BACKGROUND:The immune system is implicated in Parkinson's disease aetiology and prognosis. Although there are effective symptomatic treatments for Parkinson's disease, there are currently no therapies that slow down disease progression. We aimed to investigate the clinical efficacy of the broadly acting peripheral immunosuppressant drug azathioprine for patients with early Parkinson's disease. METHODS:We did a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial at a single site (the Parkinson's Disease Research Clinic) in Cambridge, UK. Eligible participants were aged 50-80 years and were within 3 years of Parkinson's disease diagnosis (as per UK Parkinson's Disease Society Brain Bank Diagnostic Criteria). Participants were randomly assigned (1:1) using a web-based system to receive daily oral azathioprine 2 mg/kg or placebo for 12 months. The primary outcome was change from baseline Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) gait-axial score in the off-state at 12 months, assessed in the intention-to-treat population, which included all randomly assigned patients who completed the baseline visit. Safety was assessed in all participants who were screened for eligibility. Mixed model repeated measures analysis was used to assess treatment effects. This study was registered with ISRCTN, 14616801, and EudraCT, 2018-003089-14. FINDINGS:Between May 13, 2021, and July 28, 2022, 78 participants were screened, of whom 66 were randomly assigned to azathioprine (n=32) or placebo (n=34), and included in the intention-to-treat analysis. 23 (35%) of 66 patients were female and 43 (65%) were male. At 12 months, the mean change in MDS-UPDRS gait-axial score was 0·54 points (SD 2·43) in the azathioprine group and 0·13 points (2·09) in the placebo group (effect size 0·438 [95% CI -0·694 to 1·57]; p=0·78). 159 adverse events were reported in the azathioprine group and 156 in the placebo group. Eight participants had a serious adverse event in the azathioprine group (24%) and four patients in the placebo group (12%). The most common adverse events in both groups were infections (20 [61%] of 33 participants in the azathioprine group vs 26 [76%] of 34 participants in the placebo group) and gastrointestinal disorders (19 [58%] participants vs 17 [50%] participants). INTERPRETATION:Azathioprine was well-tolerated in this population; however, the primary outcome was not met. Exploratory analyses suggested effects of azathioprine on peripheral and central immune biomarkers and on motor symptoms. Potential clinical effects could be greater in females than males, warranting further exploration. FUNDING:Cambridge Centre for Parkinson-Plus, Cure Parkinson's, National Institute for Health Research Biomedical Research Centre.

BackgroundRituximab is effective for induction and maintenance of remission in relapsing ANCA-associated vasculitis (AAV), but some patients do not achieve complete remission or experience relapse despite treatment. We aimed to describe the frequency, characteristics, and outcomes of patients with suboptimal response to rituximab within the RITAZAREM trial.MethodsPost hoc descriptive analysis, including patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) treated with rituximab for induction (N = 188) and those receiving rituximab maintenance (N = 85). Three scenarios of suboptimal response were examined: (i) failure to achieve protocol-defined remission at month 4 (n = 6); (ii) incomplete remission at month 4, defined as BVAS/WG = 1 (n = 10); and (iii) relapse during rituximab maintenance (n = 13). Data were summarized descriptively. Time to relapse from month 4 in patients with BVAS/WG = 1 versus BVAS/WG = 0 was explored using Kaplan–Meier analysis.ResultsSix of 188 patients (3%) did not achieve protocol-defined remission by month 4, 10 (5%) had residual low-grade disease activity (BVAS/WG = 1), and 13 of 85 patients (15%) receiving rituximab maintenance relapsed within 24 months during maintenance treatment. All patients with BVAS/WG = 1 at month 4 had a history of PR3-ANCA positivity and ear/nose/throat (ENT) baseline manifestations. Relapse occurred more frequently in this subgroup than in patients with BVAS/WG = 0, and time-to-relapse analysis showed shorter relapse-free survival, although interpretation is limited by the small sample size. Most first relapses were minor, and some patients subsequently experienced additional relapses, including major relapses.ConclusionIn this exploratory and hypothesis-generating analysis, a small subset of patients with relapsing AAV showed suboptimal outcomes with rituximab. Residual disease activity at month 4, particularly in patients with PR3-ANCA positivity and ENT involvement, may represent a clinical subgroup associated with an increased frequency of earlier relapse, although this observation requires confirmation.

