Suzana Jordan

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.

Performance of the new ACR/EULAR classification criteria for systemic sclerosis in clinical practice

OBJECTIVE The preliminary classification criteria for SSc lack sensitivity for mild/early SSc patients, therefore, the new ACR/EULAR classification criteria for SSc were developed. The objective of this study was to evaluate the performance of the new classification criteria for SSc in clinical practice in a cohort of mild/early patients. METHODS Consecutive patients with a clinical diagnosis of SSc, based on expert opinion, were prospectively recruited and assessed according to the EULAR Scleroderma Trials and Research group (EUSTAR) and very early diagnosis of SSc (VEDOSS) recommendations. In some patients, missing values were retrieved retrospectively from the patients records. Patients were grouped into established SSc (fulfilling the old ACR criteria) and mild/early SSc (not fulfilling the old ACR criteria). The new ACR/EULAR criteria were applied to all patients. RESULTS Of the 304 patients available for the final analysis, 162/304 (53.3%) had established SSc and 142/304 (46.7%) had mild/early SSc. All 162 established SSc patients fulfilled the new ACR/EULAR classification criteria. The remaining 142 patients had mild/early SSc. Eighty of these 142 patients (56.3%) fulfilled the new ACR/EULAR classification criteria. Patients with mild/early SSc not fulfilling the new classification criteria were most often suffering from RP, had SSc-characteristic autoantibodies and had an SSc pattern on nailfold capillaroscopy. Taken together, the sensitivity of the new ACR/EULAR classification criteria for the overall cohort was 242/304 (79.6%) compared with 162/304 (53.3%) for the ACR criteria. CONCLUSION In this cohort with a focus on mild/early SSc, the new ACR/EULAR classification criteria showed higher sensitivity and classified more patients as definite SSc patients than the ACR criteria.

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.

The European Scleroderma Trials and Research group (EUSTAR) task force for the development of revised activity criteria for systemic sclerosis: Derivation and validation of a preliminarily revised EUSTAR activity index

Background Validity of European Scleroderma Study Group (EScSG) activity indexes currently used to assess disease activity in systemic sclerosis (SSc) has been criticised. Methods Three investigators assigned an activity score on a 0–10 scale for 97 clinical charts. The median score served as gold standard. Two other investigators labelled the disease as inactive/moderately active or active/very active. Univariate–multivariate linear regression analyses were used to define variables predicting the ‘gold standard’, their weight and derive an activity index. The cut-off point of the index best separating active/very active from inactive/moderately active disease was identified by a receiver-operating curve analysis. The index was validated on a second set of 60 charts assessed by three different investigators on a 0–10 scale and defined as inactive/moderately active or active/very active by other two investigators. One hundred and twenty-three were investigated for changes over time in the index and their relationships with those in the summed Medsger severity score (MSS). Results A weighted 10-point activity index was identified and validated: Δ-skin=1.5 (Δ=patient assessed worsening during the previous month), modified Rodnan skin score (mRss) >18=1.5, digital ulcers=1.5, tendon friction rubs=2.25, C-reactive protein >1 mg/dL=2.25 and diffusing capacity of the lung for CO (DLCO) % predicted <70%=1.0. A cut-off ≥2.5 was found to identify patients with active disease. Changes in the index paralleled those of MSS (p=0.0001). Conclusions A preliminarily revised SSc activity index has been developed and validated, providing a valuable tool for clinical practice and observational studies.

ATP Induced Brain-Derived Neurotrophic Factor Expression and Release from Osteoarthritis Synovial Fibroblasts Is Mediated by Purinergic Receptor P2X4

Brain-derived neurotrophic factor (BDNF), a neuromodulator involved in nociceptive hypersensitivity in the central nervous system, is also expressed in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We investigated the role of P2 purinoreceptors in the induction of BDNF expression in synovial fibroblasts (SF) of OA and RA patients. Cultured SF from patients with symptomatic knee OA and RA were stimulated with purinoreceptor agonists ATP, ADP, or UTP. The expression of BDNF mRNA was measured by quantitative TaqMan PCR. BDNF release into cell culture supernatants was monitored by ELISA. P2X4 expression in synovial tissue was detected by immunohistochemistry. Endogenous P2X4 expression was decreased by siRNA transfection before ATP stimulation. Kinase pathways were blocked before ATP stimulation. BDNF mRNA expression levels in OASF were increased 2 h and 5 h after ATP stimulation. Mean BDNF levels in cell culture supernatants of unstimulated OASF and RASF were 19 (±9) and 67 (±49) pg/ml, respectively. BDNF levels in SF supernatants were only elevated 5 h after ATP stimulation. BDNF mRNA expression in OASF was induced both by P2X receptor agonists ATP and ADP, but not by UTP, an agonist of P2Y purinergic receptors. The ATP-induced BDNF mRNA expression in OASF was decreased by siRNA-mediated reduction of endogenous P2X4 levels compared to scrambled controls. Inhibition of p38, but not p44/42 signalling reduced the ATP-mediated BDNF mRNA induction. Here we show a functional role of the purinergic receptor P2X4 and p38 kinase in the ATP-induced expression and release of the neurotrophin BDNF in SF.

