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To assess the perspectives of physical therapists treating patients with systemic sclerosis (SSc) on their current practice and educational needs. In July 2019, 405 SSc patients attending a multidisciplinary SSc programme received a survey on physical therapy. Patients who indicated having received physical therapy in the past 2 years were asked to invite their treating physical therapist to complete a questionnaire including sociodemographic characteristics, referral process, content of treatment, perceived knowledge and skills, and educational needs (mostly yes/no answers). Forty-eight of 80 possibly eligible physical therapists treating SSc patients returned the questionnaire [median age 44 years (interquartile range 35–58); 52% female; median number of SSc patients currently treated: 1 (range 1–4)]. Eighty-one per cent (n = 39) of physical therapists had received a referral, with 69% (n = 27/39) judging its content as insufficient. The most often provided types of exercises were range of motion (96%), muscle-strengthening (85%), and aerobic (71%) exercises, followed by hand (42%) and mouth (10%) exercises. Concerning manual treatment, 65% performed either massage or passive mobilization. Regarding competences, 65% indicated feeling capable of treating SSc patients. Nevertheless, 85% expressed the need for an information website on physical therapy in SSc, and 77% for postgraduate education on SSc. Primary care physical therapists treating patients with SSc used a wide range of treatment modalities. Although most stated that they treated very few patients, the majority felt capable of treating SSc patients. Nevertheless, the large majority expressed a need for additional information and educational activities concerning SSc. [ABSTRACT FROM AUTHOR]

Objectives: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets.Methods: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed.Results: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly).Conclusions: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies). [ABSTRACT FROM AUTHOR]

Objective: To conduct a replication study to investigate whether the -945 CTGF genetic variant is associated with systemic sclerosis (SSc) susceptibility or specific SSc phenotype.Methods: The study population comprised 1180 patients with SSc and 1784 healthy controls from seven independent case-control sets of European ancestry (Spanish, French, Dutch, German, British, Swedish and North American). The -945 CTGF genetic variant was genotyped using a Taqman 5' allelic discrimination assay.Results: An independent association study showed in all the case-control cohorts no association of the CTGF -945 polymorphism with SSc susceptibility. These findings were confirmed by a meta-analysis giving a pooled OR = 1.12 (95% CI 0.99 to 1.25), p = 0.06. Investigation of the possible contribution of the -945 CTGF genetic variant to SSc phenotype showed that stratification according to SSc subtypes (limited or diffuse), selective autoantibodies (anti-topoisomerase I or anticentromere) or pulmonary involvement reached no statistically significant skewing.Conclusion: The results do not confirm previous findings and suggest that the CTGF -945 promoter polymorphism does not play a major role in SSc susceptibility or clinical phenotype. [ABSTRACT FROM AUTHOR]

Background: In patients with systemic sclerosis, interstitial lung disease (ILD) is the leading cause of mortality. Early detection of progressive ILD associated with systemic sclerosis is warranted for timely adjustment of management strategies and improved prognosis. We aimed to investigate the validity of home spirometry to detect a decline in pulmonary function in patients with systemic sclerosis-associated ILD., Methods: DecreaSSc was a prospective, observational study done in two tertiary referral centres in the Netherlands. Eligible patients were aged 18 years or older, fulfilled the American College of Rheumatology-European Alliance of Associations for Rheumatology criteria for systemic sclerosis, had a disease duration from first non-Raynaud phenomenon symptom of 5 years or less, had high-resolution CT-confirmed diagnosis of ILD, and had a maximum immunosuppressive treatment duration of 8 weeks at baseline. Patients took weekly home spirometry measurements using a handheld spirometer for 1 year. At baseline and at semi-annual study visits, patients pulmonary function testing was done in the hospital and patients completed questionnaires on patient-reported outcome measurements. The primary outcome was the κ agreement between home and hospital measurements after 1 year to detect a decline in force vital capacity (FVC) of 5% or more, estimated using separate linear regression analyses for home-based and hospital-based FVC% predicted in individual patients. The sensitivity and specificity of home spirometry to detect an absolute decline in FVC% predicted of 5% or more was assessed using the hospital pulmonary function test as the gold standard. The longitudinal correlation between hospital and home measurements was assessed with regression analysis, whereas the cross-sectional correlation was assessed with the intraclass coefficient. People with lived experience were involved at several stages of the study., Findings: Between Jan 26, 2021, and Feb 27, 2023, 43 patients were enrolled, 35 of whom completed 6 months of follow-up and 31 of whom completed 12 months of follow-up. The last follow-up visit took place on March 28, 2024. 