RHEUMATOID ARTHRITIS
Rheumatoid Arthritis
Chronic systemic progressive inflammatory disease
of unknown etiology characterized by polyarticular
symmetric joint involvement and systemic
manifestations.
Affects the Synovial Membranes of multiple joints
Prevalence 1-2%
Female : Male ratio 3:1
Rheumatoid arthritis(RA) overview
RA is a chronic disease, characterized by
periods of disease flares and remissions.
The cause of RA is not known.
In RA, multiple joints are usually, but not
always, affected in a symmetrical pattern.
Can affect people of all ages.
Damage to joints can occur early and does
not correlate with the severity of symptoms.
The "rheumatoid factor" is an antibody
that can be found in the blood of 80% of
people with RA.
EPIDEMIOLOGY
Most common systemic inflammatory disease
Prevalence: 40 individuals per 100,000)
Occurrence:
Any age
females : male is 2:1
The mortality rate in patients with RA is
higher than that of the general population.
Pathophysiology
RA results from a dysregulation of the immune
system.
The pathogenesis of RA is driven by T lymphocytes,
but the initial catalyst causing this response is
unknown.
Most patients produce antibodies called rheumatoid
factors
These seropositive patients tend to have a more
aggressive course than patients who are seronegative.
The characteristics of a synovium affected by RA
are:
1. The presence of a thickened, inflamed
membrane lining called pannus
2. The development of new blood vessels and
3. An influx of inflammatory cells in the
synovial fluid, majorly T lymphocytes.
The components of most significance are T
lymphocytes, cytokines, and B lymphocytes.
Chronic inflammation of the synovial tissue lining the joint
capsule results in tissue proliferation (pannus formation).
Pannus invades cartilage and eventually the bone surface,
producing erosions of bone and cartilage and leading to joint
destruction.
These may lead to loss of joint space, loss of joint motion,
bony fusion (ankylosis), joint subluxation, tendon
contractures, and chronic deformity.
Extra articular problems
Clinical Presentation
Nonspecific: fatigue, weakness, low-grade fever,
loss of appetite, and joint pain.
Stiffness and myalgias may precede development
of synovitis.
Joint involvement tends to be symmetric and affect
the small joints of the hands, wrists, and feet;
elbows, shoulders, hips, knees & ankles.
Joint stiffness typically is worse in the morning,
> 30 minutes, and may persist all day
Joint swelling may be visible or may be apparent
only by palpation.
The tissue feels soft and spongy and may appear
erythematous and warm
Chronic joint deformities: subluxations of the
wrists, metacarpophalangeal (MCP) joints, and
proximal interphalangeal (PIP) joints
Swan-neck deformity
Ulnar deviation
Diagnosis
1. Morning stiffness
2. Arthritis of three or more joint areas
3. Arthritis of hand joints
4. Symmetric arthritis
5. Rheumatoid nodules
6. Serum rheumatoid factor
7. Radiographic changes
Laboratory:
Elevated erythrocyte sedimentation rate (ESR) and
C-reactive protein
Positive rheumatoid factor (most pts)
Positive antinuclear antibodies (ANA)
Synovial fluid:
Turbidity, leukocytosis, reduced viscosity, and
normal or low glucose relative to serum
concentrations.
Radiologic findings:
Soft tissue swelling and osteoporosis near the joint
(periarticular osteoporosis) and distraction of the
joints.
Criteria for the Classification of Rheumatoid Arthritis
Criterion* Definition
1. Morning stiffness Stiffness of joints lasting at least 1 h before
improvement
2. Arthritis of 3 or more joints Soft-tissue swelling or fluid in joint
3. Arthritis in hand joints At least one swollen wrist, MCP, or PIP
4. Symmetric joint swelling Simultaneous involvement of bilateral joint areas
5. Rheumatoid nodules Subcutaneous nodules over extensor tendons, bony
prominences, or near joints
6. Positive rheumatoid factor Significantly elevated rheumatoid factor concentration
7. Radiographic changes Characteristic changes for rheumatoid arthritis noted on
hand radiographs including erosions and periarticular
osteoporosis
*
A patient shall be classified as having rheumatoid arthritis if at least four of these
criteria are met. Criteria 1–4 must be present for at least 6 weeks.
