Untangling the relationship between smoking and systemic sclerosis: an analysis of the EUSTAR cohort.

OBJECTIVES: To untangle the association between smoking and systemic sclerosis (SSc). METHODS: In the European Scleroderma Trials and Research cohort, the autoantibody status was compared between ever-smokers and never-smokers. Time until disease progression was assessed using Kaplan-Meier curves. Cox models were built to investigate the influence of smoking over 15 years of follow-up. All analyses were performed for the total cohort and stratified for sex and for positivity of anti-centromere (ACA) and anti-topoisomerase antibodies (ATA). RESULTS: Overall, 12 314 patients were included in the study. Of these, 10 393 were women (84%), 4637 were ACA-positive (38%), 3919 were ATA-positive (32%) and 4271 (35%) were ever-smokers. In men, but not in women, smoking was associated with mortality (HR 1.63, 95% CI 1.23 to 2.16, p=0.001). Ever-smoking women were at higher risk for skin progression (HR 1.10, 95% CI 1.00 to 1.22, p=0.046) and for 'any organ progression' (HR 1.07, 95% CI 1.00 to 1.13, p=0.036). In women, 34% of never-smokers were ATA-positive compared with 21% of ever-smokers (p<0.001). In the group of ever-smokers, higher exposure rates, reflected by the number of pack-years (OR 0.98, 95% CI 0.97 to 0.99, p<0.001) and by smoking duration (OR 0.96, 95% CI 0.95 to 0.97, p<0.001), were associated with lower frequency of ATA. In ACA-positive patients, the risk of mortality (HR 1.29, 95% CI 1.02 to 1.63, p=0.033), cardiac involvement (HR 1.25, 95% CI 1.03 to 1.43, p=0.001), skin progression (HR 1.21, 95% CI 1.03 to 1.42, p=0.018) and 'any organ progression' (HR 1.14, 95% CI 1.05 to 1.24, p=0.002) was increased among smokers. In ATA-positive smoking patients, mortality (HR 1.40, 95% CI 1.10 to 1.78, p=0.006), skin progression (HR 1.19, 95% CI 1.03 to 1.37, p=0.020) digital ulcers (HR 1.17, 95% CI 1.02 to 1.34, p=0.029) and 'any organ progression' (HR 1.11, 95% CI 1.00 to 1.22, p=0.048) occurred more frequently. CONCLUSIONS: Our stratified analysis demonstrates that smoking is associated with an increased risk for mortality in male SSc patients but not in women. Strikingly, smoking is associated with lower prevalence of ATA positivity, in particular in women. In both ATA-positive and ACA-positive patients, smoking is a risk factor for mortality, skin progression and 'any organ progression'.

Does the Impact of COVID-19 on Patients With Systemic Sclerosis Change Over Time?

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.

The long-term course of the Health Assessment Questionnaire in patients with systemic sclerosis.