20 (57%) of patients were women and 15 (43%) were men; 32 (91%) were White. Mean age was 57·7 years (SD 10·7). The agreement between hospital and home measurements had a κ value of 0·40 (95% CI 0·01-0·79). The sensitivity of home spirometry to detect a decline in FVC% predicted of 5% or more was 60% (95% CI 44-76) and specificity was 87% (75-98). Regression analysis showed that the course of pulmonary function was not different between hospital and home assessment as the interaction term was not significant (-0·0003 [95% CI -0·0006 to 0·000008]; p=0·057) with a longitudinal correlation of 0·55 (95% CI 0·26-0·74; p=0·0070). The intraclass coefficient between both measurements was 0·85 (95% CI 0·73-0·92; p<0·0001) at baseline, 0·84 (0·71-0·92; p<0·0001) at 6 months, and 0·72 (0·50-0·86; p<0·0001) at 12 months., Interpretation: Home spirometry has the potential to detect a decline in pulmonary function in patients with systemic sclerosis-associated ILD earlier when used in addition to regular health care management. Future research could reveal whether home spirometry can contribute to improved outcomes of patients with systemic sclerosis-associated ILD., Funding: Galapagos and Boehringer Ingelheim., Competing Interests: Declaration of interests CCM declares grants and consultancy fees from Boehringer Ingelheim, AstraZeneca, and Daiichi Sankyo, outside of the submitted work, paid to the institution. JKdV-B received consulting fees from AbbVie, Janssen, and Boehringer Ingelheim, and received research grants from Roche, Galapagos Janssen, National Association for People with Lupus, APA, Scleroderma, and MCTD, and ReumaNederland; all payments were made to her institution. MSW-L received consulting or speakers fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Galapagos, Galecto, Hoffmann-La Roche, Horizon Therapeutics, Kinevant Sciences, Molecure, NeRRe, Novartis, PureTech, Thyron, Trevi, and Vicore; and grants from The Dutch Pulmonary Fibrosis Patients Association, The Dutch Lung Foundation, The Netherlands Organisation for Health Research and Development, The Thorax Foundation, Sarcoidosis.nl, AstraZeneca/DaiichiSankyo, Boehringer Ingelheim, and Hoffmann-La Roche; all fees and grants were paid to her institution. MCV received consulting fees or speakers fees from Boehringer Ingelheim, GSK, Janssen, MSD, Novartis, Boehringer Ingelheim, and Janssen; and unrestricted research grants from Boehringer Ingelheim, Ferrer, and Galapagos; all fees and grants were paid to her institution. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: Patients with diffuse cutaneous systemic sclerosis (dcSSc) frequently show spontaneous improvement of skin fibrosis. Our aim was to examine whether an improvement in skin fibrosis predicts lower likelihood of visceral organ progression and better survival., Methods: Patients from the European Scleroderma Trials and Research (EUSTAR) cohort with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, and valid mRSS at 12±3 months follow up were included. Regression/progression of skin fibrosis was defined as a decrease/increase in mRSS >5 points and ≥25% from baseline to follow up. The outcomes included progression of lung, renal, cardiac and gastrointestinal manifestations using consensus derived definitions and all-cause death. Regressive, stable and progressive patients were compared by univariate, Kaplan-Meier survival curve and Cox regression analysis., Results: Of 1257 included patients, 883 (70.2%) were stable, 282 (22.4%) regressive, and 92 (7.3%) progressive. Regressive patients, adjusted for baseline mRSS, baseline immunosuppression, baseline FVC, and disease duration, showed a significantly lower probability of FVC decline ≥10% than progressive patients (p=0.00003), lower probability of all-cause mortality during follow up (p=0.035) compared to progressive patients. .Improvement of skin fibrosis was not associated with progression of other organ manifestations., Conclusion: We found that regression of skin fibrosis is associated with a lower probability of lung progression and better survival at follow up. The link between the disease course of skin and lung fibrosis in SSc can help to better stratify patients in clinical practice and enrich for ILD progressive patients in clinical trials., (© 2024. The Author(s).)

