Epidemiology

• Prevalence
  • ∼ 0.24% worldwide
  • 1% in northern Europe and US
• Sex: ♀ > ♂ (3:1)
• Peak incidence: > 65 years

Etiology

• Idiopathic inflammatory autoimmune disorder of unknown etiology
• Risk factors include:
  • Genetic disposition: associated with HLA-DR4 and HLA-DR1
  • Environmental factors (e.g., smoking)
  • Hormonal factors (premenopausal women are at the highest risk, suggesting a predisposing role of female sex hormones)
  • Infection
  • Obesity
  • Family history of RA

Pathophysiology

<aside> <img src="/icons/die3_orange.svg" alt="/icons/die3_orange.svg" width="40px" /> Rheumatoid arthritis results from an immune response directed against autoantigens in the joints.  Infiltrating CD4+ T cells secrete cytokines that promote inflammatory synovitis.  They also stimulate B cells to produce rheumatoid factor (IgM antibody specific for Fc component of IgG) and anti-citrullinated protein antibodies that contribute to chronic inflammation and joint destruction.

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• The earliest lesion in RA is microvascular injury with an increase in the number of synovial lining cells.

• Certain interstitial tissue proteins (e.g. intracellular filament protein vimentin, filaggrin, type II collagen) undergo a posttranslational modification that involves the conversion of arginine to citrulline (citrullination)
• Citrullinated proteins are recognized as foreign by the antigen-presenting cells that present them to CD4+ T cells.
• Activation of CD4+ T cells leads to the following sequences of events:
  • IL-4 production → B-cell proliferation and differentiation → production of anticitrullinated peptide antibodies → type II hypersensitivity reactionand type III hypersensitivity reaction
  • Migration of CD4+ T cells to synovial joints → secretion of cytokines (IFN-γ, IL-17) → recruitment of macrophages → secretion of cytokines (TNF-α, IL-1, IL-6) →  inflammation and proliferation
• Bouts of inflammation, angiogenesis, and proliferation → proliferative granulation tissue with mononuclear inflammatory cells → pannus and synovial hypertrophy → invasion, progressive destruction, and deterioration of cartilage and bone
• Antibodies against Fc portion of IgG (rheumatoid factor, RF) are produced to aid in removing autoantibodies and immune complexes
  • RF excess triggers formation of new immune complexes and type III HSR
  • Individuals with positive RF are more likely to develop extraarticular manifestations

Diagnosis (clinical)

• The diagnosis of RA is clinical.

  • Consider RA in patients with arthralgia, joint stiffness, and synovitis lasting ≥ 6 weeks
    • RA typically causes symmetric arthritis of the metacarpophalangeal (wrist), PIP, and other joints, but DIP joint involvement is less common.
  • Consider alternative diagnoses in patients with atypical presentations

• Perform diagnostic studies to further support the diagnosis and help establish disease severity.

  • Routine laboratory tests.
  • X-ray as the initial imaging study — baseline radiographs of both hands

• Consult rheumatology, particularly if the diagnosis is uncertain and when choosing a treatment regimen.

• RA is due to failure of immune tolerance, with development of an autoreactive immune response directed against joint components (eg, type II collagen, citrullinated vimentin).  CD4+ T-helper cells become activated by these self-antigens and release cytokines that promote chronic inflammatory synovitis.  CD4+ T cells also induce B cells to synthesize rheumatoid factor and anti-citrullinated protein antibodies (ACPAs).

• Rheumatoid factor is an antibody (typically IgM) specific for the Fc component of IgG.  Rheumatoid factor binds circulating IgG and ACPAs bind modified self-proteins, forming immune complexes that deposit on the synovium and cartilage.  These complexes activate complement in those locations, contributing to chronic inflammation and joint destruction.

• Anti-citrullinated protein antibodies

• The presence of antinuclear antibodies is a nonspecific finding in many connective tissue disorders. These can occur in IgM form, but would be found less frequently than rheumatoid factor in patients with RA.

• Osteoarthritis vs Rheumatoid Arthritis

Clinical features

• Rheumatoid arthritis is chronic, symmetric, inflammatory polyarthritis.
• In two-thirds of patients, an initial clinical presentation of fatigue, anorexia, and weakness precedes joint complaints.
• In established RA (i.e., in patients known to be diagnosed with this disorder), the most common manifestation is pain in affected joints that is worsened by movement.

Articular manifestations

• Polyarthralgia
  • Symmetrical pain and swelling of affected joints (also at rest)
  • Frequently affected joints
    • Metacarpophalangeal joints (MCP joints)
    • Proximal interphalangeal joints (PIP joints)
    • Wrist joints — MC affected joint
    • Knee joints
    • Metatarsophalangeal joints (MTP joints)
  • Rarely affected: distal interphalangeal joints (DIP joints), first carpometacarpal (CMC) joint, and the axial skeleton (except for the cervical spine)
    • Very important differentiating point from osteoarthritis where DIP is commonly affected!
• Morning stiffness (often > 30 min) that usually improves with activity
• Joint deformities
• Physical examination: compression test (Gaenslen squeeze test)

Extraarticular manifestations

• Constitutional symptoms
• Rheumatoid nodules
• Lungs
• Eye: keratoconjunctivitis sicca, scleritis, and episcleritis
• Endocrine and exocrine glands: secondary Sjogren syndrome
• Hematological
• Musculoskeletal
• Heart
• Vascular
• Adult-onset Still disease — RA + intermittent fever + transient salmon-pink maculopapular rash
• Undifferentiated Arthritis — RA develops in 1/3 of patients

Routine studies

• Nonspecific parameters

• Specific parameters (serological studies)

• Imaging

• distinguishing factor from SLE arthritis is the presence of joint destruction — SLE is non-erosive

Management