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Rheumatoid Arthritis (RA)

Diagnosis and management of rheumatoid arthritis for doctors, medical student exams, finals, OSCEs and MRCP PACES

 

Definition of rheumatoid arthritis

  • Chronic systemic inflammatory disease causing both synovitis and extra-articular features

 

Epidemiology of rheumatoid arthritis

  • Approximately 1%-3% prevalence
  • Worldwide incidence about 1 in 10,000 per year
  • Commonest age range for presentation is 30-50
  • However can occur in any age (presentation in childhood is called juvenile idiopathic arthritis)
  • Three times as common in women

 

Pathophysiology of rheumatoid arthritis

  • Synovial hypertrophy and chronic inflammation leads to joint damage
  • Abnormal production of cytokines, particularly TNF a, IL-1, IL-6
  • Smoking
    • Risk factor both for development and progression of disease
    • Possibly due to promotion of citrullination which may promote development of autoimmune disease
  • Genetics
    • 15-20% concordance in monozygotic twins
    • HLA DR4 association
  • Hormonal influences
    • Tends to remit in pregnancy with recurrence postpartum

 

Pathological findings in rheumatoid arthritis

    • Nodules
      • Central fibrinous necrosis with surrounding macrophages and fibroblasts
    • Synovium
      • Inflammatory infiltrate of T lymphocytes, plasma cells, macrophages
      • Inflammation extends to subchondral bone
      • Proliferative synovitis with synovial cell hyperplasia and hypertrophy

 

Presentation of rheumatoid arthritis (joint involvement)

    • Symmetrical deforming small joint polyarthritis
    • Gradual onset
    • Pain, stiffness and swelling
      • MCP (often affected first), PIP,  wrists, elbows, shoulders, knee, MTP
    • Worse in morning, improving on light activity
    • Deformity
      • Bone
        • Ulnar deviation
        • Swan-necking and Boutonniere deformities of fingers
        • Subluxation of the ulnar styloid
      • Soft tissue
        • Muscle wasting
        • Tendon rupture
        • Subcutaneous rheumatoid nodules (if seropositive)

 

Presentation of rheumatoid arthritis (extra-articular manifestations)

    • Systemic
      • Fatigue
      • Fever
      • Weight loss
    • Eyes
      • Sjorgren’s syndrome (30%), and episcleritis
      • Scleritis and scleromalacia are uncommon
    • Skin
      • Nodules (in 20-30%)
        • Look like malignancy in the lung – can cavitate
        • Can be induced by MTX
      • Leg ulcers – vasculitic
      • Pyoderma gangrenosum
    • Neurological
      • Carpal tunnel disease, atlanto-axial subluxation
      • Polyneuropathy (in a glove-and-stocking distribution)
      • Mononeuritis multiplex
      • Cervical myelopathy
    • Respiratory
      • Pleural thickening and effusion in 5% (most common lung issue)
        •  Usually asymptommatic
      • Pulmonary fibrosis (can be difficult to differentiate from MTX induced fibrosis)
        • More common if high titre of RF
        • May require cyclophosphamide treatment
      • Bronchiolitis obliterans
        • Rare
        • Poor prognosis
      • Bronchiectasis
      • Caplan syndrome
        • Pneumoconiosis + RA with intrapulmonary nodules
      • Increased infection risk
    • Cardiology
      • Pericarditis and effusion
        • Common, usually asymptomatic
      • Increased risk of cardiovascular disease (leading cause of mortality)
    • Increased osteoporosis  risk (independent of steroid treatment)
    • Vasculitis (most commonly affects skin)
    • Renal
      • Analgesic nephropathy
      • Amyloidosis (AL amyloid)
    • Felty’s syndrome
      • RA, splenomegaly and neutropenia
      • Occurs in seropositive longstanding RA
      • Risk of splenic rupture or life-threatening infection
      • Treat RA (e.g. MTX)

 

Diagnostic criteria for Rheumatoid Arthritis – American College of Rheumatology criteria

  • Four or more of:
    • Morning stiffness >1 hour for 6/52
    • Arthritis of three or more joints for 6/52
    • Arthritis of hand and wrist joints for 6/52
    • Symmetrical arthritis
    • Subcutaneous nodules (25%)
    • Rheumatoid factor positive (70%)
    • Erosions or periarticular osteopenia on XR

     

Differential diagnosis of rheumatoid arthritis

  • Psoriatic arthropathy
  • Crystal arthropathies
  • SLE
  • Osteoarthritis
  • Septic arthritis (can be multiple joints)
  • Viral or reactive arthritides
  • Lyme disease
  • Fibromyalgia

 

Investigations in rheumatoid arthritis

Bloods:

