proteins

2026-08-07 | Pyruvate kinase M2 is elevated in systemic sclerosis and plays a role in its pathogenesis.

Systemic sclerosis is an autoimmune fibrotic skin disease characterised by immune activation and fibrosis. Fibroblasts are at the core of this fibrotic process, differentiating into effector myofibroblasts; however, the drivers of this process remain obscure. Recently, metabolic changes in cells in fibrotic diseases have been uncovered, with changes in the TCA cycle and glycolysis being observed. The objective of this work was to elucidate the role of the glycolytic enzyme pyruvate kinase M2 (PKM2) in systemic sclerosis. Serum from early diffuse systemic sclerosis (SSc) patients and healthy controls (HC) was collected for PKM2 analysis by ELISA. Fibroblasts were isolated from HC and SSc biopsies and treated with transforming growth factor-beta 1 (TGF-β1) to assess PKM2 expression. PKM2 was pharmacologically modulated, and collagen and Extracellular Matrix (ECM) regulators were evaluated. Metabolic activity was assessed using Seahorse assays, and lactate transport was chemically inhibited. Chromatin immunoprecipitation was performed using a histone lactylation-specific or isotype antibody, and lactate or acetate supplementation experiments were conducted. We found significantly elevated circulating and fibroblast PKM2 in SSc patients. Fibroblast PKM2 could be induced in healthy fibroblasts by TGF-β1 exposure. Furthermore, PKM2 drives a metabolic shift to glycolysis that can be blocked by forced tetramerisation of PKM2 from its dimeric form; this resulted in reduced ECM and matrix regulators. Mechanistically, PKM2-mediated glycolysis results in elevated lactate, which drives collagen via epigenetic regulation by histone H3K18 lactylation. Blockade of PKM2 dimerisation reduced Histone H3 at Lysine 18 (H3K18) lactylation at the collagen promoter, which could be restored with lactate but not acetate. We further demonstrated that lactate-induced collagen is partially mediated by HIF-1α. PKM2 drives activation of fibroblasts in SSc via metabolic changes such as glycolysis. Taking advantage of PKM2 tetramerisation or blockade of lactate generation could be a possible therapeutic option in a disease with few treatment options.

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2026-02-11 | Engaging the PD-1 pathway in systemic sclerosis attenuates inflammation-driven fibrosis.

The study elucidates the impact of the programmed cell death protein 1 (PD-1) pathway on immune activation and fibrosis in diffuse cutaneous systemic sclerosis (dcSSc). We obtained blood and skin biopsies from patients with dcSSc and healthy controls (HCs). Soluble PD-1 was measured in serum. Human recombinant PD-1 protein (PD-1:Fc) and anti-PD-1 antibodies were used to stimulate peripheral blood mononuclear cells (PBMCs), HC, and systemic sclerosis (SSc) dermal fibroblast cultures, and cocultures. PD-1-positive (PD-1pos) and PD-1-negative (PD-1neg) populations of dcSSc PBMCs were characterised. We used a murine bleomycin model of pulmonary injury to study the effect of PD-1:Fc on pulmonary fibrosis in vivo. Soluble and cellular PD-1 were elevated in dcSSc compared to HC. Naïve fibroblasts differed between HC and dcSSc, but did not respond to PD-1:Fc treatment. Transforming growth factor β (TGF-β)-stimulated fibroblasts from dcSSc displayed a myofibroblast profile with a differential clustering compared to HC fibroblasts. PD-1:Fc downregulated the secretion of extracellular matrix (ECM) proteins, surface markers of fibroblast activation, and the production of inflammatory cytokines in TGF-β-stimulated in vitro cultures. PD-1pos SSc T cells had a different and more regulatory transcriptional profile than the PD-1neg T cell population. In vivo studies demonstrated that treatment with PD-1:Fc inhibited the development of lung fibrosis and the production of profibrotic cytokines. Administrating PD-1:Fc attenuated inflammation and ECM protein production in dcSSc in vitro models and decreased systemic inflammation and pulmonary fibrosis in the bleomycin-induced fibrosis model in mice. Our data indicate that modulating the PD-1/PD-Ligand 1 axis represents a novel therapeutic avenue in dcSSc.

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2025-04-01 | P130 Prolonged treatment with novel cyclical RP peptides reprogrammes M2 macrophages towards a resolving phenotype in diffuse cutaneous systemic sclerosis

Abstract Background/Aims Alternatively activated (M2) macrophages are believed to promote pathological fibrosis and represent a potential therapeutic target in fibrotic diseases including systemic sclerosis (SSc). Novel 10 amino acid therapeutic peptides targeting M2 macrophages, via binding to the CD206 receptor, represent promising therapeutics by reducing macrophage-stimulated fibrosis in tissue culture and mouse model systems. In this study, we investigate the potential for prolonged treatment with novel cyclical variants of the RP peptides to reprogramme pathogenic SSc macrophages to a pro-resolving phenotype. Methods Macrophages were derived from peripheral blood monocytes in the presence of M-CSF (4ng/ml) for 7 days from patients with diffuse cutaneous SSc (dcSSc) and healthy controls (n=3 dcSSc and 1 HC). On day 7, 9 and 11, macrophages were treated with 10µM of RP peptide (cyclical RP606-30, or comparator RP; RP class) or left untreated in n=6 replicates per treatment group. On day 14, media were removed and cells were collected, washed, lysed for RNA extraction, and profiled by qPCR for CD206 (pro-fibrotic M2-macrophage marker), CD86 (pro-inflammatory M1-macrophage marker) and MERTK (pro-resolution regulatory efferocytosis marker), relative to the reference gene TBP. The ratios of CD86/CD206 were used to assay pro-inflammatory vs. pro-fibrotic and MERTK/CD206 for pro-resolution vs. pro-fibrotic phenotypes. Results For individual patients with dcSSc, cyclical RP606-30, but not comparator RP, reduced CD206 expression (Patient 1: 5.74 vs. 4.10, p=NS; Patient 2: 7.38 vs. 3.92, p = 0.014; Patient 3: 2.17 vs. 0.26, p = 0.021, relative expression level untreated vs. RP606-30) and enhanced the ratio of MERTK/CD206 (Patient 1: 0.22 vs. 0.35, p=NS; Patient 2: 0.18 vs. 0.31, p = 0.0007, relative expression untreated vs. RP606-30). Similar effects were seen in healthy control macrophages treated with RP606-30, with a significant decrease in relative CD206 expression (p = 0.012), and increase in both the MERTK/CD206 (p < 0.0001) and CD86/CD206 (p < 0.0001) ratios. Combining data for dcSSc macrophages indicated that CD206 expression was reduced with RP606-30 treatment compared to no treatment (mean ± SEM: 2.76 ± 0.51 vs. 5.06 ± 0.73, p = 0.079), and MERTK expression was slightly increased (1.24 ± 0.07 vs. 1.13 ± 0.17, p = 0.809). Compared to untreated cells, RP606-30 treatment significantly increased both the CD86/CD206 (M1/M2) ratio (2.04 ± 0.34 vs. 0.86 ± 0.22, p = 0.0036) and MERTK/CD206 ratio (0.33 ± 0.03 vs. 0.20 ± 0.03, p = 0.016). Conclusion We found that prolonged treatment with RP606-30, a cyclical RP peptide, reduced relative CD206 expression, and significantly increased the CD86/CD206 (M1/M2) ratio and the MERTK/CD206 ratio in macrophages derived from patients with dcSSc. These findings indicate that RP peptides reprogramme macrophages from a pro-fibrotic towards a pro-resolution phenotype. To further characterise the phenotypic changes involved in the polarisation of macrophages towards this pro-resolving phenotype, we plan to assay the media for levels of pro-resolving lipid metabolites (LXA4 and RvD1). Disclosure J. Mendall: None. B. Ahmed Abdi: None. K. Shetty: None. S. Lopez Garces: None. V. Ong: None. C. Denton: None. D. Abraham: None. C. Yates: Corporate appointments; Scientific Officer Riptide. J. Jaynes: Corporate appointments; Scientific Officer Riptide. H. Lopez: Corporate appointments; CEO of Murigenics. G. Martin: Corporate appointments; Senior Scientific Officer Riptide. R.J. Stratton: None.

