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Tian X, An P, Liu R, Zuo W, Liu X, Song Z, Hu Y, Zhao R, Zhang B. Efficacy of cyclophosphamide for skin fibrosis in systemic sclerosis: a systematic review and single-arm meta-analysis. Eur J Clin Pharmacol 2025; 81:863-874. [PMID: 40198334 DOI: 10.1007/s00228-025-03837-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Accepted: 03/31/2025] [Indexed: 04/10/2025]
Abstract
PURPOSE Systemic sclerosis (SSc) is a chronic connective tissue disorder characterized by skin thickening with vascular and visceral involvements. The efficacy of cyclophosphamide for SSc-related skin fibrosis remains controversial. The aim of this study was to evaluate the effectiveness of cyclophosphamide for skin fibrosis in SSc. METHODS PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov databases were systematically searched for all published clinical trials on the treatment of SSc with cyclophosphamide until January 15, 2025.The outcome of interest was the extent of skin fibrosis, measured by the modified Rodnan skin score (mRSS). Two authors independently screened studies, extracted data, and evaluated the risk of bias. Meta-analysis was conducted with Stata/SE software. RESULTS A total of 20 articles involving 869 patients met the inclusion criteria. Cyclophosphamide reduced mRSS score by 2.30 (95% CI 0.72-3.88), 4.53 (95% CI 2.91-6.14), 6.72 (95% CI 2.74-10.70), 5.70 (95% CI 4.04-7.36), and 4.60 (95% CI 3.18-6.02) at 6-, 12-, 18-, 24- and 36-month, respectively. The estimated effect size, obtained by pooling mRSS from all studies at the follow-up endpoint, decreased by 4.71 (95% CI 2.72-6.70). In diffuse cutaneous SSc (dcSSc) subtype, the pooled mRSS decreased by 3.02 (95% CI 1.46-4.58), 6.45 (95% CI 5.02-7.87), 8.03 (95% CI 5.26-10.80), and 6.34 (95% CI 6.00-6.68) at 6-, 12-, 18-, and 24-month, respectively. And the overall reduction in mRSS at the end of follow-up in dcSSc was 7.30 (95% CI 5.61-8.99) across 11 studies. Significant heterogeneity was observed among these studies, and subgroup analysis revealed that study size and disease subtype partially explained the heterogeneity. Sensitivity analysis indicated good study stability. CONCLUSION Cyclophosphamide effectively reduced mRSS scores in SSc, particularly in dcSSc. While skin thickness improvement diminishes after 24 months, it remains a viable option for patients with worsening skin fibrosis. TRIAL REGISTRATION PROSPERO registration number: CRD42024502283. Registered on 25 January 2024.
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Affiliation(s)
- Xin Tian
- Department of Pharmacy, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - PengJiao An
- Department of Pharmacy, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - RongJi Liu
- Department of Pharmacy, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Wei Zuo
- Department of Pharmacy, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Xin Liu
- Department of Pharmacy, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - ZaiWei Song
- Department of Pharmacy, Peking University Third Hospital, No.49 Huayuan North Road, Haidian District, Beijing, 100191, China
| | - Yang Hu
- Department of Pharmacy, Peking University Third Hospital, No.49 Huayuan North Road, Haidian District, Beijing, 100191, China
| | - RongSheng Zhao
- Department of Pharmacy, Peking University Third Hospital, No.49 Huayuan North Road, Haidian District, Beijing, 100191, China.
| | - Bo Zhang
- Department of Pharmacy, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
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Chiu YH, van Dijk M, Goldschmeding R, van Laar JM, de Vries-Bouwstra JK, Spierings J. Dermal cellular senescence and EndMT in patients with systemic sclerosis undergoing cyclophosphamide or aHSCT treatment. Rheumatology (Oxford) 2025; 64:3957-3963. [PMID: 39656818 DOI: 10.1093/rheumatology/keae660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 10/30/2024] [Accepted: 11/15/2024] [Indexed: 12/17/2024] Open
Abstract
OBJECTIVES Cellular senescence and endothelial-to-mesenchymal transition (EndMT) are profibrotic cellular processes involved in systemic sclerosis (SSc), but how they respond to treatment is largely unknown. METHODS Skin biopsies from diffuse cutaneous SSc (dcSSc) patients who underwent either autologous haematopoietic stem cell transplantation (aHSCT) or cyclophosphamide pulse (iv CYC) treatment were collected before and 6 months after randomization in the Autologous Stem Cell Transplantation International Scleroderma trial. The extent of fibrosis, inflammation, senescence, EndMT and tissue remodelling were examined in histopathology. RESULTS Fourteen pairs of skin biopsies were analysed. Decrease in modified Rodnan skin score was more pronounced in aHSCT-treated patients compared with iv CYC at 6 months (median change -14 [IQR -16 to -9] vs -6 [IQR -9 to -4], respectively, P = 0.028). Histologically, expression of urokinase-type plasminogen activator receptor (uPAR) on fibroblasts, P21 on vessels and EndMT decreased after treatment in both groups, yet the reduction was more pronounced in the aHSCT group. Poor skin response was associated with high baseline connective tissue growth factor (CTGF) on fibroblasts and low baseline P21 on vessels, with an odds ratio (OR) of 1.43 and 0.41, respectively. Furthermore, poor response was also seen in patients with a rise in CTGF on fibroblasts (OR 1.29) and P21 on vessels (OR 3.02) after treatment, P < 0.001. CONCLUSION Both aHSCT and iv CYC in dcSSc reduced skin thickening clinically and attenuated EndMT, but affected cellular senescence not significantly different. EndMT and uPAR were associated with fibro-remodelling activity, whereas senescence, CTGF, uPAR and vascularity were associated with treatment response.
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Affiliation(s)
- Yu-Hsiang Chiu
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
- Division of Rheumatology/Immunology/Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Marijke van Dijk
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Roel Goldschmeding
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jacob M van Laar
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Julia Spierings
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
- Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School Royal Free Campus, London, UK
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3
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Sullivan KM. Hematopoietic stem cell transplant, chimeric antigen receptor T-cells, and other cellular therapies as stepping stones toward long-term improvement in severe scleroderma and other autoimmune diseases. Semin Arthritis Rheum 2025; 72S:152676. [PMID: 40058994 DOI: 10.1016/j.semarthrit.2025.152676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 02/12/2025] [Indexed: 04/19/2025]
Abstract
Preclinical models of inherited and induced autoimmune diseases (AIDs) have shown that hematopoietic stem cell transplantation (HSCT) following high-dose immunosuppressive conditioning could reverse organ damage and alter the course of AIDs. The rationale for both autologous and allogeneic HSCT has been based upon a reset of the immune system. Clinical application of HSCT was initially focused on severe systemic sclerosis (SSc) and three randomized trials comparing autologous HSCT with standard cyclophosphamide (CY) demonstrated significant improvement in SSc measured 12-54 months after transplant. Meta-analysis of the three trials showed the relative risk of all-cause mortality after HSCT was 0.5 compared to CY. More recently, clinical improvements in several AIDs have been reported with CY/fludarabine preparation followed by CD19 chimeric antigen receptor (CAR) T-cell infusion. With follow-up of 4-29 months, major disease responses and full B-cell reconstitution have been observed while side effects have been modest. Industry and academic centers are active in developing these and other cellular products for AID treatments including CAR-NK, off the shelf CAR-Ts, chimeric autoantibody receptor (CAAR-Ts), and mesenchymal stromal cells (MSCs). Clinical improvements after MSC administration have been reported, but as with the CAR-T trials, follow-up is still brief. Shared decision making with patients considering cellular therapy is perhaps easier for autologous HSCT since we have longer follow-up with many patients clinically improved and surviving off DMARDS for decades. Such individuals understandably view themselves as cured. Thus, the interest in the evolving role of cellular therapies in long-term improvement in severe AIDs.
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Affiliation(s)
- Keith M Sullivan
- James B. Wyngaarden Professor Emeritus of Medicine, Duke University Medical Center, Durham, NC, USA.
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Chepy A, Collet A, Launay D, Dubucquoi S, Sobanski V. Autoantibodies in systemic sclerosis: From disease bystanders to pathogenic players. J Transl Autoimmun 2025; 10:100272. [PMID: 39917316 PMCID: PMC11799969 DOI: 10.1016/j.jtauto.2025.100272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 01/15/2025] [Accepted: 01/20/2025] [Indexed: 02/09/2025] Open
Abstract
Autoantibodies (Aab) are recognized as key indicators in the diagnosis, classification, and monitoring of systemic autoimmune diseases (AID). Recent studies have expanded knowledge through the discovery of new antigenic targets, advanced methods for measuring Aab levels, and understanding their possible pathogenic roles in AID. This narrative review uses systemic sclerosis (SSc) as an example to highlight the importance of Aab associated with HEp-2 immunofluorescence assay positivity (traditionally referred as antinuclear antibodies [ANA]), exploring recent developments in the field. Firstly, we outline the various types of ANA found in SSc and their links with specific disease features. Newly discovered antibodies shed light on SSc cases where Aab had previously gone unidentified. Secondly, we emphasize the necessity for novel quantitative techniques to track Aab levels over time by gathering data regarding the timing of Aab occurrence relative to SSc symptoms and the relationships between Aab concentrations and disease severity. Finally, we discuss the experimental findings suggesting a potential direct role of Aab in the development of SSc. The advancements surrounding Aab provide insights into new disease mechanisms and may lead to innovative diagnostic and treatment approaches.
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Affiliation(s)
- Aurélien Chepy
- Univ. Lille, Inserm, CHU Lille, U1286 – INFINITE – Institute for Translational Research in Inflammation, Lille, France
- CHU Lille, Département de Médecine interne et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest, Méditerranée et Guadeloupe (CeRAINOM), Lille, France
| | - Aurore Collet
- Univ. Lille, Inserm, CHU Lille, U1286 – INFINITE – Institute for Translational Research in Inflammation, Lille, France
- CHU Lille, Institut d’Immunologie, Lille, France
| | - David Launay
- Univ. Lille, Inserm, CHU Lille, U1286 – INFINITE – Institute for Translational Research in Inflammation, Lille, France
- CHU Lille, Département de Médecine interne et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest, Méditerranée et Guadeloupe (CeRAINOM), Lille, France
| | - Sylvain Dubucquoi
- Univ. Lille, Inserm, CHU Lille, U1286 – INFINITE – Institute for Translational Research in Inflammation, Lille, France
- CHU Lille, Institut d’Immunologie, Lille, France
| | - Vincent Sobanski
- Univ. Lille, Inserm, CHU Lille, U1286 – INFINITE – Institute for Translational Research in Inflammation, Lille, France
- CHU Lille, Département de Médecine interne et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest, Méditerranée et Guadeloupe (CeRAINOM), Lille, France
- Institut Universitaire de France (IUF), Paris, France
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Franco-Fuquen P, Figueroa-Aguirre J, Martínez DA, Moreno-Cortes EF, Garcia-Robledo JE, Vargas-Cely F, Castro-Martínez DA, Almaini M, Castro JE. Cellular therapies in rheumatic and musculoskeletal diseases. J Transl Autoimmun 2025; 10:100264. [PMID: 39931050 PMCID: PMC11808717 DOI: 10.1016/j.jtauto.2024.100264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 02/13/2025] Open
Abstract
A substantial proportion of patients diagnosed with rheumatologic and musculoskeletal diseases (RMDs) exhibit resistance to conventional therapies or experience recurrent symptoms. These diseases, which include autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, are marked by the presence of autoreactive B cells that play a critical role in their pathogenesis. The persistence of these autoreactive B cells within lymphatic organs and inflamed tissues impairs the effectiveness of B-cell-depleting monoclonal antibodies like rituximab. A promising therapeutic approach involves using T cells genetically engineered to express chimeric antigen receptors (CARs) that target specific antigens. This strategy has demonstrated efficacy in treating B-cell malignancies by achieving long-term depletion of malignant and normal B cells. Preliminary data from patients with RMDs, particularly those with lupus erythematosus and dermatomyositis, suggest that CAR T-cells targeting CD19 can induce rapid and sustained depletion of circulating B cells, leading to complete clinical and serological responses in cases that were previously unresponsive to conventional therapies. This review will provide an overview of the current state of preclinical and clinical studies on the use of CAR T-cells and other cellular therapies for RMDs. Additionally, it will explore potential future applications of these innovative treatment modalities for managing patients with refractory and recurrent manifestations of these diseases.
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Affiliation(s)
- Pedro Franco-Fuquen
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Juana Figueroa-Aguirre
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - David A. Martínez
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Eider F. Moreno-Cortes
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Juan E. Garcia-Robledo
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Fabio Vargas-Cely
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | | | - Mustafa Almaini
- Rheumatology, Allergy & Clinical Immunology Division, Mafraq Hospital, United Arab Emirates
| | - Januario E. Castro
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
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Keret S, Kaly L, Schett G, Bergmann C, Feldman E, Zuckerman T, Yehudai-Ofir D, Shouval A, Awisat A, Rosner I, Rozenbaum M, Boulman N, Sawaed A, Hardak E, Henes J, Slobodin G, Rimar D. Neutrophil-to-lymphocyte ratio as a biomarker for clinical response after autologous haematopoietic stem cell transplantation in systemic sclerosis. Rheumatology (Oxford) 2025; 64:3160-3165. [PMID: 39485492 DOI: 10.1093/rheumatology/keae606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 09/02/2024] [Accepted: 10/22/2024] [Indexed: 11/03/2024] Open
Abstract
OBJECTIVE SSc is a complex disease that affects various target organs, making it difficult to assess response and determine remission or relapse. A baseline neutrophil-to-lymphocyte ratio (NLR) >2.95 is associated with severe progressive skin and lung disease and decreased 5-year survival in SSc. However, it is unknown whether NLR changes in response to treatment. To retrospectively evaluate NLR changes as a biomarker for treatment response in SSc. METHODS Progressive diffuse SSc patients who were treated with autologous haematopoietic stem cell transplantation (AHSCT group), with combination therapy of rituximab and MMF (combination group) or chimeric antigen receptor-T-cell (CAR-T) therapy group, were recruited along with healthy controls (HC group). NLR, modified Rodnan Skin Score (mRSS) and forced vital capacity (FVC)% predicted were repeatedly assessed over 2 years. RESULTS Fifteen patients were recruited in the AHSCT group, 15 in the combination group and 6 patients in the CAR-T group. Baseline mean NLR was high (>2.95) in AHSCT, combination groups and CAR-T compared with HC. All treatment arms showed a statistically significant decrease in mRSS values and an increase in FVC% at each time point up to 12 months. In a linear mixed model, NLR significantly decreased up to 24 months only in the AHSCT group. NLR correlated with mRSS and FVC exclusively in the AHSCT group. NLR increased above 3 in two patients who experienced a relapse after AHSCT. CONCLUSION NLR is a simple biomarker that correlated with outcome measures in SSc following AHSCT but not with conventional therapy or CAR-T therapy. It is suggested that a decrease in NLR following AHSCT may indicate remission, whereas an increase may be associated with exacerbation. Further research is needed to validate these novel findings.