Objectives: To explore the within-person fluctuations of fatigue in systemic sclerosis and its association with negative affect, positive affect, pain, perceived exertion of physical activity and quality of sleep., Methods: We performed an ecological momentary assessment study in adult patients with a clinical diagnosis of systemic sclerosis. During 14 days, patients completed daily assessments of fatigue severity, negative affect, positive affect, pain, quality of sleep and perceived exertion of physical activity at four fixed time points. The day-to-day fluctuations in fatigue were quantified by the intra-individual variance and probability of acute change, capturing the magnitude and frequency of clinical relevant within-person day-to-day fluctuations, respectively. Using multilevel models, the within-person association between fatigue and the daily assessments were analysed., Results: Fifty-seven patients with systemic sclerosis participated. The mean (standard deviation) intra-individual variance was 1.08 (0.42) and the probability of acute change was mean (standard deviation) 0.40 (0.14), ranging from 0.08 to 0.77. For fatigue, a within-person variation of 51% was observed. Multilevel analyses showed that higher average levels and daily increases in negative affect, pain and perceived exertion of physical activity were associated with more fatigue, while the opposite was observed for positive affect and quality of sleep. Positive affect demonstrated the strongest association with fatigue fluctuations., Conclusion: This is the first quantitative study showing that fatigue in systemic sclerosis is characterized by a dynamic course and that approximately half of the day-to-day fluctuations within persons are clinically meaningful. Furthermore, our results indicate that integrating activities with positive impact on mood into fatigue treatment strategies might reduce the frequency of fatigue fluctuations., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.C.V. received honorary as speaker from Boehringer Ingelheim, Bristol-Myers Squibb, GSK, Janssen, MSD, Novartis and Roche, as consultant from Boehringer Ingelheim and Janssen, Grant/research and received support from Research grants from Boehringer Ingelheim, Janssen, Ferrer and Galapagos, none on the subject of this study. J.E.V. received honorary as speaker from Eli Lilly, but this is not pertaining to this study. The remaining authors have declared no conflicts of interest., (© The Author(s) 2024.)

