24th February 2025

Crystal arthropathies

Gout

Overview of gout

Gout is a common, chronic condition characterised by acute, severe flares of joint pain, classically affecting the first metatarsophalangeal (MTP) joints (known as podagra). If risk factors are not managed over time, it may cause a destructive and deforming arthropathy. It manifests due to deposition of urate crystals in the joint space, typically due to raised plasma urate levels.

Risk factors for gout include male gender, advancing age, obesity, hypertension (partly due to the medications used to treat), diabetes mellitus, CKD (due to impaired urate excretion), trauma and any condition causing rapid cell turnover (such as tumour lysis syndrome classically, or indeed any condition causing haemolysis). Historically, it is associated with a diet rich in meat, fish and alcohol. There are a host of drugs associated with gout; these include: salicylates, diuretics (particularly furosemide but also bendroflumethiazide), ciclosporin, levodopa and the tuberculosis drugs pyrazinamide and ethambutol.

The acute management typically involves anti-inflammatory drugs such as NSAIDs, colchicine or corticosteroids, while the chronic management focuses on urate-lowering therapies such as allopurinol, a xanthine oxidase inhibitor (as well as managing any underlying cause).

Signs and symptoms of gout

The typical presentation for an attack of gout is a sudden-onset (over hours), severely painful, erythematous, swollen joint (typically a single joint) and, in cases of podagra (see Figure 6), exquisite difficulty in weight bearing. It typically affects joints in the lower limbs rather than the upper limbs (and almost never the spinal column). Over time, it becomes more likely that attacks are polyarticular rather than the usual monoarticular presentation. Urate crystals eventually become deposited in the soft tissues (such as the ear pinna and Achilles tendon), forming subcutaneous tophi (see Figure 7), which are a marker of chronically raised urate levels and can diagnostically be helpful.

Image source: Wikimedia Commons (2019). Gout2010, Licensed under a Creative Commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Gout2010.JPG (Accessed: 19 January 2024).

Image source: Wikimedia Commons (2010). Case 30-top, Licensed under a Creative Commons licence. Available for free at: https://en.m.wikipedia.org/wiki/File:Case_30-top.jpg (Accessed: 19 January 2024).

Investigation of gout

The diagnosis is typically suspected based on a previous history, having identifiable risk factors (especially if there is a recent temporal relationship) and clinical examination.

Gout can be confirmed by needle aspiration of synovial fluid during a flare, showing negatively birefringent needle-shaped crystals on microscopy (though their absence does not exclude the diagnosis). X-rays may highlight punched-out erosions and sclerotic margins, as well as soft tissue swelling and joint effusion (see Figure 8), and ultrasound may show tophaceous deposits.

Other differential diagnoses to consider include pseudogout, OA, RA, psoriatic arthritis, as well as both reactive arthritis and, crucially, septic arthritis in the immunosuppressed. There is no role for measuring urate levels in the acute phase to confirm or refute the diagnosis; it should only be used to confirm chronically elevated levels and the response to therapy. Note, however, that a raised serum urate may be detected in an asymptomatic patient without any previous episodes of gout and does not necessarily predict future episodes of gout; treatment in this circumstance remains controversial.

Image source: Wikimedia Commons (2010). Gichtfuss im Roentgenbild 002, Licensed under a Creative Commons licence. Available for free at:  https://commons.wikimedia.org/wiki/File:Gichtfuss_im_Roentgenbild_002.png (Accessed: 19 January 2024).

Management of gout

The management can be divided into acute and chronic.

Acute treatment relies on supportive measures such as rest, ice and elevation combined with a short course of NSAIDs, colchicine (0.5 mg, 2-4 times a day) or corticosteroids, either oral (if multiple joints affected) or intra-articular (if a single joint is affected). In this circumstance, urate-lowering drugs such as allopurinol should be continued, although if this is the first presentation, their initiation should be delayed until the flare resolves. The anti-IL-1𝛃 drugs, such as anakinra, can be initiated in repeated and/or refractory gout or where other medications are contraindicated.

The chronic management involves urate-lowering drugs, such as allopurinol, aiming for a reduction in serum urate levels <360 µmol/L. Febuxostat is an alternative from the same family of drugs, used if allopurinol does not achieve the recommended urate levels, and Rasburicase can be used in frequent, severe gout not controlled by the previous medications mentioned. Care should be used in the initiation of uricosuric drugs such as probenecid in patients who suffer with nephrolithiasis. The modification of lifestyle factors is of vital importance; weight loss and dietary modification should be encouraged. The management of other conditions triggering attacks should also be optimised, and medications such as diuretics should be continued at the lowest effective dose.

Calcium pyrophosphate dihydrate deposition (CPPD) disease

Overview of CPPD disease

Previously known as pseudogout, as the historic name suggests, calcium pyrophosphate deposition disease is similar to gout in its pathophysiology, clinical presentation and management. The deposition of calcium pyrophosphate (CPP) crystals may be asymptomatic and inconsequential. If symptoms occur, they can vary from an acute, self-limiting synovitis in an unwell hospitalised patient, to a chronic process causing inflammation and chondrocalcification in locations such as the spinal column causing arthropathy. The varying severity of symptoms related to crystal deposition is very similar to hydroxyapatite deposition disease, though this predominantly affects the tendons, characteristically of the shoulder.

The incidence rises with advancing age, and if it occurs in those less than 50 years of age, then an underlying metabolic cause should be explored. It is associated with hyperparathyroidism, haemochromatosis and Wilson’s disease, as well as hypomagnesaemia and hypophosphataemia. An isolated flare can be triggered by acute illness, the post-surgery state (especially post-parathyroidectomy), in trauma and upon initiation of levothyroxine.

Signs and symptoms of CPPD disease

The signs and symptoms are as per that of gout; they are clinically impossible to differentiate without needle aspiration of the affected joint. That being said, as a general rule, the joints affected in CPPD disease are typically larger joints, such as the knees, whilst gout typically involves the smaller joints, such as the toes and fingers.

Investigation of CPPD disease

The diagnosis is typically suspected based on the history and examination. Much like gout, the diagnosis can usually be confirmed by needle aspiration of synovial fluid during a flare, showing positively birefringent rhomboid-shaped crystals on microscopy. X-rays and ultrasound may identify calcium deposits. As with gout, other differential diagnoses should be excluded.

Management of CPPD disease

Management of acute CPPD disease is similar in rationale to gout. Supportive measures can help, and the mainstay is with anti-inflammatory agents. Colchicine is also used as prophylaxis in chronic CPPD disease. The optimal management of any underlying metabolic conditions is vital. The anti-IL-1𝛃 drugs such as anakinra can be used in refractory acute flares, and DMARDs such as methotrexate and hydroxychloroquine in chronic resistant disease.

References

• Clunie, G, Wilkinson N, Nikiphorou E, Jadon D. Oxford Handbook of Rheumatology. Fourth Edition. Oxford: Oxford University Press; 2018
• Badlissi F. Gout [Internet]. BMJ Best Practice. BMJ Publishing Group; 2022 [Cited 2023 August 17]. Available from: https://bestpractice.bmj.com/topics/en-gb/13
• Rosenthal A. Calcium Pyrophosphate Deposition [Internet]. BMJ Best Practice. BMJ Publishing Group; 2019 [Cited 2023 August 17]. Available from: https://bestpractice.bmj.com/topics/en-gb/370