconvenient and causes numerous intolerable adverse
effects. A follow-up study of patients with early RA who discon-
tinued injectable gold after about 1 year of treatment because of
side effects found that these patients experienced sustained dis-
ease improvement (i.e., remission) for several years thereafter.27
The rate of clinical remission among these patients was similar
to that of patients who continued gold or MTX therapy during a
6-year period. The oral form of gold, auranofin (AUR) is rarely
used because of poor GI tolerance, slow onset of action (up to 6
months), and low efficacy.
Although AZA is effective, it usually is reserved for patients
with severe disease who do not respond to safer alterna-
tives because of potential myelosuppression and hepatotoxicity.
d-Penicillamine is one of the slowest acting DMARDs (e.g.,
doses should be adjusted only once every 3 months).20 It is
seldom used because of a relatively low response rate and is
associated with rare, but serious, autoimmune diseases (e.g.,
systemic lupus erythematous, myasthenia gravis, Goodpasture
syndrome). Cyclosporine is reserved for severe, refractory RA
because of potential toxicity (renal insufficiency and hyperten-
sion), the inconvenience of necessary drug level monitoring, drug
interactions, and cost. Although cyclosporine has been associated
with an increased risk of malignancy in organ transplant patients,
this adverse effect does not seem to be significant in the treatment
of RA.28
The alkylating agents, cyclophosphamide and chlorambucil,
are effective in the treatment of severe progressive RA, but they
also carry the risk of potentially serious toxicity (e.g., malignancy,
infections).20 Thus, their use usually is limited to patients with
progressive RA unresponsive to more conservative management
or, in some cases, potentially life-threatening complications of RA
(e.g., rheumatoid vasculitis).
BIOLOGIC AGENTS
Section 9
Since the late 1990s, a total of nine biologic agents have been
approved for RA treatment. The earliest biologic agents targeted
proinflammatory cytokines such as TNF-α and IL-1, which play
key roles in the immunopathogenesis of RA.29 These cytokines
are abundant in rheumatoid synovial tissues and fluid. Most
Arthritic Disorders
cytokines can independently induce expression of the others,
and IL-1 is capable of upregulating its own expression.30 Exces-
sive macrophage-produced cytokines (e.g., TNF-α, IL-1, IL-6,
IL-8) correlate closely with RA disease activity and severity.
Most importantly, RA improves when the physiological action of
TNF-α or several different ILs are suppressed. In more recent
years, new agents have been developed to target additional key
November 19, 2011 2:2
processes in RA, including T-cell costimulation, the depletion of
CD20+ B cells, and the inhibition of IL-6.20
The proinflammatory cytokine TNF-α is produced by acti-
vated macrophages and T cells in RA-affected joints. It also plays
a role in keeping infections localized by increasing platelet acti-
vation and adhesion, resulting in local blood vessel occlusion and
containment of infection. This action of TNF-α is responsible for
its tumor necrosis properties, thus leading to the name.
TNF-α exerts its physiological effects by binding to two differ-
ent cell-surface receptors known as p55 (i.e., 55 kDa) and p75 (i.e.,
75 kDa) on inflammatory cells.29 These receptors, with portions
extending from within the cell cytoplasm to the cell exterior, are
capable of binding TNF-α to the domains extending above the
cell surface. Soluble forms of these receptors can be found in the
serum and synovial fluid and seem to play a role in regulating
TNF-α.
Two approaches have targeted the action of TNF-α: (a) the
use of soluble TNF receptors with high TNF binding affinity
(e.g., etanercept); and (b) antibodies against TNF-α (e.g., inflix-
imab, adalimumab, GLM, and CZP).20 Etanercept is a recom-
binant TNF-receptor Fc fusion protein with the extracellular
portion of two p75 receptors fused to the Fc portion of human
immunoglobulin (Ig)-G1.30 Infliximab is a chimeric IgG antibody
directed against TNF-α; adalimumab is a genetically engineered
human IgG1 monoclonal antibody. The newest TNF-α inhibitors
are GLM and CZP. CZP is a polyethylene glycolated (PEG) Fab
fragment of a humanized anti-TNF monoclonal antibody; GLM
is a fully human anti-TNF-α IgG1 monoclonal antibody that tar-
gets and neutralizes both soluble and membrane-bound forms
of TNF-α.31,32 All five TNF-α inhibitors render TNF biologi-
cally unavailable and are highly effective in reducing RA dis-
ease activity. There currently is no evidence from well-controlled
comparative trials that any one TNF-α inhibitor is superior to
another with regard to efficacy.33,34 Anti-infliximab antibodies
can develop with the long-term use of infliximab, but these can be
prevented by concomitant immunosuppression with MTX. Etan-
ercept has been shown to have a decreased incidence of reactiva-
tion of latent tuberculosis (TB) when compared with infliximab
and adalimumab.35 Additionally, etanercept has a rapid onset of
action and a short half-life, which helps guard against toxicity.20
Because no superiority of one agent versus another has been
shown, choice of agent is driven by cost, insurance coverage,
provider preference, and patient-specific factors.
In healthy individuals, IL-1 overexpression is prevented by nat-
urally occurring IL-1Ra.29,36 Consequently, inadequate produc-
tion of IL-1Ra, relative to IL-1, is hypothesized to be an important
contributor to active RA. In addition to proinflammatory prop-
erties, IL-1 augments cartilage damage and inhibits bone for-
mation. Although TNF-α seems to be key in RA inflammation
regulation and symptomatology, IL-1 may be largely responsible
for bony erosion and periarticular osteoporosis. Anakinra is a
recombinant form of nonglycosylated human IL-1Ra.20 Anakinra
is approved for the treatment of moderately to severely active RA
in patients who have failed one or more DMARDs. In animal stud-
ies, the combination of IL-1Ra with anti-TNF-α has synergistic
benefits.37 Nevertheless, this combination is not recommended
for use in humans because of a high risk of neutropenia and
subsequent severe infections.38
Both TNF-α and IL-1 serve important physiological func-
tions, including protection against infections.8,29 The incidence
of serious infections in patients receiving biologic agents was
not increased during clinical trials; however, hospitalizations
and deaths secondary to sepsis, TB, atypical mycobacterial
infections, fungal infections, and opportunistic infections have
occurred in patients treated with biologic agents.8,38 The FDA has
issued new warnings regarding the risk of Listeria and Legionella
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infections with TNFa inhibitors. Although these infections
occurred primarily among patients with significant risk factors
for infection (e.g., poorly controlled diabetes, concurrent corti-
costeroid or DMARD therapy), biologic agents should not be
given to patients with active infection, history of recurring infec-
tions, or medical conditions predisposing them to infection.
Increased serum levels of TNF-α seem to be associated with
worsening of heart failure through mechanisms that are not
entirely clear.39 Proposed mechanisms contributing to the onset
or worsening of heart failure include accelerated left ventricu-
lar remodeling, cardiac contractile abnormalities that result in
negative inotropic effects, and increased apoptosis of myocytes
and endothelial cells. However, despite the association between
TNF-α and worsening of heart failure, clinical trials with anti-
TNF therapy (which have included etanercept and infliximab)
have not reduced mortality and heart failure–related hospitaliza-
tions. Furthermore, significantly more deaths have occurred in
infliximab-treated patients with moderate to severe heart failure
than in placebo-treated patients.40 As a result, anti-TNF therapy
is not recommended for RA patients with moderate to severe
(New York Heart Association [NYHA] class III and IV) heart fail-
ure. Anti-TNF therapy can be used with caution in patients with
mild (NYHA class I and II) heart failure, but patients should be
closely monitored for cardiac decompensation.19
Three non-TNF biologic agents available for RA patients who
have not responded to at least one DMARD are abatacept, RXB,
and TZB. Each of these agents possesses a novel mechanism of
action targeting either T cells, B cells, or IL-6.19 Abatacept is
approved as a first-line biologic along with the TNF-α inhibitors,
whereas RXB and TZB are indicated only after the failure of one
or more TNF-α inhibitors.41–43
The first of these agents, approved in 2005, is abatacept.
It is a selective costimulation modulator that inhibits T-cell
activation.41 For T cells to be fully activated, a CD80/CD86:CD28
costimulatory signal is required.44 This costimulation is blocked
by cytotoxic T-lymphocyte–associated antigen 4.45 Abatacept,
a soluble fusion protein consisting of extracellular cytotoxic
T-lymphocyte–associated antigen 4 attached to the Fc portion
of IgG1, inhibits T-cell activation by preventing the binding of
CD80 and CD86 ligands on the surface of APCs to the CD28
receptor on the T cell.44
Safety data reflecting up to 7 years of abatacept therapy indi-
cate that abatacept is generally safe, but associated with signif-
icant adverse effects.46 All infections (54% vs. 48%) and serious
infections (3.0% vs. 1.9%) occurred at a slightly higher rate among
abatacept-treated versus placebo-treated patients, respectively.41
When combined with anti-TNF therapy, these infection rates
are significantly higher. The most common abatacept-associated
serious infections included pneumonia, cellulitis, urinary tract
infection, bronchitis, diverticulitis, and acute pyelonephritis.
Thus far, the overall risk of malignancy seems to be no different
than with placebo; however, several cases of malignancy have
been reported with abatacept when combined with anti-TNF
therapy. Abatacept-treated patients with chronic obstructive
pulmonary disease experienced significantly more pulmonary
and serious adverse effects than placebo-treated patients in one
study.41
RXB has been available since 1997 for the treatment of
B-cell lymphoma.47 RXB, a chimeric (mouse–human) mono-
clonal antibody, binds to the CD20 antigen on the surface of pre-B
cells and mature B cells, resulting in the depletion of B cells from
peripheral blood, lymph nodes, and bone marrow. Stem cells,
pro-B cells, and antibody-producing plasma cells do not express
CD20 and, therefore, are not affected by RXB. The exact role
of B cells in the RA pathogenesis is not known. However, stud-
ies have shown that B cells may contribute to the autoimmune
November 19, 2011 2:2
and inflammatory processes by producing RF, acting as APCs, 1009
activating T cells, and producing proinflammatory cytokines.42
Owing to its chimeric composition, RXB must be administered
with MTX to reduce the risk of human antichimeric antibody
(HACA) formation.48 Inhibition of T-cell activation and deple-
tion of proinflammatory B cells result in significant reductions
in RA-related inflammation and joint destruction.
RXB has a good safety profile overall, but it has several black-
box warnings regarding serious and potentially fatal adverse
effects (e.g., fatal cardiorespiratory infusion reactions that most
commonly occur within 24 hours of the first infusion, tumor lysis
syndrome, severe mucocutaneous reactions, progressive multi-
focal leukoencephalopathy).42 Mild infusion reactions (e.g., fever,
chills, urticaria, headache, rhinitis, bronchospasm, angioedema,
hypotension) occur in about 40% of patients with RA treated with
RXB, especially on administration of the first dose. These infusion
reactions can be minimized by administration of methylpred-
nisolone 100 mg intravenously (IV) 30 minutes before infusion
of RXB. RXB is also associated with a slightly increased risk of seri-
ous infection (e.g., septic arthritis, pneumonia) when compared
with placebo (3% vs. 1%, respectively), including reactivation of
hepatitis B and TB infections.20,42
The newest biologic DMARD approved for the treatment
of RA, TZB, is a humanized anti–IL-6 receptor antibody indi-
cated for patients who have failed at least one TNF-α inhibitor.43
The pleiotropic proinflammatory cytokine, IL-6, is produced by
a variety of cell types including lymphocytes, monocytes, and
fibroblasts and is involved in multiple immunologic processes
including T-cell activation and B-cell proliferation. When bound
to the soluble IL-6 receptor, IL-6 activates chemokine production
and upregulates expression of adhesion molecules. This leads
to the recruitment of leukocytes at inflammatory sites, thus
implicating IL-6 as an important factor in RA.49,50 High levels
of IL-6 have been found in the serum and joints of patients with
RA. Additionally, IL-6 has been shown to induce proliferation of
osteoclasts, which may be a component of the bone degradation
seen in RA.49,50 TZB is a humanized, monoclonal antibody that
can bind to both membranous and soluble IL-6 receptors. This
blockade prevents the interaction of IL-6 with the IL-6 receptor,
thus interrupting the inflammatory pathways that contribute to
the disease processes in RA.50
TZB is generally well tolerated, but is associated with rare
serious adverse effects. It has a black-box warning for increased
risk of developing serious or life-threatening infections.43 TZB
should be discontinued if a patient experiences a serious infec-
tion and may be restarted only after the infection is under control.
Patients should be tested for latent TB before initiation of TZB;
if the TB test is positive, patients should begin anti-TB treat-
ment before initiating TZB. All patients should be monitored for
active TB during therapy, even if the initial latent TB test is neg-
ative. The most common adverse reactions observed with TZB
(≥5% of trial patients) included upper respiratory tract infections,
nasopharyngitis, headache, hypertension, and increased levels of
Chapter 44
the liver enzyme alanine transaminase (ALT).43 TZB is associated
with a number of laboratory changes, including neutropenia,
thrombocytopenia, increased liver enzymes, and lipid abnormal-
ities. Patients should be monitored for laboratory changes, and
therapy should be adjusted accordingly. An increased rate of GI
perforation in high-risk patients (e.g., patients with history of
Rheumatoid Arthritis
diverticulitis) has also been reported with TZB therapy.43
CORTICOSTEROIDS
Corticosteroids have been used to treat RA for more than 60
years owing to their potent anti-inflammatory and immuno-
suppressive effects. Corticosteroids administered orally at low
dosages (i.e., the equivalent of 10 mg of daily prednisone or less)
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1010 or through local injections are effective in rapidly reducing dis-
ease activity and relieving RA symptoms. Corticosteroids are
particularly beneficial when patients are awaiting the onset of
DMARD action (known as “bridge therapy”) or during flares
of active RA involving a small number of joints.8,51 Oral cortico-
steroids seem to slow the rate of disease progression and have been
shown to reduce radiographic changes for 1 to 2 years.11,51,52 Use
of corticosteroids in combination with DMARD therapy appears
to improve clinical outcomes (signs and symptoms, functional-
ity, radiological damage) for patients with RA above the benefit
of a DMARD used alone.51,52 Long-term use of corticos-
teroids, however, is associated with many serious adverse effects
(e.g., osteoporosis, weight gain, diabetes, cataract formation,
adrenal suppression, hypertension, infections, impaired wound
healing).53 As a result, oral corticosteroid dosing should be lim-
ited to daily doses of 7.5 to 10 mg of prednisone (or equivalent)
and should be administered for as short a time as possible. Fre-
quent corticosteroid injections for an extended period have the
potential to accelerate bone and cartilage deterioration; there-
fore, the same joint should not be injected more than once every
3 months.53
produce the same gastroprotective effect as prostaglandins.55 The
newest class, dual-inhibitor NSAIDs that block both enzymatic
pathways of arachidonic acid metabolism (i.e., both COX and
5-lipoxygenase), further broadens the pharmacologic effects of
currently available NSAIDs. Although COX inhibition is clearly
associated with GI toxicity, inhibition of both enzymatic path-
ways of arachidonic acid metabolism has GI-sparing effects in
animal and initial human safety studies.56,57
Vaccine therapy has been studied for RA prevention. The
RA vaccine induces a specific immune response against T cells
that are reactive to joint antigens.58 Studies are ongoing; only
phase II studies have been completed. In a double-blind, placebo-
controlled phase II study of a T-cell receptor peptide vaccine in 99
patients with active RA, doses of 90 or 300 mcg were administered
at baseline and at 4, 8, and 20 weeks. At 20-week follow-up, sig-
nificantly more patients receiving the 90-mcg vaccine dose expe-
rienced improvement in RA signs and symptoms.59 Although
both vaccine dosage groups did not improve significantly when
compared with placebo, a trend toward improvement was noted
and no patients withdrew because of treatment-related adverse
effects.

OTHER THERAPIES CLINICAL USE OF DISEASE-MODIFYING

Although not US Food and Drug Administration (FDA) approved
for RA, monotherapy with the antibiotic MIN is recommended
for patients with mild disease, i.e., those with no poor prognostic
features along with low disease activity and limited duration of
disease.19 The mechanism of MIN action in RA is unknown, but
may be attributable to the inhibition of synovial tissue collagenase
activity, inhibition of protein synthesis in rapidly dividing cells, or
leukocyte activity interference. MIN is relatively safe, although
it is not recommended for use in young children and during
pregnancy and nursing, and has been associated with rare cases
of lupuslike symptoms.25
Two new classes of NSAIDs in development may provide GI
protection without COX-2 specificity.54 The first class, nitric oxide
NSAIDs, also known as COX-inhibiting nitric oxide donors, are
standard NSAIDs structurally linked to a nitric oxide moiety. By
donating nitric oxide to the gastric mucosa, nitric oxide NSAIDs
ANTIRHEUMATIC DRUGS
Traditional DMARDs (e.g., gold, penicillamine, antimalarials,
AZA, SSZ, MTX) are effective in attenuating clinical and labo-
ratory manifestations of RA. The ACR has developed evidence-
based recommendations for the use of traditional and biologic
DMARDs in RA19 (Tables 44-4, 44-5). The initial DMARDs of
choice for monotherapy are MTX or LEF. They are recom-
mended for all levels of RA severity and duration because of
relatively rapid onset, high rate of response, mild side effect pro-
file, relatively low cost, and long sustained efficacy. Furthermore,
MTX therapy is associated with a reduction in cardiovascular
morbidity and mortality in patients with RA, which is important
because of the strong association between RA and cardiovascular
disease.15,60
Monotherapy with HCQ or MIN is recommended for patients
with low RA disease activity, no features of poor prognosis, and

TA B L E 4 4 - 4
Selection Recommendations for Nonbiologic Disease-Modifying Antirheumatic Drugs

Poor Prognosis Disease MTX + MTX + MTX + SSZ + MTX +

Features?a Duration (months) MTX LEF SSZ HCQ MIN HCQ LEF SSZ HCQ SSZ + HCQ

Low Disease Activity (See Table 44-5)

Yes <6 X X X
6–24 X X X X
>24 X X X X X X
No <6 X X X X X
6–24 X X X X
>24 X X X X
Section 9

Moderate or High Disease Activity (See Table 44-5)

Yes <6 X X X X X
6–24 X X X X X X X
>24 X X X X X X
No <6 X X X X
Arthritic Disorders

6–24 X X X X X X X X
>24 X X X X X X X

a
Indicators of poor rheumatoid arthritis prognosis include functional limitation using standard measurement scales (e.g., Health Assessment Questionnaire score),
extra-articular manifestations (e.g., rheumatoid nodules, vasculitis, rheumatoid arthritis–related lung disease), positive rheumatoid factor, positive anti–cyclic citrullinated
peptide antibodies, radiographic evidence of bone erosions.
HCQ, hydroxychloroquine; LEF, leflunomide; MIN, minocycline; MTX, methotrexate; SSZ, sulfasalazine.
Source: Saag KG et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in
rheumatoid arthritis. Arthritis Rheum. 2008;59:762.
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TA B L E 4 4 - 5
Selection Recommendations for Biologic Disease-Modifying Antirheumatic Drugs
Biologic DMARDs Disease Durationa Disease Activityb
TNF-α inhibitors Early High
Intermediate/Long Moderate
Intermediate/Long High
Intermediate/Long Moderate/High
Abatacept Not specified Moderate/High
Rituximab Not specified High
Biologic Not recommended in any patients based on data indicating increased risk of adverse events or lack of additive efficacy
combination
a
Disease duration: early, <6 months; intermediate, 6–24 months; long, >24 months.
b
Disease activity: low, moderate, high.
c
Poor prognostic factors: (+) poor prognostic factors present, (–) without poor prognostic factors, (+/–) recommendation independent of prognostic factors.
DMARD, disease-modifying antirheumatic drug; MTX, methotrexate.
Source: Saag KG et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in
rheumatoid arthritis. Arthritis Rheum. 2008;59:762.
disease duration less than 24 months for HCQ and less than
6 months for MIN. Of note, the successful use of MIN seems to
support a speculation that RA might have an infectious etiology;
however, it is the immunomodulatory and anti-inflammatory
effects of MIN that more likely contribute to its efficacy in RA
than its antibiotic properties. The use of SSZ monotherapy is
recommended for all patients with low disease activity regardless
of prognosis or disease duration, and is recommended either
alone or in combination with other DMARDs for all patients
with moderate and high levels of disease activity regardless of
prognosis or disease duration.
The combination of MTX and HCQ is recommended for
patients with moderate to high disease activity regardless of
prognosis or disease duration, as well as patients with low dis-
ease activity and disease duration greater than 24 months. MTX
plus LEF is recommended for patients with high disease activ-
ity regardless of prognosis, but disease duration should be 6
months or longer. MTX plus SSZ is recommended for patients
with poor prognosis and all disease durations. HCQ plus SSZ
is recommended for only one circumstance: patients with high
disease activity, no features of poor prognosis, and disease dura-
tion between 6 and 24 months. The triple combination of MTZ,
HCQ, and SSZ is recommended for all patients with moderate
to high disease activity levels and poor prognosis, regardless of
disease duration.
According to the ACR guidelines, in early RA (duration less
than 6 months) anti TNF-α agents may be used with MTX in
patients who have never received previous DMARD therapy and
who have both high disease activity for less than 3 months and
poor prognostic features. Barriers related to cost, insurance cov-
erage, and administration must be considered. In intermediate-
or long-duration (≥6 months) RA, anti-TNF-α agents are rec-
ommended for patients who have experienced an inadequate
response to MTX and have moderate disease activity and features
of poor prognosis. Additionally, anti-TNF-α agents are recom-
mended for patients who have failed MTX monotherapy and have
high disease activity, irrespective of prognostic features. These
agents are also recommended for patients with a minimum of
intermediate duration and moderate activity for whom MTX in
combination with a nonbiologic DMARD or sequential adminis-
tration of nonbiologic DMARDs led to an inadequate response.
Abatacept and RXB are recommended for patients with a min-
imum of moderate disease activity (high activity for RXB) and
poor prognostic features for whom MTX in combination with
November 19, 2011 2:2
1011
Poor Prognostic Factorsc Previous or Concurrent Therapies
+ With MTX
+ Must have failed MTX monotherapy
+/– Must have failed MTX monotherapy
+/– Must have failed MTX + nonbiologic
DMARD
+ Must have failed MTX + nonbiologic
DMARD
+ Must have failed MTX + nonbiologic
DMARD
a nonbiologic DMARD or sequential administration of nonbio-
logic DMARDs led to an inadequate response.20
However, it should be noted that subsequent to publication of
these guidelines, a meta-analysis of 70 controlled trials involving
nonbiologic and biologic DMARDs, glucocorticoids, and com-
binations of these therapies concluded that all treatments signif-
icantly reduced 1-year radiographic progression, with no signifi-
cant differences among treatments.61 It was found that the effects
of the combination of two DMARDs plus step-down glucocor-
ticoids did not differ significantly from the effects of a biologic
agent plus MTX (mean difference, –0.07%; p = 0.44). This meta-
analysis suggests that nonbiologic DMARDs should remain the
initial DMARD of choice for most patients, particularly if cost
is a concern, and biologic agents should be reserved for patients
who demonstrate a poor response or intolerance to nonbiologic
DMARDs.20 Although comparisons between biologic agents and
traditional DMARDs have rarely been performed, the authors
noted that one study comparing a biologic agent plus MTX with
a combination of two DMARDs and initial glucocorticoid ther-
apy found no difference in radiographic progression.62
In a comprehensive review of the literature, the Agency for
Healthcare Research and Quality (AHRQ) compared the efficacy
and adverse effects of various traditional and biologic DMARDs,
including monotherapies and combination therapies.63 The effi-
cacy of traditional DMARDs (MTX, SSZ, LEF) was deemed
similar. Although MTX is the preferred first-line DMARD, SSZ
or LEF are reasonable options for patients who are unable to
tolerate MTX. All of the anti-TNF biologics reviewed (etan-
ercept, infliximab, adalimumab) seem to have similar efficacy.
Although the IL-1Ra, anakinra, might be less efficacious than
Chapter 44
anti-TNF therapies, this preliminary assessment was based
only on adjusted indirect comparisons. In comparative trials of
monotherapies of traditional DMARDs and biologic DMARDs,
adalimumab and etanercept monotherapies were equal in effi-
cacy to MTX monotherapy; however, the AHRQ report deter-
mined that biologic DMARDs performed significantly better
Rheumatoid Arthritis
than MTX-based therapies on radiographic outcomes. Although
this appears to be an important difference, the relationship
between radiographic differences in clinical trials and long-
term disease progression has not been clearly established. Both
etanercept and adalimumab improved functional capacity more
than MTX.
The combination of MTX, SSZ, and HCQ is more effective
than any one or two of these therapies for up to 2 years. This triple
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1012
TA B L E 4 4 - 6
Biologic Disease-Modifying Antirheumatic Drug Dosing Information

Mechanism of Administration Routes of Can Be Self-

Generic (Brand) Action Dosage Range Schedule Administration Administered?