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Affiliation(s)
- Shiri Keret
- Rheumatology Unit, Faculty of Medicine, Bnai Zion Medical Center, Technion Israel Institute of Technology, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Lisa Kaly
- Rheumatology Unit, Faculty of Medicine, Bnai Zion Medical Center, Technion Israel Institute of Technology, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - George Schett
- Department of Medicine Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinikum, Erlangen, Germany
| | - Christina Bergmann
- Department of Medicine Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinikum, Erlangen, Germany
| | - Erik Feldman
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Tsila Zuckerman
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
- Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa, Israel
| | - Dana Yehudai-Ofir
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
- Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa, Israel
| | - Aniela Shouval
- Rheumatology Unit, Faculty of Medicine, Bnai Zion Medical Center, Technion Israel Institute of Technology, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Abid Awisat
- Rheumatology Unit, Faculty of Medicine, Bnai Zion Medical Center, Technion Israel Institute of Technology, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Itzhak Rosner
- Rheumatology Unit, Faculty of Medicine, Bnai Zion Medical Center, Technion Israel Institute of Technology, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Michael Rozenbaum
- Rheumatology Unit, Faculty of Medicine, Bnai Zion Medical Center, Technion Israel Institute of Technology, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Nina Boulman
- Rheumatology Unit, Faculty of Medicine, Bnai Zion Medical Center, Technion Israel Institute of Technology, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Alaa Sawaed
- Rheumatology Unit, Faculty of Medicine, Bnai Zion Medical Center, Technion Israel Institute of Technology, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Emilia Hardak
- Pulmonology Unit, Faculty of Medicine, Bnai Zion Medical Center, Technion Israel Institute of Technology, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Jörg Henes
- Centre for Interdisciplinary Clinical Immunology, Rheumatology and Auto-inflammatory Diseases and Department of Internal Medicine II, University Medical Centre Tübingen, Tübingen, Germany
| | - Gleb Slobodin
- Rheumatology Unit, Faculty of Medicine, Bnai Zion Medical Center, Technion Israel Institute of Technology, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Doron Rimar
- Rheumatology Unit, Faculty of Medicine, Bnai Zion Medical Center, Technion Israel Institute of Technology, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
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Chen C, Nishtala A, Li E, Schultz WM, Baldridge AS, Groenendyk JW, Lee DC, Shah SJ, Burt RK, Freed BH. The effect of hematopoietic stem cell transplantation on cardiac mechanics in systemic sclerosis. THE INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING 2025; 41:879-887. [PMID: 40009120 DOI: 10.1007/s10554-025-03365-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 02/13/2025] [Indexed: 02/27/2025]
Abstract
Systemic sclerosis (SSc) is an autoimmune disease that causes inflammation and fibrosis. Cardiac involvement in SSc is often subclinical and portends a worse prognosis. Autologous hematopoietic stem cell transplant (HSCT) improves survival in SSc but its effect on cardiac function is unknown. This study aimed to assess HSCT's effect on cardiac mechanics in SSc. Participants with SSc who received HSCT at a single academic center between 2009 and 2018 were identified from a prospective registry. All participants underwent comprehensive conventional and speckle-tracking echocardiography (STE) pre- and post-HSCT, and right heart catheterization before HSCT. Baseline and follow-up clinical and echocardiographic variables were compared. Among 88 HSCT recipients (age 51±11 years, 75% female), there was significant improvement of right ventricular (RV) strain globally (18.1±3.9% versus 20.0±4.5%, p < 0.01) and within the RV free wall (20.7±5.3% versus 23.2±5.6%, p < 0.01). Regionally, RV free wall strain improved in the mid (20.4±9.5% versus 23.7±8.0%, p = 0.04) and apical (15.3±8.6% versus 20.9±9.0%, p < 0.01) segments, but not the basal segment. While left ventricular (LV) strain did not change, left atrial (LA) reservoir strain improved (35.9±8.7% versus 47.8±11.4%, p < 0.01) and LA stiffness index (0.24±0.12 versus 0.18±0.08, p < 0.01) decreased post-HSCT. RV and LA mechanics significantly improve after HSCT among patients with SSc. This suggests a favorable effect of HSCT on the underlying myocardial pathology caused by SSc.
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Affiliation(s)
- Chen Chen
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | | | - Emily Li
- Division of Cardiology, Department of Medicine, Montefiore Medical Center, Bronx, NY, USA
| | - William M Schultz
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Abigail S Baldridge
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, 676 N. St. Clair St., Suite 600, Chicago, IL, 60611, USA
| | - Jacob W Groenendyk
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Daniel C Lee
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, 676 N. St. Clair St., Suite 600, Chicago, IL, 60611, USA
| | - Sanjiv J Shah
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, 676 N. St. Clair St., Suite 600, Chicago, IL, 60611, USA
| | - Richard K Burt
- Division of Immunotherapy and Autoimmune Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Benjamin H Freed
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, 676 N. St. Clair St., Suite 600, Chicago, IL, 60611, USA.
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8
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Mongin D, Matucci-Cerinic M, Walker UA, Distler O, Becvar R, Siegert E, Ananyeva LP, Smith V, Alegre-Sancho JJ, Yavuz S, Limonta M, Riemekasten G, Rezus E, Vonk M, Truchetet ME, Del Galdo F, Courvoisier DS, Iudici M. Oral Glucocorticoids for Skin Fibrosis in Early Diffuse Systemic Sclerosis: A Target Trial Emulation Study From the European Scleroderma Trials and Research Group Database. Arthritis Care Res (Hoboken) 2025; 77:649-657. [PMID: 39542851 DOI: 10.1002/acr.25469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 10/22/2024] [Accepted: 11/04/2024] [Indexed: 11/17/2024]
Abstract
OBJECTIVE The objective of this study is to evaluate whether adding oral glucocorticoids to immunosuppressive therapy improves skin scores and ensures safety in patients with early diffuse cutaneous systemic sclerosis (dcSSc). METHODS We performed an emulated randomized trial comparing the changes from baseline to 12 ± 3 months of the modified Rodnan skin score (mRSS: primary outcome) in patients with early dcSSc receiving either oral glucocorticoids (≤20 mg/day prednisone equivalent) combined with immunosuppression (treated) or immunosuppression alone (controls), using data from the European Scleroderma Trials and Research Group. Secondary end points were the difference occurrence of progressive skin or lung fibrosis and scleroderma renal crisis. Matching propensity score was used to adjust for baseline imbalance between groups. RESULTS We matched 208 patients (mean age 49 years; 33% male; 59% anti-Scl70), 104 in each treatment group, obtaining comparable characteristics at baseline. In the treated group, patients received a median prednisone dose of 5 mg/day. Mean mRSS change at 12 ± 3 months was similar in the two groups (decrease of 2.7 [95% confidence interval {95% CI} 1.4-4.0] in treated vs 3.1 [95% CI 1.9-4.4] in control, P = 0.64). Similar results were observed in patients with shorter disease duration (≤ 24 months) or with mRSS ≤22. There was no between-group difference for all prespecified secondary outcomes. A case of scleroderma renal crisis occurred in both groups. CONCLUSION We did not find any significant benefit of adding low-dose oral glucocorticoids to immunosuppression for skin fibrosis, and at this dosage, glucocorticoid did not increase the risk of scleroderma renal crisis.
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Affiliation(s)
- Denis Mongin
- Geneva University Hospitals, Geneva, Switzerland
| | - Marco Matucci-Cerinic
- IRCCS San Raffaele Scientific Institute, IRCCS San Raffaele Hospital, and Vita-Salute San Raffaele University, Milan, Italy
| | | | | | | | | | - Lidia P Ananyeva
- V.A. Nasonova Research Institute of Rheumatology Russian Federation, Moskow, Russia
| | - Vanessa Smith
- Ghent University, Ghent University Hospital, and VIB Inflammation Research Center, Ghent, Belgium
| | | | - Sule Yavuz
- Istanbul Bilim University, Altunizade-Istanbul, Turkey
| | | | - Gabriela Riemekasten
- Klinik Für Rheumatologie Und Klinische Immunologie, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany
| | - Elena Rezus
- Grigore T. Popa University of Medicine and Pharmacy Iasi, Rehabilitation Hospital Iasi, Romania
| | - Madelon Vonk
- Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marie-Elise Truchetet
- National Reference Center for Systemic Autoimmune Rare Diseases, Bordeaux University Hospital, Hôpital Pellegrin, Bordeaux, France
| | - Francesco Del Galdo
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
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9
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Volkmann ER, Tashkin DP, Smith V. Re-envisioning clinical trial design in systemic sclerosis. Expert Rev Clin Immunol 2025; 21:555-565. [PMID: 40339169 DOI: 10.1080/1744666x.2025.2500612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 04/25/2025] [Indexed: 05/10/2025]
Abstract
INTRODUCTION Systemic sclerosis (SSc) is a progressive autoimmune rheumatic disease with high morbidity and mortality and few effective treatment options. Increased biopharmaceutical investment in therapeutic development for rare diseases has created new opportunities for drug discovery in SSc. However, despite the increased pipeline activity in SSc, success rates remain dismally low. AREAS COVERED This review describes the current state of therapeutic development in SSc with an in-depth coverage of cohort enrichment strategies, as well as a discussion of relevant ethical and feasibility concerns. This review also highlights lessons learned from phase 3 trials in SSc published within the last 5 years in PubMed, underscoring the impact of background therapy on SSc disease course during the trial period. Emerging clinical trial formats and endpoints are also explored. EXPERT OPINION The authors present recommendations to innovate clinical trial design in SSc, which integrate evidence from recent clinical trial and observational cohort studies in SSc. With a focus on the use of external control arms, the application of adaptive trial design and the development of global disease activity measures, the authors outline practical and ethical solutions to design precise and efficient trials in SSc with a higher probability of success.
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Affiliation(s)
| | - Donald P Tashkin
- Department of Medicine, University of California, Los Angeles, California, USA
| | - Vanessa Smith
- Department of Internal Medicine, Ghent University, Ghent, Belgium
- Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
- Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center (IRC), Ghent, Belgium
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10
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Georges GE, Khanna D, Wener MH, Mei MG, Mayes MD, Simms RW, Sanchorawala V, Hosing C, Kafaja S, Pawarode A, Holmberg LA, Kolfenbach J, Furst DE, Sullivan KM, Huang S, Gooley T, Nash RA. Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation for Diffuse Cutaneous Systemic Sclerosis: Identifying Disease Risk Factors for Toxicity and Long-Term Outcomes in a Prospective, Single-Arm Trial. Arthritis Rheumatol 2025; 77:571-581. [PMID: 39624016 PMCID: PMC12039467 DOI: 10.1002/art.43072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 10/18/2024] [Accepted: 11/13/2024] [Indexed: 01/16/2025]
Abstract
OBJECTIVE Two randomized trials for patients with diffuse systemic sclerosis (SSc) demonstrated an overall survival (OS) and event-free survival (EFS) advantage of autologous hematopoietic stem cell transplantation (AHSCT) using CD34+ selected peripheral blood stem cells (PBSCs) compared with monthly cyclophosphamide (CY). We asked if an unmodified PBSC graft followed by maintenance mycophenolate mofetil (MMF) after AHSCT, instead of a CD34+ selected graft, could provide comparable AHSCT outcomes. METHODS Twenty patients with high-risk SSc were enrolled in a prospective, single-arm trial with CY 200 mg/kg and horse antithymocyte globulin (ATG; CY200/ATG), followed by unmanipulated autologous PBSC, and then MMF maintenance starting at 2 months after AHSCT. RESULTS Point estimates of OS and EFS at 5 years after AHSCT were 85% (95% confidence interval [CI] 60.4%-94.9%) and 75% (95% CI 50%-88.7%), respectively. Median follow-up was 7.5 years (range 5.6-11.6) after transplant for living patients. Eight patients (40%) required intensive care unit treatment early after transplant. Early transplant-related mortality occurred in two patients (10%). Five patients developed relapse/progression of SSc after AHSCT. Four of nine patients with anti-RNA polymerase III antibodies had prior scleroderma renal crisis and the lowest quartile of estimated glomerular filtration rate (eGFR) on study entry; all four patients developed prolonged organ failure/death early after transplant. CONCLUSION We observed favorable OS and EFS after AHSCT for patients with SSc, using CY200/ATG, unmanipulated PBSCs, and MMF posttransplant maintenance, which was comparable to trials with CD34+ graft selection. We identified a possible risk factor, pretransplant low eGFR, for adverse outcomes after AHSCT.
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Affiliation(s)
- George E. Georges
- Northwestern University Feinberg School of Medicine, Chicago, Fred Hutchinson Cancer Center and University of WashingtonSeattle
| | | | | | | | | | - Robert W. Simms
- (current address: Dartmouth Geisel School of Medicine, Hannover, New Hampshire), Boston Medical Center and Boston UniversityBostonMassachusetts
| | - Vaishali Sanchorawala
- (current address: Dartmouth Geisel School of Medicine, Hannover, New Hampshire), Boston Medical Center and Boston UniversityBostonMassachusetts
| | | | | | | | | | | | | | | | | | - Ted Gooley
- Fred Hutchinson Cancer CenterSeattleWashington
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11
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Bautista Sanchez R, Khader Y, Khanna D. Management of cutaneous manifestations of systemic sclerosis: current approaches and emerging therapies. Curr Opin Rheumatol 2025; 37:167-175. [PMID: 40028795 DOI: 10.1097/bor.0000000000001082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
PURPOSE OF REVIEW This review summarizes the most recent approaches in managing cutaneous involvement, one of the main clinical manifestations of systemic sclerosis (SSc). The following article is written for clinicians and researchers looking for optimizing patient care and exploring new therapies. RECENT FINDINGS Recent studies have shown advancements in the management of cutaneous manifestations of SSc. While mycophenolate remains the first-line treatment, other immunosuppressive therapies targeting different pathways have shown promising results. B-cell depleting agents, such as Rituximab (RTX), are being increasingly utilized for cutaneous scleroderma with positive outcomes. Intravenous immunoglobulins (IVIG) have also demonstrated potential benefit for refractory cases with advanced skin fibrosis.Moreover, emerging approaches such as autologous hematopoietic stem cell transplant (AHSCT) have been evaluated in clinical trials, with evidence suggesting its ability to reset the immune system and achieve remission in skin involvement in severe cases. Chimeric antigen receptor (CAR) T cell therapy is the most recent potential pathway to target refractory skin and systemic disease. SUMMARY Management of cutaneous involvement in SSc remains challenging. The following study provides a comprehensive review of the most recent updates in treating cutaneous aspects (and associated complications) of SSc to help clinicians establish a more effective approach managing this condition.
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Affiliation(s)
| | | | - Dinesh Khanna
- Division of Rheumatology, Department of Medicine
- University of Michigan Scleroderma Program, University of Michigan, Ann Arbor, MI, USA
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12
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Mougiakakos D, Meyer EH, Schett G. CAR T cells in autoimmunity: game changer or stepping stone? Blood 2025; 145:1841-1849. [PMID: 39700499 DOI: 10.1182/blood.2024025413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 11/19/2024] [Accepted: 12/11/2024] [Indexed: 12/21/2024] Open
Abstract
ABSTRACT The advent of chimeric antigen receptor (CAR) T cells has revolutionized the treatment landscape for hematologic malignancies, and emerging evidence suggests their potential in autoimmune diseases (AIDs). This article evaluates the early successes and future implications of B-cell-targeting CAR T-cell therapy in AIDs. Initial applications, particularly in refractory systemic lupus erythematosus, have demonstrated significant and durable clinical remissions, with accompanying evaluation of the immune system suggesting a so-called "reset" of innate inflammation and adaptive autoimmunity. This has generated widespread interest in expanding this therapeutic approach. CAR T cells offer unique advantages over other treatment modalities, including very deep B-cell depletion and unique therapeutic activity within inflamed tissues and associated lymphoid structures. However, the field must address key concerns, including long-term toxicity, particularly the risk of secondary malignancies, and future accessibility given the higher prevalence of AIDs compared with malignancies. Technological advances in cell therapy, such as next-generation CAR T cells, allogeneic off-the-shelf products, and alternative cell types, such as regulatory CAR T cells, are being explored in AIDs to improve efficacy and safety. In addition, bispecific antibodies are emerging as potential alternatives or complements to CAR T cells, potentially offering comparable efficacy without the need for complex logistics, lymphodepletion, and the risk of insertional mutagenesis. As the field evolves, cellular therapists will play a critical role in the multidisciplinary teams managing these complex cases. The transformative potential of CAR T cells in AIDs is undeniable, but careful consideration of safety, efficacy, and implementation is essential as this novel therapeutic approach moves forward.
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Affiliation(s)
- Dimitrios Mougiakakos
- Department of Hematology, Oncology, and Cell Therapy, Otto von Guericke University, Magdeburg, Germany
| | - Everett H Meyer
- Cellular Immune Tolerance Program, Blood and Marrow Transplantation and Cellular Therapy Division, Stanford School of Medicine, Stanford University, Stanford, CA
| | - Georg Schett
- Department of Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University, Erlangen, Germany
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Jamali M, Bautista Sanchez R, Agarwal P, Khanna D. Advances and future outlook in clinical trials for treating systemic sclerosis-interstitial lung disease. Expert Rev Respir Med 2025:1-13. [PMID: 40197088 DOI: 10.1080/17476348.2025.2490729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 04/04/2025] [Indexed: 04/09/2025]
Abstract
INTRODUCTION Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is a common complication of systemic sclerosis (SSc), contributing significantly to morbidity and mortality. We aim to bridge knowledge gaps, inform clinical practice, and identify future research directions in this rapidly evolving field. AREAS COVERED This review provides a comprehensive analysis of the current understanding and emerging advances in the diagnosis, risk stratification, and treatment of SSc-ILD. High-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) remain cornerstones of diagnosis, but limitations in sensitivity underscore the need for biomarkers such as Chemokine (C-C motif) Ligand 18 (CCL18), Krebs von den Lungen-6 (KL-6), Interleukin-6 (IL-6), and C-reactive protein (CRP) to enhance prognostic precision and treatment personalization. Therapeutic strategies emphasize immunosuppressants alongside antifibrotic agents. Emerging combination therapies and advanced modalities, including hematopoietic stem cell transplantation and chimeric antigen receptor T-cell therapy, show promise in refractory cases. Ongoing clinical trials exploring innovative targets highlight the evolving therapeutic landscape. The review emphasizes challenges in clinical trial design, advocating for adaptive and platform trial methodologies to address disease heterogeneity and enhance treatment sensitivity. EXPERT OPINION Advances in biomarkers, composite indices, and personalized therapeutic approaches are key to overcoming existing limitations and improving outcomes for patients with SSc-ILD.
