6.1 Rheumatoid Arthritis: Diagnosis & Systemic Manifestations
Key Takeaways
- The rheumatoid arthritis blueprint subsection enumerates skeletal disease, systemic manifestations, adverse effects of antirheumatic drugs and other topics.
- Anti-cyclic citrullinated peptide antibody is far more specific than rheumatoid factor and predicts erosive disease.
- Symmetric small-joint synovitis with morning stiffness exceeding an hour distinguishes rheumatoid arthritis from osteoarthritis.
- Atlantoaxial subluxation from cervical spine involvement is a risk during intubation and must be evaluated before elective surgery.
- Cardiovascular disease is the leading cause of death, so risk factor modification is part of rheumatoid arthritis management.
Inflammatory arthritides represent a diverse group of systemic autoimmune and autoinflammatory conditions characterized by chronic synovial inflammation, cartilage destruction, bony erosions, and systemic extra-articular complications. On the ABIM Internal Medicine certification exam, high-yield mastery requires distinguishing symmetric inflammatory polyarthritis (e.g., Rheumatoid Arthritis) from seronegative spondyloarthropathies (e.g., Ankylosing Spondylitis, Psoriatic Arthritis, Reactive Arthritis), executing pre-treatment infectious screening, navigating DMARD toxicities, and identifying life-threatening structural complications.
1. Rheumatoid Arthritis (RA)
Pathophysiology & Synovial Immunopathology
Rheumatoid Arthritis is a chronic, systemic autoimmune disease characterized by persistent symmetric inflammatory synovitis. Genetic susceptibility is strongly linked to the HLA-DRB1 locus (encoding the "shared epitope"). Environmental triggers, especially cigarette smoking and periodontal disease (Porphyromonas gingivalis), induce post-translational conversion of arginine to citrulline via peptidylarginine deiminase (PAD) enzymes in mucosal tissues.
This loss of self-tolerance triggers the production of Anti-Citrullinated Protein Antibodies (anti-CCP / ACPA) and Rheumatoid Factor (RF) (an IgM autoantibody directed against the Fc portion of human IgG). Synovial infiltration by CD4+ T helper cells (Th1 and Th17), B cells, and activated macrophages drives massive secretion of pro-inflammatory cytokines—primarily Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), and Interleukin-1 (IL-1). This cytokine cascade stimulates synovial hypervascularization and fibroblast-like synoviocyte proliferation, forming a locally invasive hyperplastic tissue mass known as pannus. The pannus secretes matrix metalloproteinases (MMPs) that degrade articular cartilage and induces RANKL (receptor activator of nuclear factor-κB ligand) expression, triggering aggressive osteoclast-mediated marginal bone erosions.
Clinical Articular Manifestations
- Joint Distribution: Symmetric polyarthritis predominantly targeting the Metacarpophalangeal (MCP), Proximal Interphalangeal (PIP), Metatarsophalangeal (MTP), and Wrist joints. Knees, ankles, elbows, and shoulders are also commonly involved.
- Sparing Patterns: RA characteristically spares the Distal Interphalangeal (DIP) joints and the Thoracolumbar spine.
- Symptom Pattern: Severe inflammatory morning stiffness lasting >1 hour, which improves with physical activity and worsens with prolonged rest (gel phenomenon).
- Late Structural Deformities:
- Ulnar deviation of the digits at the MCP joints.
- Swan-neck deformity: Hyperextension of the PIP joint with flexion of the DIP joint.
- Boutonnière deformity: Flexion of the PIP joint with hyperextension of the DIP joint.
- Z-deformity of the thumb: Hyperextension of the interphalangeal joint with fixed flexion and subluxation at the MCP joint.
- Baker cyst (Popliteal cyst): Synovial fluid distension of the gastrocnemio-semimembranosus bursa; rupture mimics acute deep vein thrombosis (pseudothrombophlebitis with crescent-shaped ecchymosis below the medial malleolus).
2010 ACR / EULAR Classification Criteria for RA
A confirmed diagnosis requires a score of >= 6 out of 10 in patients with at least 1 joint exhibiting definite clinical synovitis not explained by another disease:
| Domain | Criteria Categories | Assigned Points |
|---|---|---|
| A. Joint Involvement | 1 medium-to-large joint (shoulders, elbows, hips, knees, ankles) | 0 |
| 2–10 medium-to-large joints | 1 | |
| 1–3 small joints (MCP, PIP, 2nd–5th MTP, thumb IP, wrists) | 2 | |
| 4–10 small joints | 3 | |
| >10 joints (at least 1 small joint) | 5 | |
| B. Serology | Negative RF and negative Anti-CCP | 0 |
| Low-positive RF or low-positive Anti-CCP (<=3x upper limit of normal) | 2 | |
| High-positive RF or high-positive Anti-CCP (>3x upper limit of normal) | 3 | |
| C. Acute-Phase Reactants | Normal CRP and normal ESR | 0 |
| Abnormal CRP or abnormal ESR | 1 | |
| D. Duration of Symptoms | <6 weeks | 0 |
| >=6 weeks | 1 |
Diagnostic Serology & Radiographic Findings
- Serologies:
- Rheumatoid Factor (RF): Present in ~70–80% of established RA (sensitive ~70%), but lacks specificity (seen in Sjögren syndrome, hepatitis C, subacute bacterial endocarditis, SLE, and healthy elderly).
