Rheumatoid Arthritis — Symptoms, Causes & Treatment | MyMedicPlus

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune inflammatory disease characterised primarily by persistent synovitis (inflammation of the joint lining — the synovium), progressive joint destruction through cartilage and bone erosion, and important extra-articular manifestations affecting multiple organs. RA affects approximately 1% of adults globally, making it the most common inflammatory arthritis. It is 3 times more common in women than men, with peak onset between 40–60 years, though it can occur at any age including childhood (juvenile idiopathic arthritis). The primary pathological mechanism is immune-mediated synovial inflammation driven by autoreactive T cells and B cells producing rheumatoid factor and anti-CCP antibodies, leading to pannus formation (invasive inflammatory synovial tissue) that destroys cartilage and bone. Without effective disease-modifying treatment, RA leads to progressive joint deformity, functional disability, and premature mortality — primarily from cardiovascular disease (RA independently doubles the risk of CVD). Modern treat-to-target strategies and the availability of biologic and JAK inhibitor therapies have transformed outcomes dramatically, with many patients achieving sustained remission with preserved joint structure and function. Early diagnosis (within the first 3 months — the 'window of opportunity') and prompt initiation of therapy are the most important prognostic factors.

RA results from autoimmune activation of CD4+ T helper cells (particularly Th17 and Th1 subtypes) and B lymphocytes producing pathogenic autoantibodies (rheumatoid factor — IgM antibody against the Fc portion of IgG; and anti-cyclic citrullinated peptide (anti-CCP) antibodies — highly specific markers of RA). These activate synovial macrophages to secrete pro-inflammatory cytokines — TNF-alpha, IL-6, IL-1, IL-17 — which drive synovial proliferation, angiogenesis, osteoclast activation (bone erosion), and cartilage destruction. Genetic susceptibility: HLA-DRB1*04:01 and DRB1*04:04 (shared epitope hypothesis — a 5-amino-acid sequence in the HLA-DR antigen-binding groove) are the strongest genetic risk factors, conferring 3–4-fold elevated risk; also associated with more severe, seropositive, and erosive disease. Smoking: the single most important modifiable risk factor — doubles the risk of developing RA (particularly seropositive RA), worsens disease activity, reduces response to biologics, and is associated with more severe extra-articular manifestations, particularly RA-related lung disease. Other triggers: occupational silica dust exposure (mining, quarrying, sandblasting — 3-fold elevated RA risk); periodontitis (Porphyromonas gingivalis bacteria citrullinate proteins, potentially triggering anti-CCP antibody production); gut and lung microbiome dysbiosis (current area of active research); female sex hormones (postpartum period — significant risk of RA onset or flare); obesity (drives systemic inflammation, worsens RA outcomes, and reduces biologic efficacy); and air pollution (PM2.5 exposure).

Articular features: symmetrical small joint synovitis predominantly affecting the metacarpophalangeal joints (MCPs), proximal interphalangeal joints (PIPs), and wrists; the distal interphalangeal joints (DIPs) are typically spared (distinguishing RA from osteoarthritis and psoriatic arthritis). Metatarsophalangeal joints (MTPs — often forefoot pain on walking is an early complaint) and ankles are commonly involved. Joints appear warm, swollen (boggy synovitis — not bony osteophytes), and tender on palpation. Bilateral, relatively symmetric distribution is characteristic but not invariable at onset. Morning stiffness lasting more than 1 hour is a hallmark feature — reflecting overnight synovial fluid accumulation and inflammatory cytokine surges that improve with activity. With progressive disease: joint space narrowing, juxta-articular osteopenia, and marginal erosions (best seen on X-ray, ultrasound, or MRI) lead to deformity. Systemic features at presentation: significant fatigue (disproportionate to joint activity — the most debilitating non-joint symptom, reported in 80%), low-grade fever, anorexia, and weight loss. Extra-articular manifestations: rheumatoid nodules (firm, non-tender subcutaneous nodules over pressure areas — olecranon, achilles tendon, finger joints — in 20–30% of seropositive RA); interstitial lung disease (UIP or NSIP pattern — present in 10–30%; can precede arthritis; most common cause of excess mortality in RA); serositis (pleuritis causing pleuritic chest pain; pericarditis); secondary Sjögren's syndrome (dry eyes — keratoconjunctivitis sicca, and dry mouth — xerostomia — in 30%); scleritis; vasculitis (rare — digital ischaemia, cutaneous ulcers); and Felty's syndrome (RA + splenomegaly + neutropenia — increased infection risk).