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Affiliation(s)
- Marzieh Jamali
- Division of Rheumatology, Department of Medicine, University of Michigan Scleroderma Program, Ann Arbor, MI, USA
- Department of Medicine, University of Michigan Scleroderma Program, Ann Arbor, MI, USA
| | - Rocio Bautista Sanchez
- Division of Rheumatology, Department of Medicine, University of Michigan Scleroderma Program, Ann Arbor, MI, USA
| | - Prachi Agarwal
- Department of Radiology, University of Michigan Division of Cardiothoracic Radiology, Ann Arbor, MI, USA
| | - Dinesh Khanna
- Division of Rheumatology, Department of Medicine, University of Michigan Scleroderma Program, Ann Arbor, MI, USA
- Department of Medicine, University of Michigan Scleroderma Program, Ann Arbor, MI, USA
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14
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Di Donato S, McMahan ZH, Hughes M. Systemic pharmacotherapy approaches for the treatment of systemic sclerosis. Expert Opin Pharmacother 2025; 26:551-566. [PMID: 39981635 DOI: 10.1080/14656566.2025.2470846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 02/14/2025] [Accepted: 02/19/2025] [Indexed: 02/22/2025]
Abstract
INTRODUCTION Systemic sclerosis (SSc) represents a complex, multisystem rheumatologic disorder characterized by immune dysregulation, vascular dysfunction, and multi-organ fibrosis. This review discusses the efficacy of the available therapeutic options and the significance of developing effective strategies against its varied manifestations, pivotal to improving patient outcomes. AREAS COVERED The review elaborates on the pharmacological treatments available for managing key manifestations of SSc, including skin and lung involvement, and vascular complications, as well as the most recent findings in the field. We evaluated recent literature and clinical trials from the past decade, as well as most recent guidelines from entities like EULAR and the ACR, to provide a comprehensive overview of current management strategies. EXPERT OPINION Despite advancements in therapeutic options, SSc remains a challenging disease to manage due to its complexity, our relatively limited understanding of disease pathogenesis, and its severe impact on quality of life. The development of targeted therapies and the refinement of existing treatment protocols offer hope for better management. Future research should focus on personalized medicine approaches and refining treatment algorithms to optimize outcomes for patients.
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Affiliation(s)
- Stefano Di Donato
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals Trust, Leeds, UK
- CNRS, ImmunoConcEpT, Univ. Bordeaux, Bordeaux, Nouvelle-Aquitaine, France
| | - Zsuzsanna H McMahan
- Department of Medicine, Division of Rheumatology, UTHealth Houston, Houston, TX, USA
| | - Michael Hughes
- Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, Centre for Musculoskeletal Research, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
- Northern Care Alliance NHS Foundation Trust, Salford Care Organisation, Department of Rheumatology, Salford, UK
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15
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Spierings J, Bandini G, Allanore Y, Papa ND, Denton CP, Distler O, Furst DE, Greco R, Khanna D, Kuwana M, Matucci-Cerinic M, Nikpour M, van Rhenen A, van Laar JM, Hughes M. Management of disease progression after autologous hematopoietic stem cell transplantation in systemic sclerosis: Results from an international questionnaire-based study. Semin Arthritis Rheum 2025; 71:152638. [PMID: 39914262 DOI: 10.1016/j.semarthrit.2025.152638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 12/16/2024] [Accepted: 12/19/2024] [Indexed: 03/08/2025]
Abstract
OBJECTIVE Autologous stem cell transplantation (AHSCT) is an established treatment in diffuse cutaneous systemic sclerosis (dcSSc). Optimal management of disease progression after AHSCT in dcSSc has not been defined. The aim of this study was to explore the experience and preferences of SSc experts on post-AHSCT management. METHODS An online questionnaire study was conducted containing 17 questions concerning respondent demographics, definition of SSc progression after AHSCT, diagnostic work-up and treatment preferences. RESULTS In total, 69 respondents from 21 countries completed the questionnaire. The majority (89.7 %) works at a university hospital, and were involved in decisions regarding AHSCT in patients with SSc (71 %). Most have 1 to 5 patients who underwent AHSCT under their care. They defined failure to improve after AHSCT as: an increase in mRSS, new onset or worsening of interstitial lung disease (ILD), new onset scleroderma renal crisis (SRC) or inflammatory arthritis. Progression after initial response was defined as: increase in mRSS, new or worsening of ILD, new SRC, inflammatory arthritis, new pulmonary arterial hypertension, digital vasculopathy or impaired physical functioning. The most frequent therapy in case of AHSCT failure was mycophenolate mofetil (N = 55, 88.7 %), rituximab (N = 54, 87.1 %), nintedanib (N = 39, 62.9 %) or/and tocilizumab (N = 36, 58.1 %). Combination therapy with more than one of these agents was considered by most respondents (N = 61, 88.4 %). CONCLUSION Our study benchmarks the unique combined experiences of post-AHSCT management among SSc experts. We summarize preferences regarding definition of AHSCT failure and progression after response, as well as approach to diagnostic work-up and treatment.
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Affiliation(s)
- Julia Spierings
- Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands; Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School Royal Free Campus, London, United Kingdom.
| | - Giulia Bandini
- Department of Experimental and Clinical Medicine, University of Florence, Careggi Hospital, Florence, Italy
| | - Yannick Allanore
- Department of Rheumatology A, Cochin Hospital, René Descartes University, Paris, France
| | - Nicoletta Del Papa
- Scleroderma Clinic, ASST Pini-CTO, Università degli Studi di Milano, Milano, Italy
| | - Christopher P Denton
- Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School Royal Free Campus, London, United Kingdom
| | - Oliver Distler
- Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | | | - Raffaella Greco
- Unit of Haematology and Bone Marrow Transplantation, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Dinesh Khanna
- University of Michigan Scleroderma Program, Ann Arbor, MI, USA
| | - Masataka Kuwana
- Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Marco Matucci-Cerinic
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), & Inflammation, fibrosis and aging Initiative (INFLAGE), IRCCS Ospedale San Raffaele, Milano, Italy; Vita Salute San Raffaele University, Milano, Italy
| | - Mandana Nikpour
- The University of Sydney School of Public Health, Royal Prince Alfred Hospital Sydney, MSK Research Flagship Centre, University of Sydney, Sydney, New South Wales, Australia
| | - Anna van Rhenen
- Department of Haematology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Jacob M van Laar
- Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Michael Hughes
- Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Northern Care Alliance NHS Foundation Trust, Salford Care Organisation, Salford, UK
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16
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Foeldvari I, Torok KS, Silva J, Denton CP, Henes J, Horvei P, Rosser F, Orteu CH, Li SC, Pain CE, Constantin T, Costa-Reis P, Curran ML, Cutolo M, Hinrichs B, Fligelstone K, Maillard S, Moinzadeh P, Pilkington C, Schraven L, Smith V. Guidance for stem cell therapy for juvenile systemic sclerosis patients. Expert Rev Clin Immunol 2025; 21:435-450. [PMID: 40056160 DOI: 10.1080/1744666x.2025.2474216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 02/10/2025] [Accepted: 02/26/2025] [Indexed: 03/10/2025]
Abstract
INTRODUCTION Autologous stem cell transplantation (ASCT) and cellular therapies (CTs) are emerging therapeutic options for both adult and juvenile-onset systemic sclerosis (jSSc) patients. However, most efficacy data are derived from adult studies, and it remains unclear whether adult stem cell transplant criteria are fully applicable to pediatric patients with jSSc. Given pediatric patients' unique potential for recovery and tissue remodeling, the stringent criteria used in adults need adaptation for children. AREAS COVERED We reviewed the current data on indications, patient selection, and outcomes of ASCT and CTs in both adult and pediatric patients with systemic sclerosis. At a multidisciplinary expert workshop held in Hamburg, Germany, in December 2023, we developed consensus guidance on when to consider ASCT and cellular therapies in jSSc. EXPERT OPINION HSCT and CT hold promise as treatment options for jSSc. Our proposed guidance aims to standardize inclusion criteria globally, enhancing comparability of outcomes across future procedures. Establishing consistent inclusion/exclusion criteria and transplant protocols will enable better data collection, interpretation, and ultimately improve outcomes and care for jSSc patients.
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Affiliation(s)
- Ivan Foeldvari
- Hamburg Centre for Pediatric and Adolescent Rheumatology, Schön Klinik Hamburg Eilbek, Hamburg, Germany
| | - Kathryn S Torok
- University of Pittsburgh School of Medicine and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | | | | | - Jörg Henes
- Centre for Interdisciplinary Clinical Immunology, Rheumatology and Autoinflammatory Diseases and Department for Internal Medicine II, University Hospital Tübingen, Tübingen, Germany
| | - Paulina Horvei
- University of Pittsburgh School of Medicine and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Franziska Rosser
- University of Pittsburgh School of Medicine and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Catherine H Orteu
- UCL Institute of Immunity and Transplantation, Royal Free London NHS Foundation Trust, London, UK
| | - Suzanne C Li
- Joseph M Sanzari Children's Hospital, Hackensack Meridian School of Medicine, Hackensack, NJ, USA
| | - Clare E Pain
- Alder Hey Children's Foundation NHS Trust, Liverpool, UK
| | | | - Patricia Costa-Reis
- Pediatrics Department, Hospital de Santa Maria, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Megan L Curran
- University of Colorado School of Medicine, Aurora, CO, USA
| | - Maurizio Cutolo
- Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology-Department of Internal Medicine and Specialties, University of Genoa and IRCCS San Martino Polyclinic Hospital, Genoa, Italy
| | - Bernd Hinrichs
- Children's pulmonology, Asklepios Klinik Nord - Heidberg, Hamburg, Germany
| | - Kim Fligelstone
- Scleroderma & Raynaud's United Kindgom (SRUK) (Research Subcommittee, Patient Research Partner, FESCA, London, UK
| | | | - Pia Moinzadeh
- Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany
| | | | | | - Vanessa Smith
- Department of Internal Medicine, Ghent University, Ghent, Belgium
- Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
- Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center (IRC), Ghent, Belgium
- ERN ReCONNET
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Wiewiórska-Krata N, Foroncewicz B, Mucha K, Zagożdżon R. Cell therapies for immune-mediated disorders. Front Med (Lausanne) 2025; 12:1550527. [PMID: 40206475 PMCID: PMC11980423 DOI: 10.3389/fmed.2025.1550527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 02/17/2025] [Indexed: 04/11/2025] Open
Abstract
Immune-mediated disorders are a broad range of diseases, arising as consequence of immune defects, exaggerated/misguided immune response or a mixture of both conditions. Their frequency is on a rise in the developed societies and they pose a significant challenge for diagnosis and treatment. Traditional pharmacological, monoclonal antibody-based or polyclonal antibody replacement-based therapies aiming at modulation of the immune responses give very often dissatisfactory results and/or are burdened with unacceptable adverse effects. In recent years, a new group of treatment modalities has emerged, utilizing cells as living drugs, especially with the use of the up-to-date genetic engineering. These modern cellular therapies are designed to offer a high potential for more targeted, safe, durable, and personalized treatment options. This work briefly reviews the latest advances in the treatment of immune-mediated disorders, mainly those related to exaggeration of the immune response, with such cellular therapies as hematopoietic stem cells (HSCs), mesenchymal stromal cells (MSCs), regulatory T cells (Tregs), chimeric antigen receptor (CAR) T cells and others. We highlight the main features of these therapies as new treatment options for taming the dysregulated immune system. Undoubtfully, in near future such therapies can provide lasting remissions in a range of immune-mediated disorders with reduced treatment burden and improved quality of life for the patients.
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Affiliation(s)
- Natalia Wiewiórska-Krata
- Laboratory of Cellular and Genetic Therapies, Center for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
- ProMix Center (ProteogenOmix in Medicine), Department of Clinical Immunology, Medical University of Warsaw, Warsaw, Poland
| | - Bartosz Foroncewicz
- ProMix Center (ProteogenOmix in Medicine), Department of Clinical Immunology, Medical University of Warsaw, Warsaw, Poland
- Department of Transplantology, Immunology, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof Mucha
- ProMix Center (ProteogenOmix in Medicine), Department of Clinical Immunology, Medical University of Warsaw, Warsaw, Poland
- Department of Transplantology, Immunology, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Radosław Zagożdżon
- Laboratory of Cellular and Genetic Therapies, Center for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
- Department of Transplantology, Immunology, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
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18
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Rieder F, Nagy LE, Maher TM, Distler JHW, Kramann R, Hinz B, Prunotto M. Fibrosis: cross-organ biology and pathways to development of innovative drugs. Nat Rev Drug Discov 2025:10.1038/s41573-025-01158-9. [PMID: 40102636 DOI: 10.1038/s41573-025-01158-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2025] [Indexed: 03/20/2025]
Abstract
Fibrosis is a pathophysiological mechanism involved in chronic and progressive diseases that results in excessive tissue scarring. Diseases associated with fibrosis include metabolic dysfunction-associated steatohepatitis (MASH), inflammatory bowel diseases (IBDs), chronic kidney disease (CKD), idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc), which are collectively responsible for substantial morbidity and mortality. Although a few drugs with direct antifibrotic activity are approved for pulmonary fibrosis and considerable progress has been made in the understanding of mechanisms of fibrosis, translation of this knowledge into effective therapies continues to be limited and challenging. With the aim of assisting developers of novel antifibrotic drugs, this Review integrates viewpoints of biologists and physician-scientists on core pathways involved in fibrosis across organs, as well as on specific characteristics and approaches to assess therapeutic interventions for fibrotic diseases of the lung, gut, kidney, skin and liver. This discussion is used as a basis to propose strategies to improve the translation of potential antifibrotic therapies.
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Affiliation(s)
- Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA.
- Program for Global Translational Inflammatory Bowel Diseases (GRID), Chicago, IL, USA.
| | - Laura E Nagy
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
| | - Toby M Maher
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- National Heart and Lung Institute, Imperial College, London, UK
| | - Jörg H W Distler
- Department of Rheumatology, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
- Hiller Research Center, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - Rafael Kramann
- Department of Nephrology and Clinical Immunology, RWTH Aachen; Medical Faculty, Aachen, Germany
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, Netherlands
| | - Boris Hinz
- Keenan Research Institute for Biomedical Science of the St Michael's Hospital, Toronto, Ontario, Canada
- Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
| | - Marco Prunotto
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland.
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Kersten BE, Lemmers JMJ, Vanhaecke A, Velauthapillai A, van den Hombergh WMT, van den Hoogen FHJ, van den Ende CHM, Smith V, Vonk MC. Efficacy of methylprednisolone in very early systemic sclerosis: results of the 'Hit Hard and Early' randomized controlled trial. Rheumatology (Oxford) 2025; 64:1261-1269. [PMID: 38552324 PMCID: PMC11879336 DOI: 10.1093/rheumatology/keae156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 02/24/2024] [Indexed: 03/06/2025] Open
Abstract
OBJECTIVE We hypothesized that glucocorticoids would induce remission in very early systemic sclerosis (SSc) patients by inhibition of inflammation driving the disease. We examined the efficacy and safety of methylprednisolone in very early SSc. METHODS In this trial adults with puffy fingers for less than 3 years, specific auto-antibodies and meeting the Very Early Diagnosis of Systemic Sclerosis criteria were randomly assigned (2:1) to methylprednisolone 1000 mg i.v. or placebo for three consecutive days three times with monthly intervals. The primary end point was nailfold capillary density at week 12. Capillary density at 52 weeks, number of megacapillaries and patient-reported outcomes were secondary outcomes. In addition, we assessed disease progression and lung function decline over 52 weeks. We used linear regression analyses adjusted for baseline values and stratification variables to estimate differences between groups. RESULTS Between February 2017 and February 2021, 87 patients were screened, of whom 30 (70% female, median [interquartile range, IQR] age 52.9 [40.8-60.8] years, median [IQR] disease duration 11.4 [4.6-18.6] months) were randomly assigned to methylprednisolone (n = 21) or placebo (n = 9). We found no difference in nailfold capillary density at 12 weeks (-0.5 [95% CI: -1.1, 0.2]) nor in any of the secondary outcomes. Eleven (37%) patients showed disease progression during 1 year follow-up, and seven (23%) patients had a relevant pulmonary function decline. No serious adverse events were reported. CONCLUSION No clinically relevant effect of short-term methylprednisolone in patients with very early SSc was observed. A substantial proportion of patients showed disease progression. TRIAL REGISTRATION clinicaltrials.gov, NCT03059979.
