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.

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.

Gastrointestinal symptom severity and progression in systemic sclerosis.

OBJECTIVES: To evaluate the severity and evolution of patient-reported gastrointestinal tract (GIT) symptoms in systemic sclerosis (SSc) patients, assess predictive factors for progression and determine the impact of standard of care treatment. METHODS: SSc patients from the Leiden and Oslo cohorts were included. We assessed clinical data and patient-reported GIT symptoms measured by the validated University of California, Los-Angeles Gastrointestinal-tract (UCLA-GIT) score at baseline and annually. GIT severity and progression was determined. Logistic regression was applied to identify risk factors associated with baseline GIT symptom severity. Linear mixed-effect models were applied to assess progression in GIT symptom burden and to identify predictive factors. We repeated all analysis in patients with early disease (inception cohort) to exclude the effect of longstanding disease and increase insights in development of GIT symptom burden early in the disease course. RESULTS: We included 834 SSc patients with baseline UCLA GIT scores, 454 from Leiden and 380 from Oslo. In the total cohort, 28% reported moderate-severe GIT symptoms at baseline, with increased risk for severity conferred by ACA, smoking and corticosteroid use, while use of calcium channel blockers appeared protective. In the inception cohort, 23% reported moderate-severe GIT symptoms at baseline, with increased risk for females and with smoking. Over time, symptom burden increased mainly for reflux/bloating. Female sex and ACA predicted GIT symptom progression. CONCLUSION: High GIT symptom burden is present early in SSc disease course. Both for prevalence and for progression of GIT symptom burden, female sex and smoking were identified as risk factors.

Evolution of Systemic Sclerosis-Associated Interstitial Lung Disease One Year After Hematopoietic Stem Cell Transplantation or Cyclophosphamide.

OBJECTIVE: Hematopoietic stem cell transplantation (HSCT) and cyclophosphamide (CYC) are treatment options for progressive systemic sclerosis associated with interstitial lung disease (SSc-ILD). The aims of our retrospective observational study were to evaluate: 1) the evolution of SSc-ILD in SSc patients treated with HSCT (assessed by high-resolution computed tomography [HRCT]; a group of patients treated with CYC was included as frame of reference); 2) how results of pulmonary function tests (PFTs) are associated with HRCT findings; and 3) which factors predict ILD reduction. METHODS: We semiquantitatively scored total ILD extent, reticulations, and ground-glass opacities (GGO) scores at baseline and at the 1-year HRCTs of SSc patients treated with HSCT or CYC. Linear association between changes in HRCT scores and PFT results and predictors of ILD improvement were studied. RESULTS: We included 51 patients (those treated with HSCT [n = 20] and those treated with CYC [n = 31]). The mean change in total ILD score was -5.1% (95% confidence interval [95% CI] -10.2, 0.0) in the HSCT treatment group (P = 0.050), and -1.0% (95% CI -4.3, 2.3) in the CYC treatment group (P = 0.535). For all patients, the evolution of HRCT scores was weakly associated with relative changes in PFT results. In univariate logistic regression, higher ground-glass opacities, higher total ILD, and lower single-breath diffusing capacity for carbon monoxide scores at baseline predicted improvement of ILD extent after treatment, but a multivariable model could not be built to assess independency of predictors. CONCLUSION: One year after treatment with HSCT, a nonsignificant but clear reduction of SSc-ILD extent was observed. Changes in PFT results were associated with changes in HRCT scores but the correlation was weak and cannot be considered conclusive.

Anticentromere Antibody Levels and Isotypes and the Development of Systemic Sclerosis.

OBJECTIVE: Little is known on the disease course of very early systemic sclerosis (SSc). Among the information yet to be elucidated is whether anticentromere antibody (ACA) isotype levels can serve as biomarkers for future SSc development and for organ involvement. This study was undertaken to evaluate whether IgG, IgM, and IgA ACA levels in IgG ACA-positive patients are associated with disease severity and/or progression from very early SSc to definite SSc. METHODS: IgG ACA-positive patients from 5 different cohorts who had very early SSc or SSc fulfilling the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 criteria were included. A diagnosis of very early SSc was based on the presence of IgG ACAs and Raynaud's phenomenon, and/or puffy fingers and/or abnormal nailfold capillaroscopy, but not fulfilling the ACR/EULAR 2013 criteria for SSc. Multivariable regression analyses were performed to determine the association between baseline ACA isotype levels and progression to definite SSc with organ involvement. RESULTS: Six hundred twenty-five IgG ACA-positive patients were included, of whom 138 (22%) fulfilled the criteria for very early SSc and 487 (78%) had definite SSc. Levels of IgG ACAs (odds ratio 2.5 [95% confidence interval 1.8-3.7]) and IgM ACAs (odds ratio 1.8 [95% confidence interval 1.3-2.3]) were significantly higher in patients with definite SSc. Of 115 patients with very early SSc with follow-up, progression to definite SSc occurred within 5 years in 48 (42%). Progression to definite SSc was associated with higher IgG ACA levels at baseline (odds ratio 4.3 [95% confidence interval 1.7-10.7]). CONCLUSION: ACA isotype levels may serve as biomarkers to identify patients with very early SSc who are at risk for disease progression to definite SSc.

Health-related quality of life in patients with systemic sclerosis: evolution over time and main determinants.

OBJECTIVES: In SSc patients, disease specific determinants that influence health-related quality of life (HRQoL) over time have not been described. We aim to, in patients with SSc, (i) evaluate if and how HRQoL changes over time, and (ii) assess how different SSc domains and functional impairments contribute to changes in HRQoL over time. METHODS: All SSc patients from the Leiden SSc cohort were included; patients with disease duration <24 months were classified as incident cases. HRQoL was assessed prospectively on an annual basis using the EQ-5D and the SF36. To assess baseline associations between clinical characteristics and HRQoL, linear regressions were performed. To identify possible associations between SSc characteristics and HRQoL change over time, linear mixed models were performed in both incident and prevalent cases. RESULTS: In total, 492 SSc patients were included (n = 202 incident cases), with a median follow-up duration of 3.4 years. At baseline, presence of organ involvement was independently associated with a worse SF36 physical component score and lower EQ-5D score. Over time, gastrointestinal symptoms, Raynaud and digital ulcers were independently associated with deterioration of HRQoL in both incident and prevalent cases. In prevalent cases, pulmonary arterial hypertension (PAH) was associated with a decrease in HRQoL over time. Worse functioning as measured by six-min walking distance, mouth-opening, finger-to-palm distance and grip-strength contributed significantly to deterioration of HRQoL over time. CONCLUSION: In SSc, key clinical burdens that contribute to worsening of HRQoL over time include digital ulcers, Raynaud and gastrointestinal involvement. In addition, PAH is a significant burden in prevalent disease.

Association Between Centromere- and Topoisomerase-specific Immune Responses and the Degree of Microangiopathy in Systemic Sclerosis.

OBJECTIVE: Autoreactive antibody responses, including the use of several isotypes of autoantibodies, have been shown to be associated with clinical outcome in several rheumatic autoimmune diseases. The goals of this study were to evaluate whether (1) anticentromere antibody (ACA)- and antitopoisomerase antibody (ATA)-specific isotype expression, and (2) organ involvement are associated with the degree of microangiopathy in systemic sclerosis (SSc). METHODS: ACA and ATA IgG, IgM, and IgA levels were measured in baseline serum samples of ACA IgG-positive (+) and ATA IgG+ patients with SSc. The degree of microangiopathy was determined based on nailfold videocapillaroscopy (NVC) images collected at the same point in time. Logistic regression analyses with autoantibodies, clinical characteristics, isotype expression, and ACA and ATA IgG, IgM, and IgA levels as independent variables, and NVC pattern as the dependent variable were performed. RESULTS: In 164 patients, isotype levels and degree of microangiopathy were evaluated. Logistic regression confirmed the association of the degree of microangiopathy with the presence of digital ulcers (OR 3.07, 95% CI 1.43-6.60), interstitial lung disease (OR 3.41, 95% CI 1.11-10.61), and pulmonary arterial hypertension (OR 5.58, 95% CI 2.05-17.81). ATA positivity was associated with more severe microangiopathy (OR 2.09, 95% CI 1.05-4.13). Patients who expressed solely ACA IgG showed a trend towards less severe microangiopathy compared to patients also expressing ACA IgM and/or IgA. Levels of ACA IgG and ATA IgM were found to be associated with microangiopathy severity. CONCLUSION: We observed an association between ACA and ATA responses and the degree of microangiopathy in SSc. These findings might indicate that the breadth of the autoimmune response, as reflected by autoantibody production and microvascular damage, interacts in the pathophysiology of SSc.

Contribution of Sex and Autoantibodies to Microangiopathy Assessed by Nailfold Videocapillaroscopy in Systemic Sclerosis: A Systematic Review of the Literature.

OBJECTIVE: Microangiopathy and dysregulation of the immune system play important roles in the pathogenesis of systemic sclerosis (SSc). Factors that trigger vascular injury in SSc have not been elucidated so far. We undertook this study to evaluate whether sex or expression of specific antinuclear autoantibodies might associate with the degree of microangiopathy through performance of a systematic review that summarizes what is known about these associations. METHODS: A standardized search of PubMed, Embase, Web of Science, and the Cochrane Library were performed to identify studies that described autoantibodies in SSc patients and microangiopathy and, for the second search, those that described sex and microangiopathy. RESULTS: We included 11 studies that described the relationship between SSc-specific autoantibodies and microangiopathy and 6 studies that reported on the association between sex and microangiopathy. Contradictory results were found on the association between SSc-specific autoantibodies and microangiopathy, and no association was found between sex and microangiopathy based on the current literature. CONCLUSION: Based on this review of the literature, we can conclude that sex does not seem to influence degree of microangiopathy in SSc, while results on association between SSc-specific autoantibodies and degree of microangiopathy were inconclusive.

Smoking and systemic sclerosis: influence on microangiopathy and expression of anti-topoisomerase I antibodies in a monocentric cohort.

OBJECTIVES: To investigate whether systemic sclerosis (SSc) patients exposed to active tobacco smoke exhibit a different autoantibody profile or are at higher risk for severe microangiopathy compared to never-smokers, and to assess differences between men and women. METHODS: We performed an exploratory observational study in a cohort of SSc patients fulfilling the 2013 ACR/EULAR classification criteria. According to the smoking habit, patients were categorised as ever-smokers or never-smokers. Microvascular damage was assessed at baseline using nailfold videocapillaroscopy. The presence of SSc-specific autoantibodies was investigated. RESULTS: The studied population was composed of 361 patients (279 women, 82 men). Of these, 208 (58%) were ever-smokers and 153 (42%) were never-smokers. Anti-centromere, anti-topoisomerase I (ATA) and anti-RNA polymerase III antibodies were found, respectively, in 90 (43%), 41 (20%), and 11 (5%) ever-smokers, and in 66 (43%), 40 (26%) and 5 (3%) never-smokers (all p>0.05). Scleroderma patterns early, active and late were present respectively in 12%, 44% and 21% of ever-smokers, and in 9%, 48%, and 29% of never-smokers (all p>0.05). In multivariable logistic regression, being a never-smoker was significantly associated with ATA positivity (OR 1.77, 95% CI 1.04-2.99, p= 0.034). In the gender-based sub-cohorts, 36 (27%) female patients who never smoked were ATA positive, compared to 16 (11%) ever-smoking women (p<0.001). CONCLUSIONS: We observed a significant association between smoking history and positivity of ATA and we outlined the idea of a different effect of smoking on autoantibody expression between men and women.

Illness perceptions, risk perceptions and worries in patients with early systemic sclerosis: A focus group study.

OBJECTIVES: This study explores illness perceptions, risk perceptions and degree of worry in patients with recently diagnosed systemic sclerosis (SSc). Specifically, it aims to answer whether and how early diagnosis in a stage that disease is relatively mild can impact patients' lives, and if and how disease severity associates with illness perceptions and risk perception. METHODS: Patients with a diagnosis of SSc <2 years were invited to participate in a focus group discussion for in-depth exploration of illness perceptions, risk perceptions and worry. In addition, illness perceptions, risk perceptions and worries were evaluated with the use of questionnaires. To explore how patients perceive SSc, we asked them to draw their disease. Physician global assessment of disease severity was used to measure disease severity. Associations between disease severity, illness/risk perceptions, drawings and elements of the focus group were assessed. RESULTS: We observed three dimensions of illness perception as most relevant for patients: personal control, concern and consequences. Patients with SSc experienced many symptoms and felt low personal control. Concerns about the future were often mentioned, and the majority of patients scored high on the worry questionnaire. None of the patients was preoccupied with prognosis or death. All drawings illustrate the impact of SSc on daily life and psychological well-being. Illness perceptions were highly variable between patients and did not associate with disease severity. CONCLUSION: This study showed that a diagnosis of early SSc had a significant impact on patients' lives, also in the absence of severe disease complications.

Lung function is associated with minimal EQ-5D changes over time in patients with systemic sclerosis.

In systemic sclerosis (SSc) therapeutic efforts are often directed to prevent progressive respiratory impairment, but it is unclear to what extent changes in pulmonary function tests (PFTs) are associated with health-related quality of life (HRQoL). The aim of our study is to evaluate how modifications in PFTs contribute to longitudinal variations in HRQoL, assessed through the multidimensional questionnaire EQ-5D, in patients with SSc. We included SSc patients with forced vital capacity (FVC%), diffusing capacity of the lungs for carbon monoxide (DLCO%) and EQ-5D assessed in at least two visits. The EQ-5D consists of two parts, a utility score ranging from - 0.59 to 1, and a 0-100 Visual Analogue Scale (VAS). Higher values represent better health. The association between changes in FVC% and DLCO%, and evolution of EQ-5D over time, was investigated using generalized estimating equations. Three hundred seventy-eight patients were included, accounting for a total of 1619 measurements. The models showed that improvement in FVC% is significantly associated with increase in both utility score (ß = 0.001; 95% CI 0.000 to 0.002; p = 0.003) and VAS over time (ß = 0.188; 95% CI 0.111 to 0.264; p < 0.001). Moreover, improvement in DLCO% is longitudinally associated with increase in utility score (ß = 0.001; 95% CI 0.000 to 0.002; p = 0.038), while the results for VAS were non-significant (ß = 0.020; 95% CI -0.079 to 0.120; p = 0.690). We show that change in PFTs has a significant, although minor, impact on HRQoL as measured by EQ-5D in SSc.Key Points• In patients with SSc, changes in PFTs have a significant, although minor, impact on HRQoL.• In patients with SSc-ILD, the perception of HRQoL is nearly not influenced by changes in pulmonary function.• The use of generic questionnaires might not be sensitive enough to evaluate the impact on quality of life of therapies targeting specific SSc manifestations.

