Saskia Decuman

Two-year Results of an Open Pilot Study of a 2-treatment Course with Rituximab in Patients with Early Systemic Sclerosis with Diffuse Skin Involvement

Objective. To study safety and potential efficacy of a 2-treatment course (month 0/6) with rituximab (RTX) in early diffuse systemic sclerosis (dcSSc). Methods. Two years’ followup (open-label study) was done of 8 patients with early dcSSc. Patients received an infusion of 1000 mg RTX 2 times at months 0 and 6, with 100 mg methylprednisolone. Clinical measurements, Disease Activity Score, functional status, and CD19+ peripheral blood count were performed at months 0, 3, 6, 12, 15, 18, and 24 and histopathological evaluation of the skin at months 0, 3, 12, and 24. Results. There was a clinically significant change in skin score, with a mean Modified Rodnan skin score of 24.8 at baseline (SD 3.4) and 13.6 at Month 24 [SD 5.6; mixed models analyses (MMA) p < 0.0001] and a significant decrease in Disease Activity Score (DAS), with a median of 4.5 at baseline (range 1.5–7.5) and 0.5 at Month 24 (range 0.0–5.5; MMA p < 0.0001). Indices of internal organ involvement remained stable throughout the study. RTX induced effective B cell depletion at baseline and Month 6 (< 5 CD19+ cells/μl blood). The blindly assessed hyalinized collagen score changed significantly over time (MMA p = 0.009), with a mean of 69.3 at baseline (SD 22.8) and 33.1 at 24 months (SD 27.0). Five serious adverse events were considered unrelated to the RTX treatment. Conclusion. A 2-treatment course (months 0/6) with RTX appears to be well tolerated and may have potential efficacy for skin disease and stabilization of internal organ status in early dcSSc. Clinical Trials Registration NCT00379431.

An EULAR study group pilot study on reliability of simple capillaroscopic definitions to describe capillary morphology in rheumatic diseases

OBJECTIVE To propose simple capillaroscopic definitions for interpretation of capillaroscopic morphologies and to assess inter-rater reliability. METHODS The simple definitions proposed were: normal--hairpin, tortuous or crossing; abnormal--not hairpin, not tortuous and not crossing; not evaluable--whenever rater undecided between normal and abnormal. Based upon an aimed kappa of 0.80 and default prevalences of normal (0.4), abnormal (0.4) and not evaluable (0.2) capillaries, 90 single capillaries were presented to three groups of raters: experienced independent raters, n = 5; attendees of the sixth EULAR capillaroscopy course, n = 34; novices after a 1-h course, n = 11. Inter-rater agreement was assessed by calculation of proportion of agreement and by kappa coefficients. RESULTS Mean kappa based on 90 capillaries was 0.47 (95% CI: 0.39, 0.54) for expert raters, 0.40 (95% CI: 0.36, 0.44) for attendees and 0.46 (95% CI: 0.41, 0.52) for novices, with overall agreements of 67% (95% CI: 63, 71), 63% (95% CI: 60, 65) and 67% (95% CI: 63, 70), respectively. Comparing only normal vs the combined groups of abnormal and not evaluable capillaries did increase the kappa: 0.51 (95% CI: 0.37 ,: 0.65), 0.53 (95% CI: 0.49, 0.58) and 0.55 (95% CI: 0.49, 0.62). On the condition that the capillaries were classifiable, the mean kappa was 0.62 (95% CI: 0.50, 0.74) for expert raters (n = 65), 0.76 (95% CI: 0.69, 0.83) for attendees (n = 20) and 0.81 (95% CI: 0.74, 0.89) for novices (n = 44). CONCLUSION This multicentre, international study showed moderate reliability of simple capillaroscopic definitions for describing morphology of capillaries by rheumatologists with varying levels of expertise. Novices were capable of distinguishing normal from abnormal capillaries by means of a 1-h training session. In future studies, the class not evaluable may be obsolete.

Growth differentiation factor 15, a marker of lung involvement in systemic sclerosis, is involved in fibrosis development but is not indispensable for fibrosis development.

Transforming growth factor β superfamily members are involved in the pathogenesis of systemic sclerosis (SSc). Growth differentiation factor 15 (GDF‐15) is a distant member of this family. We undertook this study to evaluate the role of GDF‐15 in SSc pathogenesis.

The role of endothelial cells in the vasculopathy of systemic sclerosis: A systematic review

