Mark S. Silverberg's research while affiliated with Mount Sinai Hospital and other places

Publications (554)

Article
Full-text available
Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn’s disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets...
Article
Background Endpoints to determine the efficacy and safety of medical therapies for Crohn’s disease (CD) and ulcerative colitis (UC) are evolving. Given the heterogeneity in current outcome measures, harmonizing endpoints in a core outcome set (COS) for randomized controlled trials (RCTs) is a priority for drug development in inflammatory bowel dise...
Article
Surveillance pouchoscopy is recommended for patients with restorative proctocolectomy with ileal pouch–anal anastomosis in ulcerative colitis or familial adenomatous polyposis, with the surveillance interval depending on the risk of neoplasia. Neoplasia in patients with ileal pouches mainly have a glandular source and less often are of squamous cel...
Article
Background The impact of immunosuppressants on COVID-19 vaccination response and durability in patients with immune-mediated inflammatory diseases (IMID) is yet to be fully characterized. Humoral response may be attenuated in these patients especially those on B cell depleting therapy and higher doses of corticosteroids, but data regarding other im...
Article
Background and aims Case-control studies have shown that Crohn’s disease (CD) patients have a different microbial composition than healthy individuals. Although the causes of CD are unknown, epidemiological studies suggest that diet is an important contributor to CD risk, potentially via modulation of bacterial composition and gut inflammation. We...
Article
Background: Limited information is available on the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID). Methods: This observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with inflammatory bowel disease, rheumatoid arthritis, ankylosin...
Article
Environmental and lifestyle factors play an important role in the natural history of Crohn's disease and ulcerative colitis. A group of international experts from the International Organization for the Study of Inflammatory Bowel Diseases voted on a series of consensus statements to inform the management of inflammatory bowel disease (IBD). The rec...
Article
Background Microbial composition-based risk score (MRS) was recently developed and validated to predict future risk of developing Crohn’s disease (CD) among healthy first-degree relatives (FDR) of CD patients. We hypothesized that stool metabolomic profiles, some of which are linked to the gut microbiome, are associated with future risk of CD. Aim...
Article
Background Colonic IBD encompassing ulcerative colitis (UC) and isolated colonic Crohn’s disease (cCD) shows significant clinical, therapeutic response and genetic differences compared to ileocolonic CD (icCD). Elucidating the microbial signatures characterizing these subphenotypes could help to understand the causal factors underlying these clinic...
Article
Background Crohn’s disease (CD) has been associated with a lower alpha diversity when compared to ulcerative colitis (UC) patients and healthy controls (HC), which also depends on disease location and endoscopic activity. However, it is unclear whether the resolution of histologic inflammation may influence mucosal alpha diversity in the ileum. Ai...
Conference Paper
Background The terminal ileum is the most susceptible location to develop Crohn’s disease (CD) and therefore is a valuable tissue to investigate biological mechanisms underlying chronic inflammation. Gene expression is highly affected by the level of inflammation, however, data on ileal transcriptomic profile in the absence of active inflammation i...
Article
Background and aims Clinical trials evaluating biologics and small molecules in patients with ulcerative colitis are predominantly excluding ulcerative proctitis. The objective of the PROCTRIAL (Definition and endpoints for ulcerative PROCtitis in clinical TRIALs) initiative was to develop consensus statements for definitions, inclusion criteria, a...
Preprint
Background Limited information is available on the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID). Methods This observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with inflammatory bowel disease, rheumatoid arthritis, ankylosing sp...
Article
Background Pouchitis is a common complication of ileal pouch-anal anastomosis (IPAA) after proctocolectomy in ulcerative colitis (UC). There are currently no approved therapies for chronic pouchitis. Here, we report a multicentre trial of intravenous (IV) vedolizumab (VDZ) for chronic pouchitis after IPAA in patients with UC. Methods EARNEST was a...
Article
Background Primary sclerosing cholangitis associated Inflammatory bowel disease (PSC-IBD) carries significant morbidity risk. Alterations in bile acid profiles has been shown to modulate chronic inflammation in IBD, but data in PSC-IBD comorbidity is scarce. We aimed to assess associations of serum and stool bile acids (BA) with PSC-IBD phenotype v...
Article
Background We recently developed and validated a microbial composition-based risk score (MRS) that predicts future risk of Crohn’s disease (CD) development among healthy first-degree relatives (FDR) of CD patients. We hypothesized that stool metabolomic profiles may mediate the effect of microbiome-based risk on future onset of CD. Methods Healthy...
Conference Paper
Full-text available
Background Circulating serum proteins have provided insights into disease pathogenesis and are being used to identify prognostic, diagnostic and therapeutic biomarkers for chronic inflammatory diseases. With this pilot project, the Collaborative IBD Biomarker Research Initiative (COLLIBRI) consortium aimed to unravel disease heterogeneity in inflam...
