Rheumatoid Arthritis
Medicine · Rheumatology · lean revision notes
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic, symmetrical, inflammatory polyarthritis driven by autoimmune synovitis that destroys cartilage and bone, with characteristic systemic and extra-articular features. It is one of the highest-yield rheumatology topics for NEET PG — classification criteria, anti-CCP specificity, and methotrexate as anchor DMARD recur every cycle.
Definition & Epidemiology
RA is a symmetric, additive, deforming, peripheral polyarthritis with a predilection for the small joints of the hands and feet, characterised by proliferative synovitis (pannus formation) leading to articular cartilage destruction and bony erosions.
- Prevalence ~0.5–1% worldwide; female:male = 3:1.
- Peak onset 30–50 years (but can occur at any age).
- Strong association with HLA-DR4 and HLA-DRB1 (shared epitope hypothesis).
- Genetic + environmental: smoking is the single most important modifiable environmental risk factor (promotes citrullination → anti-CCP). Porphyromonas gingivalis (periodontitis) is also implicated.
High-yield: The "shared epitope" maps to HLA-DRB1 alleles; smoking + shared epitope synergise to produce anti-CCP (ACPA) positive RA, which is the more erosive, severe phenotype.
Etiology & Pathophysiology
The central lesion is chronic synovitis. Sequence of events:
Genetic susceptibility (HLA-DRB1) + trigger (smoking, infection) → citrullination of self-peptides (by peptidyl arginine deiminase) → loss of tolerance → anti-CCP & RF production → T-cell (Th1/Th17) and B-cell activation → macrophage cytokine release (TNF-α, IL-1, IL-6) → synovial proliferation = pannus → RANKL-driven osteoclast activation + MMP release → cartilage & bone erosion.
Key effector molecules:
- TNF-α — master cytokine; central therapeutic target.
- IL-6 — drives systemic features (fever, anaemia of chronic disease, raised CRP, thrombocytosis).
- RANKL — osteoclastogenesis → periarticular osteopenia and erosions.
The pannus is the hypertrophied, invasive synovial membrane (vascular granulation tissue rich in fibroblasts, macrophages, lymphocytes) that erodes cartilage and subchondral bone.
High-yield: Rheumatoid factor (RF) is an autoantibody (usually IgM) directed against the Fc portion of IgG. It is sensitive but not specific. Anti-CCP (anti-cyclic citrullinated peptide) is the most specific serological marker (~95–98%) and appears years before clinical disease.
Clinical Features
Articular (the core)
- Insidious onset of pain, swelling, and morning stiffness lasting >1 hour (vs <30 min in osteoarthritis).
- Symmetrical small-joint involvement: MCP, PIP, wrists, MTP.
- DIP joints are characteristically SPARED (key differentiator from osteoarthritis and psoriatic arthritis).
- Cervical spine (atlanto-axial) may be involved; thoracolumbar spine spared.
Classic hand deformities (late)
| Deformity | Description |
|---|---|
| Swan-neck | PIP hyperextension + DIP flexion |
| Boutonnière | PIP flexion + DIP hyperextension |
| Z-deformity of thumb | MCP flexion + IP hyperextension |
| Ulnar deviation | of fingers at MCP joints |
| Piano-key sign | dorsal subluxation of ulnar head at wrist |
Extra-articular features
RA is a systemic disease — extra-articular manifestations correlate with high RF titres.
| System | Manifestation |
|---|---|
| Skin | Rheumatoid nodules (extensor surfaces, e.g. olecranon; central fibrinoid necrosis with palisading histiocytes) |
| Lung | Pleural effusion (exudative, low glucose, low pH), interstitial lung disease (UIP pattern), Caplan syndrome (RA + pneumoconiosis) |
| Eye | Keratoconjunctivitis sicca, scleritis, episcleritis, scleromalacia perforans |
| Heart | Pericarditis, accelerated atherosclerosis (leading cause of death) |
| Haem | Anaemia of chronic disease, Felty syndrome |
| Neuro | Carpal tunnel syndrome, atlanto-axial subluxation (cord compression) |
| Vascular | Rheumatoid vasculitis (nailfold infarcts, mononeuritis multiplex) |
| Renal | Secondary AA amyloidosis (chronic inflammation), drug-induced nephropathy |
High-yield: Felty syndrome = RA + Splenomegaly + Neutropenia (mnemonic "SANTA": Splenomegaly, Anaemia, Neutropenia, Thrombocytopenia, Arthritis). Associated with high RF titres and recurrent infections.
High-yield: Caplan syndrome = RA + pneumoconiosis (coal/silica) → multiple peripheral lung nodules.
High-yield: Pleural fluid in RA shows characteristically very LOW glucose (<60 mg/dL, often <30) and low pH — a classic exam discriminator.