Abstract Background The PROFILE trial in patients with newly-diagnosed Crohn’s disease demonstrated that “top-down” therapy, with combination infliximab and immunomodulator from diagnosis, provided superior efficacy and a better safety profile over a one-year follow-up period compared to an “accelerated step-up” approach. The current study aims to evaluate cost-effectiveness by assessing the healthcare cost and health outcomes associated with starting anti-TNF medication as soon as possible after diagnosis. Methods A de novo Markov model was developed to model the cost-effectiveness of using a “top-down” compared to “accelerated step-up” strategy in adults newly-diagnosed with moderate and severe Crohn’s disease. The model structure included three possible mutually exclusive health states (active disease, inactive disease and death). Use of infliximab and adalimumab from diagnosis was modelled with biosimilar costs based on average real-world UK contract drug costs ascertained from 20 PROFILE trial sites in 2024. Parameters were informed by individual patient data from PROFILE and data from the published literature. Key model outcomes included healthcare costs (drug acquisition, drug administration, surgery, hospitalisation, disease management) and health outcomes (quality-adjusted life years gained [QALYs]) measured over a 5-year time horizon. Results The base case cost-effectiveness analysis indicates that a “top-down” strategy dominates over an “accelerated step-up” approach. Initiating infliximab from the point of diagnosis yields greater clinical benefits, with an incremental gain of 0.17 QALYs per patient over a 5-year period, and is less costly, saving £1034 per patient over the same time frame. Similar clinical benefits were obtained when modelling use of adalimumab treatment from diagnosis, with even greater cost savings, totalling £9412 per patient over 5 years. Sensitivity analysis further supports robustness of the “top-down” approach, showing it to be the most cost-effective option in 97.6% of model simulations, based on a commonly applied UK decision-maker willingness-to-pay threshold of £30000 per QALY. Conclusion This health economic analysis demonstrates that “top-down” treatment with anti-TNF therapy from diagnosis results in lower healthcare resource use compared to an “accelerated step-up” strategy. The economic benefits align with improved clinical outcomes, as early, effective treatment better controls inflammation. Patients experience longer periods in remission, fewer disease-related flares, and enhanced quality of life. In newly-diagnosed patients with moderate and severe Crohn’s disease, “top-down” treatment with anti-TNF therapy is more efficacious, safer and cost-efficient than an “accelerated step-up” treatment strategy. References Noor NM et al. A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn’s disease (PROFILE): a multicentre, open-label randomised controlled trial. Lancet Gastroenterol Hepatol. 2024 May;9(5):415-427.

BACKGROUND:The PROFILE trial demonstrated that "top-down" therapy in Crohn's disease, with combination infliximab and immunomodulator from diagnosis, had superior efficacy and safety over 1 year compared to conventional "accelerated step-up" management. The current study aimed to evaluate the cost-effectiveness of these alternative treatment strategies. METHODS:A Markov model was developed for the cost-effectiveness of "top-down" compared to "accelerated step-up" treatment. Parameters were informed by individual patient data from PROFILE and published data. Use of anti-tumor necrosis factor (TNF) therapy was modeled, using real-world contract drug costs from 18 PROFILE sites. Key model outcomes included healthcare costs (drug acquisition, drug administration, disease management, hospitalization, and surgery) and health outcomes [quality-adjusted life years (QALYs) gained] measured over a 5-year time horizon. RESULTS:The base-case cost-effectiveness analysis indicated that a "top-down" strategy dominated over an "accelerated step-up" approach. Initiating intravenous infliximab from diagnosis yielded an incremental gain of 0.17 QALYs per patient over a 5-year period, and was less costly, saving £1681 per patient over the same time frame. Similar clinical benefits were obtained when modeling for subcutaneous infliximab and adalimumab. The greatest cost savings were with adalimumab, totaling £10 059 per patient over 5 years. Sensitivity analyses supported robustness of the results, showing "top-down" to be the most cost-effective option in 98.7% of model simulations. CONCLUSIONS:"Top-down" treatment from diagnosis with anti-TNF results in lower healthcare resource use and better clinical outcomes in patients with Crohn's disease compared to an "accelerated step-up" strategy.