Infliximab (Remicade) TNF-α inhibitor 3 mg/kga Weeks 0, 2, and 6 and IV No

then every 8 weeks
Etanercept (Enbrel) TNF-α inhibitor 25 mg twice weekly or 1–2 doses/wk SC Yes
50 mg once weekly
Adalimumab (Humira) TNF-α inhibitor 40 mg Every 14 days SC Yes
Certolizumab pegol TNF-α inhibitor Initial: 400 mg SC × 1 on Weeks 0, 2, and 4, then SC Yes
(Cimzia) weeks 0, 2, 4; every 2 or 4 weeks
Subsequent: 200 mg every
2 weeks or 400 mg
every 4 weeks
Golimumab (Simponi) TNF-α inhibitor 50 mg/0.5 mL Every 4 weeks SC Yes
Abatacept (Orencia) Costimulation Weight based: Weeks 0, 2, and 4 and IV No
modulator, T-cell <60 kg = 500 mg then every 4 weeks
activation inhibitor 60–100 kg = 750 mg
>100 kg = 1,000 mg
Rituximab (Rituxan) CD20+ B-cell inhibitor 1,000 mg IV infusion: Repeat in 14 days, then IV No
Initial: 50 mg/h, may discontinue
increase every 30
minutes to a max rate
400 mg/h
Subsequent: 100 mg/h,
may increase every 30
minutes to max rate
400 mg/hb
Tocilizumab IL-6 inhibitor Initial: 4 mg/kg every Every 4 weeks IV No
(Actemra) 4 weeks
Subsequent: Titrate to 8
mg/kg based on clinical
response Max: 800
mg/dose (8 mg/kg)
Anakinra (Kineret) IL-1 inhibitor 100 mg Once daily SC Yes

a
For incomplete response, may increase dose to 10 mg/kg or decrease dosing interval to every 4 weeks.
b
Max: total of two doses, safety data unknown past two doses. Premedicate with corticosteroid, acetaminophen, and an antihistamine before each dose.
IL, interleukin; IV, intravenous; SC, subcutaneous; TNF, tumor necrosis factor.
Source: Clinical Pharmacology Online. Elsevier Ltd; 2011. http://www.clinicalpharmacology.com. Accessed January 2, 2011.

combination has not been compared with biologic DMARDs.
Combinations of two biologic DMARDs do not show addi-
tional benefit versus biologic DMARD monotherapy, and serious
adverse effects (e.g., cellulitis, pneumonia, herpes zoster, pneu-
monitis, pyelonephritis) are increased significantly by combining
two biologic DMARDs.64 Corticosteroid therapy combined with
traditional DMARDs significantly improves functional capacity
and radiographic outcomes when compared with traditional
DMARD monotherapy, thereby reemphasizing the ability of cor-
ticosteroid therapy to modify disease.54,55 Corticosteroid ther-
apy, however, should be limited to intermittent periods of use
to manage disease flares or exacerbations because of significant
adverse effects associated with long-term therapy.56
A 2009 Cochrane review analyzed the use of biologics in the
Section 9
the other agents (9%).65 The routes of administration, dosing fre-
quencies, and propensity for infusion reactions of biologic agents
are listed in Table 44-6.
QUANTIFYING RESPONSE TO DRUG THERAPY
Drug therapy for RA, historically, has been evaluated subjec-
tively by assessing patient self-reported changes in disease activity.
The subjectivity of patient self-reporting of RA activity is being
replaced increasingly by more objective and comprehensive mea-
sures of disease control (e.g., laboratory test results, radiographic
changes). This shift has been prompted by the fact that better dis-
ease remission rates have been reported in DMARD clinical trials
than from observational studies.66 The use of validated clinical
assessment tools should yield a more accurate assessment of

treatment of RA in response to the lack of head-to-head studies
available for these relatively new agents. This review analyzed
data for abatacept, adalimumab, anakinra, etanercept, infliximab,
and RXB. It did not include the three newest agents GLM, CZP,
and TZB. The review showed that abatacept, adalimumab, etan-
Arthritic Disorders
disease activity and improve the likelihood of attaining disease
remission through modifications of drug therapy.19,67
Successful integration of objective clinical measurements into
a standard of practice requires that the measurement tools used
are validated, can be quickly administered, and are simple to

ercept, infliximab, and RXB demonstrated efficacy in improv-
ing the signs of RA, such as the number of tender or swollen
joints, pain, and disability. These agents demonstrated compara-
ble 50% improvement in ACR criteria (ACR-50) responses (22%–
36% improvement versus placebo). Anakinra also demonstrated
an improved ACR-50 response when compared with placebo,
but with a decreased percentage improvement compared with
use. Until recently, most large RA treatment trials used ACR
standards to quantify response to therapy, such as ACR-20, which
refers to a 20% reduction in tender and swollen joint counts and
20% improvement in at least three of the following: patient’s
assessment of pain, patient’s global assessment, physician’s global
assessment, patient’s assessment of disability, and acute-phase
reactant measures (i.e., erythrocyte sedimentation rate [ESR] or
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TA B L E 4 4 - 7
Tools Used to Measure Disease Activity in Rheumatoid Arthritisa

Thresholds of Disease Activity

Measurement Tool Score Range Low Moderate High

Disease Activity Score in 28 joints 0–9.4 ≤3.2 >3.2 and ≤5.1 >5.1
Simplified Disease Activity Index 0.1–86.0 ≤11 >11 and ≤26 >26
Clinical Disease Activity Index 0–76.0 ≤10 >10 and ≤22 >22
Rheumatoid Arthritis Disease Activity Index 0–10 ≤2.2 >2.2 and ≤4.9 >4.9
Patient Activity Scale (PAS) or PASII 0–10 ≤1.9 >1.9 and ≤5.3 >5.3
Routine Assessment Patient Index Data 0–30 ≤6 >6 and ≤12 >12

a
Tools incorporate multiple variables such as number of swollen joints and tender joints, erythrocyte sedimentation rate, and measures of general health or global disease
activity.
Source: Saag KG et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in
rheumatoid arthritis. Arthritis Rheum. 2008;59:762.

C-reactive protein [CRP]). Other common thresholds used to
evaluate response to therapy include ACR-50 and ACR-70, and
attempts are being made to improve ACR-20 standards for clinical
trials.68 ACR evaluation reflects a minimum 6-week period of
evaluation and, consequently, is of limited use in clinical practice
because clinicians modify therapy based on an evaluation at a
particular moment in time.
Various tools now exist to help clinicians more objectively
evaluate disease activity and track disease progression (Table
44-7). Although no single tool has yet been adopted as a standard
of practice, RA disease activity measurement tools are becoming
simpler to use in clinical settings and provide a more compre-
hensive assessment of disease status. The DAS and DAS28 (cor-
responding to a 44- and 28-joint count, respectively) are relatively
newer tools developed in the 1990s to evaluate response to RA
drug therapy (http://www.nras.org.uk/about rheumatoid
arthritis/established disease/disease activity score das/
default.aspx).69,70 Although summation of the overall DAS
score requires a complex mathematical calculation, there are
online tools available to assist with its computation.71 The
Clinical Disease Activity Index (CDAI) and the Simplified
Disease Activity Index (SDAI) scores are very similar in that
they are determined through a simple sum of swollen joint
count, tender joint count, and patient global disease activity
and evaluator global disease activity (both measured by a visual
analog scale).72 The SDAI includes CRP in the summation,
whereas the CDAI does not. The Global Arthritis Scale uses a
summation of tender joint count, modified Health Assessment
Questionnaire (HAQ), and patient self-assessment of pain and
function levels. The Routine Assessment of Patient Index Data
measurement tool includes assessments of pain and function
levels along with patient global assessment of disease activity.73
More recently, the Easy Rheumatoid Activity Measure,71,72 a
summation of patient and clinician global disease activity using
a visual analog scale with swollen joint counts from 28 joints,
The scoring tools listed above should not be relied on as
the only means for making RA therapy decisions; radiographic
changes also should be considered when managing RA treat-
ments. Radiographic changes, the tracking of which can help clin-
icians objectively evaluate arthritis-related joint damage, occur
in more than half of patients categorized as in remission based
on their DAS score.74 Conventional radiography was previously
considered the gold standard, but imaging via computed tomog-
raphy, ultrasound, and magnetic resonance imaging is now avail-
able and may offer some benefit in improved resolution compared
with standard radiograph technology.75
EARLY AND PROGRESSIVE
RHEUMATOID ARTHRITIS
CASE 44-1
QUESTION 1: T.W., a previously healthy 42-year-old, 60-kg
woman, has been suffering from morning stiffness that per-
sists for several hours, fatigue, and generalized muscle and
joint pain for the past 4 months. In addition, she reports
that her eyes seem red most of the time and are unusually
dry. Her symptoms have been much worse during the past
month and a half, causing her to limit her physical activi-
ties somewhat. She also can no longer wear her wedding
ring because of swelling of her hand. Physical examination
reveals bilaterally symmetrical swelling, tenderness, and
warmth of the metacarpophalangeal (MCP) and proximal
interphalangeal (PIP) joints of the hands and the metatar-
sophalangeal (MTP) joints of the feet. Pertinent laboratory
findings include the following:
ESR, 52 mm/hour
Hemoglobin, 10.6 g/dL
Chapter 44

demonstrated a high level of correlation with DAS28, CDAI, Hematocrit, 33%

and SDAI. It is important to note that all of these tools have Platelets, 480,000/µL
distinctly defined threshold scores corresponding to high disease Albumin, 3.8 g/dL
activity, low-moderate disease activity, low disease activity, and Serum iron, 40 mcg/dL
remission, and that there is little agreement among the tools in Total iron-binding capacity, 275 mg/dL
terms of classifying a patient’s RA activity level. Positive anti-CCP at 82 units
Positive RF performed by latex fixation method in a dilu-
Rheumatoid Arthritis

Together with the EULAR, the ACR recently published an

updated list of RA classification criteria for patients presenting
with new-onset RA symptoms (Table 44-1).2 It quantifies disease
activity with scores provided for level of joint involvement, serol-
ogy markers, acute-phase reactants (CRP and ESR), and duration
of symptoms. A score of 6 or greater is suggestive of an RA diag-
nosis.
tion of 1:320
Tests for antinuclear antibodies (ANA) and tuberculin
sensitivity are negative. Her uric acid level is normal. Radio-
graphic films of the hands and feet show soft tissue swelling,
narrowing of joint spaces, and marginal erosions of the
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1014
second and third MCP and PIP joints bilaterally with no evi-
dence of calcification. Other routine laboratory data and
physical findings are normal. What signs and symptoms of
RA are manifested by T.W.?

The presentation of RA at onset can vary, but characteristi-

cally 50% to 70% of cases have a rather insidious onset of disease
over the course of weeks to months.7,70 Early nonspecific symp-
toms such as fatigue, malaise, diffuse musculoskeletal pain, and
morning stiffness may precede more specific symptoms. Fatigue
and morning stiffness are prominent features of RA in T.W. About
half of patients initially experience fatigue that later in the disease
serves as a useful index of disease activity. Patients usually expe-
rience prolonged morning stiffness on awakening, which usually
lasts 30 to 60 minutes but can be present all day with decreasing FIGURE 44-4 Ulnar deviation and metacarpophalangeal synovitis
intensity after arising. Duration of morning stiffness also can be (left). This may progress to more marked lateral deviation with
a useful marker of disease activity. subluxation of the extensor tendons (right finger; right).
With time, nonspecific musculoskeletal pain localizes to the
joints bilaterally. Bilaterally symmetrical joint swelling and pain,
involving the MCP and PIP joints of the hands and MTP joints
decreased range of motion (ROM), and sometimes muscle atro-
of the feet, as illustrated by T.W., are characteristic of RA. The
phy around affected joints. Progressive disease is characterized
peripheral joints of the hands, wrists, and feet usually are involved
by irreversible joint deformities such as ulnar deviation of the fin-
first. Although MCP and PIP joints of the hands often are affected,
gers (Fig. 44-4), boutonniere deformities (hyperextension of the
the distal interphalangeal (DIP) joints usually are spared. Ulti-
DIP joint and flexion of the PIP joint), or swan neck deformities
mately, any or all of the diarthrodial joints (elbows, knees, shoul-
(hyperextension of the PIP joint and flexion of the DIP joint; Fig.
ders, ankles, hips, temporomandibular joints, sternoclavicular
44-5). Similar irreversible deformities also can involve the feet.
joints, glenohumeral joints) can be involved (Fig. 44-3). Joint
RA is a systemic disease, which is reflected by the extra-
involvement is characterized by soft tissue swelling and warmth,
articular manifestations that can accompany joint involvement.
Organ system involvement may be extensive. Pleuropulmonary
manifestations (e.g., pleuritis, development of pulmonary nod-
ules, interstitial fibrosis, pneumonitis, and rarely arteritis of
the pulmonary vasculature) also can accompany the articular
Temporomandibular 30% involvement of RA.7 Cardiac involvement can present as peri-
Cervical spine 40% carditis or myocarditis. Vasculitis, another extra-articular mani-
Cricoarytenoid 10% festation of RA, can involve any organ system and can vary in
Acromioclavicular 50%
seriousness from mild to potentially life-threatening.
Some extra-articular manifestations occur as syndromes.
Shoulder 60%
Sjögren syndrome includes dry eyes (keratoconjunctivitis sicca),
Sternoclavicular 30%
dry mouth (xerostomia), and connective tissue disease.76 T.W.’s
eye complaints may be an extra-articular manifestation of
her RA. Felty syndrome is characterized by chronic arthritis,
Elbow 50% splenomegaly, and neutropenia; thrombocytopenia, anemia, and
lymphadenopathy also may be present.
Hip 50%

Wrist 80% MCP

(“knuckle”) PIP DIP
MCPs, PIPs 90%

Normal finger

Knee 80%
Section 9

Swan neck deformity

(PIP hyperextension,
DIP hyperflexion)
Arthritic Disorders

Boutonniere deformity
Ankle, Subtalar 80%
(PIP hyperflexion, DIP
MTPs 90% hyperextension)

FIGURE 44-3 Frequency of involvement of different joint sites in

established rheumatoid arthritis. MCPs, metacarpophalangeal FIGURE 44-5 Characteristic finger deformities in rheumatoid
joints; MTPs, metatarsophalangeal joints; PIPs, proximal arthritis. DIP, distal interphalangeal joint; MCP,
interphalangeal joints. metacarpophalangeal joint; PIP, proximal interphalangeal joint.
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LWBK915-44 LWW-KodaKimble-educational
More than 200 images of clinical manifestations from RA
patients can be found at an ACR website. Go to http://images.
rheumatology.org/search.php?searchField=ALL&searchst
ring=rheumatoid for a multimedia selection of photographs
cataloging joint deformities, extra-articular manifestations, and
radiographic changes. For instructions on how to perform a
basic musculoskeletal examination, go to http://meded.ucsd.
edu/clinicalmed/joints.htm and scroll to select either knee,
shoulder, hand, hip, or lower back examinations.
CASE 44-1, QUESTION 2: Which laboratory values in T.W.
could be used to monitor her RA disease progression?
The laboratory findings in RA are characteristic of a chronic
systemic inflammatory disease. No test is specific for RA; T.W.’s
elevated ESR is an indistinct indication of inflammation. CRP
plasma concentrations, which correlate with RA disease activity
better than ESR, can be tested instead.76 Unfortunately, CRP, a
plasma protein of the acute-phase response, is also not disease-
specific. T.W.’s hematologic findings are consistent with a mild
anemia of chronic inflammation. Although her serum iron con-
centration is decreased, her normal iron-binding capacity makes
a diagnosis of iron deficiency anemia unlikely. Her anemia prob-
ably results from a failure of iron release from the reticuloen-
dothelial tissues and would not be expected to respond to iron
therapy. The mild thrombocytosis is additional evidence of a sys-
temic inflammatory response. The laboratory manifestations of
inflammation should improve with effective drug therapy and,
along with many of the clinical features of RA, are useful param-
eters for monitoring disease activity and response to therapy
(Table 44-7).
RF, an autoantibody (usually IgM or IgG) that reacts with the
Fc portion of antigenic IgG to form an immune complex in vitro,
is in the serum of approximately 75% of patients with RA, but
cannot be used in isolation to establish the diagnosis of RA.76 It
can be present in 3% to 5% of healthy individuals, and also in
patients with diseases other than RA, including almost any condi-
tion associated either with immune complex formation or with
hypergammaglobulinemia (e.g., chronic infections, lymphopro-
liferative and hepatic diseases, systemic forms of autoimmunity).
An RF titer of at least 1:160 is considered a positive test,77 and
patients with RA typically have titers of at least 1:320. The pres-
ence of RF remains one of the ACR criteria for establishing the
diagnosis of RA.2 Although RF titers do not parallel disease activ-
ity, high titers (greater than 1:512) early in the disease course are
associated with more severe and progressive form of the disease.
In T.W., the test for ANA ruled out systemic lupus erythemato-
sus. The ANA, however, can be positive in 10% to 70% patients
with RA.
Citrulline, a nonstandard amino acid, also is established as
a key component of RA antigenicity. Citrullinated proteins and
anti-CCP antibodies are abundant in inflamed RA synovium.
Anti-CCP antibodies can be detected in 50% to 60% of early RA
patients, and the specificity of anti-CCP is very high at 95% to
98%.78 In a study of 136 patients with a broad range of RA disease
duration (3 months to 30 years), the sensitivity of anti-CCP for
the diagnosis of RA was 63% and the specificity was 89%, versus
85% and 65%, respectively, for RF. Another study found a sensi-
tivity of 55% and a specificity of 97% for RA when both anti-CCP
and RF were positive in the early cases of arthritis. Anti-CCP was
detectable 1.5 to 9 years before the onset of RA (thereby suggest-
ing a possible pathogenic role for these antibodies for RA).79 A
positive anti-CCP also correlates with an increased likelihood of
a more erosive course of RA than either a negative anti-CCP or
a positive RF. In summary, a positive anti-CCP antibody test is
highly specific for RA, is predictive of the development of RA,
and is a marker for an erosive disease course. Studies attempting
November 19, 2011 2:2
to define the optimal manner in which to incorporate anti-CCP 1015
into RA therapy management are currently ongoing.
CASE 44-1, QUESTION 3: What nonpharmacologic therapy
should be included in the management of T.W.’s RA?
Treatment objectives in RA include reduction of joint pain
and inflammation, preservation of joint function, and preven-
tion of deformity. This is best achieved by instructing patients
on proper regular exercise, joint protection, and energy con-
servation, in combination with effective symptom-relieving and
disease-modifying drug therapy.8,76,80 Insufficient literature evi-
dence is available to support the use of spa therapy and ther-
motherapies such as ultrasound, electrotherapies (e.g., transcu-
taneous nerve stimulation, electrostimulation of muscles), and
laser therapy in the treatment of RA. Heat treatments in general
should be avoided during periods of active joint inflammation,
because heat can further exacerbate pain and swelling. Overall,
physical and occupational therapy can provide valuable assis-
tance to patients with compromised activities of daily living, and
thereby, maximize the potential for self-sufficiency.
Passive exercise (e.g., ROM exercises) should be prescribed for
T.W. until the acute inflammation subsides. Passive exercise min-
imizes muscle atrophy and flexion contractures and maintains
joint function without increasing inflammation or radiographic
progression of disease.80 A properly defined exercise program
should be developed with specific exercises on a scheduled basis
that are not harmful to inflamed joints. Examples of ideal exer-
cises include cycling (stationary if outdoor movement is consid-
ered unsafe), water exercises (e.g., swimming, water aerobics),
and walking (assuming weight-bearing joints can tolerate the
patient’s body weight).
Systemic and articular rest (achieved by splinting the affected
joints) can reduce inflammation significantly.76,80 Restful and ade-
quate sleep are important for general health and are particularly
important in a chronic, fatigue-inducing disease such as RA. Pro-
longed rest, however, can induce rapid losses in strength and
endurance. Therefore, RA patients experiencing acute inflam-
mation, such as T.W., should rest often, but daytime rest periods
should be limited to 30 to 60 minutes each. Splinting of joints is
typically prescribed throughout the day and night during periods
of active inflammation, then only at night for several weeks after
cessation of inflammation.
Some orthoses, which are medical devices secured to any part
of a patient’s body designed to support, immobilize, align, correct
or prevent deformity, or improve functioning, can reduce pain
and inflammation or improve joint function in targeted joints
for RA patients.81 For example, wrist and finger or thumb splints
can reduce wrist and hand pain while improving grip strength;
however, these can worsen dexterity. Finger splints for patients
with swan neck deformities have been shown to improve hand
function and finger stability. Special shoes and sole inserts also
can reduce pain and disability.
Chapter 44
Emotional support should be provided to all patients such as
T.W. A patient’s reaction to RA can be affected by age, personality,
and the environment at work and at home. As with all chronic
debilitating diseases, the potential loss of independence, loss of
self-esteem, altered interpersonal relationships with friends and
family, and potential loss of employment can result in a twofold to
Rheumatoid Arthritis
threefold increase in depression.82,83 Depending on each patient’s
needs, the expertise of different health care disciplines (e.g., physi-
cal therapists, occupational therapists, social workers, health edu-
cators, psychiatrists, clinical psychologists, podiatrists, vocational
rehabilitation therapists, pharmacists) should be consulted. For
example, pharmacists in capitated outpatient clinical practices
can monitor RA drug therapy for therapeutic and adverse effects
under collaborative practice agreements with other practitioners
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1016 and can counsel patients on proper medication use and clarify
expectations.84
Pharmacologic Treatment
NONSTEROIDAL ANTI-INFLAMMATORY
DRUG THERAPY
CASE 44-1, QUESTION 4: T.W. will be treated with a DMARD
and concurrent NSAID therapy initially to rapidly control
inflammation and swelling. What is the role of NSAIDs in the
treatment of T.W.’s RA and which is the NSAID of choice?
T.W.s clinical presentation clearly warrants DMARD therapy
(see Case 44-5, Question 4, and Clinical Use of Disease-Modifying
Agents section; Fig. 44-6). The purpose of NSAID therapy, which
has no disease-modifying activity, is to provide rapid pain relief
and reduction of joint inflammation.
In general, there is no NSAID of choice for treatment of
RA.8,20,76 There is no significant difference among the NSAIDs
in efficacy, and it is difficult to predict a given patient’s response
to a particular agent. The selection of an NSAID is based pri-
marily on patient preference, convenience, cost, and safety.20 A
1- to 2-week trial of any NSAID (Table 44-8) at a moderate to
high dose on a scheduled basis (i.e., not as needed) is the best
method of determining anti-inflammatory efficacy. The analgesic
and antipyretic effects are relatively prompt in onset. Although
aspirin is effective, the nonaspirin NSAIDs usually are preferred.20
Nonacetylated salicylates are weak inhibitors of COX in vitro and
have less GI toxicity than aspirin, but the risks of GI and renal
toxicity are similar to nonselective NSAIDs.20,23
The nonsalicylate NSAIDs have important differentiating
properties.76 For example, indomethacin penetrates the blood–
brain barrier better than any other NSAID, achieving levels
in the cerebrospinal fluid of up to 50% of serum levels. As a
result, the incidence of central nervous system side effects of
indomethacin such as dizziness often precludes the use of opti-
mal anti-inflammatory doses, particularly in the elderly.85 Pirox-
icam, a longer acting NSAID, has been associated with a higher
frequency of peptic ulcer disease and GI bleeding and, there-
fore, should be avoided.86 An AHRQ report identified several
NSAIDs, including celecoxib and high doses of either ibupro-
fen or diclofenac, that seem to increase the risk of MI, whereas
naproxen seems to have the best cardiovascular safety.24 The rel-
ative safety of naproxen was supported by a systematic review,
which further concluded that risk of thrombosis is greatest with
diclofenac, meloxicam, and indomethacin, and slightly increased
with ibuprofen and piroxicam.87 The relative GI safety of partially
COX-2–selective NSAIDs (e.g., nabumetone, etodolac, meloxi-
cam) versus nonselective NSAIDs is unclear. The only remain-
ing COX-2–specific inhibitor that is available in the United
States, celecoxib, has no effect on COX-1, yet the GI protec-
tive effect of celecoxib is not well understood (see Case 44-1,
Question 5).
Although aspirin is an effective anti-inflammatory agent, it is
seldom used today because of well-documented GI toxicity and
the availability of safer and more convenient NSAIDs.20 Aspirin is
inexpensive, and serum salicylate levels correlate well with both
efficacy and toxicity.76 Anti-inflammatory effects of aspirin can be
achieved with dosages sufficient to provide serum salicylate con-
centrations of 15 to 30 mg/dL. Typically, 5 to 7 days of therapy are
needed before steady-state serum concentrations of salicylate are

