Rheumatoid Arthritis

Meet the patient

A 42-year-old florist wakes every morning with hands she describes as "filled with wet cement" — it takes an hour of moving them before she can button her coat. Both wrists, several knuckles and the balls of her feet ache symmetrically, and the MCP squeeze test makes her flinch. She has lost weight, is tired by noon, and her mother had "the arthritis" too.[1][12]

Two questions will decide her next decade: is this RA or a mimic? (the DIP, the nails and the serology settle it) and how fast can I start a DMARD? (the first twelve weeks are the window of opportunity, and every month of delay is cartilage she will not get back).[2][4]

What RA is — and the one feature that anchors the diagnosis

It is a systemic autoimmune disease whose fingerprint is a symmetric, erosive polyarthritis of the diarthrodial small joints. Persistent synovial inflammation grows a hypertrophic, invasive pannus that eats cartilage and bone — the structural reason untreated RA deforms and shortens life. But the joints are only the loudest target: the same cytokines drive accelerated atherosclerosis, anaemia, osteoporosis and the cardiovascular mortality that remains the single biggest cause of premature death.[7][8]

The clinical art is not making the label stick — it is moving fast. Recognise disease within the first twelve weeks (the "window of opportunity"), classify it with the 2010 ACR/EULAR criteria, grade activity with the DAS28, and drive a treat-to-target strategy to remission or low disease activity anchored on methotrexate before reaching for a biologic. Every link in that chain has evidence of better outcomes; snapping any one — late DMARD, no target, indefinite steroids — costs the patient joints and years.[2][4]

Etymology for viva gold: rheumatoid shares its root with rheum, Greek for "that which flows" — the ancients imagined a morbid humour flowing from the brain to the joints. The metaphor is dead; the word survived because the migratory, symmetric quality it described is exactly what you still meet at the bedside.[1]

Classification — the 6-out-of-10 rule, and which joints to exclude

The 2010 ACR/EULAR criteria exist to catch early disease, not to describe the deformed hand of 1987. A patient is classified as having definite RA with a score of 6 or more out of 10, provided synovitis is not better explained by another disease and at least one joint is swollen on examination. Memorise the four domains and their weights:[1]

The number rule: 6-or-more. But the trap examiners set is the excluded joints. The DIP, the first CMC and the first MTP are OA territory, so they are struck from the count — counting them inflates the score and mislabels osteoarthritis as rheumatoid. Duration matters too: symptoms must have persisted six weeks or more to score; anything shorter pushes you toward viral, reactive or palindromic causes.[1]

Within the diagnosis, four subtypes carry different prognoses and the examiner expects you to separate them:[1]

The face-off that earns the most marks in rheumatology is the "spot-the-arthritis" picture, and the discriminator is always the DIP and the nails:[1]

• RA — symmetric, small-joint, spares the DIP.
• OA — asymmetric, hits the DIP (Heberden), PIP (Bouchard) and first CMC.
• Psoriatic — asymmetric, involves the DIP and carries nail dystrophy.
• Gout — targets the first MTP (podagra) and tophi.
• SLE (Jaccoud) — deforming but non-erosive and reducible on X-ray.[1]

Hold those five pictures simultaneously and the long-case stem almost answers itself.[1]

Epidemiology — who gets it, and why

RA is the commonest chronic inflammatory arthritis in adults, with a global prevalence of about 0.5 to 1 percent — higher in some indigenous populations, lower in rural Africa and Asia. The female-to-male ratio is roughly 3:1, and peak onset falls between 30 and 50 years, with a second bump in the elderly (EORA).[7]

The risk story is genes-plus-environment, and the single most examinable link is smoking. The strongest genetic association is HLA-DRB1 alleles carrying the "shared epitope" — a conserved motif at positions 70 to 74 of the DR beta chain that accounts for about a third of genetic risk and predicts erosive, anti-CCP positive disease. Other genes include PTPN22 (T-cell signalling), PADI4 (the citrullination enzyme, prominent in Asian populations) and STAT4.[7]

Cigarette smoking is the modifiable villain. Smoke triggers pulmonary citrullination, breaks immune tolerance to citrullinated proteins, and converts the shared-epitope genotype into ACPA-positive, erosive disease with a multiplicative effect. The cluster around it — silica and mineral dust, obesity, nulliparity, postpartum hormonal shifts, periodontitis (Porphyromonas gingivalis carries its own PAD and citrullinates host proteins) and microbiome dysbiosis — is the "exposure" half of the equation. The classic "first pregnancy improves, postpartum flares" pattern is the immunological-hormonal echo of the same mechanism.[7]

