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Related Subjects: |Polyarticular arthritis |Rheumatoid arthritis |Systemic Sclerosis (Scleroderma) |RA vs OA |Acute and Chronic Gout |Calcium Pyrophosphate Deposition (Pseudogout) |Osteoporosis |Rheumatology Autoantibodies

A chronic symmetrical deforming synovitis and polyarthropathy involving large and small joints with systemic features. Symptoms should be for > 6 weeks before diagnosis can be made. Anti CCP is a useful early marker.

About

• Affects 1% of population and Females 3:1
• The cardinal symptoms of RA are early morning stiffness > 60 mins
• Duration of stiffness relates to disease activity.
• Joint pain affects predominantly the PIP and MCP joints as well as other large/small joints

Aetiology

• Increased HLA DR4+ve in over 60% and HLA-DRB1*04
• Protein tyrosine phosphatase N22 (PTPN22), STAT4 and PADI-4 Genes
• Increased Postpartum and increased with breastfeeding
• RF+ve (antibodies to the Fc portion of Ig by B cells) have nodules
• Smoking is an environmental risk factor for seropositive RA.
• There may be a triggering antigen to this autoimmune illness

Pathology

• Main target of RA is the synovium with synovitis and hyperplasia and pannus formation
• Pannus destroys the articular cartilage and subchondral bone, producing bony erosions.
• Synovial tissues proliferate in an uncontrolled fashion
• This results in excess fluid production, destruction of cartilage, erosion of marginal bone, and damage to tendons and ligaments
• Rheumatoid nodules - Histology shows Granulomas, Fibrinoid necrosis, Palisaded histiocyte

Rheumatoid Lung

Clinical: Symptoms should be for > 6 weeks

• Systemic
  • Fatigue, Low-grade fever
  • Weight loss, Anaemia
• Skin/Mucous membranes/Eyes
  • Erythema over a joint is not common and suggests infection.
  • Dryness of mucous membranes: mouth, Genital
• Eyes
  • Scleritis (red painful eye with a threat to sight. Steroids),
  • Episcleritis
  • Scleromalacia (bilateral painless blue thinning),
  • Keratoconjunctivitis sicca
  • Scleromalacia perforans - red painful eye needs urgent immunosuppression
• Joints
  • Usually wrists, elbows, shoulders, cervical spine, knees, ankles and feet
  • Pain and tenderness on squeezing MCP or PIP suggests active disease. The DIPJ are spared.
  • Palindromic (relapsing remitting monoarthritis of large joints)
  • Occasionally a progressive severe arthritis mutilans
  • Hands
    • Ulnar deviation
    • Swan Neck deformity
    • Boutonniere deformity
    • Nail bed infarcts
    • Subcutaneous nodules at elbow
    • Skin and muscle atrophy and extensor tendon rupture.
  • Feet
    • Subluxation of MTP joints means walking on heads of Metatarsals and pain and deformity.
    • Damage to subtalar and ankle joint and development of flat feet due to rupture of the tibialis posterior tendon
  • Periarticular - tenosynovitis, bursitis, wasting and loss of muscle bulk especially in hands, subcutaneous nodules, osteoporosis
  • Cervical - Care must be taken as patients are prone to atlantoaxial C1/2 subluxation especially with GA
• Cardiac
  • Pericarditis, Endocarditis, Myocarditis
  • Pleural effusions (exudates with low glucose)
  • Coronary arteritis, aortitis
  • Nodules and pericardial effusion
• Haematological
  • Splenomegaly, anaemia
  • Eosinophilia, thrombocytosis
  • Lymph node enlargement
  • Felty’s syndrome: splenomegaly and neutropenia and AOCD
  • Increased risk of infection
• Lungs
  • Rheumatoid pneumoconiosis (Caplan’s syndrome)
  • Pulmonary nodules
  • Fibrosing alveolitis
  • Pleural effusion
  • Bronchiolitis obliterans
• Vasculitis
  • Ulcers, pyoderma gangrenosum
  • Mononeuritis multiplex, arteritis
  • Gangrene of fingers and toes
• Neurology
  • Cervical cord compression: Atlanto-axial subluxation (C1-2)
  • Peripheral neuropathy and Mononeuritis multiplex
  • Polyneuropathy, predominantly sensory
  • Compression neuropathies e.g. carpal tunnel syndrome, ulnar, lateral popliteal
• Renal Amyloidosis - nephrotic syndrome
• Renal related AKI with NSAIDs

