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Background: The anti-Nucleolar Organizer Region 90 antibodies (NOR90) are rare antinuclear antibodies (ANA) reported in systemic sclerosis (SSc). Especially due to low prevalence, the clinical relevance of NOR90 in SSc remains uncertain., Objectives: To analyze the clinical associations of NOR90 in patients with SSc in a multicentric cohort., Methods: Post-hoc, cross-sectional study of prospectively collected data from the European Scleroderma Trials and Research (EUSTAR) database, with additional information on NOR90. Further, we performed a systematic literature search, using the terms "systemic sclerosis" and "NOR90" across three databases: Medline via PubMed, Scopus, and Thomson Reuters' Web of Science Core Collection, from inception to November 1st, 2023., Results: Overall, 1318 patients with SSc were included (mean age 58.3 ± 13.7 years, 81.3 % female), of whom 44 (3.3 %) were positive for NOR90. Of these, 32 were also positive for one of the SSc-criteria antibodies: 9/44 (20.5 %) for anti-topoisomerase I, 18/42 (42.9 %) for anti-centromere, and 5/40 (12.5 %) for anti-RNA polymerase III. NOR90-positive patients were more frequently female, had lower modified Rodnan skin score (mRSS), and lower prevalence of upper and lower gastrointestinal (GI) symptoms compared to NOR90-negative patients. In multivariable analysis, NOR90 remained significantly associated with lower mRSS and less frequent GI symptoms. The literature search identified 17 articles, including a total number of 87 NOR90-positive out of 3357 SSc patients, corresponding to an overall prevalence of 2.6 %., Conclusion: To our best knowledge, this is the largest SSc cohort tested for NOR90 to date, confirming the NOR90 prevalence in SSc patients is around 3 %., Competing Interests: Declaration of competing interest DIMA Alina: Nothing to disclose. VONK Madelon: Consultancy relationship with and/or research funding from and/or speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Boehringer Ingelheim, Ferrer, Galapagos, GSK, Janssen, MSD and Novartis. GARAIMAN Alexandru: Nothing to disclose. KERSTEN E Brigit: Nothing to disclose. BECVAR Radim: Nothing to disclose. TOMCIK Michal: Nothing to disclose. HOFFMANN-VOLD Anna-Maria: Speakers bureau: Boehringer Ingelheim, Jannsen, Medscape, Merck Sharp & Dohme and Roche; Consultant: ARXX, Boehringer Ingelheim, Genentech, Jannsen, Medscape, Merck Sharp & Dohme and Roche; Grant/research support: Boehringer Ingelheim, Jannsen CASTELLVI Ivan: Speakers’ bureau: Boehringer, Janssen-Cilag, BMS, Roche, UCB; Consultant: Boehringer, Janssen-Cilag, Topandur. TANDAIPAN JAIME Jose Luis: Nothing to disclose. BRZOSKO Marek: Nothing to disclose. MILCHERT Marcin: Nothing to disclose. KRASOWSKA Dorota: Speakers’ bureau: Novartis, Abbvie, Elli Lilly; Consultant: Boehringer Ingelheim, Novartis, Janssen. MICHALSKA-JAKUBUS Małgorzata: Nothing to disclose. AIRO Paolo: Consulting fees, honoraria for lectures, presentations, or educational events, support for attending meetings and/or travel from: Bristol Myers Squibb, Bohringer Ingelheim, Roche, Novartis, CSL Behring Janssen- Cilag MATUCCI-CERINIC Marco: Speakers’ bureau: Biogen, Sandoz, Boehringer, Lilly, Galapagos; Grant/research support: MSD, Janssen; BRUNI Cosimo: Consultant: Boehringer Ingelheim; Grant/research support: Gruppo Italiano Lotta alla Sclerodermia (GILS), European Scleroderma Trials and Research Group (EUSTAR), Foundation for research in Rheumatology (FOREUM), Scleroderma Clinical Trials Consortium (SCTC); Novartis Foundation for medical-biological research, EMDO Foundation; Educational grants: AbbVie, Wellcome Trust. IUDICI Michele: Nothing to disclose. DISTLER Jorg: Nothing to disclose. GHEORGHIU Ana-Maria: Speakers’ bureau: Sandoz, Boehringer Ingelheim, Ewopharma; Consultant: Boehringer Ingelheim. POORMOGHIM Hadi: Nothing to disclose. MOTTA Francesca: FM had consulting fees from Thermo Fisher. DE SANTIS Maria: Nothing to disclose. PARVU Magda: Nothing to disclose. DISTLER Oliver: OD has/had consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, iQvia, Horizon, Inventiva, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Prometheus, Redxpharma, Roivant, Sanofi and Topadur. