TL1A Inhibition in Systemic Sclerosis-Related Skin Fibrosis and Immunological Alterations: A Proof-of-Concept In Vitro Study (FIBROSTOP)

NCT07642297 | Not Yet Recruiting

• 1 other identifier: IIS103327
• Study Type: observational
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Systemic Sclerosis (SSc); Diffuse Cutaneous Systemic Sclerosis; Skin Fibrosis

Keywords

TL1A; TNF-like ligand 1A; DR3; Fibrosis; Scleroderma; T lymphocytes; Endothelial cells; skin biopsy

Outcome Measures

Primary Outcomes (3)

• 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.

  Within 12 months from biological sample collection (single visit at T0)

• 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.

  Within 12 months from biological sample collection (single visit at T0)

• 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).

  Within 12 months from biological sample collection (single visit at T0)

Study Arms (2)

SSc Patients

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, on stable immunosuppressive therapy. Each participant undergoes a single visit (T0) for peripheral blood sampling and skin punch biopsy (3x3 mm).

Other: TL1A stimulation and inhibition (in vitro)

Healthy Controls

Ten age- and sex-matched donors not affected by SSc. Peripheral blood samples are collected for research purposes. Skin samples are derived from residual tissue of minor elective surgical procedures or voluntary skin donation.

Other: TL1A stimulation and inhibition (in vitro)

Interventions

TL1A stimulation and inhibition (in vitro) OTHER

Biological 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.

Healthy Controls; SSc Patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

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.

You may qualify if:

• For both SSc and healthy control populations:
• Signed written informed consent
• Age ≥18 years at the time of consent
• For SSc population only:
• Diagnosis of SSc according to ACR/EULAR 2013 classification criteria
• Diffuse cutaneous SSc subtype (LeRoy et al., 1988)
• Disease onset (defined as the first non-Raynaud symptom) within 5 years prior to recruitment
• No new initiation of immunosuppressive therapy (including methotrexate, mycophenolate mofetil, cyclophosphamide, rituximab, tocilizumab, or prednisone \>20 mg/day) within the 2 months preceding recruitment
• Ongoing immunosuppressive therapy must be at a stable dose for at least 1 month prior to enrollment

You may not qualify if:

• 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)
• Chronic or recurrent infections, including viral hepatitis B/C, HIV, or untreated tuberculosis
• Severe active infection or major surgery within 8 weeks before enrollment
• Non-serious skin infections within 8 weeks before enrollment
• Limited cutaneous SSc or SSc sine scleroderma
• SSc patients unable to undergo therapeutic stabilization due to severe organ complications
• Pregnancy or lactation
• Inability to provide informed consent

Sponsors & Collaborators

• Fondazione Policlinico Universitario Campus Bio-Medico: lead
• MSD Italia S.r.l.: collaborator

Study Sites (1)

Immunorheumatology Unit, Fondazione Policlinico Universitario Campus Bio-Medico

Rome, Italy, 00128, Italy

Location

Related Publications (15)

• Xu W, Su L, Qing P, Wang Y, Liang Y, Zhao Y, Zhou Q, Ma F, Liu Y. Elevated levels of TL1A are associated with disease activity in patients with systemic sclerosis. Clin Rheumatol. 2017 Jun;36(6):1317-1324. doi: 10.1007/s10067-017-3612-y. Epub 2017 Apr 10.

  PMID: 28397078 BACKGROUND

• Herro R, Miki H, Sethi GS, Mills D, Mehta AK, Nguyen XX, Feghali-Bostwick C, Miller M, Broide DH, Soloff R, Croft M. TL1A Promotes Lung Tissue Fibrosis and Airway Remodeling. J Immunol. 2020 Nov 1;205(9):2414-2422. doi: 10.4049/jimmunol.2000665. Epub 2020 Sep 21.

  PMID: 32958689 BACKGROUND

• Xu WD, Li R, Huang AF. Role of TL1A in Inflammatory Autoimmune Diseases: A Comprehensive Review. Front Immunol. 2022 Jul 14;13:891328. doi: 10.3389/fimmu.2022.891328. eCollection 2022.

