David Padua

The etiology of ulcerative colitis (UC) is complex and involves a host of genetic, epigenetic and environmental factors. Over the last thirty years, signaling pathways like the Janus kinase (JAK) signaling pathway have been implicated in its pathogenesis. Pharmacologic blockade of this pathway is available through several small molecule inhibitors, including tofacitinib. Tofacitinib is an orally administered pan-JAK inhibitor that was first approved by the Food and Drug Administration (FDA) for use in rheumatologic disorders such as rheumatoid arthritis and psoriatic arthritis. The FDA approved its use in moderate-to-severe active ulcerative colitis in 2018. The aim of this review will be to discuss the role of tofacitinib in ulcerative colitis. We will discuss the role of JAK-STAT signaling, clinical data available for tofacitinib, and the safety profile for this therapy. Tofacitinib’s place in the UC management algorithm is currently being debated. This effective oral therapy is poised to be a mainstay of UC therapeutics. This review will highlight the key clinical features and detail the UC experience to date.

Long noncoding RNA (lncRNA) biology is a new and exciting field of research, with the number of publications from this field growing exponentially since 2007. These studies have confirmed that lncRNAs are altered in almost all diseases. However, studying the functional roles for lncRNAs in the context of disease remains difficult due to the lack of protein products, tissue-specific expression, low expression levels, complexities in splice forms, and lack of conservation among species. Given the species-specific expression, lncRNA studies are often restricted to human research contexts when studying disease processes. Since lncRNAs function at the molecular level, one way to dissect lncRNA biology is to either remove the lncRNA or overexpress the lncRNA and measure cellular effects. In this article, a written and visualized protocol to overexpress lncRNAs in vitro is presented. As a representative experiment, an lncRNA associated with inflammatory bowel disease, Interferon Gamma Antisense 1 (IFNG-AS1), is shown to be overexpressed in a Jurkat T-cell model. To accomplish this, the activating clustered regularly interspaced short palindromic repeats (CRISPR) technique is used to enable overexpression at the endogenous genomic loci. The activating CRISPR technique targets a set of transcription factors to the transcriptional start site of a gene, enabling a robust overexpression of multiple lncRNA splice forms. This procedure will be broken down into three steps, namely (i) guide RNA (gRNA) design and vector construction, (ii) virus generation and transduction, and (iii) colony screening for overexpression. For this representative experiment, a greater than 20-fold enhancement in IFNG-AS1 in Jurkat T cells was observed.

Inflammatory bowel disease (IBD) is a complex disorder that is associated with significant morbidity. While many recent advances have been made with new diagnostic and therapeutic tools, a deeper understanding of its basic pathophysiology is needed to continue this trend toward improving treatments. By utilizing an unbiased, high-throughput transcriptomic analysis of two well-established mouse models of colitis, we set out to uncover novel coding and noncoding RNAs that are differentially expressed in the setting of colonic inflammation. RNA-seq analysis was performed using colonic tissue from two mouse models of colitis, a dextran sodium sulfate-induced model and a genetic-induced model in mice lacking IL-10. We identified 81 coding RNAs that were commonly altered in both experimental models. Of these coding RNAs, 12 of the human orthologs were differentially expressed in a transcriptomic analysis of IBD patients. Interestingly, 5 of the 12 of human differentially expressed genes have not been previously identified as IBD-associated genes, including ubiquitin D. Our analysis also identified 15 noncoding RNAs that were differentially expressed in either mouse model. Surprisingly, only three noncoding RNAs were commonly dysregulated in both of these models. The discovery of these new coding and noncoding RNAs expands our transcriptional knowledge of mouse models of IBD and offers additional targets to deepen our understanding of the pathophysiology of IBD. NEW & NOTEWORTHY Much of the genome is transcribed as non-protein-coding RNAs; however, their role in inflammatory bowel disease is largely unknown. This study represents the first of its kind to analyze the expression of long noncoding RNAs in two mouse models of inflammatory bowel disease and correlate them to human clinical samples. Using high-throughput RNA-seq analysis, we identified new coding and noncoding RNAs that were differentially expressed such as ubiquitin D and 5730437C11Rik.

Secukinumab is an interleukin-17 inhibitor used for the treatment of ankylosing spondylitis (AS), psoriasis, and psoriatic arthritis. The risk of exacerbating underlying inflammatory bowel disease (IBD) in patients being treated with secukinumab for other conditions is controversial. We document a patient with AS and previously undiagnosed IBD, found to be in a severe ulcerative colitis flare shortly after receiving the loading dose of secukinumab. There are no guidelines regarding biologic salvage therapy for IBD in the setting of active treatment with another biologic agent. After waiting one half-life of secukinumab, our patient had an excellent response to initiation of infliximab.