Objectives: Systemic sclerosis (SSc) is characterized by multiple clinical manifestations. Vasculopathy is a main disease hallmark and ranges in severity from an exacerbated Raynaud phenomenon to pulmonary arterial hypertension (PAH). The potential involvement of the immune system in SSc-associated vascular abnormalities is not clear. Here, we set out to study SSc-related immune parameters and determine whether and which peripheral T cell subsets associate with vascular severity in SSc patients., Methods: Peripheral blood and clinical data were collected from 30 SSc patients, 5 patients with idiopathic PAH and 15 age and sex-matched healthy donors (HD). In this cross-sectional cohort, SSc patients with PAH (n = 15) were matched for their age, sex and medication with SSc patients with no signs of PAH (n = 15). Lymphocyte subsets were quantified by multi-colour flow cytometry., Results: SSc patients exhibited elevated percentages of T peripheral helper cells (Tph), CD4+GZMB+ T cells and decreased levels of Th1 cells compared with HD. Increased presence of both CD4+ and CD8+ exhausted-like (CD28-) T cells, characterized by raised cytokine and cytotoxic signature, was also observed in SSc compared with HD blood. Furthermore, IL-4 expressing CD4+CD8+ T cells were significantly increased in SSc peripheral blood. Interestingly, the presence of PAH in SSc was accompanied by a distinct T helper profile, characterized by raised percentages of Th17 and Tph cells., Conclusion: SSc patients with severe vasculopathy (presence of PAH) exhibited a distinct T cell profile, suggesting a potential role of auto-immune inflammation in SSc vascular complications., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Fibrosis, which is primarily marked by excessive extracellular matrix (ECM) deposition, is a pathophysiological process associated with many disorders, which ultimately leads to organ dysfunction and poor patient outcomes. Despite the high prevalence of fibrosis, currently there exist few therapeutic options, and importantly, there is a paucity of in vitro models to accurately study fibrosis. This review discusses the multifaceted nature of fibrosis from the viewpoint of developing organ-on-chip (OoC) disease models, focusing on five key features: the ECM component, inflammation, mechanical cues, hypoxia, and vascularization. The potential of OoC technology is explored for better modeling these features in the context of studying fibrotic diseases and the interplay between various key features is emphasized. This paper reviews how organ-specific fibrotic diseases are modeled in OoC platforms, which elements are included in these existing models, and the avenues for novel research directions are highlighted. Finally, this review concludes with a perspective on how to address the current gap with respect to the inclusion of multiple features to yield more sophisticated and relevant models of fibrotic diseases in an OoC format., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Background: Hypothesizing that early treatment yields improved prognosis, we aimed to investigate how the timing of immunosuppressive treatment relates to interstitial lung disease (ILD) development and the course of pulmonary function in systemic sclerosis (SSc)., Methods: A cohort was created using data from the EUSTAR database and Nijmegen Systemic Sclerosis cohort, including adult patients who started their first immunosuppressive treatment (ie mycophenolate mofetil, methotrexate, cyclophosphamide, tocilizumab or rituximab) after SSc diagnosis, and no signs of ILD on high-resolution CT. ILD-free survival and the course of forced vital capacity % predicted (ppFVC) were assessed for up to 5 years follow-up comparing patients who started early (disease duration ≤ 3 years) vs late with immunosuppression., Results: 1052 patients met the eligibility criteria. The early treatment group (n = 547, 52%) showed a higher prevalence of male sex, diffuse cutaneous subtype (53.1% vs 36.5%), and anti-topoisomerase-I antibody (ATA, 51.1% vs 42.7%). Most patients were treated with methotrexate (60.1%), whereas only a few patients were treated with biologicals (1.7%). The incidence of ILD was 46.6% after mean (SD) 3.6(1.4) years; the hazards ratio for ILD in the early treatment group was 1.13 (95% CI: 0.93-1.38) after adjustment for confounders. PpFVC trajectories were comparable between groups., Conclusion: Our findings did not confirm a preventive role of early initiation of immunosuppressive therapy vs late initiation on ILD development. However, our findings should be interpreted with caution, considering the high inflammatory, ATA-positive enriched nature of the cohort, confounding by indication, and very few patients were treated with biologicals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: The evidence-based DETECT pulmonary arterial hypertension (PAH) algorithm is frequently used in patients with systemic sclerosis (SSc) to help clinicians screen for PAH by using noninvasive data to recommend patient referral to echocardiography and, if applicable, for a diagnostic right-sided heart catheterization. However, the hemodynamic definition of PAH was recently updated in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines. The