Rheumatoid Arthritis (RA)

Pathogenesis

• ~50% of RA risk is inherited. The HLA-DR4 allele ("shared epitope") is strongly associated with ACPA-positive RA. HLA-DRB1 alleles that carry the shared epitope increase RA risk 4-6 fold; combined with smoking, this rises to 20-40 fold.

• Smoking is the most reproducible risk factor: confers a relative risk of 1.5-3.5x. Risk is almost exclusively tied to RF/ACPA-positive disease and persists 15 years after cessation.
• Periodontal disease / oral microbiome: Porphyromonas gingivalis is uniquely capable of PAD (peptidyl arginine deiminase) enzyme production, catalyzing citrullination of host proteins - creating neo-antigens that trigger autoimmunity.
• Gut microbiome dysbiosis: Prevotella copri enrichment has been found in early untreated RA.
• EBV has been implicated but causation is unproven.

• Anti-citrullinated protein antibodies (ACPA / anti-CCP): Present in ~70% of RA patients. Arginine residues in fibrinogen, type II collagen, vimentin, and α-enolase are citrullinated by PAD enzymes; these modified epitopes trigger autoimmunity. ACPAs may appear >10 years before clinical disease.
• Rheumatoid factor (RF): IgM/IgA autoantibodies against the Fc region of IgG, present in ~80% of patients. Not RA-specific.

• CD4+ Th1 cells secrete IFN-γ → activate macrophages and synovial cells
• Th17 cells secrete IL-17 → recruit neutrophils and monocytes
• TNF is a key mediator of inflammation and joint destruction (basis for biologic therapy)
• Macrophages and synovial fibroblasts release proteases (MMPs), prostaglandins, and cytokines (IL-1, IL-6, TNF)
• RANKL from activated T cells stimulates osteoclasts → bone resorption
• B cells and plasma cells form germinal centers in the synovium; secrete RF and ACPAs

Pathology / Morphology

1. Synovium becomes edematous, thickened, and hyperplastic - smooth contour replaced by delicate, bulbous villi
2. Pannus formation: a mass of edematous synovium, inflammatory cells, granulation tissue, and fibroblasts that invades cartilage and bone. Composed of 6 cell types: T cells, B cells, plasma cells, dendritic cells, mast cells, granulocytes
3. Histologic features: (1) Synovial cell hyperplasia/proliferation; (2) dense CD4+ T cell, B cell, plasma cell, macrophage infiltrates (often forming lymphoid follicles); (3) increased vascularity (angiogenesis); (4) fibrin-rich neutrophilic exudate on synovial surfaces; (5) osteoclastic subchondral bone erosion
4. Bone damage: Osteoclasts at the pannus-bone interface form resorption lacunae, especially at radial sites of MCP joints
5. Periarticular osteopenia: From bone marrow inflammation; visible as MRI signal alterations ("bone marrow lesions") - a forerunner of frank erosions
6. End-stage: Fibrous ankylosis → ossification → bony ankylosis (bone fusion)

Clinical Features

• Often insidious - malaise, fatigue, generalized musculoskeletal pain in ~50% of patients, followed by joint involvement over weeks to months
• Can also have acute polyarticular onset

• Small joints first: MCP and PIP joints of hands (sparing DIP - key distinction from OA), MTP joints of feet
• Then: wrists, ankles, elbows, knees
• Morning stiffness >1 hour (worse after inactivity - "gelling")
• Joints are swollen, warm, tender, and painful

• Ulnar deviation of fingers at MCPs
• Swan-neck deformity: PIP hyperextension + DIP flexion
• Boutonniere deformity: PIP flexion + DIP hyperextension
• Z-deformity of the thumb
• Subluxation of the carpus, atlantoaxial subluxation (C1-C2, causing neck pain/myelopathy risk)

Diagnosis

• ACPA (anti-CCP): ~70% sensitivity, >95% specificity - the most specific test; predicts erosive disease
• RF: ~80% sensitivity but low specificity (also positive in SLE, Sjogren's, chronic infections, healthy elderly)
• ~20% of RA patients are seronegative (negative for both)
• ESR and CRP: elevated in active disease
• CBC: normocytic anemia, thrombocytosis in active disease

• X-ray: periarticular osteopenia, joint space narrowing, marginal erosions (especially radial aspects of MCPs), deformities
• MRI: earliest detection of synovitis and bone marrow edema (precedes erosions)
• Ultrasound: detects subclinical synovitis and tenosynovitis

• DAS28 (Disease Activity Score - 28 joints)
• SDAI (Simplified Disease Activity Index)
• CDAI (Clinical Disease Activity Index)
• ACR 20/50/70 improvement criteria (used in clinical trials)

Treatment

1. NSAIDs

• Adjunctive only; provide symptomatic relief but do not alter disease course
• Inhibit COX-1 and COX-2; risk of GI and renal toxicity with chronic use

2. Glucocorticoids

• Bridge therapy while awaiting DMARD effect (onset may take weeks-months)
• Low-dose prednisone 5-10 mg/d for active disease
• Short bursts for flares
• Minimize long-term use due to osteoporosis, infection, metabolic effects

3. Conventional (csDMARDs)

4. Biologic DMARDs (bDMARDs)

5. JAK Inhibitors (targeted synthetic DMARDs - tsDMARDs)

• Tofacitinib, Baricitinib, Upadacitinib
• Oral agents; inhibit Janus kinase signaling
• Used when bDMARDs fail or as alternatives; black box warnings for infection, malignancy, thromboembolism, MACE in patients >50 with CV risk factors

Prognosis

• Chronic, waxing-and-waning course in most patients; progressive joint damage without DMARD therapy
• ~20% of seronegative patients may stabilize or remit
• Major causes of excess mortality: accelerated cardiovascular disease (most common), infections, cervical myelopathy
• Poor prognostic factors: high ACPA/RF titers, high disease activity at onset, early erosions on imaging, extra-articular disease, functional disability

Key Distinguishing Points (RA vs OA)