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]

^[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]

^[1]

Enlarge

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]

^[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]

Enlarge

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]

^[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]

^[17]

The distribution and the stiffness do the discriminating. RA can affect any joint, but the distal interphalangeal, sacroiliac and lumbar spine joints are rarely involved — examine those sites before committing to the label. There is no single laboratory test that excludes or proves the diagnosis: ESR and CRP give the best information about the acute-phase response, and plain radiography is the standard investigation, with early disease showing soft-tissue swelling and juxta-articular osteoporosis before erosions appear.^[17]

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]

^[5]

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]

^[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 Boolean remission definition (2011) defines remission as tender joint count, swollen joint count, CRP (in mg/dL) and patient global assessment (0 to 10 scale) all at 1 or less, or an SDAI score of 3.3 or less; a patient-reported measure was deliberately included after trial data showed it mattered, and DAS28-based remission definitions predicted good radiographic outcomes less well than these alternatives.^[13] The 2022 revision (Boolean 2.0) raises only the patient-global threshold — to 2 or less on the 0 to 10 scale — and classifies more patients as in remission (14.8% to 20.6% at 6 months in early RA) with better agreement to the index-based SDAI and CDAI criteria, without jeopardising prediction of radiographic non-progression or good function.^[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 before anything else. Send synovial fluid for Gram stain, culture, cell count and crystals before any steroid injection; if septic arthritis is confirmed it needs urgent drainage and intravenous antibiotics — 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, leg ulcers) — organ-threatening extra-articular disease; urgent rheumatology input for high-dose immunosuppression.
5. Severe flare while awaiting DMARD effect — a short course of glucocorticoid, oral or intra-articular, is the accepted bridge; EULAR's induction strategy is methotrexate plus glucocorticoids at the start of therapy.^[2]

Management — the treat-to-target ladder

Enlarge

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]

^{[15] [14]}

The fatal-dosing trap: methotrexate is a weekly regimen, and confusing it for a daily one kills. In the French poison-control and pharmacovigilance series of 74 low-dose MTX medication errors, 70 patients took their methotrexate daily; 61 of 74 (82%) developed complications, 46 (62%) of them severe, and 9 patients (14.8%) died within 11 to 45 days of the first error.^[15] Co-prescribe folic or folinic acid (trial starting doses were 7 mg/week or less): supplementation reduced MTX gastrointestinal side effects by 26%, transaminase elevation by 76.9%, and withdrawal from methotrexate for any reason by 60.8%.^[14]

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]

If methotrexate gives an inadequate response, EULAR recommends stratifying within 3 to 6 months: with poor prognostic factors (autoantibodies, high disease activity, early erosions, or failure of two csDMARDs), add any bDMARD or JAK inhibitor to the csDMARD — and if that fails, use any other bDMARD (same or another class) or a tsDMARD.^[2] The all-conventional alternative — triple therapy: add sulfasalazine and hydroxychloroquine to methotrexate — was tested against methotrexate plus etanercept in a 48-week double-blind trial of 353 patients with suboptimal methotrexate response; disease activity outcomes were not different, and in open-label extension more patients stayed on triple therapy than on the biologic combination (78% versus 63% at 1 year), with significantly more switches from the biologic arm to triple therapy — evidence that the cheaper conventional combination is a defensible first escalation.^[18]

Other csDMARDs to name. EULAR lists methotrexate, leflunomide and sulfasalazine as the conventional synthetic DMARDs, and the evidence for adding to or switching between them is the same stratified pathway described above.^[2] Pregnancy planning changes the list: EULAR's points to consider find antimalarials (hydroxychloroquine), sulfasalazine, azathioprine, ciclosporin, tacrolimus and glucocorticoids compatible with pregnancy and lactation, while methotrexate must be stopped before conception because of proven teratogenicity and leflunomide should be discontinued before a planned pregnancy because fetal-safety documentation is insufficient.^[16]

Glucocorticoids as a bridge only. EULAR's induction strategy is methotrexate plus glucocorticoids, with response assessed and therapy escalated within 3 to 6 months if the target is not met; on sustained remission, DMARDs may be tapered but not stopped — glucocorticoids belong to the start of therapy, not to long-term maintenance.^[2]

Step 3 — Biologic DMARDs

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

^{[2] [16]}

Step 4 — JAK inhibitors (the ORAL Surveillance class)