Pulmonary veno-occlusive disease in a patient with recently diagnosed systemic sclerosis.

Pulmonary veno-occlusive disease is a rare cause of pulmonary hypertension in patients with systemic sclerosis that can be misclassified as pulmonary arterial hypertension. Differentiation between pulmonary veno-occlusive disease and pulmonary arterial hypertension is challenging because of the similar clinical picture. Nevertheless, discrimination is important because pulmonary veno-occlusive disease has a worse prognosis. Vasodilators including phosphodiesterase type 5 inhibitors and endothelin receptor antagonists should be started with caution and often in combination with diuretics to prevent pulmonary edema.

Sex hormones and sex hormone-targeting therapies in systemic sclerosis: A systematic literature review.

BACKGROUND: The pathophysiology of systemic sclerosis (SSc) is complex and elusive, however, considering the strong female preponderance and different clinical characteristics between men and women, a contribution of sex hormones has been proposed. OBJECTIVES: We undertook this systematic literature review to investigate: (1) the role played by male and female sex hormones in the pathogenesis of SSc; (2) how sex hormone levels change in SSc patients and how hormonal variations modify the progression of SSc; (3) the effect of therapies targeting sex hormones on the disease course. METHODS: A literature search was performed in Pubmed, Embase, Web of Science, and Cochrane library databases. Given the heterogeneity in study design, different quality assessment tools were applied where appropriate. RESULTS: We retrieved 300 articles and 30 were included in the review. The available evidence points to a fibrogenic, but also a vasodilatory, role of estrogens in SSc. With the limitation of small sample sizes, women with SSc tend to have lower levels of androgens and non-significantly higher levels of estradiol compared to healthy controls, while in men we found increased levels of estradiol and discordant results for androgens. After menopause the skin score seems to decrease and prevalence of pulmonary artery hypertension seems to rise, which might be prevented by the use of hormone replacement therapy. No recent high-quality trial evaluated the efficacy of hormone-targeting therapies in SSc. CONCLUSIONS: Few translational studies of varying quality evaluated the role of sex hormones in SSc showing possible profibrotic and vasodilatatory effects of estrogens, but more research is needed to elucidate the extent of this contribution. Insights on the influence of sex hormones, along with the availability of new compounds acting on estrogen pathways, might provide ideas for additional studies on the application of sex hormone-targeting therapies in SSc.

Cumulative endogenous estrogen exposure is not associated with severity of peripheral microangiopathy in patients with systemic sclerosis.

OBJECTIVES: To determine whether cumulative endogenous estrogen exposure (CEEE) is associated with severity of microvascular damage or with presence of clinical characteristics in women with systemic sclerosis (SSc). METHODS: The population was composed of female SSc patients from the Leiden CCISS (combined care in SSc) cohort. Reproductive life history was investigated through structured questionnaires and CEEE was calculated with a mathematical equation. Demographic, laboratory and clinical characteristics were available for all patients. The most recent nailfold videocapillaroscopy (NVC) was used to semiquantitatively score microangiopathy parameters. RESULTS: We included 97 patients, with a mean age of 59.6±14 years and a mean CEEE of 9±5.5 years. Ordinal logistic regression using CEEE as independent variable failed to demonstrate an association with loss (OR 1.05, 95% CI 0.97-1.14), dilated capillaries (OR 1.05, 95% CI 0.96-1.14), giants (OR 1.03, 95% CI 0.95-1.12) and ramifications (OR 0.99, 95% CI 0.92-1.07). Binary logistic regression did not show an effect of CEEE on presence of scleroderma pattern vs. non-scleroderma pattern, (OR 0.99, 95% CI 0.89-1.1) or of late scleroderma pattern vs. non-late patterns (OR 0.96, 95% CI 0.88-1.05) at NVC. Furthermore, no association was found between CEEE and presence of interstitial lung involvement (OR 0.98, 95% CI 0.88-1.08) but a trend for occurrence of digital ulcers (OR 1.09, 95% CI 0.99-1.19) was observed. CONCLUSIONS: In SSc patients, CEEE is not associated with the extent of microvascular derangement. No associations between CEEE and organ involvement were found.