Systemic Sclerosis (SSc)FIBROSTOPNCT07642297
TL1A Inhibition in Systemic Sclerosis-Related Skin Fibrosis and Immunological Alterations: A Proof-of-Concept In Vitro Study (FIBROSTOP)
An observational study of Systemic Sclerosis (SSc) and Diffuse Cutaneous Systemic Sclerosis, run by Fondazione Policlinico Universitario Campus Bio-Medico at 1 site in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Systemic Sclerosis (SSc), Diffuse Cutaneous Systemic Sclerosis, Skin Fibrosis
- What is being tested?
- TL1A stimulation and inhibition (in vitro)
- How many people
- 20 participants
- Where
- 1 siteItaly
- Study dates
- 1 Sep 2026to 1 Sep 2028
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
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.
Who may be able to join
- 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)
Show all 9Show fewer
- 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
Who cannot join
- 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
Show all 11Show fewer
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Italy1 site
Immunorheumatology Unit, Fondazione Policlinico Universitario Campus Bio-Medico
Rome, Italy, 00128
Luca Navarini, MD, +3906225411779, l.navarini@policlinicocampus.it
Francesca Scintu, Biologist, +3906225411779, f.scintu@policlinicocampus.it
About this study
Official title: The Potential Pharmacological Role of the TNF-Like Ligand 1A (TL1A) Inhibition in Modulating Systemic Sclerosis (SSc)-Related Skin Fibrosis and Immunological Alterations: A Proof-of-Concept, In Vitro, Study
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.
Read more
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.
Read the detailed description
BACKGROUND AND RATIONALE
Systemic sclerosis (SSc) is an immune-mediated connective tissue disease characterized by fibrosis and vasculopathy. SSc is a heterogeneous orphan disease with a broad spectrum of organ involvement and life-threatening manifestations. The hallmark feature is the presence of thickened and hardened skin (scleroderma). The disease is divided into limited cutaneous and diffuse cutaneous SSc subsets based on the extent of skin involvement. Diffuse cutaneous SSc (dcSSc) is associated with a higher risk of interstitial lung disease, renal crisis, and cardiac involvement.
The pathophysiology of SSc involves a progressive self-amplifying process starting with microvascular/endothelial damage, followed by autoimmune response, inflammation, and fibrosis. T lymphocytes, particularly CD4+ T cells with a predominant Th2 cytokine profile, play an essential role in SSc pathogenesis. Regulatory T cells (Tregs) show decreased functional ability to suppress effector T cells.
TL1A (TNF-like cytokine 1A) is a member of the TNF superfamily constitutively expressed in endothelial cells and upregulated in response to TNF-α stimulation. TL1A binds to its receptor death receptor 3 (DR3), activating downstream signaling involved in innate and adaptive immune homeostasis. Elevated TL1A levels have been detected in serum of SSc patients compared to healthy subjects and correlate with disease activity. TL1A has been demonstrated to promote lung fibrosis in bleomycin-induced mouse models. The ATHENA-SSc-ILD study is currently evaluating Tulisokibart, a TL1A inhibitor, for SSc-associated interstitial lung disease.
STUDY DESIGN
FIBROSTOP is a monocentric, non-profit, interventional proof-of-concept in vitro study on biological samples. The study is funded by an unconditional grant from MSD Italia S.r.l. and conducted at the Fondazione Policlinico Universitario Campus Bio-Medico, Rome (Principal Investigator: Prof. Roberto Giacomelli).
OBJECTIVES AND ENDPOINTS
Co-Primary Objectives:
- OBJ1: To evaluate the role of TL1A and its inhibition in modulating T lymphocyte activity in SSc. Peripheral blood T-cell subsets (CD4+, CD8+, and Tregs) will be isolated from SSc patients and controls, and cultured with TL1A ± DR3 silencing. Effects on cytokine production, cellular activation, autophagy, apoptosis, and necroptosis will be analyzed through multiplex assays, flow cytometry, and Western blot.
- OBJ2: To assess the effects of TL1A and its inhibition on endothelial cell activation and function. Human Umbilical Vein Endothelial Cells (HUVEC) cultured with SSc serum will be treated with TL1A ± DR3 silencing to evaluate adhesion molecule expression, angiogenic capacity, and cell death/autophagy pathways. Bulk RNA sequencing will profile TL1A-regulated transcriptional signatures.