Objective: The Health Assessment Questionnaire-Disability Index is an important outcome measure reflecting functional disability, but knowledge on its course over time in patients with systemic sclerosis is scarce. Therefore, we investigated the long-term course of the Health Assessment Questionnaire-Disability Index and its association with baseline characteristics in systemic sclerosis patients. Methods: Systemic sclerosis patients, fulfilling the European League Against Rheumatism and the American College of Rheumatology 2013 criteria, were included from the Leiden Combined Care in Systemic Sclerosis cohort with annual assessments including the Scleroderma Health Assessment Questionnaire-Disability Index (range = 0-3). The course of the Health Assessment Questionnaire-Disability Index was evaluated over the total follow-up (baseline to last available Health Assessment Questionnaire-Disability Index) and between yearly visits. Based on a minimal clinical important difference of 0.22, courses were categorized into worsening, stable or improvement. The course of the Health Assessment Questionnaire-Disability Index over time was evaluated with linear mixed models. Baseline characteristics were compared between patients with a worsening or improvement of the Health Assessment Questionnaire-Disability Index over the total follow-up period with logistic regression analyses. Results: A total of 517 systemic sclerosis patients were included, with a median follow-up of 7 years (interquartile range = 4-9; 2649 visits) and a baseline Health Assessment Questionnaire-Disability Index of 0.625 (interquartile range = 0.125-1.25). On group level, the Health Assessment Questionnaire-Disability Index is stable with an annual increase of 0.019 (95% confidence interval = 0.011 to 0.027). Looking at subgroups, patients >65 years or who died/were physically unable to come during follow-up had a worse mean Health Assessment Questionnaire-Disability Index. In individual courses from baseline to the last follow-up, the proportions of patients with a clinically meaningful worsening, stable or improved Health Assessment Questionnaire-Disability Index were 35%, 42% and 23%, respectively. Patients with immunosuppressants (odds ratio = 0.5, 95% confidence interval = 0.3 to 0.9) or gastrointestinal involvement (odds ratio = 0.6, 95% confidence interval = 0.4 to 0.9) at baseline showed a reduced chance of worsening of the Health Assessment Questionnaire-Disability Index over the total follow-up period. Conclusion: Over time, the average course of the Health Assessment Questionnaire-Disability Index was stable in systemic sclerosis patients. However, individual courses vary, with worsening occurring in one-third. Worsening occurred less often in individuals using immunosuppressants or with gastrointestinal involvement at baseline.

Anti-topoisomerase, but not anti-centromere B cell responses in systemic sclerosis display active, Ig-secreting cells associated with lung fibrosis.

OBJECTIVES: Almost all patients with systemic sclerosis (SSc) harbour autoantibodies. Anti-topoisomerase antibodies (ATA) and anti-centromere antibodies (ACA) are most prevalent and associate with distinct clinical phenotypes. B cell responses underlying these phenotypes are ill-defined. To understand how B cell autoreactivity and disease pathology connect, we determined phenotypic and functional characteristics of autoreactive B cells in ATA-positive and ACA-positive patients. METHODS: Levels and isotypes of autoantibodies secreted by ex vivo cultured peripheral blood mononuclear cells from patients with ATA-positive (n=22) and ACA-positive (n=20) SSc were determined. Antibody secreting cells (ASCs) were isolated by cell sorting and cultured separately. Correlations were studied between the degree of spontaneous autoantibody production and the presence and degree of interstitial lung disease (ILD). RESULTS: Circulating B cells secreting either ATA-immunoglobulin G (IgG) or ACA-IgG on stimulation was readily detectable in patients. The ATA response, but not the ACA response, showed additional secretion of autoreactive IgA. ATA-IgG and ATA-IgA were also secreted spontaneously. Additional cell sorting confirmed the presence of ATA-secreting plasmablasts. The degree of spontaneous ATA-secretion was higher in patients with ILD than in those without (p<0.001) and correlated with the degree of pulmonary fibrosis (p<0.001). CONCLUSION: In contrast to ACA-positive patients, ATA-positive patients show signs of recent activation of the B cell response that hallmarks this disease. The degree of activation correlates with the presence and severity of ILD, the most deleterious disease manifestation. This could explain differential responsiveness to B cell depleting therapy. The abundant and spontaneous secretion of ATA-IgG and ATA-IgA may point toward a continuously activating trigger.

Anti-carbamylated protein antibodies in systemic sclerosis.

