7.1 Inflammatory Arthritides

7.1 Inflammatory Arthritides

Inflammatory arthritides represent a diverse group of systemic immune-mediated disorders targeting the synovium, entheses, and articular cartilage. Mastery of clinical patterns, serological profiling, radiographic hallmarks, and pharmacotherapeutic hierarchies is essential for MRCPI General Medicine candidates.

Rheumatoid Arthritis (RA)

Pathophysiology & Synovial Pannus

Rheumatoid Arthritis (RA) is a chronic, systemic autoimmune disease characterized by persistent symmetric polyarthritis. Autoimmune targeting of modified self-proteins (citrullination by peptidylarginine deiminase enzymes) leads to synovial hyperplasia and infiltration by T-cells, B-cells, macrophages, and plasma cells. This hyperplastic synovial tissue forms a pannus—an invasive vascular tissue that releases matrix metalloproteinases (MMPs), interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), causing progressive cartilage degradation and subchondral bone erosions mediated by RANKL-activated osteoclasts.

Joint Distribution & Clinical Presentation

RA predominantly affects the small joints of the hands and feet in a symmetrical distribution:

• Commonly Involved Joints: Metacarpophalangeal (MCP) joints, Proximal Interphalangeal (PIP) joints, Metatarsophalangeal (MTP) joints, wrists, knees, ankles, and cervical spine (specifically C1–C2 atlantoaxial articulation).
• Joints Spared (Exam Classic): Distal Interphalangeal (DIP) joints and the lumbar/thoracoabdominal spine are characteristically spared in RA.
• Symptom Profile: Gel phenomenon with morning joint stiffness lasting >60 minutes, improving with movement and worsening with rest.

2010 ACR / EULAR Classification Criteria

Classification requires a score of ≥6 / 10 across four domains:

1. Joint Involvement: 1 large joint (0), 2–10 large joints (1), 1–3 small joints (2), 4–10 small joints (3), >10 joints with at least 1 small joint (5).
2. Serology: Negative RF and negative anti-CCP (0), Low-positive RF or anti-CCP (2), High-positive RF or anti-CCP (>3x upper limit of normal) (3).
3. Acute-Phase Reactants: Normal CRP and ESR (0), Abnormal CRP or ESR (1).
4. Duration of Symptoms: <6 weeks (0), ≥6 weeks (1).

Serological Markers

• Rheumatoid Factor (RF): IgM autoantibody directed against the Fc region of human IgG. Sensitivity: ~70–80%. Specificity: ~70–75%. RF is elevated in other non-rheumatic conditions (infective endocarditis, hepatitis C, chronic liver disease, Sjögren syndrome, and healthy elderly).
• Anti-Citrullinated Protein Antibodies (anti-CCP / ACPA): Sensitivity: ~70–75%. Specificity: 96–98%. Anti-CCP positivity is a key prognostic marker indicating aggressive, erosive disease, accelerated extra-articular manifestations, and worse radiological progression.

Extra-Articular Manifestations

• Rheumatoid Nodules: Subcutaneous central fibrinoid necrosis surrounded by palisading histiocytes, occurring over extensor surfaces (olecranon process, Achilles tendon) in ~25% of seropositive patients.
• Felty Syndrome: Triad of severe seropositive RA, splenomegaly, and neutropenia (<1.5 × 10⁹/L). High risk of recurrent bacterial infections and cutaneous ulceration.
• Caplan Syndrome: Combination of rheumatoid arthritis and pneumoconiosis, presenting with multiple basilar rheumatoid pulmonary nodules in miners.
• Pulmonary: Pleural effusion (characteristically low glucose <1.6 mmol/L, low pH, high LDH), Usual Interstitial Pneumonia (UIP) / Interstitial Lung Disease (ILD), and pulmonary nodules.
• Cardiovascular: Pericarditis (most common cardiac manifestation), accelerated coronary atherosclerosis, and myocarditis.
• Neurological: Cervical spine subluxation (atlanto-axial instability presenting with neck pain, quadriparesis, or Lhermitte sign); entrapment neuropathies (carpal tunnel syndrome).

