Autoimmune and autoinflammatory diseases
Home · Research areas

Systemic sclerosis

Systemic sclerosis combines involvement of the small vessels with fibrosis of the skin and of the internal organs. Prognosis depends mainly on lung and heart involvement. Arsène Mekinian works on it from Saint-Antoine, on the immunology of the disease and as a co-author of the French national cohorts.

What is systemic sclerosis?

Systemic sclerosis is a rare autoimmune disease. Three mechanisms combine in it: involvement of the small vessels, a disorder of the immune system, and fibrosis, that is to say a hardening of the tissues through accumulation of collagen. The disease often begins with Raynaud's phenomenon, that is to say fingers that turn white in the cold, sometimes several years before the other signs. The skin then thickens, first on the fingers and the face, and the fibrosis may reach the lungs, the heart, the digestive tract and the kidneys.

Two main forms are distinguished according to the extent of skin involvement, the limited cutaneous form and the diffuse cutaneous form, the latter generally progressing more quickly. The course varies greatly from one patient to another, and it is lung and heart involvement that weigh most on prognosis. There is no treatment acting on all the manifestations: care is organised organ by organ, and relies on immunosuppressants, antifibrotic drugs and vasodilators.

His work on this subject

His research team, at the Centre de Recherche Saint-Antoine (Inserm UMR_S 938, Sorbonne Université), studies the lymphocytes that sustain the disease. In 2019, in Annals of the Rheumatic Diseases, it analysed by flow cytometry the circulating follicular helper T cells of 50 patients with systemic sclerosis and 32 healthy controls. These cells are more numerous in patients, more so still in diffuse forms and in the presence of pulmonary arterial hypertension; they produce more interleukin 21 and drive B lymphocytes in vitro to differentiate into plasmablasts secreting IgG and IgM. Blockade of the IL-21 receptor, or the addition of ruxolitinib, a JAK1/2 inhibitor, reduces this effect in the test tube. Arsène Mekinian is last author and corresponding author of this work 1. Two extensions followed, on the same series and on a neighbouring one: in Clinical and Experimental Rheumatology in 2021, CD24hiCD38hi and CD24hiCD27+ regulatory B cells are decreased in 50 patients compared with 32 controls, the CD21low subpopulation is increased, and the level of CD24hiCD27+ regulatory B cells varies inversely with that of the follicular helper T cells 2; in Clinical and Experimental Immunology in 2022, 6-sulfo LacNAc monocytes are increased in 36 patients compared with 26 controls, correlated with the expansion of follicular helper T cells, but produce less interleukin 12 in vitro 3. A review by the team, published in Journal of Translational Medicine in 2021, brings together these data and the therapeutic targets under consideration 4. An earlier work, the only original scleroderma article of which he is first author, had described in 2017 a decrease in mucosal-associated invariant T cells and in gamma delta T lymphocytes in the blood of patients, without correlation with CRP, BNP, lung involvement or skin score; the abstract of this article does not give the number of subjects studied 5.

From this immunology follows a trial. Within TRANSREG, an open-label phase IIa basket trial conducted in several autoimmune diseases, nine patients with systemic sclerosis without severe organ involvement received low-dose interleukin 2, 1 million international units per day for five days then one injection every two weeks for six months. The primary endpoint, the frequency of regulatory T lymphocytes, was met at day 8, with a 1.8 plus or minus 0.5 fold increase in their proportion among CD4+ T lymphocytes (p = 0.0015), without significant change in effector T lymphocytes or in B lymphocytes. The treatment was well tolerated, with no serious adverse event attributed to it. The modified Rodnan skin score, the Valentini score, quality of life and pulmonary function tests remained broadly stable at six months. The authors conclude that this result opens the way to properly sized phase II trials. Arsène Mekinian is last author and corresponding author of this 2024 publication in RMD Open 6.

A second strand links scleroderma to haematology. In 2020, in Rheumatology, 41 genes frequently mutated in myeloid haematological malignancies were sequenced in the blood mononuclear cells of 90 patients and 44 healthy donors. Fifteen somatic variants were detected in 13 of the 90 patients (14%) and four variants in 4 of the 44 donors (9%), a difference that was not significant overall (p = 0.58). The gap appears in younger subjects: 25% (6 of 24) versus 4% (1 of 26) before the age of 50 (p = 0.045), 17% (7 of 42) versus 3% (1 of 38) before the age of 60 (p = 0.065), with no difference after the age of 70. The most frequently affected gene is DNMT3A, with seven variants. No major clinical difference was observed between patients with and without clonal haematopoiesis. The authors write explicitly that the direction of the relationship, cause or consequence, remains to be explored. Arsène Mekinian is last named author of this work, published on behalf of the MINHEMON network 7.