BACKGROUND:Evidence from randomised clinical trials (RCTs) of Janus kinase (JAK) inhibitors-compared with usual care or placebo-in adults treated in hospital for COVID-19 is conflicting. We aimed to evaluate the benefits and harms of JAK inhibitors compared with placebo or usual care and whether treatment effects differed between prespecified participant subgroups. METHODS:For this systematic review and individual participant data meta-analysis (IPDMA), we searched Medline via Ovid, Embase via Elsevier, the Cochrane Central Register of Controlled Trials, the Cochrane COVID-19 Study Register, and the COVID-19 L·OVE Platform, including backward and forward citation searching (last search Nov 28, 2024), for RCTs (unpublished or published in any format and any language) that randomly assigned adults (aged ≥16 years) admitted to a hospital due to COVID-19 to receive either a JAK inhibitor (any type) or no JAK inhibitor (ie, received site-specific standard of care with or without placebo), and requested individual participant data (IPD) from the original trial teams. The primary outcome was all-cause mortality at day 28 after random assignment. We used two-stage meta-analyses adjusting for age and respiratory support, and pooled estimates using random-effects models. The assessment of individual-level effect modifiers was based solely on within-trial information and continuous modifiers were investigated as both linear and non-linear interactions. We used the Instrument for Assessing the Credibility of Effect Modification Analyses to appraise the subgroup analyses and the Grading of Recommendations Assessment, Development, and Evaluation approach to adjudicate the certainty of evidence. Grade 3 or 4 adverse events and serious adverse events by day 28, and adverse events of special interest within 28 days, were assessed among secondary outcomes. This study was registered with PROSPERO (CRD42023431817). FINDINGS:We identified 16 eligible trials. IPD were obtained from 12 trials, corresponding to 12 902 adults admitted to hospital between May, 2020, and March, 2022. These trials represented 12 902 [96·1%] of 13 423 participants from all eligible trials worldwide. Seven trials evaluated baricitinib, three evaluated tofacitinib, and two evaluated ruxolitinib. Overall, 755 (11·7%) of 6465 participants in the JAK inhibitor group died by day 28 compared with 805 (13·2%) of 6108 participants in the no JAK inhibitor group (adjusted odds ratio [aOR] 0·67 [95% CI 0·55-0·82]; high-certainty evidence; 39 fewer per 1000 [95% CI 55 fewer to 21 fewer]). JAK inhibitors decreased the need for new mechanical ventilation or other respiratory support and allowed for faster discharge from hospital by about 1 day. We observed fewer grade 3 and 4 adverse events and serious adverse events in the JAK inhibitor group (14 fewer per 1000 [95% CI 24 fewer to 4 fewer]; moderate-certainty evidence). The rates of adverse events of special interest were similar across both groups. No credible subgroup effect on mortality at day 28 was found for ventilation status, type of JAK inhibitor, presence of comorbidities, timing of treatment initiation after symptom onset, C-reactive protein concentration, or concomitant use of dexamethasone or tocilizumab. We found a moderately credible effect modification by age, with younger participants showing larger relative treatment effects than older participants, but similar absolute treatment effects due to higher baseline risk for older participants. INTERPRETATION:This IPDMA of RCTs in adults admitted to hospital due to COVID-19 found that JAK inhibitors reduced mortality across all levels of respiratory support, independent of dexamethasone or tocilizumab, and probably decreased serious and severe adverse events compared with no JAK inhibitors. FUNDING:This project has received funding from the EU's Horizon 2020 research and innovation programme under grant agreement number 101015736.

