Treatment Of Scleroderma Research Articles

Endpoints and outcomes for localized scleroderma/morphea: a scoping literature review

BackgroundCurrent treatment for localized scleroderma (LS) has been shown to halt disease activity, but little is still known about patient experiences with these treatments, nor is there consensus about optimal measurement strategies for future clinical trials.ObjectiveConduct a scoping review of the literature for the types of outcomes and measures (i.e. clinician-, patient-, and caregiver-reported) utilized in published treatment studies of LS.MethodsOnline databases were searched for articles related to the evaluation of treatment efficacy in LS with a special focus on pediatrics.ResultsOf the 168 studies, the most common outcomes used were cutaneous disease activity and damage measured via clinician-reported assessments. The most frequently cited measure was the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT). Few patient-reported outcome measures (PROMs) were used.LimitationsSome studies only vaguely reported the measures utilized, and the review yielded a low number of clinical trials.ConclusionIn addition to evaluating disease activity with clinician-reported measures, the field could obtain critical knowledge on the patient experience by including high-quality PROMs of symptoms and functioning. More clinical trials using a variety of outcomes and measures are necessary to determine the most suitable course of treatment for LS patients.

Testing a candidate composite serum protein marker of skin severity in systemic sclerosis.

Using an integrated multi-omic analysis, we previously derived a candidate marker that estimates the modified Rodnan Skin Score (mRSS) and thus the severity of skin involvement in SSc. In the present study we explore technical and biological validation of this composite marker in a well-characterized cohort of SSc patients. Cartilage oligomeric matrix protein (COMP), collagen type IV (COL4A1), tenascin-C (TNC) and spondin-1 (SPON1) were examined in serum samples from two independent cohorts of patients with dcSSc. The BIOlogical Phenotyping of diffuse SYstemic sclerosis cohort had previously been used to derive the composite marker and Molecular Determinants to Improve Scleroderma (SSc) treatment (MODERNISE) was a novel validation cohort. Multiple regression analysis derived a formula to predict the mRSS based on serum ELISA protein concentration. The serum concentration of two of the proteins-COMP and TNC-positively correlated with the mRSS, particularly in early dcSSc patients. Interpretable data could not be obtained for SPON1 due to technical limitations of the ELISA. COL4A1 showed a correlation with disease duration but not overall mRSS. Patients receiving MMF showed lower serum concentrations of COMP, COL4A1 and TNC and a lower composite biomarker score not established on treatment. A revised ELISA-based three-protein composite formula was derived for future validation studies. Although more validation is required, our findings represent a further step towards a composite serum protein assay to assess skin severity in SSc. Future work will establish its utility as a predictive or prognostic biomarker.

Consensus statement on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: Localized scleroderma, systemic sclerosis and overlap syndromes.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present consensus provides an update to the 2017 European Dermatology Forum Guidelines, focusing on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, updated strategies for the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 1 of this consensus provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes.

International exchange on the clinical practice and research of rheumatic skin diseases: A report of the 5th International Conference of Cutaneous Lupus Erythematosus.

The 5th International Conference of Cutaneous Lupus Erythematosus was held in Tokyo, Japan on May 9 and 10, 2023. The latest topics on the pathogenesis, diagnosis, assessment, and treatment of cutaneous lupus erythematosus, dermatomyositis, and scleroderma (systemic sclerosis, morphea) were presented by experts in each field and new developments discussed. In these rheumatic skin diseases, many clinical trials of novel therapies targeting cytokines, signaling molecules, plasmacytoid dendritic cells, B cells, and other molecules are currently underway, and standardization of outcome assessment was discussed. In addition, the selection of the therapeutic agents available for the diversity of each case is becoming more important, together with the ongoing pathophysiological analysis of the diseases. The achievements of this conference will further promote the development of clinical practice and research in rheumatic skin diseases through international exchange among researchers. We hope that by reporting a summary of the conference in this manuscript, we can share its contents with readers.