Article
Background IBD patients on immune-modulatory therapies are considered high-risk for SARS-CoV-2 infection. Direct comparisons of serological responses to SARS-CoV-2 infection in IBD patients across different continents and medications are lacking. We performed SARS-CoV-2 sero-surveillance of IBD patients prior to vaccination at seven large tertiary...
Article
Background and aims A composite endpoint of histologic and endoscopic remission is proposed to be the most complete measure of mucosal healing in ulcerative colitis (UC). We aim to establish the prognosis, transcriptional and microbial features of histo-endoscopic remission and activity. Methods A cross-sectional endoscopic rectosigmoid colon samp...
Article
Inflammatory bowel disease (IBD), historically subdivided into Crohn’s disease and ulcerative colitis, is a very heterogeneous condition. While the tendency in medicine is to try and reduce complexity, IBD is a disease that cannot justify a one-size-fits-all principle. Our current clinical classification tools are suboptimal and need further refine...
Article
Pouchitis, Crohn's disease of the pouch, cuffitis, polyps, and extraintestinal manifestations of inflammatory bowel disease are common inflammatory disorders of the ileal pouch. Acute pouchitis is treated with oral antibiotics and chronic pouchitis often requires anti-inflammatory therapy, including the use of biologics. Aetiological factors for se...
Article
Background and aims: Crohn's disease (CD) recurrence following ileocolic resection (ICR) is common. We sought to identify blood-based biomarkers associated with CD recurrence. Methods: CD patients undergoing ICR were recruited across six centres. Serum samples were obtained at post-operative colonoscopy. A multiplex immunoassay was used to analy...
Article
Introduction: We investigated whether early adalimumab drug levels (ADL) at week 4 predicted biological remission at week 24. Methods: In a prospective study, we assessed clinical and biological remission at weeks 0, 4, 12, and 24 after induction of adalimumab in 33 patients with Crohn's disease. Disease activity was determined by the Harvey-Bra...
Article
Full-text available
Publicly available ulcerative colitis (UC) gene expression datasets from observational studies and clinical trials include inherently heterogeneous disease characteristics and methodology. We used meta-analysis to identify a robust UC gene signature from inflamed biopsies. Eight gene expression datasets derived from biopsy tissue samples from nonin...
Article
Restorative proctocolectomy with ileal pouch-anal anastomosis is an option for most patients with ulcerative colitis or familial adenomatous polyposis who require colectomy. Although the construction of an ileal pouch substantially improves patients' health-related quality of life, the surgery is, directly or indirectly, associated with various str...
Article
Background: Many Crohn's disease patients treated with anti-tumor necrosis factor (TNF) therapies suffer from loss of response over time and require dose escalation. The aim of this study was to evaluate the efficacy and safety of treating anti-TNF experienced Crohn's disease patients with higher maintenance regimens of adalimumab. Methods: In a...
Article
Background: /Aim: Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDR) of CD patients is an independent risk factor for future CD development. Methods: We measured...
Article
Background and Aims We constructed the Toronto IBD global endoscopic reporting (TIGER) score for inflammatory bowel disease (IBD). The aim of our study was to develop and validate the TIGER score against fecal calprotectin (FC), C-reactive protein (CRP) and IBD Disk. Methods A cross-sectional study was performed among 113 adult patients (60 CD and...
Preprint
Full-text available
Genome-wide association studies (GWAS) have identified hundreds of loci associated with Crohns disease (CD); however, as with all complex diseases, deriving pathogenic mechanisms from these non-coding GWAS discoveries has been challenging. To complement GWAS and better define actionable biological targets, we analysed sequence data from more than 3...
Article
Full-text available
Background Optimal ustekinumab levels (UST) in Crohn’s disease (CD) treatment have not been defined. We set out to define the optimal UST to differentiate between remission and active CD, as defined using the serum-based endoscopic healing index (EHI). Methods Paired serum UST and EHI tests were analyzed. Remission was defined as EHI <20. Active d...
Article
Background Crohn’s disease (CD) can affect any segment of the digestive tract but is most often localized in the ileal, ileocolonic, and colorectal regions of the intestines. It is believed that the chronic inflammation in CD is a result of an imbalance between the epithelial barrier, the immune system, and the intestinal microbiota. The aim of the...
Article
Background and Aims Microbial derived-bile acids can modulate host gene expression, and their fecal abundance is decreased in active inflammatory bowel disease (IBD). We analyzed the impact of endoscopic inflammation on microbial genes involved in bile acid biotransformation, and their interaction with host transcriptome in the intestinal mucosa of...
Article
Background Commonly used endoscopic indices in IBD lack ability to provide overall disease burden and severity, generate low inter-observer agreement, and demonstrate incomplete validation of some scores. We developed an endoscopic reporting tool, the Toronto IBD Global Endoscopic Reporting (TIGER) score for Crohn’s disease (CD) and ulcerative coli...