Blood tests: rheumatoid factor (RF — IgM anti-IgG antibody) positive in 70–80% of RA patients but is not specific (also positive in 5% of healthy adults, Sjögren's syndrome, SLE, and hepatitis C); anti-cyclic citrullinated peptide (anti-CCP) antibodies positive in 65–70% — highly specific for RA (95% specificity); presence of both RF and anti-CCP ('seropositive RA') strongly predicts more erosive and severe disease, and anti-CCP can be present years before clinical onset. CRP and ESR (erythrocyte sedimentation rate): elevated in active RA — used for monitoring disease activity and response to treatment (DAS28-CRP is the standard clinical score). Full blood count: normochromic normocytic anaemia of chronic disease, thrombocytosis (platelet count above 400 — reflects inflammation); iron studies to differentiate from iron deficiency anaemia. LFTs and renal function: pre-treatment baseline (methotrexate is hepatotoxic; NSAIDs are nephrotoxic). Hepatitis B and C serology: before starting immunosuppressive therapy. Plain X-rays of hands and feet (PA bilateral views): juxta-articular osteopenia (early), joint space narrowing (cartilage loss), and marginal bone erosions (at joint margins — pathognomonic of RA when present); radiographic erosions indicate irreversible structural damage — a treatment failure marker. Musculoskeletal ultrasound: detects synovitis (increased power Doppler signal — active inflammation), tenosynovitis, and early erosions with greater sensitivity than clinical examination and X-ray. MRI of hands and wrists: most sensitive imaging for early erosion detection, bone marrow oedema (pre-erosive), and synovitis quantification. ACR/EULAR 2010 classification criteria: 4 domains scored 0–10 — joint involvement (number/size), serology (RF/anti-CCP — up to 3 points), acute phase reactants (CRP/ESR — up to 1 point), and symptom duration (above 6 weeks — 1 point); score of 6 or above classifies as RA.

Treat-to-target (T2T) strategy: the overriding principle — aim for DAS28-CRP below 2.6 (remission) or below 3.2 (low disease activity) measured every 1–3 months; escalate therapy if the target is not achieved. Methotrexate (MTX): the anchor conventional synthetic DMARD (csDMARD) and the most widely used first-line treatment — started at 10–15 mg/week orally or subcutaneously (SC route preferable for better bioavailability above 15 mg) and escalated to 25 mg/week by 4–6 weeks if tolerated; folic acid 5 mg once weekly (on a different day to MTX) mandatory to reduce side effects (mouth ulcers, nausea, hepatotoxicity); monitoring — FBC, LFTs, and albumin at 4–6 weekly intervals initially, then 3-monthly when stable; contraindicated in pregnancy (highly teratogenic — reliable contraception for both sexes). Combination csDMARDs: hydroxychloroquine 200–400 mg/day (antimalarial — mild anti-inflammatory, safe, requires annual ophthalmology surveillance for maculopathy) and sulfasalazine 2–3 g/day added to MTX if remission not achieved (triple therapy — MTX + hydroxychloroquine + sulfasalazine — has comparable efficacy to early biologic therapy in some trials). Biologic DMARDs (bDMARDs — added when csDMARDs fail to achieve the target): TNF inhibitors (adalimumab, etanercept, certolizumab pegol, golimumab — subcutaneous; infliximab — IV infusion); IL-6 receptor inhibitors (tocilizumab IV or SC, sarilumab SC — highly effective for elevated CRP, anaemia of chronic disease, giant cell arteritis coexistence); anti-CD20 (rituximab IV — particularly suited for seropositive RA, concurrent lymphoma, or where TNF inhibitor is contraindicated); abatacept (CTLA4-Ig — T-cell costimulation inhibitor — good safety profile; preferred in ILD). JAK inhibitors (targeted synthetic DMARDs — tsDMARDs): tofacitinib (Xeljanz), baricitinib (Olumiant), upadacitinib (Rinvoq) — highly effective oral agents; cautionary use in patients over 65, smokers, or with cardiovascular risk factors due to VTE, MACE, and malignancy signals from ORAL Surveillance trial. Bridging therapy: low-dose prednisolone (5–10 mg/day) to rapidly control inflammation while waiting for DMARD onset of action — tapered over 3–6 months. Intramuscular or intra-articular steroid injections for focal flares.