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143). Research Grants: BI, Kymera, Mitsubishi Tanabe MIHAI Carina: CM received consulting fees and/or honoraria from Boehringer Ingelheim, Janssen Cilag AG, MED Talks Switzerland, Medbase, Mepha, Novartis, and PlayToKnow AG, and congress support from Boehringer Ingelheim and Roche., (Copyright © 2024 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Objective: The outcome of patients with COVID-19 improved over the pandemic, including patients with systemic rheumatic diseases. However, data on patients with systemic sclerosis (SSc) are lacking. This study aimed to assess the outcome of patients with both SSc and COVID-19 over several waves., Methods: Patients with both SSc and COVID-19 who were registered in the European Scleroderma Trials and Research group (EUSTAR) were collected between April 2020 and April 2021. Patients were assigned to waves 1, 2, or 3 depending on the date of their COVID-19 diagnosis. Primary endpoints were death, intensive care unit stay, or ventilatory support (severe outcome). Subgroup analyses of patients who were hospitalized or died were conducted. General and SSc-specific characteristics and treatment were compared over the waves. Descriptive statistics and multivariate logistic regression were applied., Results: A total of 333 patients were included; 57 patients (17%) had a severe outcome, and 30 patients (9%) died. Compared to wave 1, significantly fewer patients with SSc suffered from severe COVID-19 in waves 2 and 3 (28.2% vs 9.8% and 12.7%; P < 0.001), fewer patients required hospitalization (46.7% vs 19.6% and 25.5%; P < 0.001) or ventilatory support (24.0% vs 8.7% and 10.9%; P = 0.001), and fewer patients died (15.7% vs 5.0% and 7.5%; P = 0.011). Patients were significantly younger, more often men, had less frequent arterial hypertension, and less SSc cardiac involvement over waves 1 to 3. Patients received significantly less medium to high doses of corticosteroids as they did SSc treatment., Conclusion: The outcome of patients with both SSc and COVID-19 improved significantly over time because of intrinsic and extrinsic factors., (© 2023 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Systemic sclerosis (SSc) or scleroderma is a multiorgan rheumatoid disease characterized by skin tightening or organ dysfunction due to fibrosis, vascular damage, and autoimmunity. No specific cause has been discovered for this illness, and hence no effective treatment exists for it. On the other hand, due to the lack of diagnostic biomarkers capable of effectively and specifically differentiating the patients, early diagnosis has not been possible. Due to their potent regulatory roles in molecular pathways, microRNAs are among the novel candidates for the diagnosis and treatment of diseases like SSc. MiR-27a is a microRNA known for its role in the pathogenesis of fibrosis and cancer, both of which employ similar signaling pathways; hence we hypothesized that Mir-27a could be dysregulated in the blood of individuals affected by SSc and it might be useful in the diagnosis or treatment of this disease. Blood was collected from 60 SSc patients (30 limited and 30 diffuse) diagnosed by a rheumatologist according to ACR/AULAR criteria; following RNA isolation and cDNA synthesis; real-time qPCR was performed on the samples using Taq-Man probes and data were analyzed by the ΔΔCT method. Also, potential targets of miR-27a were evaluated using bioinformatics. It was revealed that miR-27a was significantly down-regulated in SSc patients in comparison to healthy individuals, but there was no difference in miR-27 expression between limited and diffused SSc patients. Besides, miR-27a was found to target several contributing factors to SSc. It seems that miR-27a has a protective role in SSc, and its downregulation could result in the disease's onset. Based on bioinformatics analyses, it is speculated that miR-27a likely targets factors contributing to the pathogenesis of SSc, which are elevated upon the downregulation of miR-27a; hence, miR-27a mimics could be considered as potential therapeutic agents for the treatment of SSc in future studies. Since no difference was observed between limited and diffuse patient groups, it is unlikely that this microRNA has a role in disease progression. According to ROC analysis of qPCR data, miR-27a could be employed as a valuable diagnostic biomarker for SSc., (© 2022. The Author(s).)