Initial Therapy
• Treatment of choice: DMARD (within 3 months of diagnosis)
- Severe RA: Usually MTX or combination of traditional DMARDs including MTX
- Mild RA: Usually hydroxychloroquine or sulfasalazine
• Treatment considerations: NSAID, local corticosteroid injections (few joints),
low-dose systemic steroid (multiple joints)
• Nondrug interventions: Patient education, physical therapy, occupational therapy

Satisfactory response to treatment Reassess RA

disease activity
periodically
No Yes

Modify DMARD Therapy*

• Substitute with or add MTX (if not already prescribed)
Section 9

• Substitute with alternative DMARD

• Combination treatment with traditional DMARDs
• Biological agent ± MTX (usually if MTX failure)

RA ! rheumatoid arthritis; DMARD ! disease-modifying antirheumatic drug; MTX ! methotrexate;

Arthritic Disorders

NSAID ! nonsteroidal anti-inflammatory drug

*Consider local corticosteroid injection(s) or low-dose systemic steroids if appropriate

FIGURE 44-6 Overview of rheumatoid arthritis (RA) drug therapy from the American College of
Rheumatology 2002 guidelines. DMARD, disease-modifying antirheumatic drug; MTX, methotrexate;
NSAID, nonsteroidal anti-inflammatory drug. (Source: American College of Rheumatology Subcommittee on
Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update.
Arthritis Rheum. 2002;46:328.)
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1017
TA B L E 4 4 - 8
Some Nonsteroidal Anti-Inflammatory Drugs

NSAID Generic Name Usual Dosing Maximum Daily

(Brand Name) Product Availability Interval Dose (mg)

Salicylates (acetylated and nonacetylated)a

Aspirin, enteric-coatedb Tablets: 325 mg; 325, 500, 800, 975 mg SR QID 4,000
Salsalate (Disalcid)b Tablets: 500, 750 mg BID–TID 4,800
Magnesium choline salicylate (Trilisate)b Tablets: 500, 750, 1,000 mg
Liquid: 500 mg/5 mL Daily–TID 4,800
Propionic Acid Derivatives

Fenoprofen (Nalfon)b Capsules: 200, 300 mg TID–QID 3,200

Flurbiprofen (Ansaid)b Tablets: 50, 100 mg BID–QID 300
Ibuprofen (Motrin)b Tablets: 200, 400, 600, 800 mg
Suspension: 100 mg/5 mL TID–QID 3,200
Naproxen (Naprosyn)b Tablets: 250, 375, 500 mg; 375, 500 mg SR
Suspension: 125 mg/5 mL BID 1,500
Naproxen sodium (Anaprox)b Tablets: 275, 550 mg BID 1,375
Oxaprozin (Daypro)b Tablet or capsule: 600 mg Daily 1,800
Acetic Acid Derivatives

Diclofenac (Voltaren XR)b Tablets: 25, 50, 75 mg DR; 100 mg XR BID–TID 200
Etodolac (Lodine, Lodine XL)b Capsules: 200, 300 mg
Tablets: 400, 500 mg; 400, 500, 600 mg XL BID–TID 1,200
XL: Daily XL: 1,000
Indomethacin (Indocin, Indocin SR)b Capsules: 25, 50 mg; 75 mg SR
Suppository: 50 mg
Suspension: 25 mg/5 mL TID–QID 200
SR: Daily–BID SR: 150
Ketorolac (Toradol)b Tablet: 10 mg QID 40
Nabumetone (Relafen)b Tablet: 500, 750 mg Daily 2,000
Sulindac (Clinoril)b Tablets: 150, 200 mg BID 400
Tolmetin (Tolectin)b Tablets: 200, 600 mg
Capsules: 400 mg TID–QID 1,800
Oxicam Derivatives

Piroxicam (Feldene)b Capsule: 10, 20 mg Daily 20

Meloxicam (Mobic)b Tablets: 7.5, 15 mg Daily 15
COX-2 Inhibitors

Celecoxib (Celebrex) Capsules: 50, 100, 200, 400 mg BID 400

a
Highly variable half-life; anti-inflammatory doses associated with salicylate serum concentrations from 15 to 30 mg/dL.
b
Generic version available.
BID, twice a day; COX-2, cyclo-oxygenase-2; DR, delayed release; NSAID, nonsteroidal anti-inflammatory drug; QID, four times a day; SR, sustained release; TID, three
times a day; XL/XR, extended release.
Source: [No authors listed]. Drugs for rheumatoid arthritis. Treat Guidel Med Lett. 2009;7:37.

attained. A reasonable initial aspirin dose is 45 mg/kg/day divided

denal mucosal injury? What instructions regarding NSAID
into 4- or 6-hour intervals; however, the anti-inflammatory dose
therapy should be provided to T.W., especially with regard
of aspirin varies widely because of interindividual variations in
to GI problems?
metabolism.
A low-cost NSAID with a good safety profile (e.g., naproxen, Patients should be informed that NSAID therapy is being pre-
ibuprofen) is a good choice for T.W. because she is relatively
Chapter 44

scribed to provide relief of pain and inflammation associated with

young and does not have any concomitant illnesses. If conve-
nience of administration is a more important consideration, a
longer-acting NSAID (e.g., naproxen) would be preferable. If
the first agent chosen is ineffective or not well tolerated, other
NSAIDs can be tried to identify the optimal one for this patient.
RA, but that it will not slow or stop the progression of the disease.
It should be explained that the latter can only be accomplished by
DMARD therapy. Patients should also understand that moderate
to high daily doses of NSAIDs are required for anti-inflammatory
activity, as opposed to analgesic and antipyretic effects, which can
Rheumatoid Arthritis

CASE 44-1, QUESTION 5: Naproxen 500 mg twice daily has
been prescribed for T.W. If T.W. were to experience dyspep-
sia during therapy, should she be given an antiulcer medi-
cation for prophylaxis against GI complications of NSAID
therapy or would a COX-2–selective NSAID be preferable?
What is the correlation between dyspepsia and gastroduo-
be achieved with single and low doses.
About 5% to 15% of patients with RA discontinue NSAID
therapy because of dyspepsia, and about 1.3% of patients tak-
ing NSAIDs for RA experience a serious GI complication.86,88 As
expected, the rate is somewhat lower for patients using NSAIDs
for osteoarthritis (0.7%) because these patients generally use anal-
gesics only on an as-needed basis. Serious NSAID-induced GI
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1018
TA B L E 4 4 - 9
Comparison of Cyclo-Oxygenase-1 and Cyclo-Oxygenase-2 Isoforms

COX-1 COX-2

Expression: continuous or
induced
Common organs/tissues
Primary role
Primarily continuous, although some
evidence of induction
Nearly all organs, including stomach,
kidneys, platelets, vasculature
Housekeeping/maintenance
May be important when induced in
response to inflammation
Primarily induced, but present continuously in several organs
Induced at sites of inflammation and neoplasms
Continuously active in kidneys, small intestine, pancreas, brain, ovaries, uterus
Inflammation, repair, neoplasia
May be important in housekeeping/maintenance of organs that continuously
express COX-2

COX, cyclo-oxygenase.
Source: Hawkey CJ. COX-2 inhibitors. Lancet. 1999;353:307.

complications account for about 103,000 hospitalizations annu-
ally in the United States and for approximately 16,500 NSAID-
related deaths each year.89 Although these figures warrant con-
cern, most patients who experience NSAID-induced dyspepsia
suffer only superficial and self-limiting injury. Nevertheless, pre-
vention of NSAID-induced GI bleeding should be an important
focus, particularly in high-risk patients.
Patients should be taught to recognize the signs and symp-
toms of GI bleeding (e.g., nausea, vomiting, anorexia, gastric
pain), manifested by melena (described to the patient as “dark,
tarry stool”), or emesis of coagulated blood (described to the
patient as “coughing or vomiting up what seems to be coffee
grounds”). It should be emphasized that GI bleeding can occur
without gastric pain. The patient should be instructed to contact
their health care provider immediately for further instructions if
any of these signs or symptoms occurs.
Gastroduodenal mucosal damage induced by NSAIDs primar-
ily results from inhibition of COX-1 in the mucosal lining.88 This
inhibition decreases bicarbonate secretion, mucosal blood flow,
formation of protective mucus, proliferation of gastric epithe-
lium, and the ability of the mucosa to resist injury. Topical dam-
age to the GI mucosa can occur from NSAIDs, but direct injury
plays a smaller role than COX-1 inhibition. Table 44-9 provides a
comparison of COX-1 and COX-2 isoforms.
Dyspepsia can be managed by ingesting the NSAID with meals
or a large glass of water; however, these measures usually are
ineffective in preventing GI ulcers. In addition, dyspepsia cor-
relates poorly with endoscopically confirmed mucosal injury.90
Histamine type 2 (H2 ) receptor antagonists (e.g., ranitidine,
famotidine) significantly reduce dyspepsia among NSAID users;
however, NSAID users with RA who take an H2 -receptor antag-
onist as needed might have a higher risk of developing serious
GI complications compared with those who do not take these
medications (odds ratio, 2.14; 95% confidence interval, 1.06–
4.32).91 The suppression of dyspepsia symptoms can give a false
sense of security to the patient and physician, leading to higher
doses of NSAIDs and increased risk of major gastropathy. Also,
routine use of H2 -receptor antagonists is associated with tachy-
Section 9
full dose of 200 mcg four times daily; however, intolerable GI
upset, particularly diarrhea and abdominal cramping, frequently
leads to discontinuation of therapy at this dose. Lower doses
are usually prescribed (200 mcg two or three times daily) with
better tolerance but lower efficacy. Double maximal doses of H2 -
receptor antagonists have demonstrated a reduction in NSAID-
induced endoscopic peptic ulcers; however, PPIs are significantly
more effective and no study has demonstrated that double-dose
H2 -receptor antagonists prevent ulcer complications.93 PPIs are
clearly the most efficacious and best tolerated cotherapies with
NSAIDs to reduce the risk of peptic ulcers and ulcer compli-
cations. Sucralfate or antacids are not effective in preventing
NSAID-related GI injury.
Routine concomitant antiulcer prophylactic therapy is not
warranted for all patients taking NSAIDs.8 If NSAID therapy
cannot be avoided, the patient’s risk for GI ulcer development
must be assessed to determine the need for ulcer prevention
measures. Established risk factors for NSAID-induced GI bleed-
ing include advanced age (>65 years), history of uncompli-
cated ulcers (a history of complicated ulcers, particularly recent,
increases patient risk), concurrent use of other ulcer-promoting
medications (corticosteroids, aspirin, anticoagulants), and high-
dose NSAID therapy.93 Patients can be grouped into high, mod-
erate, or low risk of NSAID-induced GI toxicity based on these
risk factors. High-risk patients should avoid NSAID therapy or
take a COX-2 inhibitor along with either a PPI or misoprostol.
Moderate-risk patients (one or two risk factors) should take a
PPI or misoprostol with an NSAID; naproxen is the preferred
NSAID for high–cardiovascular risk patients. Low-risk patients
(no risk factors) do not need concurrent GI protective therapy
and should receive a relatively less GI toxic NSAID at the lowest
effective dose; however, low–GI risk patients who also have high
cardiovascular risk are at greater risk for GI toxicity and, there-
fore, should take naproxen with either a PPI or misoprostol.93
Helicobacter pylori infection increases the risk of NSAID-
induced GI bleeding.93 A meta-analysis demonstrated that
H. pylori eradication significantly reduced the risk of endoscopic
ulcers among patients who had not started NSAID therapy; how-

phylaxis with time.92 Therefore, H2 -receptor antagonists are not
recommended for routine use in asymptomatic patients receiv-
ing NSAIDs. Proton-pump inhibitors (PPIs; e.g., lansoprazole,
omeprazole) relieve dyspepsia better than H2 -receptor antago-
nists and prevent the development of NSAID-induced gastro-
Arthritic Disorders
ever, eradication did not lower risk among patients who were
already receiving NSAIDs.94 As a result, recent guidelines recom-
mend consideration of H. pylori infection before the initiation of
long-term NSAID therapy.93
Active NSAID-induced gastroduodenal ulcers are best treated

