What is rheumatoid arthritis, its risk factors, manifestations, diagnosis, and differential diagnosis?

Rheumatoid Arthritis: Definition, Pathophysiology, Risk Factors, Manifestations, and Diagnosis

Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease characterized by symmetric inflammation of synovial joints, leading to cartilage damage, bone erosions, and joint destruction if not diagnosed early and treated aggressively. 1, 2

Definition and Pathophysiology

Rheumatoid arthritis is a systemic autoimmune inflammatory disorder that:

• Affects approximately 1% of the general population 3
• Involves inflammation primarily in synovial joints 1
• Results from dysregulated immune responses where the body's immune system attacks its own tissues
• Leads to synovitis (inflammation of the synovial membrane) which, if untreated, progresses to cartilage damage and bone erosions 3, 4
• Involves complex inflammatory cascades with pro-inflammatory cytokines (TNF-α, IL-6) playing key roles in joint destruction 4

Risk Factors

Several factors increase the risk of developing RA:

• Demographic factors:

  • Female sex (women are 2-3 times more likely to develop RA)
  • Older age 5

• Genetic factors:

  • Family history of RA
  • Presence of HLA-DR4 and other HLA-DRB1 alleles 2

• Environmental factors:

  • Smoking (strongest environmental risk factor)
  • Periodontal disease
  • Certain infections that may trigger autoimmunity

• Serological factors:

  • Presence of rheumatoid factor (RF)
  • Anti-citrullinated protein antibodies (ACPA/anti-CCP) 2

Clinical Manifestations

RA presents with both articular and extra-articular manifestations:

Articular Manifestations:

• Joint symptoms:
  • Symmetric polyarthritis (affecting multiple joints on both sides of the body)
  • Morning stiffness lasting >30 minutes
  • Pain, swelling, and tenderness of affected joints
  • Commonly affects small joints of hands and feet, particularly MCP, PIP joints, and wrists 1
  • Progressive joint deformities (boutonnière deformity, swan-neck deformity, ulnar deviation)

Extra-articular Manifestations:

• Rheumatoid nodules
• Cardiovascular disease (increased risk of myocardial infarction and stroke)
• Pulmonary involvement (interstitial lung disease, pleural effusions)
• Ocular manifestations (scleritis, episcleritis)
• Hematologic abnormalities (anemia of chronic disease, thrombocytosis)
• Neurological manifestations (peripheral neuropathy, mononeuritis multiplex)
• Felty's syndrome (RA, splenomegaly, neutropenia)

Differential Diagnosis

Consider these conditions when evaluating a patient with suspected RA:

• Other inflammatory arthritides:

  • Psoriatic arthritis
  • Systemic lupus erythematosus
  • Spondyloarthropathies (ankylosing spondylitis, reactive arthritis)
  • Inflammatory osteoarthritis

• Crystal-induced arthropathies:

  • Gout
  • Calcium pyrophosphate deposition disease (pseudogout)

• Infectious arthritis:

  • Viral arthritis (parvovirus, hepatitis)
  • Bacterial arthritis
  • Lyme disease

• Other conditions:

  • Polymyalgia rheumatica
  • Sarcoidosis
  • Paraneoplastic syndromes

Diagnosis

The diagnosis of RA relies on a combination of clinical, laboratory, and imaging findings:

Clinical Assessment:

• Evaluate joint involvement pattern (symmetric, polyarticular)
• Assess duration of symptoms (persistent synovitis)
• Document morning stiffness 2

Laboratory Testing:

• Autoantibodies:

  • Rheumatoid factor (RF) - offer to all patients with suspected RA who have synovitis 1
  • Anti-citrullinated protein antibodies (ACPA/anti-CCP) - consider if RF negative 1, 2
  • Antinuclear antibodies (ANA) - for suspected overlap syndromes 2

• Inflammatory markers:

  • Erythrocyte sedimentation rate (ESR)
  • C-reactive protein (CRP) 2

• Other laboratory tests:

  • Complete blood count (CBC) - may show anemia of chronic disease
  • Liver and kidney function tests - baseline before starting treatment
  • Uric acid - to rule out gout 2

Imaging:

• Conventional radiography:

  • First-line imaging modality
  • May show periarticular osteopenia, joint space narrowing, erosions
  • Limited sensitivity for early disease 2

• Ultrasound:

  • Superior to clinical examination for detecting synovitis
  • Can detect subclinical inflammation 2

• MRI:

  • More sensitive than conventional radiography for early erosions
  • Can detect bone edema, a predictor of radiographic progression 2

Diagnostic Criteria:

The American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010 classification criteria are used for diagnosing RA, based on:

1. Joint involvement (0-5 points)
2. Serology (0-3 points)
3. Acute phase reactants (0-1 point)
4. Duration of symptoms (0-1 point)

A score of ≥6/10 indicates definite RA 2

Common Pitfalls in Diagnosis

• Delaying referral to a rheumatologist (should be within 6 weeks of symptom onset)
• Overlooking RA in patients with only one or few affected joints initially
• Assuming that hand stiffness in older adults is always due to osteoarthritis 2
• Waiting for positive RF before referral (refer urgently even with normal acute-phase response or negative RF) 1

Key Points for Early Diagnosis

• Refer for specialist opinion anyone with suspected persistent synovitis of undetermined cause
• Refer urgently if:
  • Small joints of hands or feet are affected
  • More than one joint is affected
  • Symptoms have persisted for ≥3 months 1

Early diagnosis and aggressive treatment are crucial to prevent joint damage, preserve function, and prevent disability in patients with RA 3, 5.