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2024-07-26 | The Novel Cytokine Interleukin-41/Meteorin-like Is Reduced in Diffuse Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease with a triad of features that include vascular abnormalities, inflammation and skin and lung fibrosis. At the core of the disease is the activation of myofibroblasts from quiescent fibroblasts and this can be modified by various cytokines. IL-41 is a recently described cytokine that was initially characterised as an adipokine as it was highly expressed in adipocytes and adipose tissue. However, it has recently been identified as being widely expressed and has immunomodulatory functions. This study examined the circulating levels of IL-41 and its expression in skin biopsies. We demonstrated significantly reduced levels of IL-41 in diffuse SSc that was also mirrored in the skin of SSc patients. AMPK has been proposed as a downstream target of IL-41, so we also measure mammalian target of rapamycin in skin and found that this is elevated in SSc patients. We speculate that IL-41 maybe an antifibrotic cytokine and its reduction may facilitate the activation of fibroblasts.

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2024-06-01 | Interferon-γ Induces Interleukin-6 Production and Alpha-smooth Muscle Actin Expression in Systemic Sclerosis Fibroblasts.

Systemic sclerosis (SSc) is an autoimmune systemic disease that is characterized by immune dysregulation, inflammation, vasculopathy, and fibrosis. Tissue fibrosis plays an important role in SSc and can affect several organs such as the dermis, lungs, and heart. Dysregulation of interferon (IFN) signaling contributes to the SSc pathogenesis and interferon regulatory factor 1 (IRF1) has been indicated as the main regulator of type I IFN. This study aimed to clarify the effect of IFN-gamma (-γ) and dexamethasone (DEX) on the IRF1, extracellular signal-regulated kinase 1/2 (ERK1/2), and the expression of alpha-smooth muscle actin (α-SMA) in myofibroblasts and genes involved in the inflammation and fibrosis processes in early diffuse cutaneous systemic sclerosis (dcSSc). A total of 10 early dcSSc patients (diffuse cutaneous form) and 10 unaffected control dermis biopsies were obtained to determine IFNγ and DEX effects on inflammation and fibrosis. Fibroblasts were treated with IFNγ and DEX at optimum time and dose. The expression level of genes and proteins involved in the fibrosis and inflammation processes have been quantified by quantitative real-time PCR (RT-qPCR) and western blot, respectively. IFNγ could up-regulate some of the inflammation-related genes (Interleukin-6; IL6) and down-regulate some of the fibrosis-related genes (COL1A1) in cultured fibroblasts of patients with early dcSSc compared to the untreated group. Besides, it has been revealed that IFNγ can induce fibroblast differentiation to the myofibroblast that expresses α-SMA. Concerning the inhibitory effect of IFNγ on some fibrotic genes and its positive effect on the inflammatory genes and myofibroblast differentiation, it seems that IFNγ may play a dual role in SSc.

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small molecules

2026-08-01 | Systemic Sclerosis Induced by Immune Checkpoint Inhibitors from the Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO): A Case Series

Objectives Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, improving outcomes in multiple advanced malignancies. Their use is often limited by immune-related adverse events (irAEs), including rare rheumatic irAEs, such as ICI-induced systemic sclerosis (ICI-SSc). Compared to idiopathic SSc, ICI-SSc typically presents with fewer extra-cutaneous manifestations and negative serologies, but data remains limited.[1] This case series describes the clinical presentation, management, and outcomes of patients with ICI-SSc to guide clinicians in balancing autoimmune toxicities with cancer control. Methods A retrospective chart review was conducted on 7 adults diagnosed with systemic sclerosis following ICI exposure between March 2021 and August 2025. All patients were referred to a Canadian academic rheumatology clinic specializing in Immuno-Oncology during ICI therapy. Clinical data was abstracted from medical records, including patient demographics, malignancy type and stage, ICI type and duration, clinical features, serologies, treatment, and outcomes. Results Of the 7 patients identified, 5 (71.4%) were female and 2 (28.6%) were male, with a mean age (SD) of 63 (10.9) years. Malignancies included: metastatic melanoma (n=4), metastatic squamous cell carcinoma (n=1), breast cancer Stage IIA/IIB (n=1), and metastatic endometrial adenocarcinoma (n=1). ICIs used included: pembrolizumab (n=2), nivolumab (n=1), cemiplimab (n=1), and ipilimumab/nivolumab combination followed by nivolumab monotherapy (n=2), which were discontinued due to SSc symptoms within 1-13 months of initiation. Serologies showed ANA positivity in 4 patients (57.1%), with SSc-specific antibodies (anti-Scl-70) detected in 1 patient. Other antibodies detected included anti-RP-11, anti-RP-155, anti-Ro-52, anti-chromatin, and anti-OJ. 2 patients had negative serologies, 1 with elevated inflammatory markers. All patients had scleordactyl (diffuse 57.1%, limited 42.9%) and extra-cutaneous features, most commonly Raynaud’s phenomenon (71.4%). Other manifestations included inflammatory arthritis (42.9%), nailfold capillary changes (42.9%), esophageal dysmotility (28.6%), telangiectasia (14.3%), and sicca symptoms (14.3%). No patients developed interstitial lung disease, pulmonary arterial hypertension, or scleroderma renal crisis. Management included ICI cessation for all patients, prednisone (85.7%), disease-modifying antirheumatic drugs (mycophenolate mofetil 57.1%, methotrexate 28.6%, hydroxychloroquine 28.6%), infliximab and intravenous immunoglobulins, and vasodilatory therapies. All malignancies were stable at 6 months post-ICI therapy. Conclusion ICI-SSc is a significant irAE primarily characterized by cutaneous manifestations but, in contrast to previous reports, this case series demonstrates that extra-cutaneous manifestations and seropositivity can occur. Along with ICI-cessation, immunosuppressive therapy was effective in symptom control without compromising cancer stability. This work may assist those involved in caring of patients with ICI-SSc to initiate immunosuppressive therapy and minimize the risk of end-organ complications. References [1.] Cho LK. Rheum Dis Clin North Am 2024;50:301-12.

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2026-06-23 | Fibroblast Mitochondrial Ca2+ Overload Drives Skin Fibrosis via mtDNA Leakage and cGAS-STING Activation in Systemic Sclerosis.

To explore the clinical relevance of mitochondrial DNA (mtDNA) in systemic sclerosis (SSc) and elucidate the mechanism by which mtDNA leakage drives fibroblast activation. Plasma mtDNA was quantified by qPCR in 50 patients with SSc and 20 healthy controls (HC). Primary dermal fibroblasts from 5 diffuse cutaneous SSc (dcSSc) and 5 HC (n= 5 per group) were analyzed for mitochondrial structure, function and RNA-seq profiling. The opening of mitochondrial permeability transition pore (mPTP) and oligomerization of VDAC1 were examined with Ca2+ modulators and inhibitors. STING knockdown (siRNA) was performed for validation. The STING inhibitor H-151 was evaluated in vitro and in a bleomycin-induced skin fibrosis model (n= 6 mice per group). Plasma mtDNA levels were significanly higher in SSc than in HC, negatively correlating with forced vital capacity (FVC)% (r = -0.436, P < 0.01) , and correlating with modified Rodnan skin score (mRSS) ( r = 0.807, P < 0.001 ), IL-6 ( r = 0.667, P < 0.001 ) and TGF-β ( r = 0.678, P < 0.001 ). SSc fibroblasts exhibited abnormal mitochondrial morphology and dysfunction. Increased MCU and VDAC1 promoted mitochondrial Ca2+ overload, mPTP opening, VDAC1 oligomerization, cytosolic mtDNA accumulation, which activated the cGAS-STING pathway and triggered profibrotic responses. Pharmacologic blockade of mPTP or VDAC1 reduced cytosolic mtDNA, while H-151 suppressed profibrotic markers in SSc fibroblasts and attenuated dermal thickening and collagen deposition in bleomycin-treated mice. The Ca2+-mtDNA-cGAS/STING axis drives fibroblast activation and skin fibrosis in SSc, representing a promising therapeutic target.

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2026-06-22 | Pruritus associated with systemic sclerosis: a systematic review of treatment-based clinical trials.

This paper aims to examine the latest research on treatments for itch (pruritus) in people with systemic sclerosis (SSc), identify areas where information is lacking, and propose suggestions for future studies.A comprehensive literature search was performed in PubMed and Scopus in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify studies evaluating therapeutic interventions for pruritus in SSc. Eligible studies included randomized controlled trials, cohort studies, and case series comprising a minimum of three patients. Data extraction encompassed study design, patient demographics, pruritus assessment instruments including validated and non-validated measures, and clinical outcomes. Studies were excluded if they concerned localized scleroderma, irrelevant populations, case reports, systematic reviews, lacking relevant outcome data, or incomplete trials. Ten studies met criteria, evaluating immunomodulatory agents, mast cell stabilizers, opioid receptor antagonist, and lysophosphatidic acid receptor antagonists. Pruritus assessment varied and was often secondary to fibrosis outcomes. Oral lenabasum improved pruritus in a phase II trial; low-dose opioid receptor modulators and rituximab also showed qualitative improvement. Pruritus is a frequently overlooked yet clinically significant symptom in systemic sclerosis (SSc) that negatively impacts patients' quality of life. Existing evidence regarding effective therapeutic options remains limited. Future research should prioritize pruritus as a predefined outcome and utilize validated assessment instruments to inform treatment strategies and enhance patient quality of life.

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2026-06-15 | Real-World Safety and Effectiveness of JAK Inhibitors in Systemic Sclerosis: A Propensity-Matched Study From the EUSTAR Cohort.

JAK inhibitors (JAKi) have shown promising effects in early-phase studies of systemic sclerosis (SSc). We aimed to assess the safety and explore the effectiveness of JAKi compared to conventional immunosuppressants in SSc. A longitudinal retrospective study of the European Scleroderma Trials and Research Group (EUSTAR) cohort was performed. JAKi-treated patients were compared to patients receiving mycophenolate mofetil (MMF), rituximab (RTX), and methotrexate (MTX) using nearest-neighbor propensity score matching. Primary outcomes were safety and drug survival. Secondary outcomes included change in forced vital capacity (FVC), change in modified Rodnan skin scores (mRSS) in patients with diffuse cutaneous SSc (dcSSc), improvement in swollen joint count, digital ulcer (DU) recurrence, and a composite disease progression endpoint. Comparative analyses were performed using generalized linear models and time-to-event methods, including Kaplan-Meier and restricted mean survival time analyses. Thirty-six JAKi-treated patients from 19,601 were included (median drug exposure 37 months). Median disease duration was seven years, and 33% had dcSSc. For 98.7 patient-years, 23 adverse events were recorded, including 12 infections, 7 laboratory abnormalities, and 3 malignancies. Treatment was discontinued permanently in 39% and transiently in 19%. At 12 months, lung function remained stable (mean FVC% +1.7%, P = 0.530) during follow-up and skin fibrosis showed a numerical improvement (mean mRSS -1.8) in patients with dcSSc. These results were comparable to those observed in MMF, RTX, and MTX groups. Swollen joint counts decreased in patients with baseline synovitis (median change -1, P = 0.052). DU recurrence rates and disease progression events were comparable to those in matched immunosuppressive groups. No new calcinotic burden was observed. JAKi showed similar effectiveness compared to standard-of-care immunosuppressants. However, drug persistence and safety concerns may be a limiting factor in patients with SSc.

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2026-06-12 | Long-term safety and pulmonary function stabilization with nintedanib in systemic sclerosis-associated interstitial lung disease, 2020-2025: a real-world retrospective study from a reference centre.