duodenal ulcers.91,93 They are relatively safe and effective for the
treatment of NSAID-induced dyspepsia and should be considered
if symptoms develop in T.W.
Effective treatment options for reducing the risk of NSAID-
induced GI bleeding include a PPI, double the maximal dose
of H2 -receptor antagonists, and misprostol.93 Misoprostol, a
prostaglandin E1 analog, is most effective when given at the
by discontinuing the NSAID and initiating either an H2 -receptor
antagonist or a PPI. However, H2 -receptor antagonists often fail
to keep gastric pH above 6.0 owing to tachyphylaxis.95 There-
fore, PPIs are preferred because of greater efficacy, rapid healing
rates, and a shorter duration of treatment (4–8 weeks) versus
H2 -receptor antagonists. If discontinuation of the NSAID is not
feasible, ulcer healing can still be accomplished with a PPI, but
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requires a longer duration of therapy (8–12 weeks).95 Patients
who test positive for H. pylori should undergo H. pylori eradication
therapy. Other GI treatments, such as misoprostol and antacids,
are ineffective for managing active NSAID-induced ulcers.
COX-2–selective inhibitors such as celecoxib do not interfere
with COX-1 (the isozyme responsible for production of the stom-
ach’s mucous lining and for reduced acid secretion) at therapeutic
plasma concentrations in humans.93 In theory, COX-2 inhibitors
should therefore reduce inflammation as effectively as nonse-
lective NSAIDs while reducing the risk of GI toxicity. However,
an increased risk of thrombotic cardiovascular events led to the
withdrawal of several COX-2 inhibitors from the market. In addi-
tion, concurrent daily low-dose aspirin use negated any benefit
of COX-2 inhibitor therapy on lowering ulcer risk.96
Without risk factors other than NSAID use, T.W. does not
need concurrent ulcer prophylaxis medication at this time.
CASE 44-2
QUESTION 1: C.S., a patient who was hospitalized for evalu-
ation and treatment of his RA, has a history of aspirin allergy.
Are other NSAIDs contraindicated for this patient?
C.S. should be asked to describe his reaction to aspirin to
determine whether his symptoms are consistent with a hyper-
sensitivity reaction or with a less serious intolerance issue. Many
patients who claim to be allergic to aspirin merely experience
GI distress. In these patients, aspirin is not contraindicated, and
if administered with food or as an enteric-coated preparation,
tolerance may be improved.
Aspirin hypersensitivity, especially in association with asthma,
is cause for serious concern; challenge with aspirin in these
patients can precipitate an acute, life-threatening, bronchospas-
tic reaction.97 Between 6% and 15% of asthmatics have a his-
tory of aspirin-induced bronchospasm; it occurs more often
among women than men and rarely in children. The prevalence
of aspirin-induced asthma increases with the presence of nasal
polyps. Aspirin-sensitive patients can experience a high degree of
cross-reactivity to all nonselective NSAIDs; therefore, nonselec-
tive NSAIDs should be avoided in patients who have experienced
aspirin-induced asthma.
On the other hand, COX-2 inhibitors have been used safely
in aspirin-sensitive asthmatics.98,99 In theory, COX-2 inhibitors
might be safer because they allow COX-1 to continue produc-
ing prostaglandin E2 . Prostaglandin E2 is an important media-
tor of multiple physiological processes, including reduction of
leukotriene synthesis, suppression of the release of inflamma-
tory mediators from mast cells, and prevention of aspirin-induced
bronchoconstriction.
Aspirin desensitization, which is followed by daily aspirin
therapy, is an effective treatment option for most patients with
aspirin-induced asthma.97 Patients who appear to benefit the
most include those who rely heavily on systemic corticosteroids
or with recurrent nasal polyps.
CASE 44-3
QUESTION 1: A.L., a 53-year old woman with RA, recalls
receiving aspirin long ago, but discontinued it because of
“ringing in my ears all the time!” Is this a symptom related
to aspirin?
Aspirin-induced tinnitus (i.e., a ringing or high-pitched
buzzing sensation in the head) is noticeable to most patients
with normal hearing when aspirin serum levels reach 10 to 30
mg/dL; however, in some patients tinnitus might not be encoun-
November 19, 2011 2:2
tered until serum levels exceed 25 mg/dL.76 Serum salicylate 1019
concentrations are usually within therapeutic range when tin-
nitus is apparent. As a result, tinnitus has been used to titrate
patients on aspirin to therapeutic doses. It is important to note
that patients with pre-existing hearing loss might not experience
tinnitus despite potentially toxic concentrations.100
CASE 44-3, QUESTION 2: A.L. is scheduled to have dental
surgery. She states that she is currently taking an aspirinlike
product for arthritis pain. Why is it important to know the
specific NSAID she is taking?
Aspirin, nonacetylated salicylates, nonaspirin NSAIDs, and
COX-2 inhibitors have differing effects on platelet function.
Aspirin alters hemostasis most significantly and should be dis-
continued before surgery, even for minor procedures like tooth
extraction.76 Low doses of aspirin impair platelet aggregation
throughout the life of the platelet via irreversible binding to
COX and, thereby, prolong bleeding time for several days. New,
unbound platelets must be released into circulation before bleed-
ing time can normalize. Salicylates also can enhance blood fi-
brinolytic activity, and very large salicylate doses can induce a
hypoprothrombinemia that is reversible by vitamin K. Bleeding
times typically normalize within 3 to 6 days after discontinuation
of aspirin. Therefore, aspirin should be stopped approximately 1
week before surgery.
Nonaspirin NSAIDs can prolong bleeding times by inhibit-
ing platelet aggregation, but these drugs bind reversibly to COX,
resulting in transient platelet inhibition.76 As a result, nonaspirin
NSAIDs should be discontinued approximately 5 half-lives before
surgical procedures. For most nonaspirin NSAIDs, the impair-
ment of platelet aggregation is reversed within 2 days after the
discontinuation.
Nonacetylated salicylates have minimal effects on COX and
platelet function and are of little concern in presurgical patients.
Likewise, COX-2 inhibitors are not expected to alter platelet func-
tion because COX-2 is not found in platelets.101
CASE 44-4
QUESTION 1: R.Z. is a 28-year-old woman who is planning
a pregnancy and is concerned about the possible effects of
NSAIDs on her baby. What are the risks to the fetus with
uninterrupted consumption of NSAIDs? What are maternal-
and lactation-related effects of these medications?
Although NSAIDs, including aspirin, are not teratogenic, they
must be used cautiously in women who are pregnant and who
plan to breast-feed infants.102 Fetal effects of NSAIDs include
possible premature ductus arteriosus closure, increased cuta-
neous and intracranial bleeding, transient renal impairment, and
a reduction in urine output. High doses of aspirin (greater than
Chapter 44
3 g/day) and NSAIDs can inhibit uterine contractions, resulting
in prolonged labor. The use of NSAIDs can also increase peri-
partum blood loss and anemia. Aspirin and nonaspirin NSAIDs
should be used sparingly and at the lowest effective doses during
pregnancy and discontinued at least 6 to 8 weeks before delivery
to minimize adverse fetal and maternal effects.
Rheumatoid Arthritis
Aspirin generally should be avoided for women who plan
to nurse their baby because salicylate serum concentrations
in breast-fed neonates raise concerns about the potential for
metabolic acidosis, bleeding, and Reye syndrome. Nonaspirin
NSAIDs are generally compatible with breast-feeding, with the
best evidence supporting the use of ibuprofen, indomethacin,
and naproxen.103,104
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1020 CASE 44-5
QUESTION 1: T.Z., a 68-year-old man with heart failure
previously managed with furosemide 40 mg/day, digoxin
0.125 mg/day, metoprolol 50 mg twice daily, and lisinopril
40 mg/day, returns for a prescription refill of ibuprofen
600 mg three times daily, which he takes for his RA. Dur-
ing the past 2 weeks, he has noted increased leg swelling,
a weight gain of several pounds, exacerbated shortness of
breath, and easy fatigability. Why might these signs and
symptoms be associated with ibuprofen use?
Mild fluid retention occurs in approximately 5% of NSAID
users, and NSAID-induced kidney disease occurs in less than
1% of patients.105,106 NSAID therapy should be avoided, if pos-
sible, in patients with pre-existing heart failure, kidney disease,
or cirrhosis.104 If a patient with these conditions requires NSAID
therapy, or patients are taking angiotensin-converting enzyme
inhibitors and angiotensin receptor blockers, serum creatinine
should be checked soon after NSAID initiation. Inhibition of COX
by NSAIDs within the kidney reduces prostaglandin concentra-
tions and unopposed vasoconstriction. Consequently, urine out-
put declines, serum blood urea nitrogen and serum creatinine
levels rise, and fluid is retained. This potential complication is
associated with all of the currently marketed NSAIDs.106 In addi-
tion, ibuprofen and all other NSAIDS besides naproxen are asso-
ciated with an increased risk of MI, which is a concern for T.Z.
because of his risk of thrombotic cardiovascular events.24
The provider of T.Z.’s cardiovascular care should be informed
of his symptoms of fluid overload, and an alternative to NSAID
therapy should be pursued.
CASE 44-5, QUESTION 2: If NSAID therapy is discontinued,
what analgesic or anti-inflammatory alternatives are avail-
able for T.Z.? What other renal syndromes are associated
with NSAID use?
In several studies, sulindac has been associated with fewer
adverse effects on the kidney than other NSAIDs.24 The reasons
for this are unclear, but one explanation is that the active sulfide
metabolite undergoes renal metabolism and, therefore, might
not achieve tissue concentrations within the kidney sufficient to
reduce prostaglandin production.107 Unfortunately, patients do
not seem to benefit from sulindac as much as from other NSAIDs,
and the evidence overall supporting the safety of sulindac in renal
impairment is weak. COX-2 inhibitors do not appear to offer an
advantage for renally impaired patients.24 Although celecoxib
has been associated with a slightly lower risk of death and heart
failure exacerbation when compared with traditional NSAIDs,108
it is not a reasonable initial option for T.Z. because celecoxib is
also associated with an increased risk of MI and it may contribute
to worsening of heart failure.
NSAIDs should be used at their lowest effective doses for
minimal periods for T.Z. High-dose NSAIDs should be avoided
Section 9
owing to increased MI risk. Although acetaminophen is not an
anti-inflammatory agent, it can provide analgesic relief. Intra-
articular corticosteroid injections can be useful if inflamed joints
are limited in number, or a short course of oral corticosteroids can
provide rapid control of inflammation while reducing the need
Arthritic Disorders
for longer courses of anti-inflammatory therapy. If T.Z. is not yet
being treated with a DMARD, it should be seriously considered
because all patients with RA are candidates for DMARDs, and
DMARD use could preclude T.Z.’s need for an NSAID. If an
NSAID or short course of systemic corticosteroid is selected,
close monitoring of renal function and fluid retention status is
warranted.
November 19, 2011 2:2
In addition to acute renal failure, NSAIDs can induce vari-
ous adverse renal effects (e.g., nephrotic syndrome, interstitial
nephritis, hyponatremia, abnormalities of water metabolism,
hyperkalemia).109 The nephrotic syndrome, unlike NSAID-
induced acute renal failure, can appear anytime (i.e., from days
to years) after initiation of therapy, and can resolve as quickly as
1 month, or as long as 1 year, after discontinuation of the NSAID.
Hematuria, pyuria, and proteinuria without prior renal disease
differentiates nephrotic syndrome from other NSAID-induced
renal problems. Histologically, NSAID-induced nephrotic syn-
drome is characterized by interstitial lymphocytic infiltrates, vac-
uolar degeneration of proximal and distal tubules, and fusion of
epithelial foot processes of glomeruli.
Prostaglandin-mediated inhibition of active chloride trans-
port, regulation of medullary blood flow within the kidney,
and antagonism of antidiuretic hormone can be suppressed by
NSAIDs. As a result, urine is maximally concentrated, free water
clearance is limited, and water retention that is disproportion-
ate to sodium retention can occur. The resulting hyponatremia
can be severe and could be potentiated by thiazide diuretics.109,110
Local prostaglandin synthesis can also stimulate renin production
within the kidney. NSAID therapy can critically attenuate this
regulatory mechanism in some situations, resulting in reduced
aldosterone-mediated potassium excretion and hyperkalemia.
Although the mechanism is poorly understood, some NSAIDs
have been associated with sustained mean arterial pressure
increases of 5 to 6 mm Hg,24,111 presumably the result of
COX-2 inhibition and sodium and water retention. Several studies
suggest that only patients taking antihypertensive medications
experienced NSAID-induced mean arterial pressure elevations,
whereas those who controlled their hypertension without med-
ications were unaffected by NSAID therapy.
CASE 44-5, QUESTION 3: How frequently should T.Z.’s renal
and liver function be tested during his NSAID therapy?
Patients at high risk for NSAID-induced renal disease, like T.Z.
(see Case 44-5, Questions 1 and 2), should have their serum cre-
atinine levels checked regularly (e.g., weekly) for several weeks
after initiation of NSAID therapy because renal insufficiency
more commonly occurs early in the course of therapy rather
than later.110 NSAID-induced nephrotic syndrome and allergic
interstitial nephritis occur, on average, about 6.6 months and
15 days after NSAID initiation, respectively.109
In most cases, liver function testing (LFT) is unnecessary.110
Although NSAIDs can elevate liver enzymes, severe hepatotoxi-
city is rare. Abnormal LFTs without clinical symptoms have no
impact on patient outcome and have not been associated with
severe hepatotoxicity. Patients who seem to be at greatest risk for
hepatotoxicity are those with established or suspected intrinsic
liver disease and those taking diclofenac. These patients should
have LFTs performed no later than 8 weeks after initiation of
therapy because liver toxicity manifests early in therapy, if at all.
TRADITIONAL DISEASE-MODIFYING
ANTIRHEUMATIC DRUGS
CASE 44-5, QUESTION 4: T.Z. was diagnosed with RA 18
months ago. He exhibits no features of a poor prognosis,
and has low disease activity. Which traditional DMARD ther-
apies are most appropriate for him?
Every RA patient should receive DMARD therapy, unless
a contraindication exists.19 As previously discussed, initial
DMARD selection is based on three factors: (a) disease activity
(low vs. moderate-high), (b) whether poor prognostic findings
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are present, and (c) disease duration. For most patients, MTX or
LEF are chosen initially because of high rates of clinical response
for all levels of RA severity and radiographic evidence of slowing
joint erosion, which is most rapid during the first several years of
active disease19 (Fig. 44-7). Although most DMARDs are associ-
ated with potentially serious adverse effects, these generally are
reversible and seldom lead to serious complications if the patient
has been monitored appropriately.
Most patients with RA are treated with at least one DMARD
along with an NSAID.20 In addition, low-dose oral cortico-
steroids are often prescribed on an as-needed basis for brief
periods of severe disease activity or while awaiting the onset
of DMARD action. During periods of disease remission, NSAID
therapy can be discontinued; however, attempts to discontinue
traditional DMARDs have resulted in disease reactivation or
“rebound flare,” and resumption of the discontinued agent is not
always successful in re-establishing control. Therefore, success-
ful traditional DMARD therapy should be continued indefinitely.
Safety and efficacy data, which reflect several years of DMARD
therapy combined with biologic agents, have been excellent,
and the combination is now commonly prescribed for patients
who fail MTX monotherapy (see Case 44-7, Questions 9–11).
Guidelines for DMARD selection were discussed previously (see
Treatment section). Combination DMARD therapy is indicated
for more severe or more advanced RA patients (see Case 44-7,
Question 8).
ANTIMALARIAL DRUG DOSING
CASE 44-5, QUESTION 5: Although T.Z.’s presentation
could warrant an alternative DMARD, treatment was initi-
ated with HCQ. What dosages would be appropriate, and
when should clinical improvement be expected?
Although the manufacturer’s literature recommends an initial
HCQ adult dose of 400 to 600 mg/day (310 to 465 mg of base),
November 19, 2011 2:2
1021
PIP erosions
MCP erosions
FIGURE 44-7 Radiograph of the hand in rheumatoid
arthritis showing both active erosions at the metacarpopha-
langeal joints (MCPs) and old well-demarcated erosions at
the proximal interphalangeal joints (PIPs).
dosages for HCQ generally range from 2 to 6.5 mg/kg/day.20 If the
patient responds well, the maintenance dose can be reduced by
50% and the medication continued at a dose of 200 to 400 mg/day
(155 to 310 mg of base). About two-thirds of patients who tolerate
HCQ respond favorably. Benefits usually are apparent within 2
to 4 months of therapy, but can vary between 1 and 6 months.8
About 37% of patients discontinued HCQ within a year and 54%
within 2 years, primarily owing to lack of efficacy.110
Risk of Retinopathy
CASE 44-5, QUESTION 6: When being counseled regarding
HCQ, T.Z. was told that the drug can cause vision problems.
How great is the risk of retinopathy from antimalarials when
used for the treatment of RA? What monitoring parameters
are appropriate?
HCQ is usually well tolerated. The most serious toxicity, reti-
nal damage and subsequent visual impairment, is rare.20,110 Risk
of retinopathy is increased with high cumulative doses (>800 g),
increased age (>60 years), liver disease, and retinal disease. The
increased risk of retinopathy in the elderly seems to be related
to the increased prevalence of macular disease in this age group.
Chapter 44
HCQ doses exceeding 6.5 mg/kg are associated with increased
risk of retinal damage, particularly in patients with renal or hep-
atic dysfunction. HCQ should not be used for patients with sig-
nificant renal impairment.
Patients should be instructed to stop therapy immediately and
undergo an ophthalmologic evaluation if they are experiencing
Rheumatoid Arthritis
symptoms of antimalarial-associated retinopathy (e.g., difficulty
seeing faces or entire words, glare intolerance, poor night vision,
loss of peripheral vision).111 The fully developed lesion of anti-
malarial retinopathy is seen on ophthalmoscopy as a pigmentary
disturbance with a characteristic bull’s-eye appearance in the
macular region. The 4-amino-quinolines bind to melanin, and
as a result, concentrate in the uveal tract and retinal pigment
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1022 epithelium. The retinopathy can be progressive even after dis-
continuation of the drug.
Baseline eye examination is not required in patients younger
than 40 years of age with no family history of eye disease. Com-
plete ophthalmologic examinations are recommended before
HCQ initiation and annually for patients with high risk for retinal
damage; low-risk patients require examinations every 5 years.20
More frequent testing is recommended for patients with renal
dysfunction or patients who have received HCQ therapy for
greater than 10 years. Benign corneal deposits, which are harm-
less and reversible on discontinuation, may occur during therapy
and are not related to retinopathy.76
SULFASALAZINE
CASE 44-5, QUESTION 7: If SSZ were chosen as initial ther-
apy for T.Z., when should therapeutic effects become appar-
ent, and what adverse effects might be anticipated?
The onset of SSZ effect is generally more rapid than that of
HCQ and can become apparent within a month8,20 ; however, a
clinical response might be delayed for up to 3 to 4 months, and
doses should be adjusted only after this period has elapsed.
Overall, SSZ adverse effects are relatively mild, but SSZ is
considered to be more toxic than HCQ.20 Adverse effects include
nausea, abdominal discomfort, heartburn, dizziness, headaches,
skin rashes, and, rarely, hematologic effects such as leukopenia
(1% to 3%) or thrombocytopenia (rare). A complete blood count
(CBC) is recommended every 2 to 4 weeks for the first 3 months
of therapy, then every 3 months thereafter. Leukopenia, agranu-
locytosis, or hepatitis are rare but serious side effects of SSZ, and
usually manifest within the first 2 to 3 months of therapy. To min-
imize GI-related adverse effects, SSZ is initiated at 500 mg/day
or 1 g/day, and the dosage is increased at weekly intervals by
500 mg until 1,000 mg two or three times daily is reached.
GOLD PREPARATIONS AND ADVERSE REACTIONS
CASE 44-6
QUESTION 1: S.S., a 41-year-old Asian woman diagnosed
with RA, presents with inflammation in both hands (MCP and
PIP joints), wrists, elbows, shoulders, knees, hips, ankles,
and MTP joints. Objective test results include radiographic
evidence of joint erosion in both hands and elbows, posi-
tive RF (dilution of 1:1,280), positive anti-CCP at 102 units,
and ESR of 78 mm/hour. Her SDAI score is 30. Her symp-
toms were managed during the past year with ibuprofen
800 mg three times daily; however, pain and inflamma-
tion have progressively worsened over the course of sev-
eral months. ROM testing reveals deficits in wrist flexion
and extension (20 degrees bilaterally for both motions;
Section 9
normal, 90 and 70 degrees, respectively), elbow flexion
(90 degrees bilaterally with flexion contracture; normal,
160 degrees), shoulder abduction (70 degrees right,
90 degrees left; normal, 180 degrees), and plantar flexion
of both ankles (20 degrees bilaterally; normal, 45 degrees).
Three firm, pea-sized, nontender moveable subcutaneous
Arthritic Disorders
nodules are found on both elbows at the ulnar border, two
on the right and one on the left. In your discussion about
considering DMARD therapy, S.S. states that she does not
want gold therapy “because I’ve heard that it has terrible
side effects.” What gold preparations are available, and is
S.S.’s concern about adverse effects warranted?
November 19, 2011 2:2
Two parenteral gold preparations are available: gold sodium
thiomalate, an aqueous solution, and aurothioglucose, an oil sus-
pension. Although an oral gold formulation, AUR, is also avail-
able, it is slow in onset (4 to 6 months) and is less efficacious.8,20
The parenteral formulations, containing approximately 50%
gold by weight expressed as milligrams of complex, are equally
effective.20 Aurothioglucose must be shaken thoroughly before
withdrawal from its vial, and a large-bore needle is necessary
to draw up this viscous suspension. Lumps at the intramuscular
injection site sometimes can be troublesome to the patient.
Toxicities with both injectable gold preparations are numer-
ous and largely responsible for their high rate of discontinua-
tion. In a 6-year prospective trial, nearly half of patients receiv-
ing gold sodium thiomalate discontinued therapy, with 95% of
those discontinuing because of toxicity.27 The toxicity profiles
of the parenteral gold preparations differ. A vasomotor reaction
(also termed nitritoid reaction), which manifests as nausea, weak-
ness, flushing, tachycardia, or syncope, can occur in up to 5%
of patients receiving gold sodium thiomalate. These reactions
generally are mild, are transient, and often can be alleviated by
having the patient lie down.
Nonvasomotor reactions, consisting of transient stiffness,
arthralgias, and myalgias, developed in 15% of patients after ini-
tiation of gold sodium thiomalate therapy,112 and substituting
aurothioglucose for the thiomalate formulation decreased the
severity of this adverse reaction in 40% of patients.
Skin eruptions, stomatitis, and albuminuria are more com-
mon in patients who receive the aqueous gold sodium thioma-
late preparation than in patients who receive the oil suspension
of aurothioglucose.113 Aurothioglucose also is more commonly
associated with renal toxicity than gold sodium thiomalate,
although the overall incidence is rare.76 Membranous nephro-
pathy (most common), nephrotic syndrome, and interstitial
nephritis have been reported. Hematuria and proteinuria may
be early indicators of membranous nephropathy; however, pro-
teinuria can occur transiently in up to 50% of patients receiv-
ing aurothioglucose. Patients who experience proteinuria should
undergo a renal evaluation and a urinalysis. Gold therapy should
be discontinued if protein excretion is greater than 500 mg/24
hours.
Parenteral gold preparations have been associated with sud-
den occurrence of idiosyncratic thrombocytopenia (1%–3%) or
aplastic anemia (<1%).76 Screening for urine protein and a CBC
should be performed before each weekly injection for the first
20 to 22 weeks, then before every other injection. In addition,
patients should be asked about the occurrence of pruritus, skin
eruptions, purpura, sore throat, and stomatitis before each dose
of gold is administered.
Dermatologic reactions to gold occur in 15% to 30% of
patients.76 Pruritus, erythema, or a fine morbilliform rash on
the neck or extremities can develop after the first few injec-
tions of gold. These cutaneous reactions are common, usually
subside within several days, and do not seem to be affected by
subsequent injections. Although a highly pruritic localized erup-
tion resembling pityriasis rosea is common, gold dermatitis may
assume many different forms, including exfoliative dermatitis.76
Therapy should be discontinued if a pruritic dermatitis develops.
Mild dermal reactions may be managed with topical cortico-
steroids. Because of fears of subsequent exfoliative dermatitis
and the belief that dermatologic reactions recur on rechallenge,
there is a natural reluctance to continue gold treatment after the
appearance of dermatitis or stomatitis. However, in one series of
patients, gold treatments were reinstituted successfully in 28 of
30 patients in whom dermatologic reactions developed.114
AUR capsules, containing 3 mg of gold, are 25% bio-
available.115 The recommended AUR daily dose of 6 mg can
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be given either as single or divided doses. AUR is better tolerated
than parenteral gold formulations, but is significantly less
effective.8,19 Like parenteral chrysotherapy, benefit can occur
as early as 6 to 8 weeks after starting AUR, but objective ben-
efits might not be apparent for several months. AUR must be
monitored in a manner similar to parenteral therapy. The inci-
dence of rashes necessitating AUR withdrawal is lower than with
parenteral gold therapy, but loose stools and diarrhea are encoun-
tered more commonly (47%).
S.S.’s concerns have merit. Although gold is an effective
DMARD and can induce complete RA remission, none of the
gold formulations are ideal. Gold sodium thiomalate is easier
to administer, but is associated with more frequent side effects
compared with aurothioglucose. Aurothioglucose carries a low
but serious risk of nephrotoxicity. Both parenteral forms of gold
are commonly discontinued because of side effects. AUR is the
best-tolerated gold preparation, but the least effective, and is
associated with significant diarrhea.