BACKGROUND: To investigate the presence of different isotypes of anti-carbamylated protein (CarP) antibodies in systemic sclerosis (SSc) patients and its association with skin involvement. METHODS: Sera of 194 SSc patients from the Leiden CCISS cohort, fulfilling ACR/EULAR 2013 criteria and a clinical diagnosis of SSc, 83 patients with other connective tissue diseases/Raynaud's Phenomenon, 24 rheumatoid arthritis patients and 98 age and sex-matched healthy controls were tested for the presence of anti-CarP IgG, IgA and IgM, determined by ELISA. Clinical characteristics, that were evaluated in SSc patients, included age, anti-topoisomerase antibodies (ATA), anti-centromere antibodies (ACA) and modified Rodnan Skin Score (mRSS). RESULTS: The SSc patients were 55 (SD:13) years and 155 (80%) were female. Forty-four (23%) patients tested positive for ATA, and 80 (42%) ACA. The median mRSS was 2 (range: 0; 47). Prevalence of anti-CarP IgG was higher in SSc patients than in healthy controls (8% vs 3%, p = 0.007. Prevalence of anti-CarP IgA and IgM and levels of anti-CarP isotypes were comparable between SSc patients and healthy controls. Fifteen (8%) SSc patients tested positive for anti-CarP IgG, 16 (8%) for anti-CarP IgA, and 36 (19%) for anti-CarP IgM. There were no significant correlations between age and levels of anti-CarP isotypes. No correlation between anti-CarP IgG levels and mRSS was found (r = 0.141, p = 0.049), nor for anti-CarP IgM and IgA levels. Anti-CarP IgA levels were higher in ATA compared to ACA positive SSc patients (ATA: 616 aU/ml [359; 1103]; ACA: 424 aU/ml [300; 673], p = 0.015). CONCLUSION: SSc patients can test positive for Anti-CarP IgG, IgA and IgM. We do not observe a relevant clinical association between anti-CarP antibody response and skin involvement in SSc.

Step forward in early recognition of systemic sclerosis: data from the Leiden CCISS cohort.

BACKGROUND: Since 2009, Dutch patients with a confirmed diagnosis/suspicion of systemic sclerosis (SSc) can be referred to the Leiden Combined Care in Systemic Sclerosis (CCISS) cohort. This study evaluated whether early recognition of SSc has improved over time and whether disease characteristics and survival has changed over time. METHODS: 643 SSc patients fulfilling American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria were included and categorised into three groups based on cohort-entry year: (1) 2010-2013 (n=229 (36%)), (2) 2014-2017 (n=207 (32%)) and (3) 2018-2021 (n=207 (32%)). Variables including disease duration, interstitial lung disease (ILD), digital ulcers (DU), diffuse cutaneous SSc (dcSSc), antitopoisomerase (ATA) and anticentromere (ACA) antibodies, and survival from disease onset were compared between cohort-entry groups, including analyses stratified for sex and autoantibodies. RESULTS: Over time, duration between onset of disease symptoms and cohort entry decreased in males and females, but was always longer in females than in males.The proportion of patients presenting with DU decreased, especially in ACA+SSc patients. Almost no ACA+ patients presented with ILD, while in ATA+ patients this proportion was 25% in 2010-2013 and decreased to 19% in 2018-2021. A reduction in patients presenting with clinically meaningful ILD and dcSSc was observed.Overall 8-year survival for males was 59% (95% CI 40% to 73%) and for females 89% (95% CI 82% to 93%). Eight-year survival showed a trend for improvement over time, and was always worse in males. CONCLUSION: We observed a decrease in disease duration in Leiden CCISS cohort at cohort entry, possibly indicating more timely diagnosis of SSc. This could provide opportunities for early interventions. While symptom duration at presentation is longer in females, mortality is consistently higher in males, underlining the urge for sex-specific treatment and follow-up.

Progression from suspected to definite systemic sclerosis and the role of anti-topoisomerase I antibodies.

INTRODUCTION: Early diagnosis of systemic sclerosis (SSc) is important to start therapeutic interventions timely. Important risk factors for progression to SSc are the SSc-specific autoantibodies, of whom anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (ATA) are the most frequent. ATA is associated with a severe disease course. A more detailed characterisation of the ATA-response in SSc might increase insights in preclinical disease stages and improve prognostication. To address this we identified all patients with suspected very early ATA-positive SSc, defined as all patients who are ATA-positive not fulfilling American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 criteria, in the Leiden Combined Care in Systemic Sclerosis (CCISS)-cohort and found very low numbers. METHODS: This triggered us to search the literature on the ATA prevalence in patients with suspected very early SSc and contribution of the SSc-specific autoantibodies to progression from suspected very early to definite SSc. To increase insights on the ATA-response in suspected very early SSc, we then evaluated the association between the ATA-response and time between onset of Raynaud's phenomenon (RP) and first non-RP symptom, as a proxy for progressing to definite SSc, in all patients with ATA-positive SSc from the Leiden CCISS-cohort. RESULTS: In short, included studies show that prevalence of ATA is much lower in suspected very early SSc than in populations fulfilling ACR/EULAR 2013 criteria. After 1-15 years of follow-up, only 52% of the patients with suspected very early SSc progress to definite SSc. ATA-IgG levels tend to be higher in patients with ATA-positive SSc with more rapid disease progression. CONCLUSION: Although a role of ATA in disease progression is suggested, more studies on the ATA response in suspected very early SSc are warranted.

