Pseudogout and CPPD Disease

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

Who gets it. Prevalence rises markedly with age: CPPD is rare before 50 and present in more than 40% of those over 84. Radiographic chondrocalcinosis is found in 15% of people aged 65-74 and 44% of those aged 85 and older, yet only 25% of people with it are symptomatic. The sexes are affected about equally, with a slight female predominance in some studies.

Risk factors. Age is the strongest, and prevalence doubles each decade after 60. Osteoarthritis is strongly associated, in a chicken-and-egg relationship, and prior joint injury (meniscectomy or joint trauma) also counts. Rare autosomal dominant familial forms arise from ANKH gene mutations, and four metabolic conditions complete the list.

Pyrophosphate balance. Inorganic pyrophosphate (PPi) is produced during ATP hydrolysis, and chondrocytes are the primary source of it in the joint. Pyrophosphatases normally convert PPi to orthophosphate, and the balance between generation and breakdown keeps levels normal. CPPD results from aberrant PPi metabolism: excess PPi combines with calcium to form CPP crystals, which deposit preferentially in fibrocartilage (menisci, TFCC) and hyaline cartilage.

What tips the balance. Extracellular PPi rises with increased activity of the ANKH transporter, which exports PPi from cells, with decreased activity of tissue non-specific alkaline phosphatase (TNAP), and with chondrocyte senescence and its altered metabolism. Four factors promote crystallisation, and the metabolic associations map onto them.

• Elevated calcium concentrations - hyperparathyroidism
• Increased PPi - ANKH mutations, haemochromatosis
• Decreased PPi degradation - hypomagnesaemia
• Cartilage matrix changes with ageing

The acute attack. The inflammatory cascade runs in five steps.

1. CPP crystals shed from cartilage into the joint space
2. Synovial macrophages phagocytose them
3. The NLRP3 inflammasome is activated (similar to gout)
4. IL-1β release triggers neutrophil influx
5. Acute synovitis develops

The chronic arthropathy. Persistent low-grade inflammation damages cartilage, and crystal deposition alters its biomechanics. Secondary osteoarthritic change follows, with the distinctive pattern of joint involvement described under pyrophosphate arthropathy.

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Acute CPP Crystal Arthritis (Pseudogout)

The attack. An acute monoarthritis that mimics gout or septic arthritis, and may be triggered by illness, surgery or trauma. It is less severe than gout, and the patient can usually weight-bear. Untreated, it is self-limiting over 1-3 weeks.

Where. The knee accounts for 50% of attacks and the wrist 25%; the shoulder, ankle and elbow share the remaining 25%. The first MTP, the podagra site of gout, is uncommonly involved.

Chronic CPP Crystal Arthropathy

The chronic form resembles osteoarthritis clinically and radiographically, rather than an erosive arthritis, but it affects joints atypical for primary OA. Progressive joint destruction is possible, and morning stiffness and inflammatory features may be present. Its pattern is set out in the pyrophosphate arthropathy section below.

Crowned Dens Syndrome

The picture. Calcification around the odontoid process causes acute severe neck pain, fever and elevated inflammatory markers, and can produce marked restriction of rotation. It mimics meningitis or retropharyngeal abscess, and also giant-cell arteritis or infection.

Diagnosis and treatment. CT shows the periodontoid calcification. Treatment is with NSAIDs, and the condition is usually self-limiting.

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Extra-articular Deposition

CPPD is not confined to hyaline cartilage and fibrocartilage. Deposits can also form in tendon and fascia, as in the Achilles tendon and plantar fascia.

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Physical Examination

Look. Swelling and erythema over the affected joint, less marked than in gout, with an effusion, particularly at the knee. There are no tophi, unlike gout.

Feel. The joint is warm and tender, and a knee effusion is detectable by ballottement or patellar tap. Crepitus is a feature of chronic arthropathy.

Chronic CPP arthropathy produces a degenerative pattern that is recognisably "OA in the wrong joints", a key examiner clue that calcium pyrophosphate, or an underlying metabolic driver, is at work. It differs from primary OA in four ways.

• Distribution - the radiocarpal (wrist), metacarpophalangeal, elbow, shoulder, ankle, patellofemoral and talonavicular joints, which primary OA tends to spare
• Patellofemoral-predominant knee OA - isolated, or disproportionate to the tibiofemoral compartments, a classic CPPD pattern
• Prominent subchondral cysts and large osteophytes - out of proportion to the joint-space narrowing
• Superimposed chondrocalcinosis - frequent

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The haemochromatosis pattern. Hereditary haemochromatosis, a state of iron overload, causes a distinctive arthropathy that typically involves the 2nd-5th MCP joints, with squaring and joint-space loss, frequently accompanied by chondrocalcinosis. Hook-shaped osteophytes on the radial side of the 2nd and 3rd metacarpal heads are almost a signature sign.

What to do with it. MCP-predominant arthropathy with chondrocalcinosis should prompt ferritin and transferrin saturation, particularly in a patient under 55.

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CPPD must be distinguished from the other common articular calcium crystal, basic calcium phosphate (BCP), principally carbonated hydroxyapatite. The two frequently coexist in osteoarthritic joints, but they behave and are detected differently.

Milwaukee shoulder. The destructive shoulder arthropathy caused by BCP crystals, classically in elderly women. It produces a large, often blood-stained, non-inflammatory effusion, rotator-cuff destruction with superior migration of the humeral head, and rapid glenohumeral joint destruction.

Management. Largely supportive, with aspiration, NSAIDs and activity modification. An irreparably destroyed cuff and joint may ultimately need reverse shoulder arthroplasty.

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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 arthropathy - progressive joint destruction
• Spinal stenosis - from disc calcification and hypertrophy
• Tendon rupture - rare, but reported with periarticular deposits
• Neurological compression - carpal tunnel syndrome, cervical myelopathy

Cervical compression. Neurological deficit changes cervical CPPD from an inflammatory flare into a decompression problem.

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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 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.

CPPD remains under-researched relative to gout, and several questions are unresolved.

OA: cause or consequence? 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, and the association is joint-specific: it holds for knee OA, not hip OA.

Dissolving the crystals. Nothing reliably reduces CPP crystal burden. Drugs targeting pyrophosphate metabolism, such as probenecid, magnesium and phosphocitrate, remain experimental or unproven.

Prophylaxis. Low-dose colchicine and hydroxychloroquine are used for recurrent flares largely by extrapolation from gout and small studies, and randomised data are limited. Methotrexate was not confirmed to be effective in recent trials, although the 2024 Lancet Rheumatology review in the evidence below still lists low-dose methotrexate among agents that may help.

IL-1 blockade. Anakinra and canakinumab help refractory attacks mechanistically, through the NLRP3/IL-1β pathway, but the evidence is limited to case series and they are not formally licensed for CPPD.

Imaging thresholds. Ultrasound (with the OMERACT definitions) and dual-energy or conventional CT are increasingly used. The optimal diagnostic algorithm, and how to grade subclinical deposition, are still being standardised.

Whom to screen. There is consensus to screen young (under about 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.