11.2 Crystal Arthropathies (Gout & Pseudogout) & Septic Arthritis

Crystal Arthropathies (Gout & Pseudogout) & Septic Arthritis

An acutely painful, red, hot, swollen joint is one of the most critical presentations in acute medicine and rheumatology. Differentiating rapidly between crystal-induced synovitis and bacterial joint sepsis is paramount: while crystal arthropathies respond promptly to targeted medical anti-inflammatory therapies, delayed drainage and delayed antibiotic therapy in septic arthritis causes permanent chondrocyte death and irreversible joint destruction within 24 to 48 hours.

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Gout (Monosodium Urate Arthropathy)

Gout is a metabolic disorder characterized by the precipitation and deposition of monosodium urate (MSU) monohydrate crystals within synovial joints and surrounding soft tissues. Deposition occurs when serum urate concentrations exceed physiological solubility limits (approximately > 360 µmol/L or 6.8 mg/dL).

Pathophysiology

Uric acid is the end-product of endogenous and dietary purine degradation, catalyzed by the hepatic enzyme xanthine oxidase: $\text{Hypoxanthine} \xrightarrow{\text{Xanthine Oxidase}} \text{Xanthine} \xrightarrow{\text{Xanthine Oxidase}} \text{Uric Acid}$

• Hyperuricaemia arises from underexcretion of urate by the kidneys (~90% of cases) or overproduction of purines (~10%).
• Phagocytosis of precipitated MSU crystals by synovial macrophages triggers the intracellular NLRP3 inflammasome, driving the cleavage and massive release of pro-inflammatory cytokines, predominantly interleukin-1 beta (IL-1β). This promotes rapid neutrophil recruitment and intense acute synovitis.

Risk Factors & Secondary Triggers

• Non-Modifiable: Male sex, advanced age, postmenopausal state in women, genetic polymorphisms in renal urate transporters (SLC2A9, ABCG2).
• Modifiable / Dietary Excess: Excessive consumption of purine-dense foods (red meat, game, organ meats/offal, shellfish/seafood), high-fructose corn syrup beverages, and alcohol intake (especially beer, which contains both alcohol and absorbable purines/guanosine, and distilled spirits).
• Comorbidities: Obesity, metabolic syndrome, hypertension, type 2 diabetes mellitus, chronic kidney disease (CKD) (reduced tubular urate clearance), and myeloproliferative/lymphoproliferative disorders (accelerated cell turnover).
• Pharmacological Triggers:
  • Diuretics (Thiazide and Loop diuretics): Inhibit tubular urate secretion and increase reabsorption through volume contraction.
  • Low-dose aspirin (< 1 g daily; paradoxically blocks urate excretion, whereas high-dose is uricosuric).
  • Calcineurin inhibitors (ciclosporin, tacrolimus).
  • Cytotoxic chemotherapy (tumor lysis syndrome).

Clinical Presentation

• Acute Gout Flare: Explosive, agonizing monoarthritis reaching maximal intensity within 6 to 24 hours. The joint is intensely erythematous, swollen, warm, and exquisitely tender (even the light pressure of a bedsheet or gentle breeze provokes excruciating pain). Periarticular erythema may mimic cellulitis.
• Anatomical Predilection: The first metatarsophalangeal (MTP) joint is the site of involvement in over 70% of initial attacks (podagra). Other frequent sites include the ankle, midfoot, knee, wrist, and olecranon bursa.
• Chronic Tophaceous Gout: Untreated chronic hyperuricaemia leads to the formation of tophi: nodular, chalky aggregates of monosodium urate crystals surrounded by foreign-body giant cell granulomas. Tophi appear on the helix of the external ear, olecranon bursae, patellar tendons, Achilles tendons, and digit extensor surfaces. They can ulcerate, extruding a white, tooth-paste-like chalky paste.

Diagnostic Investigations

• Synovial Fluid Arthrocentesis (Gold Standard): Polarised light microscopy with a first-order red compensator demonstrates:
  • Needle-shaped crystals with pointed ends.
  • Strongly negative birefringence: Crystals oriented parallel to the slow axis of the red compensator filter appear bright yellow, whereas crystals lying perpendicular turn blue.
• Serum Uric Acid Warning: Serum urate concentrations can be paradoxically normal or low during an acute gout flare, because acute-phase systemic inflammation (IL-6 release) stimulates renal uricosuria. A normal serum uric acid level during a flare does NOT exclude gout. Definitive serum urate evaluation should be repeated 2 to 4 weeks after complete clinical resolution.
• Plain Radiography: Early radiographs show only non-specific soft tissue swelling. In chronic tophaceous gout, radiographs characteristically demonstrate "punched-out" periarticular cortical bone erosions with sclerotic margins and overhanging bony edges ("rat-bite" or "Martel's" erosions), with joint space preservation until terminal stages.

Acute Flare Management

1. First-Line Options (NICE NG219, 2022): offer an NSAID, colchicine or a short course of oral corticosteroid, choosing according to comorbidities, co-prescriptions and preference:
   • Oral NSAIDs: for example naproxen 500 mg twice daily (or indometacin), with a proton pump inhibitor for gastroprotection.
   • Oral Colchicine: 500 micrograms two to four times daily until symptoms settle, to a maximum of 6 mg per course (do not repeat a course within 3 days; BNF). Colchicine inhibits microtubule polymerisation and neutrophil chemotaxis; its dose-limiting adverse effect is diarrhoea, with nausea and abdominal cramps. Reduce the dose or avoid it in renal impairment and with interacting drugs (clarithromycin, statins, ciclosporin).
   • Oral Prednisolone: for example 30–35 mg daily for 3–5 days, useful when NSAIDs and colchicine are unsuitable.
2. When First-Line Options Are Unsuitable: In patients with advanced chronic kidney disease, active peptic ulcer disease, heart failure or anticoagulation, NSAIDs are contraindicated and colchicine is risky (accumulation causes myopathy, neuropathy and bone marrow toxicity). Use oral prednisolone or an intra-articular (or intramuscular) corticosteroid injection (e.g. methylprednisolone 40–80 mg) once septic arthritis is excluded.
3. Urate-Lowering Therapy and Flares:
   • If the patient is already taking allopurinol or febuxostat when a flare occurs, continue it at the current dose and add acute treatment.
   • New ULT is usually started 2–4 weeks after a flare has settled, but NICE NG219 allows starting it during a flare if flares are frequent. Rapid falls in urate can mobilise crystals and trigger flares, so ULT always starts at a low dose with flare prophylaxis considered.

Long-Term Urate-Lowering Therapy (ULT)

• Timing: Discuss ULT with everyone after their first flare; start it 2–4 weeks after a flare settles (or during a flare if flares are frequent).
• Offer ULT (NICE NG219) to people with:
  • multiple or troublesome flares
  • chronic kidney disease (stages 3–5)
  • diuretic therapy
  • tophi
  • chronic gouty arthritis
• First-Line ULT: Allopurinol or Febuxostat (treat-to-target), chosen with the patient; offer allopurinol rather than febuxostat to people with major cardiovascular disease.
  • Allopurinol competitively inhibits xanthine oxidase. Start at 100 mg daily (50 mg daily in CKD stages 3–5) and increase in 100 mg steps about every 4 weeks, checking serum urate, until target (maximum 900 mg daily).
  • Febuxostat is a non-purine selective xanthine oxidase inhibitor (80–120 mg daily).
  • Target Serum Urate: below 360 µmol/L for everyone; consider below 300 µmol/L for people with tophi or chronic gouty arthritis, or continuing flares despite a urate below 360 µmol/L.
  • Flare Prophylaxis: Consider colchicine (500 micrograms once or twice daily) while ULT is started and titrated, usually for up to 6 months; a low-dose NSAID or low-dose prednisolone is an alternative if colchicine is unsuitable.
• Pharmacogenomic Safety: Screen for the HLA-B*5801 allele prior to starting allopurinol in individuals of Han Chinese, Korean, or Thai ancestry. Presence of HLA-B*5801 confers a severe risk of life-threatening severe cutaneous adverse reactions (SCAR / Stevens-Johnson syndrome / DRESS syndrome).

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Pseudogout (Calcium Pyrophosphate Dihydrate / CPPD Deposition)

Pseudogout (acute calcium pyrophosphate crystal arthritis) is caused by the precipitation of calcium pyrophosphate dihydrate (CPPD) crystals in articular fibrocartilage and hyaline cartilage, a condition termed chondrocalcinosis.

Risk Factors & Metabolic Associations

• Advanced Age: Strongest predictor; prevalence exceeds 30% in individuals aged > 80 years.
• Prior Joint Trauma: Previous meniscectomy or joint surgery.
• Underlying Metabolic Disorders (Screening Workup):
  • Haemochromatosis: Iron overload (HFE gene; check ferritin and transferrin saturation). Characteristic involvement of the 2nd and 3rd MCP joints with hook-like osteophytes.
  • Primary Hyperparathyroidism: Hypercalcaemia driving pyrophosphate crystallization (check serum calcium, phosphate, and PTH).
  • Hypomagnesaemia: Low magnesium enhances pyrophosphate precipitation (check serum magnesium).
  • Hypophosphatasia and Wilson's disease.