On treatments, he signs several French series. A retrospective study of 2018 in Autoimmunity Reviews brought together 13 patients treated with rituximab at Saint-Antoine, compared with 26 untreated patients, then pooled them with 40 patients from the literature: in the 53 patients of the pooled analysis, the median Rodnan skin score fell from 18 at inclusion to 9 at month six (p = 0.007) and 10 at last follow-up (p = 0.0002), and forced vital capacity rose from 71% to 84% at month twelve (p = 0.001); in the subgroup of diffuse forms, 7 treated patients against 14 untreated, forced vital capacity gained 12% against a loss of 1.5% over 24 months of follow-up (p = 0.003). He is last author and corresponding author 8. A national retrospective cohort of 46 patients recruited in 19 French centres, published in 2017, measured the effect of intravenous immunoglobulins: improvement in muscle pain (74% versus 20%, p < 0.0001), in muscle weakness (45% versus 21%, p = 0.01), in joint pain (44% versus 19%, p = 0.02), in CPK and in CRP, stable skin and cardiorespiratory involvement, reduced daily corticosteroid dose, two serious adverse events; he is third author there 9. He is also co-author of SEDUCE, a placebo-controlled randomised trial of sildenafil in ischaemic digital ulcers: 83 patients in the intention-to-treat analysis, 192 ulcers, primary endpoint not met (hazard ratio for healing 1.33, confidence interval 0.88 to 2.00, p = 0.18), with a significant reduction in the mean number of ulcers per patient at week eight and at week twelve 10. Finally, a multicentre propensity-score-matched study published in 2026 in Journal of Autoimmunity compared 100 patients with a poor-prognosis diffuse cutaneous form, half of them treated with high-intensity immunosuppression followed by autologous haematopoietic stem cell transplantation, half treated conventionally: identical five-year overall survival (90%), event-free survival of 76% versus 46% (p = 0.021) and progression-free survival of 82% versus 40% (p = 0.001) in favour of transplantation, but grade 4 or higher toxicities in 36% versus 8% (p < 0.001) and 2% procedure-related mortality. He is 15th of 18 authors there 11.

He is finally a co-signatory of the large French national cohorts. The survival study published in 2019 in Arthritis Research & Therapy covers 625 incident patients (493 women, 446 limited cutaneous forms) included between 1 January 2000 and 31 December 2013 and followed until 1 July 2016: 104 deaths (16.6%), survival of 98.0%, 92.5%, 85.9% and 71.7% at one, three, five and ten years, standardised mortality ratio of 5.73 (confidence interval 4.68 to 6.94); the associated meta-analysis brings together 18 studies and 11,719 patients for mortality and 36 studies and 26,187 patients for prognostic factors 12. From the French national database, the cardiac study of 2024 in Rheumatology describes 3,528 patients, of whom 312 (10.9%) with specific cardiac involvement at inclusion, and 1,646 patients analysable at follow-up, with 98 new cardiac events at five years (event rate of 11.15%) and an associated excess mortality 13. An exploratory analysis of the same database, published the same year in RMD Open on 1,048 patients, estimates by causal methods an effect of sildenafil on diastolic dysfunction at three years of -2.83% (95% confidence interval -4.06 to -1.60; p < 0.00001) and on the occurrence of an ejection fraction below 50% of -0.88% (-1.70 to -0.05; p = 0.037), with no effect found on pulmonary arterial hypertension, nor for bosentan, angiotensin-converting enzyme inhibitors or iloprost 14. He is 32nd of 34 named authors of the first and 35th of 36 of the second. He is also co-author of a multicentre case-control study of 378 women, 129 with a vascular phenotype and 249 matched controls, recruited in 14 French centres between July 2020 and July 2022, which finds no association between a history of pre-eclampsia and the vascular phenotype (5 cases, that is 3.9%, versus 12 controls, that is 4.8%, odds ratio 0.96, p = 0.9) 15; of a national practice survey on interstitial lung disease, to which 93 practitioners responded between May 2018 and June 2020 16; and of a pilot study in Lille of 18F-FDG positron emission tomography in interstitial lung disease, covering 36 patients who had had a scan among the 545 followed in that centre, 22 of them with interstitial lung disease 17.