Pathophysiology — citrullination, pannus, and why it never switches off

RA begins when immune tolerance to citrullinated self-proteins breaks, and persists because the synovium learns to keep itself inflamed. The cascade runs in five linked stages, and each stage is the target of a drug you will name at viva.[7]

1. Citrullination and loss of tolerance. PAD enzymes (peptidylarginine deiminases, chiefly PAD2 and PAD4) convert arginine to citrulline in self-proteins — vimentin, fibrin, fibronectin, type II collagen, alpha-enolase. In a susceptible host, citrullinated peptides are presented by HLA-DRB1 shared-epitope molecules to autoreactive CD4+ T cells, which help B cells produce ACPA (what the clinical anti-CCP assay measures) and IgM rheumatoid factor (anti-Fc).[3][7]

2. Pannus formation. ACPA-IgG immune complexes deposit in the joint, fix complement, and activate macrophages and mast cells to release TNF-alpha, IL-1, IL-6, IL-17 and GM-CSF. The cytokines drive synovial capillary proliferation, massive infiltration by CD4+ T cells, B cells, plasma cells and macrophages, and the malignant transformation of fibroblast-like synoviocytes (FLS) into a tumour-like population that ignores the joint boundary. The swollen, hyperplastic synovium these cells carpet is the pannus — the destructive tissue of RA.[7]

3. Cartilage and bone destruction — two parallel killers. FLS and macrophages secrete matrix metalloproteinases (MMP-1, MMP-3, MMP-13) and aggrecanases that digest the cartilage matrix. On the bone side, activated T cells and FLS express RANKL, which binds RANK on osteoclast precursors and drives them into mature, bone-resorbing osteoclasts — the cellular basis of the marginal erosion. The inflammatory milieu simultaneously suppresses osteoblasts, so erosions do not heal.[7]

4. Why it never switches off. Three mechanisms make RA self-sustaining: ectopic lymphoid neogenesis (the synovium organises into follicle-like structures with germinal centres), epigenetic reprogramming of FLS into an aggressive "imprinted stromal memory" that survives even when inflammation is dampened, and defective regulatory T cells with impaired IL-2 signalling. This is the biological justification for starting DMARDs early — once FLS imprint and erosions form, structural damage becomes irreversible.[7]

5. The systemic spillover. The same TNF and IL-6 that drive synovitis produce the anaemia of chronic disease (hepcidin-driven iron sequestration), thrombocytosis, fatigue, weight loss, hypergammaglobulinaemia, accelerated atherosclerosis, and osteoporosis. The cardiovascular risk runs about 1.5 to 2 times population baseline and is the leading cause of premature death — a fact the examiner will test and the bedside clinician must act on.[8]

Clinical presentation — the hand that gives the diagnosis away

The textbook presentation is an insidious, symmetric polyarthritis of the small joints with morning stiffness over one hour that improves with use. An acute, explosive onset over days is less common but does occur — in elderly-onset disease and in palindromic patterns. The improves-with-use point is the half of the discriminator you must not forget: OA worsens with use and stiffens for under thirty minutes.[12]

Articular symptoms. Patients describe pain, swelling, warmth and stiffness across the MCP, PIP, wrist, elbow, shoulder, knee, ankle, MTP and cervical spine. The DIP is characteristically spared (the single most exam-rewarded observation), and the thoracic, lumbar and sacroiliac joints are spared (distinguishing RA from axial spondyloarthritis). The MCP squeeze test — pain on compression of the metacarpophalangeal row — is a sensitive early sign you can elicit in five seconds.[1]

The hand deformities every OSCE candidate must name on sight — these are the long-case centrepiece:[1]

Foot and neck involvement carry the hidden danger. Subluxed MTP heads make the patient feel they are "walking on marbles"; the lateral toes claw. In the cervical spine, atlantoaxial subluxation — anterior C1 on C2 from transverse ligament attenuation — produces occipital pain and can compress the cord. Every RA patient needs flexion-extension cervical films before any anaesthetic, because intubating an unrecognised subluxation can paralyse them.[10]

Extra-articular and systemic features cluster in longstanding seropositive disease. The list examiners want, organised by system:[1]