Investigations

• FBC: Normochromic normocytic anaemia and ↑ platelets
• Elevated ESR: acute flare
• Elevated CRP: acute flare or infections etc.
• WCC: can be high or low. Low in Felty's syndrome with splenomegaly
• U&E and urinalysis to detect renal disease
• LFTs to detect liver disease
• Rheumatoid factor is an IgM against the Fc portion of IgG1 and a titre greater than 1 in 320 is significant and related to disease activity, presence of rheumatoid nodules and seen in 100% of those with extra-articular complications. RF is found in 80% of patients
• Anti CCP in 70% but is highly specific. The presence of RF however does point to increased frequency of certain complications. Anti cyclic citrullinated peptide is a sensitive and specific test for RA seen in 70% and may predate clinical onset by years.
• Joint aspiration: may be done to exclude an infected joint. Shows Increased Neutrophils and protein and is sterile.
• X-Ray changes: If arthritis has lasted more than a year, the physician should consider taking radiographs of the hands and feet. Early on (< 6 months) - soft tissue swelling, Periarticular demineralization/osteoporosis, Later - Joint margin narrowing and erosions, Very late - atlantoaxial C1/2 subluxation
• Atlantoaxial subluxation - Lateral X-rays in flexion and extension and MRI
• MRI: may show early erosions confirming the diagnosis.

Rheumatoid Syndromes

• Felty's syndrome: PF +ve, Splenomegaly and neutropenia seen in < 1%
• Caplan's syndrome: RA in Coal miners with pneumoconiosis

1987 Criteria for the Classification of Acute Arthritis of Rheumatoid Arthritis

• Criterion Definition. * For classification purposes, a patient shall be said to have rheumatoid arthritis if he/she has satisfied at least 4 or these 7 criteria.
• Criteria 1 through 4 must have been present for at least 6 weeks. Patients with 2 clinical diagnoses are not excluded. Designation as classic, definite, or probable rheumatoid arthritis is not to be made.

Diagnostic Differential

• Systemic lupus erythematosus (SLE): rash, female
• Erythrovirus B19 infection: flu-like symptoms and a widespread rash
• Post-streptococcal arthritis: recent sore throat
• Psoriatic arthritis: rash may be seen
• Primary Sjögren’s syndrome:dry eyes (keratoconjuctivitis sicca) and dry mouth (xerostomia).
• Some systemic vasculitides.

Diagnostic Criteria

• 1. Morning stiffness - Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement
• 2. Arthritis of 3 or more joint areas - At least 3 joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints
• 3. Arthritis of hand joints - At least 1 area swollen (as defined above) in a wrist, MCP, or PIP joint
• 4. Symmetric arthritis - Simultaneous involvement of the same joint areas (as defined in 2) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry)
• 5. Rheumatoid nodules - Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxta-articular regions, observed by a physician
• 6. Serum rheumatoid factor - Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in <5% of normal control subjects
• 7. Radiographic changes - Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify)

Baseline assessments

• Functional status
• Extent and degree of synovitis
• Extra articular disease
• Radiographic damage
• FBC,ESR,U&E,LFTs,RF,Urinalysis

Poorer Prognosis

• Systemic disease, Insidious onset, RF titre > 1/512, Anti CCP antibodies
• Severe disability at presentation, HLA DR4
• Persistent activity > 12 months, Early bone erosions
• White females, More than 20 involved joints, Rheumatoid nodules