Pharmacotherapy & Treatment Hierarchy

[Early Presentation / Suspected RA]
                 │
                 ▼
[First-Line csDMARD Monotherapy / Combination]
  • Methotrexate (10–25 mg/week SC/oral)
  • Co-prescribe Folic Acid 5 mg/week (24–48h post-MTX)
  • Short-course Bridging Corticosteroids
                 │
  Failure / Intolerance after 3–6 months
                 ▼
[Add / Switch csDMARDs]
  • Leflunomide or Sulfasalazine or Hydroxychloroquine
                 │
  Inadequate Response + High Disease Activity (DAS28 >5.1)
                 ▼
[Initiate Biologic DMARD (bDMARD) or Targeted Synthetic (tsDMARD)]
  • TNF Inhibitors (Adalimumab, Etanercept, Infliximab)
  • IL-6 Receptor Antagonist (Tocilizumab)
  • Anti-CD20 Monoclonal (Rituximab — preferred in seropositive RA)
  • JAK Inhibitors (Tofacitinib, Baricitinib, Upadacitinib)

Exam Pearl: Before initiating any TNF inhibitor or biologic agent, candidates MUST screen for latent Tuberculosis (Interferon-Gamma Release Assay / Mantoux + Chest X-ray) and Hepatitis B / C. If latent TB is identified, complete 1 month of chemoprophylaxis (isoniazid) before starting the TNF inhibitor.

Seronegative Spondyloarthropathies (SpA)

The seronegative spondyloarthropathies share a common genetic background (HLA-B27 association), absence of Rheumatoid Factor/anti-CCP, inflammation of entheses (enthesitis), axial skeleton involvement (sacroiliitis, spondylitis), and asymmetrical peripheral oligobarthritis.

Axial Spondyloarthritis & Ankylosing Spondylitis (AS)

• Epidemiology: Predominantly young males (ratio 2:1 to 3:1), onset typically <45 years.
• Inflammatory Back Pain Criteria: Insidious onset, duration >3 months, morning stiffness >30 minutes, improves with exercise, no improvement with rest, and frequent awakening during the second half of the night due to pain.
• Physical Examination Metrics:
  • Modified Schober Test: Mark a baseline 10 cm line above S2 (spinous process between PSIS). Measure distance on maximal forward flexion. An expansion of <5 cm (total distance <15 cm) indicates significant lumbar spine restriction.
  • Occiput-to-Wall Distance: Normally 0 cm; increased in progressive kyphosis.
  • Chest Expansion: Measured at 4th intercostal space; <2.5 cm is abnormal.
• Radiographic Findings: Bilateral sacroiliitis (grade ≥2 bilateral or grade 3–4 unilateral), marginal syndesmophytes (vertical bony bridges across intervertebral discs), Romanus lesions (anterior spondylitis shiny corners), and the classic "bamboo spine" appearance.
• Extra-Spinal Manifestations:
  • Acute Anterior Uveitis (30–40%): Unilateral, painful red eye with photophobia and blurred vision.
  • Cardiovascular: Aortic regurgitation (aortitis causing aortic root dilation) and cardiac conduction blocks.
  • Pulmonary: Apical pulmonary fibrosis (often misdiagnosed as tuberculosis).
  • Renal: Secondary AA Amyloidosis and IgA nephropathy.
• Management: First-line treatment is continuous high-dose NSAIDs. Biologic therapy with TNF inhibitors (Adalimumab, Etanercept) or IL-17A inhibitors (Secukinumab) is indicated for active axial disease refractory to NSAIDs. Note: Conventional synthetic DMARDs (methotrexate, sulfasalazine) are ineffective for isolated axial disease!

Psoriatic Arthritis (PsA)

• CASPAR Criteria: Requires established inflammatory articular disease plus ≥3 points from: current psoriasis (2 pts) or personal/family history (1 pt), psoriatic nail dystrophy (1 pt), negative RF (1 pt), dactylitis (1 pt), and juxta-articular new bone formation on radiography (1 pt).
• Five Clinical Subtypes:
  1. Asymmetrical oligoarthritis (<5 joints involved; most common ~70%).
  2. Symmetrical polyarthritis (RA-like distribution, but RF-negative and DIP-involved).
  3. DIP joint predominant disease (strongly linked with nail dystrophy).
  4. Axial spondyloarthritis (asymmetrical syndesmophytes, non-marginal).
  5. Arthritis Mutilans: Severe osteolysis resulting in telescoping digits ("opera-glass hands") and "pencil-in-cup" deformity on plain radiographs.
• Key Features: Dactylitis ("sausage digit"), Achilles enthesitis, plantar fasciitis, and nail changes (nail pitting >20 pits, onycholysis, oil-drop discoloration).

Reactive Arthritis (ReA)

• Definition: Sterile autoimmune arthritis occurring 1 to 6 weeks following a mucosal gastrointestinal or genitourinary infection.
• Classic Triad (Reiter Syndrome): Urethritis/cervicitis, Conjunctivitis, and Asymmetrical lower-limb Oligoarthropathy.
• Trigger Pathogens:
  • Genitourinary: Chlamydia trachomatis (most common overall).
  • Gastrointestinal: Shigella flexneri, Salmonella enterica, Yersinia enterocolitica, Campylobacter jejuni.
• Cutaneous Manifestations: Keratoderma blennorrhagica (hyperkeratotic vesicopustular skin lesions on palms and soles) and Circinate balanitis (painless erythematous erosions on the glans penis).
• Management: NSAIDs first-line. Prompt antibiotic treatment for active Chlamydia infection (does not shorten arthritis duration once established). Refractory chronic arthritis (>6 months) requires csDMARDs (Sulfasalazine or Methotrexate).

