Treatment of autoimmunity: The impact of disease-modifying therapies in multiple sclerosis and comorbid autoimmune disorders.

More than 10 disease-modifying therapies (DMT) are approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the treatment of multiple sclerosis (MS) and new therapeutic options are on the horizon. Due to different underlying therapeutic mechanisms, a more individualized selection of DMTs in MS is possible, taking into account the patient's current situation. Therefore, concomitant treatment of various comorbid conditions, including autoimmune mediated disorders such as rheumatoid arthritis, should be considered in MS patients. Because the pathomechanisms of autoimmunity partially overlap, DMT could also treat concomitant inflammatory diseases and simplify the patient's treatment. In contrast, the exacerbation and even new occurrence of several autoimmune diseases have been reported as a result of immunomodulatory treatment of MS. To simplify treatment and avoid disease exacerbation, knowledge of the beneficial and adverse effects of DMT in other autoimmune disorders is critical. Therefore, we conducted a literature search and described the beneficial and adverse effects of approved and currently studied DMT in a large number of comorbid autoimmune diseases, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel diseases, cutaneous disorders including psoriasis, Sjögren´s syndrome, systemic lupus erythematosus, systemic vasculitis, autoimmune hepatitis, and ocular autoimmune disorders. Our review aims to facilitate the selection of an appropriate DMT in patients with MS and comorbid autoimmune diseases.

Impact on follow-up strategies in patients with primary sclerosing cholangitis.

BACKGROUND & AIMS: Evidence for the benefit of scheduled imaging for early detection of hepatobiliary malignancies in primary sclerosing cholangitis (PSC) is limited. We aimed to compare different follow-up strategies in PSC with the hypothesis that regular imaging improves survival. METHODS: We collected retrospective data from 2975 PSC patients from 27 centres. Patients were followed from the start of scheduled imaging or in case of clinical follow-up from 1 January 2000, until death or last clinical follow-up alive. The primary endpoint was all-cause mortality. RESULTS: A broad variety of different follow-up strategies were reported. All except one centre used regular imaging, ultrasound (US) and/or magnetic resonance imaging (MRI). Two centres used scheduled endoscopic retrograde cholangiopancreatography (ERCP) in addition to imaging for surveillance purposes. The overall HR (CI95%) for death, adjusted for sex, age and start year of follow-up, was 0.61 (0.47-0.80) for scheduled imaging with and without ERCP; 0.64 (0.48-0.86) for US/MRI and 0.53 (0.37-0.75) for follow-up strategies including scheduled ERCP. The lower risk of death remained for scheduled imaging with and without ERCP after adjustment for cholangiocarcinoma (CCA) or high-grade dysplasia as a time-dependent covariate, HR 0.57 (0.44-0.75). Hepatobiliary malignancy was diagnosed in 175 (5.9%) of the patients at 7.9 years of follow-up. Asymptomatic patients (25%) with CCA had better survival if scheduled imaging had been performed. CONCLUSIONS: Follow-up strategies vary considerably across centres. Scheduled imaging was associated with improved survival. Multiple factors may contribute to this result including early tumour detection and increased endoscopic treatment of asymptomatic benign biliary strictures.

Identification of Novel Population-Specific Cell Subsets in Chinese Ulcerative Colitis Patients Using Single-Cell RNA Sequencing.

BACKGROUND & AIMS: Genome-wide association studies (GWAS) and transcriptome analyses have been performed to better understand the pathogenesis of ulcerative colitis (UC). However, current studies mainly focus on European ancestry, highlighting a great need to identify the key genes, pathways and cell types in colonic mucosal cells of adult UC patients from other ancestries. Here we aimed to identify key genes and cell types in colonic mucosal of UC. METHODS: We performed Single-cell RNA sequencing (scRNA-seq) analysis of 12 colon biopsies of UC patients and healthy controls from Chinese Han ancestry. RESULTS: Two novel plasma subsets were identified. Five epithelial/stromal and three immune cell subsets show significant difference in abundance between inflamed and non-inflamed samples. In general, UC risk genes show consistent expression alteration in both Immune cells of inflamed and non-inflamed tissues. As one of the exceptions, IgA defection, marking the signal of immune dysfunction, is specific to the inflamed area. Moreover, Th17 derived activation was observed in both epithelial cell lineage and immune cell lineage of UC patients as compared to controls , suggesting a systemic change of immune activities driven by Th17. The UC risk genes show enrichment in progenitors, glial cells and immune cells, and drug-target genes are differentially expressed in antigen presenting cells. CONCLUSIONS: Our work identifies novel population-specific plasma cell molecular signatures of UC. The transcriptional signature of UC is shared in immune cells from both inflamed and non-inflamed tissues, whereas the transcriptional response to disease is a local effect only in inflamed epithelial/stromal cells.