INTRODUCTION Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by fibroproliferative vasculopathy, immunological abnormalities and progressive fibrosis of multiple organs including the skin. In this study, all English speaking articles concerning the role of endothelial cells (ECs) in SSc vasculopathy and representing biomarkers are systematically reviewed and categorized according to endothelial cell (EC) (dys)function in SSc. METHODS A sensitive search on behalf of the EULAR study group on microcirculation in Rheumatic Diseases was developed in Pubmed, The Cochrane Library and Web of Science to identify articles on SSc vasculopathy and the role of ECs using the following Mesh terms: (systemic sclerosis OR scleroderma) AND pathogenesis AND (endothelial cells OR marker). All selected papers were read and discussed by two independent reviewers. The selection process was based on title, abstract and full text level. Additionally, both reviewers further searched the reference lists of the articles selected for reading on full text level for supplementary papers. These additional articles went through the same selection process. RESULTS In total 193 resulting articles were selected and the identified biomarkers were categorized according to description of EC (dys)function in SSc. The most representing and reliable biomarkers described by the selected articles were adhesion molecules for EC activation, anti-endothelial cell antibodies for EC apoptosis, vascular endothelial growth factor (VEGF), its receptor VEGFR-2 and endostatin for disturbed angiogenesis, endothelial progenitors cells for defective vasculogenesis, endothelin-1 for disturbed vascular tone control, Von Willebrand factor for coagulopathy and interleukin (IL)-33 for EC-immune system communication. Emerging, relatively new discovered biomarkers described in the selected articles, are VEGF165b, IL-17A and the adipocytokines. Finally, myofibroblasts involved in tissue fibrosis in SSc can derive from ECs or epithelial cells through a process known as endothelial-to-mesenchymal transition. CONCLUSION This systematic review emphasizes the growing evidence that SSc is primarily a vascular disease where EC dysfunction is present and prominent in different aspects of cell survival (activation and apoptosis), angiogenesis and vasculogenesis and where disturbed interactions between ECs and various other cells contribute to SSc vasculopathy.

Stabilization of Microcirculation in Patients with Early Systemic Sclerosis with Diffuse Skin Involvement following Rituximab Treatment: An Open-label Study

To the Editor: Systemic sclerosis (SSc) is a multisystemic autoimmune disease characterized by fibrosis of the skin and internal organs, generalized microvasculopathy, and antibody response against various cellular antigens. Severe organ involvement occurs early in the course of diffuse cutaneous SSc (dcSSc) and has a bad prognosis1. Survival of the first years of the disease is associated with improved outcome. Therapies that may help the patient overcome this early period seem warranted2. Rituximab (RTX) has been reported as optional therapy in SSc3,4,5. Our group reported stabilization of internal organ involvement during a 2-year followup in an open pilot study of a 2–treatment course (months 0 and 6) of RTX in patients with early dcSSc6,7. In our pilot studies, modified Rodnan skin score (mRSS) decreased significantly after RTX course. The percent of decrease in the open pilot studies was corroborated by a similar decrease in the percentage of collagen score in blindly assessed histopathological skin analyses. Because SSc is characterized by a pronounced microangiopathy over time … Address correspondence to Dr. V. Smith, Department of Rheumatology, Ghent University Hospital, Faculty of Medicine and Health Sciences, Department of Internal Medicine, Ghent University, De Pintelaan 185, B – 9000 Ghent, Belgium. E-mail: vanessa.smith{at}ugent.be

Screening for pulmonary arterial hypertension in an unselected prospective systemic sclerosis cohort

Screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) improves outcomes. The DETECT screening algorithm is recommended in a high-risk SSc subgroup. This study aims to compare prospectively the positive predictive value of screening using the DETECT algorithm and the 2009 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines, and to compare their cost-effectiveness in an unselected, day-to-day SSc population. Post hoc, screening according to the 2015 ESC/ERS guidelines using echocardiographic parameters alone (“2015 echo screening”) or combined with the DETECT algorithm (“2015 combined screening”) in high-risk subjects was analysed. 195 consecutive SSc patients included in the Ghent University Hospital SSc cohort were screened using different algorithms. The referral rate for right heart catheterisation was 32% (63 out of 195 patients) (46/4/13/34/40 patients using the DETECT algorithm/2009 guidelines/both/2015 echo screening/2015 combined screening). Right heart catheterisation was performed in 53 patients (84%) (36 (78%)/four (100%)/13 (100%)/28 (82%)/32 (80%) patients recommended by the DETECT algorithm/2009 guidelines/both/2015 echo screening/2015 combined screening). PAH was diagnosed in three patients (incidence 1.5%·year–1, 95% CI 0.5–4.4), in whom all algorithms recommended a right heart catheterisation. The positive predictive value was 6% (95% CI 2–17%; three out of 49 patients) for the DETECT algorithm, 18% (95% CI 6–41%; three out of 17 patients) for the 2009 guidelines, 23% (95% CI 8–50%; three out of 13 patients) for both, 11% (95% CI 4–27%; three out of 28 patients) for the 2015 echo screening and 9% (95% CI 3–24%; three out of 32 patients) for the 2015 combined screening. The cost was EUR224/80/90/112 per patient using the DETECT algorithm/2009 guidelines/2015 echo screening/2015 combined screening. Echocardiography may remain a candidate first step for PAH screening in SSc. Echocardiography remains a candidate first step in screening for PAH in an unselected systemic sclerosis population http://ow.ly/nuoh3096nRh

Methods for the morphological and functional evaluation of microvascular damage in systemic sclerosis

Systemic sclerosis is a connective tissue disease characterized by alterations in microvascular structure and function. In these patients, numerous studies have demonstrated a relationship between capillary morphology and peripheral blood perfusion. Nailfold videocapillaroscopy reveals the peripheral microvascular morphology and thus allows classification and scoring of capillary abnormalities with respect to different microangiopathy patterns (early, active, and late). Laser Doppler flowmetry and laser speckle contrast analysis can be used to estimate cutaneous blood flow through microvessels and to assess and quantify blood perfusion at peripheral sites. These two methods are also used to identify changes in digital blood perfusion after the infusion of vasodilators.

