Arthur G. Pratt

Background: Rheumatoid arthritis is a chronic disease of immune dysregulation affecting 1% of United Kingdom adults at an estimated cost to the taxpayer exceeding £5B per annum. Recently, enhanced pathophysiological understanding and a growing array of rational therapeutic candidates have converged on the potential to intercept rheumatoid arthritis before clinically manifest arthritis occurs, raising the possibility of delaying or even preventing disease. The National Institute for Health and Care Research Efficacy and Mechanism Evaluation Acceleration Award provided 12-month support to accelerate the development of an international precision medicine platform study, within remit of the Medical Research Council-National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme. To this end, Rheumatoid Arthritis Prevention: catalysing PlatfORm Trial proposed a pan-European precision medicine platform trial for preventative interventions in people at risk of rheumatoid arthritis. Challenges of delivering a trial of this nature led by a United Kingdom Sponsor, as well as those specific to the delivery of Rheumatoid Arthritis Prevention: catalysing PlatfORm Trial, were addressed. Objectives: The overarching aim of Rheumatoid Arthritis Prevention: catalysing PlatfORm Trial was to submit a stage 1 application for the Efficacy and Mechanism Evaluation call: 23/15 precision medicine platform studies to efficiently evaluate the efficacy of interventions. In delivering this, we met the following objectives: Understand optimal sponsorship, governance and funding models for international platform trials by synthesising relevant literature in the form of systematic review. Convene and engage an international at risk of rheumatoid arthritis Precision Platform Trial Management Group with expertise in the pathobiological understanding and therapeutic management of at risk of rheumatoid arthritis, as well as the design and delivery of interception trials, with a view to developing a master protocol. Convene and consult a Rheumatoid Arthritis Prevention: catalysing PlatfORm Trial Public Advisory Group to directly inform trial design, including a strategy for mapping the level of rheumatoid arthritis progression risk to lifestyle and/or pharmacological interventions. Identify interventions to be evaluated in a platform trial, engaging appropriately with industry partners. Identify optimal clinical and/or immunological biomarkers for participant stratification. Outcomes: Five work streams were set up to target delivery of the aforementioned objectives. A systematic review entitled ‘Operational complexities in international clinical trials: a systematic review of challenges and proposed solutions’ has been registered with the Open Science Framework, completed and submitted for publication. Linked to this, a working group was established to identify barriers and solutions to acting as Sponsor for Rheumatoid Arthritis Prevention: catalysing PlatfORm Trial; purposeful interactions with European Union and United Kingdom partner sites helped prioritise governance and funding models to enable delivery, and have informed local standard operating procedures for sponsoring international trials. A patient and public involvement Advisory group was formed, and a series of events and programme of work undertaken to feed into all aspects of Rheumatoid Arthritis Prevention: catalysing PlatfORm Trial. A range of potential interventions, non-pharmacological and pharmacological, were considered and prioritised for inclusion in Rheumatoid Arthritis Prevention: catalysing PlatfORm Trial’s design. A funding framework supported by industry partners, incorporating one lifestyle and two drug interventions, was developed, along with a strategy for prioritising future interventions. A working group was furthermore convened for the management of biological samples to be collected for research in biomarker evaluations. A stage 1 application for the 23/15 Efficacy and Mechanism Evaluation call was submitted in May 2023. Limitations: In its first iteration, the substantive clinical trial proposal proposed as a result of the Accelerator award reported herein was not funded by National Institute for Health and Care Research. In part this was due to the approach adopted to address the ‘precision medicine’ element of the brief. Other challenges include the assembly of geographically diverse patient partners for an international study given time constraints, and logistical complexity in international trial design. Future work: Efforts to fund the work described in amended form are ongoing. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme as award number NIHR153955.