Dosing
CASE 44-6, QUESTION 2: How should gold be administered
to S.S., if she agrees to therapy? Is serum drug monitoring
of value in gold therapy?
The standard treatment schedule for parenteral gold consists
of an initial intramuscular (IM) test dose of 10 mg followed by a
25-mg IM dose 1 week later. The third and subsequent weekly IM
injections of 25 to 50 mg should be continued until the cumulative
dose reaches 1 g, toxicity occurs, or major benefit is derived.76 If
a satisfactory response is achieved, maintenance doses of 25 to
50 mg every other week are recommended. If the disease remains
stable, doses can be administered every third and subsequently
every fourth week for an indefinite period. The dose of AUR is
3 mg twice daily or 6 mg once daily.
Attempts to correlate serum gold concentrations with clinical
outcomes generally have been unsuccessful. Furthermore, toxi-
city has not been correlated with serum gold concentrations.116
METHOTREXATE
CASE 44-6, QUESTION 3: S.S. will be treated with MTX.
Why is MTX a good selection for her?
MTX or LEF are recommended as initial DMARD therapy for
all patients with RA.19 S.S. has many indicators of severe disease
(e.g., an SDAI score indicating high disease activity [see Table
44-7], multiple joint involvement, extra-articular manifestations
[i.e., subcutaneous nodules], radiographic evidence of erosions,
elevated ESR, positive anti-CCP, positive RF with a high titer of
1:1,280 [positive RF is generally a titer less than or equal to 1:20
and titers correlate with disease severity]).
The disease prognosis for S.S. is clearly poor, and a relatively
potent DMARD should be initiated to maximize the preservation
of joint function and minimize the risk of RA-related cardiovas-
cular disease. MTX has a rapid onset (usually 1 to 2 months before
a plateau of effectiveness), a high efficacy rate, and a long history
of successful use.19 In one study, the probability of continuing
MTX therapy for at least 5 years was 62%.117 It is an excellent
choice for treating S.S.’s very active RA.
Dosing
CASE 44-6, QUESTION 4: How should MTX be dosed and
administered to S.S.?
November 19, 2011 2:2
In general, MTX is administered orally at an initial dose of 7.5 1023
mg once a week, usually in a single weekly dose.20 The dose can
also be divided into three equal parts (e.g., starting dose of 2.5
mg every 12 hours for a total of three doses) for patients who are
unable to tolerate adverse effects, particularly hepatotoxicity. If
S.S.’s RA shows no objective response in 1 to 2 months, the dose is
increased to 15 mg/week (or 5 mg every 12 hours for three doses)
for at least 12 additional weeks.25 If no response is seen at this
time, then (a) the dose can be increased to the maximum of 25
mg/week, (b) the dose can be administered as a subcutaneous or
IM injection to address bioavailability concerns, (c) the same dose
can be continued for a longer time, or (d) another DMARD can be
added to MTX or MTX can be substituted.19 When subcutaneous
MTX was compared with oral MTX in a 6-month randomized,
controlled trial of 384 MTX-naı̈ve patients with active RA,118 78%
of patients treated with subcutaneous MTX achieved an ACR-20
response, and only 70% of those treated with oral MTX achieved
a similar response. At week 16 of this study, patients treated
with oral MTX, who failed to attain an ACR-20 response, were
switched to subcutaneous MTX; patients treated with subcuta-
neous MTX who failed to attain an ACR-20 response were given
a larger MTX dose (20 mg) subcutaneously. The patients who
were converted from oral dosing to subcutaneous dosing and the
patients who were given a larger subcutaneous dose had a 30%
and 23% ACR response rate at week 24, respectively. As a result,
subcutaneous MTX seems to be more effective than oral MTX
and not associated with a higher incidence of adverse effects.
In a 6-month clinical trial, RA patients with a short disease
duration (i.e., <3 years) who achieve disease remission with
weekly MTX therapy remained in remission when the same
MTX dose was administered every other week (i.e., monthly
dose reduced by 50%).119 It is unknown, however, whether every-
other-week dosing of MTX prevents joint destruction as effec-
tively as weekly dosing.
Adverse Effects
CASE 44-6, QUESTION 5: What subjective and objective
data should be evaluated for evidence of MTX adverse
effects in S.S.?
S.S. should be monitored for nausea and other GI distress,
malaise, dizziness, mucositis, and mild alopecia, which are com-
monly encountered adverse effects associated with low-dose
MTX therapy.110 More serious, but less common, adverse effects
include myelosuppression, pneumonitis, and hepatic fibrosis and
cirrhosis. A CBC, LFTs, and a serum creatinine concentration
should be obtained for her at baseline, monthly for the first 6
months of therapy, and then every 4 to 8 weeks during MTX ther-
apy. Renal dysfunction can result in accumulation of MTX and
higher risk of myelosuppression. Hypersensitivity pneumonitis,
occurring in 1% to 2% of patients, has no known risk factors for
development, although it may be more common in patients with
Chapter 44
a history of lung disease.20 In addition, hypersensitivity pneu-
monitis can occur at any time during therapy and at any MTX
dosage. A baseline chest radiograph is recommended within the
year before MTX initiation. If the patient is found to have pre-
existing lung disease, MTX treatment should be reconsidered
because further pulmonary damage could be devastating to the
Rheumatoid Arthritis
patient. S.S. also should be monitored carefully for cough, dys-
pnea on exertion, and shortness of breath at each clinic visit.
MTX-induced liver disease is rare, but increased age, long
duration of therapy, obesity, diabetes mellitus, ethanol consump-
tion, and a history of hepatitis B or C increase the risk of
hepatotoxicity.110 MTX should be prescribed with great caution,
if at all, in patients with pre-existing liver disease. The serum
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1024
TA B L E 4 4 - 1 0
Recommended Monitoring Intervals for Complete Blood
Count, Liver Function Tests, and Serum Creatinine Levels for
Rheumatoid Arthritis Patients Receiving Traditional
(Nonbiologic) Disease-Modifying Antirheumatic Drugs
Frequency of Monitoring Based on
Duration of Therapy
DMARD <3 Months 3–6 Months >6 Months
Hydroxychloroquine None after None None
(HCQ) baseline
Minocycline (MIN)
Leflunomide (LEF)
Methotrexate (MTX) 2–4 weeks 8–12 weeks 12 weeks
Sulfasalazine (SSZ)
DMARD, disease-modifying antirheumatic drug.
Source: Saag KG et al. American College of Rheumatology 2008
recommendations for the use of nonbiologic and biologic disease-modifying
antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59:762.
concentrations of liver enzymes commonly are modestly
increased after administration for 1 to 2 days. However, MTX
should be withheld if liver enzymes increase to three times
the baseline value or if the liver enzyme serum concentra-
tions remain elevated for sustained periods during therapy.
Patients taking MTX should avoid alcohol and be instructed to
report symptoms of jaundice or dark urine to their primary-care
provider. Routine liver biopsies to monitor for MTX-induced hep-
atotoxicity are unnecessary (see Case 44-6, Question 6). Moni-
toring recommendations for MTX and other commonly used
traditional DMARDs are listed in Table 44-10.
Liver Biopsy and Methotrexate
CASE 44-6, QUESTION 6: The following laboratory test
results were obtained for S.S. before starting MTX:
ALT, 28 international units/L
Aspartate aminotransferase (AST), 30 international
units/L
Alkaline phosphatase, 100 international units/L
Albumin, 4.5 g/dL
Total bilirubin, 0.8 mg/dL
Should a baseline liver biopsy be performed before S.S.
starts MTX?
At one time, routine liver biopsies were recommended for
RA patients receiving MTX because cirrhosis developed in up
to 26% of MTX-treated psoriasis patients.120 In patients with
RA, however, serial liver biopsies are neither recommended nor
cost-effective. Nevertheless, the liver should be biopsied before
treatment in patients with suspected liver disease and in patients
with persistent LFT abnormalities (defined as elevations above
Section 9
the upper limit of normal [ULN] in AST for 5 of 9 tests within a
12-month period [or 6 of 12 if tests are performed every month]
or a reduction in serum albumin below normal range) during,
or after discontinuation of, MTX therapy.121 Because S.S.’s LFTs
are normal and there is not a history of liver disease noted, there
is no reason to consider a baseline liver biopsy.
Arthritic Disorders
Methotrexate and Folate or Folinic Acid
CASE 44-6, QUESTION 7: When should folate (or folinic
acid) be administered to reduce the risk of MTX-related tox-
icity in S.S.?
November 19, 2011 2:2
Folate supplementation appears to reduce the incidence of
several MTX-related adverse effects including GI disturbances,
mucositis (mouth or GI ulcerations), and LFT elevations.122–126
When folic acid (1 mg/day), folinic acid (2.5 mg/week), or placebo
was added to MTX therapy (7.5 mg/week, titrated up to 25
mg/week) in more than 400 RA patients, hepatotoxicity devel-
oped in 26% in the placebo group, but in only 4% of patients
in the folic acid and folinic acid groups (p <0.001 for treatment
groups vs. placebo). Because hepatotoxicity is one of the most
common reasons for MTX discontinuation, the benefit of folate
supplementation is clearly important.
A slightly higher dose of MTX might be needed in folate users
to produce clinical benefits similar to that achieved by patients
without folate supplementation, perhaps because MTX is a folate
antagonist.127 Clinically, however, there does not seem to be a sig-
nificant attenuation of MTX efficacy associated with concomitant
folate supplementation, and, very importantly, folate supplemen-
tation reduces the incidence of MTX discontinuation secondary
to ALT elevation.
Folic acid 1 to 4 mg daily or folinic acid 2.5 to 10 mg weekly
24 hours after MTX dose can be initiated in S.S.20 Both regi-
mens are effective, although folic acid may be simpler for patients
to self-administer and is inexpensive. Although either folic acid
or folinic acid is effective, folic acid 1 mg/day or 7 mg once a
week is preferred over folinic acid because of cost and ease of
administration.110
Methotrexate-Related Pulmonary Disorders
CASE 44-6, QUESTION 8: S.S. is treated with MTX 7.5 mg
and with folic acid 7 mg orally once a week. Nine weeks
later, she returns to the clinic with subjective and objective
improvement in morning stiffness, fatigability, and joint ten-
derness and swelling. However, she has noted increased
shortness of breath and dyspnea in the past week. Why
might these symptoms be related to MTX?
Pneumonitis, a rare complication of MTX therapy, is char-
acterized by a nonproductive cough, malaise, and fever, pro-
gressing to severe dyspnea.128 Recognition of this unusual reac-
tion is important to ensure that MTX is discontinued before
the pneumonitis progresses to respiratory failure (see Case 44-6,
Question 5). After discontinuation of MTX, pulmonary function
improves. Corticosteroids can accelerate improvement in pul-
monary symptoms associated with pneumonitis. S.S.’s dyspnea
and shortness of breath might be related to MTX. If appropriate
tests rule out other causes for her pulmonary complaints, MTX-
induced pulmonary toxicity should be considered and MTX treat-
ment discontinued.
Methotrexate Interactions
CASE 44-6, QUESTION 9: What major MTX food and
drug interactions need to be discussed with S.S. by her
providers?
NSAIDs increase MTX serum concentrations and increase
the risk of toxicity.20 MTX doses should be adjusted cautiously
if S.S. is taking NSAIDs concurrently to manage her RA pain.
Trimethoprim, frequently used as part of the treatment for uri-
nary tract infections, can increase the risk of MTX-induced bone
marrow suppression. The concurrent use of MTX and LEF has
been associated with major liver damage, requiring diligent mon-
itoring for liver toxicity if used in combination. When 39 MTX-
treated RA patients consumed low doses of caffeine (less than
120 mg/day), morning stiffness and joint pain were improved
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by more than 30% compared with high caffeine consumption
(greater than 180 mg/day).129 Caffeine may interfere with the anti-
inflammatory effects of MTX. Because MTX is protein bound
and renally excreted, other drugs (e.g., salicylates, probenecid,
penicillin, ciprofloxacin) also might interact with MTX.
LEFLUNOMIDE: PLACE IN THERAPY
CASE 44-7
QUESTION 1: B.W., a 36-year-old woman, has severe, pro-
gressive RA and is not responding sufficiently to MTX ther-
apy. Would LEF be a reasonable consideration for her?
LEF, an oral traditional DMARD, seems to be similar in effi-
cacy to MTX with regard to ACR-20, radiographic response, and
work productivity.19,63 The onset of benefit (as early as 4 weeks)
and the percentage of patients who discontinue LEF therapy
because of either lack of efficacy or toxicity are similar for LEF,
MTX, and SSZ. It can be used in place of MTX for initial drug
therapy, combined with MTX therapy (see Case 44-7, Question
8), or serve as a replacement for MTX-intolerant patients.
Dosing and Monitoring
CASE 44-7, QUESTION 2: How should therapy with LEF be
initiated in B.W.? How would you monitor B.W. for adverse
effects?
The active metabolite of LEF, A77 1726 or M1, is responsible
for virtually all the pharmacologic activity of LEF.25 The serum
half-life of the M1 metabolite is approximately 2 weeks. As a
result, LEF should be initiated with a loading dose of 100 mg
orally once daily for 3 days to reduce time to steady state, followed
by 20 mg once daily. If this dose is not tolerated, the dose should
be reduced to 10 mg once daily.
Monitoring for Adverse Effects
Diarrhea (20%–30%), rash (10%), alopecia (10%–17%), and
reversible liver enzyme elevations more than three times the
ULN (2%–4%) are common adverse effects of LEF.25 Routine
laboratory testing includes a baseline ALT followed by monthly
ALT testing for several months. When it is evident that ALT
results are stable and within normal limits, testing can be per-
formed less often according to the clinician’s judgment. Because
of the risk of liver toxicity and the need for activation by the liver
to the M1 active metabolite, LEF is not recommended in patients
with pre-existing liver disease, including hepatitis B or C.
Potential hepatotoxicity is the greatest concern with LEF;
however, the rate of LEF-induced liver enzyme elevation is not
significantly different than MTX. Guidelines for managing poten-
tial hepatotoxicity include dosage reduction from 20 to 10 mg/day
if ALT increases more than two times the ULN.25 If ALT eleva-
tions remain steady between two and three times the ULN and
treatment continuation is desired, a liver biopsy is recommended.
If ALT elevations are persistently more than three times the ULN
despite dosage reduction and cholestyramine administration to
enhance elimination (see Case 44-7, Question 3), then the drug
should be discontinued and another course of cholestyramine
elimination therapy should be given.
Enhancement of Elimination With Cholestyramine
CASE 44-7, QUESTION 3: After 2 months of therapy, B.W.
does not respond to LEF and the treatment was discontin-
ued, especially because she is beginning to consider starting
November 19, 2011 2:2
1025
a family. What precautions must be taken when discontinu-
ing LEF?
LEF (pregnancy category X) has not been tested in pregnant
women, but greatly increases the risk of fetal death or terato-
genicity in animals receiving as little as 1% of human equivalent
doses.20,25 After discontinuation of therapy, however, up to 2
years may need to elapse before plasma M1 metabolite levels
of LEF are undetectable. As a result, cholestyramine is recom-
mended for all women who discontinue LEF and who are hoping
to become pregnant. After stopping the medication, cholestyra-
mine 8 g three times daily is administered for 11 days (which
need not be consecutive). Plasma levels of the M1 metabolite are
reduced by 40% to 65% in 24 to 48 hours and should become
undetectable (<0.02 mg/L) at the end of therapy. B.W.’s blood
should be tested at least 14 days apart to verify the absence of the
metabolite. If plasma M1 levels remain greater than 0.02 mg/L,
more cholestyramine should be administered. Cholestyramine
also can be used to enhance elimination of LEF in patients who
experience hepatotoxicity or who overdose with this drug. Acti-
vated charcoal also can reduce plasma M1 levels by 50% after
48 hours, and can be an effective alternative to cholestyramine
when LEF overdosages need to be managed.
HYDROXYCHLOROQUINE AND SULFASALAZINE
CASE 44-7, QUESTION 4: Would it have been reasonable
to switch B.W. from MTX to either HCQ or SSZ?
Although both HCQ and SSZ are recommended first-line
DMARDs for patients with mild to moderate RA, it is more com-
mon to add either or both of these to the regimen of patients who
are not achieving adequate RA control from MTX.19 HCQ, usu-
ally dosed at 200 to 400 mg daily, is a very well-tolerated DMARD.
The greatest adverse effect of concern, retinal damage, is rare and
easily prevented with diligent monitoring and dose limitations
(see Case 44-5, Question 6). SSZ, dosed at 2 to 3 g per day divided
into two or three doses, is also well tolerated, although toxicity
in general is greater than that with HCQ. GI distress (nausea,
anorexia) and rash are common. Although leukopenia, agranu-
locytosis, and hepatitis are serious side effects, they are rare and,
if they do occur, normally manifest in the first 2 to 3 months of
therapy. As a result, CBC, LFTs, and renal function testing is rec-
ommended more frequently early in the course of therapy (see
Table 44-10). Both HCQ and SSZ appear to be safe in pregnancy.20
MINOCYCLINE
CASE 44-7, QUESTION 5: What evidence is there support-
ing the use of MIN, a tetracycline antibiotic, as a DMARD?
How does it compare with HCQ?
Chapter 44
MIN appears to be a useful adjunctive agent in the treatment
of RA, and its successful use supports a speculation that RA
might have an infectious etiology. It is the immunomodulatory
and anti-inflammatory effects of MIN, however, that more likely
contribute to its efficacy in RA than its antibiotic properties. A
double-blind, placebo-controlled trial involving 46 patients with
Rheumatoid Arthritis
recent-onset RA evaluated the benefit of adding MIN 100 mg
twice daily to conventional therapy with NSAIDs, DMARDs,
and corticosteroids.130 At 4-year follow-up, eight MIN-treated
patients without DMARD or steroid therapy were in remission
compared with one patient in the placebo group (p = 0.02).
Perhaps even more impressive are the results of a ran-
domized trial comparing MIN 100 mg twice daily with HCQ
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1026 200 mg/day in patients with early-onset RA.131 At 2 years, signif-
icantly more MIN-treated patients experienced relief of RA signs
and symptoms, required less prednisone, and were more likely
to be completely tapered off prednisone.
AZATHIOPRINE INDICATIONS AND ADVERSE EFFECTS
CASE 44-7, QUESTION 6: In considering options for B.W.,
AZA is mentioned. B.W. knows someone who is using AZA
for prevention of kidney transplant rejection and thinks AZA
is a highly toxic drug. How can adverse effects to AZA be
minimized?
AZA is FDA approved for transplant rejection prophylaxis
and for treatment of severe RA. The starting dose of AZA for RA
is 1 mg/kg/day in single or divided doses.20 If the patient does
not respond, the dose can be increased by 0.5 mg/kg/day after 6
to 8 weeks, and subsequently increased by the same magnitude
every 4 weeks if needed until a maximal dose of 2.5 mg/kg/day
is reached.
The most common adverse effect of AZA is GI intoler-
ance, and about 10% of patients discontinue therapy because
of this problem.110 Myelosuppression can occur, but is reversible
on discontinuation of therapy. Patients with renal insufficiency
are at increased risk for myelosuppression, and doses should
be adjusted accordingly. Allopurinol decreases metabolism and
elimination of AZA via inhibition of xanthine oxidase, thereby
increasing the risk of toxicity of AZA because of increased serum
concentrations. If concomitant allopurinol therapy cannot be
avoided, the dose of AZA must be reduced by 75%. Monitoring
for AZA adverse effects should include a baseline CBC, renal func-
tion, and LFTs. When AZA doses are increased, a CBC should be
monitored every 1 to 2 weeks; thereafter, a CBC should be mon-
itored every 1 to 3 months. Although serious adverse effects have
limited the use of AZA for RA, diligent laboratory and clinical
monitoring can minimize risk to patients.
D-PENICILLAMINE
CASE 44-7, QUESTION 7: When should D-penicillamine be
considered as therapy for B.W.?
d-Penicillamine is no longer considered for the treatment of
RA because of a lengthy dose titration schedule and serious toxi-
cities (e.g., myelosuppression, autoimmune diseases).19 Because
d-penicillamine must be given in a “go low, go slow” approach
(initial dose usually is 250 mg daily), dose increases cannot be
made sooner than every 4 to 8 weeks. As a result, up to 6 months
of therapy may be necessary before therapeutic benefits become
apparent.
Rash, stomatitis, and dysgeusia are the most common adverse
effects associated with d-penicillamine.20,110 Myelosuppression
Section 9
(particularly thrombocytopenia), proteinuria, renal toxicity, and
autoimmune syndromes (e.g., systemic lupus erythematosus,
myasthenia gravis, polymyositis, Goodpasture syndrome) are
rare but potentially serious adverse effects.8 Baseline laboratory
monitoring includes a renal function test, CBC, and urine pro-
Arthritic Disorders
tein assay. A CBC and urine protein testing should be monitored
every 2 weeks until dosing is stabilized, then every 1 to 3 months
thereafter.
Although B.W. has failed to respond to MTX and LEF,
DMARDs other than d-penicillamine (including biologics) have
a more rapid onset of action, greater efficacy, and less toxicity,
and are therefore preferable.
November 19, 2011 2:2
TRADITIONAL DISEASE-MODIFYING ANTIRHEUMATIC
DRUG COMBINATION THERAPY
CASE 44-7, QUESTION 8: Is there evidence to support the
early and safe use of DMARDs in combination for B.W.?
Because most RA patients develop joint erosions within the
first 2 years of disease, the initiation of disease-modifying agents
early in the course of therapy, and using them in combination,
has been associated with improved patient outcomes. The ratio-
nale for combination therapy is based on the premise that a
combination of drugs might improve outcomes because of dif-
ferent pharmacological mechanisms of action or different sites
of actions. A combination of drugs also may allow the use of
lower doses of individual drugs, thereby reducing the risk of tox-
icity while maintaining or possibly increasing efficacy. The early
use of combinations of potent disease-modifying agents also can
expose the patient to increased risks of drug adverse effects.
Several DMARD combinations are currently recommended
based on literature supporting their efficacy and safety.19 The
combination of MTX and HCQ is recommended for patients
with moderate to high disease activity regardless of prognosis or
disease duration, as well as for patients with low disease activity
and disease duration greater than 24 months. MTX plus LEF is
recommended for patients with high disease activity regardless
of prognosis, but disease duration should be 6 months or longer.
MTX plus SSZ is recommended for patients with poor prognosis
and all disease durations. The combination of HCQ plus SSZ is
recommended for only one circumstance: patients with high dis-
ease activity, no features of poor prognosis, and disease duration
between 6 and 24 months. The triple combination of MTZ, HCQ,
and SSZ is recommended for all patients with moderate to high
disease activity levels and poor prognosis, regardless of disease
duration. In one study, a 2-year disease remission rate of 37%
was associated with this three-drug combination versus 21% in
patients treated with SSZ or MTX monotherapy, with no signifi-
cant differences in adverse effects.132 Another trial compared the
triple-drug regimen with MTX alone and with the combination
of HCQ and SSZ.133 At 2-year follow-up, 77% of the triple-drug–
treated patients responded significantly as compared with 33% of
the patients treated with MTX monotherapy (p <0.001) and 40%
of the patients treated with SSZ plus HCQ (p = 0.003). Toxicity
did not differ among the treatment groups. At 5-year follow-up,
the triple-drug therapy combination remained efficacious and
safe in 36 of 58 patients (62%).
A randomized, controlled trial of 263 MTX-treated patients
with active persistent RA found that the addition of LEF resulted
in significant clinical improvement without an increase in adverse
event and treatment discontinuation rates.134 Similarly, studies
evaluating concurrent use of MTX and HCQ or MTX and SSZ
have demonstrated clinical improvement without significantly
greater adverse events.135,136
As described in the Quantifying Response to Drug Therapy
section, clinical assessment tools (e.g., DAS, CDAI, SDAI, Global
Arthritis Scale, Routine Assessment of Patient Index Data, Easy
Rheumatoid Activity Measure) integrate measures of RA activity
(e.g., swollen joint count, tender joint count, pain, questionnaire-
derived patient- and clinician-evaluated global disease activity)
into a simple summary score.19,71 These scores can be used to
categorize disease severity and modify DMARD or biologic agent
therapy accordingly. The BeSt Study used the DAS44 (44 joints)
to compare four different treatment approaches for patients with
early-onset RA (<2 years). Three of these treatments included
exclusively traditional DMARDs.62 Group 1 patients initially
received MTX monotherapy, with dose escalation and sequen-
tial addition of SSZ and LEF if DAS44 was greater than 2.4.
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Group 2 patients also began therapy with MTX, followed by addi-
tions of SSZ, HCQ, and then prednisone if DAS44 was greater
than 2.4. In contrast, group 3 patients started with a prednisone
taper (60 mg/day tapered down to 7.5 mg/day after 7 weeks),
MTX, and SSZ. Group 4 started with infliximab and MTX. DAS44
was evaluated every 3 months. After 1 year of treatment, all
groups had similar remission rates (defined by DAS44 <1.6), aver-
age DAS44 scores, and adverse events. The BeSt Study demon-
strated that an aggressive, DAS-based titration regimen, using a
variety of traditional-based DMARDs, is a successful method of
using combination DMARD therapy for early RA.
In summary, every RA patient, including B.W., should
receive DMARD therapy at or shortly after diagnosis, either
as monotherapy or as combination therapy depending on dis-
ease duration, disease activity, and prognosis. Although signifi-
cant attention and resources have most recently been invested
in biologic DMARDs, recent evaluations indicate that tradi-
tional DMARDs are equally effective at managing symptoms
and preventing bone and joint destruction. Patients who expe-
rience loss of efficacy or intolerable adverse effects from tradi-
tional DMARDs will need to add another DMARD or substitute
with an alternative DMARD. Various combinations of traditional
DMARDs, when titrated aggressively, have proven to be very
effective in RA management. Results from studies of biologic
DMARDs have demonstrated a reduction in joint erosions along
with symptom improvement, which is why they must also be
considered as therapeutic alternatives to traditional DMARDs.
BIOLOGIC AGENTS
Etanercept: Place in Therapy
CASE 44-7, QUESTION 9: After 6 months of treatment with
