Rucsandra Dobrota

Brief Report: Pulmonary Function Tests: High Rate of False-Negative Results in the Early Detection and Screening of Scleroderma-Related Interstitial Lung Disease.

Validated methods for the screening and early diagnosis of systemic sclerosis (SSc; scleroderma)–related interstitial lung disease (ILD) are needed. The aim of this study was to evaluate the performance of pulmonary function tests (PFTs) compared with that of high‐resolution computed tomography (HRCT) of the chest for the detection of SSc‐related ILD in clinical practice, and to identify predictors of lung involvement that is functionally occult but significant on HRCT.

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.

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.

Malignancies in patients with anti-RNA polymerase III antibodies and systemic sclerosis : analysis of the EULAR Scleroderma Trials and Research cohort and possible recommendations for screening

Objective. To analyze the characteristics of anti-RNA polymerase III antibodies (anti-RNAP3)− positive patients with systemic sclerosis (SSc) in the European League Against Rheumatism Scleroderma Trials and Research group (EUSTAR) registry with a focus on the risk of cancer and the characteristics of malignancies, and the aim to provide guidelines about potential cancer screening in these patients. Methods. (1) Analysis of the EUSTAR database: 4986 patients with information on their anti-RNAP3 status were included. (2) Case-control study: additional retrospective data, including malignancy history, were queried in 13 participating EUSTAR centers; 158 anti-RNAP3+ cases were compared with 199 local anti-RNAP3− controls, matched for sex, cutaneous subset, disease duration, and age at SSc onset. (3) A Delphi exercise was performed by 82 experts to reach consensus for cancer screening in anti-RNAP3+ patients. Results. In the EUSTAR registry, anti-RNAP3 were associated in multivariable analysis with renal crisis and diffuse cutaneous involvement. In the case-control study, anti-RNAP3 were associated with gastric antral vascular ectasia, rapid progression of skin involvement, and malignancies concomitant to SSc onset (OR 7.38, 95% CI 1.61–33.8). When compared with other anti-RNAP3+ patients, those with concomitant malignancies had older age (p < 0.001) and more frequent diffuse cutaneous involvement (p = 0.008). The Delphi exercise highlighted the need for malignancy screening at the time of diagnosis for anti-RNAP3+ patients and tight followup in the following years. Conclusion. Anti-RNAP3+ patients with SSc have a high risk of concomitant malignancy. These results have implications for clinical practice and suggest regular screening for cancer in anti-RNAP3+ patients.

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.

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.

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.

Nodular Regenerative Hyperplasia of the Liver: A Rare Vascular Complication in Systemic Sclerosis

Objective. To investigate nodular regenerative hyperplasia (NRH) as a vascular complication of systemic sclerosis (SSc) with microvasculopathy as a common denominator. Methods. Cases of SSc-NRH were identified by systematic literature review and by screening the Zurich cohort. NRH had to be diagnosed by liver biopsy. Results. Literature review retrieved 22 cases. In our cohort, 1.4% of patients with SSc were diagnosed with NRH. Most had vasculopathy, were positive for anticentromere antibodies, had elevated alkaline phosphatase and gamma-glutamyl transferase levels, normal liver morphology on ultrasound yet increased stiffness on ultrasound elastography, and had portal hypertension. Conclusion. NRH might represent a rare yet potentially life-threatening vascular complication in 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.

Innovative Approaches to Clinical Trials in Systemic Sclerosis

In the last years, advances in translational and clinical research in the field of systemic sclerosis (SSc) have opened promising perspectives for new therapeutic approaches. Alongside the scientific progress and the increasing availability of specific inhibitors, interest of the pharmaceutical industry in this rare disease has also increased, leading nowadays to a dynamic and competitive field of drug development in SSc.