- OBJ3: To investigate the impact of TL1A and its inhibition on cellular interactions and fibrotic remodeling in SSc skin. Ex vivo skin biopsies from SSc patients and controls will be cultured with TL1A ± neutralizing antibody, and single-cell RNA sequencing (scRNA-seq) will identify transcriptional reprogramming in fibroblasts, lymphocytes, and endothelial cells.
Co-Primary Endpoints:
- EP1: 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 T-cell subsets following TL1A stimulation and inhibition.
- EP2: Endothelial sprouting and angiogenic capacity; changes in expression of P-selectin, E-selectin, ICAM-1, VCAM-1, and Matrigel tube formation, as well as bulk RNA-seq profiles in HUVECs following TL1A stimulation and inhibition.
- EP3: Expression of fibrotic and inflammatory markers (Col-1, alphaSMA) in ex vivo SSc skin cultures following TL1A stimulation and inhibition.
STUDY POPULATION AND PROCEDURES
Ten (n=10) patients with SSc (ACR/EULAR 2013 criteria, diffuse cutaneous subset per LeRoy et al. 1988, disease onset ≤5 years from first non-Raynaud symptom) and ten (n=10) age- and sex-matched healthy controls will be enrolled consecutively over approximately 12 months.
Each participant undergoes a single study visit (T0) involving:
- Peripheral blood sampling: PBMCs will be isolated by Ficoll-Paque density gradient centrifugation; CD4+, CD8+, and Treg subsets purified using MACS separation kits and cultured under four experimental conditions (untreated, TL1A stimulation, DR3 silencing by siRNA, TL1A + DR3 silencing).
- Skin biopsy: A 3×3 mm punch biopsy from the forearm of the most affected side (SSc patients) or from residual surgical tissue/voluntary donation (controls). Ex vivo cultures will be treated with TL1A ± neutralizing antibody and analyzed by scRNA-seq.
- Endothelial cell assays: HUVECs cultured with SSc serum under five experimental conditions will be assessed for activation markers, angiogenic function, and bulk RNA sequencing.
STATISTICAL CONSIDERATIONS
The FIBROSTOP study is exploratory in nature; no formal sample size calculation is required. Statistical analyses will include Student's t-test or Mann-Whitney U test for two-group comparisons, one-way/two-way ANOVA or Kruskal-Wallis test for multiple-group comparisons, and Spearman's rank correlation for continuous variables. Transcriptomic data will be analyzed using DESeq2 (bulk RNA-seq) and Seurat (scRNA-seq) pipelines. Pathway enrichment analyses will use Reactome, Gene Ontology (GO), and KEGG databases.
DURATION
Total study duration: 24 months (12 months enrollment + 12 months data generation and analysis). Each participant takes part in a single visit only.
- Being tested
- TL1A stimulation and inhibition (in vitro)
- Keywords
- TL1A, TNF-like ligand 1A, DR3, Fibrosis, Scleroderma, T lymphocytes, Endothelial cells, skin biopsy
- Medical subject headings
- Scleroderma, Systemic, Scleroderma, Diffuse, Fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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.
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: 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. Receives: Other: TL1A stimulation and inhibition (in vitro) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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).
Measured: Within 12 months from biological sample collection (single visit at T0)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jun 2026
- Study start1 Sep 2026 (estimated)
- Primary completion1 Sep 2027 (estimated)
- Study completion1 Sep 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (15)Papers the sponsor has linked to this study.
- Other trials for Systemic Sclerosis (SSc)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Fondazione Policlinico Universitario Campus Bio-Medico
- Sponsor type
- University, hospital or other
- Collaborators
- MSD Italia S.r.l.
- Responsible party
- Principal investigator, Luca Navarini, Fondazione Policlinico Universitario Campus Bio-Medico
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07642297
- Sponsor's protocol ID
- IIS103327
- Acronym
- FIBROSTOP
- Status last verified
- Jun 2026
- First submitted
- 4 Jun 2026
- Last updated
- 11 Jun 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 28397078Herro 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.
PubMed 32958689Xu 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.
PubMed 35911746Wei 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.
PubMed 35603223Brown 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.
PubMed 30430560Luznik 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.
PubMed 33168598Frantz 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.
PubMed 30374354Zhang 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.
PubMed 32676074Rosendahl 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.