- Anti-Citrullinated Protein Antibodies (anti-CCP / ACPA): Equal sensitivity (~70–80%) but superior specificity (95–98%). High anti-CCP titers strongly correlate with aggressive, rapidly progressive erosive disease and poor prognosis.
- Radiographic Progression:
- Early: Soft tissue swelling and periarticular osteopenia (juxta-articular demineralization).
- Intermediate/Late: Marginal bone erosions (at the bare areas of bone unprotected by hyaline cartilage) and symmetric uniform joint space narrowing.
- Cervical Spine Atlantoaxial Subluxation (C1–C2 Instability):
- Synovial inflammation of the transverse ligament of the atlas and the odontoid process leads to ligamentous laxity, pannus destruction of the dens, and posterior displacement of the odontoid into the cervical spinal cord.
- Symptoms: Occipital neck pain, electric shock-like sensations down the spine with neck flexion (Lhermitte sign), spastic quadriparesis, hyperreflexia, and bowel/bladder incontinence.
- Board Rule: Every patient with longstanding RA undergoing endotracheal intubation or elective surgical procedures requiring neck manipulation MUST undergo flexion and extension cervical spine radiographs to evaluate the anterior atlantodental interval (ADI >3 mm indicates instability; >5-9 mm warrants neurosurgical stabilization prior to elective surgery).
Extra-Articular Manifestations of RA
Extra-articular features occur in up to 40% of patients, predominantly those with high-titer RF/anti-CCP and long-standing severe disease:
| System | Extra-Articular Manifestation | Clinical Features & Pathology |
|---|---|---|
| Cutaneous | Rheumatoid Nodules | Subcutaneous, firm, non-tender nodules located over mechanical pressure points (olecranon bursa, extensor forearm, Achilles tendon); central fibrinoid necrosis surrounded by palisading histiocytes. |
| Rheumatoid Vasculitis | Necrotizing small-to-medium vessel vasculitis causing digital infarcts, palpable purpura, cutaneous ulcerations, and mononeuritis multiplex. | |
| Pulmonary | Interstitial Lung Disease (ILD) | Most common pulmonary manifestation (~10%); Usual Interstitial Pneumonia (UIP) or Nonspecific Interstitial Pneumonia (NSIP) pattern. Presents with progressive exertional dyspnea, dry cough, and bibasilar end-inspiratory crackles. |
| Pleural Effusions | Characteristically very low pleural fluid glucose (<30 mg/dL), low pH (<7.20), markedly elevated LDH (>1000 U/L), and low complement levels. | |
| Caplan Syndrome | Combination of rheumatoid arthritis and progressive pulmonary rheumatoid nodules in individuals with occupational coal-worker pneumoconiosis. | |
| Hematologic | Felty Syndrome | Classic triad: Seropositive RA, Splenomegaly, and Severe Neutropenia (Absolute Neutrophil Count [ANC] <1,500/µL, often <500/µL). Associated with high risk of recurrent life-threatening bacterial infections and lower extremity cutaneous ulcers. |
| Anemia of Chronic Disease | Normocytic or microcytic anemia driven by IL-6 induced hepcidin upregulation. | |
| Cardiovascular | Accelerated Atherosclerosis | Cardiovascular disease (ischemic heart disease/MI) is the #1 cause of mortality in RA. Chronic systemic inflammation accelerates coronary plaque formation independent of traditional Framingham risk factors. |
| Pericarditis | Asymptomatic pericardial thickening or symptomatic acute pericarditis/pericardial effusion. | |
| Ocular | Episcleritis & Scleritis | Scleritis presents with severe, deep, boring eye pain waking the patient at night, violaceous scleral injection, and potential scleral thinning (scleromalacia perforans). |
| Secondary Sjögren | Keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth) due to secondary exocrine gland inflammation. |
A 58-year-old woman with a 15-year history of seropositive, erosive rheumatoid arthritis is scheduled to undergo elective total knee arthroplasty under general endotracheal anesthesia. She has experienced stable joint symptoms on subcutaneous Methotrexate 20 mg weekly and Adalimumab 40 mg every other week. She reports mild, chronic neck stiffness but denies upper extremity paresthesias, weakness, or bowel and bladder dysfunction. Physical examination reveals bilateral ulnar deviation, stable MCP deformities, and normal motor strength (5/5) and deep tendon reflexes (2+) in all four extremities. Which of the following is the most critical next step prior to surgery?