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Affiliation(s)
- Brigit E Kersten
- Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jacqueline M J Lemmers
- Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Amber Vanhaecke
- Department of Rheumatology, University Hospital Gent, Gent, Belgium
| | - Arthiha Velauthapillai
- Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | | | | | - Vanessa Smith
- Department of Rheumatology, University Hospital Gent, Gent, Belgium
| | - Madelon C Vonk
- Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
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20
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Lungova K, Putman M. Barriers to CAR T-cell therapy in rheumatology. THE LANCET. RHEUMATOLOGY 2025; 7:e212-e216. [PMID: 39515366 DOI: 10.1016/s2665-9913(24)00240-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/01/2024] [Accepted: 08/02/2024] [Indexed: 11/16/2024]
Abstract
Chimeric antigen receptor (CAR) T cells have recently shown remarkable promise in treating rheumatic diseases, including systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies, and systemic sclerosis. Currently, there are 37 clinical trials registered for CAR T-cell therapy in rheumatic diseases and many more are being planned. Much of this enthusiasm is justifiable, but widespread adoption of CAR T-cell therapy in rheumatology faces several barriers. The trajectory of autoimmune diseases differs from malignancies and a surprisingly narrow population could be eligible for CAR T-cell therapy. Current CAR T-cell approaches rely on B-cell depletion, which has a mixed record of success for many diseases. The high cost of CAR T-cell therapy and potential safety concerns, such as cytokine release syndrome and long-term infection risks, also pose substantial challenges. Moving forward, more targeted CAR T-cell approaches, such as antigen-specific chimeric autoantibody receptors or chimeric autoantigen T-cell receptors, could offer greater efficacy and safety in treating rheumatic diseases.
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Affiliation(s)
- Karolina Lungova
- Division of Rheumatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Michael Putman
- Division of Rheumatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
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21
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Abraham DJ, Black CM, Denton CP, Distler JHW, Domsic R, Feghali-Bostwick C, Gourh P, Hinchcliff M, Kolling F, Kuwana M, Lafyatis R, Landegren U, Mahoney JM, Martin J, Matucci-Cerinic M, McMahan ZH, Mora AL, Mouthon L, Rabinovitch M, Rojas M, Rubin K, Trojanowska M, Varga J, Whitfield ML, Gabrielli A, Krieg T. An international perspective on the future of systemic sclerosis research. Nat Rev Rheumatol 2025; 21:174-187. [PMID: 39953141 DOI: 10.1038/s41584-024-01217-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2024] [Indexed: 02/17/2025]
Abstract
Systemic sclerosis (SSc) remains a challenging and enigmatic systemic autoimmune disease, owing to its complex pathogenesis, clinical and molecular heterogeneity, and the lack of effective disease-modifying treatments. Despite a century of research in SSc, the interconnections among microvascular dysfunction, autoimmune phenomena and tissue fibrosis in SSc remain unclear. The absence of validated biomarkers and reliable animal models complicates diagnosis and treatment, contributing to high morbidity and mortality. Advances in the past 5 years, such as single-cell RNA sequencing, next-generation sequencing, spatial biology, transcriptomics, genomics, proteomics, metabolomics, microbiome profiling and artificial intelligence, offer new avenues for identifying the early pathogenetic events that, once treated, could change the clinical history of SSc. Collaborative global efforts to integrate these approaches are crucial to developing a comprehensive, mechanistic understanding and enabling personalized therapies. Challenges include disease classification, clinical heterogeneity and the establishment of robust biomarkers for disease activity and progression. Innovative clinical trial designs and patient-centred approaches are essential for developing effective treatments. Emerging therapies, including cell-based and fibroblast-targeting treatments, show promise. Global cooperation, standardized protocols and interdisciplinary research are vital for advancing SSc research and improving patient outcomes. The integration of advanced research techniques holds the potential for important breakthroughs in the diagnosis, treatment and care of individuals with SSc.
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Affiliation(s)
- David J Abraham
- Department of Inflammation and Rare Diseases, UCL Centre for Rheumatology, UCL Division of Medicine, Royal Free Hospital Campus, London, UK.
| | - Carol M Black
- Department of Inflammation and Rare Diseases, UCL Centre for Rheumatology, UCL Division of Medicine, Royal Free Hospital Campus, London, UK
| | - Christopher P Denton
- Department of Inflammation and Rare Diseases, UCL Centre for Rheumatology, UCL Division of Medicine, Royal Free Hospital Campus, London, UK
| | - Jörg H W Distler
- Department of Rheumatology, University Hospital Düsseldorf, Medical Faculty of the Heinrich-Heine University, Düsseldorf, Germany
- Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, Germany
| | - Robyn Domsic
- Division of Rheumatology, Department of Internal Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Carol Feghali-Bostwick
- Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Pravitt Gourh
- Scleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Monique Hinchcliff
- Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Fred Kolling
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Masataka Kuwana
- Department of Allergy and Rheumatology. Nippon Medical School Graduate School of Medicine, Tokyo, Japan
| | - Robert Lafyatis
- Division of Rheumatology and Clinical Immunology. University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Ulf Landegren
- Department of Immunology, Genetics and Pathology, Research programme: Molecular Tools and Functional Genomics, Uppsala University, Uppsala, Sweden
| | | | - Javier Martin
- Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain
| | - Marco Matucci-Cerinic
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases and Inflammation, fibrosis and aging Initiative, IRCCS Ospedle San Raffaele and Vita Salute University San Raffaele, Milan, Italy
| | - Zsuzsanna H McMahan
- Department of Internal Medicine, Division of Rheumatology, UTHealth Houston, Houston, TX, USA
| | - Ana L Mora
- Division of Pulmonary, Critical Care and Sleep Medicine, Davis Heart and Lung research Institute, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Luc Mouthon
- Department of Internal Medicine, Reference Center for Rare Systemic Autoimmune and Auto-Inflammatory diseases in Île-de-France, East and West, Cochin Hospital, Public Assistance-Hospitals of Paris, Paris-Centre, Paris Cité University, Paris, France
| | - Marlene Rabinovitch
- Department of Paediatrics, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University School of Medicine, Stanford, CA, USA
- Basic Science and Engineering (BASE) Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA
| | - Mauricio Rojas
- Division of Pulmonary, Critical Care and Sleep Medicine, Davis Heart and Lung research Institute, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Kristofer Rubin
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Maria Trojanowska
- Boston University, Department of Medicine, Arthritis & Autoimmune Diseases Research Center, Boston, MA, USA
| | - John Varga
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, USA
| | - Michael L Whitfield
- Department of Biomedical Data Science, Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Armando Gabrielli
- Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, Germany.
- Foundation of Molecular Medicine and Cellular Therapy Polytechnic University of Marche, Via Tronto, Ancona, Italy.
| | - Thomas Krieg
- Translational Matrix Biology, Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Center for Molecular Medicine (CMMC) University of Cologne, Cologne, Germany.
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22
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Fernández-Codina A, Nevskaya T, Baron M, Appleton CT, Cecchini MJ, Philip A, El-Shimy M, Vanderhoek L, Pinal-Fernández I, Pope JE. Brentuximab vedotin for skin involvement in refractory diffuse cutaneous systemic sclerosis, an open-label trial. Rheumatology (Oxford) 2025; 64:1476-1481. [PMID: 38652570 PMCID: PMC11879290 DOI: 10.1093/rheumatology/keae235] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 04/05/2024] [Accepted: 04/14/2024] [Indexed: 04/25/2024] Open
Abstract
OBJECTIVE We explored the efficacy and safety of brentuximab vedotin, a chimeric anti-CD30 antibody drug conjugate, in patients with severe active diffuse cutaneous systemic sclerosis (dcSSc). METHODS This phase II proof-of-concept, single centre, open-label, single arm, investigator-initiated trial included patients ≥18 years, with dcSSc, modified Rodnan skin score (mRSS) ≥15 with <5 years since the first non-Raynaud's symptom and/or skin worsening despite immunosuppression who were treated with intravenous brentuximab vedotin 0.6 mg/kg q3 weeks for 45 weeks. The primary end point was a decrease in mRSS of ≥8 points at 48 weeks. RESULTS Eleven patients were treated with brentuximab vedotin, with nine completing the study. The mean mRSS reduction at week 48 was 11.3 (95% CI 6.9, 15.8; P = 0.001), meeting the primary end point in the intention to treat analysis (7/11 had a decrease in mRSS ≥8). The % forced vital capacity increased by 7.8% (12.5). The Composite Response Index in dcSSc (CRISS) suggested a beneficial treatment effect (86% ≥0.6). Most adverse events were mild. No SAEs were attributed to brentuximab vedotin. CONCLUSION In dcSSc, brentuximab vedotin improved skin and FVC without safety concerns. A placebo-controlled trial is warranted to corroborate these initial findings. TRIAL REGISTRATION ClinicalTrials.gov, http://clinicaltrials.gov, NCT03198689.
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Affiliation(s)
- Andreu Fernández-Codina
- Division of Rheumatology, Western University, London, ON, Canada
- Division of General Internal Medicine-Windsor Campus, Western University, London, ON, Canada
- Division of Systemic Autoimmune Diseases and Critical Care, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Tatiana Nevskaya
- Division of Rheumatology, Western University, London, ON, Canada
| | - Murray Baron
- Division of Rheumatology, Jewish General Hospital, McGill University, Montreal, QC, Canada
| | | | | | - Amanda Philip
- Division of Rheumatology, Western University, London, ON, Canada
| | - Maha El-Shimy
- Division of Rheumatology, Western University, London, ON, Canada
| | | | - Iago Pinal-Fernández
- Muscle Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Janet E Pope
- Division of Rheumatology, Western University, London, ON, Canada
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23
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Maltez N, Wang M, Wells GA, Tugwell P, Baron M, Marjanovic Z, Lansiaux P, Farge D, Hudson M. Improvement in Skin Fibrosis and Lung Function with Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis. Transplant Cell Ther 2025:S2666-6367(25)01011-5. [PMID: 39938806 DOI: 10.1016/j.jtct.2025.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 01/21/2025] [Accepted: 02/04/2025] [Indexed: 02/14/2025]
Abstract
Systemic sclerosis (SSc) is a severe, progressive disease with limited treatment options. Autologous hematopoietic stem cell transplantation (AHSCT) has been shown to be an effective treatment for rapidly progressive SSc. The objective of this study was to evaluate the effectiveness of AHSCT for SSc compared to real-world clinical care. SSc patients from France who underwent AHSCT were compared to patients from Canada who met criteria for AHSCT (as defined in the ASTIS trial) but received conventional care. The primary outcome was overall survival. Secondary outcomes included modified Rodnan skin score (mRSS) and forced vital capacity (FVC). Overall survival was estimated by Kaplan-Meier survival curves. Measures of mRSS and FVC were compared using linear regression models. Analyses were adjusted for baseline scores and incorporated stabilized inverse probability of treatment weights to account for confounding by indication. Propensity scores were estimated using logistic regression. Forty-one AHSCT patients and 85 conventional care patients were compared. AHSCT was associated with a suggestive, though not statistically significant trend toward improvement in overall survival (log-rank P = .115). In follow-up, the mRSS was lower with AHSCT compared to conventional care: between group difference of 8.81; P ≤ .0001 at 12 months and 11.28; P = .011 at 60 months. There was no significant difference in FVC between groups at 12 months but at 24 months, AHSCT was associated with a higher FVC (between group difference of 10.53 (P = .05)). This study demonstrates with real-world long-term data that compared with conventional care, treatment with AHSCT may offer superior outcomes for SSc patients.
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Affiliation(s)
- Nancy Maltez
- School of Epidemiology and Public Health, University of Ottawa, The Ottawa Hospital, Division of Rheumatology, Ottawa, Canada.
| | | | - Georges A Wells
- Cardiovascular Research Methods Centre, School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
| | - Peter Tugwell
- School of Epidemiology and Public Health, University of Ottawa, The Ottawa Hospital, Division of Rheumatology, Ottawa, Canada
| | - Murray Baron
- McGill University, Jewish General Hospital, Montreal, Canada
| | | | - Pauline Lansiaux
- Université de Paris, IRSL, Recherche clinique appliquée à l'hématologie, Centre de Référence des Maladies auto-immunes systémiques Rares d'Ile-de-France, AP-HP, Hôpital St-Louis, Paris, France
| | - Dominique Farge
- Université de Paris, IRSL, Recherche clinique appliquée à l'hématologie, Centre de Référence des Maladies auto-immunes systémiques Rares d'Ile-de-France, AP-HP, Hôpital St-Louis, Paris, France
| | - Marie Hudson
- Lady Davis Institute, McGill University, Jewish General Hospital, Montreal, Canada
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24
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Baker KF, Spierings J, Brom M, Radstake T, Smith E, Weiss R, Burmester GR. Cure as a treatment target in rheumatoid arthritis and systemic sclerosis-achievable aim or mission impossible? FOREUM stimulates new industry-academia collaboration. Ann Rheum Dis 2025; 84:153-157. [PMID: 39919890 DOI: 10.1136/ard-2024-226772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 10/15/2024] [Indexed: 11/16/2024]
Affiliation(s)
- Kenneth Frank Baker
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Rheumatology Department, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Julia Spierings
- Rheumatology and Clinical Immunology, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
| | | | | | | | | | - Gerd R Burmester
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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25
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Chen H, Yang D, Shi Y, Wu H, Zhu H, Jiang T, Liu S, Wang D. The effect of tocilizumab treatment for skin fibrosis by inhibiting CD38 + macrophages in systemic sclerosis. Cell Immunol 2025; 408:104914. [PMID: 39778381 DOI: 10.1016/j.cellimm.2024.104914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/18/2024] [Accepted: 12/24/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND Dermal and pulmonary fibrosis are the main clinical symptoms of systemic scleroderma (SSc), for which there are no effective therapeutic agents. Tocilizumab is thought to improve the symptoms of fibrosis, but the effect of tocilizumab on dermal fibrosis has not been explored. This study aims to investigate the therapeutic effect of tocilizumab on skin fibrosis by inhibiting CD38+ macrophages in the bleomycin-induced SSc mice model. METHODS The 8-week-old BALB/c mice were randomly divided into three groups: control group (PBS group), model group (BLM group), and tocilizumab group (TCZ group). The mRNA expression of VIMENTIN, TIMP1, and COL1A1 was measured by qPCR. Western blot was used to detect the protein expression of α-SMA, TGF-β, and COL1A1 in skin tissues. The expression of CD38+ macrophages in the BLM-induced fibrosis mouse model was verified by flow cytometry and immunofluorescence. RESULTS In comparison to the PBS control group, mice in the BLM group showed skin fibrosis, edema, thickness, and collagen deposition. The percentage of macrophages in the skin, peripheral blood, and spleen was significantly increased in the BLM group, and the percentage of CD38+ macrophages increased in the skin and peripheral blood but decreased in the spleen. After co-cultured with macrophages, L929 fibroblasts differentiated into myofibroblasts, with increased mRNA expression of COL1A1, COL3A, TGF-β, and Fibronectin. Furthermore, after being stimulated by LPS, RAW264.7 cells showed increased expression of IL-6 and CD38. The mRNA levels of COL1A1, COL1A2, COL3A, TGF-β, and Fibronectin in L929 fibroblasts were markedly increased when co-cultured with LPS-stimulated RAW264.7 cells. Tocilizumab treatment reduced dermal thickness and collagen deposition induced by BLM. Furthermore, the percentage of total macrophages and CD38+ macrophages in the skin and peripheral blood significantly decreased after tocilizumab treatment. CONCLUSION This study revealed that tocilizumab improved skin fibrosis in the SSc mice model, which was mediated by inhibiting skin and peripheral CD38+ macrophages.