MCP, metacarpophalangeal; PIP, proximal interphalangeal.
Treatment
Desired Outcome
To induce a complete remission, although this is
seldom achieved.
The primary objectives are:
to reduce joint swelling, stiffness, and pain
preserve range of motion & joint function
improve quality of life
prevent systemic complications; and
slow destructive joint changes
Treatment…
Non-Pharmacologic Therapy
Adequate rest, weight reduction if obese,
occupational therapy, physical therapy, and use of
assistive devices may improve symptoms and help
maintain joint function.
Surgical procedures such as tendon repair, and joint
replacements.
Patient education about the disease and the benefits
and limitations of drug therapy
Pharmacologic Therapy
General Approach
A disease-modifying antirheumatic drug (DMARD) should
generally be started within the first 3 months of symptom
onset.
Early use of DMARDs results in a more favorable outcome
and can reduce mortality.
First-line DMARDs include methotrexate,
hydroxychloroquine, sulfasalazine, and leflunomide.
Hydroxychloroquine or sulfasalazine may be used
initially in mild disease,
But methotrexate is often chosen initially in more
severe cases because of superior outcomes than
other DMARDs and lower cost than biologic agents.
Leflunomide appears to have long-term efficacy
similar to methotrexate.
Biologic agents with disease-modifying activity
include the anti-TNF agents (etanercept, infliximab,
adalimumab) and the interleukin-1 receptor
antagonist anakinra.
Biologic agents are effective for patients who fail
treatment with other DMARDs.
DMARDs with less frequently used due to either less efficacy or high
toxicity or both are
azathioprine, penicillamine, minocycline, cyclosporine and
cyclophosphamide
Combination therapy with two or more DMARDs may be effective when
single-DMARD treatment is unsuccessful.
Recommended combinations are: MTX+ hydroxychloroquine,
MTX+leflunomide, MTX+sulfasalazine, MTX + hydroxychloroquine
+sulfasalazine.
ALGORITHM OF TREATMENT OF RA
Methotrexate Or other DMARD ± NSAID
± Prednisone within first 3 months
Poor response
Biologic DMARD
Other DMARD mono Rx Mono or combo with DMARD
Combo DMARD Rx
(MTX if not used above)
Poor response
Try other combination, triple drug (DMARD + Biologic), add low dose of
Prednisone for long term, consider second line DMARD.
NSAIDs and/or corticosteroids may be used for
symptomatic relief if needed
They provide relatively rapid improvement compared with
DMARDs, which may take weeks to months before benefit
is seen.
However, NSAIDs have no impact on disease progression,
and corticosteroids have the potential for long-term
complications.
NSAIDs
Possess both analgesic and anti-inflammatory
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
rheumatoid arthritis.
COX-2 selective NSAIDs have a better GI safety
profile and similar efficacy as conventional NSAIDs.
Corticosteroids
Oral corticosteroids ( prednisone and methylprednisolone) can be used
to control pain and synovitis with DMARDs (bridging therapy).
• Low-dose, long-term corticosteroid may be used for patients with
difficult-to-control disease (Prednisone 7.5 mg/day or equivalent dose )
• High-dose oral or IV corticosteroids may be used for several days to
suppress disease flares in severe cases.
Methotrexate
MTX inhibits cytokine production and purine
biosynthesis, which may be responsible for its anti-
inflammatory properties.
Its onset is relatively rapid (as early as 2 to 3 weeks).
Toxicities are GI, hematologic, pulmonary, and
hepatic.
Methotrexate..
Concomitant folic acid may reduce some adverse
effects without loss of efficacy.
[AST] or [ALT]) should be monitored periodically
MTX is teratogenic, and patients should use
contraception and discontinue the drug if
conception is planned.
Leflunomide
Leflunomide inhibits pyrimidine synthesis, which reduces
lymphocyte proliferation and modulation of inflammation.