Nintedanib in systemic sclerosis treatment: a case report

BackgroundNintedanib was approved for the treatment of scleroderma and scleroderma-related interstitial lung disease, as it decrease the forced expiratory volume.Case presentationA 48-year-old Asian female patient with systemic scleroderma 6 years ago developed breathlessness, nausea, heart palpation, and sudden severe occipital headache over the preceding week. She was receiving aspirin 81 mg/day and amlodipine 5 mg/day. Her diagnosis was diffuse scleroderma with pulmonary hypertension, interstitial lung involvement, and renal crisis. The modified Rodnan score was 18. We begin captopril at a dose of 12.5 mg, progressively escalating to 200 mg/day, and oral nintedanib was started at 150 mg. A total of 12 months after initiation of treatment, the patient’s kidney function was normal. The pulmonary function tests improved. The modified Rodnan score was reduced to 10. We did not encounter any side effects in our case due to nintedanib treatment.ConclusionTreatment with nintedanib is crucial for slowing lung function decline. Diarrhea was the most common adverse event. Scleroderma renal crisis occurs in 10% of patients and typically presents with an abrupt onset of hypertension and kidney failure. The optimal antihypertensive agent for scleroderma renal crisis is an ACE inhibitor. The mainstay of therapy in scleroderma renal crisis has been shown to improve or stabilize renal function in approximately 70% of patients and improve survival in nearly 80% at 1 year. Nintedanib may be effective, and fairly safe to use. Further exploration is anticipated to advance a new period of systemic sclerosis treatment.

Treatment of juvenile scleroderma – current status of the problem

Treatment of juvenile scleroderma – current status of the problem

Global research status of localised scleroderma reported over the period 1993-2022: A 30-year bibliometric analysis.

Localised scleroderma predominantly affects the skin with an unknown aetiology. Despite its clinical importance, no comprehensive bibliometric analysis has been conducted to assess the existing research landscape and future prospects for localised scleroderma. The articles related to localised scleroderma were retrieved from the WoSCC database and analysed by VOSviewer 1.6.10.0 (Leiden University, Netherlands), CiteSpace 6.1.R1 (Dreiser University, USA), and HistCite 2.1 (New York, United States). 2049 research papers pertaining to localised scleroderma spanning the years from 1993 to 2022 were extracted from the WoSCC database. The United States exhibited the highest productivity with 644 papers, accounting for 31.43% of the total output, followed by Germany with 206 papers (10.05%) and Italy with 200 papers (9.76%). Regarding academic institutions and journals, the University of Texas System and Dermatology published the most significant number of papers, and Professor Ihn, H emerged as the most prolific contributor among scholars. The top 10 cited references primarily concentrated on the diagnosis and treatment of localised scleroderma. "Phototherapy" and "methotrexate (MTX)" surfaced as the most recent and noteworthy keywords, representing the research hotspots in the domain of localised scleroderma. This bibliometric analysis furnishes valuable insights into the contemporary research landscape of localised scleroderma.

Brown adipose tissue transplantation improves skin fibrosis in localized scleroderma.

Adipose tissue transplantation shows great therapeutic potential in reversing localized scleroderma-associated skin fibrosis. Brown adipose tissue (BAT) can specifically secrete various cytokines against fibrosis, but its therapeutic potential in improving skin fibrosis has not yet been demonstrated. In this study, we have demonstrated the superior therapeutic efficacy of BAT transplantation for sclerotic skin by transplanting two distinct types of adipose tissue. In comparison to the white adipose tissue (WAT) group, mice treated with BAT transplantation exhibited a significant reduction in dermal thickness. BAT transplantation effectively reverses skin sclerosis through mechanisms involving inflammation reduction, promotion of angiogenesis, inhibition of myofibroblast accumulation, and collagen deposition. This therapeutic effect can be attributed to its unique paracrine effects. Furthermore, transcriptome sequencing (RNA-Seq) revealed upregulation of pathways associated with lipogenesis and fatty acid metabolism in BAT while downregulating pathways are related to transforming growth factor β(TGF-β), epithelial-mesenchymal transition (EMT), and inflammatory response. These findings suggest that BAT transplantation holds great promise as a novel approach for localized scleroderma treatment.