Autoreactive B cell responses targeting nuclear antigens in systemic sclerosis: Implications for disease pathogenesis.

A hallmark of disease pathogenesis of systemic sclerosis (SSc) is the presence of autoreactive B cell responses targeting nuclear proteins. Almost all SSc-patients harbour circulating antinuclear autoantibodies of which anti-topoisomerase 1, anti-centromere protein, anti-RNA polymerase III and anti-fibrillarin autoantibodies (ATA, ACA, ARA and AFA, respectively) are the most common and specific for SSc. In clinical practice, autoantibodies serve as diagnostic biomarkers and can aid in the identification of clinical phenotypes of the disease. However, factors driving disease progression in SSc are still poorly understood, and it is difficult to predict disease trajectories in individual patients. Moreover, treatment decisions remain rather empirical, with variable response rates in clinical trials due to patient heterogeneity. Current evidence has indicated that certain patients may benefit from B cell targeting therapies. Hence, it is important to understand the contribution of the antinuclear autoantibodies and their underlying B cell response to the disease pathogenesis of SSc.

Working conditions in women with multiple pregnancy-the impact on preterm birth and adherence to guidelines: a prospective cohort study.

BACKGROUND: Women with multiple pregnancies are at risk for maternal complications such as preterm birth. Hazardous working conditions, such as physically demanding work and long and irregular working hours, might increase the risk of preterm birth. OBJECTIVE: This study primarily aimed to determine whether certain working conditions up to 20 weeks of pregnancy increase the risk of preterm birth in multiple pregnancies. The secondary objective was to evaluate whether the working conditions of Dutch women with multiple pregnancy have been adjusted to the guidelines of the Netherlands Society of Occupational Medicine. STUDY DESIGN: We performed a prospective cohort study alongside the ProTWIN trial, a multicenter randomized controlled trial that assessed whether cervical pessaries could effectively prevent preterm birth. Women with paid work of >8 hours per week completed questionnaires concerning general health and working conditions between 16 and 20 weeks of pregnancy. Univariable and multivariable logistic regression analyses were performed to identify work-related factors associated with preterm birth (32-36 weeks' gestation) and very preterm birth (<32 weeks' gestation). We analyzed a subgroup of participants who worked for more than half of the week (>28 hours). We calculated the proportion of women who reported work-related factors not in accordance with guidelines. RESULTS: We studied 383 women, of whom 168 (44%) had been randomized to pessary, 142 (37%) to care as usual, and 73 (19%) did not participate in the randomized part of the study. After adjusting for confounding variables, working >28 hours was associated with very preterm birth (n=33; 78%) (adjusted odds ratio, 3.0; 95% confidence interval, 1.1-8.1), and irregular working times were associated with preterm birth (n=26, 17%) (adjusted odds ratio, 2.0; 95% confidence interval, 1.0-4.1) and very preterm birth (n=10; 24%) (adjusted odds ratio, 2.7; 95% confidence interval, 1.0-7.3). Within a subgroup of 213 participants working >28 hours per week, multivariable analysis showed that irregular working times (n=16; 20%) (adjusted odds ratio, 3.5; 95% confidence interval, 1.2-10.1) and no/little freedom in performance of tasks (n=23; 28%) (adjusted odds ratio, 3.0; 95% confidence interval, 1.3-7.3) were associated with preterm birth. Irregular working times (n=9; 27%) (adjusted odds ratio, 3.4; 95% confidence interval, 1.0-11.1), requiring physical strength (n=9; 27%) (adjusted odds ratio, 5.3; 95% confidence interval, 1.6-17.8), high physical workload (n=7; 21%) (adjusted odds ratio, 3.9; 95% confidence interval, 1.1-13.9), and no/little freedom in performing tasks (n=10; 30%) (adjusted odds ratio, 3.2; 95% confidence interval, 1.1-9.6) were associated with very preterm birth. Before 20 weeks of pregnancy, 224 (58.5%) women with multiple pregnancy continued to work under circumstances that were not in accordance with the guidelines. CONCLUSION: In our cohort study, nearly 60% of women with multiple pregnancy continued to work under circumstances not in accordance with the guidelines to avoid physical and job strain and long and irregular working hours. Irregular hours were associated with preterm and very preterm birth, and long hours were associated with preterm birth.