Background: Gender-related factors have explained the higher prevalence of autoimmune diseases in women. Sex hormones play a key role in the immune system and parenchymal cells function; therefore, these hormones can be important in the pathogenesis of autoimmune diseases as a risk or beneficial factor. Lung fibrosis is the main cause of mortality in systemic sclerosis, a female predominant autoimmune disease. The objective of this study was to examine the effect of progesterone on lung fibrosis in a mouse model of systemic sclerosis., Methods: Mice with bleomycin-induced lung fibrosis treated with progesterone subcutaneously for 21 and 28 days. Blood was collected for hormone and cytokine measurement at the end of treatment then, skin and lung tissues were harvested for histological assessment, gene expression, cytokine, hydroxyproline, and gelatinase measurement., Results: Trichrome staining and hydroxyproline measurements showed that progesterone treatment increased the content of collagen in fibrotic and normal lung tissues. Progesterone increased α-SMA (P < 0.01), TGF- β (P < 0.05) and decreased MMP9 (P < 0.05) in fibrotic lung tissues. Also progesterone treatment decreased the gene expression of Col1a2 (P <0.05), Ctgf (P <01), End1 (0.001) in bleomycin- injured lung tissues. The serum level of TNF-α was decreased, but the serum level of cortisol was increased by progesterone treatment in fibrotic mice (P< 0.05)., Conclusion: Our results showed that progesterone aggravates lung fibrosis in a mouse model of systemic sclerosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vafashoar, Mousavizadeh, Poormoghim, Haghighi, Pashangzadeh and Mojtabavi.)

Objective: To evaluate clinical associations of anti-PM/Scl antibodies in patients with SSc in a multicentre international cohort, with particular focus on unresolved issues, including scleroderma renal crisis (RC), malignancies, and functional outcome of interstitial lung disease (ILD)., Methods: (1) Analysis of SSc patients from the EUSTAR database: 144 anti-PM/Scl+ without SSc-specific autoantibodies were compared with 7202 anti-PM/Scl-, and then to 155 anti-Pm/Scl+ with SSc-specific antibodies. (2) Case-control study: additional data were collected for 165 anti-PM/Scl+ SSc patients (85 from the EUSTAR registry) and compared with 257 anti-PM/Scl- SSc controls, matched for sex, cutaneous subset, disease duration and age at SSc onset., Results: Patients with isolated anti-PM/Scl+, as compared with anti-Pm/Scl-, had higher frequency of muscle involvement, ILD, calcinosis and cutaneous signs of DM, but similar frequency of SRC and malignancies (either synchronous with SSc onset or not). The presence of muscle involvement was associated with a more severe disease phenotype. Although very frequent, ILD had a better functional outcome in cases than in controls. In patients with both anti-PM/Scl and SSc-specific antibodies, a higher frequency of typical SSc features than in those with isolated anti-PM/Scl was observed., Conclusion: The analysis of the largest series of anti-PM/Scl+ SSc patients so far reported helps to delineate a specific clinical subset with muscle involvement, cutaneous DM, calcinosis and ILD characterized by a good functional outcome. SRC and malignancies do not seem to be part of this syndrome., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Systemic sclerosis is a fibrotic autoimmune disease in which aberrant remodeling of the extracellular matrix in organs disturbs their functionalities. The aim of this study was to investigate the expression of gelatinases on systemic sclerosis. Consequently, a mouse model of systemic sclerosis was employed and the gelatinolytic activity of gelatinases was evaluated on the fibrotic tissues of this model. Two groups of ten mice were considered in this work: a group of systemic sclerosis model and control group. For the generation of systemic sclerosis model, mice received bleomycin, while the control group was subjected to phosphate buffered saline (PBS) reception. Mice were tested for fibrosis by using trichrome staining, hydroxyproline measurement and α-SMA detection in tissue sections. Additionally, the gelatinolytic activity of matrix metalloproteinase 2 and matrix metalloproteinase 9 were measured using gelatin zymography in lungs and skin tissue homogenates. The obtained results indicated that subcutaneous injection of bleomycin-induced fibrosis in skin and lung tissues of mice. Pro and active forms of matrix methaloproteinase 9 were increased in fibrotic lung tissues (p<0.05 and p<0.01, respectively), while, the gelatinolytic activity of MMP2 was unaffected in these tissues. Additionally, in skin tissues of bleomycin-treated animals, both pro and active forms of MMP9 and MMP2 were increased (p<0.05). Pro and active forms of gelatinases increase differently in skin and lung tissues of bleomycin-induced scleroderma.