Novel indications for autologous fat grafting in reconstruction: scleroderma

Scleroderma is a chronic connective tissue disease characterized by inflammation, vascular injury, and progressive skin fibrosis, resulting in significant aesthetic and functional impairments for patients. Current therapies are limited and insufficiently treat the cutaneous manifestations of scleroderma. Autologous fat transfer (AFT) is a surgical technique that has been utilized for many decades for facial rejuvenation. The adipose stem cells (ASCs) present in fat grafts have also shown significant promise for their anti-inflammatory and regenerative properties. Recently, AFT has been repurposed to treat the skin manifestations of systemic sclerosis and localized scleroderma. Studies suggest that AFT in scleroderma patients improves mouth and hand functions, Raynaud’s symptoms, and digital ulcerations. AFT is a safe procedure with rare postoperative complications, making it a promising intervention for the treatment of scleroderma. Further studies are required to better characterize the influence of fat grafts on the recipient site and to establish standards for fat transfer in fibrotic skin diseases.

A Challenging Case of Scleroderma: Diagnosis, Treatment, and Management

Scleroderma is a relatively rare autoimmune disorder that causes progressive hardening, tightening, and scarring of the skin, as well as internal organ involvement. This case study presents a 56-year-old African American female with diffuse cutaneous scleroderma who has had recurrent complications since 2017, including earaches and fingertip infections. The patient’s medical history, clinical course, diagnosis, and treatment options, including NSAIDs, low-dose corticosteroids, and methotrexate, are discussed. Osteopathic manipulative medicine is explored as a potential symptomatic treatment for scleroderma. Early diagnosis and chronic management for scleroderma patients are emphasized to avoid severe complications such as pulmonary hypertension, which can lead to cor pulmonale and right-sided heart failure. Further research is needed on prophylactic treatments for scleroderma complications and the potential link between multiple autoimmune disorders and increased susceptibility to scleroderma. This case study provides medical professionals with a better understanding of scleroderma and the available treatment options to improve patient quality of life.

Transplantation of in vitro prefabricated adipose organoids attenuates skin fibrosis by restoring subcutaneous fat and inducing dermal adipogenesis.

Localized scleroderma is a complex autoimmune disease characterized by dermal fibrosis and loss of cutaneous fat. While cytotherapy offers a promising treatment option, stem cell transplantation results in low survival rates and fails in target cell differentiation. In this study, we aimed to prefabricate syngeneic adipose organoids (ad-organoids) using microvascular fragments (MVFs) via three-dimensional (3D) culturing and transplant them beneath the fibrotic skin to restore subcutaneous fat and reverse the pathological manifestation of localized scleroderma. We employed 3D culturing of syngeneic MVFs with stepwise angiogenic and adipogenic induction to produce ad-organoids and evaluated their microstructure and paracrine function in vitro. C57/BL6 mice with induced skin scleroderma were treated with adipose-derived stem cells (ASCs), adipocytes, ad-organoids, and Matrigel, and the therapeutic effect was assessed histologically. Our results showed that ad-organoids derived from MVF contained mature adipocytes and a well-established vessel network, secreted multiple adipokines, promoted adipogenic differentiation of ASCs, and suppressed proliferation and migration of scleroderma fibroblasts. Subcutaneous transplantation of ad-organoids reconstructed the subcutaneous fat layer and stimulated dermal adipocyte regeneration in bleomycin-induced scleroderma skin. It reduced collagen deposition and dermal thickness, attenuating dermal fibrosis. Moreover, ad-organoids suppressed macrophage infiltration and promoted angiogenesis in the skin lesion. In conclusion, 3D culturing of MVFs with stepwise angiogenic and adipogenic induction is an effective strategy for the fabrication of ad-organoids, and the transplantation of prefabricated ad-organoids can improve skin sclerosis by restoring cutaneous fat and attenuating skin fibrosis. These findings offer a promising therapeutic approach for the treatment of localized scleroderma.

Editorial introductions.

