Rheumatoid

arthritis
Ika Norcahyanti
Bagian Farmasi Klinik & Komunitas
Fakultas Farmasi UNEJ

from the pain of rheumatoid arthritis.

Definition??
Rheumatoid arthritis (RA)

a chronic and usually progressive inflammatory

disorder of unknown etiology characterized
by polyarticular symmetric joint involvement
and systemic manifestations

Pathophysiology??
Sistem imun tddr humoral dan cell-mediated
function
Komponen humoral berhub dg pembent antibodi
Antibodi dibtk di sel plasma
Kebanyakan px dg RA membtk Ab yg disebut dg
RHEUMATOID FACTORS (IgG, IgM, IgA)
Ig dpt mengaktifkan sist komplemen
Sist komplemen akan memperkuat respon imun
& mendorong kemotaksis, fagositosis, rilis
limfokin o/ sel mononuklear

Pathophysiology??

Pathophysiology??

Pathophysiology??

Pathophysiology??
TNF (Tumor necrosing factor), interleukin-1
(IL-1) & IL-6 mrp substansi kunci dlm awal
dan kelanjutan RA
Zat2 vasoaktif (histamin, kinin, PG)
..dirilis d tmp tjdnya inflamasi
menyebabkan pe aliran darah ke daerah
inflamasi, me permeab kapiler
HASIL : (KDRT-FL) edema, warm, eritema,
nyeri

Pathophysiology??
Tjd inflamasi kronik pd cairan sinovial

Inflamasi ditandai dg proliferasi membran

sinovial PANNUS

Pannus menginvasi kartilago dan perm tul

erosi tul + kartilago

destruksi joint

Clinical Presentation??
nonspecific prodromal symptoms that
develop insidiously over weeks to months

fatigue, weakness, low-grade fever,

loss of appetite, and joint pain

stiffness and myalgias may precede

development of synovitis

Clinical Presentation??
Joint involvement tends to be symmetric and affect
the small joints of the hands, wrists, and feet; the
elbows, shoulders, hips, knees, and ankles may also
be affected
Joint stiffness typically is worse in the morning,
usually exceeds 30 minutes, and may persist all day
On examination, joint swelling may be visible or may
be apparent only by palpation the tissue feels soft
and spongy and may appear erythematous and
warm, especially early in the course of the disease

Clinical Presentation??
Chronic joint deformities commonly involve
subluxations of the wrists, metacarpophalangeal
joints, and proximal interphalangeal joints (swanneck deformity, boutonniere deformity, ulnar
deviation)
Extra-articular
involvement

rheumatoid
nodules, vasculitis, pleural effusions, pulmonary
fibrosis, ocular manifestations, pericarditis, cardiac
conduction
abnormalities,
bone
marrow
suppression, and lymphadenopathy

Location??

Laboratorium Data??
Rheumatoid Factor (RF)
Anti-CCP (anticyclic cytrullinated peptide
antibody)
ESR dan CRP
Leukocytosis
Radiographs analysis
Others : CBC

Diagnosis??

Diagnosis??

Classification??

Outcome??
the ultimate goal of RA treatment

to induce a complete remission, although

this may be difficult to achieve

reduce joint swelling, stiffness, and pain;

preserve range of motion and joint function;
improve quality of life; prevent systemic
complications; and slow destructive joint changes

Non Pharmacology
Therapy??
adequate rest, weight reduction if obese,
occupational therapy, physical therapy
surgical procedures tenosynovectomy,
tendon repair, and joint replacements
patient education

Pharmacology
Therapy??

