Clinical correlates of lifetime and current comorbidity patterns in autoimmune and inflammatory diseases.

BACKGROUND: Autoimmune and inflammatory diseases (AIDs) are a heterogeneous group of disorders with diverse etiopathogenic mechanisms. This study explores the potential utility of family history, together with present and past comorbidities, in identifying distinct etiopathogenic subgroups. This approach may facilitate more accurate diagnosis, prognosis and personalized therapy. METHODS: We performed a multiple correspondence analysis on patients' comorbidities, followed by hierarchical principal component clustering of clinical data from 48 healthy volunteers and 327 patients with at least one of 19 selected AIDs included in the TRANSIMMUNOM cross-sectional study. RESULTS: We identified three distinct clusters characterized by: 1) the absence of comorbidities, 2) polyautoimmunity, and 3) polyinflammation. These clusters were further distinguished by specific comorbidities and biological parameters. Autoantibodies, allergies, and viral infections characterized the polyautoimmunity cluster, while older age, BMI, depression, cancer, hypertension, periodontal disease, and dyslipidemia characterized the polyinflammation cluster. Rheumatoid arthritis patients were distributed across all three clusters. They had higher DAS28 and prevalence of extra-articular manifestations when belonging to the polyinflammation and polyautoimmunity clusters, and also lower ACPA and RF seropositivity and higher pain scores within the polyinflammation cluster. We developed a model allowing to classify AID patients into comorbidity clusters. CONCLUSIONS: In this study, we have uncovered three distinct comorbidity profiles among AID patients. These profiles suggest the presence of distinct etiopathogenic mechanisms underlying these subgroups. Validation, longitudinal stability assessment, and exploration of their impact on therapy efficacy are needed for a comprehensive understanding of their potential role in personalized medicine.

The universal effects of low-dose interleukin-2 across 13 autoimmune diseases in a basket clinical trial.

BACKGROUND: A Tregs insufficiency is central to autoimmune and inflammatory diseases pathophysiology and low dose interleukin-2 (IL-2LD) can specifically activate Tregs. OBJECTIVE: To assess IL-2LD therapeutic potential and select diseases for further clinical development, we performed an open-label, phase 2a, disease-finding, "basket trial" involving patients with one of 13 different autoimmune diseases. METHODS: 81 patients treated with IL-2LD (1 million IU/day) for 5 days, followed by fortnightly injections. The first 48 patients received diluted Proleukin®, while the subsequent 33 received ready-to-use ILT-101®. The primary endpoint was the change in Tregs at day-8 compared to baseline. Key secondary endpoints included clinical efficacy assessments using the Clinical Global Impression (CGI) scale, disease-specific scores, and EuroQL-5D-5L. RESULTS: Our study unveiled a universal and significant expansion and activation of Tregs, without concomitant Teffs activation, across all 13 autoimmune diseases. Both Proleukin® and ready-to-use ILT-101® demonstrated identical effects on Tregs. CGI scores reflecting activity, severity, and efficacy were significantly reduced in the overall patient population. Disease-specific clinical scores improved in five of the six disease cohorts with at least six patients, namely ankylosing spondylitis, systemic lupus erythematosus, Behçet's disease, Sjögren's syndrome, and systemic sclerosis. Urticaria was the only severe adverse event related to treatment. CONCLUSION: IL-2LD was well-tolerated, exhibiting specific Treg activation and clinical improvements across the 13 autoimmune diseases. CLINICAL IMPLICATION: Tregs stimulation by IL-2LD is a promising therapeutic strategy and IL-2LD holds considerable promise for integration into combinatorial therapeutic approaches.

Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial.

OBJECTIVE: Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential. AIM: We aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases. METHODS: We performed a prospective, open-label, phase I-IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet's disease, granulomatosis with polyangiitis, Takayasu's disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation. RESULTS: ld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed. CONCLUSION: The dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases. TRIAL REGISTRATION NUMBER: NCT01988506.

Clinical and multi-omics cross-phenotyping of patients with autoimmune and autoinflammatory diseases: the observational TRANSIMMUNOM protocol.

INTRODUCTION: Autoimmune and autoinflammatory diseases (AIDs) represent a socioeconomic burden as the second cause of chronic illness in Western countries. In this context, the TRANSIMMUNOM clinical protocol is designed to revisit the nosology of AIDs by combining basic, clinical and information sciences. Based on classical and systems biology analyses, it aims to uncover important phenotypes that cut across diagnostic groups so as to discover biomarkers and identify novel therapeutic targets. METHODS AND ANALYSIS: TRANSIMMUNOM is an observational clinical protocol that aims to cross-phenotype a set of 19 AIDs, six related control diseases and healthy volunteers . We assembled a multidisciplinary cohort management team tasked with (1) selecting informative biological (routine and omics type) and clinical parameters to be captured, (2) standardising the sample collection and shipment circuit, (3) selecting omics technologies and benchmarking omics data providers, (4) designing and implementing a multidisease electronic case report form and an omics database and (5) implementing supervised and unsupervised data analyses. ETHICS AND DISSEMINATION: The study was approved by the institutional review board of Pitié-Salpêtrière Hospital (ethics committee Ile-De-France 48-15) and done in accordance with the Declaration of Helsinki and good clinical practice. Written informed consent is obtained from all participants before enrolment in the study. TRANSIMMUNOM's project website provides information about the protocol (https://www.transimmunom.fr/en/) including experimental set-up and tool developments. Results will be disseminated during annual scientific committees appraising the project progresses and at national and international scientific conferences. DISCUSSION: Systems biology approaches are increasingly implemented in human pathophysiology research. The TRANSIMMUNOM study applies such approach to the pathophysiology of AIDs. We believe that this translational systems immunology approach has the potential to provide breakthrough discoveries for better understanding and treatment of AIDs. TRIAL REGISTRATION NUMBER: NCT02466217; Pre-results.