Key Facts

RA is a destructive inflammatory arthritis that, if untreated, leads to joint deformity, disability, and increased cardiovascular mortality. The treat-to-target strategy aims for remission or low disease activity.

Epidemiology

• Prevalence: ~1% of UK population (~400,000 people)
• F:M 3:1; peak onset 40-60 years
• Smoking is the strongest modifiable risk factor
• HLA-DR4 (shared epitope) associated with susceptibility and severity

Aetiology

• Genetic: HLA-DRB1 shared epitope (60% of genetic risk), PTPN22
• Environmental: smoking (strongest modifiable risk; OR 2-3), periodontitis (Porphyromonas gingivalis), silica dust
• Hormonal: female predominance, improvement in pregnancy

Pathophysiology

• Loss of self-tolerance → T and B cell activation → autoantibody production (RF, anti-CCP)
• Citrullination of proteins in joints (triggered by smoking, periodontitis) → neoepitope recognition
• Synovial inflammation (synovitis) → pannus formation (hyperplastic synovium)
• Pannus invades cartilage and bone → marginal erosions → joint destruction
• Pro-inflammatory cytokines: TNF-α, IL-6, IL-1 (targets for biologic therapy)
• Systemic inflammation → accelerated atherosclerosis, increased CV mortality

Joint Involvement

• Symmetrical polyarthritis: MCP, PIP, wrist, MTP joints
• Morning stiffness >30 minutes (often >1 hour)
• Swelling, warmth, tenderness of affected joints
• DIP joints typically spared (unlike OA and psoriatic arthritis)
• Early disease: joint swelling; late disease: deformities

Classic Hand Deformities (Late/Untreated)

• Ulnar deviation of MCPs
• Swan neck deformity (PIP hyperextension + DIP flexion)
• Boutonnière deformity (PIP flexion + DIP hyperextension)
• Z-thumb (thumb MCP flexion + IP hyperextension)
• Subluxation of MCPs

Extra-Articular Manifestations (40%)

• Rheumatoid nodules: 20-30%, on extensor surfaces (olecranon, fingers)
• Lungs: ILD (UIP/NSIP), pleural effusions (low glucose), Caplan syndrome (nodules + pneumoconiosis)
• Eyes: scleritis, episcleritis, keratoconjunctivitis sicca (secondary Sjogren)
• Cardiovascular: pericarditis, accelerated atherosclerosis (CV mortality ×1.5-2)
• Haematological: anaemia of chronic disease, Felty syndrome
• Neurological: peripheral neuropathy, mononeuritis multiplex, atlantoaxial subluxation (C1-C2)
• Vasculitis: nail fold infarcts, digital gangrene (rare, serious)

Red Flags

• Atlantoaxial subluxation → cervical myelopathy (paraesthesiae, Lhermitte sign) → urgent MRI before intubation/surgery
• New dyspnoea → ILD, pleural effusion
• Felty syndrome → recurrent infections (neutropenia)

Bloods

• RF (rheumatoid factor): positive in 70-80%; sensitive but not specific (also positive in Sjogren, hepatitis C, SBE)
• Anti-CCP antibodies: positive in 60-70%; 95-98% specific for RA; predicts erosive disease
• ESR/CRP: elevated (disease activity markers)
• FBC: normocytic anaemia (chronic disease), thrombocytosis (inflammation)
• LFTs, renal function: baseline before DMARD therapy

Imaging

• X-ray hands and feet: early – soft tissue swelling, periarticular osteopenia, loss of joint space; late – marginal erosions, subluxation
• USS (musculoskeletal): synovitis, effusions, erosions (more sensitive than X-ray early)
• MRI: most sensitive for early erosions and synovitis; useful if diagnostic uncertainty
• Cervical spine X-ray (flexion/extension): atlantodental interval >3mm = subluxation; required pre-anaesthesia

Assessment

• DAS28 score: composite of 28 joint count (tender/swollen), ESR/CRP, patient VAS
  • <2.6 = remission; 2.6-3.2 = low; 3.2-5.1 = moderate; >5.1 = high disease activity

Non-pharmacological

• Physiotherapy: joint protection, range of motion, strengthening
• Occupational therapy: splinting, aids and adaptations
• Patient education: NRAS (National Rheumatoid Arthritis Society)
• Smoking cessation: reduces disease activity and improves DMARD response
• Cardiovascular risk management: RA carries ×1.5-2 CV risk; statin, BP control

Pharmacological (NICE NG100 – Treat to Target)

Step 1 – First-line DMARD (within 3 months of symptom onset):

• Methotrexate 7.5mg weekly (escalate to 25mg); with folic acid 5mg weekly (not same day as MTX)
• Alternative if MTX contraindicated: leflunomide 20mg OD or sulfasalazine 500mg-1g BD
• Monitoring: FBC, LFTs every 2 weeks for first 6 weeks, then monthly for 3 months, then 3-monthly

Step 2 – Combination DMARD therapy:

• Triple therapy: methotrexate + hydroxychloroquine 200-400mg OD + sulfasalazine 1g BD
• Or change to alternative csDMARD

Step 3 – Biologic DMARDs (NICE criteria: DAS28 >5.1 on 2 occasions 1 month apart despite adequate csDMARDs):

• Anti-TNF: adalimumab 40mg SC alternate weeks, etanercept 50mg SC weekly, infliximab, certolizumab, golimumab
• IL-6 inhibitor: tocilizumab 8mg/kg IV monthly or 162mg SC weekly (NICE TA375)
• B-cell depletion: rituximab 1g IV × 2 (day 1, 15); second-line after anti-TNF failure
• T-cell co-stimulation blocker: abatacept
• JAK inhibitors: tofacitinib 5mg BD, baricitinib 4mg OD, upadacitinib 15mg OD (NICE approved; oral alternatives to biologics)

Bridging therapy:

• Short-course prednisolone (≤15mg for ≤3 months) or IM depomedrone 120mg: for flares while waiting for DMARD effect
• Intra-articular corticosteroid: for individual joint flares

Surgical

• Joint replacement: hip, knee (most common), MCP
• Synovectomy: refractory synovitis
• Cervical spine stabilisation: atlantoaxial subluxation with myelopathy

Referral Criteria

• Suspected RA (joint swelling >6 weeks) → urgent rheumatology (target assessment within 3 weeks)
• Inadequate response to csDMARDs → rheumatology for biologic assessment

• Untreated RA: 50% work disability within 10 years; life expectancy reduced by 5-10 years
• Early aggressive treatment: remission achievable in 30-50% with modern therapy
• Anti-CCP positive: predicts more erosive, severe disease
• Cardiovascular mortality: leading cause of death in RA (×1.5-2 increased risk)
• Biologics have transformed outcomes: reduced disability, joint damage, and mortality
• Erosions develop within first 2 years in 70% of untreated patients → emphasises window of opportunity

ACR/EULAR 2010 Classification Criteria

Score ≥6/10 = classifiable RA:

DMARD Monitoring