Enteropathic Arthritis

Associated with Inflammatory Bowel Disease (Crohn disease and Ulcerative Colitis):

• Type 1 (Pauciarticular): Affects <5 joints, asymmetrical, strongly correlates with bowel disease activity (treating gut flares resolves the peripheral joint swelling).
• Type 2 (Polyarticular): Affects ≥5 joints, symmetrical, independent of IBD flare activity.
• Axial Spondyloarthritis: Mirrors ankylosing spondylitis and runs an independent clinical course from bowel inflammation.

Crystal-Induced Arthropathies

Crystal deposition in articular structures triggers intense NLRP3 inflammasome activation, cleavage of pro-interleukin-1β, and rapid neutrophil recruitment, causing acute exquisite monoarthritis.

Gout

• Pathophysiology: Hyperuricemia resulting from urate overproduction (10%) or renal underexcretion (90%). Serum urate >360 µmol/L (>6.0 mg/dL) exceeds physiological saturation, precipitating monosodium urate (MSU) crystals in joints and avascular tissues (tophi).
• Risk Factors: Male sex, metabolic syndrome, chronic kidney disease, loop/thiazide diuretics, excessive alcohol (beer/spirits), high-fructose diets, purine-rich foods (red meat, seafood), and cytotoxic chemotherapy (tumor lysis syndrome).
• Synovial Fluid Analysis: Strongly negatively birefringent, needle-shaped intracellular and extracellular crystals under polarized light microscopy. Synovial WBC count 2,000–50,000/µL with >50–80% neutrophils.
• Radiographic Hallmarks: Punched-out juxta-articular erosions with sclerotic borders and overhanging cortical margins ("Martel sign"); preservation of joint space until late stages.
• Acute Flare Management:
  • First-line: High-dose NSAIDs (e.g., Naproxen, Indomethacin), Colchicine (500 mcg bd to tds; microtubule polymerization inhibitor; side effect: severe dose-dependent diarrhea), or oral/intra-articular Corticosteroids.
  • Critical Rule: Do NOT initiate or stop Urate-Lowing Therapy (ULT) during an acute flare, as abrupt serum urate fluctuations prolong the attack. Continue existing ULT if already established.
• Urate-Lowering Therapy (ULT):
  • Indications: ≥2 flares per year, presence of tophi, renal impairment (CKD), urolithiasis, or young age (<40 years).
  • Target Serum Urate: <360 µmol/L (<6.0 mg/dL) for uncomplicated gout; <300 µmol/L (<5.0 mg/dL) for tophaceous gout.
  • First-line Drug: Allopurinol (xanthine oxidase inhibitor; start at 100 mg daily [50 mg in CKD], titrate every 2–4 weeks by 100 mg increments up to 800 mg daily). Screening for HLA-B*5801 allele is recommended in Han Chinese, Thai, and Korean patients due to high risk of life-threatening Allopurinol Hypersensitivity Syndrome (Stevens-Johnson syndrome / TEN).
  • Second-line Drug: Febuxostat (non-purine xanthine oxidase inhibitor).
  • Mandatory Flare Prophylaxis: When starting or titrating ULT, co-prescribe low-dose Colchicine 500 mcg daily/bd or low-dose NSAID for 3 to 6 months to prevent mobilization flares.

Calcium Pyrophosphate Deposition (CPPD) / Pseudogout

• Pathophysiology: Deposition of calcium pyrophosphate dihydrate crystals within cartilage, menisci, and synovium.
• Synovial Fluid Analysis: Weakly positively birefringent, rhomboid-shaped crystals under polarized light microscopy.
• Radiographic Findings: Chondrocalcinosis (punctate linear calcification within articular fibrocartilage, menisci of knees, triangular fibrocartilage of wrist, and symphysis pubis).
• Metabolic Workup for Underlying Triggers: Candidates presenting with CPPD <60 years must be screened for:
  1. Primary Hyperparathyroidism (Elevated Ca²⁺, low PO₄³⁻, elevated PTH).
  2. Hereditary Hemochromatosis (Elevated transferrin saturation >45%, elevated ferritin; characteristic 2nd/3rd MCP joint degenerative changes with hook-like osteophytes).
  3. Hypomagnesemia and Hypophosphatasia.
• Acute Management: Intra-articular corticosteroid injection (preferred for single large joint), oral NSAIDs, or low-dose oral colchicine.

Synovial Fluid Analysis Diagnostic Matrix