Erectile dysfunction is frequent in systemic sclerosis and associated with severe disease: a study of the EULAR Scleroderma Trial and Research group

Introduction: Erectile dysfunction (ED) is common in men with systemic sclerosis (SSc) but the demographics, risk factors and treatment coverage for ED are not well known. Method: This study was carried out prospectively in the multinational EULAR Scleroderma Trial and Research database by amending the electronic data-entry system with the International Index of Erectile Function-5 and items related to ED risk factors and treatment. Centres participating in this EULAR Scleroderma Trial and Research substudy were asked to recruit patients consecutively. Results: Of the 130 men studied, only 23 (17.7%) had a normal International Index of Erectile Function-5 score. Thirty-eight per cent of all participants had severe ED (International Index of Erectile Function-5 score ≤ 7). Men with ED were significantly older than subjects without ED (54.8 years vs. 43.3 years, P < 0.001) and more frequently had simultaneous non-SSc-related risk factors such as alcohol consumption. In 82% of SSc patients, the onset of ED was after the manifestation of the first non-Raynaud's symptom (median delay 4.1 years). ED was associated with severe cutaneous, muscular or renal involvement of SSc, elevated pulmonary pressures and restrictive lung disease. ED was treated in only 27.8% of men. The most common treatment was sildenafil, whose efficacy is not established in ED of SSc patients. Conclusions: Severe ED is a common and early problem in men with SSc. Physicians should address modifiable risk factors actively. More research into the pathophysiology, longitudinal development, treatment and psychosocial impact of ED is needed

Health Assessment Questionnaire-Disability Index (HAQ-DI) use in modelling disease progression in diffuse cutaneous systemic sclerosis: an analysis from the EUSTAR database

BACKGROUND: Patients with diffuse cutaneous systemic sclerosis (dcSSc) have a poor prognosis. The importance of monitoring subjective measures of functioning and disability, such as the Health Assessment Questionnaire-Disability Index (HAQ-DI), is important as dcSSc is rated by patients as worse than diabetes or hemodialysis for quality of life impairment. This European Scleroderma Trials and Research (EUSTAR) database analysis was undertaken to examine the importance of impaired functionality in dcSSc prognosis. The primary objectives were to identify predictors of death and HAQ-DI score progression over 1 year. HAQ-DI score, major advanced organ involvement, and death rate were also used to develop a comprehensive model to predict lifetime dcSSc progression. METHODS: This was an observational, longitudinal study in patients with dcSSc registered in EUSTAR. Death and HAQ-DI scores were, respectively, analyzed by Cox regression and linear regression analyses in relation to baseline covariates. A microsimulation Markov model was developed to estimate/predict natural progression of dcSSc over a patient's lifetime. RESULTS: The analysis included dcSSc patients with (N = 690) and without (N = 4132) HAQ-DI score assessments from the EUSTAR database. Baseline HAQ-DI score, corticosteroid treatment, and major advanced organ involvement were predictive of death on multivariable analysis; a 1-point increase in baseline HAQ-DI score multiplied the risk of death by 2.7 (p &lt; &nbsp;0.001) and multiple advanced major organ involvement multiplied the risk of death by 2.8 (p &lt; &nbsp;0.05). Multivariable analysis showed that baseline modified Rodnan Skin Score (mRSS) and baseline HAQ-DI score were associated with HAQ-DI score progression at 1 year (p &lt; &nbsp;0.05), but there was no association between baseline organ involvement and HAQ-DI score progression at 1 year. HAQ-DI score, major advanced organ involvement, and death were successfully used to model long-term disease progression in dcSSc. CONCLUSIONS: HAQ-DI score and major advanced organ involvement were comparable predictors of mortality risk in dcSSc. Baseline mRSS and baseline HAQ-DI score were predictive of HAQ-DI score progression at 1 year, indicating a correlation between these endpoints in monitoring disease progression. It is hoped that this EUSTAR analysis may change physician perception about the importance of the HAQ-DI score in dcSSc

Stratification in systemic sclerosis according to autoantibody status versus skin involvement: a study of the prospective EUSTAR cohort

Background: The current subclassification of systemic sclerosis into cutaneous subtypes does not fully capture the heterogeneity of the disease. We aimed to compare the performances of stratification into LeRoy's cutaneous subtypes versus stratification by autoantibody status in systemic sclerosis. Methods: For this cohort study, we assessed people with systemic sclerosis in the multicentre international European Scleroderma Trials and Research (EUSTAR) database. Individuals positive for systemic-sclerosis autoantibodies of two specificities were excluded, and remaining individuals were classified by cutaneous subtype, according to their systemic sclerosis-specific autoantibodies, or both. We assessed the performance of each model to predict overall survival, progression-free survival, disease progression, and different organ involvement. The three models were compared by use of the area under the curve (AUC) of the receiver operating characteristic and the net reclassification improvement (NRI). Missing data were imputed. Findings: We assessed the database on July 26, 2019. Of 16 939 patients assessed for eligibility, 10 711 patients were included: 1647 (15·4%) of 10 709 were male, 9062 (84·6%) were female, mean age was 54·4 (SD 13·8) years, and mean disease duration was 7·9 (SD 8·2) years. Information regarding cutaneous subtype was available for 10 176 participants and antibody data were available for 9643 participants. In the prognostic analysis, there was no difference in AUC for overall survival (0·82, 95% CI 0·81-0·84 for cutaneous only vs 0·84, 0·82-0·85 for antibody only vs 0·84, 0·83-0·86 for combined) or for progression-free survival (0·70, 0·69-0·71 vs 0·71, 0·70-0·72 vs 0·71, 0·70-0·72). However, at 4 years the NRI showed substantial improvement for the antibody-only model compared with the cutaneous-only model in prediction of overall survival (0·57, 0·46-0·71 for antibody only vs 0·29, 0·19-0·39 for cutaneous only) and disease progression (0·36, 0·29-0·46 vs 0·21, 0·14-0·28). The antibody-only model did better than the cutaneous-only model in predicting renal crisis (AUC 0·72, 0·70-0·74 for antibody only vs 0·66, 0·64-0·69 for cutaneous only) and lung fibrosis leading to restrictive lung function (AUC 0·76, 0·75-0·77 vs 0·71, 0·70-0·72). The combined model improved the prediction of digital ulcers and elevated systolic pulmonary artery pressure, but did poorly for cardiac involvement. Interpretation: The autoantibody-only model outperforms cutaneous-only subsetting for risk stratifying people with systemic sclerosis in the EUSTAR cohort. Physicians should be aware of these findings at the time of decision making for patient management. Funding: World Scleroderma Foundation

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P &lt; 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P &lt; 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P &lt; 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P &lt; 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P &lt; 0.001; OR(BP) = 2.4, P &lt; 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P &lt; 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P &lt; 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Erectile dysfunction is frequent in systemic sclerosis and associated with severe disease: a study of the EULAR Scleroderma Trial and Research group

INTRODUCTION: Erectile dysfunction (ED) is common in men with systemic sclerosis (SSc) but the demographics, risk factors and treatment coverage for ED are not well known. METHOD: This study was carried out prospectively in the multinational EULAR Scleroderma Trial and Research database by amending the electronic data-entry system with the International Index of Erectile Function-5 and items related to ED risk factors and treatment. Centres participating in this EULAR Scleroderma Trial and Research substudy were asked to recruit patients consecutively. RESULTS: Of the 130 men studied, only 23 (17.7%) had a normal International Index of Erectile Function-5 score. Thirty-eight per cent of all participants had severe ED (International Index of Erectile Function-5 score ≤ 7). Men with ED were significantly older than subjects without ED (54.8 years vs. 43.3 years, P < 0.001) and more frequently had simultaneous non-SSc-related risk factors such as alcohol consumption. In 82% of SSc patients, the onset of ED was after the manifestation of the first non-Raynaud's symptom (median delay 4.1 years). ED was associated with severe cutaneous, muscular or renal involvement of SSc, elevated pulmonary pressures and restrictive lung disease. ED was treated in only 27.8% of men. The most common treatment was sildenafil, whose efficacy is not established in ED of SSc patients. CONCLUSIONS: Severe ED is a common and early problem in men with SSc. Physicians should address modifiable risk factors actively. More research into the pathophysiology, longitudinal development, treatment and psychosocial impact of ED is needed

Digital pitting scars are associated with a severe disease course and death in systemic sclerosis: A study from the EUSTAR cohort

Objective: Digital pitting scars (DPS) are frequent, but little studied in SSc to date. Methods: An analysis of SSc patients enrolled in the EUSTAR database. Primary objectives were to (i) examine DPS prevalence; (ii) examine whether DPS are associated with digital ulcers (DUs) and active digital ischaemia (DUs or gangrene); and (iii) describe other associations with DPS including internal organ complications. Secondary objectives were whether DPS are associated with (i) functional impairment; (ii) structural microvascular disease; and (iii) mortality. Descriptive statistics and parametric/non-parametric tests were used. Binary logistic regression was used to examine the association between DPS and DUs, active digital ischaemia and mortality. Results: A total of 9671 patients were included with reported DPS at any time point (n = 4924) or 'never' DPS (n = 4747). The majority (86.9%) were female and mean age was 55.7 years. DPS were associated with longer disease and Raynaud's duration (both P ≤ 0.001). DPS were associated with interstitial lung disease, pulmonary hypertension, conduction blocks, telangiectases, calcinosis (all P ≤ 0.001) and joint synovitis (P = 0.021). Patients were more likely to have more severe capillaroscopic abnormality and greater hand functional impairment. Multivariable logistic regression analyses showed that DPS were associated (odds ratio) with DUs: 22.03 (19.51-24.87), active digital ischaemia: 6.30 (5.34-7.42) and death: 1.86 (1.48-2.36). Conclusion: DPS are associated with a severe disease course including death. The impact of DPS on hand function and ischaemia is significant. The presence of DPS should alert the clinician to a poor prognosis and need to optimize the therapeutic strategy

Effects and safety of rituximab in systemic sclerosis : An analysis from the European Scleroderma Trial and Research (EUSTAR) group

Objectives: To assess the effects of Rituximab (RTX) on skin and lung fibrosis in patients with systemic sclerosis (SSc) belonging to the European Scleroderma Trial and Research (EUSTAR) cohort and using a nested case-control design. Methods: Inclusion criteria were fulfilment of American College of Rheumatology classification criteria for SSc, treatment with RTX and availability of follow-up data. RTX-treated patients were matched with control patients from the EUSTAR database not treated with RTX. Matching parameters for skin/lung fibrosis were the modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), follow-up duration, scleroderma subtype, disease duration and immunosuppressive co-treatment. The primary analysis was mRSS change from baseline to follow-up in the RTX group compared with the control group. Secondary analyses included change of FVC and safety measures. Results: 63 patients treated with RTX were included in the analysis. The case-control analysis in patients with severe diffuse SSc showed that mRSS changes were larger in the RTX group versus matched controls (N=25; -24.0±5.2% vs-7.7±4.3%; p=0.03). Moreover, in RTX-treated patients, the mean mRSS was significantly reduced at follow-up compared with baseline (26.6±1.4 vs 20.3±1.8; p=0.0001). In addition, in patients with interstitial lung disease, RTX prevented significantly the further decline of FVC compared with matched controls (N=9; 0.4±4.4% vs-7.7±3.6%; p=0.02). Safety measures showed a good profile consistent with previous studies in autoimmune rheumatic diseases. Conclusions: The comparison of RTX treated versus untreated matched-control SSc patients from the EUSTAR cohort demonstrated improvement of skin fibrosis and prevention of worsening lung fibrosis, supporting the therapeutic concept of B cell inhibition in SSc

Effects and safety of rituximab in systemic sclerosis: An analysis from the European Scleroderma Trial and Research (EUSTAR) group

OBJECTIVES: To assess the effects of Rituximab (RTX) on skin and lung fibrosis in patients with systemic sclerosis (SSc) belonging to the European Scleroderma Trial and Research (EUSTAR) cohort and using a nested case-control design. METHODS: Inclusion criteria were fulfilment of American College of Rheumatology classification criteria for SSc, treatment with RTX and availability of follow-up data. RTX-treated patients were matched with control patients from the EUSTAR database not treated with RTX. Matching parameters for skin/lung fibrosis were the modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), follow-up duration, scleroderma subtype, disease duration and immunosuppressive co-treatment. The primary analysis was mRSS change from baseline to follow-up in the RTX group compared with the control group. Secondary analyses included change of FVC and safety measures. RESULTS: 63 patients treated with RTX were included in the analysis. The case-control analysis in patients with severe diffuse SSc showed that mRSS changes were larger in the RTX group versus matched controls (N=25; -24.0±5.2% vs -7.7±4.3%; p=0.03). Moreover, in RTX-treated patients, the mean mRSS was significantly reduced at follow-up compared with baseline (26.6±1.4 vs 20.3±1.8; p=0.0001). In addition, in patients with interstitial lung disease, RTX prevented significantly the further decline of FVC compared with matched controls (N=9; 0.4±4.4% vs -7.7±3.6%; p=0.02). Safety measures showed a good profile consistent with previous studies in autoimmune rheumatic diseases. CONCLUSIONS: The comparison of RTX treated versus untreated matched-control SSc patients from the EUSTAR cohort demonstrated improvement of skin fibrosis and prevention of worsening lung fibrosis, supporting the therapeutic concept of B cell inhibition in SSc

Effects and safety of rituximab in systemic sclerosis: An analysis from the European Scleroderma Trial and Research (EUSTAR) group

OBJECTIVES: To assess the effects of Rituximab (RTX) on skin and lung fibrosis in patients with systemic sclerosis (SSc) belonging to the European Scleroderma Trial and Research (EUSTAR) cohort and using a nested case-control design. METHODS: Inclusion criteria were fulfilment of American College of Rheumatology classification criteria for SSc, treatment with RTX and availability of follow-up data. RTX-treated patients were matched with control patients from the EUSTAR database not treated with RTX. Matching parameters for skin/lung fibrosis were the modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), follow-up duration, scleroderma subtype, disease duration and immunosuppressive co-treatment. The primary analysis was mRSS change from baseline to follow-up in the RTX group compared with the control group. Secondary analyses included change of FVC and safety measures. RESULTS: 63 patients treated with RTX were included in the analysis. The case-control analysis in patients with severe diffuse SSc showed that mRSS changes were larger in the RTX group versus matched controls (N=25; -24.0±5.2% vs -7.7±4.3%; p=0.03). Moreover, in RTX-treated patients, the mean mRSS was significantly reduced at follow-up compared with baseline (26.6±1.4 vs 20.3±1.8; p=0.0001). In addition, in patients with interstitial lung disease, RTX prevented significantly the further decline of FVC compared with matched controls (N=9; 0.4±4.4% vs -7.7±3.6%; p=0.02). Safety measures showed a good profile consistent with previous studies in autoimmune rheumatic diseases. CONCLUSIONS: The comparison of RTX treated versus untreated matched-control SSc patients from the EUSTAR cohort demonstrated improvement of skin fibrosis and prevention of worsening lung fibrosis, supporting the therapeutic concept of B cell inhibition in SSc

Effectiveness and safety of tocilizumab in patients with systemic sclerosis: a propensity score matched controlled observational study of the EUSTAR cohort

Objectives Tocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database. Methods Patients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months. Results Ninety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference -1.0, 95% CI -3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (-6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles. Conclusion Although this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population