More recent work concerns digestive involvement, which is frequent and poorly explained. A prospective observational study conducted at Saint-Antoine included 90 patients from December 2019 to September 2021, with questionnaires, blood and stool samples and imaging: 93.3% had oesophagogastric manifestations, 67.8% intestinal manifestations and 18.9% anorectal manifestations; smoking was significantly associated with severe digestive forms and undernutrition went together with more cardiac and lung involvement; hierarchical clustering isolates three groups of patients, one of them combining cardiac and digestive involvement. He is last author and corresponding author of it 18. In the same direction, he is coordinating investigator of SCLEROMICROBIO, an AP-HP observational cohort study of the gut microbiota in systemic sclerosis (NCT04791280), conducted at Saint-Antoine, whose public record announces an actual start on 31 March 2021 and a target of 200 participants. This record has not been updated since 21 June 2022 and ClinicalTrials.gov classes it as unknown status; no results are posted there and no result is attributed to this study here. He is moreover a member of the board and of the scientific council of the Groupe francophone de recherche sur la sclérodermie (French Scleroderma Research Group, GFRS), where he is listed as an internist at Saint-Antoine Hospital (GFRS team page, recorded on 8 September 2026).

Where care is organised

Care is provided in the department of internal medicine of Saint-Antoine Hospital (AP-HP, Sorbonne Université), which takes part in the medical and university department devoted to inflammation, immunopathology and biotherapies, designated DHU i2B until about 2019, then DMU 3iD and DMU i3 in the affiliations of his publications. Follow-up is multidisciplinary: respiratory medicine and pulmonary function testing for interstitial lung disease, cardiology and echocardiography for cardiac involvement and pulmonary hypertension, dermatology for digital ulcers, gastroenterology and nutrition for digestive involvement, nephrology in the event of renal crisis. The team's research work is conducted at the Centre de Recherche Saint-Antoine (Inserm UMR_S 938), the affiliation that appears on his scleroderma publications since 2017.

In France, systemic sclerosis falls within the network of reference and competence centres for rare autoimmune and systemic diseases coordinated by the FAI²R network, and is the subject of a French national diagnosis and care protocol (PNDS) published under the aegis of the Haute Autorité de santé. The GFRS brings together the French-speaking teams working on the disease and carries the national cohorts cited above. Complex decisions are taken in multidisciplinary team meetings, and intravenous treatments are given in the day hospital.

What is not known

The immunology results described above are biological observations, not therapeutic proof. The effect of ruxolitinib on follicular helper T cells was observed only in vitro, on cultured cells, and no clinical trial of this drug in systemic sclerosis is reported in this work. The series of 50 patients, of 36 patients or of 90 patients are single-centre and have not been replicated independently.

The low-dose interleukin 2 trial covers nine patients, it is open-label, without a comparison arm and without placebo, and its primary endpoint is biological and not clinical. The stability observed in the skin scores and the pulmonary function tests at six months cannot be interpreted as an effect of the treatment, in the absence of a control group and of a sufficient duration. The actual place of low-dose interleukin 2 in this disease remains to be established.

The treatment studies he signs are, for the most part, retrospective. The rituximab series counted 13 treated patients and raises the classical problems of this type of data: indication chosen by the clinician, non-randomised comparison, pooling with heterogeneous cases from the literature. The study of intravenous immunoglobulins is retrospective and without a control group. The matched study of 2026 on high-intensity immunosuppression followed by autologous transplantation is retrospective: propensity score matching reduces the measured differences between the groups but does not replace randomisation, and the trade-off for the efficacy observed is severe toxicity in more than a third of the transplanted patients and a procedure-related mortality of 2%. In SEDUCE, although a randomised controlled trial, the primary endpoint was not met in the intention-to-treat analysis, the authors attributing this in part to an unexpected healing rate under placebo.

On the national cohorts, his position is that of a co-author among thirty or thirty-five: these studies describe associations and incidences, not cause and effect relationships. The analysis of vasodilators is presented by its authors as exploratory and requires confirmation. The direction of the relationship between clonal haematopoiesis and scleroderma is not settled. Finally, the study of the gut microbiota has published no results and its public record has not been updated since 2022: what it will show is not known.

To place this work within the international framework in force, and without his being a signatory of it, the 2023 update of the European recommendations for the treatment of systemic sclerosis (Del Galdo et al., Annals of the Rheumatic Diseases 2025, PMID 39874231) contains 22 recommendations across eight clinical domains, with additions concerning mainly skin fibrosis and interstitial lung disease. This reference is not his.

References

Published work he has taken part in, on this subject.

General information only. This page does not replace individual medical advice. Updated: 10 September 2026.