Systemic sclerosis is a female predominant, a fibrotic autoimmune disease in which disturbance in tissue homeostasis and cell turnover including cell apoptosis are central events in pathogenesis. Sex hormones are known as the important players in sexual dimorphism of autoimmune diseases and in tissue homeostasis. Progesterone influences autoimmune disease via its immunomodulatory effect or by its direct action on parenchymal cell function. On the other hand, this hormone impacts tissue homeostasis by acting on cell apoptosis in a different situation. The objective of this study was to examine the effect of progesterone on cellular apoptosis of skin and lung tissues in a mouse model of scleroderma. Four group of mice were involved in this study with 10 mice in each. The fibrotic model was induced by daily subcutaneous injection of bleomycin for 28 days. One week after initiation of fibrosis induction, mice received subcutaneous progesterone alone or with bleomycin for 21 days. Control group received only Phosphate buffered saline PBS. After 28 days, under lethal anesthesia skin and lung tissues were harvested for histological assessment and hydroxyproline measurement. Apoptosis in tissue sections was detected by TUNEL assay technique. Bleomycin administration induced fibrosis in skin and lung tissues. Severe apoptosis was seen in skin and lung tissues of the bleomycin-treated group (p<0.001 in the skin and p<0.05 in the lung). Progesterone injection either in the skin (p>0.05) or in the lung (p>0.05) did not alter apoptosis in bleomycin-treated animals. Our data confirm the role of apoptosis in the pathogenesis of fibrosis in this model; however, progesterone does not affect cellular apoptosis in skin and lung tissues of bleomycin-injured animals.

The aims of the study were to determine prognostic factors for survival and causes of death in a cohort of patients with systemic sclerosis (SSc). This was a cohort study of SSc patients in single rheumatologic center from January 1998 to August 2012. They fulfilled the American College of Rheumatology classification criteria for SSc or had calcinosis Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia or sine sclerosis. Causes of death were classified as SSc related and non-SSc related. Kaplan-Meier and Cox proportional hazard regression models were used in univariate and multivariate analysis to analyse survival in subgroups and determine prognostic factors of survival. The study includes 220 patients (192 female, 28 male). Out of thirty-two (14.5 %) who died, seventeen (53.1 %) deaths were SSc related and in nine (28.1 %) non-SSc-related causes, and in six (18.8 %) of patients causes of death were not defined. Overall survival rate was 92.6 % (95 % CI 87.5-95.7 %) after 5 years and 82.3 % (95 % CI 73.4-88.4 %) after 10 years. Pulmonary involvement was a major SSc-related cause of death, occurred in seven (41.1 %) patients. Cardiovascular events were leading cause of in overall death (11) 34.3 % and 6 in non-SSc-related death. Independent risk factors for mortality were age >50 at diagnosis (HR 5.10) advance pulmonary fibrosis (HR 11.5), tendon friction rub at entry (HR 6.39), arthritis (HR 3.56). In this first Middle Eastern series of SSc registry, pulmonary and cardiac involvements were the leading cause of SSc-related death.

What Is Known and Objective: Calcinosis cutis (or cutaneous calcification) is a type of calcinosis wherein calcium deposits form in the skin and frequently encountered in limited cutaneous subtype of disease. So far, no treatment has shown an explicit beneficial effect. Medical therapy for calcinosis cutis with rituximab is limited and of variable benefit., Case Summary: Our patient was 54-year-old lady, a case of limited cutaneous scleroderma with widespread progressive calcinosis cutis unresponsive to current therapy. She went under treatment with rituximab with no successful outcome., What Is New and Conclusion: Results of therapy with rituximab on regression/improvement of systemic sclerosis-related calcinosis are limited and non-conclusive., (© 2015 John Wiley & Sons Ltd.)