Diagnosis: ACR/EULAR 2010 Classification Criteria
The 2010 criteria allow early diagnosis (older 1987 ARA criteria required established/erosive disease). Apply to a patient with ≥1 joint with definite clinical synovitis not better explained by another disease.
A score of ≥6 / 10 classifies as definite RA.
| Domain | Points |
|---|---|
| Joint involvement | |
| 1 large joint | 0 |
| 2–10 large joints | 1 |
| 1–3 small joints | 2 |
| 4–10 small joints | 3 |
| >10 joints (≥1 small) | 5 |
| Serology | |
| Negative RF and anti-CCP | 0 |
| Low-positive RF or anti-CCP | 2 |
| High-positive RF or anti-CCP | 3 |
| Acute-phase reactants | |
| Normal CRP and ESR | 0 |
| Abnormal CRP or ESR | 1 |
| Duration of symptoms | |
| <6 weeks | 0 |
| ≥6 weeks | 1 |
High-yield: Score ≥6/10 = definite RA. Maximum from serology is 3 (high-positive). "High-positive" = >3× upper limit of normal.
Investigations
Serology
- Anti-CCP (ACPA) → most specific, prognostic (erosive disease), can predate symptoms by years. Investigation of choice for specificity/prognosis.
- Rheumatoid factor → sensitive ~70–80%, but also positive in SLE, Sjögren (highest titres), chronic infections (HCV, endocarditis), sarcoid, healthy elderly.
Acute-phase reactants
- ESR and CRP raised; track disease activity. CRP correlates with IL-6.
Haematology
- Normocytic normochromic anaemia (anaemia of chronic disease); thrombocytosis in active disease.
Imaging — radiographic sequence
Soft tissue swelling → periarticular osteoporosis → loss of joint space → marginal erosions → subluxation/ankylosis
| Feature | Rheumatoid arthritis | Osteoarthritis |
|---|---|---|
| Osteoporosis | Periarticular (juxta-articular) | Absent |
| Joint space | Uniform/symmetric narrowing | Asymmetric narrowing |
| Erosions | Marginal erosions | None (instead osteophytes) |
| Subchondral | No sclerosis early | Sclerosis + cysts |
| New bone | None | Osteophytes |
High-yield: Earliest X-ray change in RA = soft tissue swelling + periarticular osteoporosis; first bony change = marginal erosions. MRI and ultrasound (power Doppler) detect synovitis and erosions earliest — most sensitive for early disease.
Synovial fluid
- Inflammatory: WBC 2,000–50,000/µL, predominantly neutrophils, low viscosity, sterile, no crystals (excludes gout/pseudogout).
Disease Activity Scoring — DAS28
The DAS28 (Disease Activity Score) assesses 28 joints (shoulders, elbows, wrists, MCPs, PIPs, knees) using tender + swollen joint counts, ESR/CRP, and patient global assessment.
| DAS28 score | Activity |
|---|---|
| > 5.1 | High |
| 3.2 – 5.1 | Moderate |
| 2.6 – 3.2 | Low |
| < 2.6 | Remission |
High-yield: DAS28 < 2.6 = remission; >5.1 = high activity. The modern strategy is "Treat to Target" (T2T) — escalate therapy until remission/low activity is achieved.
Management
The principle is early, aggressive DMARD therapy within a "window of opportunity" to prevent irreversible erosions, guided by treat-to-target.
Stepwise approach
- Confirm diagnosis + assess activity (DAS28) →
- Start conventional synthetic DMARD — methotrexate (anchor drug) ± short bridging steroid + NSAID for symptoms →
- Reassess at 3 months; if target not met →
- Add second csDMARD or step up to biologic DMARD (anti-TNF / others) →
- If inadequate, switch biologic class or add targeted synthetic DMARD (JAK inhibitor).
Drug classes
| Class | Examples | Key points / toxicity |
|---|---|---|
| csDMARDs | Methotrexate (1st line/anchor), sulfasalazine, leflunomide, hydroxychloroquine | MTX: weekly dosing, give folic acid; toxicity = hepatotoxicity, myelosuppression, pneumonitis; teratogenic |
| Biologic (anti-TNF) | Infliximab, etanercept, adalimumab | Screen for latent TB before starting; risk of reactivation TB, infections |
| Biologic (others) | Rituximab (anti-CD20), tocilizumab (anti-IL-6R), abatacept (CTLA4-Ig, T-cell costim block), anakinra (IL-1) | Rituximab useful in RF/anti-CCP positive, vasculitis |
| tsDMARDs (JAK inhibitors) | Tofacitinib, baricitinib | Oral; risk of VTE, herpes zoster |
| Glucocorticoids | Prednisolone (bridging/flares) | Not for long-term monotherapy |
| NSAIDs | — | Symptom relief only; do NOT alter disease progression |
High-yield: Methotrexate is the first-line anchor DMARD. Always co-prescribe folic acid to reduce mucosal/marrow toxicity. Pneumonitis is an idiosyncratic, potentially fatal MTX reaction.