    • FBC
      • Anaemia of chronic disease
      • Thrombocytosis
      • Leucopaenia
    • LFTs
      • Mildly raised transaminases common
      • Baseline for DMARD therapy
    • ESR and CRP
      • Raised in proportion with disease activity
    • U&Es
      • To guide DMARD therapy
    • Rheumatoid factor (antibody against the Fc fragment of IgG)
      • Does not rule RA in or out
      • Positive in up to 20% of normal population
        • Also positive in other autoimmune disease e.g. Sjogrens, SLE, autoimmune liver disease
      • Negative in around 30% of patients with RA
      • May become positive later on in disease course
    • ACPA (anti cyclic citrullinated peptide)
      • Does not rule RA in or out
      • More specific than RF
      • Predictor of poor prognosis if positive
    • Others
      • Consider checking urate if diagnosis uncertain
      • ANA if features suggestive of connective tissue disease

 

Other investigations

    • Aspiration of joint if effusion present
      • Inflammatory aspirate (cloudy)
        • Send to lab to exclude crystal arthropathies and septic arthritis.
    • XR hands
      • Soft tissue swelling
      • Periarticular osteopenia (particularly characteristic)
      • Loss of joint space – occurs in OA as well
      • Periarticular erosions
      • Bony deformity
      • Subluxation

 

Assessment of severity in rheumatoid arthritis

  • DAS28 scoring
    • Number of swollen joints, tender joints, ESR/CRP and self-assessment (out of 10)
      • Note does not include feet, ankles or neck
    • >5.1 = high disease activity
    • 3.2-5.1 = moderate
    • <3.2 = low
    • <2.6 = remission

 

Management of rheumatoid arthritis

Conservative management

  • Patient education and early involvement of multidisciplinary team

 

Pharmacological management

  • Regular Paracetamol
  • NSAIDs
    • Start with simple ibuprofen and work upwards
    • In patients with GI side effects, and in those over 65, add a PPI
    • COX 2 inhibitors may have a better GI side effect profile
  • Steroids
    • IM depot methylprednisolone can be given to allow time for other treatments
    • Not a good long term option
  • DMARDs
    • Start combination treatment (particularly in seropositive RA)
      • Usually should include methotrexate unless contraindicated
    • Methotrexate (MTX)
      • Dose
        • Usually up to 25mg once weekly
        • Often started at 15mg once weekly
        • Can be given orally or subcut
        • Give folic acid 5mg once weekly on a different day of the week
      • Side effects
        • Teratogenic: counsel patient
        • Nausea/vomiting (main reasons most patients discontinue; often settles after few weeks)
        • Myelosupression
        • Hepatic fibrosis
        • Pneumonitis/lung fibrosis
      • Baseline investigations
        •  FBC, LFTs, CXR and U+Es (renally excreted so modify dose if eGFR<45)
      • Monitoring
        • Fortnightly FBC, U&Es, LFTs until 6/52 after last dose increase
        • Then monthly
      • Folinic acid
        • IV bioavailable form of folic acid
        • Use in septic neutropaenic patients on MTX
    • Leflunomide
      • 10-20mg OD
      • SE include myelosuppression, deranged LFTs, increased BP
      • Teratogenic: counsel patient
      • Monitoring
        • Fortnightly FBC, U&Es, LFTs for 8/52 then monthly, monitor BP
      • Washout if conceives, septic, markedly deranged LFTs – either cholestyramine (8g TDS for 11 days) or activated charcoal
    • Hydroxychloroquine
      • 200mg OD or BD
      • Rare side effect of macular toxicity
    • Sulphasalazine
      • Dose: 500mg OD for 1/52, 500mg BD for 1/52, 500mg am + 1g pm for 1/52, then 1g BD
      • SE: diarrhoea & vomiting, immunosuppression
      • Fortnightly FBC, U&Es, LFTs until 6/52 after last dose increase
      • Then monthly
    • Others (less commonly used)
      • Azathioprine, mycophenolate, gold, penicillamine
  • Biologics
    •  NICE guidelines: DAS28>5.1 on two occasions at least 1/12 apart, failed at least 2 DMARDs
    • First line is anti-TNF: etanacept, adaluminab and golimumab.
      • Use in combination with MTX
    • Others include tociluzimab, rituximab and abatacept
    • AN adequate response is a DAS28 reduction of > 1.2 (discontinue if not achieved)

     

Surgical intervention  in rheumatoid arthritis

      • Tendon repair
      • Carpal tunnel
      • Cervical myelopathy
      • Joint replacement

 

Prognosis of rheumatoid arthritis

  • Outcome variable
  • Early treatment improves long term prognosis
  • Reduced life expectancy (increased cardiovascular risk)
  • Significant morbidity with many unable to work
  • Poor prognosis
    • RF or ACPA positivity
    • Extra-articular disease
    • HLA DR4 positivity
    • Female
    • Early bone erosions
    • Severe disability at presentation