Gout and Hyperuricaemia 53 Gout and Hyperuricaemia

Definition Gout is the most common inflammatory joint disease in men and the most common inflammatory arthritis in older women. It is caused by deposition of monosodium urate crystals in joints and soft tissues following chronic hyperuricaemia. Chronic hyperuricaemia is associated with disorders of purine metabolism due to under excretion or over production of uric acid, the final metabolite of endogenous and dietary purine metabolism.

Etiology The production of urate is dependent on the balance between purine synthesis and the ingestion of dietary purines, and the elimination of urate by the kidney (66%) and intestine (33%). Gout can be classified as primary or secondary depending on the presence or absence of an identified cause of hyperuricaemia.

causes of primary gout Genetic Hypoxanthine-guanine-phosphoribosyl transferase (HGPRT) deficiency. Phosphoribosyl- pyrophosphate synthase over activity.

Causes of secondary gout - Increased uric acid production lymphoproliferative/ myeloproliferative Chronic haemolytic anaemias Secondary polycythemia Sever exfoliative psoriasis Gauchers disease Cytotoxic drugs Glucose 6 phosphate deficiency High purine diet

- Reduced uric acid secretion Renal failure Hypertension Drugs ( diuretics, aspirin, ciclosporin) Lead nephropathy Alcohol Down s syndrome Myxoedema

Presentation and diagnosis An acute attack of gout has a rapid onset and spontaneously resolving within several days or weeks. The first attack usually affects a single joint in the lower limbs in 85–90% of cases, most commonly the first metatarsophalangeal joint (big toe). The next most frequent joints to be affected are the ankles, knees and arms. The affected joint is hot, red and swollen with shiny overlying skin. Even the touch of a sheet on the affected joint is too painful. The patient may also have a fever, leucocytosis, raised erythrocyte sedimentation rate (ESR).

Inappropriate management of gout can result in chronic tophaceous gout with polyarticular, destructive low-grade joint inflammation, joint deformity and tophi. A third of patients will have normal uric acid concentrations during an acute attack of gout due to increased urinary urate excretion. The most appropriate time to measure serum urate for monitoring purposes is when the attack has completely resolved. The gold standard for the diagnosis of gout is the Synovial Fluid Analysis.

Treatment Non-pharmacological treatment Weight reduction Changes in diet Reduced alcohol consumption

pharmacological treatment Treatment aims in gout Rapid alleviation of the acute attack Prevention of future attacks Lower serum uric acid levels Reduce risk of co-morbidities, for example, cardiovascular disease. Lifestyle modification

Treatment of gout is not only directed at alleviating acute attacks and preventing future attacks, but also identifying and treating other co-morbid conditions such as hypertension and hyperlipidaemia.

Treatment of an acute attack First line: NSAID (use maximum dose) Second line: Colchicine Third line: Corticosteroid (consider first line in mono-articular disease)

Where the pain is not adequately controlled by treatment, paracetamol and weak opiate analgesics, for example, codeine or dihydrocodeine may be added to the regimen to provide additional relief. Treatment should be continued until the attack is terminated, usually between 1 and 2 weeks. The affected joints should also be rested for 1–2 days and initially treated with ice which has a significant analgesic effect during an acute attack.

Non-steroidal anti-inflammatory drugs Maximum doses of an NSAID should be started rapidly after the onset of an attack and then tapered 24 h after the complete resolution of symptoms. The usual treatment period is 1–2 weeks.

Colchicine Colchicine has a slower onset of action than NSAIDs but is recommended in patients where NSAIDs are contraindicated. Common side effects associated with colchicine are abdominal cramps, nausea, vomiting, and rarely bone marrow suppression, neuropathy and myopathy. Side effects are more common in patients with hepatic or renal impairment. The dose of colchicine should be reduced in mild to moderate renal impairment.

Corticosteroids Corticosteroids are usually considered where use of an NSAID or colchicine is contraindicated or in refractory cases. They may be given orally, intravenously, intramuscularly or direct into a joint (intra-articular) when only one or two joints are affected. In patients with a monoarthritis, an intra-articular corticosteroid injection is highly effective in treating an attack.

