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