Consensus-based recommendations on communication and education regarding primary care physical therapy for patients with systemic sclerosis.

OBJECTIVE: This study aimed to develop recommendations for communication and postgraduate education regarding primary care physical therapy for systemic sclerosis (SSc) patients. METHODS: A virtual Nominal Group Technique was used with tasks forces for communication (n = 18) and education (n = 21). Both included rheumatologists, physical therapists (PTs) in primary, secondary or tertiary care, rheumatology nurses, advanced nurse practictioners and patient representatives. Three online meetings were organised for each task force to discuss (1) current bottlenecks; (2) potential solutions; and (3) the resulting draft recommendations. After the final adjustments, participants rated their level of agreement with each recommendation on a scale from 0 (not at all agree) to 100 (totally agree), using an online questionnaire. RESULTS: 19 and 34 recommendations were formulated for communication and education, respectively. For communication the main recommendations concerned the provision of an overview of primary care physical therapists with expertise in rheumatic and musculoskeletal diseases to patients and rheumatologists, the inclusion of the indication by the rheumatologist in the referral to the physical therapist and low-threshold communication with the rheumatologist in case of questions or concerns of the physical therapist. For postgraduate education three types of "on demand" educational offerings were recommended with varying levels of content and duration, to match the competencies and preferences of individual primary care physical therapists. CONCLUSION: Using a systematic qualitative approach, two multi-stakeholder task forces developed practical recommendations for primary care physical therapists' communication with hospital-based care providers and postgraduate education regarding the treatment of SSc patients.

Physical Therapy in Systemic Sclerosis: The Patient Perspective.

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.

The effect of silver fibre gloves on Raynaud's phenomenon in patients with systemic sclerosis: a double-blind randomized crossover trial.

OBJECTIVES: Silver fibre gloves transport heat from the palm to the fingers, possibly reducing the burden of RP in SSc patients. We aim to evaluate the clinical efficiency of this intervention. METHODS: A multicentre, double-blind, randomized trial was performed, accounting for interindividual differences and external factors using a crossover design. Patients were randomized in two groups: group 1 wore 8% silver fibre gloves in period 1 and normal gloves in period 2 and group 2 vice versa. Each period lasted 6 weeks. The primary outcome was the Raynaud Condition Score (RCS) over time (minimal clinical important difference 1.4), assessed three times per week using an online questionnaire. Secondary outcomes included vascular complications and Scleroderma-Health Assessment Questionnaire (SHAQ). Outcomes were evaluated before unblinding using linear mixed models. RESULTS: A total of 85 SSc patients were included, with 76 completing the study. The mean RCS during 2 weeks before the study (i.e. without gloves) was 6.4 (s.d. 1.6). Both with silver fibre gloves and normal gloves the mean RCS decreased to 3.9 (s.d. 2.3) with a similar course over time. There was no difference in mean RCS over time between the type of gloves [ß = 0.067 (95% CI -0.006, 0.19)]. Of secondary outcomes, total SHAQ [ß = 0.036 (95% CI 0.026, 0.046)] was slightly higher with silver fibre gloves, which is clinically irrelevant. Three patients developed new digital ulcers with normal gloves vs one patient with silver fibre gloves [odds ratio 3.2 (95% CI 0.32, 31.1)]. CONCLUSIONS: Wearing gloves in SSc patients clearly decreases the RP burden. Our results do not support the hypothesis that increased heat transport of 8% silver fibre gloves is associated with less disease burden as measured in this study by the RCS compared with normal gloves. CLINICAL TRIAL REGISTRATION NUMBER: Netherlands Trial register (https://www.trialregister.nl/) NL7904.