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MESH Headings
- Animals
- Scleroderma, Systemic/drug therapy
- Scleroderma, Systemic/immunology
- Scleroderma, Systemic/pathology
- Scleroderma, Systemic/metabolism
- Macrophages/drug effects
- Macrophages/metabolism
- Macrophages/immunology
- Antibodies, Monoclonal, Humanized/pharmacology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Mice
- Skin/pathology
- Skin/drug effects
- Skin/metabolism
- Mice, Inbred BALB C
- Fibrosis/drug therapy
- Bleomycin
- Disease Models, Animal
- Female
- Fibroblasts/drug effects
- Fibroblasts/metabolism
- Transforming Growth Factor beta/metabolism
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Affiliation(s)
- Hongzhen Chen
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Drum Tower Hospital, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Dapeng Yang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Drum Tower Hospital, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yirui Shi
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, Xuzhou 221004, China
| | - Haolin Wu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Drum Tower Hospital, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Huiming Zhu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China
| | - Tingting Jiang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Drum Tower Hospital, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Shu Liu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China
| | - Dandan Wang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Drum Tower Hospital, Nanjing University of Chinese Medicine, Nanjing 210023, China; Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
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26
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Gu J, Zhou Z, Xu S, Pan W, Wang J, Liu O, Wang S, Xu J. Topical Application of Nitrate Ameliorates Skin Fibrosis by Regulating ST2 +CD4 + T Cells in Systemic Sclerosis Mouse Model. J Invest Dermatol 2025; 145:346-358.e5. [PMID: 38945439 DOI: 10.1016/j.jid.2024.06.1273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 07/02/2024]
Abstract
Systemic sclerosis (SSc) is characterized by intractable multiorgan fibrosis caused by vascular and immune dysfunction. Currently, effective therapeutic options for patients with SSc are limited. Nitrate, an abundant nutrient in the diet, has been demonstrated to be preventative and therapeutic for several diseases. To determine whether nitrate can slow or reverse SSc progression, topical application of nitrate delivered by dissolving microneedles was used to treat a bleomycin-induced dermal fibrosis mouse model. In this study, nitrate considerably attenuated dermal thickness, stiffness, and collagen deposition. Bulk RNA sequencing of skin revealed that Cd4 was a key hub gene in SSc nitrate therapy. In addition, bleomycin-induced cytokines and chemokines were inhibited by nitrate, and CD4+ T cells infiltration markedly declined. Il4, Il6, Il13, and Tgfb expressions in CD4+ T cells isolated from skin biopsies also significantly decreased. Mechanistically, Il1rl1, a type 2 immune response inducer, was markedly repressed in isolated CD4+ T cells and dermal tissues after nitrate treatment. Remarkably, compared with wild-type mice, mice lacking Il1rl1 showed impaired transcriptional profiles after intradermal bleomycin injection. Adoptive transfer of ST2+CD4+ T cells promoted bleomycin-induced Rag2-/- mice dermal fibrosis. Collectively, these findings demonstrate that nitrate targeting ST2+CD4+ T cells is an effective therapeutic option for SSc.
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Affiliation(s)
- Jianyu Gu
- Salivary Gland Disease Center, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Zekun Zhou
- Hunan Key Laboratory of Oral Health Research, Hunan 3D Printing Engineering Research Center of Oral Care, Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Changsha, China
| | - Shihan Xu
- Salivary Gland Disease Center, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Wen Pan
- Salivary Gland Disease Center, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Jinsong Wang
- Salivary Gland Disease Center, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Ousheng Liu
- Hunan Key Laboratory of Oral Health Research, Hunan 3D Printing Engineering Research Center of Oral Care, Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Changsha, China
| | - Songlin Wang
- Salivary Gland Disease Center, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China; Immunology Research Centre for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Laboratory of Homeostatic Medicine, School of Medicine, Southern University of Science and Technology, Shenzhen, China; Research Units of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, China.
| | - Junji Xu
- Salivary Gland Disease Center, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China; Immunology Research Centre for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Department of Periodontics, Beijing Stomatological Hospital, Capital Medical University School of Stomatology, Beijing, China.
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27
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Auth J, Müller F, Völkl S, Bayerl N, Distler JHW, Tur C, Raimondo MG, Chenguiti Fakhouri S, Atzinger A, Coppers B, Eckstein M, Liphardt AM, Bäuerle T, Tascilar K, Aigner M, Kretschmann S, Wirsching A, Taubmann J, Hagen M, Györfi AH, Kharboutli S, Krickau T, Dees C, Spörl S, Rothe T, Harrer T, Bozec A, Grieshaber-Bouyer R, Fuchs F, Kuwert T, Berking C, Horch RE, Uder M, Mackensen A, Schett G, Bergmann C. CD19-targeting CAR T-cell therapy in patients with diffuse systemic sclerosis: a case series. THE LANCET. RHEUMATOLOGY 2025; 7:e83-e93. [PMID: 39542003 DOI: 10.1016/s2665-9913(24)00282-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 09/14/2024] [Accepted: 09/16/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has shown remarkable outcomes in patients with systemic lupus erythematosus. The effects of CD19-targeting CAR T cells on organ manifestations in patients with systemic sclerosis have yet to be characterised. B cells have a central role in the pathogenesis of systemic sclerosis. We present a detailed analysis of the effects of CD19-targeting CAR T-cell therapy in patients with systemic sclerosis. METHODS Six patients with severe diffuse systemic sclerosis with an insufficient response to at least two treatments were consecutively recruited at the Department of Internal Medicine 3, University Hospital Erlangen (Erlangen, Germany) to receive CD19-targeting CAR T-cell treatment (1 × 106 CAR T cells per kg bodyweight). Events were predefined by progression of interstitial lung disease, onset of congestive heart failure, onset of renal failure, onset of arterial hypertension, or initiation of new immunosuppressive or antifibrotic therapy. Event-free time or treatment intensification after study entry was the primary outcome. Key secondary outcomes included changes in the modified Rodnan Skin Score (mRSS), imaging (a component of the assessment of lung fibrosis), laboratory assessments, patient-reported outcomes, and a modified version of the American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS), assessed at baseline, 3 months, 6 months, 9 months, and 12 months. FINDINGS Between April 20, 2022, and Nov 8, 2023, six patients with severe diffuse systemic sclerosis (median age 42 years [IQR 36-53]; four men and two women; all White European) were recruited and received CD19-targeted CAR T-cell therapy. The median follow-up time was 487 days (IQR 342-585). No events occurred within the observational period. Probability of improvement in the ACR-CRISS score increased to a median of 100% (IQR 100-100) at 6 months. Median mRSS decreased by 31% (IQR 29-38), corresponding to a median of 8 points (IQR 7-13) within 100 days. The extent of disease on CT scan decreased by a median of 4% (IQR 3-4) due to reduction of ground-glass opacities while the reticular pattern remained stable. Forced vital capacity improved by a median of 195 mL (IQR 18-275) at the latest observational timepoint. INTERPRETATION We provide the first evidence that CD19-targeting CAR T-cell therapy might intercept with the progression of fibrotic organ manifestations in patients with systemic sclerosis. FUNDING Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, ELAN-Foundation Erlangen, IZKF Erlangen, and Bundesministerium für Bildung und Forschung.
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Affiliation(s)
- Janina Auth
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Fabian Müller
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Simon Völkl
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Nadine Bayerl
- Department of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Jörg H W Distler
- Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, Düsseldorf, Germany; Department of Rheumatology, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, Düsseldorf, Germany
| | - Carlo Tur
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Maria G Raimondo
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Sara Chenguiti Fakhouri
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Armin Atzinger
- Department of Nuclear Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Birte Coppers
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Markus Eckstein
- Department of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Anna-Maria Liphardt
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Tobias Bäuerle
- Department of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Koray Tascilar
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Michael Aigner
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Sascha Kretschmann
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Andreas Wirsching
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Jule Taubmann
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Melanie Hagen
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Andrea-Hermina Györfi
- Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, Düsseldorf, Germany; Department of Rheumatology, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, Düsseldorf, Germany
| | - Soraya Kharboutli
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Tobias Krickau
- Department of Pediatrics, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Clara Dees
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Silvia Spörl
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Tobias Rothe
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Thomas Harrer
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Aline Bozec
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Ricardo Grieshaber-Bouyer
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Florian Fuchs
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 1, Pulmonology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Torsten Kuwert
- Department of Nuclear Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Carola Berking
- Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Raymund E Horch
- Department of Plastic Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Michael Uder
- Department of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Andreas Mackensen
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Georg Schett
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
| | - Christina Bergmann
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
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Athanassiou P, Athanassiou L, Kostoglou-Athanassiou I, Shoenfeld Y. Targeted Cellular Treatment of Systemic Lupus Erythematosus. Cells 2025; 14:210. [PMID: 39937001 PMCID: PMC11816398 DOI: 10.3390/cells14030210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/18/2025] [Accepted: 01/30/2025] [Indexed: 02/13/2025] Open
Abstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting all organ systems. The disease preferentially affects females of childbearing age. It runs a variable course. It may run a mild course that may never lead to severe disease and manifestations from critical organ systems. However, it may also run an undulating course with periods of mild and severe disease. It may run as a mild disease, quickly deteriorating to severe disease and affecting multiple organ systems. Various immune pathways related both to the innate and adaptive immune response are involved in the pathogenesis of SLE. Various drugs have been developed targeting cellular and molecular targets in these pathways. Interferons are involved in the pathogenesis of SLE, and various drugs have been developed to target this pathway. T and B lymphocytes are involved in the pathophysiology of SLE. Various treatment modalities targeting cellular targets are available for the treatment of SLE. These include biologic agents targeting B lymphocytes. However, some patients have disease refractory to these treatment modalities. For these patients, cell-based therapies may be used. Hematopoietic stem cell transplantation involving autologous cells is an option in the treatment of refractory SLE. Mesenchymal stem cells are also applied in the treatment of SLE. Chimeric antigen receptor (CAR)-T cell therapy is a novel treatment also used in SLE management. This novel treatment method holds major promise for the management of autoimmune diseases and, in particular, SLE. Major hurdles to be overcome are the logistics involved, as well as the need for specialized facilities. This review focuses on novel treatment modalities in SLE targeting cellular and molecular targets in the immune system.
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Affiliation(s)
| | - Lambros Athanassiou
- Department of Rheumatology, Asclepeion Hospital, Voula, 16673 Athens, Greece;
| | | | - Yehuda Shoenfeld
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Reichman University, Herzliya 4610101, Israel;
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Jones XM, Bottini N, Boin F, Marbán E. Cardiac involvement in systemic sclerosis: A critical review of knowledge gaps and opportunities. JOURNAL OF SCLERODERMA AND RELATED DISORDERS 2025:23971983241313096. [PMID: 39845449 PMCID: PMC11748146 DOI: 10.1177/23971983241313096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 12/25/2024] [Indexed: 01/24/2025]
Abstract
Cardiovascular complications are observed in up to one-third of patients with systemic sclerosis (SSc). Early identification and management of SSc-associated primary cardiac disease is often challenging, given the complex disease pathophysiology, significant variability in clinical presentation, and scarce disease-modifying therapeutics. Here, we review the molecular mechanisms involved in SSc-associated cardiac disease pathogenesis, novel diagnostic tools and emerging therapies.
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Affiliation(s)
- Xaviar M Jones
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Nunzio Bottini
- Kao Autoimmunity Institute and Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Francesco Boin
- Kao Autoimmunity Institute and Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Eduardo Marbán
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Memon H, Parrondo R, Schreurs J, Ayala E, Iqbal M. Autologous Hematopoietic Cell Transplant as an Effective Treatment Modality for Systemic Sclerosis and Multiple Myeloma. J Blood Med 2025; 16:7-13. [PMID: 39802914 PMCID: PMC11720633 DOI: 10.2147/jbm.s489627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 12/13/2024] [Indexed: 01/16/2025] Open
Abstract
Systemic sclerosis (SSc) is a multi-system disease characterized by a dysregulated immune system. Autologous hematopoietic cell transplantation (AHCT) is the only treatment that has been shown to confer significant benefit in controlling disease and improving survival for patients with SSc. A diagnosis of multiple myeloma (MM) after the diagnosis of SSc is rare and optimal treatment in such cases remains unclear. We here report a case of a female patient who was diagnosed with MM while she was undergoing evaluation for AHCT due to SSc. A novel conditioning regimen for AHCT, with therapeutic efficacy in SSc and MM was offered to the patient, resulting in long term remission of both diseases.
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Affiliation(s)
- Hamda Memon
- Department of Family Medicine, Geisinger Health in Wilkes Barre, Wilkes Barre, Pennsylvania, USA
| | - Ricardo Parrondo
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida, USA
| | - Julianna Schreurs
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida, USA
| | - Ernesto Ayala
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida, USA
| | - Madiha Iqbal
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida, USA
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Beland B, Storek J, Quartermain L, Hahn C, Pringle CE, Bourque PR, Kennah M, Kekre N, Bredeson C, Allan D, Jamani K, White C, Atkins H. Refractory myasthenia gravis treated with autologous hematopoietic stem cell transplantation. Ann Clin Transl Neurol 2025; 12:56-68. [PMID: 39737848 PMCID: PMC11752101 DOI: 10.1002/acn3.52246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/22/2024] [Accepted: 10/23/2024] [Indexed: 01/01/2025] Open
Abstract
OBJECTIVES Patients with refractory myasthenia gravis (MG) have few treatment options. Autologous hematopoietic stem cell transplantation (HSCT) has been used to treat immune diseases; however, its use in the treatment of MG is not broadly considered. Our objective is to report on the efficacy and safety of HSCT in refractory MG. METHODS Twenty-one patients who underwent HSCT for MG were retrospectively reviewed. All patients had severe MG refractory to multiple therapies. Stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor. The grafts were depleted of immune cells by selecting CD34+ cells. HSCT conditioning consisted of high-dose cytoreductive therapy and anti-thymocyte globulin. The primary efficacy outcome was achieving clinically stable remission or minimal manifestations without treatment and remaining as such until most recent follow-up. RESULTS The median time from MG diagnosis to HSCT was 4.0 years. The primary outcome was reached in 16 of 18 evaluable patients (89%) at a median of 1.7 years and maintained with a median follow-up of 6.7 years (range 1.0-21.9 years). Three patients were not evaluable for the primary outcome: one due to confounding illness and two died within 12 months of transplant. The transplant-related mortality at 100 days was 9.5%. Two late deaths occurred, with uncertain relation to the HSCT. INTERPRETATION After HSCT for refractory MG, most patients achieved sustained disease remission. However, HSCT-related mortality in medically complex MG patients may be high. Prospective studies investigating the efficacy and safety of HSCT in the treatment of refractory MG are warranted.
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Affiliation(s)
- Benjamin Beland
- Division of Neurology, Department of Clinical Neurosciences, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - Jan Storek
- Division of Hematology, Department of Medicine, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - Liam Quartermain
- Transplant and Cell Therapy Program, Division of Hematology, Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
| | - Christopher Hahn
- Division of Neurology, Department of Clinical Neurosciences, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - C. Elizabeth Pringle
- Division of Neurology, Department of Medicine, Faculty of MedicineUniversity of OttawaOttawaOntarioCanada
| | - Pierre R. Bourque
- Division of Neurology, Department of Medicine, Faculty of MedicineUniversity of OttawaOttawaOntarioCanada
| | - Michael Kennah
- Transplant and Cell Therapy Program, Division of Hematology, Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
| | - Natasha Kekre
- Transplant and Cell Therapy Program, Division of Hematology, Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
| | - Christopher Bredeson
- Transplant and Cell Therapy Program, Division of Hematology, Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
| | - David Allan
- Transplant and Cell Therapy Program, Division of Hematology, Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
| | - Kareem Jamani
- Division of Hematology, Department of Medicine, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - Christopher White
- Division of Neurology, Department of Clinical Neurosciences, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - Harold Atkins
- Transplant and Cell Therapy Program, Division of Hematology, Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
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Del Galdo F, Lescoat A, Conaghan PG, Bertoldo E, Čolić J, Santiago T, Suliman YA, Matucci-Cerinic M, Gabrielli A, Distler O, Hoffmann-Vold AM, Castellví I, Balbir-Gurman A, Vonk M, Ananyeva L, Rednic S, Tarasova A, Ostojic P, Boyadzhieva V, El Aoufy K, Farrington S, Galetti I, Denton CP, Kowal-Bielecka O, Mueller-Ladner U, Allanore Y. EULAR recommendations for the treatment of systemic sclerosis: 2023 update. Ann Rheum Dis 2025; 84:29-40. [PMID: 39874231 DOI: 10.1136/ard-2024-226430] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/20/2024] [Indexed: 10/13/2024]
Abstract
OBJECTIVES To update the 2017 European Alliance of Associations for Rheumatology (EULAR) recommendations for treatment of systemic sclerosis (SSc), incorporating new evidence and therapies. METHODS An international task force was convened in line with EULAR standard operating procedures. A nominal group technique exercise was performed in two rounds to define questions underpinning a subsequent systematic literature review. The evidence derived was discussed and overarching principles, recommendations and future research agenda were iteratively developed with voting rounds. RESULTS The task force agreed on 22 recommendations covering 8 clinical/organ domains including Raynaud's phenomenon, digital ulcers, pulmonary arterial hypertension, scleroderma renal crisis, skin fibrosis, interstitial lung disease (ILD), gastrointestinal manifestations and arthritis. Most new recommendations are related to skin fibrosis and ILD. These included novel recommendations for the use of mycophenolate mofetil, nintedanib, rituximab and tocilizumab for the treatment of these crucial disease manifestations. The recommendations also included first-line and second-line interventions, providing increased utility for rheumatology practitioners. Important additions to the future research agenda included consideration of novel interventions for the management of vascular, musculoskeletal and gastrointestinal manifestations and calcinosis, as well as for the local management of digital ulcers. CONCLUSION These updated recommendations include the first set of synthetic and biological targeted therapies recommended for key fibrotic manifestations of SSc as well as first-line combination treatment for newly diagnosed pulmonary artery hypertension and prioritise a new research agenda for the coming years.