performance of DETECT PAH in identifying patients with a high risk of PAH according to this new definition was assessed., Methods: In this post hoc analysis of DETECT, which comprised 466 patients with SSc, the performance of the DETECT PAH algorithm in identifying patients with a high risk of PAH as defined in the 2022 ESC/ERS guidelines (mean pulmonary arterial pressure [mPAP] >20 mm Hg, pulmonary capillary wedge pressure [PCWP] ≤15 mm Hg, and pulmonary vascular resistance >2 Wood units) was assessed using summary statistics and was descriptively compared to the known performance of DETECT PAH as defined in 2014, when it was developed (mPAP ≥25 mm Hg and PCWP ≤15 mm Hg)., Results: The sensitivity of DETECT PAH in identifying patients with a high risk of PAH according to the 2022 ESC/ERS definition was lower (88.2%) compared to the 2014 definition (95.8%). Specificity improved from 47.8% to 50.8%., Conclusion: The performance of the DETECT algorithm to screen for PAH in patients with SSc is maintained when PAH is defined according to the 2022 ESC/ERS hemodynamic definition, indicating that DETECT remains applicable to screen for PAH in patients with SSc., (© 2023 Actelion Pharmaceutical company Ltd, a Janssen pharmaceutical Company of Johnson & Johnson. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Aims: Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation, and fibrosis, and carries one of the worst prognoses if patients also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, patients with SSc-PAH demonstrate disproportionately high mortality, presumably due to cardiac involvement. In this cross-sectional study, the relationship between cardiac involvement revealed by cardiovascular magnetic resonance (CMR) and systemic microvascular disease severity measured with nailfold capillaromicroscopy (NCM) in patients with SSc-PAH is evaluated and compared with patients with idiopathic PAH (IPAH)., Methods and Results: Patients with SSc-PAH and IPAH underwent CMR, echocardiography, and NCM with post-occlusive reactivity hyperaemia (PORH) testing on the same day. CMR imaging included T2 (oedema), native, and post-contrast T1 mapping to measure the extracellular volume fraction (ECV, fibrosis) and adenosine-stress-perfusion imaging measuring the relative myocardial upslope (microvascular coronary perfusion). Measures of peripheral microvascular function were related to CMR indices of oedema, fibrosis, and myocardial perfusion. SSc-PAH patients (n = 20) had higher T2 values and a trend towards a higher ECV, compared with IPAH patients (n = 5), and a lower nailfold capillary density (NCD) and reduced capillary recruitment after PORH. NCD correlated with ECV and T2 (r = -0.443 and -0.464, respectively, P < 0.05 for both) and with markers of diastolic dysfunction on echocardiography. PORH testing, but not NCD, correlated with the relative myocardial upslope (r = 0.421, P < 0.05)., Conclusion: SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared with IPAH patients. These markers correlated well with peripheral microvascular dysfunction, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may contribute to the disproportionate high mortality in SSc-PAH., Competing Interests: Conflict of interest: A.P.J.v.D. received a research grant from Janssen Pharmaceuticals and a speaker fee from Janssen. A.L.D. received a research grant from Actelion Pharmaceuticals and consulting fees from Janssen Pharmaceuticals and Merck. M.C.P. received research grants from the St. Antonius Hospital, Janssen Pharmaceuticals, and ZonMw. M.C.V. received research grants from Boehringer Ingelheim, Grupo Ferrer Internacional, Galapagos NV (Mechelen, Belgium) (Mechelen, Belgium), and Janssen Pharmaceuticals and consulting fees from Boehringer Ingelheim, Corbus Pharmaceuticals Holdings, and Janssen Pharmaceuticals. R.N. received research grants from Biotronik and Philips and consulting fees from Sanofi Genzyme, Bayer, and Bristol Myers Squib., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: We hypothesized that glucocorticoids would induce remission in very early Systemic Sclerosis patients by inhibition of inflammation driving the disease. We examined the efficacy and safety of methylprednisolone in very early Systemic Sclerosis., Methods: In this trial adults with puffy fingers for less than three years, specific auto-antibodies and meeting the Very Early Diagnosis of Systemic Sclerosis criteria were randomly assigned (2:1) to methylprednisolone 1000 mg intravenously or placebo for 3 consecutive days 3 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 (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, 7 (23%) patients had a relevant pulmonary function decline. No serious adverse events were reported., Conclusions: No clinically relevant effect of short-term methylprednisolone in patients with very early Systemic Sclerosis was observed. A substantial proportion of patients showed disease progression., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To evaluate the experiences, perceived benefits and disadvantages of home monitoring of pulmonary function in SSc patients with interstitial lung disease (ILD)., Methods: Semistructured interviews were conducted among