Is it IBD or Something Else? Key Characteristics Offer Clues

Nancy A. Melville

February 24, 2022

Immune-mediated inflammatory diseases (IMIDs) of the gastrointestinal (GI) tract, with features that often mimic each other, commonly present clinical challenges. But key characteristics can help distinguish the most common – inflammatory bowel disease (IBD) – from other IMIDs, allowing for proper diagnosis and treatment, according to a new review.

“Although these disorders share a common pathophysiology, the defects can occur anywhere in the complex network of cytokines, inflammatory mediators, and innate and adaptive systems, leading to unregulated inflammation,” the authors of the review reported in JGH Open.

“Precise knowledge about them will help determine the possible targeted therapy. Thus, it is essential to distinguish these disorders from IBD,” underscored the authors, who were affiliated with the department of gastroenterology at All India Institute of Medical Sciences, New Delhi, India.

IBD, with its two major phenotypes of Crohn’s disease and ulcerative colitis, represents the most common IMIDs of the GI tract.

However, alternative diagnoses with overlapping features that can often be confused with IBD are plentiful, including celiac disease, GI vasculitis, eosinophilic gastroenteritis, some monogenic disorders, sarcoidosis, immune checkpoint inhibitor-induced colitis (ICI colitis), and microscopic colitis, explained the authors.

They recommended that, when evaluating patients with the common features that the disorders share, “one should think with an open mind and look for other possibilities, especially in patients not responding to conventional therapies.”

Monogenic disorders that mimic IBD

To determine monogenic disorders that mimic IBD, a key starting point can be the utilization of next-generation sequencing methods, which have become more available and less costly, the authors explained.

Most monogenic IBD variants present in the first decade of life and can be classified into different groups based on the pathways involved, they noted. These include disorders of epithelial barrier integrity, immune dysregulation, immunodeficiency, autoinflammatory disorders, and innate immune defects, including phagocyte killing.

Though monogenic IBD phenotypes are rare, measures to identify them are important, and can include taking peripheral blood counts, immunoglobulin profiles, and lymphocyte assays to identify common immunodeficiency disorders such as CVID and lymphocyte disorders.

While treatment can be difficult, “targeting the underlying defective immune pathway might be beneficial,” the authors noted, adding that some monogenic disorders, such as mutations of IL-10, can be effectively cured by hematopoietic stem cell transplantation (HSCT), while IL-1b receptor antagonists may be helpful in those with excesses in IL-1b.

Celiac disease

Celiac disease, previously believed to be a childhood disease, can occur at any age and, unlike IBD, has known environmental and genetic causes, with genetically predisposed individuals experiencing symptoms triggered by the ingestion of gluten proteins.

The disease can be diagnosed by the presence of serological markers including IgA tTG, anti-endomysial antibody, and anti-deamidated gliadin peptide antibodies, the authors noted.

In addition, they may have evidence of villous atrophy of the duodenal epithelium “with the exception in children, where more than 10 times elevation of IgA tTG is sufficient to make a diagnosis.”

Management includes avoidance of gluten-containing food products and nutritional supplementation of deficient nutrients and vitamins, and fewer than 5% of patients do not respond if they adhere to a gluten-free diet.

Other considerations besides IBD

Additional non-IBD phenotype disorders mimicking IBD to consider include the following:

Vasculitis-related enteropathy, characterized by inflammation of blood vessels and with clinical manifestations varying from abdominal pain and diarrhea to acute intestinal perforation. Symptoms can vary according to the type of vasculitis, ranging from mild abdominal pain and diarrhea to acute intestinal perforation.

Eosinophilic gastroenteritis, a rare eosinophil-mediated inflammatory disorder that can be difficult to diagnose and mimics IBD and other GI disorders.

“Mucosal disease is the most common clinical presentation, occurring in approximately 50% of cases and presents with abdominal pain, malabsorption, and protein-losing enteropathy,” the authors explained. “Whereas muscular disease presents as intestinal obstruction and serosal disease presents with eosinophilic ascites and pleural effusion.”

