Rheumatoid Arthritis (RA)

Rheumatoid Arthritis (RA)

• RA is a chronic inflammatory disorder of autoimmune
origin principally attacks the joints, producing a
nonsuppurative proliferative and inflammatory synovitis,
that progresses to joint destruction and ankylosis
• Extraarticular lesions may occur in the skin, heart, blood
vessels, and lungs.
• It is three times more common in women than in men.

• The peak incidence is in the 3rd - 5th decades of life.

• Pathogenesis:

• RA results from exposure of a genetically susceptible host to

environmental factors.
• Genetic susceptibility:

• Association with HLA-DR alleles (DR4, DR1, DRE10, DR14)

• Environmental factors:

• Infectious agents (EBV, retroviruses, mycobacteria, Borrelia,

and Mycoplasma), and smoking.
• Infection and smoking may promote citrullination of self-
proteins that trigger autoimmune reactions.
• The pathologic changes are mediated by antibodies against
self-antigens and inflammation caused by cytokines
secreted by CD4+ T cells.
• CD4+ T helper (TH) cells initiate the autoimmune response
by reacting with an arthritogen, (microbial or a chemically
modified self-antigen).
• The T cells produce cytokines that stimulate other
inflammatory cells to effect tissue injury:

1. IFN-γ from TH1 cells activates macrophages and synovial

cells.

2. IL-17 from TH17 cells recruits neutrophils and monocytes.

3. RANKL expressed on activated T cells stimulates osteoclasts

and bone resorption.

4. TNF and IL-1 from macrophages stimulate resident synovial

cells to secrete proteases that destroy hyaline cartilage.
• Antibodies are produced against self antigens (citrullinated
peptides).
• In RA, complexes of antibodies with citrullinated peptides
deposit in the joints.
• About 80% of patients have serum IgM or IgA
autoantibodies that bind to the Fc portions of their own
IgG.
• These autoantibodies are called rheumatoid factor.
• Morphology:

• Grossly, the synovium becomes edematous, thickened, and

hyperplastic.
• Hallmark is synovitis leading to formation of a pannus (a
mass of edematous synovium, inflammatory cells,
granulation tissue, and fibroblasts
• The pannus can bridge apposing bones to form a fibrous
ankylosis that will eventually ossify.
• The characteristic histologic features include:

1. Synovial cell hyperplasia and proliferation.

2. Dense inflammatory infiltrates of CD4+ helper T cells, B

cells, plasma cells, dendritic cells, and macrophages.

3. Increased vascularity resulting from angiogenesis.

4. Neutrophils and aggregates of organizing fibrin on the

synovial and joint surfaces.

5. Osteoclastic activity in underlying bone causing

periarticular erosions and subchondral cysts.
Rheumatoid arthritis.
(A) Schematic view of the joint lesion. (B) Low magnification shows
marked synovial hypertrophy with formation of villi.
(C) At higher magnification, subsynovial tissue containing a dense
lymphoid aggregate.
• Rheumatoid nodules are an infrequent manifestation of RA
and typically occur in subcutaneous tissue including the
forearm, elbows, occiput, and lumbosacral area.
• Microscopically, they resemble necrotizing granulomas.

• Rarely, RA can involve the lungs (rheumatoid nodules,

interstitial lung disease).
Rheumatoid Nodule
• Clinical Course:

• Non-specific malaise, fatigue, and generalized

musculoskeletal pain.
• Arthritis with morning stiffness that improves with activity.

• Symmetric involvement of PIP joints of the fingers (swan-

neck deformity), wrists (ulnar deviation), elbows, ankles,
and knees is characteristic.
• DIP is usually spared (unlike osteoarthritis).

• Affected joints are swollen, warm, and painful.

• Atlanto-axial joint subluxation may threaten the spinal cord
• Laboratory findings:

• Positive Rheumatoid factor.

• Anticyclic citrullinated peptide antibodies (ACPA/anti-CCP)

are highly specific (~98%) for RA.
• There is often anaemia of chronic disease.

• Inflammation causes ↑platelets, ↑ESR, ↑CRP.

• Neutrophils and high protein in synovial fluid.

• X-rays show soft tissue swelling, joint effusions, juxta-
articular osteopenia and ↓joint space.
• Later there may be bony erosions, subluxation or complete
carpal destruction.
• Ultrasound and MRI can identify synovitis more accurately,
and have greater sensitivity in detecting bone erosions
than conventional X-rays.
• Complications:

• Anemia of chronic disease

• Secondary amyloidosis.

• Management:

• Corticosteroids, methotrexate, and TNF antagonists.

• NSAIDS

• Physiotherapy

• Surgery may relieve pain, improve function and prevent

deformity.