Pseudogout

Pseudogout is a crystal arthropathy, which may cause an acute inflammatory arthritis from deposition of calcium pyrophosphate.

The principle mechanism underlying pseudogout is deposition of calcium pyrophosphate dihyrate (CPP). In fact, pseudogout is an old term that refers to one of the clinical syndromes within a spectrum of conditions associated with CPP deposition (CPPD) in connective tissue.

The term pseudogout is still used commonly in clinical practice. This is because of the close resemblance to gout in both pathophysiology (crystal arthropathy) and clinical features (acute inflammatory arthropathy).

CPPD is an umbrella term that covers all clinical conditions linked to the deposition of CPP in connective tissue. 

The term CPPD was originally proposed by the European League Against Rheumatism (EULAR). When associated with arthritis, it is termed CPPD disease. 

In total, there are six clinical syndromes associated with CPPD, but the majority are asymptomatic.

• Asymptomatic CPPD disease: radiographic evidence of CPPD without features of arthritis.
• Acute CPP crystal arthritis (i.e. pseudogout): acute self-limiting episodes of crystal arthropathy.
• Chronic CPP crystal inflammatory arthritis: chronic inflammatory arthritis. Typically multiple joints. Occurs in < 5% of symptomatic CPPD disease.
• Osteoarthritis with CPPD +/- acute episodes: most common form. Progressive osteoarthritis-like joint degeneration. Acute episodes in 50%. 
• Severe joint degeneration: joint degeneration similar to neuropathic joints (i.e. Charcot joints).
• Spinal disease: typically presents with spinal stiffness. Imaging may reveal changes similar to ankylosing spondylitis. More common in familial form.

The majority of cases of pseudogout are idiopathic.

Several secondary conditions have been associated CPPD disease. These are particularly important to consider in younger patients. 

• Hereditary haemochromatosis
• Hyperparathyroidism
• Trauma
• Hypomagnesaemia
• Familial CPPD disease: early onset, more severe phenotype, widespread arthritis.
• Gout: up to 5% of patients have both CPP and monosodium urate crystals.

Calcium pyrophosphate crystal formation and deposition is central to the pathogenesis of pseudogout.

Chondrocytes are the principle cell involved in the formation and deposition of CPP. Chondrocytes are the only cell type found in articular cartilage. They are essential for the generation of the structural component of cartilage, which then embeds them. 

In pseudogout, excess pyrophosphate production causes local CPP supersaturation, crystal formation and deposition. CPP crystals stimulate a proinflammatory response leading to activation of phagocytes and neutrophils. The inflammatory response is usually self-limited due to the modification of CPP crystals (e.g. addition of lipoproteins), which reduces the inflammation.

Pseudogout presents with acute severe joint inflammation that is characterised by pain, redness, swelling and restricted movement.

Signs and symptoms

Pseudogout characteristically leads to asymmetrical arthropathy of ‘larger’ peripheral joints. Patients presenting with a first episode affecting the upper extremity should raise suspicion of pseudogout over gout. 

• Joint pain: typically one, but may be multiple
• Joint swelling
• Erythema
• Restricted movement
• +/- systemic features (e.g. fever)

Commonly affected joints

• Knees: 50% of cases
• Wrists
• Shoulders
• Ankles
• Feet
• Elbows

Diagnosis of pseudogout is based on synovial fluid analysis and plain film radiography.

A definitive diagnosis of pseudogout (i.e. acute CPPD disease) requires evidence of both CPP crystals on synovial fluid analysis and classical radiographic changes.

• Definitive: CPP crystals and typical cartilage or joint capsule calcification.
• Probable: CPP crystals OR typical cartilage or joint capsule calcification.
• Possible: acute arthritis of large joints (e.g. knee) or chronic osteoarthritis-type joint with acute episodes.

Due to the pattern of joints affected in pseudogout, it is difficult to confidently make a diagnosis without evidence of CPP crystals.

Synovial fluid analysis

Patients with an acutely swollen joint should undergo arthrocentesis. Samples should be sent for microbiology (white cell count + microscopy, culture and sensitivity) and biochemistry (crystal analysis). 

Crystal characteristics

• Shape: rhomboid
• Size: small (0.5 - 10 microns)
• Birefringence: weakly positive on plane-polarised light

NOTE: if there is any concern about septic arthritis a joint aspiration should always be performed.

Plain film radiography

Conventional radiographs should be used to identify cartilage calcification (CC), previously known as chondrocalcinosis. X-rays are useful for assessing other features of CPPD disease (e.g. degenerative changes). 

Typical sites of CC include the menisci of the knee or the triangular fibrocartilage complex (TFCC) of the wrist. In hyaline cartilage, CC will appear as a thin opaque line. Some x-ray changes are suggestive of a secondary disorder (e.g. second and third MCPs in hereditary haemochromatosis). 

The treatment of pseudogout involves steroid injections, NSAIDs and/or colchicine.

The majority of acute flares of pseudogout will resolve within 7-14 days. However, treatment is highly effective in reducing the severity of the illness.

• Conservative measures: based on expert opinion. Include ice/cool packs alongside immobilisation and resting the joint, particularly within the first 48-72 hours.
• Joint injection: useful if symptoms limited to ≤2 joints. Medication choice is corticosteroid in combination with lidocaine. Relief within 8-24 hours. Suspected or confirmed septic arthritis a contraindication.
• Medications: commonly if multiple joints affected or joint injection not possible. Treatment is with NSAIDs (e.g. naproxen 500 mg BD) unless contraindicated. Colchicine is an alternative. A short course of corticosteroids can be used in patients who don’t respond to first line treatments. Recurrent episodes (≥3 annually) may require prolonged treatment with colchicine.

Last updated: March 2021