Celiac Disease and IBD Show Strong Bidirectional Link

Marcia Frellick

June 09, 2022

New research shows a strong bidirectional relationship between celiac disease and inflammatory bowel disease (IBD) that may hold clues for patient diagnoses and care.

After the first year postdiagnosis, researchers found that patients with celiac disease had an almost 4-fold increased risk of IBD, and patients with IBD had more than a 5-fold increased risk of celiac disease.

“The risk of IBD in celiac disease (and vice versa) showed a distinct increase even 10 years after the first diagnosis,” the authors write. “During 20 years of follow-up, 2.5% of celiac disease patients developed incident IBD, and 1.3% of IBD patients developed celiac disease.”

The findings were published online in The American Journal of Gastroenterology.

Nationwide Cohort Study

The study, led by Karl Mårild, MD, PhD, with the Department of Pediatric Gastroenterology, Queen Silvia Children’s Hospital, in Gothenburg, Sweden, reports absolute and relative risk estimates in more than 48,000 patients with celiac disease and more than 83,000 patients with IBD diagnosed from 1969 to 2016. The patients were compared with a general population control group matched by sex and age.

Dr Karl Marild

The authors excluded the first year of diagnosis in follow-up analysis because misdiagnosis of celiac disease and IBD in the first year of follow-up can overstate the magnitude of risk. Excluding the first year also helps avoid surveillance bias, they write.

Overall, 784 (1.6%) patients with celiac disease were also diagnosed with IBD compared with 1015 (0.4%) in the control group. In patients with celiac disease, the hazard ratio (HR) for IBD was 3.91 (95% CI, 3.56-4.31).

The HRs were largely similar for Crohn’s disease (HR, 4.36; 95% CI, 3.72-5.11) and ulcerative colitis (HR, 3.40; 95% CI, 3.00-3.85).

Conversely, 644 (0.8%) patients with IBD and 597 (0.1%) in the control group were diagnosed with celiac disease. The HR for celiac disease in patients with IBD was 5.49 (95% CI, 4.90-6.16). The highest risk estimates were seen in ulcerative colitis (HR, 6.99; 95% CI, 6.07-8.05). The HR for Crohn’s disease was 3.31 (95% CI, 2.69-4.06).

Celiac disease has been linked with IBD, but estimates of the crossover have varied widely and population-based estimates are scarce. Few studies have adjusted for surveillance bias.

The authors write, “the significantly increased risk of celiac disease and IBD even 10 years after diagnosis of the other condition suggests an etiological link between celiac disease and IBD. Common immunological, genetic, and environmental factors may play a role here.”

Clinical Implications

Dr Stephen Hanauer

Stephen Hanauer, MD, professor of medicine at Northwestern University Feinberg School of Medicine in Chicago, Illinois, told Medscape Medical News the main message of the bidirectional link in clinical practice is for providers “to consider an alternative diagnosis for patients who are not having the expected response to one disease or when patients have residual or new symptoms that are not accounted for or expected during treatment and monitoring.”

This study, he notes, quantifies the co-association in the Swedish population. 

“The association has long been recognized, just not the effect size,” he said.

Dr Alberto Rubio-Tapia

Alberto Rubio-Tapia, MD, director of the celiac program at Cleveland Clinic in Ohio, was a senior author for a similar recent study on the cross-association and was happy to see their results were extremely similar to what the researchers found in the Swedish population.

He told Medscape that the similarities may point more to genetic causes of the risk for both diseases rather than environmental or geographic causes.

At the Cleveland Clinic, he noted that the new evidence of bidirectional association prompts physicians to think about considering the alternate diagnosis when there are persistent symptoms such as diarrhea with celiac disease or IBD.

When patients with celiac disease are following a strict gluten-free diet and those symptoms persist, for instance, “we start thinking about a differential diagnosis. Inflammatory bowel disease, especially in the context of diarrhea, should be considered.”

Conversely, if a patient has IBD and suddenly is not responding, “especially if they have persistent anemia or diarrhea, then we need to think about celiac disease as a potential differential diagnosis,” he said.

The findings are especially interesting, Rubio-Tapia noted, because the two inflammatory diseases are very different in symptom presentation and treatment of the disease and immunology.

But the strong bidirectional association, “suggests that there’s a possible link between the genetic risk in the two conditions,” he said.

“We know that HLA (human leukocyte antigen) — that is a genetic risk for celiac disease — is not shared with inflammatory bowel disease, but other genes that are not HLA may be the link,” he added.

Rubio-Tapia said it’s also possible that changes in the microbiome could be at the root of the risk for both diseases.

In one limitation of the study in Sweden, researchers did not have data on IBD medication or data on whether patients with celiac disease followed a gluten-free diet. They also said they could not rule out that steroids and other therapies for IBD reduce the risk for celiac disease or result in an underdiagnosis of the disease.

Coauthor Ludvigsson coordinates a study on behalf of the Swedish IBD Quality Registry (SWIBREG). That study has received funding from the Janssen corporation.

Coauthor Olén has been PI for projects (unrelated to the current paper) at Karolinska Institutet partly financed by investigator-initiated grants from Janssen and Pfizer. Karolinska Institutet has received fees for lectures and participation on advisory boards from Janssen, Ferring, and Takeda.

Coauthor Halfvarson has served as a speaker or advisory board member for AbbVie, Celgene, Celltrion, Ferring, Hospira, Janssen, MEDA, Medivir, MSD, Olink Proteomics, Pfizer, Prometheus Laboratories, Sandoz/Novartis, Shire, Takeda, Tillotts Pharma, Vifor Pharma, and UCB. He has also received grant support from Janssen, MSD, and Takeda.

Coauthor Pinto-Sanchez has served as a scientific advisory board member or consultant for Lupin, Proventionbio, and Takeda.

The other authors report no conflicts of interest.

Hanauer and Rubio-Tapia report no relevant financial relationships.

The American Journal of Gastroenterology. Published online May 25, 2022. Abstract.

Marcia Frellick is a freelance journalist based in Chicago, Illinois. She has previously written for the Chicago Tribune, Science News, and Nurse.com, and was an editor at the Chicago Sun-Times, The Cincinnati Enquirer, and the St. Cloud (Minnesota) Times. Follow her on Twitter at @mfrellick.

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