Risk-stratified monitoring for sulfasalazine toxicity: prognostic model development and validation.

BackgroundSulfasalazine induced cytopenia, nephrotoxicity, and hepatotoxicity is uncommon during long-term treatment. Some guidelines recommend three monthly monitoring blood-tests indefinitely while others recommend stopping monitoring after one year. To rationalise monitoring we developed and validated a prognostic model for clinically significant blood, liver, or kidney toxicity during established sulfasalazine treatment. DesignRetrospective cohort study. SettingUK primary-care. Data from Clinical Practice Research Datalink Gold and Aurum formed independent development and validation cohorts. ParticipantsAge [&ge;]18 years, new diagnosis of an inflammatory condition and sulfasalazine prescription. Study period01/01/2007 to 31/12/2019. OutcomeSulfasalazine discontinuation with abnormal monitoring blood-test result. Analysis: Patients were followed-up from six months after first primary-care prescription to the earliest of outcome, drug discontinuation, death, 5 years, or 31/12/2019.Penalised Cox regression was performed to develop the risk equation. Multiple imputation handled missing predictor data. Model performance was assessed in terms of calibration and discrimination. Results8,936 participants were included in the development cohort (473 events, 23,299 person-years) and 5,203 participants were included in the validation cohort (280 events, 12,867 person-years).Nine candidate predictors were included. The optimism adjusted R2D and Royston D statistic in the development data were 0.13 and 0.79 respectively. The calibration slope (95% confidence interval (CI)) and Royston D statistic (95% CI) in validation cohort was 1.19 (0.96-1.43) and 0.87 (0.67-1.07) respectively. ConclusionThis prognostic model for sulfasalazine toxicity utilises readily available data and should be used to risk-stratify blood-test monitoring during established sulfasalazine treatment.<colcnt=1> Evidence before this study?O_LIHepatic, haematological, and renal toxicity from sulfasalazine occurs uncommonly after the first-few months of treatment. Nevertheless, the manufacturers and some specialist societies e.g., the American College of Rheumatology recommend monitoring blood-tests at three monthly intervals during established treatment. Other guidelines e.g., from the British Society of Rheumatology recommend no monitoring after the first two years of treatment. C_LIO_LIIt is not known whether hepatic, haematological, and renal toxicities due to sulfasalazine can be predicted and monitoring be risk-stratified. C_LI Added value of this study?O_LIThis study developed a prognostic model that discriminated patients at varying risk of sulfasalazine toxicity during long-term treatment. It had excellent performance characteristics in an independent validation cohort. C_LIO_LIThe model performed well across age-groups, and in people with rheumatoid arthritis and other inflammatory conditions. C_LIO_LIAny cytopenia or liver enzyme elevation prior to start of follow-up, chronic kidney disease stage-3, diabetes, methotrexate prescription, leflunomide prescription, and age were strong predictors of sulfasalazine toxicity. C_LI Implications of all the available evidenceO_LIThis prognostic model utilises information that can be easily ascertained during clinical visits. It can be used to inform decisions on the interval between monitoring blood-tests. C_LIO_LIThe results of this study ought to be considered by national and international Rheumatology guideline writing groups to rationalise monitoring during long-term sulfasalazine treatment. C_LI