nonbiologic DMARDs (MTX with LEF, then MTX with HCQ),
B.W.’s response is inadequate and her RA remains highly
active. She is prescribed etanercept. Why is etanercept a
reasonable therapeutic option?
Etanercept is the first biologic response modifier to be
approved by the FDA for reducing the signs and symptoms of
moderate to severe active RA, either alone or in combination
with MTX.137 Etanercept is also approved for use in juvenile RA,
ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.
Etanercept is a soluble TNF receptor that competitively binds
two TNF molecules, rendering both molecules inactive. Etaner-
cept consists of two extracellular portions of the TNF receptor,
and TNF primarily exists as a trimer in the human body. The
dimeric structure of etanercept is believed to have a higher bind-
ing affinity for the trimeric TNF than the naturally occurring
monomeric receptor.
In a randomized, placebo-controlled trial of 234 patients with
active RA, significantly more patients met ACR-20 criteria after 6
months of treatment with etanercept 10 mg (51% of patients) and
25 mg (59% of patients) than with placebo (11%).30 Etanercept
was administered subcutaneously twice weekly for 26 weeks.
All patients who were enrolled in this study had experienced an
inadequate response to at least one of several DMARDs, simi-
lar to patient B.W. Furthermore, 24% and 40% of the patients
taking etanercept 10 mg and 25 mg, respectively, met ACR-
50 response criteria compared with 5% of the placebo group
(p <0.001 for both doses compared with placebo, no signifi-
cant difference between doses). Significant ACR-20, ACR-50, and
ACR-70 responses to either etanercept dose were seen after only
2 weeks of therapy.
Another randomized, placebo-controlled trial evaluated the
use of combination MTX and etanercept therapy in 89 patients
November 19, 2011 2:2
with active RA refractory to at least 6 months of MTX therapy.138 1027
A dose of 25 mg etanercept or placebo was given subcutaneously
twice weekly, and a stable dose of MTX (between 15 and 25
mg/week) was provided to all patients. At 24 weeks of follow-up,
an ACR-20 response was found in 71% of the MTX plus etaner-
cept group and 27% of the MTX plus placebo group (p <0.001).
Similarly, 39% of the MTX plus etanercept group met ACR-50
response criteria compared with 3% of the MTX plus placebo
group (p <0.001). Etanercept was also associated with signifi-
cantly greater improvement in ESR or CRP test results. The addi-
tion of etanercept to MTX provided greater clinical efficacy when
compared with MTX monotherapy. Etanercept provides rapid
and significant improvement in subjective and objective measures
of RA, either alone or in combination with MTX. In other stud-
ies, etanercept has demonstrated decreased radiographic pro-
gression and long-term safety and efficacy.139–141 Although cost
is a significant consideration, etanercept is a reasonable choice
for B.W.
Dosing and Monitoring
CASE 44-7, QUESTION 10: How should etanercept therapy
be initiated in B.W., and what are the most common and
serious potential adverse effects about which she should
be counseled?
The FDA-approved dose of etanercept for the treatment of
active RA is 50 mg once weekly with or without MTX.137 This
medication may be self-injected subcutaneously by the patient
after proper training. Etanercept is available in a prefilled syringe
or a multiple-use vial. If the multiple-use vial is used, it must
be reconstituted using only the diluent supplied; the contents
should be swirled, not shaken, to avoid excessive foaming. Injec-
tion sites (e.g., thigh, abdomen, upper arm) should be rotated.
Clinical response usually appears within 1 to 2 weeks of treat-
ment, and nearly all patients respond within 3 months. In fact,
patients who fail to respond to DMARD or biologic agent therapy
within 3 months should receive consideration for an alternative
treatment. When reviewing pooled data from early RA trials,
which evaluated MTX, anti-TNF, and the combination of MTX
with anti-TNF, a significant response at 3 months correlated with
response 1 year after start of therapy based on SDAI, CDAI, and
DAS28 scores.142
Injection site reactions (37% vs. 10% with placebo), upper
respiratory infections (29% vs. 10% with placebo), and the devel-
opment of autoantibodies are encountered with etanercept treat-
ments. Injection site reactions generally are mild to moderate in
severity and usually occurred within the first month of treatment
with decreased frequency with time. Upper respiratory infections
(e.g., sinusitis) occur at a rate of 0.82 events per patient-year in
patients treated with etanercept versus 0.68 events per patient-
year in the placebo group. Autoantibodies that developed dur-
ing etanercept treatment included ANA (11% vs. 5% in placebo
Chapter 44
group) and new positive anti–double-stranded DNA antibodies
(15% vs. 4% in placebo group). Patients with severe heart fail-
ure (e.g., NYHA class III or IV) may be at increased risk for
heart failure exacerbation and mortality when taking any anti-
TNF agent.19,20,141 Although not a contraindication, caution is
advised if etanercept is prescribed for patients with heart failure.
Rheumatoid Arthritis
An increased incidence of lymphoma has been observed among
patients with RA receiving any of the available anti-TNF agents;
however, causation has not been established because both RA and
MTX are associated with an increased rate of lymphoma.137 Addi-
tionally, the FDA has recently received reports of hepatosplenic
T-cell lymphoma, a rare cancer of the white blood cells, in patients
being treated with TNF blockers, AZA, or mercaptopurine. The
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1028 majority of these cases were found in adolescents and young
adults with Crohn’s disease or ulcerative colitis. Incidence was
also more common in patients on a combination of immuno-
suppressant agents. Although it is difficult to measure the added
risk associated with anti-TNF agents, caution and monitoring
is advised.143 Other adverse effects, in order of decreasing fre-
quency, include headache, rhinitis, dizziness, pharyngitis, cough,
asthenia, abdominal pain, and rash.
The greatest concern with etanercept therapy is the risk of
immunosuppression and subsequent serious infections, includ-
ing sepsis. TNF-α is a key mediator of inflammation and plays
a major role in immune system regulation. Approximately 6
months after FDA approval of etanercept, 30 patients receiving
etanercept experienced serious infections.137 Although the num-
ber of reports was not more than what was expected from clinical
trials, six of these patients died within 2 to 16 weeks of starting
therapy. Postmarketing reports of other infections such as TB (a
black-box warning for all anti-TNF agents), mycobacterial infec-
tions, and fungal infections further reinforces the strong recom-
mendation against the initiation of etanercept therapy in patients
with sepsis or any chronic or localized active infection.8,19,20
Mycobacterium tuberculosis skin testing and a baseline chest radio-
graph should be undertaken before initiation of anti-TNF ther-
apy. Therapy should be postponed for patients identified as hav-
ing latent TB until appropriate antituberculosis therapy has been
completed. Clinicians also must be cautious when prescribing
etanercept to patients with a history of recurring infection or
with underlying illnesses that predispose them to infection (e.g.,
diabetes). B.W. should receive a TB skin test, undergo a chest
radiograph, and be warned of the potential adverse effects of
etanercept, particularly the risk of immunosuppression and sub-
sequent infection. Any sign of infection must be reported imme-
diately to her health care provider.
INFLIXIMAB AND ADALIMUMAB: DOSING AND PLACE
IN THERAPY
CASE 44-7, QUESTION 11: After 3 weeks of etanercept
therapy, B.W. seems to respond well. However, she dislikes
the subcutaneous administration of etanercept once weekly
and wants another medication that can be administered on
a more convenient basis. How do the other TNF inhibitors
differ from etanercept? Is B.W. a candidate for one of these
alternatives?
Four anti-TNF monoclonal antibodies are FDA approved for
the treatment of RA. Infliximab and adalimumab have been avail-
able since 1998 and 2002, respectively. CZP and GLM have been
available since 2008 and 2009, respectively, and will be discussed
in the next section.
Infliximab is a chimeric (mouse–human) IgG antibody
directed against TNF that is approved for the treatment of a
variety of conditions including Crohn’s disease, ulcerative col-
itis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis,
Section 9
and RA. Specifically, infliximab is approved in combination with
MTX for the treatment of moderately to severely active RA.144
The usual dose of infliximab is 3 mg/kg IV at 0, 2, and 6 weeks,
then every 8 weeks thereafter; thus, the convenience of infre-
quent dosing is tempered by the need for supervised IV adminis-
Arthritic Disorders
tration. Infliximab should be given with MTX therapy to prevent
the formation of antibodies to infliximab.
In a randomized, placebo-controlled trial of 101 patients
with active RA who responded suboptimally to MTX therapy,
60% of patients receiving 3 or 10 mg/kg of infliximab with
or without MTX (7.5 mg/week) responded to treatment after
26 weeks.145 In another randomized, double-blind, multicenter,
placebo-controlled trial of 428 active RA patients who failed to
November 19, 2011 2:2
respond adequately to at least 12.5 mg/week of MTX, inflix-
imab 3 or 10 mg/kg or placebo was administered every 4 or 8
weeks along with MTX therapy. This study was unblinded after
1 year because of radiographic evidence of disease modification
in patients receiving infliximab. Analysis of radiographic results
after 2 years demonstrated that infliximab significantly protected
against joint erosion.146
Adalimumab is a genetically engineered, fully humanized
IgG1 monoclonal antibody, as opposed to the chimeric inflix-
imab. Adalimumab is self-administered subcutaneously by the
patient as a 40-mg injection every other week, either as monother-
apy or in combination with traditional DMARDs (e.g., MTX).147
When administered weekly or every other week, monotherapy
with adalimumab 40 mg significantly improved ACR-20 response
rates in a randomized, controlled trial of 544 RA patients refrac-
tory to traditional DMARDs.148 Patients receiving 40 mg/week
had a higher response rate than patients who received the drug
every other week. When adalimumab 40 mg every other week
was added to the treatment regimen of RA patients receiving sta-
ble MTX doses, significantly more adalimumab-treated patients
(67%) achieved an ACR-20 response than those receiving only
MTX (14.5%, p <0.001) after 24 weeks.149 In radiographic data
reflecting 1 or 2 years of treatment, adalimumab slowed the pro-
gression of joint damage.150 Data are available supporting the
efficacy and safety of adalimumab for more than 8 years.151
Adverse Effects of Anti-Tumor Necrosis Factor Antibodies
Infliximab and adalimumab have treatment risks and side effect
profiles very similar to etanercept (e.g., injection site pain,
local reactions, upper respiratory tract infections, nausea, flulike
symptoms, rash).147 Serious adverse effects (e.g., serious infec-
tions, increased incidence of lymphoma) are similar as well. As
with all anti-TNF agents, a TB skin test result and chest radio-
graph must be obtained before initiating treatment. The devel-
opment of antibodies against infliximab occurs frequently with
monotherapy owing to the chimeric nature of the medication,
and concurrent use with MTX decreases the formation of these
HACA antibodies. Although adalimumab is a fully humanized
product, approximately 5% of patients develop antibodies against
it at least once during therapy when used as a single agent.148
This reaction is attenuated with weekly dosing of adalimumab or
concurrent use of MTX. Patients who switch from one anti-TNF
agent to another owing to loss of efficacy of the initial agent are
able to attain a good response from the second.152,153 After the
switch, many patients respond even better to the second drug as
demonstrated by HAQ score improvement.154
B.W. seems to be a reasonable candidate for either infliximab
or adalimumab therapy. Her interest in a biologic agent with less
frequent dosing is understandable. Although clinical trials have
not directly compared the biologic agents, key differentiating
variables among these drugs need to be considered. No evidence
suggests that there are any significant efficacy differences among
etanercept, infliximab, and adalimumab. Although infliximab is
ultimately administered every 2 months, it must be administered
IV and in combination with MTX (or possibly at a higher dose) to
minimize HACA formation. Adalimumab’s ease of administra-
tion (self-injected subcutaneous injection) and infrequent dosing
interval compares favorably with etanercept (once-weekly injec-
tions) and anakinra (daily injections), but it is administered more
frequently than infliximab (Table 44-6). Although it is difficult to
estimate exact costs of these agents, the ACR lists approximate
annual costs to be similar among etanercept, infliximab, and adal-
imumab ($15,436, $13,940, and $14,522, respectively).155 These
costs are subject to change based on patient weight for infliximab,
and optional adjusted intervals for adalimumab and infliximab.
Additional therapeutic benefit might be achieved from weekly
dosing of adalimumab or monthly dosing of infliximab.144,147
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If the dosing interval is decreased, the costs of therapy would
increase considerably.
Anti-TNF Agents: Dosing, Administration, Efficacy,
and Safety
CASE 44-7, QUESTION 12: B.W.’s physician has little experi-
ence with the two newest anti-TNF-α agents CZP and GLM.
He would like to know how these newer agents compare
with the older TNF-α inhibitors in regard to efficacy, safety,
and administration.
CZP and GLM have demonstrated similar efficacy and safety
data when compared with the other approved TNF-α inhibitors.
CZP is a novel pegylated anti-TNF agent approved for the treat-
ment of adult patients with moderately to severely active RA and
Crohn’s disease.31 CZP consists of a Fab attached to a 40-kDa
PEG moiety. The attachment to the PEG moiety increases the
half-life of CZP to approximately 2 weeks, which allows dosing
every 2 to 4 weeks.156 Additionally, CZP’s unique structure lacks
an Fc region, so it may not induce complement- or antibody-
dependent cell-mediated cytotoxicity, which has been observed
in vitro with adalimumab, etanercept, and infliximab.157
The efficacy of CZP has been demonstrated in patients with
moderate to severe active RA in combination with MTX and
as monotherapy.158–161 In a randomized, double-blind, placebo-
controlled study in 619 patients with active RA, significantly more
patients met ACR-20 response rates at week 24 with CZP 200
mg and 400 mg plus MTX (57.3% and 57.6%, respectively) than
patients treated with placebo plus MTX (8.7%, p <0.001).160
Additionally, ACR-50 and ACR-70 response rates were signifi-
cantly improved in the CZP treatment groups versus the placebo
group (p <0.001). Physical function, as evidenced by the mean
change in the HAQ disability index (DI) score, as well as DAS28
remission were improved in patients who received combination
treatment compared with MTX monotherapy. CZP 200 mg and
400 mg also significantly inhibited radiographic progression of
RA.160 An open-label extension of this trial demonstrated that
ACR responses and improvements in DAS28, HAQ-DI, and pain
from baseline were sustained for patients remaining on CZP for
up to 3 years. The progression of structural damage was sustained
until the final radiograph evaluation at 2.5 years.161
GLM is a human IgG1 monoclonal antibody specific for
human TNF-α. It was created using genetically engineered mice
immunized with human TNF. GLM binds to both the soluble
and transmembrane bioactive forms of human TNF. This bind-
ing prevents the binding of TNF-α to its receptors, thus inhibiting
the biologic activity of TNF-α.32 GLM shares common charac-
teristics with both adalimumab and infliximab. Similar to adal-
imumab, GLM is a fully humanized bivalent immunoglobulin
monoclonal antibody.162 GLM is made up of light and heavy
chains, which are identical to infliximab, but whereas infliximab is
derived from both mice and humans, GLM is completely human-
ized. GLM is approved for the treatment of moderate to severe
active RA in combination with MTX, as well as active psoriatic
arthritis and active ankylosing spondylitis.32
Clinical trials have demonstrated GLM efficacy in patients
with no previous MTX use and in patients with an inadequate
response to MTX or a TNF-α inhibitor.163,164 A randomized,
placebo-controlled trial conducted in 444 patients examined the
efficacy of GLM in patients with active RA despite concomi-
tant MTX use.165 In this double-blind, four-arm, dose-ranging,
52-week trial, patients were allowed stable doses of NSAIDs and
corticosteroids, but no history of prior biologic use. Significantly
more patients in the combined GLM plus MTX groups achieved
an ACR-20 response compared with the MTX plus placebo group
November 19, 2011 2:2
(55.6% vs. 33.1%, respectively, p <0.001). These results were sus- 1029
tained at 52 weeks.
A Cochrane review of the efficacy and safety data available
for GLM showed that patients treated with GLM plus MTX were
2.6 times more likely to reach ACR-50 and were no more likely
to have any adverse event when compared with patients treated
with placebo plus MTX. Additionally, patients treated with GLM
were significantly more likely to achieve remission, low disease
activity, and improvement in functional ability compared with
patients treated with placebo.166
Adverse Effects and Safety
CZP and GLM have been found to be generally well tolerated,
with similar safety profiles to the other anti-TNF agents.31,32 As
with all of the anti-TNF agents, the labeling for these agents
contains black-box warnings for increased risk of serious infec-
tions, and lymphoma and other malignancies. The manufacturer
recommends that all patients be screened for latent TB before
treatment. Patients found to be TB positive should initiate TB
treatment before therapy (see Case 44-7, Questions 10 and 11).
For CZP, the most commonly reported infectious adverse
effects included urinary tract infections, nasopharyngitis, and
upper respiratory tract infections.31 Serious infections were
observed more frequently in the CZP groups than in the placebo
group (5.3 and 7.3 per 100 patient-years in the 200-mg and 400-
mg CZP groups, respectively, versus 2.2 per 100 patient-years in
the placebo group).167 The incidence of injection site pain was
low across all randomized, controlled trials. A 2-year open-label
extension of one randomized, controlled trial showed no evi-
dence of increased incidence of adverse effects after longer-term
exposure to CZP.168 The overall percentage of patients with anti-
bodies to CZP detectable on at least one occasion was 7% (105
of 1,509 patients). Patients treated with concomitant immuno-
suppressants (MTX) had a lower rate of antibody development
than patients not taking immunosuppressants at baseline.31
GLM has also produced relatively consistent data across avail-
able clinical trials. In one randomized, controlled clinical trial
injection site reactions occurred most commonly in patients
receiving GLM 100 mg (8.8%–10.8%), followed by GLM 50 mg
plus MTX (4.4%), and placebo plus MTX (1.9%).169 Incidence of
injection site reactions were similar across clinical trials, and in
all studies none of the injection site reactions were considered
severe or resulted in discontinuation of the study drug.110,169,170
Based on the summarized data from four randomized, controlled
trials, GLM 50 mg was associated with no significantly higher risk
of infections, serious infections, lung infections, TB, cancer, or
death than placebo.166 The presence of MTX treatment has been
shown to decrease anti-GLM antibody incidence.32
Dose and Administration
For the treatment of moderately to severely active RA, CZP is
initiated with a dose of 400 mg injected subcutaneously at weeks
0, 2, and 4, and maintained with 200 mg per week every other
Chapter 44
week thereafter.31 A more convenient dosing regimen of 400
mg every 4 weeks can be considered. CZP is self-administered
subcutaneously in 200 mg/mL prefilled syringes or as a
lyophilized powder for reconstitution. The lyophilized powder
solution should be reconstituted and administered by a health
care professional.171 For a video demonstration on how to
Rheumatoid Arthritis
use the prefilled syringe, please go to http://www.cimzia.com/
rheumatoidarthritis/hcp/dosing-administration/cimziapre-
filled-syringe.aspx.
The usual dose of GLM is 50 mg/0.5 mL administered sub-
cutaneously every 4 weeks. GLM is administered every 4 weeks,
but has similar pharmacokinetics to adalimumab, which is dosed
every 2 weeks; thus, dosing may be adjusted for each drug based
on patient response to therapy. The dosing regimen for GLM does
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1030 not require adjustment for patient weight, age, sex, or ethnicity.32
It is available as a single-dose prefilled SmartJect autoinjector or
as a single-dose prefilled syringe. GLM may be self-injected by
patients. For an instructional video on how to use the GLM
SmartJect autoinjector, go to https://www.simponi.com/
about-simponi/smartject-autoinjector. For a video demon-
stration on how to use the prefilled syringe, please go to https://
www.simponi.com/about-simponi/prefilled-syringe.
ANAKINRA
CASE 44-7, QUESTION 13: B.W. would prefer to avoid
anakinra because it requires daily subcutaneous injection
dosing. Apart from this inconvenience, how does anakinra
compare with the anti-TNF agents?
Anakinra is currently the only available IL-1Ra that is almost
identical in composition to human IL-1Ra (see Biologic Agents
in the Treatment section). Anakinra is approved for the treat-
ment of moderate to severe active RA in patients who have failed
one or more DMARDs. It may be used alone or in combina-
tion with MTX or other DMARDs.172 The recommended dose
of anakinra is 100 mg daily by self-administered subcutaneous
injection.20 Anakinra significantly, but modestly, improves signs
and symptoms and radiographic evidence of joint erosion in
RA patients.20,173 In a study of 472 patients with serious active
RA, three different doses of anakinra monotherapy (30, 75, and
150 mg/day) were compared with placebo.174 At 24-week follow-
up, 34% of patients receiving anakinra 75 mg demonstrated an
ACR-20 response; however, 27% of placebo patients achieved
the same response. Although modest, this difference is statisti-
cally significant. Although the higher dose of 150 mg produced
improvement in 43% of patients, this dose exceeds the manu-
facturer’s recommended dose. The most commonly reported
adverse event with anakinra is local injection site reaction. Injec-
tion site reactions have been reported in up to 71% of clinical trial
patients, usually occurring within the first month of treatment.172
Although neutropenia and severe infections are more common
with anakinra than placebo, there have been no reports of patients
experiencing TB reactivation. Combining anakinra with an anti-
TNF agent seems to be logical based on their different mecha-
nisms of action; however, the combination is not recommended
because of a significantly increased incidence of serious infec-
tions and leukopenia.172 Unlike anti-TNF agents, anakinra is not
associated with decompensation of heart failure.
Although the anti-TNF agents have not been compared
directly, anakinra seems to be relatively less effective. In a
Cochrane review of biologic agents for RA, anakinra was found
to be less effective when trial data were compared with data for
TNF-α inhibitors, RXB, and abatacept.65 In addition, the advan-
tage of being able to self-administer anakinra is offset by the need
for daily injections. Anakinra is a therapeutic alternative for RA
patients in whom traditional DMARD treatment fails; however,
it seems to offer no advantages and some real and potential dis-
Section 9
advantages when compared with the other available biologic
agents.
MANAGEMENT OF METHOTREXATE NONRESPONDERS
Arthritic Disorders
CASE 44-8
QUESTION 1: S.K., a 71-year-old woman, was diagnosed
with RA approximately 15 years ago. Her initial drug ther-
apy included MTX, followed by the addition of SSZ and
HCQ, which seemed to keep her RA in near-remission until
2002. She began etanercept along with MTX (without SSZ
and HCQ) with good results until 2005. In response to
November 19, 2011 2:2
declining disease control, infliximab was substituted for
MTX with excellent results. Then last month, she experi-
enced a flare in RA activity. At that time, her CRP was 5.1
mg/dL, ESR was 90 mm/hour, and anti-CCP was positive at
112 units. She also experienced morning stiffness lasting
several hours and multiple joints with swelling (n = 26) and
tenderness (n = 38). What are reasonable treatment options
for S.K. at this stage of her disease?
Clinical studies have consistently demonstrated that TNF-α
inhibitors improve the signs and symptoms of RA, as well as
slow the progression of structural damage. However, TNF-α
inhibitors fail to produce an ACR-20 response in approximately
30% of patients (primary failure). Even more patients experience
acquired resistance to treatment, known as secondary failure,
which is defined as a loss of response with time and is illustrated
by S.K.175 Most patients who lose responsiveness to an initial trial
of anti-TNF therapy can often be successfully treated with an
alternative anti-TNF agent (see Case 44-7, Questions 11 and 12).
However, no evidence supports switching to a third anti-TNF
agent if the first two agents fail. Abatacept (inhibitor of T-cell
activation), RXB (selective depletor of CD20+ B cells), and TZB
(anti-IL-6 receptor antibody) have demonstrated great potential
to fill this void. These agents have demonstrated excellent efficacy
in patients with inadequate response to traditional DMARDs
(e.g., MTX) as well as to anti-TNF therapy (see discussion in
Treatment section, Biologic Agents).19,155 Although there is a
lack of head-to-head comparisons of these agents, there is a
strong body of evidence detailing efficacy and safety data for
each agent, which will be considered for S.K.
Abatacept
Abatacept is a selective costimulation inhibitor of T-cell acti-
vation indicated for the treatment of moderately to severely
active RA.41 Abatacept may be prescribed as monotherapy or in
combination with other DMARDs other than TNF antagonists.
The Abatacept in Inadequate Responders to Methotrexate (AIM)
study compared abatacept 10 mg/kg plus MTX versus placebo
plus MTX.44 At 12-month follow-up, significantly more patients
in the abatacept group attained ACR-20 response when compared
with the placebo group (73.1% vs. 39.7%, respectively, p <0.001).
Patients in the abatacept group also achieved better quality-of-life
survey scores. After 1 year of abatacept therapy, patients demon-
strated statistically significant slowing of structural damage pro-
gression compared with patients receiving placebo. Abatacept
efficacy was maintained in the 5-year open-label extension of
this trial. At year 5, 83.6% of patients had achieved ACR-20 and
33.7% had achieved DAS28 remission.176 Structural damage pro-
gression was reduced by 50% in the second year relative to the
first year, with approximately half (45.1%) of the 120 patients
who completed all 5 years of abatacept treatment exhibiting no
structural damage progression.
Abatacept has also demonstrated efficacy in patients such
as S.K. with an inadequate response to one or more TNF-α