Quality of Life Is Associated With Wearable-Based Physical Activity in Patients With Inflammatory Bowel Disease: A Prospective, Observational Study.

OBJECTIVES: Patient-reported outcomes such as quality of life are gaining importance in the assessment of patients suffering from inflammatory bowel disease (IBD). The association of objectively measured physical activity and quality of life in patients with IBD has not been studied in depth. To investigate the association of disease-specific quality of life and physical activity as well as clinical and biochemical disease activity in patients with IBD. METHODS: A total of 91 patients with IBD were stratified into 4 groups (Crohn's disease and ulcerative colitis, in remission and with moderate-severe activity, respectively) and evaluated in terms of disease-specific quality of life (Inflammatory Bowel Disease Questionnaire [IBDQ]), physical activity (accelerometry), body composition (bioelectrical impedance analysis), as well as clinical (Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index) and biochemical (C-reactive protein and fecal calprotectin) parameters of disease activity. RESULTS: In patients with moderate-severe disease activity, the IBDQ was significantly lower as compared to patients in remission (Mann-Whitney U test and Kruskal-Wallis test, P < 0.001). The physical activity level was higher in remission than in active disease (Mann-Whitney U test, P < 0.05). The IBDQ was significantly correlated with the duration of strenuous physical activity per day (P = 0.029178, r = 0.235), skeletal muscle mass (P = 0.033829, r = 0.229), and biomarkers of inflammation (C-reactive protein: P < 0.005, r = -0.335 and fecal calprotectin: P < 0.005, r = -0.385). DISCUSSION: In this prospective, cross-sectional study, disease-specific quality of life was significantly associated with accelerometrically determined physical activity and disease activity in patients with IBD. This may be related to a reciprocal impact of these factors (DRKS00011370).

Association of a common AKAP9 variant with breast cancer risk: a collaborative analysis.

Data from several studies have suggested that polymorphisms in A-kinase anchoring proteins (AKAPs), which are key components of signal transduction, contribute to carcinogenesis. To evaluate the impact of AKAP variants on breast cancer risk, we genotyped six nonsynonymous single-nucleotide polymorphisms that were predicted to be deleterious and found two (M463I, 1389G>T and N2792S, 8375A>G) to be associated with an allele dose-dependent increase in risk of familial breast cancer in a German population. We extended the analysis of AKAP9 M463I, which is in strong linkage disequilibrium with AKAP9 N2792S, to 9523 breast cancer patients and 13770 healthy control subjects from seven independent European and Australian breast cancer studies. All statistical tests were two-sided. The collaborative analysis confirmed the association of M463I with increased breast cancer risk. Among all breast cancer patients, the combined adjusted odds ratio (OR) of breast cancer for individuals homozygous for the rare allele TT (frequency = 0.19) compared with GG homozygotes was 1.17 (95% confidence interval [CI] = 1.08 to 1.27, P = .0003), and the OR for TT homozygotes plus GT heterozygotes compared with GG homozygotes was 1.10 (95% CI = 1.04 to 1.17, P = .001). Among the combined subset of 2795 familial breast cancer patients, the respective ORs were 1.27 (95% CI = 1.12 to 1.45, P = .0003) and 1.16 (95% CI = 1.06 to 1.27, P = .001).

The CASP8 -652 6N del promoter polymorphism and breast cancer risk: a multicenter study.

A recent study on an Asian population reported a six-nucleotide insertion-deletion polymorphism (-652 6N del) in the CASP8 promoter region to be strongly associated with a decreased risk of multiple types of cancer, including breast cancer (BC). Here, we investigate the effect of this deletion in four independent large European BC case-control studies, including data from a total of 7,753 cases and 7,921 controls. The combined per allele odds ratio (OR) was 0.97 (95% confidence interval (CI), 95% CI = 0.93-1.02). The present result indicates that the CASP8 -652 6N del variant has no significant effect on BC risk in Europeans.