Article
Full-text available
Background Histologic remission (HR) in ulcerative colitis (UC) has been associated with better clinical outcomes. However, this therapeutic target is hard to achieve with the available medications. We aim to assess the relapse-free survival (RFS) of patients with persistent histologic activity (HA) upon achieving endoscopic healing (EH) and the mi...
Article
Background Commonly used endoscopic indices in IBD lack ability to provide overall disease burden and severity, generate low inter-observer agreement, and demonstrate incomplete validation of some scores. We developed a new endoscopic reporting tool, the Toronto IBD Global Endoscopic Reporting (TIGER) score for Crohn’s disease (CD) and ulcerative c...
Article
Background and aims: Crohn's disease (CD) patients who previously failed anti-TNF therapy are at higher risk of treatment failure with subsequent biologics. This study aims to determine the effectiveness and safety of higher maintenance dose regimens of adalimumab compared to standard doses in CD patients who failed anti-TNF. Methods: In this re...
Article
Inflammatory bowel disease (IBD) is a group of chronic diseases, affecting different parts of the gastrointestinal tract, that mainly comprises Crohn's Disease (CD) and Ulcerative Colitis (UC). Most IBD genomic research to date has involved genome-wide association studies (GWAS) of common genetic variants, mostly in Europeans, resulting in the iden...
Article
Full-text available
Background: Pouchitis is a condition with large unmet medical needs and no approved therapies. Lack of validated instruments to measure disease activity and treatment response is a major barrier to drug development. Aim: To conduct a modified RAND/University of California Los Angeles appropriateness process to produce a standardised assessment o...
Article
Introduction Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess if host seroreactivity to microbial antigens in healthy first-degree relatives (FDR) of CD patients is an independent risk factor of future CD development. Methods We measured host seroreactivity to six...
Article
The majority of patients with Crohn's disease and a proportion of patients with ulcerative colitis will ultimately require surgical treatment despite advances in diagnosis, therapy, and endoscopic interventions. The surgical procedures that are most commonly done include bowel resection with anastomosis, strictureplasty, faecal diversion, and ileal...
Article
Full-text available
Background and aims This study aimed to compare real-world clinical effectiveness and safety of vedolizumab, an α4β7-integrin inhibitor, and anti-tumour necrosis factor-α (anti-TNFα) agents in biologic-naïve ulcerative colitis (UC) and Crohn’s disease (CD) patients. Methods This was a 24-month retrospective medical chart study in adult UC and CD p...
Article
Background: We investigated relationships between induction ustekinumab levels and clinical and biochemical outcomes in Crohn's disease. Methods: Following standard IV induction, ustekinumab levels were measured at week 2 (wk2) and week 6 (wk6). Ustekinumab levels were compared in patients receiving 260, 390 and 520 mg at induction. Crohn's dise...
Article
Full-text available
Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644...
Article
Full-text available
Therapeutic drug monitoring (TDM) with measurement of serum drug and antidrug antibodies (ADAb) is used widely to confirm therapeutic exposure, rule out immunogenicity, and optimize treatment of biologics in patients with inflammatory bowel diseases.1 A recent genome-wide association study found the variant HLA-DQA1∗05 to increase the risk of devel...
Article
Full-text available
Background & Aims Recent literature has implicated a key role for mast cells in murine models of colonic inflammation, but their role in human ulcerative colitis (UC) is not well-established. A major advance has been the identification of mrgprb2 (human orthologue, MRGPX2) as mediating IgE-independent mast cell activation. We sought to define mecha...
Article
Background Up to 60% of patients with ulcerative colitis (UC) ultimately fail anti-tumor necrosis factor (TNF) treatment. We aimed to investigate early predictive markers of clinical and endoscopic outcomes in patients with UC who were anti-TNF-naïve commencing anti-TNF treatment, with particular focus on changes in albumin and C-reactive protein l...
Article
Full-text available
Background and aims Polygenic risk scores (PRS) may soon be used to predict inflammatory bowel disease (IBD) risk in prevention efforts. We leveraged exome-sequence and SNP array data from 29,358 individuals in the multi-ethnic, randomly-ascertained health system-based BioMe biobank to define effects of common and rare IBD variants on disease predi...
Article
Endoscopy is an essential component in the management of inflammatory bowel disease [IBD]. There is a risk of SARS-CoV-2 transmission during endoscopic procedures. The International Organization for the study of IBD [IOIBD] has developed 11 position statements, based on an online survey, that focus on how to prioritise endoscopies in IBD patients d...
Article
Full-text available
Background Genetic analyses have identified many variants associated with the risk of inflammatory bowel disease (IBD) development. Among these variants, the ones located within the NOD2 gene have the highest odds ratio of all IBD genetic risk variants. Also, patients with Crohn’s disease (CD) have been shown to have an altered gut microbiome, whic...
Article
Spread of the novel coronavirus SARS-CoV-2 has resulted in a global pandemic that is affecting the health and economy of all WHO regions. Clinical and translational research activities have been impacted drastically by this global catastrophe. In this document we provide a suggested roadmap for resuming gastrointestinal translational research activ...