{
  "abstract": "Introduction Immune checkpoint inhibitors (ICIs) have revolutionised cancer treatment through targeted disruption of the physiological pathways that maintain tissue tolerance, but which are co-opted by cancers to evade immunosurveillance. Thus, the resultant T-cell activity often causes immune-related adverse events including immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA). ICI-IA results in functional impairment that frequently persists, even after ICI discontinuation, with substantial quality-of-life impacts for cancer survivors.A high-quality body of evidence to guide ICI-IA management remains an unmet need. Pharmacological treatment may be prolonged, typically begins with non-specific immunosuppression, including systemic steroids, and is usually only rationalised to more targeted therapy in resistant cases. Moreover, retrospective data suggest the high dose glucocorticoids sometimes used in new-onset ICI-IA may be associated with worse cancer outcomes.Tumour necrosis factor (TNF) inhibition strategies are well established with excellent efficacy and safety profiles in ‘spontaneous’ inflammatory arthritides including rheumatoid and psoriatic arthritis. Mechanistic evidence from ex vivo and murine studies also supports the utility of anti-TNF therapy for steroid-refractory cases of ICI-IA. Although good clinical responses have been reported in this setting, the REACT trial (REmission induction of Arthritis caused by Cancer ImmunoTherapy) aims to provide randomised and robust clinical evidence for deploying targeted therapy earlier in ICI-IA management. It will test whether up-front anti-TNF therapy can more effectively and quickly control symptoms, reduce glucocorticoid exposure, prevent early ICI discontinuation and increase the frequency of drug-free ICI-IA remission.Methods and analysis REACT is a prospective, multicentre, open-label, superiority, two-arm, randomised controlled clinical trial to guide initial therapy for patients with ICI-IA. The trial will compare the current standard of care (initial prednisolone; Arm A) with the anti-TNF drug, adalimumab without glucocorticoids (Arm B).The primary outcome is glucocorticoid-free arthritis remission rate at 24 weeks where remission is defined as: (i) No use of systemic or intra-articular glucocorticoids (except when used for adrenal insufficiency) within 4 weeks prior to assessment at 24 weeks; and (ii) absence of synovitis on clinical examination.Ethics and dissemination The protocol was approved by East Midlands—Leicester South Research Ethics Committee on 31-Oct-2024 (Ref: 24/EM/0202). Participants are required to provide written informed consent. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications.Trial registration number ISRCTN18217497.",
  "authors": [
    {
      "affiliations": [
        "School of Infection, Inflammation and Immunology, University of Birmingham, Birmingham, UK",
        "Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK",
        "NIHR Birmingham Biomedical Research Centre, Birmingham, UK"
      ],
      "name": "Benjamin A Fisher"
    },
    {
      "affiliations": [
        "Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK",
        "NIHR Birmingham Biomedical Research Centre, Birmingham, UK"
      ],
      "name": "Anna Rowe"
    },
    {
      "affiliations": [
        "Patient partner, Birmingham, UK"
      ],
      "name": "Chris Hodson"
    },
    {
      "affiliations": [
        "Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK"
      ],
      "name": "Manpreet Wilkhu"
    },
    {
      "affiliations": [
        "Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK"
      ],
      "name": "Emily Williams"
    },
    {
      "affiliations": [
        "Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK"
      ],
      "name": "Elliot Turner"
    },
    {
      "affiliations": [
        "Royal National Hospital for Rheumatic Diseases, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK"
      ],
      "name": "Andrew Allard"
    },
    {
      "affiliations": [
        "Rheumatology Department, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK"
      ],
      "name": "Tim Blake"
    },
    {
      "affiliations": [
        "Centre for Experimental Medicine and Rheumatology, Queen Mary University of London, London, UK"
      ],
      "name": "Michele Bombardieri"
    },
    {
      "affiliations": [
        "Centre for Rheumatic Diseases, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK"
      ],
      "name": "Andrew P Cope"
    },
    {
      "affiliations": [
        "Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK",
        "Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK"
      ],
      "name": "Shirish Dubey"
    },
    {
      "affiliations": [
        "Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK",
        "NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK"
      ],
      "name": "Kulveer Mankia"
    },
    {
      "affiliations": [
        "Rheumatology Department, Royal Free Hospital, London, UK"
      ],
      "name": "Tamir Malley"
    },
    {
      "affiliations": [
        "Department of Rheumatology, Derriford Hospital, University Hospitals Plymouth NHS Trust, Plymouth, UK"
      ],
      "name": "Owen Moore"
    },
    {
      "affiliations": [
        "Oxford Cancer Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK"
      ],
      "name": "Miranda Payne"
    },
    {
      "affiliations": [
        "Sir Bobby Robson Cancer Trials Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK",
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Ruth Plummer"
    },
    {
      "affiliations": [
        "Oncology Department, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK"
      ],
      "name": "Michael Tilby"
    },
    {
      "affiliations": [
        "Oncology Department, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK"
      ],
      "name": "Tania Tillett"
    },
    {
      "affiliations": [
        "Rheumatology Department, Queen Alexandra Hospital, Portsmouth University Hospital NHS Trust, Portsmouth, UK"
      ],
      "name": "Ernest Wong"
    },
    {
      "affiliations": [
        "Centre for Inflammation Biology and Cancer Immunology, King’s College London, London, UK",
        "Department of Medical Oncology, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, UK"
      ],
      "name": "Yin Wu"
    },
    {
      "affiliations": [
        "School of Infection, Inflammation and Immunology, University of Birmingham, Birmingham, UK",
        "NIHR Birmingham Biomedical Research Centre, Birmingham, UK"
      ],
      "name": "Andrew Filer"
    },
    {
      "affiliations": [
        "Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK",
        "Musculoskeletal Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK",
        "NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK"
      ],
      "name": "Arthur Pratt"
    },
    {
      "affiliations": [
        "Department of Oncology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"
      ],
      "name": "Lalit Pallan"
    },
    {
      "affiliations": [
        "Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK",
        "NIHR Birmingham Biomedical Research Centre, Birmingham, UK"
      ],
      "name": "Victoria Homer"
    }
  ],
  "title": "Pragmatic, open-label, multicentre, randomised controlled trial to guide initial therapy for immune checkpoint inhibitor-induced inflammatory arthritis comparing standard of care (prednisolone) to adalimumab without glucocorticoids: REACT trial protocol",
  "uid": "af5aea1b-1662-507b-9824-b9e4910ea683"
}