Clinical Presentation & Joint Distribution

• Typically presents as an acute monoarthritis or oligoarthritis.
• Characteristically involves large joints: Knee (#1, > 50% of cases), wrist, shoulder, ankle, and hip. First MTP joint involvement is distinctly rare.
• Clinical symptoms mirror gout: acute pain, erythema, swelling, and joint effusion, though onset is often slightly more insidious than gout (taking 24–48 hours to peak).

Diagnostic Hallmarks

• Polarised Light Microscopy:
  • Rhomboid-shaped or rectangular crystals with blunt ends.
  • Weakly positive birefringence: Crystals lying parallel to the slow axis of the red compensator filter appear pale blue, whereas crystals lying perpendicular turn yellow.
• Plain Radiography: Pathognomonic chondrocalcinosis: fine, punctate, linear calcifications outlining the fibrocartilage (e.g., knee menisci, triangular fibrocartilage complex of the wrist, pubic symphysis) and hyaline articular cartilage.

Management

• Joint aspiration (arthrocentesis) alone provides immediate pain relief by decompressing capsular tension.
• Pharmacotherapy: Intra-articular corticosteroid injection; oral NSAIDs or low-dose colchicine. Unlike gout, there is no pharmacological agent available to dissolve intra-articular CPPD crystal deposits.

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Septic Arthritis (The Acute Orthopaedic Emergency)

Septic arthritis is a closed-space bacterial infection of the synovial joint space. It is a true medical and surgical emergency: chondrocyte proteases and bacterial endotoxins trigger rapid, irreversible articular cartilage destruction and permanent joint dysfunction within 24 to 48 hours of onset.

Route of Infection & Microbiology

• Pathogenesis: Haematogenous seeding of the richly vascularized synovial membrane (#1 route); direct percutaneous inoculation (penetrating trauma, arthrocentesis, intra-articular injection); or contiguous spread from adjacent osteomyelitis.
• Microbial Pathogens:
  • Staphylococcus aureus (#1 cause overall, > 50% of adult cases): Including methicillin-resistant S. aureus (MRSA).
  • Streptococcus species (~20%): Streptococcus pyogenes (Group A strep), Streptococcus pneumoniae.
  • Neisseria gonorrhoeae: Young, sexually active adults. Manifests either as localized septic monoarthritis or Disseminated Gonococcal Infection (DGI: triad of migratory tenosynovitis, maculopapular/pustular skin lesions, and polyarthralgia followed by purulent monoarthritis).
  • Gram-Negative Bacilli (E. coli, Pseudomonas aeruginosa): Elderly, immunosuppressed, diabetes, or intravenous drug users (IVDUs; sternoclavicular and sacroiliac joint predilection).

Clinical Presentation

• Acute, severe, monoarticular pain, swelling, and heat.
• Exquisite limitation of both ACTIVE and PASSIVE joint movement in all planes.
• Complete inability to bear weight on the affected limb.
• Systemic upset: High-grade pyrexia (> 38.5°C), rigors, tachycardia, and diaphoresis (note: elderly, immunocompromised, and cirrhotic patients may be afebrile).
• Most Commonly Affected Joint: Knee (~50% of cases), followed by hip, shoulder, ankle, and wrist.

MANDATORY URGENT CLINICAL PATHWAY

Suspected Septic Joint (Red, Hot, Swollen, Immobile Joint)
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1. EMERGENCY DIAGNOSTIC ARTHROCENTESIS (Synovial Fluid Aspiration)
   • MUST be performed BEFORE any antimicrobial administration
   • Send for urgent Microscopy, Gram Stain, Leukocyte Count, and Culture
   • Send Blood Cultures (2 sets) simultaneously
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2. IMMEDIATE EMPIRICAL INTRAVENOUS ANTIBIOTIC THERAPY
   • Commenced IMMEDIATELY AFTER joint aspiration
   • First-Line: IV Flucloxacillin 2 g QDS
   • High MRSA Risk / Penicillin Allergy: IV Vancomycin
   • Gonococcal / Gram-Negative Risk: Add IV Ceftriaxone 2 g daily
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3. EMERGENCY ORTHOPAEDIC REFERRAL FOR SURGICAL JOINT WASHOUT
   • Arthroscopic debridement or Open Arthrotomy in Theatre
   • Evacuates purulent material, decompresses capsular pressure, halts necrosis

Synovial Fluid Interpretation

• Macroscopic Appearance: Turbid, cloudy, or frankly purulent (pus).
• White Cell Count (WCC): Characteristically > 50,000 cells/µL (often > 100,000 cells/µL), with > 90% polymorphonuclear neutrophils.
• Gram Stain: Positive in 50–70% of staphylococcal infections.
• Culture: Yields definitive identification and antimicrobial sensitivities (prolonged culture required for gonococcus and fastidious organisms).

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Comparison: Gout vs Pseudogout vs Septic Arthritis