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Gout and Other Crystal-Associated Arthropathies¶

Chapter 384 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic analysis · Part 11 – Rheumatology & Immunology · Chapter 384

Key Clinical Points¶

Gout is a hyperuricemic metabolic condition characterized by episodic inflammatory arthritis with disabling pain, primarily affecting middle-aged to elderly men and postmenopausal women.
The first metatarsophalangeal joint (podagra) is involved in 70–90% of acute gout cases; flares typically begin at night and subside within 1–2 weeks.
Synovial fluid analysis is the gold standard: MSU crystals are needle-shaped with strong negative birefringence; CPP crystals are rhomboid/rod-shaped with weak positive or non-birefringent properties.
Target serum urate for urate-lowering therapy (ULT) is <5–6 mg/dL to prevent flares and eliminate tophi.
Allopurinol is first-line ULT; screening for HLA-B*5801 is required in Southeast Asian, Pacific Islander/Native Hawaiian, and Black patients due to risk of severe cutaneous adverse reactions (SCARs).
CPPD prevalence doubles with each decade >60 years; associated with aging, osteoarthritis, and metabolic conditions like hyperparathyroidism and hemochromatosis.
Apatite deposition disease can present as Milwaukee shoulder (hemorrhagic effusions) or calcific periarthritis; diagnosis may require electron microscopy.
Calcium oxalate arthropathy is linked to renal failure/dialysis and ascorbic acid supplementation.
ULT must not be initiated during active flares without concurrent anti-inflammatory prophylaxis (colchicine, NSAIDs) to avoid paradoxical flares from crystal shedding.
Total joint arthroplasty is indicated for advanced OA when non-surgical treatments fail; failure rates are ~1% per year.

DEFINITION & OVERVIEW¶

• Gout: ◦ Definition: A hyperuricemic metabolic condition characterized by episodic inflammatory arthritis with disabling pain, primarily in middle-aged to elderly men and postmenopausal women. ◦ Pathophysiology: Chronic hyperuricemia → supersaturation → crystal formation of monosodium urate (MSU) in joints/connective tissue → inflammatory response. ◦ Inflammatory Mechanism: Crystal shedding from inert deposits → activation of the NLRP3 inflammasome → release of pro-inflammatory cytokines (e.g., IL-1β, IL-6, IL-8, TNF-α). ◦ Tissue Damage: Physical, inflammatory, and catalytic effects (metalloproteinase, collagenase, prostaglandin E) → chronic erosive/destructive changes. • Other Crystal-Associated Arthropathies: ◦ Calcium pyrophosphate (CPP) deposition disease ◦ Calcium apatite deposition disease ◦ Calcium oxalate arthropathy

Musculoskeletal Manifestations¶

• Clinical Presentations: ◦ Acute arthritis (episodic) ◦ Mono-, oligo-, or polyarthritis ◦ Periarticular inflammation ◦ Bursitis, Tendinitis, Enthesitis ◦ Tophaceous deposits ◦ Chronic arthropathy & Destructive arthropathies ◦ Chronic inflammatory arthritis ◦ Peculiar type of osteoarthritis ◦ Spinal arthritis ◦ Carpal tunnel syndrome • Table 384-1: Lists the above musculoskeletal manifestations of crystal-induced arthritis.

EPIDEMIOLOGY¶

• Gout Demographics: ◦ Primarily middle-aged to elderly men. ◦ Women (5–20% of cases) are typically postmenopausal and often have comorbidities (OA, hypertension, renal insufficiency) or use diuretics. ◦ Premenopausal gout is rare but can occur with reduced renal urate clearance. • CPPD Demographics: ◦ Predominantly affects the elderly; prevalence doubles each decade >60 years of age (e.g., nearly 50% for those >85 years old).

