Note on your request: Davidson's Principles and Practice of Medicine, 24th Edition is not available in this textbook library. The most current and authoritative internal medicine references available are Goldman-Cecil Medicine (International Edition) and Harrison's Principles of Internal Medicine, 22nd Edition (2025). The content below draws from both, which share a very high degree of overlap with Davidson's coverage of RA, and reflects current clinical standards.

Rheumatoid Arthritis

Definition

Epidemiology

• Global prevalence: 0.5-1% of adults
• Women are affected ~3x more than men before menopause
• Overall annualized incidence: ~40/100,000 in women, ~20/100,000 in men
• Can occur at any age; prevalence increases with each decade
• Extreme geographic variation: near-zero prevalence in some rural Nigerian cohorts vs. ~5% in certain Native American populations (Chippewa, Yakima, Inuit)
• Incidence may be declining, possibly related to reduced smoking rates

Pathobiology

Genetics

• Monozygotic twin concordance: 12-15%; dizygotic twins: 2-5%
• Heritability: ~60%
• Polygenic disorder with >100 identified SNPs - most implicate immune genes
• ~40% of genetic risk in the HLA region
• Key HLA-DR alleles: DRB*0401, DRB*0404, DRB*0101, DRB*1402 - all share the "shared epitope" in the peptide-binding groove
• Non-HLA loci include PTPN22, CTLA-4, STAT4, PADI4

Environmental Factors

• Smoking is the strongest environmental risk factor; causes citrullination of proteins in the lung
• Periodontal disease, gut and respiratory microbiome alterations implicated
• Female sex hormones, vitamin D deficiency, obesity also contribute

Pathogenesis

• Citrullination or acetylation of self-proteins triggers autoantibody formation
• Anti-citrullinated protein antibodies (ACPAs/anti-CCP) appear years before clinical arthritis
• Rheumatoid factor (RF) - IgM anti-IgG antibody - also appears early

• T cells (especially CD4+ Th17 and Th1 cells), B cells, macrophages, mast cells, and fibroblast-like synoviocytes (FLS) accumulate in the synovium
• Key cytokines: TNF-α, IL-1, IL-6, IL-17, GM-CSF, IL-8
• RF and ACPAs form immune complexes that activate complement, promote macrophage activation via FcR binding, and activate osteoclasts

• FLS are partially transformed cells with anchorage independence, loss of contact inhibition, and TLR expression; they release MMPs (MMP1, MMP3, MMP13) and prostanoids, attacking the cartilage-pannus junction
• Osteoclasts - activated by RANKL, IL-1, TNF, IL-17 - cause the characteristic periarticular bone erosions
• "Bone edema" on MRI precedes visible erosions on X-ray

• Circulating cytokines and immune complexes activate endothelium, accelerate atherosclerosis, drive systemic osteoporosis, fatigue, and depression

Pathogenesis of RA synovitis - from initiation through immune activation to joint destruction. Goldman-Cecil Medicine

Clinical Features

Articular Manifestations

• Typically starts in small joints of hands (MCP, PIP) and feet (MTP)
• DIP joints are spared (distinguishing from OA and psoriatic arthritis)
• Symmetric polyarthritis is characteristic
• Later: wrists, knees, elbows, ankles, hips, shoulders
• Cervical spine (C1-C2) commonly involved - atlantoaxial subluxation can cause myelopathy

• Ulnar deviation of MCP joints
• Swan-neck deformity (PIP hyperextension, DIP flexion)
• Boutonniere deformity (PIP flexion, DIP hyperextension)
• Z-thumb deformity
• Baker's cyst (popliteal synovial cyst)

Severe advanced RA: ulnar deviation at MCPs, swan-neck deformities, dorsal tendon swelling, and muscle wasting. Goldman-Cecil Medicine

• Temporomandibular, cricoarytenoid (hoarseness, rarely acute respiratory distress), sternoclavicular joints may be involved

Extra-articular Manifestations

Diagnosis

Classification Criteria (2010 ACR/EULAR)