Joint deformities from progressive cartilage and bone destruction: swan-neck deformity (PIP hyperextension, DIP flexion), boutonnière deformity (PIP flexion, DIP hyperextension), ulnar deviation of the MCPs, and Z-deformity of the thumb — all consequences of tendon and ligament damage. Atlantoaxial subluxation (C1-C2 instability from destruction of the transverse ligament by cervical synovitis) can cause myelopathy — cord compression requiring urgent imaging and surgical stabilisation. Interstitial lung disease (ILD — predominantly UIP or NSIP patterns) is the most common extra-articular cause of excess mortality in RA, affecting up to 30% of patients; can present insidiously with progressive dyspnoea and dry cough before clinical arthritis. Cardiovascular disease risk is doubled in RA (equivalent to diabetes as a cardiovascular risk factor) — due to chronic systemic inflammation accelerating atherosclerosis and platelet aggregation — the leading cause of excess mortality. Lymphoma risk is elevated approximately 2-fold — linked to disease activity rather than treatment. Treatment complications: methotrexate hepatotoxicity (liver fibrosis, cirrhosis with prolonged high-dose use — Fibroscan monitoring every 3 years recommended); methotrexate-induced pneumonitis (rare — subacute dyspnoea and low-grade fever — requires immediate drug cessation and corticosteroids); biologic-related serious infections (TNF inhibitor reactivation of TB — mandatory IGRA/Mantoux screening before starting); hepatitis B reactivation from rituximab; VTE, MACE, and malignancy risk with JAK inhibitors particularly in high-risk populations. Secondary Felty's syndrome, vasculitis, and amyloidosis are rare but serious systemic complications of long-standing poorly controlled RA.

Smoking cessation is the single most important preventive and management measure — smoking doubles the risk of developing RA, worsens disease activity and severity, reduces response to biologic therapy (particularly TNF inhibitors), and significantly increases cardiovascular mortality risk; the rheumatology team should deliver smoking cessation support at every appointment. Strict treat-to-target: formal DAS28-CRP assessment at every clinic visit (every 1–3 months in active disease); escalate therapy promptly if not at target by 3 months — do not continue the same therapy if it is not working after an adequate trial. Cardiovascular risk management: all RA patients should have annual cardiovascular risk assessment (QRISK3 — multiply score by 1.5 to account for RA's additional risk); statin therapy for elevated risk; blood pressure and blood glucose monitoring; encourage physical activity and weight management. Vaccination before immunosuppression: live vaccines are contraindicated on biologic or JAK inhibitor therapy; inactivated vaccines (influenza annually, pneumococcal PCV13 + PPV23, COVID-19 boosters, hepatitis B, herpes zoster shingrix) should be given before or at least 4 weeks before starting therapy. Physiotherapy: hand exercises (Nordic regime), range-of-motion exercises, hydrotherapy — delay functional decline and maintain grip strength. Occupational therapy: adaptive aids, joint protection education (avoiding high-force or prolonged joint stress), assistive devices for daily activities. Regular monitoring of drug toxicity as per BSR/BHPR guidelines. DEXA scan for bone density with long-term steroid use. Psychosocial support — fatigue, pain, and disability from RA frequently cause depression and reduced quality of life.

See your GP promptly for: persistent swelling, pain, and morning stiffness in small joints of the hands and feet (lasting more than 30 minutes) — do not wait months before seeking assessment. The NICE 'don't wait' target is referral to a rheumatologist within 3 weeks of presentation with suspected inflammatory arthritis. Early treatment within the window of opportunity (first 3-6 months) dramatically reduces joint damage and improves long-term outcomes. See a rheumatologist urgently for: newly diagnosed RA — early DMARD therapy (methotrexate) must be started promptly. Seek emergency care for: acute compression of the spinal cord from atlantoaxial subluxation (neck instability in established RA — sudden or worsening neck pain with arm tingling, numbness, or weakness after trauma), vasculitis, or ischaemic complications of RA medication. Contact your rheumatologist if new infections, abnormal blood counts, or adverse drug reactions occur on DMARDs.