MTX (DMARD)...
MTX inhibits cytokine production and purine
biosynthesis, which may beresponsible for its
antiinflammatory properties its onset is
relatively rapid (as early as 2 to 3 weeks)
Toxicities are GI (stomatitis, diarrhea, nausea,
vomiting),
hematologic
(thrombocytopenia,
leukopenia), pulmonary (fibrosis, pneumonitis),
and hepatic (elevated enzymes, rare cirrhosis)
concomitant folic acid may reduce some adverse
effects without loss of efficacy

MTX (DMARD)...
Absorption of MTX is variable and averages 70%
of an oral dose
MTX is 35-50% bound to albumin; it may
displaced by highly protein-bound drugs such as
NSAIDs
Liver injury tests (aspartate aminotransferase or
alanine aminotransferase) should be monitored
periodically a liver biopsy is recommended
during therapy only in patients with persistently
elevated hepatic enzymes

MTX (DMARD)...
MTX is teratogenic
MTX is contraindicated in pregnant and nursing
women, chronic liver disease, immunodeficiency,
pleural or peritoneal effusions, leukopenia,
thrombocytopenia, preexisting blood disorders,
and creatinine clearance <40 mL/min

Leflunomide
(DMARD)...
Leflunomide (Arava) inhibits pyrimidine synthesis,
which reduces lymphocyte proliferation and
modulation of inflammation
Its efficacy for RA is similar to that of MTX
A loading dose of 100 mg/day for the first 3 days
may result in a therapeutic response within the
first month. The usual maintenance dose of 20
mg/day may be lowered to 10 mg/day in cases of
GI intolerance, complaints of hair loss, or other
dose-related toxicity

Leflunomide
(DMARD)...
The drug may cause liver toxicity and is
contraindicated in patients with preexisting
liver disease
Leflunomide may cause bone marrow toxicity; a
complete blood cell count with platelets is
recommended monthly for 6 months and then
every 6 to 8 weeks thereafter
It is teratogenic and should be avoided during
pregnancy

Hydroxychloroquine
(DMARD)...
Hydroxychloroquine lacks the myelosuppressive, hepatic,
and renal toxicities seen with some other DMARDs, which
simplifies monitoring
Its onset may be delayed for up to 6 weeks, but the drug
should not be considered a therapeutic failure until after 6
months of therapy with no response
Short-term toxicities include GI (nausea, vomiting,
diarrhea), ocular (accommodation defects, benign corneal
deposits, blurred vision, scotomas, night blindness,
preretinopathy), dermatologic (rash, alopecia, skin
pigmentation), and neurologic (headache, vertigo,
insomnia) effects

Sulfasalazine
(DMARD)...
A prodrug, is cleaved by bacteria in the colon into
sulfapyridine and 5-aminosalicylic acid
The exact mechanism for RA is unknown
Sulfasalazine use is often limited by adverse effects.
Antirheumatic effects should be seen in 2 months
Adverse effects include GI (anorexia, nausea,
vomiting, diarrhea), dermatologic (rash, urticaria),
hematologic (leukopenia, rare agranulocytosis), and
hepatic (elevated enzymes) effects
GI symptoms may be minimized by starting with low
doses, dividing the dose more evenly throughout the
day, and taking the drug with food

Other DMARD...
The drugs in this section can be effective and may
be of value in certain clinical settings. However,
they are used less frequently today because of
toxicity, lack of long-term benefits, or both
Aurothioglucose (Solganol) (suspension in oil) and
gold sodium thiomalate (Myochrysine, Aurolate)
(aqueous solution) are intramuscular (IM) gold
Auranofin (Ridaura) is an oral gold preparation
that is more convenient but less effective than IM
gold. Azathioprine is a purine analog that is
converted to 6-mercaptopurine and is thought to
interfere with DNA and RNA synthesis

Other DMARD...
Penicillamine is usually reserved for patients
who are resistant to other therapies because
of the rare but potentially serious induction
of autoimmune diseases (e.g., Goodpastures
syndrome, myasthenia gravis)
Cyclosporine reduces production of cytokines
involved in T-cell activation and has direct
effects on B cells, macrophages, bone, and
cartilage cells

Biology Agent...
Etanercept (Enbrel) is a fusion protein consisting
of two p75-soluble TNF receptors linked to an Fc
fragment of human IgG1. It binds to and
inactivates TNF, preventing it from interacting
with the cell-surface TNF receptors and thereby
activating cells
Most clinical trials used etanercept in patients
who failed DMARDs, and responses were seen in
60% to 75% of patients