Objective: Endogenous retroelements (EREs) stimulate type 1 interferon (IFN‐I) production but have not been explored as potential interferonogenic triggers in rheumatoid arthritis (RA). We investigated ERE expression in early RA (eRA), a period in which IFN‐I levels are increased.Methods: ERE expression (long terminal repeat [LTR] 5, long interspersed nuclear element 1 [LINE‐1], and short interspersed nuclear element [SINE]) in disease‐modifying treatment‐naïve eRA whole‐blood and bulk synovial tissue samples was examined by reverse transcription–polymerase chain reaction and NanoString alongside IFN‐α activity. Circulating lymphocyte subsets, including B cell subsets, from patients with eRA and early psoriatic arthritis (ePsA) were flow cytometrically sorted and similarly examined. Existing established RA and osteoarthritis (OA) synovial single‐cell sequencing data were reinterrogated to identify repeat elements, and associations were explored.Results: There was significant coexpression of all ERE classes and IFNA in eRA synovial tissue samples (n = 22, P < 0.0001) and significant positive associations between whole‐blood LINE‐1 expression (n = 56) and circulating IFN‐α protein (P = 0.018) and anti–cyclic citrullinated peptide (anti‐CCP) titers (P < 0.0001). ERE expression was highest in circulating eRA B cells, particularly naïve B cells compared with ePsA, with possible ERE regulation by SAM and HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase 1 transcription (SAMDH1) implicated and associations with IFNA again observed. Finally, in established RA synovium, LTRs, particularly human endogenous retroviral sequence K (HERVK), were most increased in RA compared with OA, in which, for all synovial subsets (monocytes, B cells, T cells, and fibroblasts), ERE expression associated with increased IFN‐I signaling (P < 0.001).Conclusion: Peripheral blood and synovial ERE expression is examined for the first time in eRA, highlighting both a potential causal relationship between ERE and IFN‐I production and an intriguing association with anti‐CCP autoantibodies. This suggests EREs may contribute to RA pathophysiology with implications for future novel therapeutic strategies.

Background: The value of patient and public involvement (PPI) during the earliest stages of clinical trial development, and prior to the award of substantive funding, is widely recognised. However, it is often under-resourced and PPI processes during this phase are rarely reported in detail. Having benefitted from seed funding to develop an international clinical trial proposal, we sought to describe and appraise PPI activities and processes that support pre-award co-development. Methods: A 12-month “accelerator” award facilitated development of a substantive funding application to deliver the Rheumatoid Arthritis Prevention PlatfORm Trial (RAPPORT), conceived to prioritise preventative interventions for people at risk of RA. PPI partners, including individuals at risk of rheumatoid arthritis (RA), RA patients, relatives and members of the public, provided feedback on key trial design issues through online meetings, a feedback form and emails. PPI processes employed during the one-year accelerator project were thereafter evaluated by PPI partners using an anonymous online feedback form with reference to National Institute of Health and Care Research (NIHR) UK standards for public involvement in research. Results: Sixteen out of the 25-strong PPI partner panel completed an online feedback form (64%). Respondents perceived PPI processes positively in relation to all NIHR standard domains. Several key facilitators and challenges were identified, including the need for adequate PPI funding during pre-award phases of research, strategies for creating an inclusive environment, flexibility around levels of involvement, and challenges in achieving representatively diverse participation, and the importance of communicating transparent processes for role-assignment and time-reimbursement. Conclusions: In general, RAPPORT was considered an example of PPI well done, and in line with UK standards for public involvement in research. Facilitators and challenges of relevance for the development of future translational and clinical trial funding applications are highlighted.

