Background and rationale
Gout is the most common form of inflammatory arthritis worldwide, and its incidence appears to be increasing. Gout is particularly prevalent in Aotearoa/New Zealand. In 2019, 13.1% of Māori men, 22.9% of Pacific men and 7.4% of New Zealand European men and 4.3% of Māori women, 7.0% of Pacific women and 2.1% of New Zealand European women were estimated to be affected by gout.1 The primary biochemical abnormality in gout is an elevation in serum urate (hyperuricaemia). When supersaturation is reached, monosodium urate (MSU) crystals are formed and can deposit in joints and surrounding tissues. These MSU crystals trigger painful attacks of inflammatory arthritis within joints (gout flares). Inadequately treated gout leads to recurrent flares, formation of tophi (accumulation of MSU crystals in joints and soft tissues) and joint damage. Significant time off work, poor health-related quality of life and disability are common, also impacting families and friends.
Long-term urate-lowering therapy is key to the successful management of gout. Current international guidelines recommend the reduction of serum urate to <0.36 mmol/L for all people with gout.2 3 The basis for this recommendation is evidence that sustained reductions in urate below this target will lead to cessation of gout flares, regression of tophi and prevention of joint damage.
Allopurinol is the first-line urate-lowering therapy recommended by the American College of Rheumatology (ACR)3 and the European Alliance of Associations for Rheumatology (EULAR).2 It is inexpensive (<5 NZ cents/day for 300 mg tablets) and typically taken once daily. Both nationally and internationally, allopurinol accounts for more than 90% of all urate-lowering therapy.4 Allopurinol has a key role in gout management in Aotearoa/New Zealand where funding for newer, more expensive therapies is not currently available or is restricted to those experiencing allopurinol failure. However, there are important inequities in allopurinol use, with non-Māori, and non-Pacific peoples more likely to receive regular allopurinol prescriptions than Māori or Pacific peoples.1
Recent data from a community-based randomised controlled trial (RCT) in the UK comparing general practitioner care and intensive nurse-led care showed that nurse-led care resulted in significantly greater long-term adherence to allopurinol. Furthermore, more people achieved target serum urate (30% vs 95%, respectively) and had fewer gout flares (mean (SD) flares 0.94 (2.03) vs 0.33 (0.93)) at 2 years in the intensive nurse-led arm.5 On the basis of this, intensive nurse-led care is currently considered best practice. However, while such community-based interventions have reported improvements in the clinical trial setting, real-life clinical studies in primary healthcare settings have not been as successful. For example, a study examining the effects of a gout package of care delivered in a rural Aotearoa/New Zealand general practice showed significantly more serum urate testing, but allopurinol dose escalation failed to occur for many despite being above target urate.6 Thus, more effective and easier ways to optimise the use of allopurinol are required.
Current recommendations advocate for gradual dose escalation of allopurinol to achieve target urate to minimise the risk of the rare but potentially life-threatening allopurinol hypersensitivity syndrome (AHS).3 7 This dose escalation treat-to-target serum urate strategy with allopurinol has been criticised as difficult to implement8 9 for several reasons. First, there is a wide dose range for allopurinol (50–900 mg daily) with no one fixed dose, allowing target urate to be achieved in the majority. This was highlighted in our recent allopurinol dose escalation study, in which the mean (range) allopurinol dose in those who achieved target urate was 400 (100–900) mg/day.10 11 Second, the allopurinol dose escalation strategy is labour intensive, costly and time consuming for health providers and those with gout. It requires monthly blood tests for serum urate with any dose changes based on the result. This requires the person with gout to attend for the blood tests, the result to be reviewed and the appropriate allopurinol dose communicated back to the patient. Achieving target urate can take months of intensive medical input and time for the patient. Finally, the majority of gout is managed in primary care where such intensive intervention is challenging, resulting in many people not receiving optimal care.
Individualised allopurinol dosing models that accurately predict allopurinol dose could result in a more streamlined and cost-effective dose escalation strategy without the requirement for monthly blood tests. This is particularly relevant for Aotearoa/New Zealand, where barriers within the healthcare system (including inconvenience, cost of treatment, time off work) disproportionately affect working-age Māori men and Pacific men with gout, which contribute to inequitable outcomes.12 This clinical trial tests an easier patient-led strategy for introducing allopurinol, which primarily aims to reduce the burden of healthcare visits for patients and, by default, benefits the health system.
A number of variables that influence the dose of allopurinol required to achieve target urate have been identified. We have developed an allopurinol dosing model in the Aotearoa/New Zealand gout population13 14 and further refined this model to predict the dose of allopurinol required to reach target urate using the following readily available clinical variables: weight, baseline urate, renal function and ethnicity. This model has been developed to accurately predict the allopurinol dose required to achieve serum urate target (<0.36 mmol/L) in >80% of people with estimated glomerular filtration rate (eGFR)>30 mL/min/1.73 m2.15 Of note, in our previous allopurinol clinical trial, which employed the intensive treat-to-target approach, 80% achieved target urate.11 The doses predicted by the dosing model range from 200 to 700 mg daily.
This post was originally published on https://bmjopen.bmj.com