Evaluation of left cardiac chamber function with cardiac magnetic resonance and association with outcome in patients with systemic sclerosis.

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.

Exploring the effects of a combined exercise programme on pain and fatigue outcomes in people with systemic sclerosis: study protocol for a large European multi-centre randomised controlled trial.

BACKGROUND: Pain, related to Raynaud's phenomenon or digital ulceration, has been identified as very prevalent and debilitating symptoms of systemic sclerosis (SSc), both significantly affecting patients' quality of life (QoL). Pharmacological therapeutic strategies were found not to be sufficiently effective in the management of SSc-induced pain and fatigue, and evidence for exercise is scarce. As yet, the effects of a long-term, tailored exercise programme on pain and fatigue in patients with SSc have not been explored. In addition to pain and fatigue, this study aims to evaluate the effects of exercise on QoL, physical fitness, functional capacity, and vascular structure in people with SSc (PwSSc). METHODS: This will be a multicentre (n = 6) randomised controlled clinical trial to assess the effect of a previously established, supervised 12-week combined exercise programme on pain and fatigue as compared to no exercise in PwSSc. The study will recruit 180 patients with SSc that will be allocated randomly to two groups. Group A will perform the exercise programme parallel to standard usual care and group B will receive usual care alone. Patients in the exercise group will undertake two, 45-min sessions each week consisting of 30-min high-intensity interval training (HIIT) (30-s 100% peak power output/30-s passive recovery) on an arm crank ergometer and 15 min of upper body circuit resistance training. Patients will be assessed before as well as at 3 and 6 months following randomisation. Primary outcomes of the study will be pain and fatigue assessed via questionnaires. Secondary outcomes include quality of life, structure of digital microvasculature, body composition, physical fitness, and functional capacity. DISCUSSION: Data from this multi-centre research clinical trial will primarily be used to establish the effectiveness of a combined exercise protocol to improve pain and fatigue in SSc. In parallel, this study will be the first to explore the effects of long-term exercise on potential microvascular alterations assessed via NVC. Overall, this study will provide sufficient data to inform current clinical practice guidelines and may lead to an improvement of QoL for patients with SSc. TRIAL REGISTRATION: ClinicalTrials.gov NCT05234671. Registered on 14 January 2022.

Improvement of microangiopathy after haematopoietic stem cell transplantation in systemic sclerosis.

OBJECTIVES: Haematopoietic stem cell transplantation (HSCT) is a treatment option for patients with severe systemic sclerosis (SSc), but the efficacy of the procedure in remodelling the nailfold microvascular array is largely unknown. Therefore, this study aimed to evaluate the effect of HSCT on microangiopathy assessed through nailfold capillaroscopy (NC) and to compare the results with findings in patients receiving conventional immunosuppression. METHODS: We included SSc patients with severe SSc and whose pre- and post-treatment NC images were available. Findings in patients treated with HSCT were compared with patients not treated with HSCT. Images were scored by two independent observers blinded for clinical data and treatment history. Capillary pattern was determined and semiquantitative scores from 0 (no changes) to 3 (>66% alterations per millimetre) were used to quantify the degree of specific microvascular characteristics. Changes in severity of microangiopathy between baseline and post-treatment were compared between groups. RESULTS: Images of 18 HSCT patients and 21 controls were scored. From baseline to follow-up, 33% of HSCT patients showed improvement from scleroderma pattern to normal NC, compared to 6% of controls (p=0.15). Pre- to post-treatment differences in semiquantitative scores showed significant improvement in HSCT patients compared to controls regarding capillary loss (-0.5 vs. 0.0, p<0.05) and disorganisation (-0.8 vs. 0.0, p<0.05). CONCLUSIONS: The degree of microangiopathy improved significantly in severe SSc patients treated with HSCT compared with patients receiving conventional immunosuppressive therapy.