Background The value of patient and public involvement (PPI) during the earliest stages of clinical trial development, and prior to the award of substantive funding, is widely recognised. However, it is often under resourced and PPI processes during this phase are rarely reported in detail. Having benefitted from seed funding to develop an international clinical trial proposal, we sought to describe and appraise PPI activities and processes that support pre-award co-development. Methods A 12-month “accelerator” award facilitated development of a substantive funding application to deliver the Rheumatoid Arthritis Prevention PlatfORm Trial (RAPPORT), conceived to prioritise preventative interventions for people at risk of RA. PPI partners, including individuals at risk of rheumatoid arthritis (RA), RA patients, relatives and members of the public, provided feedback on key trial design issues through online meetings, a feedback form and emails. PPI processes employed during the one-year accelerator project were thereafter evaluated by PPI partners using an anonymous online feedback form with reference to National Institute of Health and Care Research (NIHR) UK standards for public involvement in research. Results Sixteen out of the 25-strong PPI partner panel completed an online feedback form (64%). Respondents perceived PPI processes positively in relation to all NIHR standard domains. Several key facilitators and challenges were identified, including the need for adequate PPI funding during pre-award phases of research, strategies for creating an inclusive environment, flexibility around levels of involvement, and challenges in achieving representatively diverse participation, and the importance of communicating transparent processes for role-assignment and time-reimbursement. Conclusions In general, RAPPORT was considered an example of PPI well done, and in line with UK standards for public involvement in research. Facilitators and challenges of relevance for the development of future translational and clinical trial funding applications are highlighted. PLAIN ENGLISH SUMMARY Patient and public involvement (PPI) in the development of funding applications to deliver clinical trials is desirable, but the PPI activities and processes involved at this early, “pre-award” stage are rarely reported. In the current paper we describe such activities during a 12-month project to develop a grant proposal for a substantive, international clinical trial. Three PPI partners were co-recipients of “seed funding” to conduct the 12-month Accelerator project, an additional 22 PPI partners being subsequently recruited to co-develop the funding application for the trial, entitled the “Rheumatoid Arthritis Prevention: catalysing PlatfORm Trial (RAPPORT).” PPI partners contributed through meetings, email discussions and the completion of feedback forms. The PPI processes used in the project were evaluated by 16 of the PPI partners using an anonymous online feedback form. The form asked about the areas covered by the UK Standards for Public Involvement. PPI partners indicated that PPI in RAPPORT was done well in relation to all areas of the UK Standards. PPI partners felt they were heard, and their input valued, and that the communication was effective. Furthermore, they appreciated online format of the PPI activities, the flexible levels of involvement offered and the support from staff with expertise in both research and PPI. Some areas for potential improvement in future initiatives were also identified, which are discussed alongside challenges to co-development of projects during the “pre-award” stage in general, and the benefit of seed funding to support effective PPI.

Background: Checkpoint inhibitors (CPIs) are widely used in cancer treatment, with transformative impacts on survival. They nonetheless carry a significant risk of toxicity in the form of immune-related adverse events (IrAEs), which may be sustained and life-altering. IrAEs may require high-dose and/or prolonged steroid use and represent a significant healthcare burden. They mimic immune-mediated inflammatory diseases (IMIDs) but understanding of their pathogenesis is limited. The MEDALLION project aims to determine targetable mechanisms of immune dysregulation in IrAE development, employing an immune monitoring approach to determine changes in circulating and tissue resident cells of CPI recipients who do/do not develop them and assessing the contribution of the microbiome in parallel. Methods: MEDALLION is a non-randomised longitudinal cohort study aiming to recruit 66 cancer patient recipients of anti-PD1/PD-L1, anti-CTLA-4 or combination therapy. Eligible participants include those with malignant melanoma in the adjuvant or metastatic setting, mesothelioma and non-small cell lung carcinoma (NSCLC) treated in the metastatic setting. Comprehensive clinical evaluation is carried out alongside blood, skin swab and stool sampling at the time of CPI initiation (baseline) and during subsequent routine hospital visits on 6 occasions over a 10-month follow-up period. It is conservatively anticipated that one third of enrolled patients will experience a “significant IrAE” (SirAE), defined according to pre-determined criteria specific to the affected tissue/organ system. Those developing such toxicity may optionally undergo a biopsy of affected tissue where appropriate, otherwise being managed according to standard of care. Peripheral blood mononuclear cells will be analysed using multi-parameter flow cytometry to investigate immune subsets, their activation status and cytokine profiles. Stool samples and skin swabs will undergo DNA extraction for 16 S ribosomal RNA (rRNA) sequencing and internal transcribed spacer (ITS) gene sequencing to determine bacterial and fungal microbiome diversity, respectively, including species associated with toxicity. Stored tissue biopsies will be available for in situ and single-cell transcriptomic evaluation. Analysis will focus on the identification of biological predictors and precursors of SirAEs. Discussion: The pathogenesis of IrAEs will be assessed through the MEDALLION cohort, with the potential to develop tools for their prediction and/or strategies for targeted prevention or treatment. Trial Registration: The study was registered on 18/09/2023 in the ISRCTN registry (43,419,676).