• Nodules — firm, non-tender, on extensor surfaces (olecranon, ulna, Achilles, occiput); histology shows central fibrinoid necrosis ringed by palisading histiocytes.
• Sicca / Sjogren overlap — dry eyes, dry mouth; the commonest extra-articular feature.
• Lung — interstitial lung disease (UIP pattern), pleural effusion (low glucose, high LDH exudate), rheumatoid lung nodules (Caplan syndrome if pneumoconiosis coexists), bronchiectasis.
• Heart — accelerated atherosclerosis and ischaemic heart disease (the leading cause of premature death), pericarditis, myocarditis, vasculitis.[8]
• Eye — episcleritis, scleritis (scleromalacia perforans is sight-threatening), keratoconjunctivitis sicca, peripheral ulcerative keratitis.
• Nerve — carpal tunnel, cervical myelopathy, mononeuritis multiplex (vasculitis).
• Blood — anaemia of chronic disease, thrombocytosis, Felty syndrome (longstanding seropositive RA plus splenomegaly plus neutropenia, with leg ulcers and recurrent infection).
• Vessel — rheumatoid vasculitis (digital infarcts, leg ulcers, palpable purpura, mononeuritis multiplex).
• Kidney — secondary AA amyloidosis with nephrotic proteinuria after years of uncontrolled inflammation.
• Constitutional — low-grade fever, fatigue, weight loss, morning "gelling".[1]

The atypical presentations examiners deliberately probe:[1]

• Elderly — onset after 60 with oligo-articular, large-joint, very systemic disease mimicking polymyalgia rheumatica; high ESR/CRP, often seronegative; co-consider giant-cell arteritis.
• Pregnancy — RA often improves (immune shift to Th2) but flares postpartum; methotrexate is teratogenic and must be stopped 3 months before conception.
• Diabetic or immunocompromised — septic arthritis mimics a flare; always aspirate a hot monoarticular joint before assuming flare.
• Children — chronic inflammatory polyarthritis under 16 is juvenile idiopathic arthritis (JIA), a related but distinct entity.[1]

Differential diagnosis — the mimic that costs the patient

A symmetric small-joint polyarthritis with morning stiffness is not always RA. The dangerous omissions are three: missing septic arthritis in a hot monoarticular presentation, missing a treatable mimic (parvovirus, HBV/HCV, sarcoid, gout), and mislabelling OA or SLE as RA because nobody looked at the DIP and the nails.[12]

The single safest bedside rule for a hot, swollen joint: any acutely inflamed monoarticular joint must be aspirated to exclude septic arthritis and crystals before NSAIDs or steroids are given. Crystals in the fluid do not exclude infection — they coexist in roughly five to twenty percent of culture-positive septic joints.[1]

Clinical and bedside assessment — the long-case centrepiece

Examination rarely provides a diagnostic sign; its job is to stage the disease and screen for complications. Run the focused assessment in this order.[1]

General — posture, gait, functional independence (can she lace a shoe, button a coat, grip a pen?). Look for nodules on extensor surfaces, psoriasis (scalp, umbilicus, natal cleft, nails), sicca features, eye signs (scleritis, episcleritis), leg ulcers and digital infarcts.[1]

The hand exam — where the marks live:[1]

• Inspection — symmetric swelling of MCPs and PIPs, spared DIP, ulnar deviation, swan-neck, boutonniere, Z-thumb, muscle wasting (thenar, interossei), nodules, surgical scars (carpal tunnel release, arthroplasty).
• Palpation — synovial boggy thickening (the pathognomonic feel of RA), warmth, tender and swollen joint count, squeeze test across MCPs and MTPs, restricted range, crepitus.
• Functional tests — grip strength, key pinch, button-fastening, writing, and a validated HAQ (Health Assessment Questionnaire) score.[1]

Other joints and the cervical spine — elbows, shoulders, knees (effusion, Baker cyst that can rupture and mimic DVT), ankles, MTPs ("walking on marbles", claw toes), TMJ, and the neck (assess for pain, Lhermitte sign, myelopathy; check flexion-extension views before any anaesthesia).[10]

Systemic examination — chest (ILD, effusion), heart (pericardial rub, ischaemic signs, valves), eyes (sicca, scleritis), abdomen (Felty splenomegaly), nerves (carpal tunnel, mononeuritis multiplex), skin (vasculitic ulcers, nodulosis).[1]