Interleukin-1 inhibitors Anakinra, an IL-1 receptor antagonist, has been shown to reduce the pain of gout and bring about complete resolution by day 3 in the majority of patients after a course of three 100-mg subcutaneous injection.

Management of chronic gout Criteria for starting prophylactic therapy for gout One or more acute attacks within 12 months of the first attack Tophi present at the first presentation of an acute attack Presence of uric acid stones Need to continue medication associated with raised uric acid levels, for example diuretics Young patients with a family history of renal or cardiac disease

The aim of prophylactic gout treatment is to maintain the serum urate level below the saturation point of monosodium urate (300 μmol/L). Prophylactic treatment should not be initiated until an acute attack of gout has completely resolved, usually 2-3 weeks after symptom resolution.

Uricostatic agents Allopurinol Allopurinol is the prophylactic agent of choice in the management of recurrent gout. In order to become pharmacologically active, allopurinol must be metabolised by the liver to oxypurinol. Oxypurinol has a much longer half-life than allopurinol, 14–16 h compared to 2 h. Both allopurinol and oxypurinol are renally excreted. In patients with reduced renal function, the half-life of oxypurinol is increased with the risk of accumulation and toxicity. It is, therefore, essential that a patient's renal function is checked prior to the prescribing of allopurinol and the dose adjusted accordingly.

Adverse effects reported with allopurinol therapy include rash, fever, worsening renal failure, hepatotoxicity, vasculitis and even death. The risk of toxicity increases with renal impairment.

Febuxostat It is recommended as a second line agent in patients who are intolerant of allopurinol or for whom allopurinol is contraindicated. Febuxostat should not be given to patients with ischaemic heart disease or congestive heart failure because of cardiovascular side effects. The most common adverse effects include respiratory infection, diarrhoea, headache and liver function abnormalities. It is recommended liver function should be tested in all patients prior to the initiation of therapy.

Uricosuric agents They are indicated as second-line agents in those who are urate under-excreters and are dependent on the patient having an adequate level of renal function. These agents should be avoided in patients with urate nephropathy or those who are over producers of uric acid due to the high risk of developing renal stones. Patients receiving a uricosuric agent are required to maintain an adequate fluid intake.

Benzbromarone It is indicated where there is a contraindication to other agents used in the management of gout such as allopurinol and febuxostat. It remains active in mild to moderate renal impairment. its use was associated with hepatoxicity , regular liver function tests must be monitored.

Sulphinpyrazone. The use of sulphinpyrazone is reserved for use in patients with adequate renal function who are underexcretors of uric acid and intolerant or resistant to treatment with allopurinol. Sulphinpyrazone inhibits prostaglandin synthesis resulting in a similar adverse effect profile to NSAIDs, for example gastro-intestinal ulceration, acute renal failure, fluid retention, elevated liver enzymes and blood disorders.

Probenecid Probenecid monotherapy is less effective than the other agents in this group and generally not recommended. It may have a role as an add-on agent when allopurinol alones insufficient . As with sulphinpyrazone, it is ineffective in renal impairment.

Uricolytics Uricolytics are indicated for hyperuricaemia associated with tumour lysis syndrome and are not indicated for other forms of hyperuricaemia. Rasburicase Rasburicase has long half-life of approximately 19 h. No dosage adjustment is required in patients with renal or hepatic impairment. Adverse effects of Rasburicase include fever, nausea, vomiting, rash, diarrhoea, headache, llergic reactions and the development of auto-antibodies. Polyethylene glycol-uricase (PEG-uricase). Pegylation of the molecule reduces the risk of patients developing auto- antibodies and lengthens the half-life of the drug.

Preventing gout flare When prophylactic treatment is started, there is a risk of precipitating an acute gout attack, or ‘mobilisation flare’, for approximately 12 months. Colchicine NSAIDs