Systemic Sclerosis (SSc) is a rare autoimmune connective tissue disease characterized by microvascular injury, immune activation, and progressive fibrosis of the skin and internal organs. Diffuse cutaneous SSc (dcSSc), particularly in its early phase, is associated with aggressive fibrotic evolution and high morbidity. Despite advances in immunomodulatory therapy, no treatment has proven capable of consistently halting or reversing fibrosis, highlighting the need for new mechanistic targets.
TL1A (TNF-like ligand 1A) is a cytokine of the TNF superfamily expressed by endothelial and immune cells, which interacts with death receptor 3 (DR3) to regulate immune activation, endothelial dysfunction, and tissue remodeling. Elevated TL1A levels have been observed in SSc patients and correlate with disease activity. TL1A has also been shown to promote lung fibrosis in preclinical models.
The FIBROSTOP study is a proof-of-concept, in vitro, interventional study on biological samples aimed at elucidating the immunological and fibrotic mechanisms regulated by TL1A, and at assessing whether TL1A inhibition can reverse pathogenic processes in SSc.
Ten (n=10) patients with early diffuse cutaneous SSc and ten (n=10) age- and sex-matched healthy controls will be enrolled at a single center (Fondazione Policlinico Universitario Campus Bio-Medico, Rome). Each participant will undergo a single visit (T0) involving peripheral blood sampling and skin biopsy. No follow-up visits are planned.
The study pursues three co-primary objectives: (1) evaluating the role of TL1A and its inhibition in modulating T lymphocyte activity; (2) assessing the effects of TL1A and its inhibition on endothelial cell activation and function; (3) investigating the impact of TL1A and its inhibition on fibrotic remodeling in ex vivo SSc skin cultures using single-cell RNA sequencing.
The findings may inform future targeted antifibrotic interventions in SSc and other fibrotic diseases.
Signed written informed consent
Age ≥18 years at the time of consent
Diagnosis of SSc according to ACR/EULAR 2013 classification criteria
Diffuse cutaneous SSc subtype (LeRoy et al., 1988)
Coexisting active or treated skin diseases (e.g., atopic dermatitis), except for SSc
Diagnosis of other systemic autoimmune rheumatic diseases, including overlap syndromes (e.g., SSc + dermatomyositis)
History or current signs/symptoms of severe or uncontrolled non-rheumatic diseases
Active malignancy or history of malignancy within the previous 5 years (except adequately treated non-melanoma skin cancer or in situ cervical carcinoma)
Ten patients with early diffuse cutaneous Systemic Sclerosis (dcSSc) fulfilling the 2013 ACR/EULAR classification criteria and the LeRoy subset definition, with disease onset ≤5 years from the first non-Raynaud symptom, consecutively recruited from the Scleroderma Unit of Fondazione Policlinico Universitario Campus Bio-Medico, Rome. Ten age- and sex-matched healthy controls without SSc diagnosis, donating peripheral blood and residual skin tissue from elective surgical procedures or voluntary donation.
Case-control
Prospective
TL1A stimulation and inhibition (in vitro)
Other interventionBiological samples (T-cell subsets, HUVECs, and ex vivo skin cultures) are treated in vitro under experimental conditions including TL1A stimulation, DR3 silencing by siRNA, and TL1A neutralizing antibody. No intervention is administered to study participants.
T-cell cytokine production and activation following TL1A stimulation and inhibition
Changes in cytokine production (IFN-gamma, IL-1beta, IL-6, IL-10, IL-17A, IL-35, TNF-alpha, TGF-beta), cellular activation, autophagy, apoptosis, and necroptosis in CD4+, CD8+, and Treg subsets isolated from SSc patients and healthy controls, following TL1A stimulation and DR3 silencing by siRNA, assessed by multiplex assays, flow cytometry, and Western blot.
Endothelial cell activation and angiogenic capacity following TL1A stimulation and inhibition
Changes in expression of P-selectin, E-selectin, ICAM-1, VCAM-1, and Matrigel tube formation capacity in HUVECs cultured with SSc serum and treated with TL1A stimulation and DR3 silencing by siRNA, assessed by Western blot, Matrigel assay, and bulk RNA sequencing.
Fibrotic and inflammatory marker expression in ex vivo skin cultures following TL1A modulation
Expression of fibrotic markers (Col-1, alphaSMA) and transcriptional reprogramming in fibroblasts, lymphocytes, and endothelial cells in ex vivo skin cultures treated with TL1A and TL1A neutralizing antibody, assessed by single-cell RNA sequencing (scRNA-seq).
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Fondazione Policlinico Universitario Campus Bio-Medico
Lead sponsor
MSD Italia S.r.l.
Collaborator
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