inhibitors. In the Abatacept Trial in Treatment of Anti-TNF Inad-
equate Responders study, patients in the abatacept arm achieved
an ACR-20 response of 50.4% compared with 19.5% in the
placebo arm.177 The ACR-50 and ACR-70 responses were also
significantly improved in the abatacept arm versus the placebo
arm. Efficacy and safety data from 7 years of abatacept ther-
apy indicate that abatacept maintains sustained improvements
in disease activity and ACR-70 scores during this period, with no
change in safety profile.46
The side effects of greatest concern include infections such
as pneumonia, cellulitis, urinary tract infection, bronchitis,
diverticulitis, and acute pyelonephritis (see Treatment section,
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Biologic Agents). Infections are significantly more common
when abatacept is combined with anti-TNF therapy; thus this
combination is not recommended.41 A few case reports of
malignancy have been associated with abatacept, and patients
with chronic obstructive pulmonary disease are noted to suf-
fer from more respiratory-related and nonrespiratory-related
adverse effects than patients with chronic obstructive pulmonary
disease treated with placebo.41
Rituximab
RXB is a chimeric monoclonal antibody that binds to the antigen
CD20 on B cells. It is approved in combination with MTX for the
treatment of moderately to severely active RA in patients who
have had an inadequate response to one or more TNF antago-
nist medications. In a placebo-controlled trial of 161 RA patients
who responded inadequately to MTX therapy (≥10 mg/week),
the ACR-50 response was significantly higher among treatment
groups receiving RXB (33%, 41%, and 43% in the RXB only,
RXB plus cyclophosphamide, and RXB plus MTX groups, respec-
tively) versus the MTX only group (13%). At week 48, however,
significantly more patients in the RXB plus MTX group (35%)
maintained an ACR-50 response than patients in the RXB plus
cyclophosphamide group (27%). Although cyclophosphamide is
reserved for severe cases of RA (usually involving rheumatoid
vasculitis), the combination of RXB plus cyclophosphamide does
not seem to be as effective as RXB plus MTX.178
The REFLEX (Randomized Evaluation of Long-Term Effi-
cacy of Rituximab in RA) trial evaluated the use of RXB (two
IV infusions 2 weeks apart, 1,000 mg/infusion) plus MTX versus
placebo plus MTX in 499 patients with active, long-standing RA
who responded inadequately to one or more anti-TNF medica-
tions, such as S.K.179 At 24-week follow-up, significantly more
patients in the RXB group demonstrated an ACR-20 response
than those in the placebo group (51% vs. 18%, respectively).
Peripheral CD20+ B cells were depleted among RXB-treated
patients at about 4 to 5 months after treatment. The incidence of
all side effects was similar in the two treatment groups (85% of
RXB patients, 88% of placebo patients), as were side effects iden-
tified as being related to any of the study drugs, including placebo
(39% and 47%, respectively). Infusion reactions were common
during or soon after the first dose among RXB-treated patients
(23% vs. 18% of placebo patients). In another randomized, con-
trolled trial, it was found that premedication with IV methyl-
prednisolone reduced the frequency and intensity of first infu-
sion adverse drug reactions, but the addition of oral prednisone
did not provide additional benefit.179 The rate of infections was
slightly higher among RXB patients (41%) than placebo patients
(38%). Similarly, the rate of serious infections was higher among
RXB than placebo-treated patients (5.2 versus 3.7 per 100 patient-
years). No cases of TB or opportunistic infections were reported.
In a 56-week follow-up report of the REFLEX trial, RXB signifi-
cantly inhibited radiographic progression of joint damage.180 In
the 2-year extension of this trial, MTX showed significant and
sustained inhibition of joint damage. Patients were eligible for
repeat courses of RXB every 6 months. Within the RXB group,
87% who had no progression of joint damage at 1 year remained
nonprogressive at year 2. These findings support the efficacy and
appropriateness of RXB for RA patients such as S.K. who are
refractory to anti-TNF therapy.
The safety and efficacy of repeated courses of RXB was
reported in an open-label extension analysis of three randomized,
controlled trials. Patients were eligible for retreatment with RXB
if they demonstrated a greater than or equal to 20% reduction in
both the swollen joint count and the tender joint count at any visit
16 weeks after initial treatment or later and had active disease,
defined as a swollen joint count of 8 (in 66 joints) or a tender
joint count of 8 (in 68 joints). Patients were eligible for addi-
November 19, 2011 2:2
tional courses after the second course if they had active disease 1031
as described above.181 A minimum interval of 16 weeks between
courses was required. Retreatment courses were administered
as 1,000 mg on days 1 and 15. The ACR (20, 50, and 70) response
rates at week 24 were comparable after courses 1 and 2 of RXB.
Additionally, EULAR good and moderate response rates were
comparable after course 2 compared with course 1, and EULAR
remission was doubled after course 2 compared with course 1.
Safety data were consistent with previous trials and retreatment
demonstrated no additional safety issues.
Although repeated treatment with RXB has demonstrated
efficacy and raised no additional safety concerns, it is still unclear
what dosage regimen is optimal for retreatment. Another ran-
domized trial studied the safety and efficacy of various repeat
treatment regimens for RXB.182 The results of this trial showed
no statistically significant difference between retreatment with
RXB 500 mg on days 1 and 15, 500 mg on day 1 and 1,000 mg on
day 15, or 1,000 mg on days 1 and 15. The 1,000 mg × 2 group pro-
duced consistently improved ACR and EULAR response rates;
however, statistical significance was not reached. It was found
that retreatment at week 24 produced sustained benefits through
week 48.
Tocilizumab
TZB is a humanized anti-IL-6 receptor antibody indicated for the
treatment of adult patients with moderately to severely active RA
who have had an inadequate response to one or more TNF antag-
onist therapies, such as S.K.43 It may be prescribed as monother-
apy or in combination with MTX or other DMARDs other than
TNF antagonists. In a double-blind, placebo-controlled, multi-
center study of 1,216 patients with moderately to severely active
RA despite treatment with DMARDs, the ACR-20 response was
significantly higher in the TZB 8 mg/kg than in the placebo
group (61% and 25% respectively, p <0.0001) at week 24.183 The
superiority of TZB plus DMARD therapy versus placebo plus
DMARD therapy was also demonstrated with improved results
for all of the secondary end points (ACR-50, ACR-70, DAS28,
DAS28 remission [<2.6], and CRP and hemoglobin levels).
In another 24-week double-blind, placebo-controlled, multi-
center trial (RADIATE), 499 patients with an inadequate response
to one or more TNF-α inhibitors were randomly assigned to
receive 8 mg/kg or 4 mg/kg of TZB or placebo every 4 weeks
for 24 weeks.184 An ACR-20 response was achieved at 24 weeks
by 50.0%, 30.4%, and 10.1% of patients in the TZB 8 mg/kg, 4
mg/kg, and placebo arms, respectively (p <0.001). The impact of
TZB on radiographic progression of RA compared with conven-
tional DMARD therapy was studied in 302 Japanese patients with
active RA.185 At week 52, patients in the TZB group showed sig-
nificantly less radiographic progression compared with the tra-
ditional DMARD group. However, it remains unclear how these
changes translate to patient quality of life or disability.
The most serious side effects associated with TZB therapy
include severe infections, GI perforation, and laboratory abnor-
Chapter 44
malities (see Treatment section, Biologic Agents). As with the
TNF-α inhibitors, TZB has a black-box warning for increased
risk of developing serious infections, especially those caused by
opportunistic pathogens. The risk for infection is increased when
TZB is taken in combination with other immunosuppressant
agents (e.g., MTX, corticosteroids). As with the anti-TNF agents,
Rheumatoid Arthritis
a TB skin test result and chest radiograph must be obtained before
initiating treatment. In clinical studies the rates of serious infec-
tions in the 4-mg/kg and 8-mg/kg TZB plus DMARD groups
were 4.4 and 5.3 events per 100 patient-years, respectively, com-
pared with 3.9 events per 100 patient-years in the placebo plus
DMARD group. The most common serious infections included
pneumonia, urinary tract infection, cellulitis, herpes zoster,
gastroenteritis, diverticulitis, sepsis, and bacterial arthritis. The
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1032 overall rate of fatal serious infections was low at 0.13 per
100 patient-years.43
The risk of GI perforation is also connected with TZB use,
with a rate of 0.26 per 100 patient-years in the 6-month controlled
clinical trial population. The reports of GI perforation in these
trials were primarily found to be complications of diverticulitis;
thus patients with a history of diverticulitis should be monitored
closely.20,43
TZB has also been associated with a number of blood chem-
istry changes including neutropenia, thrombocytopenia, ele-
vated LFTs, and lipid changes. In the 6-month, controlled clinical
studies, decreases in neutrophil counts to less than 1,000 cells/µL
occurred in 1.8% and 3.4% of patients in the 4-mg/kg and 8-mg/kg
TZB plus DMARD groups, respectively, compared with 0.1%
of patients in the placebo plus DMARD group. A relationship
between decreases in neutrophils less than 1,000 cells/µL and
the occurrence of serious infections was not established. Platelet
counts less than 100,000 platelets/µL occurred in 1.3% and 1.7%
of patients on 4 mg/kg and 8 mg/kg TZB plus DMARD, respec-
tively, compared with 0.5% of patients on placebo plus DMARD,
without associated bleeding events. In the 6-month, controlled
clinical studies, increases in ALT to 3 times the ULN occurred in
45% and 48% of patients in the 4-mg/kg and 8-mg/kg TZB plus
DMARD group, respectively, compared with 23% of patients
in the placebo plus DMARD group. In patients experiencing
liver enzyme elevations, modifications of the treatment (dosage
adjustment of TZB or concomitant DMARD or interruption of
TZB therapy) regimen resulted in decrease or normalization of
liver enzymes. Liver enzyme elevations were not associated with
clinical evidence of hepatitis or hepatic insufficiency. Increases
in lipids (total cholesterol, low-density lipoprotein, high-density
lipoprotein, and triglycerides) have been shown in clinical trials.
This increase in lipids may be caused in part by the decrease in
inflammatory activity with TZB use. Lipid elevations respond
to lipid-lowering agents, and further studies are necessary to
assess the effects of TZB on cardiovascular risk factors. The most
common adverse reactions with TZB include upper respiratory
tract infections, nasopharyngitis, headache, hypertension, and
increased ALT.43
In addition to the role of IL-6 on the joint inflammation associ-
ated with RA, IL-6 also participates in osteoclast maturation and
activation and may alter osteoblast differentiation and function.49
Systemic and periarticular bone loss, which is associated with
severe RA, is correlated with increased IL-6 levels in the bone mar-
row. In patients with RA, increased levels of IL-6 are present in
the serum and synovial fluid. The impact of IL-6 inhibition with
TZB on bone health has been examined in one randomized, con-
trolled trial. This study included 416 of the 623 patients included
in the OPTION study. In this study, TZB treatment resulted in
dose-dependent decreases in markers of bone resorption and car-
tilage turnover and increased bone formation markers.186 More
data are needed to assess the impact of TZB on bone health and
fracture risk.
Section 9
Dosing and Administration for Abatacept, Rituximab,
and Tocilizumab
Abatacept is supplied as a lyophilized powder in preservative-
free, single-use vials containing 250 mg of abatacept.41 Abatacept
must be reconstituted with 10 mL of sterile water for injection,
Arthritic Disorders
using only the silicone-free syringe provided, along with an 18- to
21-gauge needle. Reconstitution using a siliconized syringe can
result in the development of translucent particles in the medica-
tion solution; solutions prepared using siliconized syringes must
be discarded. The reconstituted solution must be diluted to 100
mL using 0.9% sodium chloride, with a final concentration of no
more than 10 mg/mL. Abatacept dosing is based on body weight
November 19, 2011 2:2
(500 mg for patients <60 kg, 750 mg for patients 60–100 kg, and
1,000 mg for patients >100 kg) and should be infused IV for 30
minutes. The abatacept dose should be repeated at 2 and 4 weeks
after the first dose, then every 4 weeks thereafter. Abatacept can
be given as monotherapy or in combination with nonbiologic
(traditional) DMARDs.20
RXB, provided in 100-mg and 500-mg single-use vials at a
concentration of 10 mg/mL, is administered as two 1,000-mg IV
infusions separated by 2 weeks.42 RXB must be diluted to a final
concentration of 1 to 4 mg/mL with either 0.9% sodium chloride
or 5% dextrose in water. To reduce the incidence and severity of
infusion-related adverse effects, premedication with IV methyl-
prednisolone 100 mg, or its equivalent, 30 minutes before each
infusion is strongly recommended; other premedications (e.g.,
acetaminophen, antihistamine) may also be beneficial. Antihy-
pertensive medications should be discontinued 12 hours before
RXB administration to avoid transient hypotension, which has
been reported during RXB infusions. RXB must be given with
MTX for maximal efficacy based on clinical trials and to help
reduce the risk of developing HACA, which occurs in approxi-
mately 9% of patients receiving RXB.
The first IV infusion of RXB solution should be initiated at
a rate of 50 mg/hour. In the absence of infusion reactions, the
infusion rate can be increased in 50-mg/hour increments every
30 minutes to a maximal rate of 400 mg/hour. In the event of
an infusion reaction, the infusion should be halted or slowed
until symptoms improve, at which time the infusion can con-
tinue at one-half the previous rate. In patients who tolerated the
first infusion well, subsequent infusions of RXB can be initiated
at a higher rate (100 mg/hour) and increased by 100-mg/hour
increments every 30 minutes to a maximal rate of 400 mg/hour.
Patients poorly tolerant to the first infusion should receive sub-
sequent RXB infusions at 50 mg/hour.42 It is recommended that
subsequent courses of RXB be given every 24 weeks. The dosing
interval may be decreased on the basis of clinical evaluation, but
must be no less than every 16 weeks.
TZB is provided in 80-mg, 200-mg, and 400-mg single-use vials
with a concentration of 20 mg/mL.43 The recommended initial
dose of TZB is 4 mg/kg, infused IV every 4 weeks. Doses can be
increased to 8 mg/kg as needed based on clinical response. The
maximal dose must not exceed 800 mg per infusion. The indi-
cated dose should be diluted to 100 mL in 0.9% sodium chloride
using aseptic technique. This infusion should be administered by
a health care professional through an IV drip for 1 hour. Dose
adjustments are recommended for certain dose-related labora-
tory changes including elevated liver enzymes, neutropenia, and
thrombocytopenia. TZB should not be initiated in patients with
an absolute neutrophil count less than 2,000 cells/µL, platelet
count less than 100,000 platelets/µL, or in patients who have an
ALT or AST value greater than 1.5 times the ULN.43 TZB treat-
ment should be interrupted if a patient experiences a serious
infection; therapy may be resumed once the infection is con-
trolled. The half-life of TZB is concentration-dependent. For the
4-mg/kg dose, the half-life is up to 11 days, whereas the half-life
for the 8-mg/kg dose is up to 13 days.
Abatacept, RXB, and TZB are all appropriate agents for S.K.
Efficacy has been demonstrated in patients with inadequate
response to DMARDs, including anti-TNF agents. All three of
these agents are generally well tolerated, and unlike the anti-TNF
agents, they have not been associated with cardiovascular events
or worsening heart failure. However, both RXB and TZB have
a black-box warning as described in the Treatment section, Bio-
logic Agents, and the risk of infection in S.K., an older patient,
must be taken into consideration when selecting a treatment
option. Experience with these agents remains relatively limited
compared with experience with etanercept, adalimumab, and
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infliximab; therefore, the full range of adverse effects from these
agents may not be fully manifested. In summary, abatacept, RXB,
and TZB are potent treatment options with novel mechanisms
of action and proven efficacy at improving RA symptoms and
slowing joint erosion. However, based on a combination of cur-
rent research findings, lack of long-term safety data, and cost,
these agents should generally not be used before a trial with anti-
TNF agents, except for patients with relative contraindications
to anti-TNF agents (e.g., multiple sclerosis, moderate to severe
heart failure).
CORTICOSTEROIDS
CASE 44-9
QUESTION 1: W.M., a 57-year-old man, has progressive RA
that has not been responsive to SSZ. He is having difficulty
working a full day and is seeking an alternative medication.
After a discussion of therapeutic options, W.M. declines
MTX therapy and asks to start HCQ. Would it be appro-
priate to initiate corticosteroids concurrently?
Despite the potential for serious adverse effects with long-
term therapy, the judicious use of low-dose corticosteroids rep-
resents an important component of treatment during the course
of unremitting disease. In addition, low-dose corticosteroids may
offer some disease-modifying properties, although this is con-
troversial because of the long-term negative effects of cortico-
steroid use.20 Considering that W.M.’s RA is sufficiently active
to compromise his ability to earn an income, MTX is a much
better DMARD selection. Regardless, concurrent initiation of a
DMARD and an intermediate-acting corticosteroid (e.g., pred-
nisone in a daily or divided dose of 5 to 10 mg) is justified.70 In
large cohort studies, prednisone doses greater than 7.5 mg/day
have been associated with a greater than twofold increased risk
of cardiovascular events (MI, stroke, heart failure), as well as the
risk of developing hypertension with long-term use (at least 6–12
months).39,187 Therefore, the lowest effective corticosteroid dose
is preferred for the shortest duration of time possible. The onset
of action of corticosteroids is relatively rapid, and their immediate
benefits will allow W.M. to maintain his current employment and
continue taking care of home responsibilities. The corticosteroid
dose can be decreased gradually and eventually discontinued as
W.M. begins to respond to HCQ therapy. An important goal of
low-dose corticosteroid treatment is to provide bridge therapy
until the DMARD therapy becomes effective, in hopes of then
being able to taper and discontinue the corticosteroid.
DOSING
CASE 44-9, QUESTION 2: How should corticosteroids be
dosed for W.M.? What are the considerations regarding
divided daily doses rather than as single daily doses or an
every-other-day regimen when used to treat RA?
Administering intermediate- or short-acting corticosteroids
as a single daily dose each morning most closely mimics the early
morning physiological secretion of cortisol, and, thereby, mini-
mizes hypothalamic-pituitary-adrenal axis suppression. Adminis-
tering corticosteroids on alternate mornings further reduces the
risk of hypothalamic-pituitary-adrenal axis suppression by allow-
ing the adrenal glands to respond to hypothalamic and pituitary
mediators during the “off ” day.188 Once-a-day and alternate-day
steroid therapies are most advantageous when used to prevent
reactivation of some diseases (e.g., asthma, ulcerative colitis,
chronic active hepatitis, sarcoidosis).76 In contrast, when cor-
ticosteroids are used to provide symptomatic relief in RA during
November 19, 2011 2:2
periods of active, ongoing inflammation, switching patients to 1033
single daily doses or every-other-day regimens frequently results
in increased symptoms during the latter part of each day and dur-
ing the “off ” day. The anti-inflammatory effect of prednisone or
prednisolone is attenuated after 12 hours, and is either diminished
or absent after 24 hours. As a result, daily prednisone doses may
need to be divided in half and administered twice daily to ensure
24-hour anti-inflammatory activity. Although a larger single daily
dose may provide comparable therapeutic benefits, dividing the
daily dose of prednisone is preferable because larger doses are
associated with more frequent and severe adverse effects. To min-
imize adverse effects and maximize 24-hour symptom relief, an
initial prednisone dose of 2.5 mg administered twice daily should
be recommended for W.M.
CASE 44-9, QUESTION 3: Why are corticosteroids given in
the evening in RA as opposed to the usual morning dosing?
It has been well studied that RA patients experience diurnal
variations in symptoms such as joint pain, stiffness, and func-
tional disability, with the worst symptoms occurring in the early
morning.189 Nocturnal surges in proinflammatory cytokines
(IL-6, cortisol) have been implicated in the occurrence of these
typical early morning symptoms. Corticosteroids have been
shown to promote increased reduction in morning stiffness if
administered in the evening or during the night as opposed to
usual morning dosing.51 Recently a modified-release prednisone
has been developed, which releases active drug approximately 4
hours after ingestion. This is designed to deliver the drug during
nighttime hours and prevent nocturnal surges in inflammatory
cytokines. Two large phase III clinical trials have been conducted
to assess the efficacy and safety of modified-release prednisone.
The CAPRA-1 trial randomly assigned patients to receive 3 to 10
mg/day of either the immediate-release or modified-release pred-
nisone for 12 weeks. A statistically significant decrease in duration
of morning stiffness was demonstrated in the modified-release
prednisone group (reduction of 29 minutes in the modified-
release group vs. the immediate-release group).190 The safety
profile did not differ between the treatment groups. These
effects were sustained in the 9-month open-label extension of
this trial.191 The use of modified-release prednisone may provide
decreased morning stiffness for W.M.; however, this agent has
not yet been approved in the United States.
STEROID-INDUCED OSTEOPOROSIS
CASE 44-9, QUESTION 4: Is W.M. at risk for developing glu-
cocorticoid osteoporosis? What therapeutic interventions
are available to prevent it?
Chronic corticosteroid therapy induces osteoporosis by
inhibiting bone formation and enhancing bone resorption.
Chapter 44
Steroids impair bone formation by inhibiting the production
of bone-forming osteoblasts and enhance bone resorption by
reducing GI calcium absorption and increasing the renal excre-
tion of calcium.76 In addition, corticosteroids reduce the secre-
tion of luteinizing hormone from the pituitary, resulting in a
reduction in estrogen production in women and testosterone
Rheumatoid Arthritis
production in men.192 This leads to deficiencies in circulating
levels of anabolic hormones (e.g., estradiol, estrone, androstene-
dione, progesterone), which contribute to the development of
osteoporosis. Trabecular bone of the spine and ribs seems to
be affected primarily by corticosteroid therapy, with most rapid
skeletal wasting occurring during the first 6 months (see Chapter
105, Osteoporosis).
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1034 Before starting long-term (i.e., 6 months) corticosteroid ther-
apy at a dose of 7.5 mg of daily prednisone or equivalent,
bone mineral density should be evaluated.192 Anteroposterior
measurement of the lumbar spine or hip by dual-energy x-ray
absorptiometry is the preferred procedure. Follow-up measure-
ments can be repeated up to every 6 months to monitor for
corticosteroid-related bone loss, or annually for patients already
receiving bone loss prevention treatment. A complete history
should be obtained to identify potentially modifiable osteoporo-
sis risk factors (e.g., smoking, alcohol consumption, other drugs
that can induce osteoporosis, calcium and vitamin D intake, indi-
cators of hormone deficiency such as menopause in women
and infertility or impotence in men, lack of participation in
weight-bearing exercises). Height and weight should be mea-
sured. Lifestyle changes should be encouraged to modify those
risk factors that do not require drug therapy. Physical therapy
referral is recommended.
All patients on corticosteroid therapy should receive calcium
(1,000 mg/day) and vitamin D (800 international units/day) or
an activated form of vitamin D (e.g., alfacalcidol or calcitriol) to
maintain calcium balance. Supplementation with calcium and
an activated form of vitamin D is needed to prevent bone loss in
patients receiving medium- to high-dose corticosteroid therapy
(e.g., prednisone ≥5 mg/day).192
Bisphosphonates effectively prevent and treat corticosteroid-
induced bone loss.192 In radiographic studies, bisphospho-
nates effectively reduced vertebral fractures in postmenopausal
women with corticosteroid-induced osteoporosis. Bisphospho-
nate therapy is recommended for men and postmenopausal
women receiving greater than 5 mg/day of prednisone, or its
equivalent, to prevent bone loss. In addition, bisphosphonates are
recommended for men and postmenopausal women receiving
long-term corticosteroids with a bone mineral density T-score
below normal at either the lumbar spine or hip. Bisphosphonates
should be considered for premenopausal women receiving corti-
costeroids, even though data in this population are limited. How-
ever, premenopausal women receiving bisphosphonates must
be counseled about contraception because bisphosphonates are
classified as FDA pregnancy risk category C. Bisphosphonates
adversely affect fetal skeletal development in animals, and reduce
serum calcium. Although data are limited, hypogonadal patients
receiving long-term corticosteroid treatment should be offered
hormone-replacement therapy. Thiazide diuretics reduce uri-
nary calcium excretion and maintain bone mineral content.193 A
thiazide diuretic is recommended if hypercalciuria is present.
INTRA-ARTICULAR CORTICOSTEROIDS
CASE 44-9, QUESTION 5: Would intra-articular cortico-
steroid injections be a safe and effective treatment option
for W.M.?
Section 9
Intra-articular corticosteroid injections are safe and effective
for patients with RA and are often underused. This strategy is
most sensible when flaring occurs in one or a few joints.20 Sys-
temic side effects are minimal when compared with oral cortico-
steroid therapy. Although onset of action is virtually immediate,
Arthritic Disorders
effects are often short-lived; however, a corticosteroid injection
alone can be sufficient to relieve a temporary RA flare. If the deci-
sion is made to reinject a given joint, the injection site should be
rotated and administration frequency should be no more than
every 3 months. W.M. could benefit from the use of intermittent
intra-articular corticosteroid injections for the treatment of RA
flares.
November 19, 2011 2:2
JUVENILE IDIOPATHIC ARTHRITIS
All chronic arthritides of childhood are now identified as juvenile
idiopathic arthritis ( JIA) as defined by the International League
