What are the classification and pathogenesis of Rheumatoid Arthritis (RA)?

Classification and Pathogenesis of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is classified according to the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria, which requires a score of ≥6/10 points based on joint involvement, serology, acute phase reactants, and symptom duration, with the pathogenesis involving a complex autoimmune process characterized by synovial inflammation leading to joint destruction. 1, 2

Classification Criteria

2010 ACR/EULAR Classification Criteria

• Target population includes patients with at least one joint with definite clinical synovitis (swelling) not better explained by another disease 1

• A score-based algorithm requiring ≥6/10 points for definite classification of RA 1, 2

• Four scoring domains:

  1. Joint involvement (0-5 points):

     • 1 large joint = 0 points 1
     • 2-10 large joints = 1 point 1
     • 1-3 small joints = 2 points 1
     • 4-10 small joints = 3 points 1

     • 10 joints (at least 1 small joint) = 5 points 1

  2. Serology (0-3 points):

     • Negative RF and negative ACPA = 0 points 1, 3
     • Low positive RF or low positive ACPA = 2 points 1, 3
     • High positive RF or high positive ACPA = 3 points 1, 3

  3. Acute phase reactants (0-1 points):

     • Normal CRP and normal ESR = 0 points 1
     • Abnormal CRP or abnormal ESR = 1 point 1

  4. Duration of symptoms (0-1 points):

     • <6 weeks = 0 points 1
     • ≥6 weeks = 1 point 1

• Additional classification considerations:

  • Patients with erosive disease typical of RA with compatible history should be classified as having RA 1
  • Patients with long-standing disease who previously fulfilled the criteria should be classified as having RA 1
  • Patients scoring <6/10 can be reassessed over time as criteria might be fulfilled cumulatively 1

Historical Context

• The 2010 criteria replaced the 1987 ACR criteria, which required 4 of 7 criteria including morning stiffness, arthritis in ≥3 joint areas, arthritis of hand joints, symmetric arthritis, rheumatoid nodules, serum RF, and radiographic changes 4
• The newer criteria allow for earlier diagnosis and intervention, focusing on features present in early disease 5

Pathogenesis of Rheumatoid Arthritis

Autoimmune Mechanisms

• RA is a systemic autoimmune disease characterized by chronic inflammation targeting synovial tissues 5, 6
• Autoantibody production, particularly RF and ACPA, is central to the pathogenesis 7
• ACPA has high specificity (96-98%) for RA and can appear years before clinical symptoms, suggesting a pre-clinical autoimmune phase 7

Inflammatory Cascade

• Initial synovial inflammation (synovitis) progresses to tenosynovitis 6
• Persistent inflammation leads to cartilage destruction and bone erosions 6, 8
• The inflammatory process involves complex interactions between:
  • Activated T cells (particularly Th1 and Th17) 8
  • B cells producing autoantibodies 8, 7
  • Macrophages and synoviocytes releasing pro-inflammatory cytokines 6
  • Pro-inflammatory cytokines including TNF-α, IL-6, and IL-1 that drive the inflammatory process 6, 8

Genetic and Environmental Factors

• Genetic susceptibility, particularly HLA-DRB1 shared epitope alleles, contributes to disease risk 8
• Environmental triggers may include smoking, infections, and microbiome alterations 8
• Epigenetic modifications influence gene expression patterns in immune cells 8

Disease Progression

• Uncontrolled inflammation leads to progressive joint damage 6
• Extra-articular manifestations can affect multiple organ systems, including the lungs, heart, and eyes 1
• Systemic inflammation contributes to comorbidities including accelerated cardiovascular disease 1, 7

Clinical Implications and Disease Assessment

Disease Activity Measurement

• Quantitative assessment using composite measures is essential for monitoring and treatment decisions 1
• Recommended composite measures include:
  • Disease Activity Score using 28 joint counts (DAS28) 1
  • Simplified Disease Activity Index (SDAI) 1
  • Clinical Disease Activity Index (CDAI) 1

Treatment Targets

• The primary goal is clinical remission or low disease activity 1
• Early diagnosis and treatment are critical to prevent joint destruction and disability 1, 6
• Regular assessment and treat-to-target strategies improve outcomes 1

Common Pitfalls in Classification and Diagnosis

• Relying solely on serology without clinical evidence of synovitis can lead to misdiagnosis 2, 3
• Failing to consider differential diagnoses such as systemic lupus erythematosus, psoriatic arthritis, and gout 1
• Not recognizing that DIP joints, first carpometacarpal joints, and first MTP joints are typically spared in RA 2
• Overlooking the value of advanced imaging (ultrasound, MRI) in detecting subclinical synovitis when diagnosis is uncertain 2