Current Opinion in Rheumatology was launched in 1989. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of Rheumatology is divided into 15 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Section Editors for this issue. SECTION EDITORS W. Joseph McCuneW. Joseph McCuneDr W. Joseph McCune, MD, is Michael and Marcia Klein Professor of Rheumatic Diseases and Director of the Lupus Program at the University of Michigan. Following an Internal Medicine residency at the University of Michigan and a fellowship in Immunology and Rheumatology at Harvard Medical School and the Brigham and Woman's Hospital, Dr McCune has been a member of the faculty at the University of Michigan where he specializes in the epidemiology, diagnosis, and treatment of lupus and systemic vasculitis. Sara K. TedeschiSara K. TedeschiDr. Sara K. Tedeschi, MD, MPH, received her medical degree from Vanderbilt University, USA and her MPH degree from the Harvard School of Public Health, USA. She joined the rheumatology faculty at Brigham and Women's Hospital, USA, after completing her internal medicine residency and rheumatology fellowship there. Her clinical research on calcium pyrophosphate crystal deposition disease is supported by the National Institutes of Health. David FoxDavid FoxDr. Fox is a graduate of the Massachusetts Institute of Technology and Harvard Medical School. Following internal medicine residency and rheumatology fellowship at the Brigham and Women's Hospital, he joined the faculty of the University of Michigan School of Medicine in 1985. Dr. Fox is Professor of Internal Medicine and, from 1990 to 2018, was Chief of the Division of Rheumatology. In 2013, Dr. Fox became the Frederick G. L. Huetwell and William D. Robinson, M.D. Professor of Rheumatology. He is currently a Deputy Director of the Immune Tolerance Network. Dr. Fox's research focuses on defining and characterizing pathways of human T cell activation, determining the role of these pathways in the pathogenesis of autoimmune disease, investigating T cell interactions with synovial fibroblasts, and exploring novel approaches to the treatment of rheumatoid arthritis and scleroderma. He is author of more than 260 scientific papers and book chapters. Dr. Fox is also active in the clinical care of patients with rheumatic diseases and in teaching students and fellows in both clinical and research settings. From 2007–2008, Dr. Fox served as the seventy-first President of the American College of Rheumatology and the sixth ACR President from the University of Michigan

352 Endothelial cells – additional targets for alpha7 nicotinic acetylcholine receptor agonists in the future treatment of skin fibrosis and scleroderma?

352 Endothelial cells – additional targets for alpha7 nicotinic acetylcholine receptor agonists in the future treatment of skin fibrosis and scleroderma?

UVA1 irradiation attenuates collagen production via Ficz/AhR/MAPK signaling activation in scleroderma

Scleroderma is an autoimmune disease mainly characterized by progressive fibrosis of the skin. There are two types of scleroderma, namely localized scleroderma (LS) and systemic sclerosis (SSc); skin lesions in both types of scleroderma are histologically identical. Progressive skin sclerosis induces psychological and ecological burden for scleroderma patients. However, there is no effective treatment for scleroderma due to its unclear etiology. Aryl hydrocarbon receptor (AhR) is recognized as an environmental chemical effector that can respond to ultraviolet radiation, which has been demonstrated to participate in the pathogenesis of SSc in our previous study. In this study, we verify whether the anti-fibrosis effect of ultraviolet A1 (UVA1) phototherapy could be partially induced through Ficz/AhR/MAPK signaling activation for fibrotic lesions in both SSc and LS patients. This is the first study to show the association between the AhR pathway and the anti-fibrotic mechanism of UVA1 phototherapy, which provides additional evidence of the role of AhR in the fibrotic mechanism of systemic scleroderma from different perspectives. Ficz and other AhR agonists may replace UVA1 phototherapy as anti-fibrotic agents in scleroderma.

Editorial introductions.

Editorial introductions.

The impact of COVID-19 on clinical course and treatment among patients with juvenile systemic sclerosis.