Randomized trials have demonstrated that nintedanib is beneficial for Systemic Sclerosis-associated interstitial lung disease (SSc-ILD) with an acceptable safety profile. We evaluated the long-term safety and efficacy of nintedanib in a real-world SSc-ILD cohort. Medical records of SSc patients receiving nintedanib for newly diagnosed fibrotic or progressive ILD between 2020 and 2025 in our center were retrospectively reviewed. Forced vital capacity (FVC%) and diffusing capacity for carbon monoxide (DLCO%), were recorded 12 months before and 12/24/36 months after nintedanib initiation and compared by Wilcoxon signed-rank test. Safety analyses included all treated patients; efficacy analyses excluded patients initiating immunosuppression simultaneously with nintedanib. Fifty-one patients (41 female; 34 diffuse SSc; median age and disease duration of 53 and 6 years, respectively) received nintedanib for a median of 33 months (range 4-60). Diarrhea was the most frequent adverse event leading to dosage reduction in 31% and permanent discontinuation in 14% of patients, respectively. No additional safety signals emerged in patients receiving mycophenolate (n = 18), tocilizumab (n = 14), rituximab (n = 1), mycophenolate plus tocilizumab (n = 5) or mycophenolate plus rituximab (n = 2). FVC% and DLCO%, that had declined significantly during the preceding year, remained stable after nintedanib initiation in 23/35 patients with median FVC changes of + 1% and - 3% and median DLCO% changes of -2% and - 4% after 24 and 36 months, respectively), including patients on reduced dosage. Real-world data show that nintedanib seems to stabilize pulmonary function in progressive SSc-ILD, even at reduced doses, during 3 years of follow-up in about half of patients, without safety concerns when combined with biologic agents.

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cell therapies

2026-08-01 | Isolated Neck Extensor Myositis and Chest Wall Skin Thickening: Case Report of a Rare Initial Presentation of Systemic Sclerosis and Overlap Myositis

Background Systemic sclerosis is a multisystemic connective tissue characterized by immune dysregulation, fibrosis and vasculopathy. Skin thickening, a cardinal feature of this disease process, characteristically progresses in a centripetal pattern.[1] Overlap disease with idiopathic inflammatory myositis can be seen, classically involving weakness of the proximal muscle groups of the upper and lower limbs.[2] Case Report We report the case of a 46-year-old female referred for assessment of possible systemic sclerosis with a several month history of neck extensor weakness, Raynaud’s phenomenon, moderate skin thickening isolated to the chest, positive ANA 1:640 nucleolar, and elevated CK of 436. Over the next few months, she developed rapidly progressive and severe skin thickening of the proximal and distal extremities, face and hands with associated sclerodactyly. Advanced serological testing was negative for myositis or systemic sclerosis associated with autoantibodies. Baseline investigations including echocardiogram, pulmonary function test and high-resolution CT scan of the lungs were normal. MRI of the extremities and neck demonstrated mild edema to the posterior neck paraspinal muscles, EMG of the neck extensors was positive for irritable myopathy, and subsequent muscle biopsy of the cervical paraspinal muscles demonstrated marked fibrosis with end-stage muscle atrophy in keeping with partially treated myositis. Punch biopsies of the skin demonstrated sclerosing dermatitis. A diagnosis of diffuse cutaneous systemic sclerosis with overlap myositis was made. She was treated initially with methotrexate followed by mycophenolate, however due to rapidly progressive cutaneous disease she underwent autologous hematopoietic stem cell transplant approximately 8 months after initial presentation. With ongoing follow-up 6 months post-transplant, the patients’ skin thickening had significantly improved, her myositis and Raynaud’s phenomenon had resolved, and she remained in remission off all immunosuppressive therapies. Conclusion Isolated neck extensor myositis and initial skin thickening of the chest is a rare presentation of early diffuse cutaneous systemic sclerosis. This case highlights the importance of close follow up of patients with atypical disease manifestations and seeking histopathological correlation to assist in making a definitive diagnosis. References [1.] Volkmann E. Lancet 2022;401:304-18. [2.] Bhansing K. Arthritis Res Ther 2014;16:R111.

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2026-06-27 | High-intensity immunosuppression versus modern standard care in poor-prognosis diffuse cutaneous systemic sclerosis: A propensity-matched study.

Purpose: The 2023 EULAR update recommends autologous hematopoietic stem-cell transplantation preceded by high-intensity immunosuppression (HI-IS/HSCT) for selected poor-prognosis early diffuse cutaneous systemic sclerosis (dcSSc). As real-world data remain scarce, we compared 5-year outcomes of HI-IS/HSCT recipients with propensity-matched controls receiving standard care. Because undergoing HI-IS/HSCT identifies poor-prognosis systemic sclerosis (SSc), we compared their 5-year outcomes with those of propensity-matched dcSSc controls receiving standard care. This retrospective multicenter study analyzed ACR/EULAR-2013 dcSSc patients treated after 2013 from the Greater Paris University Hospitals and French national registry. Patients had poor-prognosis SSc defined by early disease and rapid skin progression or organ involvement. HI-IS/HSCT recipients were matched 1:1 with conventional immunosuppression controls using nearest-neighbor 20-variable propensity scores (covering demographics, antibodies, organ involvement, and prior treatments). Outcomes included overall survival (OS), event-free survival (EFS), progression-free survival (PFS), and toxicities at 60 months. Exploratory multivariable logistic regression identified predictors of EFS. We analyzed 100 patients, equally divided between the HI-IS/HSCT and control groups. Five-year OS was similar (90%) in both groups. However, HI-IS/HSCT was associated with significantly improved 5-year event-free survival (76% vs 46%, p = 0.021) and progression-free survival (82% vs 40%, p = 0.001), a more favorable Global Rank Composite Score (p = 0.001), greater skin improvement (p < 0.001), and stabilization of FVC (p = 0.034) compared with controls. Prior DMARD burden was significantly lower in the transplant group (median 1 vs 2, p < 0.0001). Conditioning containing fludarabine/rituximab showed a non-significant trend towards higher EFS compared to CYC + ATG alone (82.6% vs 66.7%, p = 0.33). HI-IS/HSCT caused higher grade ≥4 toxicities (36% vs 8%, p < 0.001), with a 2% procedure-related mortality. Older age and pre-existing cardiac involvement were independently associated with worse EFS after transplant. In patients with poor-prognosis dcSSc, 5-year overall survival was high and similar between HI-IS/HSCT and modern conventional care. However, HI-IS/HSCT provided significantly superior event-free and progression-free survival, skin improvement, and pulmonary stabilization. These findings support early HSCT as a highly effective disease-stabilizing therapy in carefully selected patients, provided they undergo rigorous cardiac screening.