High-yield: Screen for latent TB (and hepatitis B/C) before starting anti-TNF agents — they reactivate tuberculosis. Live vaccines are contraindicated on biologics.
High-yield: In pregnancy, methotrexate and leflunomide are contraindicated (teratogenic); hydroxychloroquine and sulfasalazine are the safer DMARD choices.
Mnemonic for csDMARDs — "My SLH" / "HSLM": Hydroxychloroquine, Sulfasalazine, Leflunomide, Methotrexate.
Complications
- Joint destruction & disability — deformities, secondary osteoarthritis.
- Atlanto-axial subluxation → cervical myelopathy (caution during intubation/anaesthesia).
- Accelerated cardiovascular disease — the leading cause of death in RA.
- Secondary AA amyloidosis — chronic inflammation → nephrotic syndrome/renal failure.
- Felty syndrome → infections (neutropenia), large granular lymphocyte leukaemia risk.
- Lymphoma — increased risk (esp. DLBCL) with high disease activity.
- Osteoporosis — disease + steroid driven.
- Drug toxicity — MTX hepatotoxicity/pneumonitis, biologic-related infections/TB.
Key Differentials
| Disease | Distinguishing features |
|---|---|
| Osteoarthritis | DIP/PIP Heberden & Bouchard nodes, no morning stiffness (<30 min), osteophytes, no systemic features |
| Psoriatic arthritis | DIP involvement, dactylitis ("sausage digit"), nail pitting, "pencil-in-cup" X-ray, RF negative |
| SLE | Non-erosive, reducible arthritis (Jaccoud arthropathy), ANA/anti-dsDNA positive, multisystem |
| Gout | Acute monoarthritis (1st MTP — podagra), MSU crystals (negative birefringence), tophi |
| Reactive arthritis | Asymmetric oligoarthritis, post-dysentery/STI, "can't see/pee/climb a tree", HLA-B27 |
| Polymyalgia rheumatica | Elderly, proximal girdle stiffness, very high ESR, dramatic steroid response, no erosions |
| Viral (parvovirus B19, rubella, HCV) | Self-limiting, history of exposure/rash |
High-yield: RA = DIP sparing + erosive + symmetrical. Psoriatic & osteoarthritis = DIP involvement. SLE arthritis = non-erosive (Jaccoud's).
Recently asked / exam angle
- "Most specific marker for RA?" → Anti-CCP (anti-citrullinated peptide antibody).
- "Which joint is spared in RA?" → DIP joints.
- Pleural effusion with very low glucose → think RA pleuritis.
- Felty syndrome triad → RA + splenomegaly + neutropenia.
- First-line DMARD / anchor drug → methotrexate (+ folic acid).
- Mandatory screening before anti-TNF → latent TB.
- Earliest radiographic finding → periarticular osteoporosis + soft-tissue swelling; MRI/USG most sensitive early.
- DAS28 < 2.6 → remission.
- Safe DMARDs in pregnancy → hydroxychloroquine, sulfasalazine.
- Image-based: swan-neck / boutonnière / ulnar deviation / "Z-thumb" of hand; X-ray showing marginal erosions & symmetric joint-space loss.
- Cause of death in RA → cardiovascular disease.
- Caplan syndrome association → coal worker's pneumoconiosis + RA.
Rapid revision
- RA = symmetrical inflammatory polyarthritis, F:M = 3:1, HLA-DRB1 (shared epitope).
- Morning stiffness >1 hour; DIP joints spared; MCP/PIP/wrist/MTP involved.
- Anti-CCP = most specific; RF = sensitive but non-specific (anti-Fc IgG); highest RF titres in Sjögren.
- ACR/EULAR 2010 score ≥6/10 = definite RA (joints + serology + APR + duration ≥6 wk).
- Earliest X-ray = periarticular osteoporosis + soft-tissue swelling; hallmark = marginal erosions, symmetric joint-space loss; no osteophytes.
- Deformities: swan-neck, boutonnière, Z-thumb, ulnar deviation.
- Felty = RA + splenomegaly + neutropenia; Caplan = RA + pneumoconiosis.
- RA pleural effusion = exudate with very low glucose & low pH.
- Methotrexate = first-line anchor DMARD (+ folic acid); pneumonitis & hepatotoxicity feared; teratogenic.
- Screen latent TB before anti-TNF; biologics: rituximab (anti-CD20), tocilizumab (anti-IL-6R), abatacept (CTLA4-Ig).
- DAS28 <2.6 = remission; manage by Treat-to-Target; NSAIDs give symptom relief only, no disease modification.
- Cardiovascular disease = leading cause of death; secondary AA amyloidosis and lymphoma are recognised complications.