Pseudogout and CPPD Disease

Calcium pyrophosphate deposition (CPPD) disease is a crystal arthropathy caused by the deposition of calcium pyrophosphate dihydrate (CPP) crystals in articular and periarticular tissues. It encompasses a spectrum from asymptomatic chondrocalcinosis to acute pseudogout attacks to chronic pyrophosphate arthropathy.

Epidemiology:

• Prevalence increases markedly with age: rare before age 50, present in greater than 40% of those over 84 years
• Male to female ratio: approximately equal (slight female predominance in some studies)
• Radiographic chondrocalcinosis: 15% at age 65-74, 44% at age 85 and older
• Only 25% of those with radiographic chondrocalcinosis are symptomatic

Risk Factors:

• Age: Strongest risk factor - prevalence doubles each decade after 60
• Prior joint injury: Meniscectomy, joint trauma
• Osteoarthritis: Strong association, chicken-and-egg relationship
• Metabolic conditions: Hemochromatosis, hyperparathyroidism, hypomagnesemia, hypothyroidism
• Familial: Rare autosomal dominant forms (ANKH gene mutations)

Understanding the pathophysiology of CPPD is essential for both diagnosis and management. The disease results from aberrant pyrophosphate metabolism leading to crystal formation in cartilage.

Pyrophosphate Metabolism

Normal physiology:

• Inorganic pyrophosphate (PPi) is produced during ATP hydrolysis
• PPi is normally converted to orthophosphate by pyrophosphatases
• Balance between PPi generation and breakdown maintains normal levels
• Chondrocytes are the primary source of articular PPi

Pathological crystal formation:

• Excess PPi combines with calcium to form CPP crystals
• Crystals deposit preferentially in fibrocartilage (menisci, TFCC) and hyaline cartilage
• Crystal shedding into joint space triggers acute inflammation

Mechanisms of Crystal Formation

Elevated extracellular PPi:

• Increased ANKH transporter activity (exports PPi from cells)
• Decreased tissue non-specific alkaline phosphatase (TNAP) activity
• Chondrocyte senescence with altered metabolism

Factors promoting crystallization:

• Elevated calcium concentrations (hyperparathyroidism)
• Increased PPi (ANKH mutations, hemochromatosis)
• Decreased PPi degradation (hypomagnesemia - Mg is TNAP cofactor)
• Cartilage matrix changes with aging

Inflammatory Response

Crystal-induced inflammation:

1. CPP crystals shed from cartilage into joint space
2. Crystals phagocytosed by synovial macrophages
3. NLRP3 inflammasome activation (similar to gout)
4. IL-1beta release triggers neutrophil influx
5. Acute synovitis develops

Chronic arthropathy:

• Persistent low-grade inflammation damages cartilage
• Crystal deposition alters cartilage biomechanics
• Secondary osteoarthritic changes develop
• Distinctive pattern of joint involvement

Acute CPP Crystal Arthritis (Pseudogout)

Classic presentation:

• Acute monoarticular arthritis mimicking gout or septic arthritis
• Knee is the most common site (50% of attacks)
• Less severe than gout - can usually weight-bear
• Self-limiting over 1-3 weeks without treatment
• May be triggered by illness, surgery, or trauma

Other common joints:

1. Knee - 50%
2. Wrist - 25%
3. Shoulder, ankle, elbow - remaining 25%
4. 1st MTP (podagra) - uncommon unlike gout

Chronic CPP Crystal Arthropathy

Features:

• Resembles osteoarthritis clinically and radiographically
• Affects joints atypical for primary OA
• MCP joints, wrists, shoulders, ankles - unusual OA sites
• Progressive joint destruction possible
• Morning stiffness and inflammatory features may be present

Crowned Dens Syndrome

Cervical spine involvement:

• Calcification around the odontoid process
• Acute severe neck pain, fever, elevated inflammatory markers
• Mimics meningitis or retropharyngeal abscess
• Diagnosis: CT showing periodontal calcification
• Treatment: NSAIDs, usually self-limiting

Physical Examination

Inspection:

• Swelling and erythema over affected joint (less marked than gout)
• Joint effusion, particularly at knee
• No tophi (unlike gout)

Palpation:

• Warmth and tenderness over affected joint
• Effusion detectable at knee (ballottement, patellar tap)
• Crepitus in chronic arthropathy

Laboratory Studies

Synovial fluid analysis (Gold Standard):

• CPP crystal identification under polarized microscopy
• Rhomboid or rod-shaped, positively birefringent crystals
• Blue when parallel to the polarizer (opposite of gout)
• WBC count: 10,000-50,000/microL (predominantly neutrophils)

Metabolic screen (if under 55 years or recurrent):

• Ferritin and transferrin saturation - hemochromatosis
• Calcium, PTH - hyperparathyroidism
• Magnesium - hypomagnesemia
• TSH - hypothyroidism

Other labs:

• ESR, CRP - elevated during acute attack
• Uric acid - may help differentiate from gout

Imaging

Plain Radiographs:

