Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients.

OBJECTIVES: The analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations. METHODS: Samples from 162 patients and 252 controls were collected in RNA stabilisers. Cases and controls were divided into a discovery (n=79+163; Southern Europe) and validation cohort (n=83+89; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. In parallel, immunophenotyping of 28 circulating cell populations was performed. We tested the presence of differentially expressed genes/pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated. RESULTS: Overall, 15 224 genes and 1277 functional pathways were available; of these, 99 and 225 were significant in both sets. Among replicated pathways, we found a deregulation in type-I interferon, Toll-like receptor cascade, tumour suppressor p53 protein function, platelet degranulation and activation. RNA transcripts or FAIME scores were jointly correlated with cell subtypes with strong geographical differences; neutrophils were the major determinant of gene expression in SSc-WB samples. CONCLUSIONS: We discovered a set of differentially expressed genes/pathways validated in two independent sets of patients with SSc, highlighting a number of deregulated processes that have relevance for the pathogenesis of autoimmunity and SSc.

Abatacept to treat chronic intestinal pseudo-obstruction in five systemic sclerosis patients with a description of the index case.

Chronic intestinal pseudo-obstruction is a severe complication of systemic sclerosis. Inflammatory neuropathy and immunological alterations have a prominent role in the development of systemic sclerosis-related chronic intestinal pseudo-obstruction and immunomodulation might be beneficial in this context. An accidental observation of a patient with juvenile arthritis and a biopsy-proven diagnosis of autoimmune ganglionitis led us to experiment with a new approach to treat systemic sclerosis-related chronic intestinal pseudo-obstruction. In our arthritis patient, the severity and frequency of recurrent episodes of chronic intestinal pseudo-obstruction and aspiration pneumonia were reduced whenever steroids were used to treat arthritic flares, which dramatically improved with abatacept therapy. A systemic sclerosis patient presented typical chronic intestinal pseudo-obstruction features that were neither controlled by dietary interventions nor by prokinetics and were often complicated by acute episodes (5-year) requiring hospitalization. Increased food tolerance was observed whenever parenteral steroids were used during hospitalization. An adequate long-term control of symptoms was then obtained with the use of intramuscular methylprednisolone 20 mg/day; however, symptoms promptly recurred after tapering. Following this motivating example, immunomodulation with abatacept was started. Symptoms were then well controlled and steroids could be weaned off without further acute episodes of sub-occlusion. We postulate that inflammatory neuropathy resembling myenteric ganglionitis may be suspected in selected systemic sclerosis patients with chronic intestinal pseudo-obstruction features. Immunomodulation with drugs that act on T function and restore the regulatory/effector T cell balance may be beneficial in these subjects. The outcomes of four additional systemic sclerosis patients with severe and refractory symptoms of intestinal pseudo-obstruction successfully treated with abatacept are also presented.

When and how ruling out cystic fibrosis in adult patients with bronchiectasis.

BACKGROUND: Bronchiectasis is the final result of different processes and most of the guidelines advocate for a careful evaluation of those etiologies which might be treated or might change patients' management, including cystic fibrosis (CF). MAIN BODY: CFTR mutations have been reported with higher frequency in bronchiectasis population. Although ruling out CF is considered as a main step for etiological screening in bronchiectasis, CF testing lacks of a standardized approach both from a research and clinical point of view. In this review a list of most widely used tests in CF is provided. CONCLUSIONS: Exclusion of CF is imperative for patients with bronchiectasis and CFTR testing should be implemented in usual screening for investigating bronchiectasis etiology. Physicians taking care of bronchiectasis patients should be aware of CFTR testing and its limitations in the adult population. Further studies on CFTR expression in human lung and translational research might elucidate the possible role of CFTR in the pathogenesis of bronchiectasis.