The DIP, the first CMC and the first MTP are excluded — they are OA sites. The 28-joint set also omits ankles and hips. The reason is not arbitrary: those joints are where OA lives, and including them would dilute the inflammatory signal the DAS28 is built to measure.[5]

Investigations — confirm, classify, monitor

No single test diagnoses RA. Investigations serve three purposes — to confirm inflammation, to classify the disease (anti-CCP/RF, X-ray), and to monitor activity and drug toxicity. The diagnosis itself is clinical, supported by serology and imaging.[1]

Acute-phase and routine bloods. ESR and CRP track with activity (though up to forty percent of patients have normal inflammatory markers at presentation). FBC shows anaemia of chronic disease (normocytic, normochromic, high hepcidin), thrombocytosis, and sometimes neutropenia (Felty). U&E, LFTs and a baseline chest X-ray are needed before methotrexate and other DMARDs.[2]

Serology — the diagnostic core:[1]

• Anti-CCP (ACPA) — high specificity (95 to 98 percent), moderate sensitivity (70 percent), positive early, predicts erosive disease. The single best serology.[3]
• Rheumatoid factor (IgM anti-Fc) — sensitivity 70 percent, specificity 70 to 80 percent; also positive in Sjogren, SLE, chronic infection (HBV, HCV, endocarditis, TB) and 5 percent of healthy elderly.
• ANA — to exclude SLE; ANA positivity with absent dsDNA and absent anti-Smith in RA does not change management.
• Viral and infection screens — parvovirus B19 IgM, HBsAg/HCV RNA, HIV when an acute symmetric polyarthritis could be viral; chikungunya in endemic areas.

Synovial fluid — sterile and inflammatory (WBC 2,000 to 50,000 per microlitre, neutrophilic), negative culture, negative crystals. Always aspirate a hot, monoarticular joint to exclude septic arthritis (WBC typically over 50,000, positive culture) and crystal arthropathy.[12]

Imaging:[1]

• Plain X-rays of hands, wrists and feet are the workhorse. Early changes are periarticular osteopenia and soft-tissue swelling; the pathognomonic feature is the marginal erosion at the bare area; later, uniform joint-space narrowing, subchondral cysts, subluxation and ankylosis. Foot films (especially the 5th MTP head) often show erosions earlier than the hands.
• Ultrasound and power Doppler — detect subclinical synovitis, erosions and active hyperaemia; more sensitive than X-ray and useful for joint injection.
• MRI — most sensitive for early erosions, synovitis and bone marrow oedema.
• Cervical spine lateral flexion/extension — when neck pain or pre-operative: an atlantodens interval over 3 mm (over 5 mm in children) suggests atlantoaxial subluxation.[10]
• High-resolution CT chest — when ILD is suspected (RA-ILD carries significant mortality).

Disease activity scores — reproduced verbatim

The DAS28 is the score you drive the treat-to-target strategy with. It is calculated from tender joint count (TJC28), swollen joint count (SJC28), ESR (or CRP) and patient global health (0 to 100 mm VAS).[5]

The EULAR response criteria combine the current DAS28 with the change from baseline — a good responder improves by more than 1.2 and reaches low activity or remission.[5]

The ACR/EULAR 2022 Boolean remission criteria define true remission as TJC28 at most 1 AND SJC28 at most 1 AND CRP at most 1 mg/dL AND patient global (0 to 10) at most 1 (Boolean 2.0 permits patient global up to 2). The simpler CDAI and SDAI are clinic-friendly alternatives requiring no lab (CDAI) or only CRP (SDAI).[6]

Management — the acute scenarios you cannot miss first

RA is not a resuscitation disease, but several acute scenarios demand immediate action before chronic therapy even starts. The two non-negotiables: rule out septic arthritis in any hot monoarticular joint, and exclude or stabilise cervical cord compression with any new neurological sign.[1]

The acute scenarios that must be addressed before chronic therapy:[2]