Risk Factors¶

• Gout Risk Factors: ◦ Modifiable: Obesity, Western diet, alcohol, sedentary lifestyle, diuretics. ◦ Comorbidities: Hypertension, type 2 diabetes, myocardial infarction, stroke, chronic kidney disease (CKD), and urate nephrolithiasis. • CPPD Risk Factors (Table 384-2): ◦ Primary factors: Aging, Osteoarthritis, Postmeniscectomy or joint trauma. ◦ Genetic/Metabolic: Familial-genetic factors, primary hyperparathyroidism, hemochromatosis, hypophosphatasia, hypomagnesemia. ◦ Drugs: Thiazide and loop diuretics, potentially proton pump inhibitors (PPIs). ◦ Other: Malabsorption, Gitelman's syndrome, gout, X-linked hypophosphatemic rickets, and familial hypocalciuric hypercalcemia.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Urate Metabolism: ◦ Excretion: ≈2/3 renal, 1/3 gastrointestinal. ◦ Renal Proximal Tubule: ◦ Apical membrane: Sodium-dependent reabsorption via URAT1 and OAT10. ◦ Basolateral membrane: Excretion via GLUT9. ◦ Intestinal Tract: Facilitated by ABCG2; degradation by gut bacteria (intestinal uricolysis). • Genetic & Metabolic Pathways: ◦ HPRT mutations → Lesch-Nyhan syndrome (hyperuricemia, neurologic/behavioral issues). ◦ PRS mutations → Overactive purine pathway → increased PRPP, purine nucleotides, and urate production. • Crystal-Induced Inflammation: ◦ MSU crystals → phagocytosis by neutrophils → activation of NLRP3 inflammasome → release of IL-1β, IL-6, IL-8, TNF-α. ◦ Neutrophil response → respiratory burst → release of lysosomal enzymes, superoxide anion, leukotriene B4. • CPPD Pathogenesis: ◦ Inorganic pyrophosphate from breakdown of extracellular ATP. ◦ Regulation: ANKH protein (mutations increase pyrophosphate export). ◦ Contributing factors: Decreased glycosaminoglycans, increased transglutaminase activity. • Apatite Pathogenesis: ◦ Dystrophic calcification (tissue damage) or metastatic calcification (hypercalcemic/hyperparathyroid states). ◦ Mechanism: Synovial cells exposed to apatite → increased prostaglandin E, cytokines, collagenases, and proteases. • Calcium Oxalate Pathogenesis: ◦ CaOx aggregates in bone, cartilage, synovium. ◦ Risk Factor: Ascorbic acid metabolism → oxalate; poorly cleared in uremia/dialysis.

CLINICAL FEATURES¶

• Acute Gout Flares: ◦ Presentation: Sudden, intense pain; joint becomes warm, red, tender, and swollen (mimics cellulitis). ◦ Location: 70–90% involve the first metatarsophalangeal joint (podagra); others include tarsal joints, ankles, knees, fingers, wrist, elbow. ◦ Timing: Often begin at night or early morning; typically subside in 1–2 weeks. ◦ Triggers: Purine-rich food, alcohol, diuretics, initial ULT, local trauma, HF, respiratory distress. • Chronic Gouty Arthritis: ◦ Features: Low-grade persistent synovitis, tophi (granulomatous inflammation), deformity, and bony destruction. • CPPD Clinical Manifestations: ◦ Appearance: Mimics gout; most common site is the knee, followed by wrist. Podagra is rare. ◦ Duration: Often lasts longer than gout (weeks to months). ◦ Triggers: Trauma, severe illness, surgery (e.g., parathyroidectomy → drop in Ca/Mg → crystal shedding). ◦ Chronic form: Polyarticular arthritis resembling osteoarthritis (pseudosteoarthritis). • Apatite Crystal Deposition Disease: ◦ Sites: Bursae and tendons (knee, shoulder, hip, fingers). ◦ Clinical forms: ◦ Calcific periarthritis (e.g., supraspinatus tendon rupture). ◦ Milwaukee shoulder (hemorrhagic effusions in elderly). ◦ Chronic erosive monoarthritis. ◦ Table 384-3 highlights specific manifestations including Hydroxyapatite pseudopodagra and association with hyperparathyroidism/calciphylaxis. • Calcium Oxalate Arthropathy: ◦ Appearance: Often indistinguishable from MSU or CPP; synovial fluid usually noninflammatory (<2000 leukocytes/μL). ◦ Morphology: Bipyramidal crystals, strong birefringence, stain with alizarin red S.