Microscopic colitis, an inflammatory disease of the large intestine, is often missed or confused with diarrhea-predominant irritable bowel syndrome (IBS), and the symptoms can result in severe impairment in the quality of life.

Unlike some other disorders, its incidence tends to increase with age, with a peak incidence in the sixth and seventh decades of life, the authors noted.

Immune checkpoint inhibitor–induced colitis, a major immune-mediated adverse event associated with checkpoint inhibitor drugs. Immune-mediated colitis (IMC) has clinical, radiological, and histopathological manifestations that mimic those of IBD, and may require urgent therapy depending on the grade of severity.

Major risk factors include the dose, type of agent, use of NSAIDs, preexisting IBD, as well as the type of tumor, the authors wrote.

“Management is more or less similar to that of IBD, and it depends on the severity of IMC,” they added.

Gastrointestinal sarcoidosis occurs in fewer than 1% of cases of sarcoidosis, a systemic granulomatous disease of unknown etiology, characterized by the formation of nonnecrotizing granulomas.

Diagnosis can be made by demonstrating nonnecrotizing granulomas on histopathology, with pulmonary and thoracic involvement suggesting sarcoidosis, and corticosteroid treatment.

Key indicators that it’s not IBD

Overall, key red flags that should raise suspicion of non-IBD disorder should include the presence of atypical features such as very young age of onset, being refractory to biologics, and involvement of other organ systems, the authors noted.

“Immunoglobulin assays, lymphocyte profiling, and neutrophilic functional assays should be carried out in patients with suspected underlying immunodeficiency disorder,” they added. “Whole-exome/genome sequencing and targeted gene analysis should be reserved for cases with a strong suspicion of monogenic disorders with IBD-like phenotype.”

Dr Joseph Murray

Joseph A. Murray, MD, professor of medicine at the Mayo Clinic in Rochester, Minn., noted in an interview that the review offers some important insights.

“This is a very good review for people who are seeing patients and considering whether they have inflammatory bowel disease, and is comprehensive in the area of monogenic causes of inflammation,” he said.

In addition to the disorders described in the review, Murray noted that “other types of diseases that I often see include drug-induced enteropathy, tropical sprue [a chronic diarrheal disease], autoimmune enteropathy, and lymphoproliferative diseases.”

Other drug-induced enteropathies include those associated with angiotensin receptor blockers and azathioprine enteritis, he noted.

Murray and colleagues previously reported on further nonceliac enteropathies in a separate review, titled “Not All That Flattens Villi Is Celiac Disease: A Review of Enteropathies” in the Mayo Clinic Proceedings.

Dr Tauseef Ali

Further commenting, Tauseef Ali, MD, executive medical director, Saints Digestive Health Institute, SSM Health, Oklahoma City, noted that “the publication is one of the first and most comprehensive reviews summarizing the gastrointestinal tract’s different immune-mediated inflammatory diseases.

“The review gives us an excellent glimpse of the complex interplay of shared genetic and immune pathways involved in many inflammatory bowel conditions,” he added, noting that it also provides “an excellent platform for developing future clinical research methodologies and designs.” 

The review authors had no disclosures to report. Murray has received grant support from the NIH, Alvine Pharmaceuticals and Alba Therapeutics, and receives ongoing support from Oberkotter Foundation and Broad Medical Research Program at CCFA. He serves on the advisory board of Celimmune and ImmunoGenx, was a consultant to BioLineRx, GlaxoSmithKline, Genentech and Glenmark Pharmaceuticals, and currently serves as a consultant to ImmunosanT, Institute for Protein Design (PvP Biologics), Takeda Pharmaceuticals, Innovate Biopharmaceuticals, and Intrexon. Ali has received honoraria for speaking, teaching, and consultation from AbbVie, Janssen, Pfizer, RedHill Biopharma, and Takeda.

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