1. Hot, swollen single joint — aspirate. Send synovial fluid for Gram stain, culture, cell count and crystals before any steroid injection. If septic arthritis is confirmed, washout plus IV antibiotics (e.g., flucloxacillin 2 g IV QDS; vancomycin 1 g IV BD if MRSA risk or penicillin-allergic) — never inject a steroid into a possibly septic joint.
2. Suspected cervical cord compression (neck pain, hand paraesthesia, gait change, hyperreflexia, sphincter disturbance) — urgent MRI cervical spine, neurosurgical referral, immobilise; routine intubation in unrecognised atlantoaxial subluxation can injure the cord.[10]
3. Acute scleritis, scleromalacia or peripheral ulcerative keratitis — sight-threatening; urgent ophthalmology.
4. Rheumatoid vasculitis (digital infarcts, mononeuritis multiplex, mesenteric vasculitis, leg ulcers) — high-dose glucocorticoid (e.g., methylprednisolone 500 mg to 1 g IV daily for 3 days, then prednisolone 1 mg/kg/day) and urgent rheumatology; often requires cyclophosphamide or rituximab.
5. Severe flare — short course of oral prednisolone (10 to 15 mg/day for 1 to 2 weeks then taper) or intramuscular methylprednisolone 80 to 120 mg, or intra-articular steroid (e.g., triamcinolone acetonide 20 to 40 mg into a knee), with gastric protection and bone protection for repeated courses.

Symptom control while the DMARD takes effect: an NSAID (e.g., naproxen 500 mg BD PO, ibuprofen 400 to 600 mg TDS, diclofenac 50 mg TDS, celecoxib 100 to 200 mg BD) with a PPI (omeprazole 20 mg) for the shortest effective duration; consider cardiovascular, renal and GI risk; avoid NSAIDs in pregnancy (especially third trimester) and in advanced CKD.[2]

Management — the treat-to-target ladder

The backbone of modern RA care is the treat-to-target strategy: a defined target (remission or low disease activity), measured every visit with a validated score, with therapy escalated every 3 to 6 months until the target is reached. Tight control doubles the chance of remission and halves radiographic progression. Therapy is layered: symptom relief, then a conventional synthetic DMARD, then combination csDMARDs, then a biologic or a JAK inhibitor.[4]

Step 1 — Methotrexate, the anchor DMARD

Methotrexate is the first-line treatment of choice in nearly every patient with active RA.[2]

The fatal-dosing trap: methotrexate is given weekly, not daily. Writing it daily causes fatal marrow suppression — the single most dangerous prescription error in rheumatology. Co-prescribe folic acid (e.g., 5 mg weekly) to cut mucosal, hepatic and GI toxicity.[2]

Pre-treatment and monitoring: CBC, LFT, U&E at baseline, then every 2 to 4 weeks for 3 months, then monthly, then every 2 to 3 months. Withhold for transaminases over 3 times the upper limit of normal, cytopenia, infection or pregnancy. Contraindications: pregnancy (teratogenic — stop 3 months before conception, both men and women), active infection, decompensated cirrhosis, significant renal impairment (reduce dose), and concurrent live vaccines. Pulmonary toxicity (acute methotrexate pneumonitis) is rare but important — stop and investigate any new dry cough and dyspnoea.[2]

Step 2 — Triple csDMARD therapy

If methotrexate alone fails (DAS28 still above target at 3 to 6 months), add sulfasalazine (1 to 3 g/day PO in divided doses) and hydroxychloroquine (200 to 400 mg/day PO). The triple-therapy combination is non-inferior to anti-TNF in some trials and far cheaper — the point that earns marks in a resource-constrained viva.[2]

Other csDMARDs to name:[1]

• Leflunomide (loading 100 mg daily for 3 days, then 10 to 20 mg daily) — alternative to methotrexate; also teratogenic (cholestyramine washout needed before pregnancy); monitor LFT and BP.
• Hydroxychloroquine monotherapy — mild disease; annual ophthalmology screening for bull's-eye maculopathy.
• Sulfasalazine — useful when methotrexate is contraindicated; monitor CBC and LFT; causes reversible male infertility and orange discolouration of bodily fluids; avoid in G6PD deficiency.[1]

Glucocorticoids as a bridge only. A short course of prednisolone 5 to 10 mg/day (or equivalent IM/IA) is acceptable as a temporary bridge while the DMARD takes effect; minimise dose and duration because of osteoporosis, diabetes, infection, hypertension, cataracts and cardiovascular risk. Add calcium and vitamin D (and a DEXA plus bisphosphonate if appropriate) for any patient on long-term steroids. The long-term goal is glucocorticoid-free.[1]

Step 3 — Biologic DMARDs

Indicated for moderate to severe RA failing csDMARD therapy.[2]

Step 4 — JAK inhibitors (the boxed-warning class)