of Associations for Rheumatology.194 Previously, terminology
such as juvenile rheumatoid arthritis or juvenile chronic arthritis
was used, but these names have now been replaced, and JIA is
used to describe a broad group of pediatric diseases. JIA afflicts
approximately 300,000 children in the United States, affecting all
races equally and girls more often than boys. The peak age of
onset ranges from 2 to 4 years. However, new cases are seen
throughout childhood.
By definition, symptoms of JIA (joint inflammation involving
swelling, pain, limited ROM, warmth, erythema) present before
the age of 16 and must last for at least 6 weeks in at least one
joint.195 Similarly to other rheumatologic disease classifications,
the diagnosis of JIA is a diagnosis of exclusion; infectious, trau-
matic, and other etiologies must be ruled out.8,196
CASE 44-10
QUESTION 1: J.R., a 4-year-old girl, is brought to the hospi-
tal for high fever and arthritis. Several weeks before admis-
sion, J.R. had a daily fever ranging from 103◦ F to 106◦ F.
One week before admission, her knees became painful
and swollen. J.R. is listless and irritable during her physical
examination, and her rectal temperature measures 102.4◦ F.
She refuses to walk. The right hip is tender, and the right
wrist and both knees are warm, red, and swollen. Mini-
mal generalized lymphadenopathy and splenomegaly are
present. The Westergren ESR is 82 mm/hour, the white
blood cell count is 37,000 cells/µL with a mild left shift,
and hematocrit is 33%. Cultures of the throat, urine, stool,
and blood are negative. An intermediate-strength purified-
protein derivative, antistreptolysin-O titer, ANA titer, and
RF titer are normal, as are radiographs of the chest and
involved joints. An electrocardiogram reveals only tachycar-
dia. After withholding aspirin, an evanescent rash becomes
apparent in conjunction with fever spikes. What signs and
symptoms of JIA does J.R. manifest?
As with adult RA, JIA begins with synovial inflammation.197
Because children often cannot articulate complaints, morning
stiffness and joint pain may manifest as increased irritability,
guarding of involved joints, or refusal to walk. Fatigue and
low-grade fever, anorexia, weight loss, and failure to grow are
other symptoms. Patients with JIA are categorized as having
one of the following types of disease as established by the
International League of Associations for Rheumatology: (a) sys-
temic, (b) oligoarthritis (previously referred to as pauciarticular),
(c) polyarthritis RF+, (d) polyarthritis RF–, (e) psoriatic, (f )
enthesitis-related, and (g) undifferentiated (patients who do
not fulfill criteria of other JIA subsets).194,195 For a cata-
log of JIA images, including radiography and ophthalmologic
photographs, please go to http://images.rheumatology.org/
search.php?searchField=ALL&searchstring=JIA.
Systemic JIA is a disease that is distinguished from other forms
of JIA by the presence of hallmark systemic features such as rash,
lymphadenopathy, or cyclical high-spiking fever at onset.194,195
Joint pain, typically of the knees, wrists, and ankles, often worsens
when the fever is elevated, but also may not be clinically evident
at disease onset.194 Systemic JIA occurs equally in girls and boys
and comprises approximately 10% to 20% of all JIA cases.194,195
About 50% to 60% of all JIA cases are classified as oligoarthritis,
or oligoarticular JIA, the most common type of JIA.194 This type
of JIA typically presents before the age of 6 years, and 80% of
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oligoarthritis patients are girls. Patients with oligoarthritis must
present with four or fewer affected joints, most commonly the
ankles and not necessarily symmetrically, but 50% may even-
tually develop arthritis in additional joints, requiring a change
in disease classification.194 A common disease complication is
uveitis, inflammation of the eye, which may not necessarily cor-
relate with disease progression. Affecting 30% to 50% of patients,
uveitis can cause further problems such as glaucoma, cataracts,
and vision loss if the JIA is left untreated.194 Images of JIA are
available through the ACR: http://images.rheumatology.org/
viewphoto.php?albumId=75693&imageId=2862544.
JIA is classified as a polyarthritis when the disease involves
five or more joints with few or no systemic manifestations of
disease.194 Polyarthritis may be RF+ or RF– and accounts for up
to 40% of all JIA disease, the majority of which is RF–.197 Both
types affect girls more often than boys. Disease onset is typi-
cally seen at age 8 or older, and most often in adolescents. RF+
polyarthritis presents very similarly to adult-onset RA, involv-
ing aggressive, erosive, and symmetric joint inflammation as
well as fatigue, morning stiffness, and elevated inflammatory
markers.194 Uveitis is uncommon in this category of JIA.
Psoriatic JIA accounts for a small number of all JIA cases (about
5%) and is diagnosed if chronic arthritis and psoriasis are both
evident.194 Children may also be diagnosed with psoriatic JIA
if any two of the following are present: dactylitis (finger or toe
inflammation), onycholysis or nail pitting, or family history of
psoriasis.
Enthesitis-related JIA is manifested as inflammation of the
enthesis (the site of attachment of tendon to bone) along with
arthritis. Children with enthesitis-related JIA have at least two
of the following in addition to arthritis or enthesitis: inflamma-
tory lumbosacral or sacroiliac joint pain, onset in males older
than 6 years of age, HLA-B27 positivity, symptomatic anterior
uveitis, or a family history of enthesitis-related JIA or ankylosing
spondylitis (first-degree relative).194
The signs and symptoms (i.e., the spiking fever episodes, rash,
arthritis, lymphadenopathy, splenomegaly) that J.R. shows are
characteristic of systemic JIA. Children presenting with this sub-
type of JIA may also have a normocytic, hypochromic anemia,
elevated ESR, and thrombocytosis. Leukocytosis is common, and
a white blood cell count of 30,000 to 50,000 cells/µL is seen occa-
sionally. A positive RF titer is uncommon in JIA and is present in
only 5% to 10% of all cases.194
Prognosis
CASE 44-10, QUESTION 2: What is the expected prognosis
for J.R.?
Features of poor prognosis for patients with JIA generally
include arthritides that involve cervical spine or hip joints,
involvement of the ankle or wrist coupled with significant or
prolonged elevation of ESR or other inflammatory markers, and
radiographic damage.198 Disease remission is qualified by lack
of active arthritis in joints, absence of systemic symptoms (rash,
fever, lymphadenopathy, etc.), symptomatic uveitis not present,
normal ESR or CRP, and no disease activity measured on a physi-
cian’s global assessment scale.199 Many pediatric and adolescent
patients with JIA avoid physical and functional limitation in adult-
hood; it has been estimated that up to 50% of patients achieve
remission of disease symptoms.196 Despite this good prognosis,
complete remission is uncommon, and up to one-third of patients
with JIA do experience long-term disability and decreased quality
of life.199,200 Preservation of joint function is least promising in
children with RF+ polyarthritis. Although J.R. is exhibiting some
November 19, 2011 2:2
poor prognostic indicators (hip and wrist involvement, elevated 1035
ESR), it is unclear whether these are long-term manifestations.
Normal ANA and RF titers and the absence of radiographic dam-
age are favorable for R.F.
Treatment
The goals of JIA treatment are to minimize joint inflammation
and its destructive effects, control pain, preserve or restore ROM,
facilitate an acceptable quality of life, and achieve long-term
disease remission. Choice of medication therapy requires con-
sideration of type of JIA, current treatment, degree of disease
progression, level of disease activity, and prognosis.198
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
CASE 44-10, QUESTION 3: What is the initial drug therapy
for treatment of JIA in patient J.R.?
Typically, NSAID therapy is the first-line treatment to target
joint inflammation as well as the febrile episodes in systemic JIA,
especially in patients such as J.R. who appear to have low disease
activity and lack of poor prognosis predictors.194,195 These medi-
cations work to control pain, fever, and inflammation by inhibit-
ing prostaglandin synthesis and are usually fairly well tolerated
by children. Analgesic effects usually occur first, and with con-
tinued use NSAIDs’ anti-inflammatory effects will begin within
a few weeks.201
The most commonly prescribed NSAIDs for JIA are naproxen
and ibuprofen. Naproxen is dosed at 10 to 15 mg/kg/day (max-
imum, 750 mg) given in two daily divided doses, and is advan-
tageous in school-age children because of the convenient dos-
ing interval and availability in liquid or tablet formulations.25,76
Ibuprofen is dosed 30 to 50 mg/kg/day (maximum, 2.4 g) given
in three or four divided doses. Ibuprofen is also available in tablet
and liquid form.
Other NSAIDs approved by the FDA for use in JIA include
oxaprozin, tolmetin, and meloxicam. Oxaprozin can be admin-
istered as a weight-based, once-daily dose (600 mg if the patient
weighs 22 to 31 kg, 900 mg if 32 to 54 kg, and 1,200 mg if >55
kg). Tolmetin is usually dosed at 20 mg/kg/day in three to four
divided doses, but may require a maintenance dose of 15 to 30
mg/kg/day, with a maximal daily dose of 1,800 mg. Meloxicam
is approved for use in patients age 2 and older. The usual dose is
0.125 mg/kg/day given once daily, with a maximal daily dose of
7.5 mg.25
In most cases, at least two different NSAIDs should be tried
before ruling out this group of medications owing to lack of
efficacy or tolerability.201 Failure to respond to an NSAID in a
particular chemical class does not rule out the efficacy of others
in the same class. As with adults, it is not possible to predict a
pediatric patient’s response to any one NSAID. For J.R., ibuprofen
appears to be the most sensible first choice because it is available
Chapter 44
over the counter in liquid and chewable forms, which is an impor-
tant consideration for a 4 year-old. Naproxen is available in an
oral liquid suspension by prescription and can also be considered
initially.
Rheumatoid Arthritis
CASE 44-10, QUESTION 4: Is aspirin safe to use for treat-
ment of JIA in pediatric patients like J.R.?
Aspirin is initiated in divided doses totaling 60 to 80 mg/
kg/day.76 Dosages up to 130 mg/kg/day may be needed to
achieve anti-inflammatory serum salicylate concentrations (20 to
30 mg/dL).
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1036 Aspirin is seldom used because of its association with Reye
syndrome. Reye syndrome occurs in association with the use of
aspirin as an antipyretic in children during the prodromal phase of
viral illnesses such as influenza or chickenpox. Reye syndrome is
characterized by nausea, vomiting, liver damage, and progressive
encephalopathy leading to a change in mental status. Virtually
all cases of Reye syndrome involved patients who were exposed
to salicylates during an antecedent illness. In the control popula-
tion, salicylate use varied from approximately 40% to 70%. Based
on these findings, the Committee of Infectious Diseases of the
American Academy of Pediatrics issued a statement that aspirin
should not be given to febrile children who are at risk for Reye
syndrome by virtue of possible infection with either influenza
virus or chickenpox.202
The risk of Reye syndrome in children receiving salicylate
therapy, such as aspirin, for JIA is unknown. It is recommended
that patients with JIA avoid salicylate ingestion during febrile
illnesses that represent possible infection with either influenza
or chickenpox.
CORTICOSTEROIDS
CASE 44-11
QUESTION 1: Twelve-year-old A.M. was diagnosed with a
moderately active form of polyarthritis and has thus far
treated it unsuccessfully with naproxen 325 mg twice daily
and ibuprofen 800 mg three times daily. His rheumatologist
is now discontinuing NSAID therapy and prescribing MTX
and prednisone. What is the rationale behind the physi-
cian’s decision to order concurrent DMARD and cortico-
steroid therapy, and how long should A.M. expect to take
steroids?
Despite the potential for serious adverse effects associated
with high-dose or long-term therapy, the use of low-dose cor-
ticosteroids (e.g., prednisone 0.5–1.0 mg/kg/day) is sometimes
necessary to control disease flares or provide therapeutic relief
during initiation of DMARDs with slow onset of action.20 The
benefit of starting both medications together at once is to avoid
delay in DMARD treatment while receiving immediate inflam-
matory relief from the corticosteroid.
It is preferable that patients take the lowest effective cortico-
steroid dose for the shortest duration possible to avoid long-term
side effects such as hypertension and osteoporosis. Oral corti-
costeroids are typically dosed once daily in the morning to best
mimic physiological cortisol release and minimize suppression of
the hypothalamic-pituitary-adrenal axis. The corticosteroid dose
can be tapered off and eventually discontinued as A.M. begins to
respond to MTX therapy.198
CASE 44-11, QUESTION 2: What corticosteroid side effects
should A.M. be counseled about?
Section 9
Common side effects of steroids include GI upset and dam-
age to the GI mucosa, mood changes including depression or
hyperactivity, and increases in blood pressure and blood sugar.25
Corticosteroids may also cause impaired skin healing, osteoporo-
sis (especially with long-term use), and vision problems such
Arthritic Disorders
as cataracts and glaucoma. Both A.M. and his parents should
also be counseled about receiving vaccinations during cortico-
steroid therapy because immunosuppression may attenuate an
appropriate immune response. Inactivated vaccines are safe for
use in immunocompromised patients and should be adminis-
tered if indicated.25 Immunocompromised patients typically have
a weaker immune response to vaccines when compared with
November 19, 2011 2:2
healthy patients; therefore, higher doses or more frequent revac-
cinations may be necessary.
Greater caution must be taken with live-virus vaccines in
immunosuppressed patients. The risk of immunosuppression in
patients receiving corticosteroids is dependent on corticosteroid
dose, duration, and route of administration; local corticosteroid
treatments (e.g., topical, inhalation, intra-articular) do not put
patients at risk.203 Patients receiving short-term corticosteroid
therapy (i.e., <2 weeks), every-other-day dosing with a short-
acting corticosteroid, or doses of no more than moderate range
can usually receive live-virus vaccines. Corticosteroid dosing that
is considered high risk for immunosuppression is the equiva-
lent of at least prednisone 2 mg/kg/day or 20 mg/day; patients
receiving corticosteroid dose equivalents in this range should not
receive live-virus vaccines. Patients receiving high-dose cortico-
steroids systemically for 2 or more weeks should wait at least
3 months before receiving a live-virus vaccine.203
INTRA-ARTICULAR CORTICOSTEROID THERAPY
CASE 44-12
QUESTION 1: H.Y. is a 17-year-old young man recently diag-
nosed with JIA. He complains of joint pain limited to both
knees and his right ankle. He currently takes sulfasalazine
1,000 mg twice daily with good relief of inflammation, but
he reports it occasionally gives him bad heartburn and he is
looking toward other medication options, preferably some-
thing he will not have to take more than once a day. Is H.Y. a
good candidate for intra-articular corticosteroid injections?
Intra-articular corticosteroid therapy seems to be highly effec-
tive in JIA. Injections are typically reserved for patients who have
not responded to conventional NSAID therapy or who present
with monoarthritis or oligoarthritis, and current guidelines sug-
gest they are recommended for all patients with JIA having active
disease in four or fewer joints, regardless of activity level, progno-
sis, or joint deformity.194 Compared with NSAIDs, steroid injec-
tions are much better able to reduce duration of joint pain.201 Full
disease remission of injected joints lasting longer than 6 months
can be expected in more than 80% of patients with JIA, and 60%
of patients may be able to discontinue all oral medications with
lasting disease remission in treated joints.204 In one study, after
an average of 30 months of follow-up, long-term negative effects
of corticosteroid therapy (e.g., joint stability, osteonecrosis, soft
tissue atrophy) were not encountered. As a result, intra-articular
corticosteroid therapy seems to be a safe and effective option for
JIA, particularly in oligoarticular disease limited to a few joints.194
Intra-articular steroid injections would be appropriate for H.Y.
given that he has a limited amount of joint involvement. He
should be advised to limit use of his knees and ankle for a couple
days after the injection, but should be encouraged to resume
non–weight-bearing physical therapy to maintain joint flexibility
and ROM soon after the treatment.201 Repeated intra-articular
injections are usually given several months apart. Side effects
include local lipoatrophy or articular calcification, both of which
do not present many issues clinically.
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS
CASE 44-13
QUESTION 1: T.T. presents to rheumatology clinic on refer-
ral from her primary-care provider. She is 9 years old and
has been complaining at home of her shoes hurting her feet
and not being able to run with her classmates at school. On
physical examination it is noted she has multiple swollen,
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erythematous joints (tarsometatarsal and metatarso-
cuneiform joints bilaterally on the feet, ankles bilaterally,
knees bilaterally). Her CBC values are all normal, her ESR is
normal, and her RF is positive. In addition to NSAID and
steroid therapy, the rheumatologist would like to start a
DMARD agent. What DMARD options are available to treat
T.T.’s JIA?
Patients with RF+ polyarthritis and early-onset JIA both
have poor prognosis in terms of long-term joint function and
should receive early consideration for DMARD therapy. MTX
is the DMARD of choice for polyarthritic JIA.205 Patients with
oligoarthritic JIA seem to respond best to MTX, whereas patients
with systemic JIA experience little to no benefit.
T.T. is showing classic signs of RF+ polyarthritis and it would
be appropriate to choose MTX as a first-line agent for her ther-
apy. The recommended dose of MTX for JIA treatment is 10 to
15 mg/m2 orally or subcutaneously each week. Food reduces
the bioavailability of MTX, so MTX should be administered
on an empty stomach. Oral doses greater than 12 mg/m2 are
poorly absorbed; as a result, higher doses of MTX are usually
given parenterally (subcutaneous or IM). Radiologic evidence of
improvement or slowing of joint damage has been demonstrated
in patients with JIA who responded to MTX therapy during a 2-
year period.206
Other DMARD options for JIA include SSZ, which is often
the second-line treatment behind MTX, or HCQ. SSZ (30 to 50
mg/kg/per day in two divided doses with a maximum of 2 g/day)
is effective for oligoarthritis JIA and polyarthritis JIA, but numer-
ous adverse effects (e.g., elevation of liver enzymes, leukopenia,
diarrhea, anorexia) lead to discontinuation of the medication in
about 30% of patients.207
CASE 44-13, QUESTION 2: What is the expected response
to MTX treatment for T.T.?
The likelihood of long-term or permanent JIA-related joint
damage is less than that associated with adult RA; therefore,
discontinuation of MTX should be attempted when disease
remission is apparent. The optimal time to discontinue MTX
therapy remains unknown; however, it probably should not
be stopped sooner than 1 year after disease remission, with
slower withdrawal in patients at high risk for relapse.208,209
Young age at diagnosis (<4.5 years) and oligoarthritis that pro-
gresses to polyarthritis seem to be the greatest risk factors for
relapse.209,210
Children tolerate MTX therapy well and generally experience
few serious or troublesome adverse effects (e.g., transient liver
enzyme elevations, nausea, vomiting, oral ulcerations).208 These
adverse effects are reduced with daily folic acid therapy (1 mg)
or weekly folinic acid (the day after MTX dosing). Liver toxicity
monitoring in JIA is the same as the guidelines recommend for
MTX therapy in adult RA, including biopsy recommendations
(see Case 44, Question 6). The combination therapy of MTX and
other DMARDs has not been fully evaluated in pediatric patients.
BIOLOGIC AGENTS
CASE 44-14
QUESTION 1: Seven-year-old C.E. has oligoarthritis that
consistently has not responded to NSAID or MTX therapy.
Given their many side effects, her parents are concerned
about her taking steroids and refuse to let their daughter
take them. They are worried about permanent joint damage
November 19, 2011 2:2
1037
and wish to try a biologic agent in hopes of finally suppress-
ing disease activity. They have heard that biologic drugs are
“safer than steroids” and want to know which agents are
available to treat JIA in C.E.
There are currently three FDA-approved biologic agents avail-
able to treat JIA: etanercept, adalimumab, and abatacept.
Etanercept is a recombinant TNF-receptor Fc fusion protein
indicated for patients 4 years of age and older whose conditions
have failed to respond to one or more DMARDs.25 The recom-
mended dose is 0.4 mg/kg (maximum, 25 mg) subcutaneously
twice weekly. The safety of etanercept in children is compara-
ble to adults with the exception of significantly more abdominal
pain (17% of patients with JIA vs. 5% of adult patients with
RA) and vomiting (14.5% of patients with JIA vs. <3% of adult
patients with RA). Patients with JIA should be up-to-date on their
immunizations before initiation of etanercept therapy because
the effect of etanercept on vaccine response is unknown. Safety
and efficacy data reflecting up to 10 years of treatment support
the long-term use of etanercept for JIA.211
Adalimumab is a human monoclonal TNF-α antibody
approved for use in patients with JIA aged 4 to 17 years.147 It
is a weight-based dose (20 mg for patients 15 to 30 kg, 40 mg
for patients >30 kg) given as a subcutaneous injection every
other week. In a study involving 171 patients on adalimumab
monotherapy and in combination with MTX, children taking
combination therapy showed better disease improvement than
patients on adalimumab monotherapy.147 Concomitant steroids,
salicylates, NSAIDs, or other analgesic agents may also be con-
tinued during adalimumab use.25
Abatacept is an injectable biologic agent that inhibits T-cell
activation. This drug received approval for JIA in 2008, and is
indicated for use in patients 6 years and older. Patients weighing
less than 75 kg receive a dose of 10 mg/kg via IV infusion for
30 minutes, patients 75 to 100 kg receive 750 mg, and patients
greater than 100 kg receive 1,000 mg. All patients receive doses
at 2 and 4 weeks after the first infusion and then every 4 weeks
thereafter. Unlike TNF-α agents, abatacept does not have an
immediate onset and seems to exert its effect best after repeated
doses over the course of several months.201
Other biologic agents, including infliximab and anakinra, are
not FDA approved for JIA but have been studied.25,205 Available
data from clinical trials suggest that all of these treatments may
be safe and effective for JIA with no evidence of significant risk for
serious adverse reactions. Owing to their mechanisms of action,
all biologic agents share the side effect of lowered infection resis-
tance, and patients must be monitored for signs of infection dur-
ing treatment.
Of all FDA-approved biologic agents, C.E. is a candidate for
etanercept and adalimumab therapy, and may prefer to receive
adalimumab given its semi-weekly dosing schedule versus etan-
ercept’s twice-daily regimen. She will also be able to continue her
concurrent NSAID and MTX therapy during adalimumab treat-
Chapter 44
ment as it is possible she will clinically improve on combination
therapy better than on adalimumab alone.
NONPHARMACOLOGIC THERAPY
Rheumatoid Arthritis
CASE 44-14, QUESTION 2: C.E.’s parents want to encour-
age her to exercise as a way to promote health and com-
bat disease complications. What recommendation can the
physician give to C.E. and her family?
In addition to treatment with medication, many patients with
JIA can benefit from nonpharmacologic efforts to help preserve
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1038 joint flexibility, maintain ROM, and prevent disability in adult-
hood. Patients with JIA are often less physically active and more
easily fatigued than their disease-free peers, and may meet devel-
opmental milestones later than children of the same age.212 Chil-
dren with JIA are also more prone to decreased bone mineral
density than their peers.
Heat and cold therapy, massage, and regular physical activity
can all help reach disease treatment goals of minimizing joint
inflammation, controlling pain, and improving quality of life.213
Weight-bearing exercise can help prevent bone loss, but should be
avoided when joints are acutely inflamed.209 At these times low-
impact sports such as swimming or bicycling can be enjoyed.193
Physical therapy and occupational therapy can also help pediatric
patients hone gross and fine motor skills, balance, and coordina-
tion. C.E. should be encouraged to participate in regular exercise
and organized therapy sessions to improve exercise capacity and
preserve joint functioning.
KEY REFERENCES AND WEBSITES
A full list of references for this chapter can be found at http://
thepoint.lww.com/AT10e. Below are the key references and
websites for this chapter, with the corresponding reference num-
ber in this chapter found in parentheses after the reference.
Key References
Aletaha D et al. 2010 rheumatoid arthritis classification crite-
ria: an American College of Rheumatology/European League
Against Rheumatism collaborative initiative [published correc-
tion appears in AnnRheumDis. 2010;69:1892]. AnnRheumDis 2010;
69:1580. (2)
Beukelman T et al. 2011 American College of Rheumatology rec-
ommendations for the treatment of juvenile idiopathic arthritis:
initiation and safety monitoring of therapeutic agents for the
Section 9
Arthritic Disorders
November 19, 2011 2:2
treatment of arthritis and systemic features. Arthritis Care Res
(Hoboken). 2011;63:465. (198)
Felson DT et al. American College of Rheumatology/European
League Against Rheumatism provisional definition of remis-
sion in rheumatoid arthritis for clinical trials. Arthritis Rheum.
2011;63:573. (11)
Lanza FL et al. Guidelines for prevention of NSAID-related ulcer
complications. Am J Gastroenterol. 2009;104:728. (93)
[No authors listed]. Drugs for rheumatoid arthritis. Treat Guidel
Med Lett. 2009;7:37. (20)
Peters MJ et al. EULAR evidence-based recommendations for
cardiovascular risk management in patients with rheumatoid
arthritis and other forms of inflammatory arthritis. Ann Rheum
Dis. 2010;69:325. (16)
Saag KG et al. American College of Rheumatology 2008 rec-
ommendations for the use of nonbiologic and biologic disease-
modifying antirheumatic drugs in rheumatoid arthritis. Arthritis
Rheum. 2008;59:762. (19)
Singh JA et al. Biologics for rheumatoid arthritis: an overview
of Cochrane reviews. Cochrane Database Syst Rev. 2009;(4):
CD007848. (65)
Key Websites
The American College of Rheumatology. Rheumatology image
bank. http://images.rheumatology.org/. Accessed June 5,
2011.
UCTelevision. Rheumatoid arthritis: part 1. http://www.
youtube.com/watch?v=djZfEi-ztVQ. Accessed June 5, 2011.
UCTelevsion. Rheumatoid arthritis: part 2. http://www.
youtube.com/watch?v=bjzMylQeor4&feature=relmfu.
Accessed June 5, 2011.