Rheumatoid Arthritis

A chronic, inflammatory, autoimmune disease characterised by an inflammation of the synovial joints.

Background/Epidemiology

  • Common: Around 1% of the population in the UK
  • More commonly presents later on in life (onset in 40s/50s; average age of patients 70)
  • More common in women than men (2-4:1)
  • Associated with significant morbidity
    • Pain/disability
    • About 1/3 stop working within 2 years

Pathophysiology

  • Genetic Susceptibility
    • HLA-DR4 and HLA-DRB1
    • Hereditability
      • Monozygotic vs Dizygotic vs Gen Pop (15-35% vs 5% vs 1%)
  • Triggers
    • Smoking (increasing evidence that this could be a trigger as well as an exacerbating factor)
    • Viral infection
    • Bacterial infection
      • Periodontal infection (Porphyromonas gingivalis can cause citrullination of proteins)
  • Citrullination
    • A normal post-translational modification required for normal function of many proteins (including filaggrin in the skin) and as part of inflammatory change in other proteins (e.g. fibrin)
    • In RA- an immune response is mounted to citrullinated proteins
  • Immune Reaction
    • The triggering event causes T cells to migrate to the synovium/joint where they are activated
    • B-cell activation and the production of autoantibodies (anti-cyclic-citrullinated peptide antibodies)
    • Formation of immune complexes and subsequent activation of the complement system and further recruitment of macrophages and other inflammatory cells
    • Further inflammation is proposed to cause further citrullation and further reaction

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Presentation

  • Joint features
    • Arthritis is usually insidious onset, symmetrical polyarthritis, typically the small joints of the hands and feet (particularly PIP/MCP cf OA and DIP)
      • Pain is often worse at rest (may waken sleep) or just after rest; improves with activity
    • Other features of inflammation e.g. red, hot, swollen, joints
      • Swelling is around the joint (not bony- described often as boggy)
    • Stiffness
      • Often in the morning/after rest and will usually last >30mins
    • On examination
      • As well as the above, there may be reduced range of movement
      • Hand deformities
        • Ulnar deviation
        • Swan neck (hyperextension of PIP and flexion of DIP caused by flexor synovitis that increases the flexor pull on the MCP joint)
        • Boutonniere’s (flexion of PIP and hyperextension of DIP caused by chronic synovitis in which the PIP is forced into flexion, raising tension in the extensors of the DIP)
        • Z-deformities of thumb (hyperextension of the IP joint and fixed flexion and subluxation of the MCP)
        • Piano-key deformity of the wrist (the ulnar head can be depressed (like a piano key))
      • Rheumatoid nodules
        • hard, firm swellings over the extensor surfaces
  • Constitutional symptoms are common
    • profound fatigue
    • mild fever
    • sweats
    • weight loss
  • Extra-articular features
    • Eyes
    • Skin
      • vasculitic rash (palpable purpura)
    • Nervous system
    • Lung
      • Pleural involvement (pleural effusion); pulmonary fibrosis (interstitial disease)
    • Cardiac
      • Increased risk of atherosclerosis (atherosclerotic events); pericarditis
    • (NB Renal involvement is rare)
  • Constitutional symptoms are common
    • Fatigue, malaise, mild fever, weight loss

Investigations

  • Blood tests
    • FBC may be normal or may show normocytic anaemia and/or reactive thrombocytosis.  LFTs: Alk Phos is commonly mildly raised; U&Es (not often helpful in diagnosis but raised urate may suggest polyarticular gout rather than RA)
    • Serology
      • Rheumatoid factor is still occasionally used (positive in 70% of patients) but is going out of practice
      • Anti-CCP antibody is more sensitive and specific for rheumatoid arthritis
  • Imaging
    • X-rays of the hands/feet
      • May show soft tissue swelling, periarticular osteopenia, loss of joint space, erosions and deformity
    • Chest x-ray may help in identifying any lung involvement

Management

  • In a new patient
    • First line (SIGN- thus in Tayside) recommended treatment is DMARD treatment (methotrexate usually first line) within 3 months
      • Combination therapy can be tried in patients who do not have an adequate response (NOTE: many are now treating RA initially with combination (e.g. Methotrexate and sulfasalazine) treatment as there is growing evidence that if the disease can be controlled/suppressed quickly, there is a better prognosis)
      • aim is to get a DAS28 score of <2.6 (remission); if this isn’t possible then at least <3.2 (low DAS28)
      • *Varies by case, depending on patient.
    • NSAIDs should be co-prescribed, where necessary, for symptomatic relief.  Lowest dose possible.  Gastroprotection (PPI) is also recommended for those at risk of gastroduodenal ulcer
    • Low-dose oral corticosteroids can be used in combination with DMARD tx for short term relief of symptoms
      • If long-term use is required, ensure bone protection
  • Biological agents
    • Considered only
      • after a trial of at least 2 DMARDs (6 months each, with 2 months at a standard dose)
      • persistently severe disease (DAS28 >5.1 on at least 2 occasions, 1 month apart)
    • At 6 months, if there is an inadequate response (DAS28 reduction <1.2), the agent should be discontinued

Notes about treatments

Methotrexate

  • Prior to treatment
    • FBC, LFTs, U&Es
      • Contraindicated (or at least caution should be taken) in patients with liver impairment, renal impairment, active infection, immunodeficiency syndromes
    • (Usually) CXR
      • see side effects below)
    • NB Do not use if pregnant/planning pregnancy (clear for 3 months)
  • Initiation of treatment
    • Start at sub-maximal dose (10-15mg/week) and increase dose by 5mg every 2-4 weeks up to 20-25mg/week (depends on response/tolerability)
    • Folic acid 5mg daily (except day of methotrexate) should be co-prescribed
    • FBC, ESR, LFTs and U&Es every 2 weeks until the dose and disease have been stable for 6 weeks.
      • Thereafter, monthly until stable for a year.  After that, 3 monthly.
  • Stopping treatment
    • Development of rash/ulcerations
    • Development of dry cough, dyspnoea and fever (see below)
    • Low WBC/neutrophil/platelet count
    • Raised (>x2-fold) AST/ALT
    • Renal impairment
    • Moderate/Severe infection
  • Side effects
    • Common
      • GI
        • Anorexia; nausea (may be treated pharmacologically if troublesome); vomiting; diarrhoea; oral ulcers (ask about)
      • Alopecia
    • Less common
      • Myelosuppression
    • Rare
      • Hepatotoxicity (cirrhosis)- Avoid alcohol where possible
      • Pulmonary toxicity (interstitial pneumonitis, rarely fibrosis)
        • be wary of dry cough, dyspnoea, fever

Biological Agents

  • Prior to treatment, the main thing to evaluate is risk of TB exposure.  If, from the history, there is a risk, testing for TB should be done
    • Skin test (mantoux) may be considered but may be false negative if patients are on DMARD treatment
    • Elispot test may be a better alternative (specialist)
    • Chest x-ray should also be considered
  • Treatment should be stopped/not started if there is evidence of infection.
  • If there is a significant history of cancer (family or personal), there may be a risk of cancer – risk/benefit should be considered.

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