Its efficacy for RA is similar to that of MTX.
The drug may cause liver toxicity and is contraindicated in
patients with preexisting liver disease.
The ALT should be monitored monthly initially and
periodically thereafter.
It is teratogenic and should be avoided during pregnancy.
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.
Hydroxychloroquine…
Short-term toxicities include GI, ocular, dermatologic,
and neurologic effects.
Periodic ophthalmologic examinations are necessary
for early detection of reversible retinal toxicity.
Sulfasalazine
Sulfasalazine use is often limited by adverse effects.
Antirheumatic effects should be seen in 1 to 2 months.
Adverse effects include GI, dermatologic,
hematologic, and hepatic effects.
GI symptoms may be minimized by starting with low
doses and taking the drug with food.
Azathioprine
Azathioprine is a purine analog that is converted to
6-mercaptopurine and is thought to interfere with
DNA and RNA synthesis.
Antirheumatic effects may be seen in 3 to 4 weeks.
It should be discontinued if no response is observed
after 12 weeks at maximal doses.
Azathioprine…
Its major adverse effects are bone marrow
suppression, stomatitis, GI intolerance, infections,
drug fever, hepatotoxicity, and oncogenic potential.
Dosage and Laboratory Monitoring
Drug Usual Dose Initial Maintenance
NSAIDs Usual anti inflammatory Scr or BUN, CBC q 2–4 wk Same as initial plus stool
dose p starting therapy x 1–2 mo guaiac q 6–12 mo
Salicylates: Serum salicylate
levels if therapeutic dose
and no response
Methotrexate Oral, SC, or IM: 7.5–15 Baseline: AST, ALT, alk CBC w/plt, AST, alb q 1–
mg q week phos, alb, t. bili, hep B and 2 mo
C studies, CBC w/plt, Scr
Leflunomide Oral: 100 mg daily for Baseline: ALT, CBC ALT, CBC monthly
3 d then 10–20 mg initially and then
daily periodically when stable
Hydroxychloroquine Oral: 200 mg bid Baseline: Color fundus Peripheral visual field
photography and automated testing q 9–12 mo or
central perimetric analysis Amsler grid at home q 2
wk
Sulfasalazine Oral: 500 mg bid, then Baseline: CBC w/plt, then q Same as initial q 1–2 mo
8 to 1 g bid max. week x 1 mo
Etanercept 50 mg SC weekly None None
Infliximab 3 mg/kg IV at 0, 2, 6 wk None None
then q 8 wk
Adalimumab 40 mg SC q 2 wk None None
Anakinra 100 mg SC daily None None
Dosage and Laboratory Monitoring
Drug Usual Dose Initial Maintenance
Rituximab 1000 mg x 2 doses, 14 d None None
apart
Abatacept <60 kg = 500 mg None None
60–100 kg = 750 mg
>100 kg = 1000 mg
given at 0, 2, and 4 wk
then every 4 wk by IV
infusion
Azathioprine Oral: 50–150 mg daily CBC w/plt, AST q 2 wk x CBC w/plt, AST q 4–6 wk
1–2 mo
d-Penicillamine Oral: 125–250 mg daily, baseline: UA, CBC w/plt, CBC w/plt, UA q 4–6 wk
may 8 by 125–250 mg q then q week x 1 mo
1–2 mo, max 750 mg daily
Cyclophosphamide Oral: 1–2 mg/kg per day UA, CBC w/plt q wk x 1 UA, CBC w/plt q 4–6 wk
mo
Cyclosporine Oral: 2.5 mg/kg per day Scr, blood pressure at 4 wk Scr, blood pressure 4 wk
Corticosteroids Oral, IV, IM, IA, and Glucose, blood pressure Glucose, blood pressure q
soft-tissue injections: 3–6 mo, bone density
variable annually
Alb, albumin; alk phos, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate
aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count; hep, hepatitis; IA, intra-articular;
IM, intramuscular; IV, intravenous; p, after; plt, platelet; q, every; Scr, serum creatinine; t. bili, total bilirubin;
UA, urinalysis.
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