Major adverse cardiovascular (CV) events (MACE) occur in a substantioal percentage of individuals following acute coronary syndromes (ACS), primarily driven by residual vascular inflammation. Anti-inflammatory drugs have improved CV outcomes but their use is limited by significant side-effects. Low-dose interleukin 2 (IL2) increases regulatory T (Treg) cells, which are powerful endogenous regulators of the immune response, and could provide a new, targeted anti-inflammatory strategy in high-risk ACS patients. In IVORY, we hypothesised that treatment with low-dose IL2 would reduce arterial inflammation measured by 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT), compared to placebo. In IVORY FINALE we hypothesised that low dose IL2 could reduce MACE compared to placebo at follow up (up to 5 years.) IVORY was a double-blind, placebo-controlled, Phase IIb trial randomising ACS patients with high-sensitivity CRP levels ≧ 2mg/L to receive either 1.5×10 6 IU IL2 or placebo (1:1). Dosing consisted of a daily induction (5 days) and a weekly maintenance phase (7 weeks). 18 F-FDG-PET/CT imaging of the ascending aorta and carotid arteries was performed before and after treatment. The primary outcome was the difference in the mean maximum target-to-background ratio (TBRmax) in the index vessel on follow-up imaging between the groups. 60 patients (IL2:placebo, n=31:29) completed the trial. Arterial inflammation in the index vessel was lower at the end of treatment in the IL2 group than in placebo (TBRmax = -0.171[-7.7%], 95% CI -0.308 to -0.034, p=0.015)[Fig1]. In more inflamed areas with a mean TBRmax ≧ 2 (active slices), the difference between the groups was greater (-0.185 [-8.3%], P=0.009, 95% CI -0.323 to -0.0478). Overall, the additive treatment effect of low-dose IL2 was greater at higher baseline inflammation [Fig 2]. Low-dose IL2 significantly increased circulating Tregs compared to placebo (p<0.001) [Fig 3]. There was no difference between the groups for changes in effector T cells. It was well-tolerated in ACS. At a median follow-up of 2.5 years, a trend towards lower MACE in the IL2 group (number of events [n]=0), compared to placebo (n= 7; 2 deaths, 2 non-fatal MIs, 3 unplanned revascularisations) was seen. In summary, in high-risk ACS, immunomodulation with low-dose IL2 produces a safe and significant reduction in arterial inflammation, compared to placebo. Larger trials are needed to confirm its impact on CV outcomes.

BACKGROUND:Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. METHODS:PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 μg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 μg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). FINDINGS:Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight). INTERPRETATION:Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. FUNDING:Wellcome and PredictImmune Ltd.

Background Healthcare system data (HSD) are increasingly used in clinical trials, augmenting or replacing traditional methods of collecting outcome data. This study, PRIMORANT, set out to identify, in the UK context, issues to be considered before the decision to use HSD for outcome data in a clinical trial is finalised, a methodological question prioritised by the clinical trials community. Methods The PRIMORANT study had three phases. First, an initial workshop was held to scope the issues faced by trialists when considering whether to use HSDs for trial outcomes. Second, a consultation exercise was undertaken with clinical trials unit (CTU) staff, trialists, methodologists, clinicians, funding panels and data providers. Third, a final discussion workshop was held, at which the results of the consultation were fed back, case studies presented, and issues considered in small breakout groups. Results Key topics included in the consultation process were the validity of outcome data, timeliness of data capture, internal pilots, data-sharing, practical issues, and decision-making. A majority of consultation respondents ( n = 78, 95%) considered the development of guidance for trialists to be feasible. Guidance was developed following the discussion workshop, for the five broad areas of terminology, feasibility, internal pilots, onward data sharing, and data archiving. Conclusions We provide guidance to inform decisions about whether or not to use HSDs for outcomes, and if so, to assist trialists in working with registries and other HSD providers to improve the design and delivery of trials.

Abstract Background Clinical outcomes differ substantially between patients with Crohn’s disease and there is variability in how newly-diagnosed patients are managed. Recent interest has focused on developing biomarkers to predict outcomes and guide therapy. PROFILE was designed to evaluate the clinical utility of a blood-based prognostic biomarker in patients randomised to "top-down" or "accelerated step-up" treatment strategies for newly-diagnosed Crohn’s disease. Methods PROFILE (PRedicting Outcomes For Crohn's dIsease using a moLecular biomarker, ISRCTN 11808228) was an open-label, biomarker-stratified, randomised controlled trial. It enrolled adults with newly-diagnosed active Crohn’s disease (Harvey Bradshaw Index ≥7 and C-reactive protein > upper limit of normal or faecal calprotectin ≥200 ug/g, plus endoscopic evidence of active inflammation) in 40 UK hospitals. Following biomarker testing patients were randomised to "top-down" (infliximab/immunomodulator) or "accelerated step-up" (conventional) treatment stratified by: biomarker subgroup (termed IBDhi/IBDlo), endoscopic inflammation (mild/mod/severe) and extent (colonic/other). The primary endpoint was sustained steroid and surgery-free remission to week 48. The key secondary endpoint was endoscopic remission (absence of ulcers). The full analysis population (equivalent to ‘intention-to-treat’) was analysed. Results 386 patients were randomised from 29 December 2017 to 5 January 2022. Median time from diagnosis to trial enrollment was 12 days (0-191). Primary outcome data were available for 379 eligible participants. Sustained steroid and surgery-free remission was significantly more frequent in "top-down" (79% of 189 patients) compared to the "accelerated step-up" arm (15% of 190 patients), with an absolute difference of 64% (95% CI=57-72%, p<0.001). There was no biomarker-treatment interaction effect (absolute difference 1%, 95% CI=-14 - +14%, p=0.944). Endoscopic remission at week 48 was greater in "top-down" vs "accelerated step-up" (67% vs 44%, 95% CI=11-36%, p<0.001), with no biomarker-treatment interaction. Incidence of adverse events (including disease flares) and serious adverse events was lower in "top-down" vs "accelerated step-up" (168 vs 315; 16 vs 25 respectively), with fewer complications requiring abdominal surgery (1 vs 10, odds ratio=0.095, 95% CI=0.001-0.505) and no increase in infections. Conclusion "Top-down" treatment with combination infliximab/immunomodulator achieved substantially higher sustained steroid and surgery-free remission compared to "accelerated step-up". The biomarker did not show clinical utility in PROFILE. "Top-down" should now be considered standard-of-care for patients with newly-diagnosed active Crohn’s disease.

