Determinants of health-related quality of life across the spectrum of connective tissue diseases using latent profile analysis: results from the LEAP cohort.

OBJECTIVES: Poor health-related quality of life (HRQoL) is well recognized in patients with CTD. We hypothesized that subgroups of patients across the spectrum of CTD experience different HRQoL patterns and aimed to determine patient-level characteristics associated with these different subgroups. METHODS: Using the eight continuous domains of the Medical Outcomes Study 36-item Short Form (SF-36) questionnaire we performed data-driven clustering to derive latent profiles (LPs) of patients with distinct HRQoL patterns. Multivariable ordinal logistic regression was used to determine patient-level characteristics associated with each HRQoL subgroup identified. RESULTS: A total of 309 CTD patients completed the SF-36 questionnaire. The most impaired SF-36 domains in each disease group were vitality, general health and bodily pain. The physical component of the SF-36 was consistently more impaired compared with the mental component, with similar scores across disease groups. Three LPs were identified with poor [n = 89 (29%)], average [n = 190 (61.4%)] and excellent [n = 30 (9.7%)] HRQoL. LPs were not associated with diagnostic grouping or autoantibody profiles. Black background [odds ratio (OR) 0.22 (95% CI 0.08, 0.63)], Indo-Asian background [OR 0.39 (95% CI 0.19, 0.78)], concomitant fibromyalgia [OR 0.40 (95% CI 0.20, 0.78)], sicca symptoms [OR 0.56 (95% CI 0.32, 0.98)] and multimorbidity [Charlson Comorbidity Index; OR 0.81 (95% CI 0.67, 0.97)] were associated with the 'poor' HRQoL LP. CONCLUSION: Distinct HRQoL subgroups exist that are not primarily driven by a specific diagnosis or autoantibody profiles. We identified a number of key demographic and clinical factors associated with poor HRQoL. These factors need to be addressed across the whole CTD spectrum as part of a holistic management approach aimed at improving overall patient outcomes.

Predictors and prognostic factors influencing outcomes of anti-CD20 monoclonal antibodies in systemic lupus erythematosus: A systematic review update.

BACKGROUND: Anti-C20 monoclonal antibodies (MAb), such as rituximab, are commonly used for the treatment of patients with severe or refractory systemic lupus erythematosus (SLE) but clinical outcomes are highly variable. We aimed to provide an update of a systematic review of predictive and prognostic factors of anti-CD20 MAb treatment in SLE. METHODS: A systematic literature search was undertaken to identify predictive and prognostic factors of clinical response following treatment with anti-CD20 therapies in SLE patients. Studies examining rituximab published prior to 2015 were excluded. Risk of bias was assessed for randomized controlled trials (RCTs) using the Cochrane Collaboration (RoB2) tool for RCTs and the Quality In Prognosis Studies Tool (QUIPS) for cohort studies. A narrative synthesis of the evidence was undertaken and quality of evidence (QoE) was assessed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: From 850 studies identified, 17 studies met the inclusion criteria. A further 8 studies were identified and included through search updates. There were two post-hoc analyses of RCTs of rituximab, one RCT of ocrelizumab and one of obinutuzumab; and 16 cohort studies examining rituximab treatment. The overall QoE was low or very low. There was wide heterogeneity in definitions of clinical disease activity and outcome measures, non-standardized laboratory cut-offs, failure to account for confounders and multiple subgroup analyses of differing outcomes. B cell depletion as well as novel biomarkers, such as S100 proteins, FCGR genotype, anti-vimentin and anti-drug antibodies showed some evidence of prognostic value but QoE was limited due to moderate to high risk of bias, early phase of investigation and imprecision of results. CONCLUSION: There has been no validation of previously identified prognostic factors to guide outcome in anti-CD20 treated lupus patients. Hypothesis-driven studies of several novel markers however, demonstrate prognostic value and require replication and validation to support their use in routine clinical practice. PROSPERO REGISTRATION NUMBER: CRD42020220339.

Clinical trial eligibility of a real-world connective tissue disease cohort: Results from the LEAP cohort.

INTRODUCTION: Classification criteria aim to identify a homogenous population of patients for research. We aimed to quantify how well phase-III trials in connective tissue diseases (CTDs) represent a real-world cohort. METHODS: A comprehensive review of all major published phase-III trials in CTDs was performed (clinicaltrials.gov). Classification criteria utilised most commonly in clinical trials were applied to a multicentre unselected CTD cohort. RESULTS: There were 42 CTD trials identified, with no trials in mixed (MCTD) or undifferentiated CTD (UCTD). The majority of trials (N = 38, 90 %) required patients to meet classification criteria for their respective disease. Eight (19.0 %) excluded patients with overlapping CTDs and a further two (4.8 %) excluded specific overlapping features, such as pulmonary arterial hypertension. One study explicitly allowed overlap syndromes. Our real-world CTD cohort included 391 patients. Patients with UCTD or MCTD (91/391, 23.3 %) would be excluded from participation in clinical trials for not having an eligible diagnosis. Of patients with primary Sjögren's syndrome (pSS), SLE, systemic sclerosis (SSc) or idiopathic inflammatory myopathy (IIM), 211/300 (70.3 %) met the classification criteria for their respective diagnosis and 24/211 (11.4 %) met criteria for >1 CTD. In total, 187/391 (47.8 %) would be eligible for recruitment, based upon their physician diagnosis, and most stringent trial eligibility criteria. CONCLUSION: In an unselected, real-world CTD cohort, up to half of patients are ineligible for clinical trials due to not meeting classification criteria, overlapping features or a lack of trials within their primary disease. To address this inequality in access to novel therapies, clinical trial design should evolve eligibility criteria in CTDs.

Coalition for Health and Gender Equity (CHANGE)-a protocol for a global cross-sectional survey of health and gender equity in rheumatology.

Objectives: The primary aim of the CHANGE survey is to determine the current state of gender equity within rheumatology, and secondarily, to review the physician perspective on bullying, harassment and equipoise of opportunities within rheumatology. Methods: The CHANGE e-survey is a cross-sectional self-reported questionnaire adapted from EULAR's gender equity in academic rheumatology task force. The survey was launched in January 2023; it is available in six languages and distributed widely via rheumatology organizations and social media. Eligible participants include rheumatologist physicians and rheumatology health-care professionals. Survey responses will undergo descriptive analysis and inter-group comparison aiming to explore gender-based discrimination using logistic regression, with subgroup analyses for country/continent variations. Conclusion: This e-survey represents a comprehensive global initiative led by an international consortium, aimed at exploring and investigating the gender-related disparities and obstacles encountered by rheumatologists and rheumatology health-care professionals across diverse communities and health-care environments. By pursuing this initiative, we aim to take the broader rheumatology community a step closer to understanding the underlying origins of inequities and their determinants. Such insights are pivotal in identifying viable interventions and strategies to foster gender equity within the field. Ultimately, our collective objective is to ensure equitable access to opportunities for every individual, irrespective of gender, thereby promoting inclusivity and fairness across the entire spectrum of professional practice and career development.

Listening to patients, for the patients: The COVAD Study-Vision, organizational structure, and challenges.

BACKGROUND: The pandemic presented unique challenges for individuals with autoimmune and rheumatic diseases (AIRDs) due to their underlying condition, the effects of immunosuppressive treatments, and increased vaccine hesitancy. OBJECTIVES: The COVID-19 vaccination in autoimmune diseases (COVAD) study, a series of ongoing, patient self-reported surveys were conceived with the vision of being a unique tool to gather patient perspectives on AIRDs. It involved a multinational, multicenter collaborative effort amidst a global lockdown. METHODS: Leveraging social media as a research tool, COVAD collected data using validated patient-reported outcomes (PROs). The study, comprising a core team, steering committee, and global collaborators, facilitated data collection and analysis. A pilot-tested, validated survey, featuring questions regarding COVID-19 infection, vaccination and outcomes, patient demographics, and PROs was circulated to patients with AIRDs and healthy controls (HCs). DISCUSSION: We present the challenges encountered during this international collaborative project, including coordination, data management, funding constraints, language barriers, and authorship concerns, while highlighting the measures taken to address them. CONCLUSION: Collaborative virtual models offer a dynamic new frontier in medical research and are vital to studying rare diseases. The COVAD study demonstrates the potential of online platforms for conducting large-scale, patient-focused research and underscores the importance of integrating patient perspective into clinical care. Care of patients is our central motivation, and it is essential to recognize their voices as equal stakeholders and valued partners in the study of the conditions that affect them.

Early infection risk in patients with systemic lupus erythematosus treated with rituximab or belimumab from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR): a prospective longitudinal study.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) are at an increased risk of infection relative to the general population. We aimed to describe the frequency and risk factors for serious infections in patients with moderate-to-severe SLE treated with rituximab, belimumab, and standard of care therapies in a large national observational cohort. METHODS: The British Isles Lupus Assessment Group Biologics Register (BILAG-BR) is a UK-based prospective register of patients with SLE. Patients were recruited by their treating physician as part of their scheduled care from 64 centres across the UK by use of a standardised case report form. Inclusion criteria for the BILAG-BR included age older than 5 years, ability to provide informed consent, a diagnosis of SLE, and starting a new biological therapy within the last 12 months or a new standard of care drug within the last month. The primary outcome for this study was the rate of serious infections within the first 12 months of therapy. Serious infections were defined as those requiring intravenous antibiotic treatment, hospital admission, or resulting in morbidity or death. Infection and mortality data were collected from study centres and further mortality data were collected from the UK Office for National Statistics. The relationship between serious infection and drug type was analysed using a multiple-failure Cox proportional hazards model. FINDINGS: Between July 1, 2010, and Feb 23, 2021, 1383 individuals were recruited to the BILAG-BR. 335 patients were excluded from this analysis. The remaining 1048 participants contributed 1002·7 person-years of follow-up and included 746 (71%) participants on rituximab, 119 (11%) participants on belimumab, and 183 (17%) participants on standard of care. The median age of the cohort was 39 years (IQR 30-50), 942 (90%) of 1048 patients were women and 106 (10%) were men. Of the patients with available ethnicity data, 514 (56%) of 911 were White, 169 (19%) were Asian, 161 (18%) were Black, and 67 (7%) were of multiple-mixed or other ethnic backgrounds. 118 serious infections occurred in 76 individuals during the 12-month study period, which included 92 serious infections in 58 individuals on rituximab, eight serious infections in five individuals receiving belimumab, and 18 serious infections in 13 individuals on standard of care. The overall crude incidence rate of serious infection was 117·7 (95% CI 98·3-141·0) per 1000 person-years. Compared with standard of care, the serious infection risk was similar in the rituximab (adjusted hazard ratio [HR] 1·68 [0·60-4·68]) and belimumab groups (1·01 [0·21-4·80]). Across the whole cohort in multivariate analysis, serious infection risk was associated with prednisolone dose (>10 mg; 2·38 [95%CI 1·47-3·84]), hypogammaglobulinaemia (<6 g/L; 2·16 [1·38-3·37]), and multimorbidity (1·45 [1·17-1·80]). Additional concomitant immunosuppressive use appeared to be associated with a reduced risk (0·60 [0·41-0·90]). We found no significant safety signals regarding atypical infections. Six infection-related deaths occurred at a median of 121 days (IQR 60-151) days from cohort entry. INTERPRETATION: In patients with moderate-to-severe SLE, rituximab, belimumab, and standard immunosuppressive therapy have similar serious infection risks. Key risk factors for serious infections included multimorbidity, hypogammaglobulinaemia, and increased glucocorticoid doses. When considering the risk of serious infection, we propose that immunosupppressives, rituximab, and belimumab should be prioritised as mainstay therapies to optimise SLE management and support proactive minimisation of glucocorticoid use. FUNDING: None.

Predicting progression from undifferentiated connective tissue disease to definite connective tissue disease: A systematic review and meta-analysis.

PURPOSE: Undifferentiated connective tissue disease (UCTD) encapsulates a broad range of conditions including incomplete forms of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), some of whom progress to a formal clinical diagnosis over time. This systematic review (SR) and meta-analysis aimed to identify clinical and laboratory features and biomarkers that can predict progression of UCTD. METHODS: A systematic literature search was carried out on MEDLINE, EMBASE and the Cochrane Central Register of Randomized Controlled Trials. Abstracts and full-text manuscripts were screened by two reviewers. Publications were included if they included at least 20 UCTD patients, a minimum of six months of follow up, and provided data on at least one risk factor for developing a defined CTD. The QUIPS tool was used to assess risk of bias (RoB) and GRADE for grading the quality of the evidence. The study is registered with PROSPERO (ID: CRD42021237725). RESULTS: Fifty-nine studies were included in the SR, and forty-one in the meta-analysis. The predictors for progression to SLE with the highest certainty of evidence included those with younger age (MD -5.96 [-11.05-0.87 years]), serositis (RR 2.69 [1.61-4.51]), or the presence of anti-dsDNA antibodies (RR 4.27 [1.92-9.51]). For SSc, the highest certainty of evidence included puffy fingers (RR [3.09 [1.48-6.43]), abnormal nailfold changes (NFC) (avascular areas [RR 5.71 (3.03-10.8)] or active or late SSc pattern [RR 2.24 (1.25-4.01)] and anti-topoisomerase-I (RR 1.83 [1.45-2.30]). No novel biomarkers were included in the meta-analysis; however HLA molecules, regulatory T cell shift, pro-inflammatory cytokines and complement activation products were identified as potential predictors for evolution of disease. CONCLUSIONS: Clinical and immunological parameters may predict which patients with UCTD progress to definitive disease; however, the heterogeneous nature and RoB in most studies limits the ability to apply these results in routine clinical practice. Limited data suggest that some novel biomarkers may provide additional predictive value but these will need larger well designed studies to fully delineate their clinical utility.

Lupus clinical trial eligibility in a real-world setting: results from the British Isles Lupus Assessment Group-Biologics Register (BILAG-BR).

OBJECTIVE: To quantify how well phase III randomised clinical trials in both SLE and lupus nephritis (LN) represents a real-world SLE cohort. METHODS: Literature reviews were performed of major published phase III SLE (n=12) and LN (n=6) clinical trials (ClinicalTrials.gov). Inclusion and exclusion criteria common across these trials were collated for non-renal SLE or LN trials, and applied to patients recruited to the British Isles Lupus Assessment Group-Biologics Register (BILAG-BR) starting either biological or standard-of-care (SOC) therapies. RESULTS: We recruited 837 patients to the BILAG-BR from September 2010 to June 2018, starting either SOC (n=125, 15%) or a biological medication (n=712, 85%). Active LN, defined as a BILAG A in the renal domain occurred in 20% (n=166). Overall, 530 (63%) patients were ineligible to participate in non-renal SLE clinical trials and 72 (43%) patients with active LN would be ineligible for LN trials. The most common reasons for ineligibility from the non-renal lupus trials included active renal involvement (n=166, 20%) and low disease activity (n=114, 15%). For LN trials, the most common exclusion met was pre-existing renal impairment (n=15, 9%). Patients with fewer comorbidities were more likely to be eligible to participate in non-renal SLE trials. CONCLUSIONS: In this national register of patients with moderate-to-severe SLE, nearly two-thirds would not be eligible for recruitment to key SLE clinical trials nor would almost half of those with active LN. Eligibility criteria may excessively constrain enrolment and thus, how we can generalise trial results in a real-world setting.

Acute paraquat exposure impairs colonic motility by selectively attenuating nitrergic signalling in the mouse.

Paraquat, a common herbicide, is responsible for large numbers of deaths worldwide through both deliberate and accidental ingestion. Previous studies have eluded that the bioavailability of paraquat increases substantially with increasing dose and that these changes may in part be due to the effects that these high concentrations have on the gastrointestinal tract (GI tract). To date, the actions of acute, high concentrations (20mM for 60 min) of paraquat on the GI tract, particularly the colon which is a major site of paraquat absorption, are unknown. This study examined the effects of acute paraquat administration on colonic motility in the C57BL/6 mouse. Acute paraquat exposure decreased colonic motility and the amplitude of colonic migrating motor complexes (CMMCs), which are major motor patterns involved in faecal pellet propulsion. In isolated segments of distal colon, paraquat increased resting tension and markedly attenuated electrical field stimulation-evoked relaxations. Pharmacological dissection of paraquat's mechanism of action on both the CMMCs and field stimulated tissue using the nitric oxide synthase inhibitor NG-nitro-L-arginine and direct measurement of NO release from the myenteric plexus, demonstrated that paraquat selectively attenuates nitrergic signalling pathways. These changes did not appear to be due to alterations in colonic oxidative stress, inflammation or complex 1 activity, but were most likely caused by paraquat's ability to act as a redox couple. In summary, these data demonstrate that acute paraquat exposure attenuates colonic transit. These changes may facilitate the absorption of paraquat into the circulation and so facilitate its toxicity.