If a biologic fails or is unavailable, oral JAK inhibitors are an option.[11][9]

• Tofacitinib 5 mg BD PO (or 11 mg XR OD); baricitinib 2 to 4 mg OD; upadacitinib 15 mg OD.
• The warning examiners now test: the ORAL Surveillance study prompted an FDA/EMA boxed warning for venous thromboembolism, major adverse cardiovascular events, malignancy and all-cause mortality — particularly in patients over 50 with at least one cardiovascular risk factor. Also monitor lipids (LDL rises), LFT, neutrophils, haemoglobin, and beware herpes zoster (vaccinate). Avoid in active infection, severe hepatic impairment, pregnancy and lactation.[9][11]

Escalation triggers (move up a step): persistent DAS28 above target after 3 to 6 months of optimised csDMARD; rapidly progressive erosions on imaging; extra-articular disease; functional decline; intolerable drug toxicity.[4]

De-escalation: once a patient has been in sustained remission (at least 6 to 12 months), a gradual dose taper of biologics or csDMARDs may be attempted under close monitoring — never stop abruptly, and have a clear flare plan.[1]

Surgery for severe structural damage or refractory pain: synovectomy, tendon repair, joint replacement (especially hip and knee), arthrodesis (wrist, cervical spine), and atlantoaxial fusion for symptomatic subluxation. Always obtain pre-operative flexion-extension cervical spine X-rays in any RA patient before anaesthesia.[10]

Non-pharmacological and multidisciplinary: physiotherapy (mobility, strength, conditioning), occupational therapy (joint protection, aids, splints), podiatry, dietitian (Mediterranean diet, omega-3, vitamin D, smoking cessation, weight loss), psychology, and social work for employment and disability support. Smoking cessation is one of the few modifiable factors that improves treatment response and cuts cardiovascular risk.[1]

The named subtypes and syndromes

• Seropositive RA — ACPA and/or RF positive; classical erosive course with nodules and extra-articular disease; responds well to rituximab and abatacept; needs tight control to prevent erosions.
• Seronegative RA — both negative; milder and less erosive but a diagnosis of exclusion — actively exclude psoriatic, reactive, viral, sarcoid and crystal arthropathies before labelling.
• Elderly-onset RA (EORA, age over 60) — abrupt, oligo-articular, large-joint, very systemic, polymyalgia-like; often seronegative; the differential includes PMR (responds dramatically to 15 mg prednisolone), paraneoplastic arthritis and crystal arthropathies.[12]
• Felty syndrome — the triad of longstanding seropositive RA plus splenomegaly plus neutropenia, often with anaemia, thrombocytopenia, leg ulcers, recurrent infections and hyperpigmentation. Associated with HLA-DR4 and clonal large granular lymphocyte (T-LGL) expansion. Methotrexate is first-line; rituximab for refractory; G-CSF for severe neutropenia with infection; splenectomy is rarely used.
• Secondary (AA) amyloidosis — chronic uncontrolled inflammation drives serum amyloid A deposition; presents as nephrotic-range proteinuria, progressive renal failure, hepatosplenomegaly and malabsorption. Diagnose on biopsy (Congo-red apple-green birefringence); treat the underlying RA aggressively.
• Palindromic RA — episodic attacks of mono- or oligo-arthritis (each 1 to 3 days with complete resolution); roughly 30 to 50 percent evolve into classic RA; treat flares with NSAIDs or short steroid bursts; hydroxychloroquine may reduce attack frequency.
• Juvenile idiopathic arthritis (JIA) — chronic inflammatory arthritis in a child under 16 lasting at least 6 weeks; subtypes include oligo-articular (most common; ANA positive; uveitis risk), polyarticular RF-negative, polyarticular RF-positive, systemic (Still disease), enthesitis-related, psoriatic and undifferentiated. Treated with methotrexate, biologics (etanercept) and intra-articular steroids.
• Rheumatoid vasculitis — small-to-medium vessel vasculitis in severe seropositive longstanding disease; digital gangrene, leg ulcers, palpable purpura, mononeuritis multiplex, mesenteric and coronary vasculitis; treat aggressively with high-dose glucocorticoid plus cyclophosphamide or rituximab.
• Caplan syndrome — multiple, rapidly progressive rheumatoid lung nodules in a patient with pneumoconiosis (coal-workers', silicosis, asbestosis).
• Sjogren overlap — secondary Sjogren syndrome in RA is common; manage sicca with saliva substitutes, pilocarpine 5 mg QDS, punctal plugs and topical ciclosporin eye drops.[1]