INTRODUCTION:Relapses in ANCA-associated vasculitis (AAV) increase the incidence of end-organ damage and their prevention requires prolonged immunosuppressive therapy. Rituximab, a type I anti-CD20 B cell depleting monoclonal antibody, is the current standard of care for induction of disease remission. Rituximab is not always effective and is associated with a high subsequent relapse risk. Obinutuzumab is a type II anti-CD20 humanised monoclonal antibody with the potential to obtain greater tissue B cell depletion than rituximab and reduce relapse risk in AAV. METHODS AND ANALYSIS:ObiVas is a randomised, phase II, double-blind controlled trial that will compare the mechanistic effects of rituximab and obinutuzumab in the induction treatment of patients with AAV positive for proteinase 3 ANCA (PR3-ANCA). 26 patients, either newly diagnosed or relapsing, will be recruited from a single centre and randomised in a 1:1 ratio to receive 1000 mg rituximab or obinutuzumab as induction therapy on days 1 and 15, alongside a tapering glucocorticoid regimen. The primary end point is CD19+ B cell depletion in nasal-associated lymphoid tissue (NALT), assessed as change from baseline to week 26. Secondary outcomes will compare the safety and clinical efficacy of rituximab and obinutuzumab and their impact on immune biomarkers, including tissue and peripheral blood lymphocyte subsets and PR3-ANCA binding levels. Patients are followed through to week 78. The trial opened for recruitment in January 2023 and is forecasted to complete recruitment by the end of 2024. ETHICS AND DISSEMINATION:For all patients, informed written consent will be obtained in keeping with Good Clinical Practice. Trial results will be disseminated to the relevant scientific, clinical and patient communities on trial closure. NALT data analysis will start before trial completion. Other analyses will be reported after trial completion. This trial was given ethical approval by Edgbaston (West Midlands) Research Ethics Committee (approval reference 22/WM/0174). TRIAL REGISTRATION NUMBER:ISRCTN13069630.

Objectives:Rituximab is used for remission induction and the prevention of relapse in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). This study evaluated the incidence of safety events and compared time to first serious adverse event (SAE) between a rituximab cohort and a cohort treated with non-rituximab therapies in a real-life setting. Methods:Rituximab surveillance study in vasculitis was a retrospective observational study of patients with AAV who received rituximab (MabThera) or other treatments between 2003 and 2017 at a specialist vasculitis clinic. The primary endpoint was time to first SAE. Results:392 patients were enrolled: 247 in the rituximab and 145 in the control cohorts with a total follow up of 2217 person-years (mean study duration 5.7 years). Mean age was 61 years, 77% had granulomatosis with polyangiitis (GPA). There were differences in baseline characteristics (disease duration and prior immunosuppressive use) between groups. 134/247 patients (54%) in the rituximab and 58/145 (40%) of controls experienced at least one SAE. Time to first SAE was shorter in the rituximab group (hazard ratio (HR) 1.55, 95% CI 1.07-2.26, P = 0.022). Predictors of first SAE were higher vasculitis damage index and the presence of chronic pulmonary or kidney disease. The risk of serious infection was higher in the rituximab group (relative risk (RR) 2.12, 95% CI 1.31-3.43). Conclusion:Over 40% of patients with AAV experienced at least one SAE. Although shorter time to first SAE and higher risk of infection were observed in the rituximab group, baseline imbalances necessitate a careful interpretation of these results.