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

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
    • Secondary Sjogren’s; Scleritis and episcleritis
  • Skin
    • vasculitic rash (palpable purpura)
  • Nervous system
    • Peripheral nerve entrapment; polyneuropathy; mononeuritis multiplex
  • 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.