The aim of this study was to evaluate efficacy of azathioprine (AZA) and cyclophosphamide (CYC) as a therapeutic regimen for interstitial lung disease associated with systemic sclerosis (SSc). Thirty-six selected patients included in this retrospective cohort and received one of the two drugs; the first group consists of 15 patients who were treated with AZA (1.5-2 mg/kg/day) and the second group with 21 patients received oral CYC (up to 2 mg/kg/day). Both groups received additional low dose of prednisolone (≤10 mg) for 6 months. Forced vital capacity (FVC), diffusion lung capacity for carbon monoxide (DLCO) and skin score were assessed as outcome measures. Modified Rodnan skin score (mRSS), pulmonary function test and DLCO were evaluated at entry and at the end of study after 12 months. The mean (SD) FVC percentages obtained at baseline and post-treatment in AZA-treated patients were 62.8 ± 9.8 and 71.1 ± 20.9 with mean difference of FVC% +7.6 ± 13.1, p = 0.05, and in CYC-treated patients 59.5 ± 10.7, 63.1 ± 16.2 and +2.9 ± 11.5, respectively, p = 0.19. Baseline and post-treatment DLCO% in AZA-treated patients were 61.4 ± 25.8 and 76.7 ± 24.0 with mean difference of +15.0 ± 14.5, respectively, p = 0.01. In CYC-treated patients, those measures were 67.7 ± 27.5 and 60.0 ± 22.9 with mean difference of -8.0 ± 23.7 (p = 0.12). Following 12 months of treatment in AZA-treated patients, mean difference of changes in mRSS was -2.9 ± 3.7 and -1.4 ± 4.5 in CYC-treated patients. Our results indicated that AZA can be effective in ameliorating or stabilizing lung function in selected SSc patient groups.

To evaluate demographic, clinical and laboratory features associated with scleroderma-specific auto-antibodies. Sera of 100 patients with systemic sclerosis (SSc) were analyzed by an indirect immunofluorescence technique with HEp-2 cells as a substrate. Specific ANA such as anti-centromere antibodies (ACA), anti-topoisomerase (TOPO), anti-RNA polymerase III (Pol 3), anti-U3-RNP (U3-RNP), anti-Th/To (Th/To) and anti-PM/Scl (PM/Scl) were detected by line immunoassay and anti-U1-RNP (U1-RNP) by ELISA. Frequency of clinical features associated with a specific antibody group was reported cumulatively over the follow-up period. Frequency of specific clinical features was compared across the two disease subtype including limited cutaneous (lcSSc) or diffuse cutaneous (dcSSc) as well as the auto-antibody groups. Ninety-four percent of patients were ANA positive with significant higher skin score, Raynauds and digital ulcer/gangrene. Anti-TOPO was detected in 71% of all patients, in 90.5% of dcSSC and in 65.8% of lcSSc. Anti-TOPO was significantly associated with dcSSc, higher skin score, digital ulcer/gangrene, pulmonary fibrosis, DLCO <70%. U1-RNP antibody was associated with lower fibrosis in lung. ACA was positive in 7% of patients and exclusively in those with lcSSc. We did not find association between gender and presence of auto-antibodies. Anti-TOPO antibody had a high prevalence in contrast to low prevalence of ACA antibody. There were no differences in clinical subtypes of the disease in patients with positive anti-TOPO and positive ACA. Differences in prevalence of auto-antibodies are suggestive of further genetic study.

To assess the effectiveness of cyclophosphamide in the management of scleroderma-related interstitial lung disease (ILD). In this systematic review study, the primary outcome measures were change in forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (D(L)CO) of the patients after 6 and 12 months. To assess the effect of cyclophosphamide on early stage of ILD, alveolitis, in SSc patients, we selected the studies that used the BAL findings or HRCT or recent deterioration of PFT with minimal chest X-ray finding in early stage of disease as diagnosis of alveolitis. A sensitive systematic search strategy was used to find all relevant studies. Finally, 17 trials were included in the analysis that was performed using STATA. (Version 8) and Review Manager (version 4.1; MetaView version 4.1) softwares. Results from 10 studies were pooled for the outcome variable of FVC after 12 months. The summary WMD (random effects) was 2.45 (95% CI, 0.760-4.149 P = 0.005), which means that cyclophosphamide was able to prevent deterioration of FVC after 12 months. In pooled data of 13 studies, about DLCO after 12 months WMD (random effects) was 2.003 2.96 (95% CI, -0.228 to 6.159 P = 0.069), which means that cyclophosphamide was not able to prevent deterioration of D(L)CO after 12 months. If we considered clinically sensible improvement as absolute value ≥10% in DLCO and VC, then result of treatment with cyclophosphamide treatment in scleroderma patients with ILD was not significant.