Clinical Differentiation¶

• Gout: Podagra (70–90%), 1–2 week duration. ◦ CPPD: Knee/wrist common, longer duration (weeks to months). ◦ Apatite: Milwaukee shoulder, calcific periarthritis. ◦ CaOx: Bipyramidal crystals, often noninflammatory fluid.

DIFFERENTIAL DIAGNOSIS¶

• Septic Arthritis: Must be ruled out as bacterial infection can coexist with crystal deposition; joint fluid must be stained and cultured. ◦ Other Crystal Arthropathies: ◦ Differentiation based on morphology/birefringence: ◦ MSU: Needle-shaped, strong negative birefringence. ◦ CPP: Rhomboid or rod-shaped, weak positive/non-birefringent. ◦ Apatite: Small, non-birefringent globules. ◦ CaOx: Bipyramidal, strong birefringence. ◦ Other Mimics: Palindromic rheumatism and psoriatic arthritis.

DIAGNOSTIC APPROACH¶

Synovial Fluid Analysis (Gold Standard):
Perform needle aspiration of involved joints or tophi.
Leukocyte Count: ◦ Gout: 5,000–75,000/μL. ◦ CPPD: ≈24,000/μL (mean). ◦ Apatite: <2,000/μL. ◦ CaOx: <2,000/μL or mildly inflammatory.
Polarized Light Microscopy: ◦ MSU: Needle-shaped, strong negative birefringence. ◦ CPP: Rhomboid/rod-shaped, weak positive/non-birefringent. ◦ CaOx: Bipyramidal, strong birefringence.
Radiographic Evaluation:
Gout: Look for cystic changes, erosions with sclerotic margins (advanced), and soft tissue masses (tophi).
CPPD: Identify chondrocalcinosis (punctate/linear radiodense deposits in fibrocartilage or hyaline cartilage).
Apatite: Identify intra- and periarticular calcifications; distinguish from linear calcifications of CPPD.
Specialized Testing:
Apatite: Electron microscopy with energy-dispersive elemental analysis (if clinical diagnosis is unclear).
CaOx: Alizarin red S staining for bipyramidal crystals.

Clinical Correlation¶

• Serum Urate: ◦ Note: Serum urate may be lower by ≈2 mg/dL during acute flare due to IL-6. ◦ Value: Serum urate is rarely elevated at the time of a flare, but historical values are essential for diagnosis and setting ULT targets.

MANAGEMENT & TREATMENT¶

Acute Gout Care:
Nonpharmacologic: Ice pack application and rest.
Colchicine: ◦ Low-dose regimen: 1.2 mg at first sign of flare → 0.6 mg in 1 h → subsequent day dosing.
NSAIDs (for patients without complications): ◦ Indomethacin: 25–50 mg tid. ◦ Naproxen: 500 mg bid. ◦ Ibuprofen: 800 mg tid. ◦ Celecoxib: 800 mg followed by 400 mg 12 h later, then 400 mg bid.
Glucocorticoids: ◦ Oral: Prednisone 30–50 mg/d (tapered as attack resolves). ◦ Intra-articular: Effective for single or few joints.
Biologics: Anakinra or canakinumab if other treatments fail or are contraindicated.
Urate-Lowering Therapy (ULT):
Timing: Do not initiate during active flares without concurrent anti-inflammatory prophylaxis (colchicine, NSAIDs) to avoid paradoxical flares from crystal shedding.
Target: <5–6 mg/dL (300–360 μmol/L).
Agents: Allopurinol, Febuxostat.
Management of CPPD:
Treatment of underlying causes (e.g., hyperparathyroidism, hemochromatosis) and management of associated OA.
Management of Apatite Deposition:
Management of underlying conditions (e.g., hyperparathyroidism, calciphylaxis).
Management of Calcium Oxalate Arthropathy:
Avoid ascorbic acid supplements and high-oxalate foods in patients with renal failure/dialysis.

