Post-marketing surveillance of high-dose methotrexate (&gt;8 mg/week) in Japanese patients with rheumatoid arthritis: A post hoc sub-analysis of patients according to duration of prior methotrexate use

Suzuki, Yasuo; Hirose, Tomohiro; Sugiyama, Nobuo; Nomura, K.; Campos-Alberto, Eduardo

doi:10.1080/14397595.2020.1823604

Cited by 3 publications

(1 citation statement)

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“…Abnormal blood-test results during the first six-months of therapy were strong independent predictors of discontinuing sulfasalazine with abnormal monitoring blood-test results, like findings for methotrexate and leflunomide 24 42 . Elevated liver enzymes and cytopenia before starting treatment have previously been associated with abnormal blood-test results in patients treated with methotrexate and biologics respectively [43][44][45][46][47][48][49] .…”

Section: Discussionmentioning

confidence: 99%

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

Abhishek,

Grainge,

Card

et al. 2023

Preprint

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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 ≥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 R2Dand 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?Hepatic, 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.It is not known whether hepatic, haematological, and renal toxicities due to sulfasalazine can be predicted and monitoring be risk-stratified.Added value of this study?This 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.The model performed well across age-groups, and in people with rheumatoid arthritis and other inflammatory conditions.Any 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.Implications of all the available evidenceThis 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.The results of this study ought to be considered by national and international Rheumatology guideline writing groups to rationalise monitoring during long-term sulfasalazine treatment.

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Section: Discussionmentioning

confidence: 99%

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

Abhishek,

Grainge,

Card

et al. 2023

Preprint

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Prognostic factors for liver, blood and kidney adverse events from glucocorticoid sparing immune-suppressing drugs in immune-mediated inflammatory diseases: a prognostic systematic review

Leaviss,

Carroll,

Essat

et al. 2024

RMD Open

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BackgroundImmune-suppressing drugs can cause liver, kidney or blood toxicity. Prognostic factors for these adverse-events are poorly understood.PurposeTo ascertain prognostic factors associated with liver, blood or kidney adverse-events in people receiving immune-suppressing drugs.Data sourcesMEDLINE, Web of Science, EMBASE and the Cochrane library (01 January 1995 to 05 January 2023), and supplementary sources.Data extraction and synthesisData were extracted by one reviewer using a modified CHARMS-PF checklist and validated by another. Two independent reviewers assessed risk of bias using Quality in Prognostic factor Studies tool and assessed the quality of evidence using a Grading of Recommendations Assessment, Development and Evaluation-informed framework.ResultsFifty-six studies from 58 papers were included. High-quality evidence of the following associations was identified: elevated liver enzymes (6 studies) and folate non-supplementation (3 studies) are prognostic factors for hepatotoxicity in those treated with methotrexate; that mercaptopurine (vs azathioprine) (3 studies) was a prognostic factor for hepatotoxicity in those treated with thiopurines; that mercaptopurine (vs azathioprine) (3 studies) and poor-metaboliser status (4 studies) were prognostic factors for cytopenia in those treated with thiopurines; and that baseline elevated liver enzymes (3 studies) are a prognostic factor for hepatotoxicity in those treated with anti-tumour necrosis factors. Moderate and low quality evidence for several other demographic, lifestyle, comorbidities, baseline bloods/serologic or treatment-related prognostic factors were also identified.LimitationsStudies published before 1995, those with less than 200 participants and not published in English were excluded. Heterogeneity between studies included different cut-offs for prognostic factors, use of different outcome definitions and different adjustment factors.ConclusionsPrognostic factors for target-organ damage were identified which may be further investigated for their potential role in targeted (risk-stratified) monitoring.PROSPERO registration numberCRD42020208049.

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

Abhishek,

Grainge,

Card

et al. 2024

RMD Open

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BackgroundSulfasalazine-induced cytopenia, nephrotoxicity and hepatotoxicity is uncommon during long-term treatment. Some guidelines recommend 3 monthly monitoring blood tests indefinitely during long-term treatment while others recommend stopping monitoring after 1 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 ≥18 years, new diagnosis of an inflammatory condition and sulfasalazine prescription.Study period1 January 2007 to 31 December 2019.OutcomeSulfasalazine discontinuation with abnormal monitoring blood-test result.AnalysisPatients were followed up from 6 months after first primary care prescription to the earliest of outcome, drug discontinuation, death, 5 years or 31 December 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.Results8936 participants were included in the development cohort (473 events, 23 299 person-years) and 5203 participants were included in the validation cohort (280 events, 12 867 person-years). Nine candidate predictors were included. The optimism adjusted R2Dand Royston D statistic in the development data were 0.13 and 0.79, respectively. The calibration slope (95% CI) and Royston D statistic (95% CI) in validation cohort was 1.19 (0.96 to 1.43) and 0.87 (0.67 to 1.07), respectively.ConclusionThis prognostic model for sulfasalazine toxicity uses readily available data and should be used to risk-stratify blood-test monitoring during established sulfasalazine treatment.

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Post-marketing surveillance of high-dose methotrexate (>8 mg/week) in Japanese patients with rheumatoid arthritis: A post hoc sub-analysis of patients according to duration of prior methotrexate use

Abstract: Campos-Alberto (2021): Post-marketing surveillance of high-dose methotrexate (>8 mg/week) in Japanese patients with rheumatoid arthritis: A post hoc sub-analysis of patients according to duration of prior methotrexate use, Modern Rheumatology,

Cited by 3 publications

References 17 publications

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

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

Prognostic factors for liver, blood and kidney adverse events from glucocorticoid sparing immune-suppressing drugs in immune-mediated inflammatory diseases: a prognostic systematic review

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

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