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2026-06-01 | P.013 The stromal vascular fraction mitigates bleomycin-induced fibrosis in mice

Systemic sclerosis (SSc), or scleroderma, is a refractory autoimmune disorder marked by microvascular dysfunction and progressive fibrosis affecting the skin and multiple internal organs. Currently, treatment options for scleroderma-related fibrosis remain limited. The stromal vascular fraction (SVF), derived from adipose tissue, contains multiple regenerative cell components, including adipose-derived stem cells, has demonstrated promising therapeutic potential in various fibrotic diseases. SVF was obtained from the subcutaneous adipose tissue of C57BL/6 mice and delivered via different administration routes to evaluate its efficacy against skin and pulmonary fibrosis. Dermal thickness and collagen deposition were assessed through histological examination. SVF retention within fibrotic subcutaneous tissue was monitored longitudinally using in vivo imaging and immunofluorescence. Cutaneous vascular architecture and the production of antifibrotic factors—including hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF-2)—were analyzed via flow cytometry and immunofluorescence. Additionally, the functional roles and mechanistic contributions of key SVF subpopulations in attenuating fibrosis were investigated. SVF effectively alleviates skin and pulmonary fibrosis in mice through distinct mechanisms at different disease stages. In the early phase of skin fibrosis, SVF modulates vascular lesions and inflammation via endothelial cells, while in the late stage, stromal cells mediate antifibrotic effects by secreting reparative cytokines. The CD45- subpopulation is identified as the primary effector cell group responsible for these therapeutic effects. Additionally, tracheal delivery of SVF demonstrates superior efficacy compared to tail-vein injection in alleviating pulmonary fibrosis, with prolonged retention of SVF in the lungs under this administration route. These findings provide mechanistic insights into the therapeutic potential of SVF and support its clinical application in treating SSc-related fibrosis. The CD45- negative subset of SVF exhibits strong therapeutic potential for mitigating skin fibrosis in systemic sclerosis. Intratracheal administration significantly potentiates the efficacy of SVF in treating pulmonary fibrosis. Collectively, these findings underscore the utility of SVF-based therapies for fibrotic diseases and provide a robust rationale for future clinical translation.

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2026-06-01 | OC.54 Timing matters: early autologous stem cel transplantation shows a lower mortality in high-risk diffuse cutaneous systemic sclerosis – preliminary results from the upside trial

Diffuse cutaneous systemic sclerosis (dcSSc) carries high morbidity and mortality. Several treatments aim to modify disease course, including immunosuppressants and autologous hematopoietic stem cell transplantation (HSCT). The optimal timing of HSCT remains unclear, particularly whether it should be used upfront or reserved for patients refractory to immunosuppressive therapy. This open-label randomized trial compares two strategies for early dcSSc: (A) upfront HSCT versus (B) conventional immunosuppressants, with rescue HSCT for treatment failure. Here, we present preliminary interim data on enrolment and safety. Patients with early progressive dcSSc with poor prognosis were recruited from seven sites across three European countries. Patients with extensive organ damage or prior cyclophosphamide (CYC) or DMARD use >12 months were excluded. Arm A (upfront HSCT) included mobilization with CYC, CD34+ selection, and conditioning with ATG and CYC. Arm B received 12 monthly CYC pulses (750 mg/m2) followed by at least one year of mycophenolate mofetil. Criteria for rescue HSCT or DMARD use post-HSCT were predefined and reviewed by the study team. Patients will be followed for 5 years and the primary outcome is the global rank composite score taking into account death, event-free survival, forced vital capacity, Health Assessment Questionnaire - Disability Index, and Modified Rodnan Skin Score (mRSS), at 2 years after randomisation. From October 2020 to October 2025, 52 patients were randomized (26 per study arm; recruitment target is 60). Mean age was 48.6 years (SD 10.6), 46% was female, mean disease duration 11.4 months (SD 7), mean mRSS 23.6 (SD 8.1) and interstitial lung disease present in 62% (table 1). During follow-up 11 (42%) patients in arm B required rescue HSCT, while 3 (12%) needed DMARDs post-HSCT. There were 23 severe adverse events (SAE) in arm A and 12 in arm B, of which respectively 30% and 33% were definitely treatment-related. The most frequent SAEs was infection with 39% vs 8% cases. The infections were viral (37.5%), bacterial (25%), and fungal (37.5%). Two deaths occurred in arm A, one due to disease progression and one related to cytokine release syndrome. In arm B, one patient died due to disease progression. Treatment related mortality (TRM) in arm A was 4% (N=1), TRM in the HSCT treated patients including rescue HSCTs (N=37) was 3% (N=1). Early intensive treatment in high-risk dcSSc appears feasible and safe. In fact, the markedly lower HSCT-related mortality compared to previous trials might suggest that earlier intervention improves safety while maintaining efficacy.

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2026-06-01 | OC.56 Safety and early efficacy of rapcabtagene autoleucel, an autologous CD19-directed chimeric antigen receptor T-cell therapy, in severe refractory diffuse cutaneous systemic sclerosis

Diffuse cutaneous systemic sclerosis (dcSSc) can be severe, with potential significant organ involvement, leading to end-organ failure and death. Therapeutic options for dcSSc are limited and inadequately address clinical manifestations or modify disease progression. CD19-targeted chimeric antigen receptor (CAR)-T cell therapy shows promise, with the potential to induce deep and sustained B cell depletion, thereby facilitating an immune system reset and offering the prospect of long-term remission in autoimmune diseases, including dcSSc. This Phase 2 open-label, AUTOGRAPH study (CYTB323K12201) evaluates rapcabtagene autoleucel, an autologous CD19-directed CAR-T cell therapy, in participants with severe, refractory (inadequate response to >2 prior systemic therapies) dcSSc. The study consists of two sequential cohorts: Cohort 1, a single-arm safety cohort, followed by a randomized and controlled Cohort 2. All participants in Cohort 1 underwent lymphodepleting chemotherapy with cyclophosphamide and fludarabine, followed by a single intravenous infusion of rapcabtagene autoleucel, with the initial three dosed sequentially with a 28-day observation period between participants; subsequent participants were dosed in parallel. All participants were hospitalized >=14 days post-infusion. Cohort 1 included 5 females and 1 male, with median: age of 49 years (range: 32–56), disease duration of 22 months (range: 10–35) and modified Rodnan skin score (mRSS) of 36.5 (range: 34–48); 5/6 participants were anti-Scl-70 positive and, 1/6 were anti-RNA polymerase 3 positive. All participants had progressive skin disease; two with concurrent progressive interstitial lung disease and one with clinically significant cardiac involvement. Participants treated with rapcabtagene autoleucel in Cohort 1 demonstrated rapid and profound B cell depletion following CAR-T expansion. Two participants with >=20 weeks of follow-up demonstrated a >=30% reduction in the mRSS along with stabilization or improvement in pulmonary function and were able to discontinue immunosuppressive therapies. Rapid improvements were noted in patient and physician global assessment and disability index. In all 3 participants with >=4 months of follow-up, circulating CD19 B cells reappeared 90 days post-infusion. Rapcabtagene autoleucel was well tolerated (table 1). All cases of cytokine release syndrome resolved without sequelae. No instances of immune effector cell-associated neurotoxicity syndrome were observed. Adverse events were manageable and aligned with the established safety profile of CAR-T cell therapies. Preliminary data from Cohort 1 suggests a favorable safety profile, CAR-T cell expansion, B cell depletion and promising initial efficacy of rapcabtagene autoleucel in severe refractory dcSSc, supporting its continued evaluation. Novartis Pharma AG, Basel, Switzerland.