PubMed 35234358Cutolo 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.
PubMed 31046487LeRoy 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.
PubMed 3361530Perelas 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.
PubMed 32113575Ingegnoli 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.
PubMed 30527428Ranque 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.
PubMed 19906362Denton 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.
PubMed 28413064
Study at a glance
From the registry record, last updated by the sponsor on 11 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Potential Pharmacological Role of the TNF-Like Ligand 1A (TL1A) Inhibition in Modulating Systemic Sclerosis (SSc)-Related Skin Fibrosis and Immunological Alterations: A Proof-of-Concept, In Vitro, Study
- ClinicalTrials.gov ID
- NCT07642297
- Acronym / sponsor ID
- FIBROSTOP / IIS103327
- Keywords
- TL1A, TNF-like ligand 1A, DR3, Fibrosis, Scleroderma, T lymphocytes, Endothelial cells, skin biopsy
- Study type
- Observational
- Recruitment status
- Not yet recruiting
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- Fondazione Policlinico Universitario Campus Bio-MedicoUniversity, hospital or other
- Collaborators
- MSD Italia S.r.l.
- Study start
- 1 Sep 2026 (estimated)
- Primary completion
- 1 Sep 2027 (estimated)
- Study completion
- 1 Sep 2028 (estimated)
- First posted
- 11 Jun 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
BACKGROUND AND RATIONALE
Systemic sclerosis (SSc) is an immune-mediated connective tissue disease characterized by fibrosis and vasculopathy. SSc is a heterogeneous orphan disease with a broad spectrum of organ involvement and life-threatening manifestations. The hallmark feature is the presence of thickened and hardened skin (scleroderma). The disease is divided into limited cutaneous and diffuse cutaneous SSc subsets based on the extent of skin involvement. Diffuse cutaneous SSc (dcSSc) is associated with a higher risk of interstitial lung disease, renal crisis, and cardiac involvement.
The pathophysiology of SSc involves a progressive self-amplifying process starting with microvascular/endothelial damage, followed by autoimmune response, inflammation, and fibrosis. T lymphocytes, particularly CD4+ T cells with a predominant Th2 cytokine profile, play an essential role in SSc pathogenesis. Regulatory T cells (Tregs) show decreased functional ability to suppress effector T cells.
TL1A (TNF-like cytokine 1A) is a member of the TNF superfamily constitutively expressed in endothelial cells and upregulated in response to TNF-α stimulation. TL1A binds to its receptor death receptor 3 (DR3), activating downstream signaling involved in innate and adaptive immune homeostasis. Elevated TL1A levels have been detected in serum of SSc patients compared to healthy subjects and correlate with disease activity. TL1A has been demonstrated to promote lung fibrosis in bleomycin-induced mouse models. The ATHENA-SSc-ILD study is currently evaluating Tulisokibart, a TL1A inhibitor, for SSc-associated interstitial lung disease.
STUDY DESIGN
FIBROSTOP is a monocentric, non-profit, interventional proof-of-concept in vitro study on biological samples. The study is funded by an unconditional grant from MSD Italia S.r.l. and conducted at the Fondazione Policlinico Universitario Campus Bio-Medico, Rome (Principal Investigator: Prof. Roberto Giacomelli).
OBJECTIVES AND ENDPOINTS
Co-Primary Objectives:
- OBJ1: To evaluate the role of TL1A and its inhibition in modulating T lymphocyte activity in SSc. Peripheral blood T-cell subsets (CD4+, CD8+, and Tregs) will be isolated from SSc patients and controls, and cultured with TL1A ± DR3 silencing. Effects on cytokine production, cellular activation, autophagy, apoptosis, and necroptosis will be analyzed through multiplex assays, flow cytometry, and Western blot.
- OBJ2: To assess the effects of TL1A and its inhibition on endothelial cell activation and function. Human Umbilical Vein Endothelial Cells (HUVEC) cultured with SSc serum will be treated with TL1A ± DR3 silencing to evaluate adhesion molecule expression, angiogenic capacity, and cell death/autophagy pathways. Bulk RNA sequencing will profile TL1A-regulated transcriptional signatures.
- OBJ3: To investigate the impact of TL1A and its inhibition on cellular interactions and fibrotic remodeling in SSc skin. Ex vivo skin biopsies from SSc patients and controls will be cultured with TL1A ± neutralizing antibody, and single-cell RNA sequencing (scRNA-seq) will identify transcriptional reprogramming in fibroblasts, lymphocytes, and endothelial cells.