  PMID: 35911746 BACKGROUND

• Wei L, Abraham D, Ong V. The Yin and Yang of IL-17 in Systemic Sclerosis. Front Immunol. 2022 May 4;13:885609. doi: 10.3389/fimmu.2022.885609. eCollection 2022.

  PMID: 35603223 BACKGROUND

• Brown M, O'Reilly S. The immunopathogenesis of fibrosis in systemic sclerosis. Clin Exp Immunol. 2019 Mar;195(3):310-321. doi: 10.1111/cei.13238. Epub 2018 Dec 10.

  PMID: 30430560 BACKGROUND

• Luznik Z, Anchouche S, Dana R, Yin J. Regulatory T Cells in Angiogenesis. J Immunol. 2020 Nov 15;205(10):2557-2565. doi: 10.4049/jimmunol.2000574.

  PMID: 33168598 BACKGROUND

• Frantz C, Auffray C, Avouac J, Allanore Y. Regulatory T Cells in Systemic Sclerosis. Front Immunol. 2018 Oct 15;9:2356. doi: 10.3389/fimmu.2018.02356. eCollection 2018.

  PMID: 30374354 BACKGROUND

• Zhang M, Zhang S. T Cells in Fibrosis and Fibrotic Diseases. Front Immunol. 2020 Jun 26;11:1142. doi: 10.3389/fimmu.2020.01142. eCollection 2020.

  PMID: 32676074 BACKGROUND

• Rosendahl AH, Schonborn K, Krieg T. Pathophysiology of systemic sclerosis (scleroderma). Kaohsiung J Med Sci. 2022 Mar;38(3):187-195. doi: 10.1002/kjm2.12505. Epub 2022 Mar 2.

  PMID: 35234358 BACKGROUND

• Cutolo M, Soldano S, Smith V. Pathophysiology of systemic sclerosis: current understanding and new insights. Expert Rev Clin Immunol. 2019 Jul;15(7):753-764. doi: 10.1080/1744666X.2019.1614915. Epub 2019 May 13.

  PMID: 31046487 BACKGROUND

• LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, Rowell N, Wollheim F. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988 Feb;15(2):202-5. No abstract available.

  PMID: 3361530 BACKGROUND

• Perelas A, Silver RM, Arrossi AV, Highland KB. Systemic sclerosis-associated interstitial lung disease. Lancet Respir Med. 2020 Mar;8(3):304-320. doi: 10.1016/S2213-2600(19)30480-1. Epub 2020 Feb 27.

  PMID: 32113575 BACKGROUND

• Ingegnoli F, Ughi N, Mihai C. Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis. Best Pract Res Clin Rheumatol. 2018 Apr;32(2):223-240. doi: 10.1016/j.berh.2018.08.005. Epub 2018 Sep 14.

  PMID: 30527428 BACKGROUND

• Ranque B, Mouthon L. Geoepidemiology of systemic sclerosis. Autoimmun Rev. 2010 Mar;9(5):A311-8. doi: 10.1016/j.autrev.2009.11.003. Epub 2009 Nov 10.

  PMID: 19906362 BACKGROUND

• Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017 Oct 7;390(10103):1685-1699. doi: 10.1016/S0140-6736(17)30933-9. Epub 2017 Apr 13.

  PMID: 28413064 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Peripheral blood samples and skin punch biopsies (3x3 mm) will be collected from all participants. From peripheral blood, serum, plasma, and peripheral blood mononuclear cells (PBMCs) will be isolated, including CD4+, CD8+, and regulatory T-cell (Treg) subsets. Skin biopsy samples will be used for ex vivo culture and single-cell RNA sequencing (scRNA-seq).

MeSH Terms

Conditions

Scleroderma, Systemic; Scleroderma, Diffuse; Fibrosis

Interventions

In Vitro Techniques

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Investigative Techniques

Central Study Contacts

Roberto Giacomelli, MD, PhD

CONTACT

0622541179; r.giacomelli@policlinicocampus.it

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 4, 2026
• First Posted: June 11, 2026
• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2028
• Last Updated: June 11, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)