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Affiliation(s)
- Francesco Del Galdo
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, LIRMM, Leeds, UK; NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals Trust, Leeds, UK.
| | - Alain Lescoat
- Department of Internal Medicine and Clinical Immunology, Rennes University Hospital, Rennes, France
| | - Philip G Conaghan
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, LIRMM, Leeds, UK; NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals Trust, Leeds, UK
| | - Eugenia Bertoldo
- Department of Medicine, Rheumatology Unit, Universita degli Studi di Verona, Verona, Italy
| | - Jelena Čolić
- Rheumatology, University of Belgrade Faculty of Medicine, Beograd, Serbia
| | - Tânia Santiago
- Rheumatology Department, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal
| | - Yossra A Suliman
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, Assiut University, Assiut, Egypt; Rheumatology division, Ain Alkhaleej Hospital, Alain, Abu-Dhabi, UAE
| | - Marco Matucci-Cerinic
- Unit of Immunology, Rheumatology, Allergy and Rare diseases (UnIRAR), and Inflammation, fibrosis and ageing initiative (INFLAGE), IRCCS San Raffaele Hospital, Milano, Italy
| | - Armando Gabrielli
- Scienze Cliniche e Molecolari, Università Politecnica delle Marche Facoltà di Medicina e Chirurgia, Ancona, Italy
| | - Oliver Distler
- University Hospital Zürich Center of Experimental Rheumatology, Zurich, Switzerland
| | | | - Ivan Castellví
- Rheumatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. https://twitter.com/IvanCastellvi
| | - Alexandra Balbir-Gurman
- B. Shine Department of Rheumatology, Department of Internal Medicine B, Rambam Health Care Campus, Haifa, Israel
| | - Madelon Vonk
- Department of Rheumatic diseases, Radboud Universiteit, Nijmegen, Netherlands
| | - Lidia Ananyeva
- Institute of Rheumatology, Russian Academy of Medical Sciences, Moskva, Russian Federation
| | - Simona Rednic
- Clinica Reumatologie, UMF Iuliu Haţieganu Cluj-Napoca, Cluj-Napoca, Romania
| | - Anna Tarasova
- Nasonova Research Institute of Rheumatology of RAMS, Moskva, Moskva, Russian Federation
| | - Pedrag Ostojic
- Institute of Rheumatology, University of Belgrade Faculty of Medicine, Belgrade, Serbia
| | | | - Khadija El Aoufy
- Department of Clinical and Experimental Medicine, University of Florence Faculty of Medicine and Surgery, Firenze, Italy
| | - Sue Farrington
- Scleroderma and Raynaud's UK, London, UK; Federation of European Scleroderma Associations, Milan, Italy
| | - Ilaria Galetti
- Federation of European Scleroderma Associations, Milan, Italy
| | | | - Otylia Kowal-Bielecka
- Department of Rheumatology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Ulf Mueller-Ladner
- Rheumatology and Clinical Immunology, University of Giessen, Giessen, Germany
| | - Yannick Allanore
- Department of Rheumatology, Université Paris Cité UFR de Médecine, Paris, France
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Lescoat A, Ghosh M, Kadauke S, Khanna D. Innovative cell therapies for systemic sclerosis: available evidence and new perspectives. Expert Rev Clin Immunol 2025; 21:29-43. [PMID: 39279565 DOI: 10.1080/1744666x.2024.2402494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 09/03/2024] [Indexed: 09/18/2024]
Abstract
INTRODUCTION Systemic sclerosis (SSc) is the rheumatic disease with the highest individual mortality rate with a detrimental impact on quality of life. Cell-based therapies may offer new perspectives for this disease as recent phase I trials support the safety of IV infusion of allogeneic mesenchymal stromal cells in SSc and case reports highlight the potential use of Chimeric Antigen Receptor (CAR)-T cells targeting CD19 in active SSc patients who have not responded to conventional immunosuppressive therapies. AREAS COVERED This narrative review highlights the most recent evidence supporting the use of cellular therapies in SSc as well as their potential mechanisms of action and discusses future perspectives for cell-based therapies in SSc. Medline/PubMed was used to identify the articles of interest, using the keywords 'Cellular therapies,' 'Mesenchymal stromal cells,' 'Chimeric Antigen Receptor' AND 'systemic sclerosis.' Milestones articles reported by the authors were also used. EXPERT OPINION Cellular therapies may represent an opportunity for long-term remission/cure in patients with different autoimmune diseases, including SSc who have not responded to conventional therapies. Multiple ongoing phase I/II trials will provide greater insights into the efficacy and toxicity of cellular therapies.
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Affiliation(s)
- Alain Lescoat
- Inserm, EHESP, Irset -Institut de Recherche en Santé, Environnement et Travail-UMRS, University of Rennes CHU Rennes, Rennes, France
- Department of Internal Medicine and Clinical Immunology, CHU Rennes, Rennes, France
| | - Monalisa Ghosh
- Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI, USA
- Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Stephan Kadauke
- Division of Transfusion Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Dinesh Khanna
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
- Scleroderma Program, University of Michigan, Ann Arbor, MI, USA
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de la Rubia Navarro M, Leal Rodríguez S, Román Ivorra JA. Autologous stem cell transplantation in systemic sclerosis: 4 cases. REUMATOLOGIA CLINICA 2025; 21:501810. [PMID: 39855976 DOI: 10.1016/j.reumae.2025.501810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 11/14/2024] [Indexed: 01/27/2025]
Abstract
OBJECTIVE The aim is to describe clinical and serological features, previous and current therapies, and adverse events in four systemic sclerosis patients (SSc) who undergo autologous hematopoietic stem cells transplantation (AHSCT). METHODS Descriptive, cross-sectional study including SSc patients according ACR/EULAR 2013 criteria. Clinical and serological data, data related to current and previous therapy and adverse events were collected from 2014 to 2023. RESULTS Four female patients were included, with a mean age of 49 (6.78) years old and a mean of 32.5 (7) months since diagnosis to AHSCT. Mean mRodnan score (mRSS) was 33.75. All cases underwent a skin improvement measured by mRSS (mean difference of 14.75) and lung function (DLCO) remained stable. Only one patient presented a pneumonia post-AHSCT, that required admission to intensive care unit, with improvement and complete resolution of infection a few days after admission. CONCLUSIONS AHSCT is an appropriate therapeutic option in rapidly progressive diffuse SSc patients, with a good safety profile in our cohort.
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Affiliation(s)
| | - Samuel Leal Rodríguez
- Servicio de Reumatología, Hospital Universitario y Politécnico La Fe, Valencia, Spain
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Galli G, De Pous-Gerardin C, Hanguehard R, Berthy F, Le Moal C, Lourde C, Barnetche T, Skopinski S, Contin-Bordes C, Delva F, Carles C, Truchetet ME. Occupational quantitative exposure to crystalline silica, solvents and pesticides and risk of clinical forms of systemic sclerosis. Rheumatology (Oxford) 2024; 63:3397-3406. [PMID: 37963059 DOI: 10.1093/rheumatology/kead602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 10/01/2023] [Accepted: 10/17/2023] [Indexed: 11/16/2023] Open
Abstract
OBJECTIVES To estimate the association between SSc clinical phenotypes and quantitative occupational exposure to crystalline silica, chlorinated solvents, trichloroethylene and pesticides using job-exposure matrices. METHODS In the VISS-EXPOSITION transversal study, data on declarative occupational exposure to crystalline silica, solvents and pesticides were retrieved. In parallel, the lifetime occupational history was evaluated using a questionnaire and cursus laboris for SSc patients followed at Bordeaux University Hospital (France). Using job-exposure matrices, we assessed patients' occupational exposure in relation to relevant clinical phenotypic forms of the disease. RESULTS Toxic exposure to crystalline silica and pesticides is underestimated by patients. Non-biased job-exposure matrices retrieved more exposed patients than the declarative assessment (10.1% of patients by job-exposure matrices vs 6.3% by declaration for crystalline silica and 25.9% vs 12.2% for pesticides). Patients overestimate their solvent exposure (7.9% for chlorinated solvents and 4.8% for trichlorethylene assessed by job-exposure matrices and 24.4% declarative exposure to solvents at large). Clinical form evaluation revealed a non-significant trend toward an increased risk of crystalline silica occupational exposure in the pulmonary fibrotic group of SSc patients [odds ratio (OR) 3.12 (95% CI 0.80, 12.15)]. We also observed a non-significant trend toward an elevated OR ([2.89 (95% CI 0.93, 8.95)] for chlorinated solvent occupational exposure and the vascular phenotype of SSc. Of note, pesticide occupational exposure evaluation represents one of the largest to date in SSc patients. CONCLUSION This study emphasizes that many exposed SSc patients are unaware of their occupational exposure. Job-exposure matrices allow better exposure screening for SSc secondary prevention and occupational exposure compensation. CLINICAL TRIAL REGISTRATION clinicaltrials.gov (https://www.clinicaltrials.gov), NCT03543956.
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Affiliation(s)
- Gaël Galli
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, Nouvelle-Aquitaine, France
- CHU de Bordeaux, FHU ACRONIM, Centre National de référence Des Maladies Autoimmunes et Systémiques Rares Est/Sud-Ouest (RESO), Bordeaux, Nouvelle-Aquitaine, France
| | | | - Remi Hanguehard
- University of Bordeaux, INSERM, UMR 1219, Equipe EPICENE, Bordeaux, Nouvelle-Aquitaine, France
| | - Florine Berthy
- University of Bordeaux, INSERM, UMR 1219, Equipe EPICENE, Bordeaux, Nouvelle-Aquitaine, France
| | - Cyril Le Moal
- Centre Hospitalier des Pays de Morlaix, Service de Médecine Interne, Morlaix, Bretagne, France
| | - Come Lourde
- 14èbme Centre Médical des Armées, 97ème Antenne Médicale, Olivet, Centre Val de Loire, France
| | - Thomas Barnetche
- CHU de Bordeaux, FHU ACRONIM, Centre National de référence Des Maladies Autoimmunes et Systémiques Rares Est/Sud-Ouest (RESO), Bordeaux, Nouvelle-Aquitaine, France
| | - Sophie Skopinski
- CHU de Bordeaux, FHU ACRONIM, Centre National de référence Des Maladies Autoimmunes et Systémiques Rares Est/Sud-Ouest (RESO), Bordeaux, Nouvelle-Aquitaine, France
| | - Cecile Contin-Bordes
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, Nouvelle-Aquitaine, France
- CHU de Bordeaux, FHU ACRONIM, Centre National de référence Des Maladies Autoimmunes et Systémiques Rares Est/Sud-Ouest (RESO), Bordeaux, Nouvelle-Aquitaine, France
| | - Fleur Delva
- University of Bordeaux, INSERM, UMR 1219, Equipe EPICENE, Bordeaux, Nouvelle-Aquitaine, France
| | - Camille Carles
- CHU de Bordeaux, Service Santé Travail Environnement, Bordeaux, Nouvelle-Aquitaine, France
- University of Bordeaux, INSERM, UMR 1219, Equipe EPICENE, Bordeaux, Nouvelle-Aquitaine, France
| | - Marie-Elise Truchetet
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, Nouvelle-Aquitaine, France
- CHU de Bordeaux, FHU ACRONIM, Centre National de référence Des Maladies Autoimmunes et Systémiques Rares Est/Sud-Ouest (RESO), Bordeaux, Nouvelle-Aquitaine, France
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Worm M, Günther C, Claussen M, Keyßer G, Kötter I, Riemekasten G, Siegert E, Blank N, Sunderkötter C, Zeidler G, Korsten P. [Interdisciplinary centers for autoimmune diseases in Germany]. Z Rheumatol 2024; 83:844-851. [PMID: 39052075 PMCID: PMC11614946 DOI: 10.1007/s00393-024-01542-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/06/2024] [Indexed: 07/27/2024]
Abstract
BACKGROUND Interdisciplinary medical treatment is required to care for patients with complex autoimmune diseases. Although there are an increasing number of interdisciplinary centers for autoimmune diseases in Germany, they are not yet available throughout the country and the focuses and interdisciplinary structures are not organized according to a generally agreed standard. Furthermore, they are not regularly reflected in the general care structure. THE AIM OF THE WORK To analyze the care structure using as an example an established center and a clinical case to demonstrate the usefulness of in-house standardized procedures. MATERIAL AND METHODS In order to determine the status quo regarding interdisciplinary centers for autoimmune diseases in Germany, a university hospital is exemplarily presented for a structural analysis and a case presentation from another center to demonstrate the importance of an interdisciplinary patient care. RESULTS At the selected center for autoimmune diseases of the university hospital, patients with autoimmune diseases receive interdisciplinary care from experts from various disciplines. The structures are anchored in an organizational chart. The case report demonstrates a standardized diagnostic and therapeutic pathway (standardized operating procedures, SOP) in a patient with systemic sclerosis and lung involvement. DISCUSSION The article discusses which measures are necessary across disciplines for comprehensive diagnostics and treatment of certain autoimmune diseases, which challenges arise during implementation and which advantages can arise compared to guidelines because, among other things, they can be immediately adapted. The establishment of a national consensus for the structure, necessary settings and implementation into patient care within an interdisciplinary center for autoimmune diseases is desirable.
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Affiliation(s)
- Margitta Worm
- Abteilung für Allergologie und Immunologie, Klinik für Dermatologie, Venerologie und Allergologie, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Deutschland.