This study aimed to explore the influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic among patients with juvenile systemic sclerosis (JSS). Twenty-seven patients (22 females, 5 males; mean age: 20 years; range, 17 to 22 years) diagnosed with JSS and followed up at the department of pediatric rheumatology were included in the cross-sectional study. A web-based survey was performed by focusing on patients' complaints, accessibility to health care, and compliance with routine treatment from January 1, 2021, to January 10, 2021. Five (18.5%) patients had deterioration of the disease, while six (22.2%) patients reported irregular usage of their routine scleroderma treatment during the last six months. Nine (33.3%) patients had missed their routine clinic control since the proclamation of the SARS-CoV-2 pandemic. Seven (25.9%) patients had household contact with coronavirus disease 2019 (COVID-19). Four (14.8%) patients were diagnosed with COVID-19, and only one (3.7%) was hospitalized. Nine patients were under biological treatment (tocilizumab); however, only one of them was diagnosed with COVID-19. The COVID-19 pandemic has not significantly disrupted the medical care of JSS patients. Telemedicine could be an acceptable option for JSS patients disenabled to come to the hospital.

Total glucosides of paeony alleviates scleroderma by inhibiting type I interferon responses

Ethnopharmacological relevanceType I interferon (IFN) is believed to play a pathogenic role in systemic sclerosis (SSc, also called scleroderma), which is an autoimmune rheumatic disease. Our previous studies have found that Chinese medicine formula Si–Ni-San (SNS, composed of Glycyrrhiza uralensis Fisch., Bupleurum chinense DC., Paeonia lactiflora Pall., and Citrus aurantium L.) had inhibitory effects on type I IFN responses. Among these herbal products, Paeonia lactiflora Pall. has been traditionally used to treat inflammation-related diseases, yet its therapeutic effects against type I IFN-related diseases and potential bioactive ingredients are not characterized. Aim of the studyWe aim to identify bioactive ingredient with anti-type I IFN activity from herbal products in SNS and further elucidate its therapeutic effect against scleroderma and underlying mechanisms. Materials and methodsWe constructed a Gaussia-luciferase (Gluc) reporter assay system to identify ingredients with anti-type I IFN activities from SNS. In RAW264.7 cells, real-time PCR (RT-PCR) and western blotting were used to investigate the induction of type I IFN pathway. Additionally, in a bleomycin (BLM)-induced experimental scleroderma model, the expression of fibrotic genes, type I IFN-related genes, inflammatory cytokines, and cytotoxic granules were measured by RT-PCR, and the histopathological changes were determined by H&E staining, Masson's staining and immunohistochemistry analysis. ResultsOur data demonstrated that total glucosides of paeony (TGP) was the bioactive component of SNS that selectively inhibited TLR3-mediated type I IFN responses and blocked type I IFN-induced downstream JAK-STAT signaling pathways. In the BLM-induced scleroderma mouse model, TGP ameliorated skin fibrosis by inhibiting multiple targets in the upstream and downstream of type I IFN signaling. Further research found that TGP hindered polarization of M2 macrophages and their profibrotic effects and reduced cytotoxic T lymphocytes and their cytotoxic granules by suppressing Cxcl9 and Cxcl10 in the skin tissue of scleroderma mice. ConclusionsOur study not only sheds novel lights into the immunoregulative effects of TGP but also provides convincing evidence to develop TGP-based therapies in the treatment of scleroderma and other autoimmune diseases associated with type I IFN signatures. ClassificationSkin

Adipose-Derived Stem Cells Attenuate Skin Fibrosis and Improve Fat Retention of a Localized Scleroderma Mouse Model.

Although autologous fat grafting is a feasible surgical technique to improve facial deformity in patients with localized scleroderma, its success is limited by the low graft retention induced by the local inflammatory environment. This study investigated the potential effect of adipose-derived stem cells (ASCs) on skin fibrosis and fat retention in a localized scleroderma mouse model. BALB/C nude mice that were induced by bleomycin to establish a localized scleroderma model were divided randomly into five groups: blank control; fat grafting; and low, moderate, and high doses of ASC-assisted fat grafting. The backs of the mice were subcutaneously injected with phosphate-buffered saline or fat, or fat with low, moderate, and high doses of ASCs (1 × 10 5 /mL, 5 × 10 5 /mL, and 25 × 10 5 /mL, respectively). The skin fibrosis and fat retention were analyzed after 1 month or 3 months, respectively. Compared to the disease model group, the fat-grafting group, and the low- and moderate-dose ASC-enriched groups, the high-dose ASCs significantly attenuated skin fibrosis, inhibited the production of type III collagen and transforming growth factor-β1, increased fat graft retention, enhanced the expression of angiogenesis-related cytokines and angiogenesis, and increased the expression of adipogenesis-related cytokines. The results demonstrated that high-dose ASCs attenuated skin fibrosis and improved fat retention in a localized scleroderma model by reducing inflammation and by promoting angiogenesis and adipogenesis. The authors further demonstrated that ASCs enhanced adipogenesis through the AKT/ERK signaling pathway. Fat grafting has been used to treat localized scleroderma patients but with low fat retention. In this study, ASC attenuated skin fibrosis and improved fat retention in the localized scleroderma model, providing evidence for cell therapy in future application of localized scleroderma treatment.