Functional Prognosis

• Half of patients too disabled to work after 10 years
• A quarter have mild disease
• Excess mortality is predominantly cardiovascular

Management

• The aim of treatment is to reduce and prevent synovitis and damage that can occur early in disease so one must consider Rheumatology referral and initiation of DMARDs early. Delays in starting appropriate therapy can cause long term differences in outcome.
• Rest, passive movements and targeted anti-inflammatory therapy
• NSAIDs reduce inflammation and pain and stiffness but do not alter the course of the disease
• Non-medical - rest, hot baths. Physiotherapy and OT are important in maintaining activities of daily living (ADLs) and splinting and protecting joints, adaptations.

Disease modifying anti rheumatic drugs (DMARDS)

• These alter the course of the disease. Steroids, methotrexate, sulfasalazine and hydroxychloroquine and others below but not NSAIDs. They should be started early to improve outcomes. Usually started at 6 weeks to 6 months after onset. They appear to reduce joint destruction.
• Before DMARDs, perform a screening history, CXR and an interferon gamma release assay (IGRA) in high-risk patients to exclude tuberculosis
• Methotrexate is the anchor drug in RA therapy. Avoid however in pregnancy or in women or men in the 3 months prior to conception in those planning a pregnancy. Folate should be prescribed if pregnancy possible.
• Sulfasalazine is for mild/moderate disease especially younger patients and women who are planning a family.
• Leflunomide blocks T-cell proliferation. Similar to sulfasalazine. Can be combined with methotrexate. Monitor blood tests.
• Hydroxychloroquine: mild disease or with other DMARDs. Needs formal eye exam prior to therapy and after.
• Azathioprine, gold (IM/PO), penicillamine are used less frequently nowadays.
• Common side effects shared by many DMARDs are Skin rash, mouth ulcers and Low Neutrophils, Low platelets and proteinuria

Drugs (check all doses with BNF)

• Sulfasalazine 1 g bd or TDS benefit in 6-12 weeks
• Methotrexate orally (or injectable) 7.5-30 mg weekly benefit in 6-12 weeks
• Leflunomide 10-20 mg od orally blocks T cell proliferation
• Prednisolone 7.5 mg od for 2 years can reduce radiological progression over 2 years
• D-Penicillamine 250-750 mg/day orally

Monitoring

• Methotrexate: FBC/LFT
• Sulfasalazine: FBC/LFTs
• Leflunomide: FBC/LFT/BP
• Hydroxychloroquine: Ophthalmology

Biological Agents

• TNF-α inhibitors (etanercept, infliximab, adalimumab, certolizumab). These are main choice and slow or halt erosion formation in up to 70% of patients. Often given with methotrexate to reduce loss of efficacy due to anti-drug antibody formation.
• Interleukin 1 receptor blocker (anakinra)
• Lysis of B cells (rituximab) Anti CD20 (B cells)
• Interleukin 6 receptor antibody (tocilizumab)
• Blocks T-cell activation (abatacept).
• Abatacept: CTLA4 Ig (T cell)
• Biological agents are expensive. Costs are offset by the introduction of biosimilar medicines which are similar to another (originator) drug with no drop in quality, safety or efficacy from the originator compound. It is likely to be used more as cost falls.

Side effects of biological agents

• Infusion and injection reactions
• Risk of infections
• Reactivates TB, Viral hepatitis, PML
• Avoid live vaccines
• Malignancy
• Autoantibodies e.g. ANA

Surgery

• Synovectomy and joint replacement are useful in preserving function and pain control and improving quality of life.

Shared care

• The GP and Specialist nurse often plays a pivotal role in management led by the rheumatologist
• Patient education and support networks

Poorer Prognosis

• Systemic disease, Insidious onset, RF titre > 1/512, Anti CCP antibodies
• Severe disability at presentation, HLA DR4
• Persistent activity > 12 months, Early bone erosions
• White females, more than 20 involved joints, Rheumatoid nodules

References

• Diagnosis and management of rheumatoid arthritis