In systemic sclerosis (SSc), major determinant of morbidity and mortality is pulmonary complication including pulmonary interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). In this study, the natural course of pulmonary involvement in SSc patients was investigated. This was a historical cohort study of SSc patients at a referral center for SSc in Iran between February 1998 and December 2007. Patients had a standardized initial evaluation, and interstitial pulmonary involvement was established by high-resolution CT scan (HRCT). Pulmonary hypertension was assessed by tricuspid gradient on echocardiography. Development of abnormal FVC or DLCO was considered as secondary outcome. Analysis of pulmonary survival was performed for primary and secondary outcomes. Ninety-one SSc patients were included in the study with the mean age of 44.1 (14.8). Among these, 65 (71.4%) patients were classified as limited subtype (lcSSc) and 84 (93.3%) were women. PAH was investigated in 8 (8.2%) patients, 1 (6.7%) in dcSSc and 7 (15.9%) in lcSSc subtype of disease. ILD had developed after a median of 107 (SE = 24.4) months after the first symptom of SSc, and 29 patients (31.9%) developed pulmonary fibrosis. Alveolitis and fibrosis had developed after a median of 129.0 (22.9) and 259.0 (74.2) months, respectively. There was a significant difference in Alveolitis-free pulmonary survival between two subgroups of the disease, which showed pulmonary alveolitis developed later in limited SSc (P = 0.03). The difference was not significant in two subtypes when Cox regression model was used to identify the effect of other prognostic factors on pulmonary survival in patients. In the present study, clinical manifestations of two subtypes of disease were divergent at first; however they became convergent in late stages, and this was the same as results in previous studies. Echocardiography for evaluation of pulmonary hypertension and pulmonary function tests for early detection of ILD and PAH is recommended for SSc patients to detect early stages of pulmonary involvement before significant vascular and fibrotic changes occur.

Objective: To describe the demographic, clinical, and laboratory features and natural history of patients with systemic sclerosis sine scleroderma (ssSSc), and to compare them with those of patients with SSc and limited cutaneous involvement (IcSSc)., Methods: The University of Pittsburgh Scleroderma Databank served as the data source. Patients were divided into those who had no skin thickening (ssSSc) and those who had skin thickening only distal to elbows or knees and/or of the face (IcSSc) during their disease course. These two groups were compared with regard to demographic characteristics, clinical, laboratory, and serologic features, and survival rates. Chi-square and Student's t-test analyses were performed, and Fisher's exact test was used as appropriate., Results: Of 555 consecutive patients without diffuse cutaneous SSc, 48 (9%) had ssSSc and 507 (91%) had IcSSc. The ssSSc patients had a mean total disease duration of 18.6 years (15.1 years before study entry and 3.5 years of followup after study entry), and had not developed IcSSc or another connective tissue disease. Other than the absence of skin thickening, the ssSSc group had no significant differences in individual internal organ involvements, laboratory features, serum autoantibody type, or survival rate compared with patients with IcSSc. Within the category of lung involvement, patients with ssSSc had a significantly greater frequency of dyspnea with mild exertion or at rest, and a tendency toward reduced carbon monoxide diffusing capacity (<70% of predicted normal) and primary pulmonary arterial hypertension. Patients with IcSSc had significantly more frequent individual manifestations of digital pitting scars, digital-tip ulcers, telangiectasia, and calcinosis than those with ssSSc, in part related to increased time of observation. Puffy fingers and finger joint contractures were detected significantly more often in IcSSc patients., Conclusion: Systemic sclerosis sine scleroderma should be included in the spectrum of SSc with limited cutaneous involvement and should not be considered a distinct or separate disorder.