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antibodies

2026-08-02 | Treating skin involvement in diffuse cutaneous systemic sclerosis: results from an international scleroderma specialist survey.

To evaluate contemporary global treatment of diffuse cutaneous systemic sclerosis (dcSSc) skin by SSc specialists. An anonymous survey was distributed via the Scleroderma Clinical Trials Consortium, European Scleroderma Trials and Research Group (EUSTAR), and Collaborative National Quality and Efficacy Registry (CONQUER) distribution lists between June and September 2025. The survey comprised four sections: Demographics, Treatment of dcSSc Skin, Impact of Recent Guidelines, and Clinical Trials. Responses included 103 physicians (93 completed): 43% North America, 31% Europe, 15% South America and 12% elsewhere. The majority practice within an SSc centre (80%) and participate in clinical trials (84%). Mycophenolate mofetil (MMF) was preferred first-line treatment (71%) for dcSSc without ILD, rising to 92% for dcSSc with mild/non-progressive ILD. For active skin involvement despite MMF, trial referral was preferred as next step irrespective of ILD (59% without ILD and 58% with ILD). Treatment preferences have evolved, with 40% increasing MMF use and 47% decreasing methotrexate use, over the previous 2-3 years. Biologic use has increased, with 56% and 37% reporting increasing rituximab and tocilizumab use, respectively. For dcSSc without ILD, 85% have prescribed rituximab, and 65% have prescribed tocilizumab. Biologic availability has impacted trial enrolment (73% agreement). Treatment decision-making for dcSSc skin involvement has been materially influenced by recent BSR and/or EULAR guidelines (43% agreement). MMF is preferred first-line for dcSSc. In the absence of compelling scientific justification for combination or step-up immunomodulatory approaches, trial referral is currently the preferred next treatment option. Biologic use is increasing, which impacts trial enrolment.

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2026-06-19 | Efficacy of different pharmacological therapies for diffuse cutaneous systemic sclerosis: a systematic review and network meta-analysis.

This study aims to compare the effectiveness of different pharmacological therapies for diffuse cutaneous systemic sclerosis (dcSSc) through a network meta-analysis (NMA). Randomized controlled trials (RCTs) on pharmacological interventions for dcSSc were systematically searched in PubMed, Embase, Cochrane Library, and Web of Science up to 2026. A Bayesian network meta-analysis was carried out using Markov Chain Monte Carlo (MCMC) methods via R software and its GeMtc package. Outcomes assessed included Modified Rodnan Skin Score (MRSS), pulmonary functions (forced vital capacity [FVC], and diffusing capacity of the lung for carbon monoxide [DLCO]), and Health Assessment Questionnaire (HAQ). Effect sizes were reported as standardized mean differences (SMDs) with corresponding 95% credible intervals (95% CrIs). A total of 20 RCTs involving 1,760 patients and 16 interventions were included. The results revealed that rituximab was the most effective intervention for reducing MRSS (SMD = - 3.4, 95% CrI (- 4.2, - 2.7)), followed by cyclophosphamide (CTX) (SMD = - 2.8, (- 3.3, - 2.2)), and belimumab (SMD = - 1.5, (- 2.5, - 0.39)). Belimumab (SMD = 1.9, (0.75, 3.1)) and CTX (SMD = 1.3, (0.86, 1.8)) topped FVC improvement. Methotrexate (MTX) was the most effective for enhancing DLCO (SMD = 0.52, (0.046, 0.99)). Belimumab (HAQ: SMD = - 3.8, (- 5.5, - 2.1)) and CTX (HAQ: SMD = - 2.9, (- 3.4, - 2.3)) were significantly effective in lowering HAQ scores. B-cell-targeted therapies (e.g., rituximab and belimumab) seemed to outperform other therapeutic agents in lowering MRSS and HAQ scores. Conventional immunosuppressants (e.g., CTX and MTX) might be more effective in enhancing pulmonary functions. Treatment strategies should be tailored according to the extent and severity of organ involvement.

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2026-06-10 | Safety and effectiveness of tocilizumab in systemic sclerosis: a multicentre French-Italian study.

Tocilizumab (TCZ) has shown beneficial effects on interstitial lung disease (ILD) in systemic sclerosis (SSc). We aimed to assess the real-life safety and effectiveness of TCZ on several SSc-related domains using data from a French-Italian multicentre cohort. We conducted a retrospective analysis of patients with SSc treated with TCZ across 15 referral centres. The following clinical data were collected at 12 months before TCZ initiation, at baseline and at 12 and 24 months of treatment: modified Rodnan skin score (mRSS), pulmonary function tests, Disease Activity Score in 28 joints using C reactive protein, digital ulcers and cardiac biomarkers. ILD progression was defined as a decline ≥5 in %predicted forced vital capacity (%pFVC) over 12±3 months. 197 patients were included (88% female; median age 57 years; median disease duration 9 years); 67% were antitopoisomerase I positive. TCZ monotherapy was used in 29% of cases, methotrexate was the most frequent combined treatment (35%). In SSc-associated ILD, %pFVC declined significantly from -12 months to baseline (81% to 77%; p=0.003). On TCZ introduction, %pFVC stabilised and the proportion of progressors declined from 43% to 24% (p=0.015). Among diffuse cutaneous patients, mRSS decreased significantly at 12 and 24 months. Digital ulcers, arthritis activity and cardiac biomarkers also improved. Infections were the most frequent adverse events (22.8%). TCZ was discontinued in 32% of patients, mainly for inefficacy. Pulmonary arterial hypertension and older age predicted TCZ failure, whereas elevated CRP predicted better response. In this large real-life cohort, TCZ was safe and associated with consistent benefits across different domains, supporting its role as a potential disease-modifying treatment in selected patients with SSc.