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.

Preclinical and translational research to discover potentially effective antifibrotic therapies in systemic sclerosis.

Purpose of reviewTo discuss the strategies for preclinical and early clinical characterization of targeted antifibrotic therapies in order to optimize the probability of positive results in later stage clinical trials. Recent findingsThere is a high unmet clinical need for effective antifibrotic therapies in systemic sclerosis (SSc), and in parallel a rapid development in the identification of potential molecular targets in preclinical research. Herein, we discuss the strategies for the improvement of preclinical and early clinical trials. These strategies include identification and characterization of molecular targets for therapy in vitro, selection of relevant parameters in translational animal models, confirmation of target activation in human SSc, analysis of successful target coverage after drug exposure in human SSc, and conduct of biomarker-driven proof-of-concept studies as a bridge between animal studies and Phase IIB/III studies with clinical endpoints. SummaryThese strategies could increase the possibility to develop successful drugs against the fibrotic manifestations 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.

FRI0377 High rate of false negatives in the early detection of interstitial lung disease associated with systemic sclerosis by pulmonary function tests

Background Pulmonary function tests (PFT) are recommended and frequently used as a single test for routine screening and early detection of interstitial lung disease (ILD) in systemic sclerosis (SSc). However, more sensitive screening tests might be required for early detection of SSc-ILD and low dose HRCT has been recently developed (1). Objectives (1) To evaluate the sensitivity of PFTs in comparison to HRCT for the detection of SSc-ILD in routine clinical practice, and (2) To identify predictors of patients with normal PFTs but significant SSc-ILD on HRCT. Methods Consecutive SSc patients fulfilling ACR criteria were included in our study. Routine assessment was prospectively done according to EUSTAR guidelinesincluding PFT and HRCT in all patients. ILD on HRCT was graded by an experienced, blinded radiologist as follows: mild < 20%, intermediate =20% and severe > 20%. FVC < 80% was considered restrictive lung function. All baseline variables provided from the patients’ database were considered for separating patients with normal FVC and HRCT without fibrosis (PFT-/HRCT-) from patients with normal FVC and HRCT with fibrosis (PFT-/HRCT+). Parameters with p<0.2 in the univariate regression analysis were included in the multivariate analysis. Results From a total 102 patients available for the analysis, 42 (41%) had diffuse SSc, mean age was 59 years (28-90) and disease duration was 6 years (1-57). There were 27 patients with restrictive pattern on PFT (n=13 FVC 70-80%; n=8 FVC 60-70%; n=6 FVC< 60%) and 64 patients (63 %) had fibrosis on HRCTs (n=45 mild; n=2 intermediate; n=17 severe). Notably, 40/102 (40%) of patients with normal PFTs showed significant ILD on HRCT. Of those, 6 patients (6 %) had severe fibrosis on HRCT with normal PFTs. Vice versa; there were 3 patients (3%) with FVC < 80%, but no significant fibrosis on HRCT. Next, we aimed to define predictors for patients with PFT-/HRCT+. Patients with PFT-/HRCT+ had more frequent anti-Scl-70 antibodies (18/40 vs. 5/35, p < 0.006), less frequent limited SSc (21/40 vs.28 /35, p < 0.02), and less frequent anti-centromere antibodies (ACA) (8/40 vs. 19/35, p < 0.003) in comparison to PFT-/HRCT- . On multivariate analysis, in backward selection, stomach symptoms (OR=0.239, 95% CI=0 .068-0.843, p =0.026), pulmonary artery pressure on echocardiography (OR= 1.062, 95% CI= 1.000 -1.128, p =0.048 ), and ACA (OR=0.250, 95% CI=0.070 -0.892, p =0.033) were identified as independent predictors of lung fibrosis on HRCT in patients with normal FVC, which was confirmed for ACA (OR=0.207, 95% CI=0.072-0.601, p =0.004) in forward selection. Conclusions PFTs alone have an unacceptable high rate of false negatives in the screening and early detection of SSc-ILD, in particular in patients with diffuse SSc. These data have impact on clinical practice, as they call for the development of more sensitive measures such as low-dose HRCT in the screening for SSc-ILD. References: Winklehner A, et al, Screening for interstitial lung disease in systemic sclerosis: the diagnostic accuracy of HRCT image series with high increment and reduced number of slices. Ann Rheum Dis,2012;71:549-52. Disclosure of Interest: Y. Suliman: None Declared, D. Huscher: None Declared, T. D. L. Nguyen-Kim: None Declared, B. Maurer: None Declared, S. Jordan: None Declared, U. Treder: None Declared, R. Speich: None Declared, T. Frauenfelder: None Declared, O. Distler Consultant for: Actelion, Pfizer, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, Roche/Genentech, medac, Biovitrium, Boehringer Ingelheim Pharma, Novartis, 4 D Science, Active Biotec and Sinoxa.

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.