• The safety signal examiners now test: the ORAL Surveillance trial randomised rheumatoid arthritis patients aged 50 or older with at least one additional cardiovascular risk factor to tofacitinib (5 or 10 mg twice daily) or a TNF inhibitor, and tofacitinib was statistically inferior to TNF inhibitors for major adverse cardiovascular events and malignancy. Venous thromboembolism and pulmonary embolism incidences were higher with tofacitinib than TNF inhibitors, and higher with 10 mg twice daily than 5 mg twice daily; VTE risk factors across both treatments were prior VTE, body mass index of 35 kg/m² or more, older age and chronic lung disease. Regulatory agencies have since issued guidance advising caution in the use of JAK inhibitors in certain patients. Across registrational trials and registries, herpes zoster is the infection reported more with JAK inhibitors than with biologic DMARDs; post-hoc analyses found that age of 65 or more, high baseline cardiovascular risk, a history of smoking, sustained inflammation and suboptimally treated cardiovascular comorbidities all increased the risk of these outcomes.^[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 versus seronegative RA — the 2010 ACR/EULAR criteria score serologic abnormality (negative, low-positive or high-positive RF/ACPA) as one of the four domains, and EULAR counts autoantibody presence as a poor prognostic factor that justifies earlier addition of a bDMARD or JAK inhibitor.^[1][2]
• Palindromic onset — a recognised RA presentation with recurrent episodes of oligoarthritis and no residual radiologic damage between attacks.^[17]
• Polymyalgic-like (elderly-onset) RA — may be clinically indistinguishable from polymyalgia rheumatica in elderly subjects; acute or subacute onset accounts for roughly a quarter of RA presentations.^[17]
• Felty syndrome, rheumatoid nodules and rheumatoid vasculitis — the classical extra-articular cluster, named alongside haematological abnormalities and visceral involvement among the extra-articular manifestations of RA.^[17]
• Constitutional-onset RA — malaise, fatigue, weight loss and fever can open the disease, with or without joint symptoms, and should not be mistaken for infection or malignancy alone.^[17]

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]

^[1]

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 and lactation — EULAR's points to consider, built on a systematic literature review and data from several pregnancy registries, find antimalarials (hydroxychloroquine), sulfasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, intravenous immunoglobulin and glucocorticoids compatible with pregnancy and lactation. Methotrexate, mycophenolate mofetil and cyclophosphamide require discontinuation before conception due to proven teratogenicity; leflunomide and tofacitinib (with abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakinra) should be discontinued before a planned pregnancy because fetal-safety documentation is insufficient. Among biologics, TNF inhibitors are the best studied and appear reasonably safe with first- and second-trimester use — effective treatment of active inflammatory disease remains possible through pregnancy with reasonable fetal safety.^[16]
• Patients with cardiovascular or thrombotic risk — assess before choosing a JAK inhibitor or TNF inhibitor: in the ORAL Surveillance analyses, age of 65 or more, high baseline cardiovascular risk, a history of smoking, sustained inflammation, active disease and suboptimally treated cardiovascular comorbidities all increased the risk of the major cardiovascular and malignancy outcomes, and prior VTE, body mass index of 35 kg/m² or more, older age and chronic lung disease predicted venous thromboembolism across both treatment arms.^[11][9]
• Smokers — smoking appears on the same risk lists: in the post-hoc ORAL Surveillance analysis a history of smoking was among the factors that increased the risk of major cardiovascular events and malignancy, and the JAK safety review stresses that treatment goals, cardiovascular risk and patient preferences should be discussed with the patient before committing to a JAK inhibitor.^[11]

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; outcomes matched methotrexate-etanercept in head-to-head comparison, with better treatment durability.^[18]
8. Biologics: anti-TNF, tocilizumab (IL-6), rituximab (CD20), abatacept (costimulation) — screen TB and HBV first.^[2]
9. JAK inhibitors carry regulatory-agency warnings for MACE, malignancy and VTE; the ORAL Surveillance signal was in patients over 50 with at least one cardiovascular risk factor.^[9][11]
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, mycophenolate and cyclophosphamide must be stopped before conception; hydroxychloroquine and sulfasalazine are compatible with pregnancy and lactation; TNF inhibitors are the best-studied biologics in pregnancy.^[16]

Ward-round test — three stems, thirty seconds each

Stem 1 — the florist from the top of the topic (answer)ShowHide

The 42-year-old florist with symmetric MCP and PIP swelling, morning stiffness over an hour, a positive MCP squeeze test and a mother with "the arthritis". What is your first investigation and your first drug? Model: Confirm inflammation and classify — the 2010 ACR/EULAR criteria apply to undifferentiated inflammatory arthritis with at least one swollen joint and score joint involvement (number and site), serologic abnormality, acute-phase response and symptom duration. No single test proves the diagnosis: ESR and CRP give the best acute-phase information, and plain radiographs of the hands and feet are the standard investigation — early disease shows soft-tissue swelling and juxta-articular osteoporosis. The first drug is methotrexate plus a short course of glucocorticoids, with folic or folinic acid supplementation to cut gastrointestinal and hepatic toxicity; reassess and escalate within 3 to 6 months if the target is not met.^{[1][17][2][14]}