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2026-06-07 | Targeting the IL-23p19/Th17 Axis with Guselkumab in Systemic Sclerosis: A Domain-Based Review of All Four Published Cases

Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterized by immune dysregulation, microvascular injury, and progressive cutaneous and internal organ fibrosis. Despite advances in the understanding of SSc pathogenesis, effective disease-modifying therapies remain limited, and there is ongoing interest in targeted approaches that may modulate early inflammatory-vascular mechanisms linked to subsequent fibrotic remodeling. The IL-23/Th17 axis contributes to SSc biology, providing a rationale for IL-23p19 blockade as a potential therapeutic strategy. This focused narrative review summarizes currently available clinical signals of IL-23p19 inhibition in SSc, centered on guselkumab, and interprets reported outcomes using a domain-based framework. Published evidence remains confined to uncontrolled reports totaling 4 patients (one case report of early limited cutaneous SSc and a three-patient case series of early diffuse cutaneous SSc with comorbid psoriasis). Across these reports, investigators described improvements most consistently in the cutaneous domain (modified Rodnan skin score [mRSS], modified Rodnan total skin score [mRTSS], and the American College of Rheumatology Combined Response Index in Systemic Sclerosis [CRISS]) and in microvascular manifestations, including Raynaud’s phenomenon and nailfold microangiopathy, whereas pulmonary and gastrointestinal findings remain preliminary. We discuss key limitations of the current literature, including publication and reporting bias, the heterogeneity of phenotypes and endpoints, and confounding by comorbid psoriatic disease and natural disease fluctuation. Overall, IL-23p19 inhibition offers a pathway-specific approach in SSc, but establishing efficacy and defining responsive phenotypes requires adequately powered controlled evidence. Findings pertain specifically to guselkumab and cannot be generalized to IL-23 inhibition as a class.

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2026-06-01 | P.006 S100A4 regulated genes are differentially activated in systemic sclerosis skin across limited and diffuse cutaneous subsets

S100A4 is one of a family of damage-associated molecular peptide proteins causing downstream intracellular and extracellular fibrotic effects. Pre-clinical animal and functional studies have shown that S100A4 is implicated in skin and lung fibrosis in systemic sclerosis (SSc). Previous work [Denton et al, 2023] demonstrated that recombinant S100A4 protein promotes a fibrotic phenotype in normal fibroblasts whilst anti-S100A4 neutralising monoclonal antibody (AX-202) attenuated the profibrotic phenotype of SSc fibroblasts (SScF). Integrated analysis determined a set of 475 genes (the ‘’S100A4 signature’’) that are differentially expressed between normal (NDF) and SScF, induced in NDF by recombinant S100A4, and significantly attenuated in SScF by AX-202. Gene set enrichment analysis interrogated the S100A4 signature gene expression in whole skin in 68 well characterised SSc patients or healthy controls prospectively from a large tertiary centre over the course of 24 months (BIOPSY cohort). These included early diffuse cutaneous (dc)SSc (n=21), limited cutaneous (lc)SSc (n=15) and established dcSSc (n=14) with 16 matched healthy controls. Bulk RNA sequencing assessed genome-wide gene expression of whole skin samples to obtain normalised gene expression values for each sample. Of the 475 S100A4 signature genes, 460 genes were also identified in the BIOPSY cohort. 191 of the 460 genes showed statistically significant expression (p value <0.01) across all subsets of SSc compared to healthy controls. Principal component analysis shows the variability of expression of the top 50 differentially expressed genes with the tightest expression profile in the healthy control samples. The early diffuse subset scatter more widely and overlap with the established subset suggesting transitional heterogeneity. Supervised hierarchical clustering by samples and genes (figure 1) revealed distinct genetic signatures as illustrated by the dendrograms. Expression values of each gene are calculated using normalised z scores to highlight relative over and under expression of the gene in each sample. The relative expression by fold change of each of the top 20 differentially expressed genes by subset (early diffuse, all SSc and established diffuse SSc) compared to healthy controls is shown in the bar plot (figure 2). Our findings confirm differential activation of S100A4 regulated genes across the spectrum of SSc subsets that is not present in healthy skin. Since S100A4 is a potential molecular marker and target in different SSc subgroups our findings may inform future clinical study design to help understand differential treatment response.

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2023-06-20 | Regulation of MicroRNA Expression in Scleroderma and Idiopathic Pulmonary Fibrosis: A Research Study

Introduction: Scleroderma (SSc) is an autoimmune disorder with the hallmark of fibrosis of the skin, vasculature and internal organs. Patients with SSc and undifferentiated connective tissue disease (UCTD) are susceptible to interstitial lung disease (ILD), leading to decreased lung function and death. Idiopathic pulmonary fibrosis (IPF) is a form of ILD that is not associated with extrapulmonary manifestations. In this study, lung involvement of SSc was studied by observing how disease progression and pathogenesis differ among patients with SSc, UCTD, and ILD compared to healthy controls and patients with IPF. Our group has previously identified disease targets through microRNA sequencing, including the DICER enzyme, which works closely with the protein DGCR8 and the enzyme DROSHA in the RNA interference pathway. The canonical pathway stipulates that DICER processes microRNAs in the cytosol while DGCR8 and DROSHA process microRNAs in the nucleus. DICER, DROSHA, and DGCR8 are hypothesized to contribute to ILD progression. Methods: Human peripheral blood mononuclear cells (PBMCs) were isolated from voluntary participants, including healthy controls. PBMCs were subsequently lysed with subcellular fractionation buffer. Western blotting was done on the resulting cytosolic and nucleic fractions for DICER, DROSHA, and DGCR8 protein expression. The cytosolic fractions were normalized to GAPDH, while the nucleic fractions were normalized to B2M. Nonparametric Kruskal‐Wallis tests were used for statistical analysis. Results: The medians were significantly higher for healthy controls for DICER in the nucleus with a p-value of 0.0302, and DROSHA in the cytosol with a p-value of 0.0406 compared to patients with SSc, UCTD, and IPF. Discussion: Differences in expression were found for DROSHA in the cytosol and DICER in the nucleus, suggesting dysregulation of the non-canonical RNA interference pathways in SSc, UCTD, and IPF patients. Variability of disease progression within the groups could lead to variable enzyme and protein levels within the same disease status. With larger sample sizes, statistically insignificant differences would become significant. Lipid nanoparticle technology could be used to deliver deficient microRNAs to silence mRNA in patients. Conclusion: Due to dysregulation of the RNA interference pathway, microRNAs may be inadequately processed in the patient groups.

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2023-05-30 | Differentially expressed genes in systemic sclerosis: Towards predictive medicine with new molecular tools for clinicians.