The observation that certain therapeutic strategies for targeting inflammation benefit patients with distinct immune-mediated inflammatory diseases (IMIDs) is exemplified by the success of TNF blockade in conditions including rheumatoid arthritis, ulcerative colitis, and skin psoriasis, albeit only for subsets of individuals with each condition. This suggests intersecting “nodes” in inflammatory networks at a molecular and cellular level may drive and/or maintain IMIDs, being “shared” between traditionally distinct diagnoses without mapping neatly to a single clinical phenotype. In line with this proposition, integrative tumour tissue analyses in oncology have highlighted novel cell states acting across diverse cancers, with important implications for precision medicine. Drawing upon advances in the oncology field, this narrative review will first summarise learnings from the Human Cell Atlas in health as a platform for interrogating IMID tissues. It will then review cross-disease studies to date that inform this endeavour before considering future directions in the field.

The observation that certain therapeutic strategies for targeting inflammation benefit patients with distinct immune-mediated inflammatory diseases (IMIDs) is exemplified by the success of TNF blockade in conditions including rheumatoid arthritis, ulcerative colitis and skin psoriasis, albeit only for subsets of individuals with each condition. This suggests intersecting "nodes" in inflammatory networks at a molecular and cellular level may drive and/or maintain IMIDs, being “shared” between traditionally distinct diagnoses without mapping neatly to a single clinical phenotype. In line with this proposition, integrative tumour tissue analyses in oncology have highlighted novel cell states acting across diverse cancers, with important implications for precision medicine. Drawing upon advances in the oncology field, this narrative review will first summarise learnings from the Human Cell Atlas in health as a platform for interrogating IMID tissues. It will then review cross-disease studies to date that inform this endeavour, before considering future directions in the field.

Objective International trials can be challenging to operationalise due to incompatibilities between country-specific policies and infrastructures. The aim of this systematic review was to identify the operational complexities of conducting international trials and identify potential solutions for overcoming them. Design Systematic review. Data sources Medline, Embase and Health Management Information Consortium were searched from 2006 to 30 January 2023. Eligibility criteria All studies reporting operational challenges (eg, site selection, trial management, intervention management, data management) of conducting international trials were included. Data extraction and synthesis Search results were independently screened by at least two reviewers and data were extracted into a proforma. Results 38 studies (35 RCTs, 2 reports and 1 qualitative study) fulfilled the inclusion criteria. The median sample size was 1202 (IQR 332–4056) and median number of sites was 40 (IQR 13–78). 88.6% of studies had an academic sponsor and 80% were funded through government sources. Operational complexities were particularly reported during trial set-up due to lack of harmonisation in regulatory approvals and in relation to sponsorship structure, with associated budgetary impacts. Additional challenges included site selection, staff training, lengthy contract negotiations, site monitoring, communication, trial oversight, recruitment, data management, drug procurement and distribution, pharmacy involvement and biospecimen processing and transport. Conclusions International collaborative trials are valuable in cases where recruitment may be difficult, diversifying participation and applicability. However, multiple operational and regulatory challenges are encountered when implementing a trial in multiple countries. Careful planning and communication between trials units and investigators, with an emphasis on establishing adequately resourced cross-border sponsorship structures and regulatory approvals, may help to overcome these barriers and realise the benefits of the approach. Open science framework registration number osf-registrations-yvtjb-v1.

Objectives: Long-term outcomes in rheumatoid arthritis (RA) depend on early and effective disease control. Methotrexate (MTX) remains the first-line disease modifying therapy, however there are no biomarkers with which to identify those most likely to achieve remission. To address this unmet need we explored metabolic pathways involved in MTX mechanism of action within circulating CD4+T cells in a cohort of treatment naive patients with early RA. Methods: Purified CD4+T cells were isolated from peripheral blood of 68 patients with early RA commencing MTX. The expression of a range of putative MTX metabolism and mechanism of action targets were explored by flow-cytometry and transcriptional analysis. From these data significant predictors of Disease Activity Score 28-C reactive protein (DAS28-CRP) remission (AMPD1 (pADORA2b (p=0.039) and ADORA3 (p=0.047). When combined into a single predictive metric, a combination of these variables outperformed baseline DAS28-CRP in prediction of early remission (area under the curve 0.92 vs 0.67, p=0.001) Conclusions: Adenosine signalling is important in the achievement of early remission with MTX in RA and biomarkers of adenosine activity may hold utility for the stratification of therapy in early disease.