Biology Agent...
It has been shown to slow erosive disease
progression to a greater degree than oral
MTX in patients with inadequate response to
MTX monotherapy
Adverse effects include local injection-site
reactions, and there have been case reports
of
pancytopenia
and
neurologic
demyelinating syndromes

Biology Agent...
Infliximab (Remicade) is a chimeric anti-TNF antibody
fused to a human constant-region immunoglobulin G1
(IgG1). It binds to TNF and prevents its interaction with
TNF receptors on inflammatory cells
To prevent formation of antibodies to this foreign protein,
MTX should be given orally in doses used to treat RA for
as long as the patient continues on infliximab
In clinical trials, the combination of infliximab and MTX
halted progression of joint damage and was superior to
MTX monotherapy
Autoantibodies and lupus-like syndrome have also been
reported

Biology Agent...
Adalimumab (Humira) is a human IgG1
antibody to TNF that is less antigenic than
infliximab
It has response rates similar to other TNF
inhibitors
Local injection site reactions were the most
common adverse event reported in clinical
trials

Biology Agent...
Anakinra (Kineret) is an IL-1 receptor antagonist (IL1ra) that binds to IL-1 receptors on target cells,
preventing the interaction between IL-1 and the cells.
IL-1 normally stimulates release of chemotactic factors
and adhesion molecules that promote migration of
inflammatory leukocytes to tissues
The drug is approved for moderately to severely active
RA in adults who have failed one or more DMARDs
It can be used alone or in combination with any of the
other DMARDs except for TNF-blocking agents

Biology Agent...
Abatacept (Orencia) is a costimulation modulator
approved for patients with moderate to severe
disease who fail to achieve an adequate
response from one or more DMARDs
By binding to CD80/CD86 receptors on antigenpresenting cells, abatacept inhibits interactions
between the antigen-presenting cells and T cells,
preventing T cells from activating to promote the
inflammatory process

Biology Agent...
Rituximab (Mabthera) is a monoclonal chimeric antibody
consisting of mostly human protein with the antigenbinding region derived from a mouse antibody to CD20
protein found on the cell surface of mature B lymphocytes.
Binding of rituximab to B cells results in nearly complete
depletion of peripheral B cells, with a gradual recovery
over several months
Rituximab is useful in patients failing MTX or TNF inhibitors
Methylprednisolone 100 mg should be given 30 minutes
prior to rituximab to reduce the incidence and severity of
infusion reactions
Acetaminophen and antihistamines may also benefit
patients who have a history of reactions

NSAID...
NSAIDs
act
primarily
by
inhibiting
prostaglandin synthesis, which is only a small
portion of the inflammatory cascade
They
possess
both
analgesic
and
antiinflammatory properties and reduce
stiffness but do not slow disease progression
or prevent bony erosions or joint deformity
They should seldom be used as monotherapy
for RA

Corticosteroid...
Corticosteroids
have
antiinflammatory
and
immunosuppressive properties
They interfere with antigen presentation to T
lymphocytes, inhibit prostaglandin and leukotriene
synthesis, and inhibit neutrophil and monocyte
superoxide radical generation
Oral
corticosteroids
(e.g.,
prednisone,
methylprednisolone) to control pain and
synovitis while DMARDs are taking effect
(bridging therapy)

Corticosteroid...
High-dose oral or intravenous bursts may be
used for several days to suppress disease flares
after symptoms are controlled, the drug
should be tapered to the lowest effective dose
Adverse effects of systemic glucocorticoids limit
their long-term use
Dosage tapering and eventual discontinuation
should be considered at some point in patients
receiving chronic therapy

Evaluation...
Clinical signs of improvement include reduction in joint
swelling, decreased warmth over actively involved joints,
and decreased tenderness to joint palpation
Symptom improvement includes reduction in joint pain
and morning stiffness, longer time to onset of afternoon
fatigue, and improvement in ability to perform daily
activities
Periodic joint radiographs may be useful in assessing
disease progression
Laboratory monitoring is of little value in monitoring
response to therapy but is essential for detecting and
preventing adverse drug effects

Terima
kasih