| | - Claudia Günther
- Klinik und Poliklinik für Dermatologie, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Deutschland
| | - Martin Claussen
- Abteilung Pneumologie, LungenClinic Grosshansdorf, Grosshansdorf, Deutschland
| | - Gernot Keyßer
- Arbeitsbereich Rheumatologie, Universitätsklinik und Poliklinik für Innere Medizin II (Nephrologie, Rheumatologie, Endokrinologie/Diabetologie), Universitätsklinikum Halle (Saale), Halle, Deutschland
| | - Ina Kötter
- Klinik für Rheumatologie und Immunologie Bad Bramstedt und Sektion Rheumatologie, III. Medizinische Klinik und Poliklinik (Nephrologie/Rheumatologie/Endokrinologie), Zentrum für Innere Medizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg-Eppendorf, Deutschland
| | - Gabriela Riemekasten
- Klinik für Rheumatologie und klinische Immunologie, Campus Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, Deutschland
| | - Elise Siegert
- Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Charité Universitätsmedizin Berlin, Berlin, Deutschland
| | - Norbert Blank
- Medizinische Klinik V, Sektion Rheumatologie, Zentrum für Innere Medizin, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - Cord Sunderkötter
- Universitätsklinik und Poliklinik für Dermatologie und Venerologie, Universitätsklinikum Halle (Saale), Halle, Deutschland
| | - Gabriele Zeidler
- Klinik I - Internistische Rheumatologie, Osteologie und spezielle Schmerztherapie, Johanniter Krankenhaus Treuenbrietzen, Treuenbrietzen, Deutschland
| | - Peter Korsten
- Klinik für Rheumatologie und Klinische Immunologie, St. Josef-Stift Sendenhorst, Sendenhorst, Deutschland
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Keret S, Chutko B, Dobrecky-Mery I, Wolak A, Hardak E, Slobodin G, Shouval A, Henig I, Zuckerman T, Yehudai-Ofir D, Farge D, Rimar D. Cardiac safe hematopoietic stem cell transplantation protocol for systemic sclerosis with myocarditis-a two-step approach. Rheumatology (Oxford) 2024; 63:e328-e330. [PMID: 38741216 DOI: 10.1093/rheumatology/keae268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 04/05/2024] [Accepted: 05/03/2024] [Indexed: 05/16/2024] Open
Affiliation(s)
- Shiri Keret
- Rheumatology Unit, Bnai Zion Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Boris Chutko
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
- Cardiology, Shaare Zedek Medical Center, Jerusalem, Israel
- Cardiology, Bnai Zion Medical Center, Haifa, Israel
| | - Idit Dobrecky-Mery
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
- Cardiology, Bnai Zion Medical Center, Haifa, Israel
| | - Arik Wolak
- Cardiology, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Emilia Hardak
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
- Pulmonary Unit, Bnai Zion Medical Center, Haifa, Israel
| | - Gleb Slobodin
- Rheumatology Unit, Bnai Zion Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Aniela Shouval
- Rheumatology Unit, Bnai Zion Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Israel Henig
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
- Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa, Israel
| | - Tsila Zuckerman
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
- Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa, Israel
| | - Dana Yehudai-Ofir
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
- Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa, Israel
| | - Dominique Farge
- Department of Internal Medicine: CRMR MATHEC, Maladies Auto-Immunes et Thérapie Cellulaire, Centre de Référence des Maladies Auto-Immunes Systémiques Rares d'Ile-de-France, FAI2R, Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris, Paris, France
- Université de Paris-Cité, Paris, France
- Department of Medicine, McGill University, Montreal, QC, Canada
| | - Doron Rimar
- Rheumatology Unit, Bnai Zion Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
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Foeldvari I, Branton S, Li SC, Rosser FJ, Torok KS. What are Juvenile-onset systemic sclerosis providers thoughts, experiences, and reasons for autologous stem cell transplant? Result of a multinational survey. JOURNAL OF SCLERODERMA AND RELATED DISORDERS 2024:23971983241293297. [PMID: 39544894 PMCID: PMC11559529 DOI: 10.1177/23971983241293297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 10/05/2024] [Indexed: 11/17/2024]
Abstract
Objective Juvenile-onset systemic sclerosis (jSSc) is a rare and life-threatening disease with no formal studies evaluating the indications for, access to, or benefits of autologous stem cell transplantation (ASCT). As a first step toward understanding pediatric jSSc specialist thoughts and experiences with ASCT, we conducted a multinational survey. Methods An electronic survey was developed and distributed in November 2023 to members of the Pediatric Rheumatology European Society (PRES) and/or Childhood Arthritis and Rheumatology Research Alliance (CARRA) pediatric scleroderma workgroups. Results Twenty-nine (69%) jSSc specialists completed the survey. All participants have considered or would consider ASCT referral for a jSSc patient. Nearly all respondents indicated disease-modifying anti-rheumatic drugs (DMARDs) should be trialed prior to ASCT referral, with most indicating two to four DMARDs. The most common reasons selected for referral were rapidly progressive disease (despite DMARD) (90%), followed by severe disease status (83%), and significant impact on quality of life (83%). All respondents selected pulmonary disease as an indication for referral, followed by cardiac (93%), gastrointestinal (72%), and skin disease (66%). While pulmonary and cardiac involvement were considered individually sufficient for referral for ASCT, only a minority considered musculoskeletal involvement (28%) sufficient on its own. Conclusion This survey is the first explore thoughts and experience with ASCT for jSSc. Results indicate pediatric rheumatologists were aware of and would consider ASCT for their patients. Our results indicate there is likely some variability in clinical practice regarding who is referred for ASCT, and further research is needed to guide development of evidence-based clinical care guidelines.
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Affiliation(s)
- Ivan Foeldvari
- Hamburger Zentrum für Kinder-und Jugenrheumatologie, Hamburg, Germany
- Hamburg Centre for Pediatric and Adolescence Rheumatology, Centre for Treatment of Scleroderma and Uveitis in Childhood and Adolescence, Teaching Unit of the Asklepios Campus of the Semmelweis Medical School, Budapest, Schön Klinik Hamburg Eilbek, Hamburg, Germany
| | | | - Suzanne C Li
- Joseph M. Sanzari Children’s Hospital, Hackensack Meridian School of Medicine, Hackensack, NJ, USA
| | - Franziska J Rosser
- Division of Pulmonary Medicine, Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Kathryn S Torok
- Division of Rheumatology, Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Zielonka J, Higuero Sevilla JP. Autologous hematopoietic stem cell transplant for systemic sclerosis associated interstitial lung disease. Curr Opin Rheumatol 2024; 36:410-419. [PMID: 39348419 DOI: 10.1097/bor.0000000000001050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/02/2024]
Abstract
PURPOSE OF REVIEW Over the last 25 years, the role of autologous hematopoietic stem cell transplant (HSCT) in the treatment of diffuse cutaneous systemic sclerosis (dcSSc) has been elucidated. However, multiple critical questions remain regarding this therapy. Of particular interest is the role of HSCT in the treatment of systemic sclerosis (SSc)-associated interstitial lung disease since this is the leading cause of death in SSc. RECENT FINDINGS Most clinical trials and observational studies of HSCT for the treatment of dcSSc have reported pulmonary outcomes as secondary outcomes, Also, most studies have excluded patients with significant pulmonary function impairment. Despite these limitations, there is increasing evidence that suggests that HSCT leads to interstitial lung disease stabilization and possibly improvement of lung function based on pulmonary function tests and imaging. SUMMARY HSCT has demonstrated improved long-term outcomes compared to conventional therapies for dcSSC. Future research is needed to refine or expand patient selection, optimize conditioning regimens, and evaluate the potential role of maintenance immunosuppression. We recommend an increased focus on interstitial lung disease since this is the primary cause of death in SSc.
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Affiliation(s)
- Jana Zielonka
- Yale School of Medicine, Department of Internal Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, Connecticut, USA
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Xu Y, Wang X, Hu Z, Huang R, Yang G, Wang R, Yang S, Guo L, Song Q, Wei J, Zhang X. Advances in hematopoietic stem cell transplantation for autoimmune diseases. Heliyon 2024; 10:e39302. [PMID: 39492896 PMCID: PMC11530805 DOI: 10.1016/j.heliyon.2024.e39302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 09/14/2024] [Accepted: 10/10/2024] [Indexed: 11/05/2024] Open
Abstract
Autoimmune diseases (ADs) are a collection of immunological disorders in which the immune system responds to self-antigens by producing autoantibodies or self-sensitized cells. Current treatments are unable to cure ADs, and achieving long-term drug-free remission remains a challenging task. Hematopoietic stem cell transplantation (HSCT) stands out from other therapies by specifically targeting ADs that target various cell subpopulations, demonstrating notable therapeutic benefits and resulting in sustained drug-free remission. Since different ADs have distinct mechanisms of action, the comprehensive understanding of how HSCT works in treating ADs is crucial. This review provides a detailed overview of the latest research and clinical applications of HSCT in treating ADs, offering new insights for clinicians aiming to optimize its use for ADs management.
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Affiliation(s)
- Yuxi Xu
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Sichuan, 637000, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
| | - Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Ziyi Hu
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Sichuan, 637000, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
| | - Ruihao Huang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Guancui Yang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Rui Wang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
| | - Shijie Yang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Liyan Guo
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Qingxiao Song
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
| | - Jin Wei
- Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Sichuan, 637000, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
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Schmalzing M, Gernert M, Fröhlich M, Henes J, Schwindl N, Zerhusen L, Berthold L, Hewig J, Kübler A, Pecher AC, Kleih-Dahms S, Strunz PP, Ziebell P. Psychological impact of autologous hematopoietic stem cell transplantation in systemic sclerosis patients and influence of resilience. Front Immunol 2024; 15:1436639. [PMID: 39512343 PMCID: PMC11540678 DOI: 10.3389/fimmu.2024.1436639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 10/10/2024] [Indexed: 11/15/2024] Open
Abstract
Objective In severe cases of systemic sclerosis (SSc), autologous hematopoietic stem cell transplantation (aHSCT) is superior compared to cyclophosphamide. But treatment related morbidity and mortality have to be considered. To date, data on major physical and psychological impacts of aHSCT are scarce. Therefore, subjectively experienced physical and psychological impact of aHSCT and exploration of internal and external factors helping to cope with aHSCT was assessed. Methods Retrospective assessment of physical and psychological variables in an SSc cohort after aHSCT to describe: Health-related quality of life (HRQL), SSc-associated impairment, coping strategies, body image, and resilience. Additionally, semi-structured interviews were conducted and analyzed via mixed methods qualitative content analysis. Results Thirty-two patients were included. HRQL correlated with impairment due to SSc and with depressive coping. An unfavorable body image correlated with reduced HRQL and increased impairment but improves after aHSCT. Patients with good resilience had a better HRQL, less depressive coping, and less SSc-associated impairment. The semi-structured interviews revealed that resilience is important for a successful disease management as patients with higher resilience were more satisfied with aHSCT, patients with lower resilience would have wished for more psychological support. Thirty-one patients would recommend aHSCT to other patients. Conclusion A transient negative impact of aHSCT on mental well-being is present but can be relieved by a team specialized to aHSCT. Psychological support seems to be an unmet need, particularly in patients with low resilience. Patients with higher resilience described a lower negative impact caused by aHSCT and higher satisfaction after therapy.
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Affiliation(s)
- Marc Schmalzing
- Department of Internal Medicine 2, Rheumatology/Clinical Immunology, University Hospital Würzburg, Würzburg, Germany
| | - Michael Gernert
- Department of Internal Medicine 2, Rheumatology/Clinical Immunology, University Hospital Würzburg, Würzburg, Germany
| | - Matthias Fröhlich
- Department of Internal Medicine 2, Rheumatology/Clinical Immunology, University Hospital Würzburg, Würzburg, Germany
| | - Jörg Henes
- Centre for Interdisciplinary Clinical Immunology, Rheumatology and Auto-inflammatory Diseases and Department of Internal Medicine II (Oncology, Hematology, Immunology, Rheumatology), University Hospital Tübingen, Tübingen, Germany
| | | | - Leona Zerhusen
- Institute of Psychology, University of Würzburg, Würzburg, Germany
| | - Lukas Berthold
- Department of Internal Medicine 2, Rheumatology/Clinical Immunology, University Hospital Würzburg, Würzburg, Germany
| | - Johannes Hewig
- Institute of Psychology, University of Würzburg, Würzburg, Germany
| | - Andrea Kübler
- Institute of Psychology, University of Würzburg, Würzburg, Germany
| | - Ann-Christin Pecher
- Centre for Interdisciplinary Clinical Immunology, Rheumatology and Auto-inflammatory Diseases and Department of Internal Medicine II (Oncology, Hematology, Immunology, Rheumatology), University Hospital Tübingen, Tübingen, Germany
| | | | - Patrick-Pascal Strunz
- Department of Internal Medicine 2, Rheumatology/Clinical Immunology, University Hospital Würzburg, Würzburg, Germany
| | - Philipp Ziebell
- Institute of Psychology, University of Würzburg, Würzburg, Germany
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Del Papa N, Cavalli S, Rindone A, Onida F, Saporiti G, Minniti A, Pellico MR, Iannone C, Trignani G, D'Angelo N, Sette M, Greco R, Vitali C, Caporali R. Long-term outcome of autologous haematopoietic stem cell transplantation in patients with systemic sclerosis: a comparison with patients treated with rituximab and with traditional immunosuppressive agents. Arthritis Res Ther 2024; 26:182. [PMID: 39444017 PMCID: PMC11515700 DOI: 10.1186/s13075-024-03408-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 09/25/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Autologous haematopoietic stem cell transplantation (AHSCT) is more effective than conventional immunosuppressive therapies (CIT) in improving the outcome of patients with rapidly progressive diffuse cutaneous systemic sclerosis (dcSSc). So far, there is still a paucity of data comparing AHSCT with rituximab (RTX). Aim of the study is to retrospectively compare, in patients with dcSSc, the effectiveness of AHSCT with that of RTX and CIT. METHODS Thirty-five dcSSc AHSCT-treated patients were compared with 29 and 36 matched cases treated with RTX and CIT, respectively. The patients were followed up for 5 years by assessing selected outcome measures every year. Overall survival, modified Rodnan skin score (mRSS), lung function tests (FVC and DLCO), and the revised EUSTAR Activity Index (REAI) were the outcome measures chosen to evaluate the therapy efficacy. RESULTS AHSCT was significantly more effective than RTX and CIT in prolonging survival, inducing a rapid reduction of the mRSS and REAI and maintaining the baseline level of lung function tests for a longer time. RTX therapy was also superior to CIT in reducing REAI, mRSS and in saving lung function. CONCLUSION AHSCT is more effective than both RTX and CIT in prolonging survival and inducing prolonged remission in patients with rapidly progressive dcSSc.
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Affiliation(s)
- Nicoletta Del Papa
- Scleroderma Clinic, UOC Clinica Reumatologica, ASST Pini-CTO, Milano, Italy.
| | - Silvia Cavalli
- Scleroderma Clinic, UOC Clinica Reumatologica, ASST Pini-CTO, Milano, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy
| | - Andrea Rindone
- Scleroderma Clinic, UOC Clinica Reumatologica, ASST Pini-CTO, Milano, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy
| | - Francesco Onida
- Department of Oncology and Onco-Hematology, Università degli Studi di Milano, Milano, Italy
- Ospedale Fatebenefratelli e Oftalmico, Oncoematologia, Milano, Italy
| | - Giorgia Saporiti
- Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Antonina Minniti
- Scleroderma Clinic, UOC Clinica Reumatologica, ASST Pini-CTO, Milano, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy
| | - Maria Rosa Pellico
- Scleroderma Clinic, UOC Clinica Reumatologica, ASST Pini-CTO, Milano, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy
| | - Claudia Iannone
- Scleroderma Clinic, UOC Clinica Reumatologica, ASST Pini-CTO, Milano, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy
| | - Giorgia Trignani
- Scleroderma Clinic, UOC Clinica Reumatologica, ASST Pini-CTO, Milano, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy
| | - Nicoletta D'Angelo
- Scleroderma Clinic, UOC Clinica Reumatologica, ASST Pini-CTO, Milano, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy
| | - Manuel Sette
- Scleroderma Clinic, UOC Clinica Reumatologica, ASST Pini-CTO, Milano, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy
| | - Raffaella Greco
- Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Hospital, Vita- Salute San Raffaele University, Milano, Italy
| | - Claudio Vitali
- Rheumatology Outpatient Clinic, Mater Domini Humanitas Hospital, Castellanza, Italy
| | - Roberto Caporali
- Scleroderma Clinic, UOC Clinica Reumatologica, ASST Pini-CTO, Milano, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy
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El Hasbani G, Madi M, Zoghbi MASE, Srour L, Uthman I, Jawad ASM. The Impact of Tobacco Smoking on Systemic Sclerosis, Idiopathic Inflammatory Myositis, and Systemic Lupus Erythematosus. CLINICAL MEDICINE INSIGHTS. ARTHRITIS AND MUSCULOSKELETAL DISORDERS 2024; 17:11795441241290522. [PMID: 39430769 PMCID: PMC11490952 DOI: 10.1177/11795441241290522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 09/23/2024] [Indexed: 10/22/2024]
Abstract
This narrative review aims specifically to explore the relationship between tobacco exposure and systemic sclerosis (SSc), idiopathic inflammatory myositis (IIM), and systemic lupus erythematosus (SLE). Relevant articles were obtained by searching key terms such as "tobacco," "smoking," "scleroderma," "myositis," "lupus," and "Sjögren's" in PubMed and Google Scholar databases. The selected articles ranged from the years 2010 to 2023. Inclusion criteria were based on the relevance and contribution to the field of study. Systemic sclerosis is a complex condition involving multiple immune cell lines that can be influenced by tobacco. However, the existing literature does not provide sufficient evidence to support an increased risk of SSc in smokers or the impact on treatment options. Cigarette smoking does increase the risk of skin ulcerations in SSc patients. In addition, cigarette smoking has been associated with IIM through genetic and molecular mechanisms. Smokers with dermatomyositis or polymyositis are at an elevated risk of atherosclerosis and interstitial lung disease. Similarly, smoking in patients with SLE increases the risk of organ damage, thrombosis, and disease severity compared with non-smokers. Smokers with SLE also have more difficulty in controlling disease flares compared with non-smokers. Tobacco exposure can lead to secondary complications in patients with IIM and SLE, although the course of treatment may not differ significantly. No definitive conclusions can be drawn to the clear relationship between tobacco smoking and Sjögren's's syndrome.