Systemic sclerosis (SSc) is a rare and chronic autoimmune disease characterized by a pathogenic triad of immune dysregulation, vasculopathy, and progressive fibrosis. Clinical tools commonly used to assess patients, including the modified Rodnan skin score, difference between limited or diffuse forms of skin involvement, presence of lung, heart or kidney involvement, or of various autoantibodies, are important prognostic factors, but still fail to reflect the large heterogeneity of the disease. SSc treatment options are diverse, ranging from conventional drugs to autologous hematopoietic stem cell transplantation, and predicting response is challenging. Genome-wide technologies, such as high throughput microarray analyses and RNA sequencing, allow accurate, unbiased, and broad assessment of alterations in expression levels of multiple genes. In recent years, many studies have shown robust changes in the gene expression profiles of SSc patients compared to healthy controls, mainly in skin tissues and peripheral blood cells. The objective analysis of molecular patterns in SSc is a powerful tool that can further classify SSc patients with similar clinical phenotypes and help predict response to therapy. In this review, we describe the journey from the first discovery of differentially expressed genes to the identification of enriched pathways and intrinsic subsets identified in SSc, using machine learning algorithms. Finally, we discuss the use of these new tools to predict the efficacy of various treatments, including stem cell transplantation. We suggest that the use of RNA gene expression-based classifications according to molecular subsets may bring us one step closer to precision medicine in Systemic Sclerosis.

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2022-11-14 | MiR-27a as a diagnostic biomarker and potential therapeutic target in systemic sclerosis.

Systemic sclerosis (SSc) or scleroderma is a multiorgan rheumatoid disease characterized by skin tightening or organ dysfunction due to fibrosis, vascular damage, and autoimmunity. No specific cause has been discovered for this illness, and hence no effective treatment exists for it. On the other hand, due to the lack of diagnostic biomarkers capable of effectively and specifically differentiating the patients, early diagnosis has not been possible. Due to their potent regulatory roles in molecular pathways, microRNAs are among the novel candidates for the diagnosis and treatment of diseases like SSc. MiR-27a is a microRNA known for its role in the pathogenesis of fibrosis and cancer, both of which employ similar signaling pathways; hence we hypothesized that Mir-27a could be dysregulated in the blood of individuals affected by SSc and it might be useful in the diagnosis or treatment of this disease. Blood was collected from 60 SSc patients (30 limited and 30 diffuse) diagnosed by a rheumatologist according to ACR/AULAR criteria; following RNA isolation and cDNA synthesis; real-time qPCR was performed on the samples using Taq-Man probes and data were analyzed by the ΔΔCT method. Also, potential targets of miR-27a were evaluated using bioinformatics. It was revealed that miR-27a was significantly down-regulated in SSc patients in comparison to healthy individuals, but there was no difference in miR-27 expression between limited and diffused SSc patients. Besides, miR-27a was found to target several contributing factors to SSc. It seems that miR-27a has a protective role in SSc, and its downregulation could result in the disease's onset. Based on bioinformatics analyses, it is speculated that miR-27a likely targets factors contributing to the pathogenesis of SSc, which are elevated upon the downregulation of miR-27a; hence, miR-27a mimics could be considered as potential therapeutic agents for the treatment of SSc in future studies. Since no difference was observed between limited and diffuse patient groups, it is unlikely that this microRNA has a role in disease progression. According to ROC analysis of qPCR data, miR-27a could be employed as a valuable diagnostic biomarker for SSc.

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2022-06-30 | SARS-CoV-2 vaccine in patients with systemic sclerosis: impact of disease subtype and therapy.

To analyse the safety, immunogenicity and factors affecting antibody response to Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) vaccination in patients with SSc. This is a phase 4 prospective study within a larger trial of two doses of inactivated SARS-CoV-2 vaccine (CoronaVac) in 51 SSc patients compared with 153 controls. Anti-SARS-CoV-2-IgG and neutralizing antibodies (NAb) were assessed at each vaccine shot (D0/D28) and 6 weeks after the second dose(D69), only in individuals with negative baseline IgG/NAb and those who did not have coronavirus-19(COVID19) during follow-up. Vaccine safety was also assessed in all participants. Patients and controls had comparable median ages [48(38.5-57) vs 48(38-57) years, P =0.945]. Patients had mostly diffuse SSc (68.6%) and the majority (74.5%) had interstitial lung disease. Most patients were under immunosuppressive therapy (72.5%), mainly MMF (52.9%). After full vaccination (D69), anti-SARS-CoV-2-IgG frequency (64.1% vs 94.2%, P < 0.001) and NAb positivity (53.8% vs 76.9%; P =0.006) were moderate, although lower than controls. The first dose response (D28) was low and comparable for both seroconvertion rates (SC) (P =0.958) and NAb positivity (P =0.537). SSc patients under MMF monotherapy vs other (no therapy/other DMARDs) had lower immunogenicity (SC: 31.3% vs 90%, P < 0.001) and NAb(18.8% vs 85%, P < 0.001). Multiple regression analysis confirmed that MMF use, but not disease subtype, is associated with insufficient seroconversion [odds ratio (OR)=0.056(95% CI: 0.009, 0.034), P =0.002] and NAb positivity [OR = 0.047(95% CI: 0.007, 0.036), P =0.002]. No moderate/severe side-effects were observed. CoronaVac has an excellent safety profile and moderate response to anti-SARS-CoV-2 vaccine in SSc. Vaccine antibody response is not influenced by disease subtype and is greatly affected by MMF, reinforcing the need for additional strategies to up-modulate vaccine response in this subgroup of patients. ClinicalTrials.gov, https://clinicaltrials.gov, NCT04754698.

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2022-01-26 | Global gene expression analysis of systemic sclerosis myofibroblasts demonstrates a marked increase in the expression of multiple NBPF genes.

Myofibroblasts are the key effector cells responsible for the exaggerated tissue fibrosis in Systemic Sclerosis (SSc). Despite their importance to SSc pathogenesis, the specific transcriptome of SSc myofibroblasts has not been described. The purpose of this study was to identify transcriptome differences between SSc myofibroblasts and non-myofibroblastic cells. Alpha smooth muscle actin (α-SMA) expressing myofibroblasts and α-SMA negative cells were isolated employing laser capture microdissection from dermal cell cultures from four patients with diffuse SSc of recent onset. Total mRNA was extracted from both cell populations, amplified and analyzed employing microarrays. Results for specific genes were validated by Western blots and by immunohistochemistry. Transcriptome analysis revealed 97 differentially expressed transcripts in SSc myofibroblasts compared with non-myofibroblasts. Annotation clustering of the SSc myofibroblast-specific transcripts failed to show a TGF-β signature. The most represented transcripts corresponded to several different genes from the Neuroblastoma Breakpoint Family (NBPF) of genes. NBPF genes are highly expanded in humans but are not present in murine or rat genomes. In vitro studies employing cultured SSc dermal fibroblasts and immunohistochemistry of affected SSc skin confirmed increased NBPF expression in SSc. These results indicate that SSc myofibroblasts represent a unique cell lineage expressing a specific transcriptome that includes very high levels of transcripts corresponding to numerous NBPF genes. Elevated expression of NBPF genes in SSc myofibroblasts suggests that NBPF gene products may play a role in SSc pathogenesis and may represent a novel therapeutic target.

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