Title: The development of risk-stratified, cost-effective, and acceptable blood-test monitoring strategies for inflammatory conditions treated with commonly used immune suppressing drugs: a multi-method study using evidence synthesis, modelling and qualitative research
Funder: Department of Health and Social Care

Abstract: Medicines such as methotrexate that damp down the immune system are used to treat inflammatory conditions such as rheumatoid arthritis. However, these medicines can reduce the blood count and cause liver and kidney damage especially early on. In order to detect these changes early, people who start these treatments have blood tests every two to four weeks for the first few months. After this, blood test checks are done every three months. We have looked at previous studies and found that liver, kidney and blood side-effects are pretty rare after the first year of treatment. It is not clear if three-monthly blood tests are needed at all for people on long-term immune suppressing treatment. Many people with inflammatory conditions view indefinite three-monthly monitoring as cumbersome and think that it should be offered to people who have a medical need for such monitoring. Many doctors and nurses also agree with this viewpoint._x000D_ _x000D_ Our survey of prescriptions from 731 GP surgeries found that more than 750,000 adults are prescribed these drugs in the UK. These adults will require approximately 3 million monitoring tests each year. If these tests do not provide additional safety information for everyone, then not doing them would save patients and GPs a lot of hassle and could save the NHS £15 million per year._x000D_ _x000D_ We want to find out the best strategy to do blood tests in adults with common inflammatory conditions like rheumatoid arthritis, inflammatory bowel disease, psoriasis (with or without arthritis), ankylosing spondylitis and lupus, who are treated with common immune-suppressing drugs for more than 6 months. The study will be delivered in three parts. _x000D_ _x000D_ In part 1, we will review all published studies in a systematic way to find out what blood testing strategies have been used in the past, and how well they can detect side effects in the blood, kidney and liver. We will also try to find out what things increase the risk of these side effects in some people._x000D_ _x000D_ In part 2, we will use anonymized information from the treatment and monitoring of UK adults with common inflammatory conditions available from the Clinical Practice Research Datalink to develop a prediction score to pick out people who are at higher risk of blood, liver, and kidney problems when treated with different drugs long-term. We will calculate the benefits, possible harms and costs of monitoring people at differing risks of side-effects, using different frequencies of testing. This will help us to pick out the best monitoring strategies for patients that are also cost-effective for the NHS._x000D_ _x000D_ Finally in part 3, we will interview people with common inflammatory diseases prescribed immune suppressing medicines and health care professionals to explore their experience of what happens right now and what our study suggests might be a better approach. If the recommended cost-effective testing strategy from part 2 is not acceptable to them, then we will tweak it as there is no point in suggesting something that patients are uncomfortable with._x000D_ _x000D_ We will do everything to make sure that those who need to know and act on our results are informed. That includes presenting results at medical conferences, publishing them in medical journals, and by contacting Royal Colleges, specialist societies, the National Patient Safety Association, patient organisation and manufacturers. We will work closely with NICE and specialist societies to help them to consider changing their guideline.

Lay abstract: Background: The optimal monitoring strategy for adults with inflammatory conditions treated with long-term stable dose immune-suppressing drugs is not known. _x000D_ _x000D_ Question: What is the optimum strategy of blood testing after the first 6 month of immune-suppressing drug prescription?_x000D_ _x000D_ Objectives: [1] Investigate association between different strategies of testing and target-organ damage detection. [2] Identify prognostic factors associated with target-organ damage. [3] Develop a prediction model for target-organ damage conditional on the prognostic factors. [4] Evaluate cost-effectiveness of risk-stratified testing strategies. [5] Assess patients’ and clinicians’ views and experiences of current testing strategies, and the acceptability of recommended strategies._x000D_ _x000D_ Methods: The study will be delivered in 3 interlinked work packages (WPs) with patient and public input throughout._x000D_ _x000D_ WP 1 (Evidence synthesis): Delivers objectives 1-2. A conventional (Review 1) and prognostic (Review 2) systematic review will be performed adhering to the York CRD guidance and PROGRESS framework respectively. Cochrane Risk of Bias, ROBINS-I and QUIPS checklists will be used for quality assessment as appropriate. Data on patient characteristics, monitoring strategies, adverse events, drug discontinuations (Review 1); and prognostic factors for developing adverse events (Review 2) will be extracted. Evidence will be assessed using the GRADE and meta-analysed using random effects model if appropriate._x000D_ _x000D_ WP 2 (Prediction, health economic modelling): Delivers objectives 3-4. Routine healthcare data from Clinical Practice Research Datalink (CPRD) Gold and Aurum will be used to develop and validate a prognostic model. CPRD is an anonymized, longitudinal database of UK primary-care records established in 1987. It provides data on demographics, lifestyle factors, diagnoses, blood test results, and GP prescriptions. Data on prognostic factors identified in WP1 (Review 2) will be extracted from the CPRD and used to develop a risk-score using a penalized flexible parametric survival model. _x000D_ _x000D_ Risk thresholds to be used in the health economic models will be agreed using decision curve analysis and with patient and clinician involvement. After this, a mathematical model will be formed to compute cost-effectiveness of frequency of testing at different levels of risk. The model will be in line with the NICE reference case using a lifetime horizon and estimating a cost per QALY gained for alternative frequency of testing strategies. The uncertainty of results will be explored with confidence intervals, cost-effectiveness planes and cost-effectiveness acceptability curves._x000D_ _x000D_ WP 3 (Qualitative): Delivers objective 5. Patients and healthcare professionals will be recruited to explore their views on current and recommended monitoring strategies. Both purposive stratified and maximum variation sampling will be employed to include patients with different diseases, treatments, and at varying risk of adverse-events. Semi-structured interviews will be conducted using interview topic guide created with PPI input. Data will be transcribed verbatim, anonymised, and analysed using inductive thematic analysis._x000D_ _x000D_ Impact and dissemination: The findings will be disseminated to patients, healthcare professionals, commissioners, Royal colleges, specialty societies, and will change clinical practice through guideline change._x000D_ _x000D_ Timeline: WP1 months 1-12; WP2 months 7-17; WP3 months 6-24.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM