BACKGROUND AIMS:Systemic lupus erythematosus (SLE) is a rare and highly heterogeneous autoimmune disease in which standard treatment is based on corticosteroids and conventional or biological immunosuppressive drugs. In severe SLE patients (resistant to first- and second-line therapies), the 10-year mortality rate remains around 10-15%. Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has recently demonstrated sustained remission in this subset of SLE patients, but the number of treated patients remains low. The objective of this study was to assess the clinical practices (CPs) and various challenges in recruiting severe SLE patients eligible for CAR T-cell therapy. METHODS:A 1-year (February 2024 to February 2025) retrospective multicenter study was conducted across seven certified autoimmune disease reference centers. All adult SLE patients fulfilling the 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology criteria were screened for disease activity and severity according to the 2024 EBMT-International Society for Cell & Gene Therapy expert consensus. Eligibility for CAR T-cell or other non-cell and gene therapy trials and reasons for non-inclusion were analyzed. RESULTS:Among 1844 SLE patients screened over this 1-year retrospective study: 54 (2.9%) demonstrated severe disease criteria and, three (0.16 %) were ultimately treated by CAR- T while 49 were not selected for CAR T-cell trials because of either disease remission, lack of specific autoantibody, participation in other trials, physician/patient refusal or exclusion criteria at time of enrollment. CONCLUSIONS:Retrospective analysis of CPs showed that very few severe SLE patients were enrolled in the CAR T-cell trial despite eligibility criteria. Streamlined referral pathways, multidisciplinary coordination and improved physician education are needed to enhance access to advanced cell and gene therapies.

Background Systemic Lupus Erythematosus (SLE) is a rare and highly heterogeneous autoimmune disease (AD), where standard treatment is based on corticosteroids and conventional or biological immunosuppressive drugs. In severe SLE patients, resistant to 1st and 2nd line therapies, the 10-year mortality remains around 10-15%. Autologous anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy has recently demonstrated sustained remission in this subset of SLE patients, but real-word treated cases remain low. Objective To assess Clinical Practices (CPs) and the various challenges in recruiting severe SLE patients eligible for CAR-T cell therapy. Methods A one year retrospective multicenter study (February 2024–February 2025) was conducted across seven certified AD reference centers. All adult SLE patients fulfilling the 2019 EULAR/ACR criteria were screened for disease activity and severity according to the 2024 EBMT-ISCT expert consensus. Eligibility for CAR-T or other non-cell and gene (CGT) therapy trials and reasons for non-inclusion were analyzed. Results Among 1,844 SLE patients, 54 (2.9%) demonstrated severe disease criteria. Of these, 49 patients were not selected for CAR-T trials, due to either disease remission, lack of specific autoantibody, participation in other trials, physician/patient refusal or exclusion criteria at enrollment and three (1.8%) were ultimately treated. Conclusions Retrospective analysis of CPs showed that very few severe SLE patients were enrolled for CAR-T trial despite eligibility criteria. Streamlined referral pathways, multidisciplinary coordination, and improved physician education are needed to enhance access to advanced CGT therapies. Keywords : CAR-T cell; SLE; Lupus; Cell and Gene therapy (CGT) Acknowledgements “This work was supported as part of the national plan for rare diseases by the French Ministry of Health, FAI2R”

Objective. The optimal treatment choice for an individual with rheumatoid arthritis (RA) is yet unknown. Although novel approaches, such as pragmatic randomized clinical trials (pRCTs) and biomarker-driven trials are needed to advance personalized RA care, end user views of these approaches have not been extensively studied. This study aimed to gain insight into patients' and physicians' perspectives to enhance the success of future RA research innovations. Methods. As part of a larger pRCT, we conducted 3 focus groups with 17 patients with RA and 1 focus group with 5 rheumatologists from 2 major university hospitals. The discussions, which revolved around the challenges of innovative research, were transcribed verbatim and thematically analyzed adopting a self-management framework aligned with a patient engagement perspective. Results. Patients' discussions revolved around 3 themes: (1) patients' preferences for information related to medical management decision making; (2) necessary behavior change due to treatment-related challenges; and (3) patient-physician relationship as a foundation for constructively approaching shared decision making. As for physicians, their discussion was organized into 3 themes: (1) the impact of research on medical management of a patient; (2) the feasibility of pRCT and biomarker-driven trials; and (3) how randomization could challenge shared decision making with patients. Conclusion. Patients and physicians shared their concerns regarding how being part of research in the setting of clinical care could disrupt day-to-day activities and threaten shared decision making. Understanding patients' and physicians' perspectives regarding pRCT and biomarker-driven trials is key to enhance the success of these research innovations.

Background Patients with systemic lupus erythematosus (SLE) with inadequate responses to standard therapies have unmet therapeutic needs. The immunomodulatory, proangiogenic, and antifibrotic properties of mesenchymal stromal cells support their use in treating patients with SLE. We aimed to assess the safety of a single intravenous infusion of allogeneic umbilical cord-derived mesenchymal stromal cells in patients with severe SLE. Methods This prospective, single-centre, open-label, dose-escalation, Bayesian phase 1 study was done at the SaintLouis University Hospital (Paris, France). Eligible patients were aged 18-70 years, were diagnosed with SLE according to American College of Rheumatology criteria with positive antinuclear antibodies, had a baseline Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score of 6 or more, and had disease that was refractory to first and second line SLE therapies. Patients were to receive a single intravenous infusion of 1 x 106, 2 x 106, or 4 x 106 umbilical cord-derived mesenchymal stromal cells per kg (manufactured from a single umbilical cord) in cohorts of five patients per dose, starting at 2 x 106 cells per kg. The primary endpoint was the rate of treatment-related severe adverse events (grade >= 3) in the first 10 days after infusion of umbilical cord-derived mesenchymal stromal cells. People with lived experience were involved in study design, patient enrolment, and dissemination of the study findings. This study is registered with ClinicalTrials.gov, NCT03562065, and the EU Clinical Trials Register, EudraCT2017-001400-29. Findings From May 14, 2019, to March 6, 2023, 29 patients were screened for eligibility, eight of whom were enrolled in the study. Enrolment was terminated early after inclusion of eight patients and no patients received the 1 x 106 dose of umbilical cord-derived mesenchymal stromal cells. Seven (88%) of eight participants were cisgender women and one (13%) was a cisgender man. The median age was 35 years (range 26-57) and the median SLE disease duration was 12 years (5-19). All patients received at least 2 x 106 cells per kg (range 2 x 106 to 4 x 106). No severe adverse events and three infusion-related adverse events (two grade 1 and one grade 2) occurred in two patients in the first 10 days after infusion. After 124 months (range 12-13) of follow-up, no treatment-related severe adverse events and three non-treatment-related severe adverse events occurred in one patient after relapse. Interpretation Our results suggest that a single infusion of 2 x 106 cells per kg or 4 x 106 cells per kg of allogeneic umbilical cord-derived mesenchymal stromal cells was safe in patients with severe SLE. Placebo-controlled trials are needed to confirm clinical efficacy and the role of B-cell modifications in clinical benefit. Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Background Systemic sclerosis rem ains an orphan life-threatening autoimmune disease. The unique immunomodulatory, proangiogenic, and antifibrotic properties of mesenchymal stromal cells provide a strong rationale for mesenchymal stromal cell-based therapy for systemic sclerosis, and treatment with mesenchymal stromal cells has shown benefits in preclinical models of this disease. The safety of allogeneic bone marrow-derived mesenchymal stromal cell administration in patients with severe systemic sclerosis has not yet been established. We aimed to test the safety and feasibility of a single intravenous injection of intrafamilial allogeneic bone marrow-derived mesenchymal stromal cells to treat severe diffuse systemic sclerosis. Methods We did an open-label, dose-escalation, proof-of-concept, phase 1/2 study at Saint-Louis-Hospital, Paris, France. Eligible patients were aged 18-70 years with severe diffuse systemic sclerosis, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism systemic sclerosis criteria, had a minimum modified Rodnan skin score of 15 (range 0-51), had severe lung, heart, or kidney involvement, and had inadequate response or contraindications to conventional immunosuppressive therapy or autologous haematopoietic stem cell transplantation. Patients with severe comorbidities were excluded. The first ten recipients were to receive a single intravenous infusion of 1 x 10(6) bone marrow-derived mesenchymal stromal cells per kg bodyweight, and the subsequent ten recipients were to be infused with a single dose of 3 x 10(6) bone marrow-derived mesenchymal stromal cells per kg bodyweight. The primary endpoint was immediate tolerance during infusion and within the first 10 days after infusion, measured as the occurrence of serious adverse events (grade 3 or higher) in all infused patients. Safety was assessed in all participants during the 24-month follow-up period. This study is registered with ClinicalTrials.gov, NCT02213705. Findings Between March 24, 2014, and Jan 6, 2020, 20 cisgender individuals (13 women and seven men) with severe diffuse systemic sclerosis were enrolled. All 20 patients were included in the primary outcome analysis. No infusion-related severe adverse events and three infusion-related adverse events occurred in the first 10 days after treatment; one patient had grade 1 flushing and another patient had grade 1 nausea and grade 2 asthenia. After ten days and up to a median follow-up of 24.1 months (IQR 20.8-24.5), 36 non-treatment-related severe adverse events in 14 (70%) patients and no treatment- related adverse event were reported. Interpretation A single infusion of allogeneic bone marrow-derived mesenchymal stromal cells was safe in patients with severe diffuse systemic sclerosis. Future placebo-controlled trials will help to definitively ascertain the efficacy of mesenchymal stromal cell-based cell therapy from various tissue sources in larger number of patients with systemic sclerosis. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

Two randomised trials (ASTIS, SCOT) of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) versus monthly Cyclophosphamide for severe Systemic Sclerosis (SSc) patients used similar inclusion criteria, but different primary endpoints: event-free-survival (EFS) at 24 months in ASTIS versus the global rank composite score (GRCS) at 54 months in SCOT. Here we analysed the French ASTIS cohort (n = 49) outcome using the same GRCS endpoint as reported in SCOT. All patients, randomised to AHSCT (n = 26) or Cyclophosphamide (n = 23), were evaluated for the non-parametric GRCS endpoint based on: death, EFS, forced vital capacity (FVC), Health Assessment Questionnaire Disability Index (HAQ-DI) and modified Rodnan skin score (mRSS) at 60 months. Secondary endpoints were: EFS, overall survival (OS), HAQ DI and organ status. In intention-to-treat analysis, the GRCS demonstrated superiority for AHSCT (median: 9 versus −19, p = 0.018), mRSS (Δ mRSS: −16 versus −9, p = 0.02), and HAQ-DI (ΔHAQ-DI: −0.89 versus −0.2, p = 0.05) with no significant difference in OS, EFS, lung, heart and kidney function between the groups. In conclusion, this study demonstrates long term benefits of non-myeloablative AHSCT when assessed by the five longitudinal measures within GRCS affording direct primary endpoint comparison between ASTIS and SCOT.

ObjectiveTo quantify the magnitude, domains, and duration of change in health‐related quality of life (HRQoL) in patients with systemic sclerosis (SSc) who underwent autologous hematopoietic stem cell transplantation (HSCT) as compared to SSc patients with similar characteristics who did not undergo autologous HSCT.MethodsThe study was designed as a retrospective study comparing SSc patients who underwent autologous HSCT and SSc patients who met the criteria for transplantation but were treated with conventional care. Outcomes included scores on the 36‐item Short Form (SF‐36) health survey and the Health Assessment Questionnaire (HAQ) and its disease‐specific symptom scales. Differences in scores between the groups were compared using linear models, adjusting for baseline scores and inverse probability of treatment and censoring weights.ResultsIn total, 41 SSc patients who underwent autologous HSCT and 65 SSc patients treated with conventional care were compared. In marginal linear weighted models, the SF‐36 physical component summary score was a mean ± SEM 7.02 ± 1.94 points higher at the first annual visit (P = 0.001) and 14.40 ± 6.16 points higher at the seventh annual visit (P = 0.03) in patients treated with autologous HSCT compared to the conventional care group. HAQ scores were significantly better in the autologous HSCT group compared to the conventional care group during follow‐up (mean ± SEM difference from baseline −0.57 ± 0.13 [P < 0.001] at the first annual visit and −0.94 ± 0.49 [P = 0.07] at the seventh annual visit). There were no differences in the SF‐36 mental component summary scores between the 2 groups either at baseline or during follow‐up.ConclusionThis study provides robust complementary HRQoL data, including overall and event‐free survival data, to expand on the standard repertoire of biomedical variables, thus potentially supporting the physical benefits of autologous HSCT in patients with SSc.