In a recent publication in Gastroenterology, researchers from Cedars-Sinai conducted the most extensive multicohort data set to date to examine the clinical, serologic, and genetic factors correlated with extraintestinal manifestations (EIMs) complications in inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC).
The authors wrote, “Extraintestinal manifestations (EIMs) occur frequently in inflammatory bowel disease (IBD), but their causes are unknown, and understanding the underlying mechanisms may help target therapeutic choices for IBD in the future.”
This multicenter study involved a total of 12,083 participants with IBD with the presence or absence of EIMs (e.g., ankylosing spondylitis [ankylosing spondylitis and sacroiliitis], primary sclerosing cholangitis [PSC], peripheral arthritis, and skin and ocular manifestations) across four cohorts.
Employing a mixed-effects model, researchers assessed clinical and serologic parameters by means of univariable and multivariable regression analyses, and within-case logistic regression was conducted to evaluate genetic associations.
Results revealed that the majority of EIMS transpired more frequently in females (overall EIM: P = 9.0E-05, odds ratio [OR], 1.2; 95% CI, 1.1-1.4), with CD (especially colonic disease location; P = 9.8E-09, OR, 1.7; 95% CI, 1.4-2.0), and in subjects who required surgery (both CD and UC; P = 3.6E-19, OR, 1.7; 95% CI, 1.5-1.9). Factors, such as smoking, were also associated with an augmented risk of EIMs, except for PSC, where a “protective” effect was observed.
The authors noted that multiple serologic correlations were observed, “including with PSC (IgG [immunoglobulin G] and IgA [immunoglobulin A], perinuclear anti-nuclear cytoplasmic antibody; anti-Saccharomyces cerevisiae antibodies; and anti-flagellin) and any EIM (IgG and IgA, perinuclear anti-nuclear cytoplasmic antibody; anti-Saccharomyces cerevisiae antibodies; and anti-Pseudomonas fluorescence-associated sequence).”
The authors indicated that they recognized significant genome-wide correlations within major histocompatibility complex (ankylosing spondylitis and sacroiliitis, P = 1.4E-15; OR, 2.5; 95% CI, 2.0-3.1; PSC, P = 2.7E-10; OR, 2.8; 95% CI, 2.0-3.8; ocular, P = 2E-08, OR, 3.6; 95% CI, 2.3-5.6; and overall EIM, P = 8.4E-09; OR, 2.2; 95% CI, 1.7-2.9) and CPEB4 (skin, P = 2.7E-08; OR, 1.5; 95% CI, 1.3-1.8).
Their findings also revealed that genetic associations implicated tumor necrosis factor, Janus kinase/signal transducers and activators of transcription (JAK-STAT), and interleukin-6 (IL6) as prospective targets for EIMs, and contrary to previous reports, only 2% of the study cohort had multiple EIMs and most co-occurrences were negatively correlated.
The authors concluded that their findings discovered demographic, clinical, and genetic correlations with EIMs that revealed underlying mechanisms and implicated novel and existing drug targets, which are critical steps to developing a more personalized approach to managing IBD.
In a press release on the Cedars-Sinai website, Talin Haritunians, PhD, cosenior author of the study and associated professor of Medicine at Cedars-Sinai, stated, “We found that being female, smoking, or having a history of surgeries to treat Crohn’s disease or ulcerative colitis puts patients more at risk for developing other serious inflammatory conditions.”
Dr. Haritunians also stated, “Genetic variations of IBD, as well as the location of the disease in the gastrointestinal tract, were also associated with developing debilitating extraintestinal manifestations of the disease affecting the eyes, joints, skin, liver, and spine.”
Dermot McGovern, MD, PhD, the corresponding author of the study and director of translational research in the Cedars-Sinai F. Widjaja Inflammatory Bowel Disease Institute, stated, “These inflammatory manifestations outside the gut impact about 40% of our patients with IBD. The disorders can have a very significant effect on quality of life and, in some instances, are life-threatening. Our findings will help us identify those at risk of developing these related conditions,”
Lastly, Dr. McGovern stated, “Our clinical findings in this study shed light on the risk factors for morbidity associated with IBD. Our genetic findings highlight pathways that are targets for existing drugs or therapeutics in development. These discoveries are critical for developing more personalized approaches to the management of IBD and its various manifestations.”
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