Authors' objectives: The optimal monitoring strategy for adults with inflammatory conditions established on immune-suppressing treatment is unknown. To ascertain the optimum strategy of monitoring blood tests for patients established on immune-suppressing drugs. The objectives were to: investigate the association between different strategies of monitoring and detection of pre-specified haematological, hepatic or renal side effects identify prognostic factors associated with pre-specified haematological, hepatic or renal side effects develop prediction models for pre-specified haematological, hepatic or renal side effects evaluate cost-effectiveness of testing strategies, and explore patients’ and clinicians’ experiences of current testing strategies, and acceptability of recommended strategies. The purpose of this study was to ascertain the optimum strategy of monitoring blood tests for patients established on immune-suppressing drugs. The specific objectives were to: investigate the association between different strategies of monitoring and detection of pre-specified hepatic, renal and haematological adverse reactions identify prognostic factors associated with pre-specified hepatic, renal and haematological adverse reactions develop a prediction model for pre-specified hepatic, renal and haematological adverse reactions evaluate cost-effectiveness of alternate testing strategies, and assess patients’ and clinicians’ views and experiences of current testing strategies, and the acceptability of recommended strategies.

Authors' results and conclusions: There were differences in testing strategies used, outcome definitions and follow-up precluding evidence synthesis. However, clinically significant pre-specified side effects were found to be uncommon or very uncommon during long-term treatment. There was high-quality evidence for elevated liver enzymes and folate non-supplementation being prognostic for methotrexate hepatotoxicity, mercaptopurine being prognostic for thiopurine hepatotoxicity and myelotoxicity; poor thiopurine metabolizer being prognostic for cytopenia; and elevated liver enzymes being prognostic for hepatotoxicity due to anti-tumour necrosis factor-alpha. Five prediction models were developed and validated. They had excellent performance characteristics. The calibration slope (95% confidence interval) in validation cohort was 0.94 (0.85 to 1.02) for methotrexate, 1.10 (0.84 to 1.36) for thiopurines, 0.91 (0.74 to 1.07) for leflunomide, 1.19 (0.96 to 1.43) for sulfasalazine, and 0.90 (0.61 to 1.19) for 5-aminosalicylates. Prediction modelling could not be undertaken for anti-tumour necrosis factor-alpha and mycophenolate due to few outcomes. Health economic modelling found it was cost-effective to increase the interval between monitoring blood tests except in very high-risk scenarios for some drugs (e.g. biennial testing in leflunomide). Eighteen patients from a range of risk profiles, and 13 health professionals were interviewed remotely. They found it acceptable to increase the interval between monitoring blood tests from 3-monthly to 6-monthly or annually depending on their risk profiles. Clinically significant myelotoxicity, hepatotoxicity and nephrotoxicity are uncommon during long-term immune-suppressing drug treatment and were predicted using readily available information. Extending the intervals between monitoring blood tests was more cost-effective than the current practice. It was acceptable to patients and health professionals to increase the interval between monitoring blood tests. Work package 1 Review 1 included 166 studies. These were of varying follow-up, utilised varying monitoring strategies, and reported outcomes using very different threshold abnormalities. Overall, the incidence of minor abnormalities was high but reduced dramatically when only clinically significant outcomes were considered. Review 2 included 56 studies published from 1995 to January 2023. Most of these were designed as retrospective cohort studies. The most consistent finding was that, across drug types, baseline elevated liver enzymes were associated with increased risk of subsequent hepatotoxicity after adjusting for many other prognostic factors. The largest quantity of evidence related to prognostic factors associated with an increased risk of hepatotoxicity, with much of this from low- or moderate-quality evidence. The main reasons for downgrading evidence were single study, imprecision and inconsistency. Factors shown to increase risk included body mass index, age, comorbidities and the specific drug prescribed or use of concomitant drugs. These findings varied by drug type (anti-TNF-alpha, methotrexate or thiopurines). Conversely, there was strong evidence that supplementation of folates reduced risk in patients prescribed methotrexate. Several factors were shown to predict an increased risk of cytopenia. These included previous neutropenia, comorbidities and poor metaboliser based on thiopurine methyl transferase/nucleoside diphosphate-linked moiety X-type motif genotype +/− intermediate or low enzyme activity. Little evidence was identified for prognostic factors for nephrotoxicity, and the quality was low, but included concomitant use of non-steroidal anti-inflammatory drugs and methotrexate. Identifying patients at the earliest opportunity who are at increased risk due to these factors could potentially help to reduce the means that they may avoid risk of AEs and ensure benefit from appropriate adjustments to treatment are being made. Clinically significant side effects affecting the blood, kidney and liver organ systems were uncommon. It was possible to predict them using readily available information and increasing the interval between monitoring blood tests was acceptable to patients and HCPs. Further research is needed to undertake knowledge mobilisation to change practice. Model may need to be validated in non-UK populations.

Authors' methods: The study undertook systematic review, prognostic modelling, health economic modelling of alternate monitoring intervals, and qualitative study. Primary and secondary care. Data from the UK’s Clinical Practice Research Datalink and British Association of Dermatologists Biologics Register were used for prediction modelling. Patients with inflammatory conditions treated with immune-suppressing drugs and health professionals were interviewed. It was not possible to synthesise the association between different strategies of testing and detection of pre-specified side effects. A meta-analysis of prognostic factors was not possible. The study was delivered in three work packages (WPs). Work package 1 (objectives 1 and 2) Review 1, addressed objective 1, was a conventional systematic review of adverse events (AEs) and was conducted in accordance with York Centre for Reviews and Dissemination guidance (CRD42020208042). Review 2, addressed objective 2, was a systematic review of prognostic factor studies, and was conducted in accordance with PROGnosis RESearch Strategy (PROGRESS) framework and Cochrane prognosis methods group guidance (CRD42020208049). Studies published after the year 1995, with ≥ 200 participants that included patients ≥ 18 years old and diagnosed with either rheumatoid arthritis (RA), inflammatory bowel disease, psoriasis +/− arthritis, ankylosing spondylitis (AS), systemic lupus erythematosus, or reactive arthritis and newly treated with one or more of methotrexate; anti-tumour necrosis factor-alpha (anti-TNF-α) agents, leflunomide, mycophenolate, thiopurines (azathioprine, mercaptopurine), 5-aminosalicylate (5-ASA) and sulfasalazine for ≥ 3 months were included. Randomised controlled trial (RCT), controlled clinical trials, cohort studies were included in both reviews. In addition, case-control studies were also included in review 2. The outcomes were frequency of blood testing, blood tests included, AEs, drug withdrawal or interruption due to specific AEs in review 1. In review 2, outcomes were AEs. Any patient factors, comorbidities, index condition or concomitant treatments were exposures of interest. Comparators were their absence of or the lowest category.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/NIHR130580

Year Published: 2026

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/PLRF8845

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/PLRF8845

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk