Arthritis in patients with very early systemic sclerosis: a comprehensive clinical and prognostic analysis.

OBJECTIVE: Arthritis is associated with a worse prognosis in established systemic sclerosis (SSc). However, knowledge about its relevance in very early SSc (veSSc) is scarce. We aimed to assess the prevalence and phenotype of arthritis, as well as its prognostic impact, in patients with veSSc. METHODS: We analysed patients with veSSc, defined as presence of Raynaud's phenomenon and/or at least one of: puffy fingers, antinuclear antibodies (ANA), abnormal capillaroscopy, not fulfilling the ACR/EULAR classification criteria for SSc at baseline. We investigated associations between arthritis and clinical parameters, followed by a longitudinal analysis to investigate arthritis as a potential predictor of progression towards established SSc. RESULTS: We included 159 patients, of whom 108 had at least one follow-up visit. SSc-related arthritis occurred in 22/159 (13.8%) patients at baseline. Arthritis was mostly seronegative, symmetrical, oligo- or polyarticular, non-erosive, and rarely associated with elevation of inflammatory markers. More than half of the patients needed treatment with DMARDs. Anti-centromere antibodies were negatively associated with arthritis (OR: 0.707, 95% confidence interval 0.513-0.973, p = 0.033). Overall, 43/108 (39.8%) patients with follow-up progressed to established SSc during the observation time. Arthritis was not a significant predictor for progression to established SSc in a multivariable Cox regression. CONCLUSION: In this first comprehensive analysis, we found a similar prevalence of arthritis in veSSc as seen in established SSc. Moreover, the use of DMARDs indirectly suggests a relevant disease burden.

Histogram-Based Densitometry Index to Assess the Severity of Interstitial Lung Disease in Systemic Sclerosis in Standard and Low-Dose Computed Tomography.

OBJECTIVE: Mean lung attenuation, skewness, and kurtosis are histogram-based densitometry variables that quantify systemic sclerosis-associated interstitial lung disease (SSc-ILD) and were recently merged into a computerized integrated index (CII). Our work tested the CII in low-dose 9-slice (reduced) and standard high-resolution computed tomography (CT) scans to evaluate extensive SSc-ILD and predict mortality. METHODS: CT scans from patients with SSc-ILD were assessed using the software Horos to compute standard and reduced CIIs. Extensive ILD was determined following the Goh staging system. The association between CIIs and extensive ILD was analyzed with a generalized estimating equation regression model, the predictive ability of CIIs by the area under the receiver-operation characteristic curve (AUC), and the association between CIIs and death by Kaplan-Meier analysis. RESULTS: Among 243 patients with standard and reduced CT scans available, 157 CT scans from 119 patients with SSc-ILD constituted the derivation cohort. The validation cohort included 116 standard and 175 reduced CT scans. Both CIIs from standard (odds ratio [OR] 0.53, 95% CI 0.37-0.75; AUC 0.77, 95% CI 0.68-0.87) and reduced CT scans (OR 0.54, 95% CI 0.35-0.82; AUC 0.78, 95% CI 0.70-0.87) were significantly associated with extensive ILD. A threshold of CII ≤ -0.96 for standard CT scans and CII ≤ -1.85 for reduced CT scans detected extensive ILD with high sensitivity in both derivation and validation cohorts. Extensive ILD according to Goh staging (OR 2.94, 95% CI 1.10-7.82) and standard CII ≤ -0.96 (OR 1.78, 95% CI 1.24-2.56) significantly predicted mortality; a marginal P value was observed for reduced CII ≤ -1.85 (OR 1.27, 95% CI 0.93-1.75). CONCLUSION: Thresholds for both standard and reduced CII to identify extensive ILD were developed and validated, with an additional association with mortality. CIIs might help in clinical practice when radiology expertise is missing.

Use of platelet inhibitors for digital ulcers related to systemic sclerosis: EUSTAR study on derivation and validation of the DU-VASC model.

OBJECTIVE: To develop and validate the prognostic prediction model DU-VASC to assist the clinicians in decision-making regarding the use of platelet inhibitors (PIs) for the management of digital ulcers in patients with systemic sclerosis. Secondly, to assess the incremental value of PIs as predictor. METHODS: We analysed patient data from the European Scleroderma Trials and Research group registry (one time point assessed). Three sets of derivation/validation cohorts were obtained from the original cohort. Using logistic regression, we developed a model for prediction of digital ulcers (DUs). C-Statistics and calibration plots were calculated to evaluate the prediction performance. Variable importance plots and the decrease in C-statistics were used to address the importance of the predictors. RESULTS: Of 3710 patients in the original cohort, 487 had DUs and 90 were exposed to PIs. For the DU-VASC model, which includes 27 predictors, we observed good calibration and discrimination in all cohorts (C-statistic = 81.1% [95% CI: 78.9%, 83.4%] for the derivation and 82.3% [95% CI: 779.3%, 85.3%] for the independent temporal validation cohort). Exposure to PIs was associated with absence of DUs and was the most important therapeutic predictor. Further important factors associated with absence of DUs were lower modified Rodnan skin score, anti-Scl-70 negativity and normal CRP. Conversely, the exposure to phosphodiesterase-5 inhibitor, prostacyclin analogues or endothelin receptor antagonists seemed to be associated with the occurrence of DUs. Nonetheless, previous DUs remains the most impactful predictor of DUs. CONCLUSION: The DU-VASC model, with good calibration and discrimination ability, revealed that PI treatment was the most important therapy-related predictor associated with reduced DU occurrence.

Development and validation of a patient-reported outcome measure for systemic sclerosis: the EULAR Systemic Sclerosis Impact of Disease (ScleroID) questionnaire.

OBJECTIVES: Patient-reported outcome measures (PROMs) are important for clinical practice and research. Given the high unmet need, our aim was to develop a comprehensive PROM for systemic sclerosis (SSc), jointly with patient experts. METHODS: This European Alliance of Associations for Rheumatology (EULAR)-endorsed project involved 11 European SSc centres. Relevant health dimensions were chosen and prioritised by patients. The resulting Systemic Sclerosis Impact of Disease (ScleroID) questionnaire was subsequently weighted and validated by Outcome Measures in Rheumatology criteria in an observational cohort study, cross-sectionally and longitudinally. As comparators, SSc-Health Assessment Questionnaire (HAQ), EuroQol Five Dimensional (EQ-5D), Short Form-36 (SF-36) were included. RESULTS: Initially, 17 health dimensions were selected and prioritised. The top 10 health dimensions were selected for the ScleroID questionnaire. Importantly, Raynaud's phenomenon, impaired hand function, pain and fatigue had the highest patient-reported disease impact. The validation cohort study included 472 patients with a baseline visit, from which 109 had a test-retest reliability visit and 113 had a follow-up visit (85% female, 38% diffuse SSc, mean age 58 years, mean disease duration 9 years). The total ScleroID score showed strong Pearson correlation coefficients with comparators (SSc-HAQ, 0.73; Patient's global assessment, Visual Analogue Scale 0.77; HAQ-Disability Index, 0.62; SF-36 physical score, -0.62; each p<0.001). The internal consistency was strong: Cronbach's alpha was 0.87, similar to SSc-HAQ (0.88) and higher than EQ-5D (0.77). The ScleroID had excellent reliability and good sensitivity to change, superior to all comparators (intraclass correlation coefficient 0.84; standardised response mean 0.57). CONCLUSIONS: We have developed and validated the EULAR ScleroID, which is a novel, brief, disease-specific, patient-derived, disease impact PROM, suitable for research and clinical use in SSc.

The Hospital Anxiety and Depression Scale in patients with systemic sclerosis: a psychometric and factor analysis in a monocentric cohort.

OBJECTIVES: To evaluate the feasibility, validity, reliability, and responsiveness of the Hospital Anxiety and Depression Scale (HADS) and to analyse its model structure in patients with systemic sclerosis (SSc). METHODS: In this study, 316 SSc patients were included; of these, 159 participated in the responsiveness analysis. Psychometric properties were tested in analogy to the Outcome Measures in Rheumatology (OMERACT) filter and an exploratory and confirmatory factor analysis was performed to examine the structure of HADS. RESULTS: The HADS showed adequate feasibility, validity, reliability, and responsiveness to clinically relevant worsening of the disease. For our population of SSc patients, the HADS model with two sub-scales, HADS-A and HADS-D, and a general scale HADS-S, measuring anxiety, depression, and distress, respectively, was most appropriate. The rates of anxiety, depression, mixed anxiety-depressive disorder (MADD) and distress identified by HADS were 32.2%, 25.9%, 18.5%, and 49.5%, respectively, in our cohort. CONCLUSIONS: The psychometric properties of the HADS make it useful for screening in SSc, where anxiety, depression, MADD, and distress represent a significant burden to patients.

Incidence and risk factors for gangrene in patients with systemic sclerosis from the EUSTAR cohort.

OBJECTIVE: In patients with SSc, peripheral vasculopathy can promote critical ischaemia and gangrene. The aim of this study was to investigate the prevalence, incidence and risk factors for gangrene in the EUSTAR cohort. METHODS: We included patients from the EUSTAR database fulfilling the ACR 1980 or the ACR/EULAR 2013 classification criteria for SSc, with at least one visit recording data on gangrene. Centres were asked for supplementary data on traditional cardiovascular risk factors. We analysed the cross-sectional relationship between gangrene and its potential risk factors by univariable and multivariable logistic regression. Longitudinal data were analysed by Cox proportional hazards regression. RESULTS: 1757 patients were analysed (age 55.9 [14.5] years, disease duration 7.9 [10.3] years, male sex 16.7%, 24.6% diffuse cutaneous subset [dcSSc]). At inclusion, 8.9% of patients had current or previous digital gangrene, 16.1% had current digital ulcers (DUs) and 42.7% had ever had DUs (current or previous). Older age, DUs ever and dcSSc were statistically significant risk factors for gangrene in the cross-sectional multivariable model. During a median follow-up of 13.1 months, 16/771 (0.9%) patients developed gangrene. All 16 patients who developed gangrene had previously had DUs and gangrene. Further risk factors for incident gangrene were the dcSSc subset and longer disease duration. CONCLUSION: In unselected SSc patients, gangrene occurs in about 9% of SSc patients. DUs ever and, to a lesser extent, the dcSSc subset are strongly and independently associated with gangrene, while traditional cardiovascular risk factors could not be identified as risk factors.

Evaluation of botulinum toxin A injections for the treatment of refractory chronic digital ulcers in patients with systemic sclerosis.

OBJECTIVES: To evaluate the therapeutic benefit of botulinum toxin A (BTX-A) injections for digital ulcers (DU) in patients with systemic sclerosis (SSc). METHODS: A systematic literature review was performed and the identified articles were selected by two reviewers and analysed with respect to date of publication, inclusion and exclusion criteria, number and age of participants, volume of BTX-A, injection sites, outcomes, and adverse events. In addition, in the Zurich cohort, 7 SSc patients were eligible for the study and were assessed for the duration of DU to heal, duration of DU-free periods, changes in frequency and numbers of prescribed vasodilators, pain and blood flow. RESULTS: In five articles from the systematic review, at least 48% of DU had healed and up to 100% reduction in VAS for pain was reported. Our 7 patients (median age of 53 (47-82) years) had in median 2.5 (2-4) DU and were injected with a median BTX-A volume of 90 (50-100) units per hand. Of the 31 DU in all patients, 77% (n=24) healed. Time to wound closure was in median 8 (4-12) weeks and the DU-free duration was in median 8 (3-10) months. In 80% of the cases, at least one vasodilator was stopped or could be administered less frequently. An improvement of blood flow and pain was reported in 60% of the cases. CONCLUSIONS: BTX-A injections might be of benefit for the treatment of chronic, refractory DU in selected SSc patients, yet a sufficiently powered prospective study will be needed as ultimate proof.

Impaired micronutrients and prealbumin in patients with established and very early systemic sclerosis.

OBJECTIVES: Gastrointestinal involvement and impaired nutritional status are frequent in patients with systemic sclerosis (SSc). Hereby, we hypothesised that micronutrients and/or prealbumin could be deficitary in SSc. METHODS: Patients with SSc and very early SSc (veSSc) were prospectively included. Clinical assessment, data recording and quality controls followed EUSTAR standards. The UCLA SCTCGIT 2.0 questionnaire was applied and the serum levels of zinc, selenium, prealbumin, holotranscobalamin, folic acid were measured. RESULTS: Half (52.4%) of the 176 patients with established SSc showed a deficiency in at least one of the measured nutrients. The most frequent deficit was seen in folic acid (17.9%), followed closely by selenium, prealbumin and zinc (around 15% each). Nearly a fifth (19%) of these patients had multiple deficiencies. Patients with more severe disease, including advanced skin fibrosis, positive ACR 1980 classification criteria, anemia and elevated serum inflammation markers were more likely to be nutrient deficient. Lower BMI<20kg/m2 was associated with several nutrient deficiencies. Prealbumin deficiency was associated with more frequent stomach symptoms and methotrexate therapy. A third of veSSc patients (27%, 44/74) presented a nutrient deficiency, mostly of zinc (10%). Surprisingly, micronutrient deficiencies were not associated with usual parameters of gastrointestinal involvement. CONCLUSIONS: These novel data reveal deficiencies in micronutrients and/or prealbumin are a frequent burden in patients with SSc. Moreover, these correlate with clinical aspects of the disease. Especially patients with advanced disease appear at high risk for an impaired nutrient status, suggesting that screening of micronutrients status should be performed in these patients.

Prediction of progression of interstitial lung disease in patients with systemic sclerosis: the SPAR model.

OBJECTIVES: To identify the predictive clinical characteristics and establish a prediction model for the progression of mild interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). METHODS: Patients with SSc from two independent prospective cohorts were included in this observational study. All patients fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism criteria, had mild ILD at baseline diagnosed by High-Resolution Computed Tomography (HRCT), available baseline and ≥1 annual follow-up pulmonary function tests and no concomitant pulmonary hypertension or airflow obstruction. ILD progression was defined as a relative decrease in forced vital capacity (FVC)%≥15%, or FVC%≥10% combined with diffusing capacity for carbon monoxide %≥15% at 1-year follow-up. Candidate predictors for multivariate logistic regression were selected by expert opinion based on clinical significance. A prediction model for ILD progression was established in the derivation cohort and validated in the multinational validation cohort. RESULTS: A total of 25/98 and 25/117 patients with SSc showed ILD progression in the derivation cohort and the validation cohort, respectively. Lower SpO2 after 6 min walk test (6MWT) and arthritis ever were identified as independent predictors for ILD progression in both cohorts. The optimal cut-off value of SpO2 after 6MWT for predicting ILD progression was determined as 94% by receiver operating characteristic curve analysis. The derived SPAR model combining both predictors (SPO2 and ARthritis) increased the prediction rate from 25.5% to 91.7% with an area under the curve (95% CI) of 0.83 (0.73 to 0.93). CONCLUSIONS: The evidence-based SPAR prediction model developed in our study might be helpful for the risk stratification of patients with mild SSc-ILD in clinical practice and cohort enrichment for future clinical trial design.

Factors associated with disease progression in early-diagnosed pulmonary arterial hypertension associated with systemic sclerosis: longitudinal data from the DETECT cohort.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc). In this longitudinal study, we aimed to identify factors associated with an unfavourable outcome in patients with SSc with early PAH (SSc-PAH) from the DETECT cohort. METHODS: Patients with SSc-PAH enrolled in DETECT were observed for up to 3 years. Associations between cross-sectional variables and disease progression (defined as the occurrence of any of the following events: WHO Functional Class worsening, combination therapy for PAH, hospitalisation or death) were analysed by univariable logistic regression. RESULTS: Of 57 patients with PAH (median observation time 12.6 months), 25 (43.9%) had disease progression. The following factors (OR (95% CI)) were associated with disease progression: male gender (4.1 (1.2 to 14.1)), high forced vital capacity % predicted/carbon monoxide lung diffusion capacity (DLCO)% predicted ratio (3.6 (1.2 to 10.7)), high Borg Dyspnoea Index (1.7 (1.1 to 2.6)) and low DLCO% predicted (non-linear relationship). CONCLUSION: More than 40% of early-diagnosed patients with SSc-PAH had disease progression during a short follow-up time, with male gender, functional capacity and pulmonary function tests at PAH diagnosis being associated with progression. This suggests that even mild PAH should be considered a high-risk complication of SSc.

The emerging application of semi-quantitative and quantitative capillaroscopy in systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease with high morbidity and mortality, characterized by autoimmunity, obliterative vasculopathy involving mainly the microvasculature, and fibrosis. SSc-specific nailfold capillaroscopic changes have been defined, and nailfold capillaroscopy (NFC) is now unequivocally accepted to be a cornerstone for the early diagnosis of SSc. However, the use of NFC in patients already diagnosed with SSc is still not standardized. Several studies have shown that NFC abnormalities correlate with disease activity and severity and are predictive for disease worsening, such as occurrence of new digital ulcers. More importantly, successful treatment has been shown to diminish NFC abnormalities in severe SSc cases. These findings support the importance of NFC in monitoring patients with SSc and even its role as an outcome measure in SSc clinical trials. It is a matter of debate if Semi-quantitative and Quantitative NFC would be a more sensitive tool than qualitative NFC for meeting these objectives. This review is presenting the emerging application of Semi-quantitative and Quantitative NFC in SSc and its potential benefits.

Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis.

OBJECTIVES: Improvement of skin fibrosis is part of the natural course of diffuse cutaneous systemic sclerosis (dcSSc). Recognising those patients most likely to improve could help tailoring clinical management and cohort enrichment for clinical trials. In this study, we aimed to identify predictors for improvement of skin fibrosis in patients with dcSSc. METHODS: We performed a longitudinal analysis of the European Scleroderma Trials And Research (EUSTAR) registry including patients with dcSSc, fulfilling American College of Rheumatology criteria, baseline modified Rodnan skin score (mRSS) ≥7 and follow-up mRSS at 12±2 months. The primary outcome was skin improvement (decrease in mRSS of >5 points and ≥25%) at 1 year follow-up. A respective increase in mRSS was considered progression. Candidate predictors for skin improvement were selected by expert opinion and logistic regression with bootstrap validation was applied. RESULTS: From the 919 patients included, 218 (24%) improved and 95 (10%) progressed. Eleven candidate predictors for skin improvement were analysed. The final model identified high baseline mRSS and absence of tendon friction rubs as independent predictors of skin improvement. The baseline mRSS was the strongest predictor of skin improvement, independent of disease duration. An upper threshold between 18 and 25 performed best in enriching for progressors over regressors. CONCLUSIONS: Patients with advanced skin fibrosis at baseline and absence of tendon friction rubs are more likely to regress in the next year than patients with milder skin fibrosis. These evidence-based data can be implemented in clinical trial design to minimise the inclusion of patients who would regress under standard of care.

A Romanian version of the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument.

OBJECTIVES: UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT 2.0) Instrument is a comprehensive, self-administered survey for the assessment of gastrointestinal involvement in scleroderma patients, developed and validated in English. Our objective was to translate and validate a Romanian version of UCLA SCTC GIT 2.0. METHODS: Translation from English into Romanian has been made using the forward-backward method. Sixty-four patients, attending a referral centre as part of an extensively studied cohort, were approached in a consecutive manner over a period of two years for administration of the questionnaire. We evaluated the reproducibility, internal consistency, construct validity and discriminative capacity of the translation (Romanian GIT). RESULTS: Fifty-four patients returned completed questionnaires. Internal consistency was demonstrated by Cronbach's alpha coefficient (0.931). Construct validity is supported by moderate, but significant correlations of Romanian GIT total score with the Mental Component Summary (MCS) of SF-36 (r=0.541, Spearman correlation) and among subscales, by significant correlations with SHAQ total score (r=0.559, Spearman correlation) and by strong correlations with gastrointestinal subscale of SHAQ (SHAQ GI) (r=0.726, Spearman correlation). Reproducibility was good as well. Divergent validity was supported by significant differences between patients with or without a clinical diagnosis of gastrointestinal disease. Other differences in the Romanian GIT total score were tested among subgroups of patients. CONCLUSIONS: The Romanian GIT has acceptable reliability and validity. This questionnaire can be used for the assessment of gastrointestinal involvement in scleroderma patients.

Screening for interstitial lung disease in systemic sclerosis: performance of high-resolution CT with limited number of slices: a prospective study.

OBJECTIVES: Early diagnosis of interstitial lung disease (ILD), currently the main cause of death in systemic sclerosis (SSc), is needed. The gold standard is high-resolution CT (HRCT) of the chest, but regular screening faces the risk of increased radiation exposure. We performed a prospective validation of a dedicated, 9-slice HRCT protocol with reduced radiation dose for the detection of ILD in patients with SSc. METHODS: We analysed 170/205 consecutive patients with SSc. Whole-chest HRCT, serving as standard of reference, and the reduced HRCT with nine slices allocated according to a basal-apical gradient were obtained. ILD presence, extent (> or <20%) and diagnostic confidence were assessed. The reduced HRCT was independently analysed by two blinded radiologists, who also evaluated image quality. Radiation dose parameters were calculated. RESULTS: Standard chest HRCT showed ILD in 77/170 patients. With the reduced HRCT, 68/77 cases with ILD were identified (sensitivity 88.3%, both readers). The accuracy (91.8%, reader 1; 94.7%, reader 2), diagnostic confidence (98.8%, reader 1; 95.3%, reader 2) and image quality rates were high. Minimal ILD was correctly quantified in 73.1% (reader 1)/71.2% (reader 2) and extensive ILD in 88% (reader 1)/100% (reader 2). Importantly, the reduced HRCT had a significantly lower radiation dose. The mean dose length product (effective dose) was only 5.66±4.46 mGycm (0.08±0.06 mSv) compared with the standard protocol dose of 149.00±95.90 mGycm (2.09±1.34 mSv). CONCLUSIONS: The above-described reduced chest HRCT protocol reliably detects even mild SSc-ILD in clinical practice, with the advantage of a much lower radiation dose compared with standard whole-chest HRCT.

Personalized medicine in systemic sclerosis: facts and promises.

The concept of personalized medicine has led to a paradigm shift in recent years. It integrates multiple clinical and biological levels of investigation aimed at offering the best possible and patient-tailored healthcare. This holds great potential in a rare and heterogeneous disease such as systemic sclerosis (SSc). The development of validated clinical screening algorithms and the identification of predictors for disease outcomes can help in stratifying patients according to their individual risk of progression. The ongoing search for biomarkers and key pathogenic molecules has brought valuable insights into molecular networks operative in SSc. In parallel, genetic and genomic studies have revealed new SSc susceptibility loci and validated gene expression profiles that might identify patients benefiting from specific therapies. In this review, we focus on recent findings relevant for the concept of personalized medicine in patients with SSc.

Characteristics and disease course of untreated patients with interstitial lung disease associated with systemic sclerosis in a real-life two-centre cohort.

BACKGROUND: Interstitial lung disease (ILD) is the leading cause of death in systemic sclerosis (SSc). According to expert statements, not all SSc-ILD patients require pharmacological therapy. OBJECTIVES: To describe disease characteristics and disease course in untreated SSc-ILD patients in two well characterised SSc-ILD cohorts. METHODS: Patients were classified as treated if they had received a potential ILD-modifying drug. ILD progression in untreated patients was defined as (1) decline in forced vital capacity (FVC) from baseline of ≥10% or (2) decline in FVC of 5%-9% associated with a decline in diffusing capacity for carbon monoxide (DLCO)≥15% over 12±3 months or (3) start of any ILD-modifying treatment or (4) increase in the ILD extent during follow-up. Multivariable logistic regression was performed to identify factors associated with non-prescription of ILD-modifying treatment at baseline. Prognostic factors for progression in untreated patients were tested by multivariate Cox regression. RESULTS: Of 386 SSc-ILD included patients, 287 (74%) were untreated at baseline. Anticentromere antibodies (OR: 6.75 (2.16-21.14), p=0.001), limited extent of ILD (OR: 2.39 (1.19-4.82), p=0.015), longer disease duration (OR: 1.04 (1.00-1.08), p=0.038) and a higher DLCO (OR: 1.02 (1.01-1.04), p=0.005) were independently associated with no ILD-modifying treatment at baseline. Among 234 untreated patients, the 3 year cumulative incidence of progression was 39.9% (32.9-46.2). Diffuse cutaneous SSc and extensive lung fibrosis independently predicted ILD progression in untreated patients. CONCLUSION: As about 40% of untreated patients show ILD progression after 3 years and effective and safe therapies for SSc-ILD are available, our results support a change in clinical practice in selecting patients for treatment.

Therapeutic management of fibrosis in systemic sclerosis patients - an analysis from the Swiss EUSTAR cohort.

OBJECTIVES: Systemic sclerosis is a chronic autoimmune connective tissue disease leading to microvascular and fibrotic manifestations in multiple organs. Several treatment options and recommendations from different European countries are available. In this study, for which the ambit is Switzerland specifically, we aim to describe the treatment patterns of systemic sclerosis patients with fibrotic manifestations. METHODS: Systemic sclerosis patients were selected from six Swiss tertiary centres recorded in the multicentre, prospective European Scleroderma Trials and Research (EUSTAR) registry. Patients fulfilling the 2013 ACR/EULAR systemic sclerosis classification criteria at baseline were included. To determine the differences in treatment of varying degrees of fibrosis, four groups were identified: (1) patients with a modified Rodnan skin score (mRSS) >0; (2) those with mRSS ≥7; (3) those with interstitial lung disease (SSc-ILD), diagnosed by either chest X-Ray or high-resolution computed tomography; and (4) patients fulfilling one of the additional criteria for extensive interstitial lung disease, defined as interstitial lung disease involvement of >20% in high-resolution computed tomography, dyspnea NYHA-stage 3/4, or a predicted forced vital capacity (FVC) of <70%. RESULTS: A total of 590 patients with systemic sclerosis fulfilled the inclusion criteria. In this cohort, 421 (71.4%) had mRSS >0, of whom 195 (33.1%) had mRSS ≥7; interstitial lung disease was diagnosed in 198 of 456 (43.4%), of whom 106 (18.0 %) showed extensive interstitial lung disease. Regarding non-biologic disease-modifying medications (DMARDs), the most frequently prescribed was methotrexate, followed by hydroxychloroquine and mycophenolate mofetil. Rituximab and tocilizumab were most frequently used among the biologic DMARDs. Specifically, 148/372 (39.8%) of treated patients with skin fibrosis received methotrexate, mycophenolate mofetil or rituximab, and 80/177 (45.2%) with interstitial lung disease received cyclophosphamide, mycophenolate mofetil, tocilizumab or rituximab. Most patients received a proton-pump inhibitor, and few patients underwent hematopoietic stem cell transplantation. CONCLUSION: Overall, in Switzerland, a wide range of medications is prescribed for systemic sclerosis patients. This includes modern, targeted treatments for which randomised controlled clinical trial have been recently reported.

Dysregulation of circulating collagen turnover markers in very early systemic sclerosis.