Complications — the disease and the drugs

Articular and structural — joint destruction, secondary OA, tendon ruptures (especially extensor tendons at the ulnar styloid), Baker cyst (popliteal, may rupture and mimic DVT), atlantoaxial and subaxial cervical subluxation with cord compression risk, osteoporosis (disease- and steroid-driven), reduced grip and functional disability.[10]

Systemic — premature cardiovascular disease (the leading cause of excess death; risk comparable to diabetes), interstitial lung disease (UIP pattern carries the worst prognosis), pleural effusion and pericarditis, scleritis and scleromalacia, secondary amyloidosis, Felty syndrome, rheumatoid vasculitis, anaemia of chronic disease, depression, lymphoma (modestly increased in severe active disease), infections (disease and immunosuppression), and peptic ulcer disease (NSAIDs and steroids).[8]

Treatment-related — methotrexate (hepatotoxicity, marrow suppression, pneumonitis, teratogenicity), leflunomide (hepatotoxicity, neuropathy, hypertension, teratogenicity), sulfasalazine (hepatotoxicity, cytopenia, rash, reversible male infertility), hydroxychloroquine (maculopathy), glucocorticoids (osteoporosis, diabetes, hypertension, cataracts, peptic ulcer, infection), anti-TNF (TB reactivation — always screen with IGRA and CXR, HBV reactivation, heart failure exacerbation, demyelination, infection), JAK inhibitors (herpes zoster, VTE/MACE/malignancy boxed warning).[9][11]

The classic pitfalls that cost patients: labelling OA, psoriatic or viral arthritis as RA without examining the DIP and the nails; missing parvovirus B19 in a young woman with acute symmetric polyarthritis and a rash; injecting a steroid into a septic joint; forgetting cervical spine screening before anaesthesia; giving methotrexate to a pregnant or planning-pregnancy patient; starting a biologic without screening for TB/HBV; treating the ESR instead of the patient; indefinite oral steroids without bone protection; failing to vaccinate patients on immunosuppression.[1]

Prognosis and disposition

Untreated RA destroys joints within two years and shortens life by 5 to 10 years, driven largely by cardiovascular disease, infection and pulmonary complications. With early DMARD therapy and treat-to-target, the picture is transformed — 30 to 50 percent of patients achieve sustained remission, radiographic progression is largely arrested, and life expectancy approaches normal in well-controlled disease.[4][8]

Poor-prognosis markers (drive early aggressive therapy): ACPA positivity (especially high titre), high RF, HLA-DRB1 shared epitope, early radiographic erosions, elevated and persistent CRP/ESR, extra-articular disease, smoking, female sex with disability, and failure to respond to initial methotrexate within 3 to 6 months.[1]

Disposition: most patients are managed as outpatients by a rheumatology-led multidisciplinary team in a treat-to-target clinic. Admit for septic arthritis, atlantoaxial cord compression, vasculitic crisis, interstitial lung disease with respiratory failure, severe infection and occasionally for IV cyclophosphamide or rescue therapy. The safety-net is a named rheumatology nurse or telehealth line and a written flare plan.[1]

Special populations

• Pregnancy — RA often improves during pregnancy (immune shift to Th2) but flares postpartum. Methotrexate and leflunomide are teratogenic — stop 3 months before conception (men and women; cholestyramine washout for leflunomide). Safe in pregnancy: hydroxychloroquine, sulfasalazine (continue with folic acid 5 mg/day), azathioprine (at most 2 mg/kg/day), low-dose prednisolone (avoid fluorinated steroids after first trimester), and certolizumab (minimal placental transfer — the preferred biologic in pregnancy). Avoid: NSAIDs (especially third trimester — premature ductus arteriosus closure, oligohydramnios), high-dose steroids, live vaccines, methotrexate, leflunomide, mycophenolate.[2]
• Children (JIA) — chronic inflammatory arthritis before 16 lasting at least 6 weeks; oligo-articular JIA carries the highest risk of chronic anterior uveitis — mandatory slit-lamp screening every 3 months in ANA-positive children under 7; managed by paediatric rheumatology.[1]
• Elderly — more comorbidity, drug interactions (NSAID renal/GI risk, steroid osteoporosis), atypical presentations; start DMARDs just as early; favour methotrexate over alkylating agents.[1]
• Renal impairment — methotrexate and leflunomide need dose reduction or avoidance in CKD; hydroxychloroquine is preferred; NSAIDs contraindicated in advanced CKD; avoid colchicine if misdiagnosed as gout.[2]
• Hepatic disease — methotrexate and leflunomide avoided in decompensated cirrhosis and active hepatitis; screen HBV/HCV before biologic.[2]
• Pre-existing infection (TB, HBV, HCV, HIV) — treat before biologic; choose rituximab (lowest TB reactivation) for latent TB if a biologic is essential.[1]
• Anticoagulated patients — additional bleeding risk from NSAIDs (avoid); methotrexate and biologics are generally safe; JAK inhibitors add VTE risk — caution with warfarin or DOAC.[9]
• Smokers — counsel that smoking reduces anti-TNF and methotrexate efficacy, drives ACPA-positive disease and increases cardiovascular risk; offer cessation as part of treatment.[7]