Effect of Adipose-Derived Stem Cell on Collagen Deposition in Nude Mouse Model of Scleroderma

Systemic sclerosis is an autoimmune disease featured by uncontrolled fibrosis and collagen deposition. This study aimed to investigate the impact of adipose-derived stem cells (ADSCs) transplantation on collagen in scleroderma. After establishment of scleroderma model using Bleomycin, the animals received subcutaneous injection of 0.3 ml fat (group B) or 0.3 ml fat+1×106 ADSCs (group C), or 1×106 ADSCs alone (group D). Mice treated with PBS were taken as control group (group A). One month after operation, the skin tissue at injection site was collected for H&E staining, and immunohistochemistry to determine the content of TGF-β1 and type III collagen. Compared to control group, group B, C, and D exhibited improvement in collagen deposition and reduction in TGF-β1 content and type III collagen. Combined graft of fat and ADSCs exerted more significant effect compared to single ADSCs treatment. In conclusion, fat and ADSCs transplantation improves collagen deposition in nude mice with scleroderma and the combined treatment exerts a higher efficacy, suggesting that ADSCs need adipose carrier and microenvironment. These findings provide a novel insight into the treatment of scleroderma.

Adipose‐Derived Regenerative Cell Transplantation for the Treatment of Hand Dysfunction in Systemic Sclerosis: A Randomized Clinical Trial

ObjectiveHand dysfunction is common in systemic sclerosis (SSc). We undertook this study to evaluate the capacity of autologous adipose‐derived regenerative cells (ADRCs) to improve hand function in SSc patients.MethodsThe Scleroderma Treatment with Celution Processed Adipose Derived Regenerative Cells Trial was a prospective, randomized, double‐blind trial of ADRCs, in which ADRCs were obtained from patients with SSc by small‐volume adipose tissue harvest, and the fingers of each patient were injected with ADRCs. The primary end point was change in hand function at 24 and 48 weeks, assessed using the Cochin Hand Function Scale (CHFS). One of the secondary end points included the change in Health Assessment Questionnaire disability index (HAQ DI) at 48 weeks. Separate prespecified analyses were performed for patients with diffuse cutaneous SSc (dcSSc) and those with limited cutaneous SSc (lcSSc).ResultsEighty‐eight patients were randomized to receive ADRCs (n = 48 [32 patients with dcSSc and 16 with lcSSc]) or placebo (n = 40 [19 patients with dcSSc and 21 with lcSSc]). Change in hand function according to CHFS score was numerically higher for the ADRC group compared to the placebo group but did not achieve statistical significance (mean ± SD improvement in the CHFS score at 48 weeks 11.0 ± 12.5 versus 8.9 ± 10.5; P = 0.299). For patients with dcSSc, the between‐group difference in the CHFS at 48 weeks was 6.3 points (nominal P = 0.069). For the secondary end point, the dcSSc group exhibited a between‐group difference of 0.17 points in the HAQ DI (nominal P = 0.044) at 48 weeks. Of the ADRC‐treated patients with dcSSc, 52% reported improvement greater than the minimum clinically important difference for both CHFS and HAQ DI compared to 16% in the placebo group (nominal P = 0.016). Small‐volume adipose tissue harvest and ADRC treatment were well tolerated.ConclusionWhile the primary end point of this trial was not achieved, efficacy trends were observed in patients with dcSSc. Adipose tissue harvest and ADRC injection were demonstrated to be feasible. Further clinical trials of this intervention in the setting of dcSSc are warranted.