SSc-ILD patients who used the home monitoring application of pulmonary function for at least 3 months. In our program, patients are instructed to perform home spirometry weekly at fixed time points using a mobile application with results being directly visible for patients and physicians. Audiotapes of the interviews were transcribed verbatim and analysed using inductive thematic analysis after performing a member check., Results: A total of 13 patients were interviewed, with a median age of 58 years (range 36-75) and a median experience with home monitoring of 12 months (range 3-12). We identified four major themes, including routine of telemonitoring, impact of telemonitoring, trust in telemonitoring and implementation in regular healthcare. Overall, patients found performing home spirometry to be feasible. Major perceived benefits of performing home spirometry are an increase in patient empowerment, better understanding of the disease course and a reduction in hospital visits, whereas identified disadvantages are an emotional burden of telemonitoring, heightened awareness of illness, doubts about its validity and the need for digital competencies. All patients expressed their willingness to continue, although some patients emphasized the need for face-to-face visits., Conclusion: Telemonitoring of pulmonary function is accepted by SSc-ILD patients with the perceived benefits outweighing the disadvantages. Adopting a patient-centred strategy that considers individual factors and addresses concerns proactively is warranted to successfully implement home spirometry., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP., Methods: Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites., Results: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated., Conclusion: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Pulmonary hypertension is one of the leading causes of death in systemic sclerosis. Early detection and treatment of pulmonary hypertension in systemic sclerosis is crucial. Nailfold capillaroscopy microscopy, vascular autoantibodies AT1R and ETAR, and several candidate-biomarkers have the potential to serve as noninvasive tools to identify systemic sclerosis patients at risk for developing pulmonary hypertension. Here, we explore the classifying potential of nailfold capillaroscopy microscopy characteristics and serum levels of selected candidate-biomarkers in a sample of systemic sclerosis patients with and without different forms of pulmonary hypertension., Methods: A total of 81 consecutive systemic sclerosis patients were included, 40 with systemic sclerosis pulmonary hypertension and 41 with no pulmonary hypertension. In each group, quantitative and qualitative nailfold capillaroscopy microscopy characteristics, vascular autoantibodies AT1R and ETAR, and serum levels of 24 soluble serum factors were determined. For evaluation of the nailfold capillaroscopy microscopy characteristics, linear regression analysis accounting for age, sex, and diffusing capacity of the lungs for carbon monoxide percentage predicted was used. Autoantibodies and soluble serum factor levels were compared using two-sample t test with equal variances., Results: No statistically significant differences were observed in quantitative or qualitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibody ETAR and AT1R titer between systemic sclerosis-pulmonary hypertension and systemic sclerosis-no pulmonary hypertension. In contrast, several serum levels of soluble factors differed between groups: Endostatin, sVCAM, and VEGFD were increased, and CXCL4, sVEGFR2, and PDGF-AB/BB were decreased in systemic sclerosis-pulmonary hypertension. Random forest classification identified Endostatin and CXCL4 as the most predictive classifiers to distinguish systemic sclerosispulmonary hypertension from systemic sclerosis-no pulmonary hypertension., Conclusion: This study shows the potential for several soluble serum factors to distinguish systemic sclerosis-pulmonary hypertension from systemic sclerosis-no pulmonary hypertension. We found no classifying potential for qualitative or quantitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibodies., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.P.J.van.D. reports Grants or contracts from Janssen Pharmaceutical Company in the past 36 months, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen Pharmaceutical Company and Bayer. M.C.V. reports Research grants from Boehringer Ingelheim, Janssen, Ferrer and Galapagos in the past 36 months, Consulting fees from Boehringer Ingelheim and Janssen, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, Bristol-Myers Squibb, GSK, Janssen, MSD, Novartis and Roche, Participation on a Data Safety Monitoring Board or Advisory Board from Corbus pharmaceuticals, Leadership or fiduciary role in other board, society, committee or advocacy group at the Eustar extended board (unpaid). For the other authors competing interests are not applicable. The Editor/Editorial Board Member of JSRD is an author of this paper; therefore, the peer-review process was managed by alternative members of the Board and the submitting Editor/Board member had no involvement in the decision-making process., (© The Author(s) 2023.)

