Epidemiology

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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)

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Pathophysiology

• 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 reaction and 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
  • Pannus: latin, means cloth (the abnormal tissue growth in rheumatoid arthritis resembles a sheet or cloth-like layer spreading over the joint surface.)
    • A granulation tissue growth in the inflamed synovium that causes it to become thickened and edematous in patients with chronic rheumatoid arthritis. It can cause fibrous ankylosis and/or joint deformities and the destruction of other intraarticular structures, such as cartilage.
• 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.
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Clinical features

Extraarticular manifestations

• Rheumatoid nodules
  • Skin
    • Nontender, firm, subcutaneous swellings (2 mm–5 cm)
    • Commonly occur in areas exposed to higher pressure, e.g., extensor side of the forearm, bony prominences
  • Lungs
    • Typically bilateral and peripheral
    • Rheumatoid pulmonary nodules may be accompanied by fibrosis and pneumoconiosis (Caplan syndrome).

Subtypes and variants

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Atlantoaxial subluxation (Vertebral subluxation)

• Definition: a potentially life-threatening complication caused by the inflammatory destruction of the ligaments affecting the atlantoaxial joint and the intervertebral joints
• Clinical features
  • Pain and stiffness of the neck (typically early-morning neck pain at rest)
  • Head tilt
  • Neurological deficits
    • Cervical radiculopathy with peripheral paresthesias of the upper limb
    • In some cases, symptoms of high spinal cord compression
      • Slowly progressive spastic quadriparesis
      • Hyperreflexia or positive Babinski reflex
      • Respiratory insufficiency
• Diagnostics
  • Extension and flexion x-rays of the cervical spine
  • MRI

Warning

Endotracheal intubation can acutely worsen the subluxation and cause compression of the spinal cord and/or vertebral arteries.

Diagnostics

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• Anticitrullinated peptide antibodies (ACPA), e.g., anticyclic citrullinated peptide (anti-CCP)
  • Tissue inflammation causes arginine residues in proteins such as vimentin to be enzymatically converted into citrulline through a process called citrullination. This alters the shape of the proteins, which can then serve as neoantigens that generate an immune response.
• Rheumatoid factor (RF): IgM autoantibodies against the Fc region of IgG antibodies

Differential diagnostics

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• Parvovirus B19 will presents with similar symptoms, except for rash, normal ESR, and acute onset
• See Osteoarthritis > Differential diagnosis

Characteristic	Osteoarthritis (OA)	Rheumatoid Arthritis (RA)
Age of onset	>50 years	30-50 years
Cause	”Wear and tear” or trauma causing cartilage deterioration	Autoimmune inflammatory reaction against synovium
Primary joints affected	Weight-bearing joints (hips, knees), DIP, CMC of thumb	PIP, MCP, ankle, elbow, wrist; spares DIP Atlantoaxial subluxation
Joint characteristics	Hard and bony	Soft, warm, and tender
Pain pattern	Worse during or after activity	Worse in the morning or with inactivity
Stiffness	<30 minutes in morning, worse with activity	>30 minutes in morning, worse with inactivity
Joint symmetry	Often asymmetric, reflecting use patterns	Typically symmetric, diffuse involvement
Lab findings	Normal rheumatoid factor, normal anti-CCP antibody, normal ESR and CRP	Positive rheumatoid factor, positive anti-CCP antibody, elevated ESR and CRP
Associated signs	Heberden’s nodes (DIP), Bouchard’s nodes (PIP)	Ulnar deviation, boutonniere deformity, swan-neck deformity
Systemic involvement	None	Potential pulmonary and cardiac disease
Gender predilection	None	2x more common in females
X-ray findings	Osteophytes, subchondral sclerosis, asymmetric joint space narrowing	Symmetric joint space loss, osteopenia, “apple coring” bone erosion
Exam findings	Effusion, tenderness	Effusion, tenderness, redness, warmth, synovitis

Treatment

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Acute anti-inflammatory treatment

• Glucocorticoids
  • Systemic prednisone
    • Longer-term therapy: Only use in patients with highly active RA
• NSAIDs and selective COX-2 inhibitors: relieve symptoms, but do not improve the prognosis

Long-term pharmacological treatment

Disease-modifying antirheumatic drugs (DMARDs)

• Methotrexate (MTX): first-line treatment in patients with moderate to high disease activity
  • To minimize adverse effects, administer folic acid.

Biologic DMARDs

• Indication: persistent moderate or severe disease activity after 3 months of conventional DMARD therapy
• Agents
  • TNF-α inhibitors: e.g., adalimumab, infliximab, etanercept
    • See Immunosuppressants > Etanercept

Complications

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• Amyloidosis > AA amyloidosis (secondary amyloidosis)
• Septic arthritis