OBJECTIVE: Clinical observation suggests that vascular activation and autoimmunity precede remodelling of the extracellular matrix (ECM) in systemic sclerosis (SSc). We challenge this paradigm by hypothesising that ECM biomarkers are already disturbed in patients with very early SSc (veSSc) when fibrosis is not yet clinically detectable. METHODS: 42 patients with veSSc, defined as the presence of Raynaud's phenomenon and at least one of puffy fingers, positive antinuclear antibodies or pathological nailfold capillaroscopy, not meeting the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for SSc, were compared with healthy controls (HCs, n=29). ECM degradation (BGM, C3M, C4M and C6M) and ECM formation biomarkers (PRO-C3, PRO-C4 and PRO-C5) were measured in serum using ELISAs. A cross-sectional analysis at baseline and a longitudinal analysis was performed. RESULTS: Compared with HC, veSSc patients showed a strongly dysregulated turnover of type III and IV collagens (higher C3M, C4M, both p<0.0001 and PRO-C3, p=0.004, lower turnover ratios PRO-C3/C3M and PRO-C4/C4M, both p<0.0001). The biglycan degradation biomarker BGM was higher in veSSc than in HC (p=0.006), whereas the degradation biomarker for type VI collagen, C6M, was lower (p=0.002). In an ROC analysis, biomarkers of type III and IV collagen excellently distinguished between veSSc and HC: C3M, AUC=0.95, p<0.0001; C4M, AUC=0.97, p<0.0001; turnover ratios PRO-C3/C3M, AUC=0.80, p<0.0001; PRO-C4/C4M, AUC=0.97; p<0.0001. CONCLUSION: These findings indicate ECM remodelling as a very early phenomenon of SSc occurring in parallel with microvascular and autoimmune changes. Biomarkers of type III and IV collagens distinguished between veSSc patients and HC, indicating them as potential biomarkers for the detection of veSSc.

Characteristics of ScleroID highlighting musculoskeletal and internal organ implications in patients afflicted with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a multi-organ disease with impaired health-related quality of life (HRQoL). The EULAR SSc Impact of Disease (ScleroID) is a newly introduced SSc-specific patient-reported outcome to evaluate HRQoL in SSc. OBJECTIVE: To investigate the correlation between the ScleroID and the involvement of organ systems as well as disease activity/damage in a SSc cohort from a large tertiary care centre. PATIENTS AND METHODS: The ScleroID and clinical characteristics including internal organ involvement and hand function were investigated in 160 consecutive patients with SSc (median age 46 (43;56) years; diffuse cutaneous SSc 55%). RESULTS: A strong correlation was found between the ScleroID and articular disease activity scores (DAS28-CRP, DAS28-ESR, CDAI, SDAI), a hand function performance test, the Hand Anatomy Index and muscle strength tests. Additionally, a strong significant correlation was discovered using instruments representing hand function and musculoskeletal disability including the Cochin Hand Function Scale, the Quick Questionnaire of the Disability of the Hands, Arms and the Shoulders and the Health Assessment Questionnaire Disability Index. A significant negative correlation was found between the ScleroID score and the 6-min walking test (6MWT) (rho - 0.444, p < 0.001). Clinically mild lung/heart disease did not show increased ScleroID values. The Mouth Handicap in the Scleroderma Scale and the University of California Los Angeles Scleroderma Clinical Trials Consortium gastrointestinal tract 2.0 also showed significant positive correlations to the ScleroID score (rho: 0.626, p < 0.001; rho: 0.646, p < 0.001, respectively). Patients experiencing oesophageal difficulties bore a significantly higher score compared to individuals with a normal functioning oesophagus (3.2/1.5;4.5/ vs. 2.2/1.0;3.2/, p = 0.011). Moreover, the ScleroID showed a significant positive correlation to the revised EUSTAR disease activity index and modified activity index. CONCLUSION: In a large single-centre cohort, the previously described ScleroID-related findings were confirmed. Furthermore, several organ involvement-related functional and performance tests showed a good correlation to the ScleroID including the 6MWT and gastrointestinal-related complaints. Many aspects of musculoskeletal damage, overall disease activity, pain and fatigue were also well represented in the ScleroID, which efficiently reflects the impact of organ involvement, disease activity and functional damage.