Surgical Management¶

• Total Joint Arthroplasty: ◦ Indicated for knee or hip OA when non-surgical treatments fail and quality of life is compromised. ◦ Success: Failure rates ≈1% per year for loosening or infection.

SPECIAL CONSIDERATIONS¶

• CKD Patients: ◦ Risk of Calcium Oxalate arthropathy in patients on dialysis receiving ascorbic acid. ◦ Avoid high-oxalate foods/supplements to prevent hyperoxalosis. • Genetic Screening: ◦ Allopurinol: Screen for HLA-B*5801 before starting in Southeast Asian, Pacific Islander/Native Hawaiian, and Black patients to avoid severe cutaneous adverse reactions (SCARs).

KEY PEARLS & CLINICAL TRAPS¶

• Diagnostic Clues: ◦ Needle-shaped + strong negative birefringence = MSU (Gout). ◦ Rhomboid/rod-shaped + weak positive/non-birefringent = CPP. ◦ Bipyramidal + strong birefringence = CaOx. ◦ Low leukocyte count (<2000) in synovial fluid despite severe symptoms suggests Apatite or CaOx. • Clinical Traps: ◦ Do not assume low serum urate during a flare means no gout; IL-6 can lower levels by ≈2 mg/dL. ◦ Always provide anti-inflammatory prophylaxis when starting ULT to prevent paradoxical flares from crystal shedding. ◦ Use the low-dose colchicine regimen (1.2mg → 0.6mg) for better tolerability.

Reference Tables¶

TABLE 384-1 Musculoskeletal Manifestations of Crystal-Induced Arthritis Acute arthritis (episodic) Periarticular…¶

Harrison's 22e, p.2956

Acute arthritis (episodic)
Mono-, oligo-, or polyarthritis
Periarticular inflammation
Bursitis
Tendinitis
Enthesitis
Tophaceous deposits
Chronic arthropathy
Destructive arthropathies
Chronic inflammatory arthritis
Peculiar type of osteoarthritis
Spinal arthritis
Carpal tunnel syndrome

TABLE 384-2 Factors and Conditions Associated with Calcium Pyrophosphate Crystal Deposition Disease Aging…¶

Harrison's 22e, p.2960

Aging
Osteoarthritis
Postmeniscectomy or joint trauma
Familial-genetic
Endocrine-metabolic conditions
Primary hyperparathyroidism
Hemochromatosis
Hypophosphatasia
Hypomagnesemia
Certain drugs: thiazide and loop diuretics, potentially proton pump inhibitors
Malabsorption
Gitelman’s syndrome
Gout
X-linked hypophosphatemic rickets
Familial hypocalciuric hypercalcemia

TABLE 384-3 Clinical Manifestations of Apatite Crystal Deposition Periarticular¶

Harrison's 22e, p.2961

Periarticular
Calcific periarthritis (e.g., supraspinatus tendon apatite deposit rupture)
Bursitis and tendinitis
Hydroxyapatite pseudopodagra
Polyarticular involvement
Asymptomatic deposition
Articular
Hemorrhagic shoulder effusions in the elderly (Milwaukee shoulder)
Chronic destructive arthropathy
Chronic erosive monoarthritis (resembling erosive osteoarthritis)
Acute synovitis
Association with osteoarthritis
Secondary apatite crystal deposition
Tumoral calcinosis
Hyperparathyroidism
Calciphylaxis (renal failure/long-term dialysis)
Connective tissue diseases (e.g., systemic sclerosis, dermatomyositis)
Heterotopic calcification after neurologic catastrophes (e.g., stroke, spinal
cord injury)
Fibrodysplasia ossificans progressiva