• Chondrocalcinosis - linear calcification in cartilage
• Fibrocartilage: Menisci (triangular), TFCC (linear), symphysis pubis
• Hyaline cartilage: Parallel lines within cartilage
• Pyrophosphate arthropathy: Subchondral cysts, osteophytes, joint space narrowing

Key radiographic locations:

1. Knee: Meniscal calcification, femoral condyle cartilage
2. Wrist: TFCC, scapholunate ligament
3. Pelvis: Symphysis pubis
4. Spine: Intervertebral disc calcification

Ultrasound:

• Hyperechoic deposits within cartilage
• Distinguishable from gout (cartilage surface vs within cartilage)

CT:

• Best for crowned dens syndrome (periodontal calcification)
• Useful for spinal involvement

Differential Diagnosis of an Acute Hot Joint

The single most important step in acute monoarthritis is to exclude infection. Crystals and sepsis can coexist, so positive crystals never fully exclude a septic joint.

Indications for Surgery

1. End-stage arthropathy: Joint destruction requiring arthroplasty
2. Mechanical symptoms: Loose bodies, meniscal pathology
3. Carpal tunnel syndrome: From crystal deposition
4. Crowned dens syndrome: Rarely requires surgical decompression

Disease Complications

• Chronic erosive arthropathy: Progressive joint destruction
• Spinal stenosis: From disc calcification and hypertrophy
• Tendon rupture: Rare but reported with periarticular deposits
• Neurological compression: Carpal tunnel, cervical myelopathy

Surgical Complications

• Acute flare: Perioperative pseudogout attack
• Stiffness: May be more common after TKA
• Wound healing: Generally not affected unlike gout with tophi
• Recurrent symptoms: Crystal deposition continues

CPPD remains under-researched relative to gout, and several questions are unresolved - useful material for higher-order viva discussion.

• Causality with osteoarthritis: CPPD and OA are tightly linked but the direction is unclear. CPP crystals may accelerate cartilage degradation, or degenerate cartilage may simply favour crystal nucleation. The association is also joint-specific (associates with knee OA, not hip OA).
• No crystal-dissolving therapy: Unlike urate-lowering therapy in gout, nothing reliably reduces CPP crystal burden. Drugs targeting pyrophosphate metabolism (e.g. probenecid, magnesium, phosphocitrate) remain experimental or unproven.
• Prophylaxis evidence is weak: Low-dose colchicine and hydroxychloroquine are used for recurrent flares largely by extrapolation from gout and small studies; randomised data are limited. Methotrexate was not confirmed to be effective in recent trials.
• Role of IL-1 blockade: Anakinra and canakinumab help refractory attacks mechanistically (NLRP3/IL-1beta pathway) but evidence is limited to case series; they are not formally licensed for CPPD.
• Imaging thresholds: Ultrasound (and the OMERACT definitions) and dual-energy/conventional CT are increasingly used, but the optimal diagnostic algorithm and how to grade subclinical deposition are still being standardised.
• Whom to screen metabolically: There is consensus to screen young (under ~55-60) or polyarticular patients, but the yield in older sporadic disease is low and the exact age cut-off and panel vary between guidelines.

CPPD is a global disease of the ageing joint. Because no therapy dissolves CPP crystals anywhere in the world, international guidance converges on the same two pillars: confident diagnosis (crystal identification plus imaging) and control of inflammation, while excluding sepsis and treating any underlying metabolic driver.

Global epidemiology

• Radiographic chondrocalcinosis is strongly age-dependent and varies by population: knee chondrocalcinosis in adults aged 60 and over is around 6-8% in US white cohorts (Framingham) but under 3% in Beijing Chinese cohorts using identical protocols.
• CPPD may be the commonest inflammatory arthritis in people over 60 years; most radiographic chondrocalcinosis is asymptomatic.
• Familial autosomal-dominant forms (ANKH mutations) are rare but cause young, often polyarticular, onset.

Side-by-side guidance

Registry and arthroplasty evidence

• Large arthroplasty registries (NJR, AOANJRR, AJRR, Swedish/Norwegian) do not list CPPD as a distinct indication, but cohort data (e.g. 1500-knee CORR series) show chondrocalcinosis does not increase TKA revision risk and yields comparable Knee Society scores.
• Implication: standard implant and bearing selection applies; CPPD changes perioperative flare prophylaxis, not prosthesis choice.

High- vs limited-resource practice variation

• Well-resourced settings: routine polarised microscopy and high-frequency ultrasound enable confident crystal/imaging diagnosis; IL-1 blockade (anakinra/canakinumab) available for refractory attacks.
• Limited-resource settings: diagnosis often rests on plain radiographs and clinical pattern; management relies on NSAIDs, colchicine and intra-articular or oral corticosteroids, with aspiration to exclude sepsis remaining the universal safety step.
• Everywhere: screen young or polyarticular patients for haemochromatosis, hyperparathyroidism, hypomagnesaemia and hypothyroidism, and refer for definitive metabolic treatment.