As skin involvement is the hall mark of systemic sclerosis (SSc) and changes of skin involvement have shown to correlate with internal organ involvement, assessing the extend of skin involvement is key. Although the modified Rodnan skin score is a validated tool used to evaluate the skin in SSc, it has its drawbacks. Novel imagine methods are promising but should be further evaluated. As for molecule markers for skin progression there are conflicting data on the predictive significance of baseline SSc skin gene expression profiles, but immune cell type signature in SSc skin correlates with progression., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: This study aimed to determine whether lower values of feature-tracking cardiovascular magnetic resonance (CMR)-derived left atrial reservoir strain (LARS) and impaired left ventricular (LV) global longitudinal strain (GLS) were associated with the presence of symptoms and long-term prognosis in patients with SSc., Methods: A total of 100 patients {54 [interquartile range (IQR) 46-64] years, 42% male} with SSc who underwent CMR imaging at two tertiary referral centres were included. All patients underwent analysis of LARS and LV GLS using feature-tracking on CMR and were followed-up for the occurrence of all-cause mortality., Results: The median LV GLS was -21.8% and the median LARS was 36%. On multivariable logistic regression, LARS [odds ratio (OR) 0.964 per %, 95% CI 0.929, 0.998, P = 0.049] was independently associated with New York Heart Association (NYHA) class II-IV heart failure symptoms. Over a median follow-up of 37 (21-62) months, a total of 24 (24%) patients died. Univariable Cox regression analysis demonstrated that LARS [hazard ratio (HR) 0.94 per 1%, 95% CI 0.91, 0.97, P < 0.0001) and LV GLS (HR 1.10 per %, 95% CI 1.03, 1.17, P = 0.005) were associated with all-cause mortality, while LV ejection fraction was not. Likelihood ratio tests demonstrated that LARS provided incremental value over prognostically important clinical and imaging parameters, including late gadolinium enhancement., Conclusion: In patients with SSc, LARS was independently associated with the presence of NYHA class II-IV heart failure symptoms. Although both LARS and LV GLS were associated with all-cause mortality, only LARS provided incremental value over all evaluated variables known to be prognostically important in patients with SSc., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To assess the use, satisfaction, needs, and preferences regarding physical therapy (PT) in patients with systemic sclerosis (SSc)., Methods: A total of 405 SSc patients, treated in the Leiden University Medical Center multidisciplinary care program and fulfilling American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 SSc criteria, received a questionnaire containing 37 questions on use and satisfaction regarding PT over a 2-year period, and their needs and preferences for future PT., Results: A total of 204 SSc patients (median age 63 years, 81% female) completed the questionnaire. One hundred twenty-eight patients (63%) had used or were using PT in a primary care setting. For 39% of patients not using PT, lack of referral or lack of knowledge was the reason for not using it. The most frequently reported active treatments were muscle-strengthening (n = 92 [72%]), range of motion (n = 77 [60%]), and aerobic exercises (n = 72 [56%]). Specific SSc hand- and mouth-opening exercises were reported by 20 (15%) and 7 (6%) patients, respectively. Manual treatment (massage or passive mobilization) was reported by 83 patients (65%). The mean ± SD satisfaction score (range 0-10) was 8.2 ± 1.6. Regarding patients' needs, 96 patients (47%) of the total group wanted to receive more information concerning PT, and 128 (63%) wanted to continue, start, or restart PT in the near future, with 56 of the 128 patients (44%) favoring individual treatment on a continuous basis., Conclusion: We observed a significant variation in the use and