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Affiliation(s)
- Georges El Hasbani
- Department of Medicine, Hartford Healthcare St. Vincent’s Medical Center, Bridgeport, CT, USA
| | - Mikel Madi
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | | | - Lara Srour
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Imad Uthman
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ali SM Jawad
- Department of Rheumatology, The Royal London Hospital, London, UK
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Panopoulos S, Tzilas V, Bournia VK, Tektonidou MG, Sfikakis PP. Tocilizumab plus Nintedanib for progressive interstitial lung disease in systemic sclerosis: a one-year observational study. Rheumatol Int 2024; 44:1959-1966. [PMID: 39180531 DOI: 10.1007/s00296-024-05695-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 08/09/2024] [Indexed: 08/26/2024]
Abstract
Randomized controlled trials have recently shown that both the IL-6 inhibitor Tocilizumab and the antifibrotic Nintedanib are efficacious for Systemic Sclerosis (SSc)-associated progressive interstitial lung disease (ILD). Since real-world clinical data on Tocilizumab/Nintedanib combination are lacking, we report on their long-term safety and efficacy. Consecutive patients who received off-label Tocilizumab for SSc plus Nintedanib for progressive ILD were retrospectively studied. Adverse events, and changes in Forced Vital Capacity (FVC), Diffucing Capacity for Carbon Monoxide (DLCO) and high resolution chest tomography (HRCT) between baseline and 6 and 12 months were assessed. Tocilizumab/Nintedanib combination was well tolerated by all 20 patients [aged 52 ± 13 years (mean ± SD), 14 women, 15 diffuse SSc, disease duration of 5.7 ± 4.9 years]; 7 of 20 patients received concomitant mycophenolate mofetil safely. No serious adverse events or laboratory abnormalities were noted. Five patients developed persistent diarrhea and 2 of them reduced dosage of Nintedanib. Baseline FVC (74%±12%) and DLCO (45%±10%) remained overall stable both at 6 months (73.5%±13% and 46%±11%, respectively) and 12 months (73%±14% and 45%±11%, respectively), regardless of disease duration. The extent of fibrotic reticular pattern in available pairs of HRCTs (n = 12) remained also stable at 12 months, whereas proportion (%) of ground glass opacities decreased from 29%±16 to 21%±14% (p = 0.048); improvement in HRCTs by almost 75% was noted in 2 of these12 patients. Tocilizumab/Nintedanib combination for one year was safe and stabilized lung function in real-world SSc patients with progressive ILD. Additional studies of this combination treatment in SSc-ILD are warranted.
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MESH Headings
- Humans
- Female
- Middle Aged
- Indoles/therapeutic use
- Indoles/administration & dosage
- Indoles/adverse effects
- Lung Diseases, Interstitial/drug therapy
- Lung Diseases, Interstitial/etiology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Male
- Scleroderma, Systemic/complications
- Scleroderma, Systemic/drug therapy
- Adult
- Aged
- Retrospective Studies
- Drug Therapy, Combination
- Treatment Outcome
- Disease Progression
- Vital Capacity
- Lung/physiopathology
- Lung/drug effects
- Lung/diagnostic imaging
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Affiliation(s)
- Stylianos Panopoulos
- 1st Department of Propaedeutic and Internal Medicine, and Joint Rheumatology Program, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
| | - Vasilios Tzilas
- 2nd Respiratory Medicine Department, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
| | - Vasiliki-Kalliopi Bournia
- 1st Department of Propaedeutic and Internal Medicine, and Joint Rheumatology Program, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
| | - Maria G Tektonidou
- 1st Department of Propaedeutic and Internal Medicine, and Joint Rheumatology Program, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
| | - Petros P Sfikakis
- 1st Department of Propaedeutic and Internal Medicine, and Joint Rheumatology Program, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
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45
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Hellmich B, Mucke J, Aringer M. [Head-to-head studies on connective tissue diseases and vasculitides]. Z Rheumatol 2024; 83:620-628. [PMID: 39017966 DOI: 10.1007/s00393-024-01537-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/05/2024] [Indexed: 07/18/2024]
Abstract
Head-to-head (H2H) studies enable the direct comparison of several alternative therapeutic approaches and thus provide the evidence-based foundation for the relative position of one treatment as compared to others for a specific indication. These trials constitute an important addition to placebo-controlled clinical trials. Among the controlled clinical trials not performed by the pharmaceutical industry, there are a relevant number of H2H trials for connective tissue diseases (CTDs) and vasculitides, particularly for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This article encompasses a review of the H2H trials for CTDs and vasculitides and discusses their relevance for current treatment algorithms. For SLE the H2H trials were predominantly performed for the treatment of lupus nephritis, demonstrating the impact of low-dose cyclophosphamide and mycophenolate as well as azathioprine for maintenance therapy. In recent H2H trials rituximab could be established as induction and maintenance therapy for AAV, which has now been incorporated into current treatment guidelines. Further comparative trials will be necessary in order to select the most effective and safest treatment for every patient, in the sense of personalized medicine.
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Affiliation(s)
- Bernhard Hellmich
- Klinik für Innere Medizin, Rheumatologie, Pneumologie, Nephrologie und Diabetologie, Europäisches Vaskulitis-Referenzzentrum (ERN-RITA), medius KLINIKEN KIRCHHEIM & NÜRTINGEN, Akademisches Lehrkrankenhaus der Universität Tübingen, Eugenstr. 3, 73230, Kirchheim unter Teck, Deutschland.
| | - Johanna Mucke
- Klinik für Rheumatologie, Hiller-Forschungszentrum für Rheumatologie, Medizinische Fakultät, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland
| | - Martin Aringer
- Bereich Rheumatologie, Medizinische Klinik und Poliklinik III und Universitätscentrum für Autoimmun- und Rheumatische Erkrankungen (UCARE), Universitätsklinikum und Medizinische Fakultät, TU Dresden, Dresden, Deutschland
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46
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Penglase R, Girgis L, Englert H, Ma D, Moore J. Australian rheumatologists' perception of autologous haemopoietic stem cell transplantation for the treatment of systemic sclerosis: a cross-sectional survey. Intern Med J 2024; 54:1478-1482. [PMID: 38821884 DOI: 10.1111/imj.16422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 05/08/2024] [Indexed: 06/02/2024]
Abstract
BACKGROUND Autologous haemopoietic stem cell transplantation (AHSCT) is an effective treatment for systemic sclerosis (SSc); however, treatment-related toxicity remains a key issue. AIMS To investigate the perceptions of rheumatologists on the use of AHSCT for SSc. METHODS Australian rheumatologists were asked for their opinion on the role of AHSCT, the indications for treatment and the barriers to the use of AHSCT for SSc. A secondary analysis assessed what factors influenced the perception of AHSCT. RESULTS A total of 77.8% rheumatologists agreed or strongly agreed with the statement that AHSCT is an accepted treatment for SSc. While 65.1% agreed or strongly agreed that treatment-associated mortality was a significant barrier to referral for AHSCT, only 15.2% agreed or strongly agreed that this risk was unacceptable. Progressive lung or skin disease, or lack of response to other therapies, were considered the main referral criteria. A total of 92.0% of respondents agreed or strongly agreed that reduction of treatment toxicity would increase their likelihood to refer patients for AHSCT. Rheumatologists who were aware of the correct evidence base were more likely to consider AHSCT an acceptable treatment for SSc (4.21 ± 0.7 vs 3.64 ± 0.9, P = 0.007). Rheumatologists desire improved patient selection criteria and access to treatment. CONCLUSION In this national survey of rheumatologists, AHSCT is considered an accepted therapy. However, concern about toxicity remains a potential barrier to patient referral. Access, studies to refine patient selection and development of AHSCT protocols that improve safety were identified as key areas of need.
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Affiliation(s)
- Ross Penglase
- Department of Rheumatology, St Vincent's Hospital, Sydney, New South Wales, Australia
- School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia
- St Vincent's Centre for Applied Medical Research, Sydney, New South Wales, Australia
| | - Laila Girgis
- Department of Rheumatology, St Vincent's Hospital, Sydney, New South Wales, Australia
- School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Helen Englert
- Department of Rheumatology, St Vincent's Hospital, Sydney, New South Wales, Australia
| | - David Ma
- School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia
- St Vincent's Centre for Applied Medical Research, Sydney, New South Wales, Australia
- Department of Haematology and Bone Marrow Transplantation, St Vincent's Hospital, Sydney, New South Wales, Australia
| | - John Moore
- School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia
- St Vincent's Centre for Applied Medical Research, Sydney, New South Wales, Australia
- Department of Haematology and Bone Marrow Transplantation, St Vincent's Hospital, Sydney, New South Wales, Australia
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47
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Bautista-Sanchez R, Khanna D. Systemic sclerosis-associated interstitial lung disease: How to manage in 2024? RHEUMATOLOGY AND IMMUNOLOGY RESEARCH 2024; 5:157-165. [PMID: 39439972 PMCID: PMC11492822 DOI: 10.2478/rir-2024-0022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 08/03/2024] [Indexed: 10/25/2024]
Abstract
Systemic sclerosis (SSc) or scleroderma is an autoimmune disease characterized by immune dysregulation which leads to progressive fibrosis of the skin and internal organs. Interstitial lung disease (ILD) is present in approximately 65% of patients with SSc and it accounts for approximately 40% of all SSc deaths. Risk factors associated with the development of systemic sclerosis related interstitial lung disease (SSc-ILD) include male sex, African heritage, high modified Rodnan skin score (mRSS), presence of anti-Scl-70/Topoisomerase I antibodies, and nucleolar pattern on antinuclear antibody (ANA). The primary tool to diagnose ILD in patients with SSc is high-resolution computed tomography (HRCT). Full pulmonary function tests (PFTs) with diffusing capacity of the lungs for carbon monoxide (DLco) and ambulatory desaturation testing should be obtained following the diagnosis of SSc-ILD for disease monitoring. The purpose of this review is to provide an updated guide for the management of SSc-ILD. Our proposed first line treatment for SSc-ILD is immunosuppressive therapy such as mycophenolate mofetil, tocilizumab, and rituximab which are discussed in depth, and we present the evidence-based data that has justified the use of these pharmacotherapies. Other immunosuppressive treatments are also reviewed, and we discuss the role of antifibrotic therapy. Finally, we dive into other avenues of treatments such as chimeric antigen receptor (CAR)-T cell therapy and hematopoietic stem cell transplant.
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Affiliation(s)
| | - Dinesh Khanna
- Scleroderma Program, University of Michigan, Ann Arbor, MI, MichiganUSA
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Samad A, Wobma H, Casey A. Innovations in the care of childhood interstitial lung disease associated with connective tissue disease and immune-mediated disorders. Pediatr Pulmonol 2024; 59:2321-2337. [PMID: 38837875 DOI: 10.1002/ppul.27068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 04/05/2024] [Accepted: 05/07/2024] [Indexed: 06/07/2024]
Abstract
Childhood interstitial lung disease (chILD) associated with connective tissue and immune mediated disorders is the second most common chILD diagnostic category. As knowledge of the molecular and genetic underpinnings of these rare disorders advances, the recognized clinical spectrum of associated pulmonary manifestations continues to expand. Pulmonary complications of these diseases, including ILD, confer increased risk for morbidity and mortality and contribute to increased complexity for providers tasked with managing the multiple organ systems that can be impacted in these systemic disorders. While pulmonologists play an important role in diagnosis and management of these conditions, thankfully they do not have to work alone. In collaboration with a multidisciplinary team of subspecialists, the pulmonary and other systemic manifestations of these conditions can be managed effectively together. The goal of this review is to familiarize the reader with the classic patterns of chILD and other pulmonary complications associated with primary immune-mediated disorders (monogenic inborn errors of immunity) and acquired systemic autoimmune and autoinflammatory diseases. In addition, this review will highlight current, emerging, and innovative therapeutic strategies and will underscore the important role of multidisciplinary management to improving outcomes for these patients.
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Affiliation(s)
- Aaida Samad
- Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Holly Wobma
- Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Alicia Casey
- Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
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Wareing N, Wang X, Keyes-Elstein L, Goldmuntz EA, Lyons MA, McSweeney P, Furst DE, Nash RA, Crofford LJ, Welch B, Pinckney A, Mayes MD, Sullivan KM, Assassi S. Myeloablation Followed by Hematopoietic Stem Cell Transplantation and Long-Term Normalization of Systemic Sclerosis Molecular Signatures. Arthritis Rheumatol 2024; 76:1288-1293. [PMID: 38497141 PMCID: PMC11288782 DOI: 10.1002/art.42847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 02/16/2024] [Accepted: 03/14/2024] [Indexed: 03/19/2024]
Abstract
OBJECTIVE In the randomized Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, myeloablation, followed by hematopoietic stem cell transplantation (HSCT), led to the normalization of systemic sclerosis (SSc) peripheral blood cell (PBC) gene expression signature at the 26-month visit. Herein, we examined long-term molecular changes ensuing 54 months after randomization for individuals receiving an HSCT or 12 months of intravenous cyclophosphamide (CYC). METHODS Global PBC transcript studies were performed in study participants at pretreatment baseline and at 38 months and 54 months after randomization, as well as in healthy controls using Illumina HT-12 arrays. RESULTS Thirty (HSCT = 19 and CYC = 11) participants had 38-month samples available, and 26 (HSCT = 16 and CYC = 11) had 54-month samples available. In the paired comparison to baseline, a significant down-regulation of interferon modules and an up-regulation of cytotoxic/natural killer module were observed at the 38-month and 54-month visits in the HSCT arm, indicating a long-term normalization of baseline SSc gene expression signature. No differentially expressed modules were detected in the CYC arm. In comparison to samples from healthy controls, 38-month visit samples in the HSCT arm showed an up-regulation of B cell and plasmablast modules and a down-regulation of myeloid and inflammation modules. Importantly, 54-month HSCT samples did not show any differentially expressed modules compared to healthy control samples, suggesting completion of immune reconstitution. Participants in the CYC arm continued to show an SSc transcript signature in comparison to controls at both time points. CONCLUSION Paralleling the observed clinical benefit, HSCT leads to durable long-term normalization of the molecular signature in SSc, with completion of immune resetting to 54 months after HSCT.
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Affiliation(s)
- Nancy Wareing
- UTHealth Houston McGovern Medical School, Houston, Texas, USA
| | - Xuan Wang
- Baylor Institute for Immunology Research, Dallas, Texas, USA
| | | | | | - Marka A. Lyons
- UTHealth Houston McGovern Medical School, Houston, Texas, USA
| | | | - Daniel E. Furst
- University of California Los Angeles, Los Angeles, California, USA
- University of Washington, Seattle, Washington, USA
| | | | | | | | | | | | | | - Shervin Assassi
- UTHealth Houston McGovern Medical School, Houston, Texas, USA
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50
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Ohno R, Nakamura A. Advancing autoimmune Rheumatic disease treatment: CAR-T Cell Therapies - Evidence, Safety, and future directions. Semin Arthritis Rheum 2024; 67:152479. [PMID: 38810569 DOI: 10.1016/j.semarthrit.2024.152479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 04/20/2024] [Accepted: 05/08/2024] [Indexed: 05/31/2024]
Abstract
INTRODUCTION Despite advancements in managing autoimmune rheumatic diseases (ARDs) with existing treatments, many patients still encounter challenges such as inadequate responses, difficulty in maintaining remission, and side effects. Chimeric Antigen Receptor (CAR) T-cell therapy, originally developed for cancer, has now emerged as a promising option for cases of refractory ARDs. METHODS A search of the literature was conducted to compose a narrative review exploring the current evidence, potential safety, limitations, potential modifications, and future directions of CAR-T cells in ARDs. RESULTS CAR-T cell therapy has been administered to patients with refractory ARDs, including systemic lupus erythematosus, antisynthetase syndrome, and systemic sclerosis, demonstrating significant improvement. Notable responses include enhanced clinical symptoms, reduced serum autoantibody titers, and sustained remissions in disease activity. Preclinical and in vitro studies using both animal and human samples also support the efficacy and elaborate on potential mechanisms of CAR-T cells against antineutrophil cytoplasmic antibody-associated vasculitis and rheumatoid arthritis. While cautious monitoring of adverse events, such as cytokine release syndrome, is crucial, the therapy appears to be highly tolerable. Nevertheless, challenges persist, including cost, durability due to potential CAR-T cell exhaustion, and manufacturing complexities, urging the development of innovative solutions to further enhance CAR-T cell therapy accessibility in ARDs. CONCLUSIONS CAR-T cell therapy for refractory ARDs has demonstrated high effectiveness. While no significant warning signs are currently reported, achieving a balance between therapeutic efficacy and safety is vital in adapting CAR-T cell therapy for ARDs. Moreover, there is significant potential for technological advancements to enhance the delivery of this treatment to patients, thereby ensuring safer and more effective disease control for patients.
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Affiliation(s)
- Ryunosuke Ohno
- Department of Medicine, Division of Rheumatology, Queen's University, Kingston, Ontario, Canada; Department of Medicine, Okayama University, Okayama, Japan
| | - Akihiro Nakamura
- Department of Medicine, Division of Rheumatology, Queen's University, Kingston, Ontario, Canada; Translational Institute of Medicine, School of Medicine, Queen's University, Ontario, Canada; Rheumatology Clinic, Kingston Health Science Centre, Kingston, Ontario, Canada.
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