Timing of Delivery for Twins With Growth Discordance and Growth Restriction: An Individual Participant Data Meta-analysis.

OBJECTIVE: First, to evaluate the risks of stillbirth and neonatal death by gestational age in twin pregnancies with different levels of growth discordance and in relation to small for gestational age (SGA), and on this basis to establish optimal gestational ages for delivery. Second, to compare these optimal gestational ages with previously established optimal delivery timing for twin pregnancies not complicated by fetal growth restriction, which, in a previous individual patient meta-analysis, was calculated at 37 0/7 weeks of gestation for dichorionic pregnancies and 36 0/7 weeks for monochorionic pregnancies. DATA SOURCES: A search of MEDLINE, EMBASE, ClinicalTrials.gov, and Ovid between 2015 and 2018 was performed of cohort studies reporting risks of stillbirth and neonatal death in twin pregnancies from 32 to 41 weeks of gestation. Studies from a previous meta-analysis using a similar search strategy (from inception to 2015) were combined. Women with monoamniotic twin pregnancies were excluded. METHODS OF STUDY SELECTION: Overall, of 57 eligible studies, 20 cohort studies that contributed original data reporting on 7,474 dichorionic and 2,281 monochorionic twin pairs. TABULATION, INTEGRATION, AND RESULTS: We performed an individual participant data meta-analysis to calculate the risk of perinatal death (risk difference between prospective stillbirth and neonatal death) per gestational week. Analyses were stratified by chorionicity, levels of growth discordance, and presence of SGA in one or both twins. For both dichorionic and monochorionic twins, the absolute risks of stillbirth and neonatal death were higher when one or both twins were SGA and increased with greater levels of growth discordance. Regardless of level of growth discordance and birth weight, perinatal risk balanced between 36 0/7-6/7 and 37 0/7-6/7 weeks of gestation in both dichorionic and monochorionic twin pregnancies, with likely higher risk of stillbirth than neonatal death from 37 0/7-6/7 weeks onward. CONCLUSION: Growth discordance or SGA is associated with higher absolute risks of stillbirth and neonatal death. However, balancing these two risks, we did not find evidence that the optimal timing of delivery is changed by the presence of growth disorders alone. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42018090866.

Health-related quality of life in patients with mixed connective tissue disease: a comparison with matched systemic sclerosis patients.

OBJECTIVES: Health-Related Quality of Life (HRQoL) in adult patients with mixed connective tissue disease (MCTD) has not been described so far. Therefore, we performed an explorative study to evaluate HRQoL in MCTD patients. METHODS: MCTD patients fulfilling the Kahn criteria and participating in the prospective follow-up cohort for MCTD of the Leiden University Medical Center were included; and matched to systemic sclerosis (SSc) patients based on age, sex and disease duration. Data on disease characteristics and HRQoL (SF36 and EQ-5D) were collected annually. HRQoL was compared between MCTD and SSc patients at baseline. Factors associated with HRQoL in MCTD were identified using linear regression and change in HRQoL over 3 years using linear mixed models. RESULTS: Thirty-four MCTD patients (121 visits) and 102 SSc patients (424 visits) were included. At baseline, MCTD patients presented with interstitial lung disease, cardiac involvement, synovitis and myositis more frequently compared to SSc patients, while use of immunosuppressive medication was less frequent. In both groups, mean SF36 scores were lower than in the general Dutch population. The SF36 subscore "general health perception" was impacted most in both groups (MCTD: 38.5 [SD:7.0], SSc: 39.9 [SD:8.9]). During follow-up, SF36 scores improved in MCTD patients, while EQ5DNL remained stable. No specific characteristics were identified that associated with baseline HRQoL or change in HRQol over time. CONCLUSIONS: Like in SSc, HRQoL in MCTD is significantly impaired, especially the general health perception of patients. Evaluation in larger prospective cohorts is needed to identify characteristics that impact HRQol most.