content of PT for SSc patients in a primary care setting. Our results suggest potential underuse of PT care, in particular for hand and oral dysfunction, and underpin the need for initiatives to improve the quality and accessibility of PT care for SSc patients., (© 2021 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: The cytokine oncostatin M (OSM) is implicated in the pathology of SSc. Inhibiting OSM signalling using GSK2330811 (an anti-OSM monoclonal antibody) in patients with SSc has the potential to slow or stop the disease process., Methods: This multicentre, randomized, double-blind, placebo-controlled study enrolled participants ≥18 years of age with active dcSSc. Participants were randomized 3:1 (GSK2330811:placebo) in one of two sequential cohorts to receive GSK2330811 (cohort 1: 100 mg; cohort 2: 300 mg) or placebo s.c. every other week for 12 weeks. The primary endpoint was safety; blood and skin biopsy samples were collected to explore mechanistic effects on inflammation and fibrosis. Clinical efficacy was an exploratory endpoint., Results: Thirty-five participants were randomized to placebo (n = 8), GSK2330811 100 mg (n = 3) or GSK2330811 300 mg (n = 24). Proof of mechanism, measured by coordinate effects on biomarkers of inflammation or fibrosis, was not demonstrated following GSK2330811 treatment. There were no meaningful differences between GSK2330811 and placebo for any efficacy endpoints. The safety and tolerability of GSK2330811 were not favourable in the 300 mg group, with on-target, dose-dependent adverse events related to decreases in haemoglobin and platelet count that were not observed in the 100 mg or placebo groups., Conclusion: Despite a robust and novel experimental medicine approach and evidence of target engagement, anticipated SSc-related biologic effects of GSK2330811 were not different from placebo and safety was unfavourable, suggesting OSM inhibition may not be a useful therapeutic strategy in SSc., Trial Registration Number: ClinicalTrials.gov, NCT03041025; EudraCT, 2016-003417-95., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: This COnsensus-based Standards for the selection of health measurement INstruments (COSMIN)-based systematic review aims to identify and summarise the quality of measurement properties of dyspnoea-specific patient-reported outcome measures (PROMs) for patients with interstitial lung disease (ILD), pulmonary hypertension (PH) or connective tissue diseases (CTDs)., Methods and Results: Relevant articles in PubMed and Embase were screened. Based on COSMIN analysis and the Grading of Recommendations, Assessment, Development and Evaluation approach, overall rating and level of evidence were assessed to formulate recommendations. We identified 26 publications on 10 PROMs. For patients with ILD, including CTD-associated ILD, nine PROMs were evaluated, of which the Dyspnea-12 (D12), EXACT-Respiratory Symptoms Idiopathic Pulmonary Fibrosis Breathlessness subscale (ERS-IPF-B), King's Brief Interstitial Lung Disease Health Status Questionnaire breathlessness and activities subscale (KBILD-B) and the University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) had high-quality evidence for sufficient internal consistency, without high-quality evidence of insufficient measurement properties. We reached this same conclusion regarding the D12 for use in patients with PH, including CTD-associated PH. Most PROMs in this systematic review have moderate- or low-quality evidence on construct validity and responsiveness., Conclusion: Four dyspnoea-specific PROMs, D12, ERS-IPF-B, KBILD-B and UCSD-SOBQ, can be recommended for use in patients with ILD, including CTD-associated ILD. Of these four, the D12, despite the limited evidence and the lack of evidence on several important domains, is also suitable for use in patients with PH, including CTD-associated PH., Competing Interests: Conflict of interest: The authors have no conflicts of interest to report., (Copyright ©The authors 2022.)