Co-Primary Endpoints:
- EP1: 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 T-cell subsets following TL1A stimulation and inhibition.
- EP2: Endothelial sprouting and angiogenic capacity; changes in expression of P-selectin, E-selectin, ICAM-1, VCAM-1, and Matrigel tube formation, as well as bulk RNA-seq profiles in HUVECs following TL1A stimulation and inhibition.
- EP3: Expression of fibrotic and inflammatory markers (Col-1, alphaSMA) in ex vivo SSc skin cultures following TL1A stimulation and inhibition.
STUDY POPULATION AND PROCEDURES
Ten (n=10) patients with SSc (ACR/EULAR 2013 criteria, diffuse cutaneous subset per LeRoy et al. 1988, disease onset ≤5 years from first non-Raynaud symptom) and ten (n=10) age- and sex-matched healthy controls will be enrolled consecutively over approximately 12 months.
Each participant undergoes a single study visit (T0) involving:
- Peripheral blood sampling: PBMCs will be isolated by Ficoll-Paque density gradient centrifugation; CD4+, CD8+, and Treg subsets purified using MACS separation kits and cultured under four experimental conditions (untreated, TL1A stimulation, DR3 silencing by siRNA, TL1A + DR3 silencing).
- Skin biopsy: A 3×3 mm punch biopsy from the forearm of the most affected side (SSc patients) or from residual surgical tissue/voluntary donation (controls). Ex vivo cultures will be treated with TL1A ± neutralizing antibody and analyzed by scRNA-seq.
- Endothelial cell assays: HUVECs cultured with SSc serum under five experimental conditions will be assessed for activation markers, angiogenic function, and bulk RNA sequencing.
STATISTICAL CONSIDERATIONS
The FIBROSTOP study is exploratory in nature; no formal sample size calculation is required. Statistical analyses will include Student's t-test or Mann-Whitney U test for two-group comparisons, one-way/two-way ANOVA or Kruskal-Wallis test for multiple-group comparisons, and Spearman's rank correlation for continuous variables. Transcriptomic data will be analyzed using DESeq2 (bulk RNA-seq) and Seurat (scRNA-seq) pipelines. Pathway enrichment analyses will use Reactome, Gene Ontology (GO), and KEGG databases.
DURATION
Total study duration: 24 months (12 months enrollment + 12 months data generation and analysis). Each participant takes part in a single visit only.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| SSc Patients | – | Other: TL1A stimulation and inhibition (in vitro)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). |
| Healthy Controls | – | Other: TL1A stimulation and inhibition (in vitro)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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (9 listed)
- 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)
- Disease onset (defined as the first non-Raynaud symptom) within 5 years prior to recruitment
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TL1A stimulation and inhibition (in vitro)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. | Other | Healthy Controls, SSc Patients |
Primary outcome
T-cell cytokine production and activation following TL1A stimulation and inhibition
Time frame: Within 12 months from biological sample collection (single visit at T0)
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
Time frame: Within 12 months from biological sample collection (single visit at T0)
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
Time frame: Within 12 months from biological sample collection (single visit at T0)
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).
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jun 2026.
- Background: PubMed 28397078Xu 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.
- Background: PubMed 32958689Herro 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.
- Background: PubMed 35911746Xu 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.
- Background: PubMed 35603223Wei 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.
- Background: PubMed 30430560Brown 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.
- Background: PubMed 33168598Luznik 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.
- Background: PubMed 30374354Frantz 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.
- Background: PubMed 32676074Zhang 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.
- Background: PubMed 35234358Rosendahl 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.
- Background: PubMed 31046487Cutolo 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.
- Background: PubMed 3361530LeRoy 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.
- Background: PubMed 32113575Perelas 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Systemic Sclerosis (SSc) and Diffuse Cutaneous Systemic Sclerosis, run by Fondazione Policlinico Universitario Campus Bio-Medico at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 11 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Roberto Giacomelli, MD, PhD (0622541179, r.giacomelli@policlinicocampus.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
T-cell cytokine production and activation following TL1A stimulation and inhibition (time frame: Within 12 months from biological sample collection (single visit at T0)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07642297, which also lists 15 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jun 2026.