Two years follow-up of an open-label pilot study of treatment with rituximab in patients with early diffuse cutaneous systemic sclerosis

Abstract Objectives: Following results in open-label studies of rituximab in patients with systemic sclerosis, a Belgian three-centre initiative was launched to explore safety and efficacy of rituximab in early, diffuse cutaneous systemic sclerosis (dcSSc). Methods: Open-label study of 17 patients with early dcSSc, treated with two courses of rituximab, at month 0 and 6. Clinical examination, lung function testing, echocardiography, disease activity score (DAS) and functional status were performed at baseline and over 24 months of follow-up. Results: Modified Rodnan skin score (MRSS) changed significantly over time, with a mean of 25.5 (standard deviation [SD] 6.0) at baseline to 12.6 (SD 5.1) at month 24 (Mixed Model Analysis [MMA] p < 0.0001), which is a decrease of 51% at month 24 vs. baseline. DAS showed significant decrease over the total study period, with a score of 4.1 (SD 1.7) at baseline to 1.5 (SD 1.8) at month 24 (MMA p < 0.0001). Additionally, this was significant at all time points vs. baseline, both for MRSS and DAS. Internal organ status remained clinically stable throughout the study period. No statistically significant differences compared to baseline were found at the follow-up time points. Seven serious adverse events took place, all except for one, considered unrelated to study medication. Conclusions: This is the first multicentre Belgian collaboration investigating potential efficacy of rituximab in early dcSSc. Rituximab appears to be safe and tolerable and it may have beneficial effects on skin involvement, on overall disease activity and on stabilization of internal organ status in early dcSSc.

Assessment of Activity Limitations with the Health Assessment Questionnaire Predicts the Need for Support Measures in Patients with Rheumatoid Arthritis: A Multicenter Observational Study

Objective This study investigated whether the Health Assessment Questionnaire (HAQ) can be used as an instrument to assess the need for social support measures that address activity limitations and participation issues in patients with rheumatoid arthritis (RA). Methods This multicenter observational study included patients with RA and disease duration of at least one year, consulting their rheumatologist for routine evaluation of disease activity. In the single study visit data on demographics, disease history and current treatment were collected. DAS28 values were collected to evaluate current RA disease activity. Patients were asked to fill out the HAQ and SF-36 questionnaires. Receiver Operator Characteristics (ROC) curves were constructed to evaluate the performance of the HAQ, SF-36 and DAS28 in predicting the need for nine supporting measures available for chronically ill patients in the Belgian social security system. The expert opinion of the treating rheumatologist was used as a reference. Results The study included 316 patients with a mean age of 59.8±12.6 years, disease duration of 11.4±9.3 years, mean DAS28 values of 2.83±1.17. Mean HAQ score was 0.95±0.73, mean SF-36 score 56.5±21.3. HAQ scores >1 were observed in 39.4% of patients. The area under the HAQ ROC curve was consistently >0.7 and higher for the HAQ than for SF-36 or DAS28 for all support measures. Rheumatologists on average recommended 3.67 support measures. Conclusion The HAQ score was found to be a good predictor of the need for social support measures in patients with RA.

The heart and pulmonary arterial hypertension in systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of the skin and visceral organs (gastrointestinal tract, heart, kidneys and lungs). Although the prevalence is low, SSc is a disease with high morbidity and mortality. Since pulmonary arterial hypertension (PAH) associated with SSc (SSc-PAH) and clinically evident cardiac involvement is associated with increased mortality, the cardiac complications and PAH in SSc are reviewed. Both diffuse cutaneous (DcSSc) and limited cutaneous (LcSSc) subgroups are at risk for cardiac involvement and SSc-PAH. Cardiac involvement can be divided in pericardial involvement, myocardial involvement and rhythm disturbances and mostly occurs asymptomatically. However, when symptomatic, it is associated with a poor prognosis. Screening for asymptomatic cardiac involvement should be considered in SSc in order to initiate treatment in an early stage. However, there are no randomized controlled trials on treatment options for cardiac involvement in SSc. SSc-PAH is a devastating complication of SSc, which can develop early in DcSSc and LcSSc. Screening for PAH should be performed since screening leads to earlier diagnosis and earlier treatment is associated with a better prognosis. Today, screening is performed by clinical judgement and echocardiography. Recently the DETECT algorithm, a 2-step screening algorithm is proposed in a SSc-subgroup at increased risk for PAH, but further validation is needed. Despite current treatment options with prostacyclins, endothelin-1 receptor antagonists and phosphodiesterase type-5 inhibitors, mortality remains high. Several promising new treatment options for PAH are evaluated in phase II and III clinical trials.