Laboratory Findings

• RF positive in ~75% of patients; associated with more severe disease and extra-articular features
  • RF is non-specific - also positive in SLE, Sjogren, hepatitis, endocarditis, etc.
• ACPA (anti-CCP antibodies) - highly specific (~96%), appear early; even in first weeks of arthritis suggests more aggressive RA
• ESR and CRP elevated (reflect disease activity)
• Full blood count: normochromic normocytic anaemia, thrombocytosis in active disease
• Seronegative RA: ~25-30% with true RA are RF and ACPA negative
• Synovial fluid: turbid, WBC 5,000-50,000/mm³ (predominantly neutrophils), low glucose, low complement

Imaging

• X-ray: Periarticular osteoporosis (early), joint space narrowing, marginal erosions (later - at MCP, wrist); cervical spine subluxation
• MRI: Most sensitive for early synovitis and bone erosions - "bone edema" predates X-ray changes
• Ultrasound: Confirms synovitis and erosions in early disease; power Doppler shows active vascularity

Differential Diagnosis

Management

Principles

1. Early, aggressive therapy to prevent joint damage and disability
2. Treat-to-target (T2T) - aim for low disease activity or remission
3. Frequent modification of DMARD therapy if target not achieved
4. Individualization of therapy
5. Minimize chronic glucocorticoid use
6. Combination DMARD therapy where appropriate

Monitoring Disease Activity

• DAS-28 (Disease Activity Score - 28 joints)
• SDAI (Simplified Disease Activity Index)
• CDAI (Clinical Disease Activity Index)
• ACR 20/50/70 improvement criteria (used in trials)
• RAPID3 (Routine Assessment of Patient Index Data)

Step 1: NSAIDs

• Role: Adjunctive - symptom control only, no disease modification
• Mechanism: Non-selective COX-1/COX-2 inhibition
• Minimize chronic use due to GI and renal toxicity

Step 2: Glucocorticoids

• "Bridge therapy" while waiting for DMARD effect (weeks to months)
• Short bursts (1-2 weeks) for acute flares
• Chronic low-dose: prednisone 5-10 mg/day only if DMARD therapy inadequate
• Avoid prednisone >10 mg/day for articular disease
• Always combine with a DMARD; osteoporosis prophylaxis mandatory (bisphosphonates - avoid in women of childbearing age)

Step 3: Conventional (Synthetic) DMARDs

Step 4: Biologic DMARDs

• MTX + anti-TNF is superior to MTX alone for both symptoms and radiographic progression
• Switching to abatacept may be more effective than switching between anti-TNF agents after failure
• Screen for TB (latent TB), hepatitis B/C before starting biologics

Step 5: Targeted Synthetic DMARDs (JAK Inhibitors)

Treatment Algorithm (ACR 2021 Guidelines)

DMARD-naive with moderate/high disease activity
        ↓
Start METHOTREXATE (±short-term glucocorticoids as bridge)
        ↓ (reassess at 3-6 months)
Inadequate response?
        ↓
Add HCQ + SSZ (triple therapy) OR Add biologic (anti-TNF ± MTX) OR Non-TNF biologic ± MTX
        ↓
Inadequate response to anti-TNF?
        ↓
Switch to another anti-TNF OR Switch to non-TNF biologic (abatacept, rituximab, tocilizumab) OR JAK inhibitor

Prognosis

• Most patients have a lifelong, fluctuating course
• Predictors of worse outcome: high RF/ACPA titers, elevated CRP/ESR, early erosions, high burden of joint involvement
• Increased mortality mainly from accelerated cardiovascular disease
• Preclinical RA trials: some DMARDs may delay but not yet prevent disease onset

Recent Evidence

• Rheumatoid arthritis: key clinical features and challenges (2024) - DI Matteo A, Emery P, Panminerva Med [PMID: 39621317]
• Management strategies in rheumatoid arthritis (2024) - Konzett V, Aletaha D, Nat Rev Rheumatol [PMID: 39448800]