Stem 2 — the hot single joint in a known RA patient (answer)ShowHide

A 58-year-old with longstanding seropositive RA presents with a single knee that is hot, swollen and exquisitely tender, distinctly worse than her other joints. The registrar wants to inject a steroid. What is the right move? Model: Aspirate before any injection. Send synovial fluid for cell count, Gram stain, culture and crystals. RA patients on biologics or steroids are at high risk of septic arthritis, and sepsis mimics a flare — injecting a steroid into a septic joint is catastrophic. If the fluid is inflammatory with negative culture and negative crystals, treat as a flare with intra-articular steroid; if septic, urgent washout and IV antibiotics.^[1]

Stem 3 — the pre-operative neck (answer)ShowHide

A 65-year-old with chronic RA is listed for a hip replacement. The anaesthetist asks if there is anything rheumatological to check first. What do you do? Model: Flexion-extension lateral cervical spine X-rays before any intubation. Measure the atlantodens interval (ADI) — over 3 mm suggests atlantoaxial subluxation from transverse ligament attenuation, and intubation in flexion can compress the cord. If abnormal, alert anaesthesia (consider awake fibreoptic intubation) and consider neurosurgical referral for atlantoaxial fusion if symptomatic. This is the pre-operative check every RA patient needs, and missing it is the classic preventable harm.^[10]

References18ShowHide

1. [1]Neogi T, Aletaha D, Silman AJ, et al. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: Phase 2 methodological report Arthritis Rheum, 2010.PMID 20872596
2. [2]Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update Ann Rheum Dis, 2020.PMID 31969328
3. [3]Schellekens GA, Visser H, de Jong BA, et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide Arthritis Rheum, 2000.PMID 10643712
4. [4]Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force Ann Rheum Dis, 2016.PMID 25969430
5. [5]Prevoo ML, van 't Hof MA, Kuper HH, et al. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis Arthritis Rheum, 1995.PMID 7818570
6. [6]Studenic P, Aletaha D, de Wit M, et al. American College of Rheumatology/EULAR remission criteria for rheumatoid arthritis: 2022 revision Ann Rheum Dis, 2023.PMID 36280238
7. [7]McInnes IB, Schett G. Pathogenetic insights from the treatment of rheumatoid arthritis Lancet, 2017.PMID 28612747
8. [8]Yazdani K, Xie H, Avina-Zubieta JA, et al. Has the excess risk of acute myocardial infarction in rheumatoid arthritis relative to the general population declined? A population study of trends over time Semin Arthritis Rheum, 2021.PMID 33735663
9. [9]Charles-Schoeman C, Fleischmann R, Mysler E, et al. Risk of Venous Thromboembolism With Tofacitinib Versus Tumor Necrosis Factor Inhibitors in Cardiovascular Risk-Enriched Rheumatoid Arthritis Patients Arthritis Rheumatol, 2024.PMID 38481002
10. [10]Neva MH, Isomäki P, Hannonen P, et al. Early and extensive erosiveness in peripheral joints predicts atlantoaxial subluxations in patients with rheumatoid arthritis Arthritis Rheum, 2003.PMID 12847673
11. [11]Szekanecz Z, Buch MH, Charles-Schoeman C, et al. Efficacy and safety of JAK inhibitors in rheumatoid arthritis: update for the practising clinician Nat Rev Rheumatol, 2024.PMID 38216757
12. [12]Combe B, Landewe R, Daien CI, et al. 2016 update of the EULAR recommendations for the management of early arthritis Ann Rheum Dis, 2017.PMID 27979873
13. [13]Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials Arthritis Rheum, 2011.PMID 21294106
14. [14]Shea B, Swinden MV, Ghogomu ET, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis J Rheumatol, 2014.PMID 24737913
15. [15]Vial T, Patat AM, Boels D, et al. Adverse consequences of low-dose methotrexate medication errors: data from French poison control and pharmacovigilance centers Joint Bone Spine, 2019.PMID 30243781
16. [16]Götestam Skorpen C, Hoeltzenbein M, Tincani A, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation Ann Rheum Dis, 2016.PMID 26888948
17. [17]Grassi W, De Angelis R, Lamanna G, et al. The clinical features of rheumatoid arthritis Eur J Radiol, 1998.PMID 9652497
18. [18]Peper SM, Lew R, Mikuls T, et al. Rheumatoid Arthritis Treatment After Methotrexate: The Durability of Triple Therapy Versus Etanercept Arthritis Care Res (Hoboken), 2017.PMID 28388820