Evidence, guidelines and regional differences

The landmark shifts an examiner expects you to cite:[1]

• 1987 ACR criteria — designed for established, erosive RA; superseded by the 2010 ACR/EULAR criteria, which were built to catch early disease and trigger early DMARD therapy.[1]
• Treat-to-target (T2T) — the international task force set remission or low disease activity as the goal, with escalation every 3 to 6 months; updated 2014, repeatedly shown to double remission rates.[4]
• Anchor DMARD revolution — methotrexate confirmed first-line; triple csDMARD therapy effective in early RA and non-inferior to anti-TNF in some studies.[2]
• Biologics era — anti-TNF, tocilizumab, rituximab and abatacept transformed moderate to severe disease; biosimilars improved affordability.[2]
• JAK inhibitor era — tofacitinib, baricitinib and upadacitinib offer an oral option, but ORAL Surveillance raised the VTE/MACE/malignancy signal in older, at-risk patients, prompting boxed warnings.[9][11]
• 2019/2020 EULAR update — methotrexate first csDMARD; glucocorticoid short-term only; bDMARD or tsDMARD after csDMARD failure; taper in sustained remission.[2]

Vaccination in immunosuppressed RA: pneumococcal (PCV15/20 followed by PPSV23), annual influenza, COVID-19, hepatitis B, recombinant zoster (Shingrix) — give before starting biologics where possible; avoid live vaccines (MMR, yellow fever, oral polio, live zoster) once on biologic or JAK therapy.[1]

The mantra, and the pearls that decide the answer

The mantra: spares the DIP, methotrexate weekly, treat to a DAS28 under 2.6 — everything else is escalation.[2]

The twelve pearls that decide an RA answer:[1]

1. Symmetric small-joint polyarthritis that spares the DIP plus morning stiffness over 1 hour points to RA.[1]
2. Anti-CCP specificity is 95 to 98 percent; RF is sensitive but non-specific (Sjogren, SLE, infection, elderly).[3]
3. 2010 ACR/EULAR: at least 6 out of 10 from joints plus serology plus acute phase plus duration; DIP, 1st CMC and 1st MTP are excluded.[1]
4. DAS28 (ESR): remission under 2.6; low 2.6 to 3.2; moderate over 3.2 to 5.1; high over 5.1.[5]
5. Methotrexate is first-line DMARD — weekly, with folic acid; bridge with a short steroid.[2]
6. Treat-to-target, escalate every 3 to 6 months to remission or low activity.[4]
7. Triple csDMARD therapy equals methotrexate plus sulfasalazine plus hydroxychloroquine; non-inferior to anti-TNF in some trials.[2]
8. Biologics: anti-TNF, tocilizumab (IL-6), rituximab (CD20), abatacept (costimulation) — screen TB and HBV first.[2]
9. JAK inhibitors carry a boxed warning for VTE, MACE and malignancy; risk in over-50s with CV risk.[9]
10. Atlantoaxial subluxation — lateral flexion-extension cervical X-ray before any intubation; ADI over 3 mm is abnormal.[10]
11. Cardiovascular disease is the leading cause of premature death — apply a 1.5x risk multiplier.[8]
12. Methotrexate and leflunomide are teratogenic — stop 3 months pre-conception; hydroxychloroquine and sulfasalazine are safe in pregnancy.[2]

Ward-round test — three stems, thirty seconds each