Y-ECCO Literature Review: Panagiotis Markopoulos

Panagiotis Markopoulos

The influence of proton pump inhibitor therapy on the outcome of infliximab therapy in inflammatory bowel disease: a patient-level meta-analysis of randomized controlled studies

Lu TX, Dapas M, Lin E, Peters T, Sakuraba A

Gut 2021 Nov;70(11):2076-2084.

P. Markopoulos
© P. Markopoulos


The management of Inflammatory Bowel Disease (IBD) has evolved significantly over the last two decades [1, 2], as the development of biologic therapy has increased dramatically the rates of induction and prolonged maintenance of remission in patients with IBD. Infliximab (an anti-tumour necrosis factor) was the first biologic therapy to be approved for the treatment of IBD [3] and remains the biologic therapy with which clinicians have the most clinical experience [4].

Due to comorbidities, patients are frequently on other medications in addition to infliximab. How these other concomitant medications influence the response to infliximab therapy is largely unexplored.

Proton pump inhibitors (PPIs) are the first-line treatment for many digestive disorders such as gastro-oesophageal reflux disease (GORD), peptic ulcers, eosinophilic oesophagitis and dyspepsia [5]. PPIs are one of the most used family of medications in the United States, with more than 50 million prescriptions filled every year [6].

A few retrospective trials have attempted to investigate the impact of concomitant PPI therapy on response to infliximab in patients with IBD; however, these studies have suffered from the presence of many confounders, such as the lack of data on smoking status or the increased risk for gastroenteritis and C. difficile infection amongst patients treated with PPIs.

To increase the power to detect differential effects of PPI treatment on patients treated with infliximab in randomised trials and to allow adjustment for confounding factors, the investigators performed a patient-level meta-analysis of IBD randomised controlled clinical trials from the Yale Open Data Access (YODA) Framework.


This study included five randomised control studies of adult patients with moderate-to-severe IBD, treated with infliximab. Patient-level data were obtained from the YODA Framework. Baseline patient characteristics (age, sex, race, smoking status, concomitant immunomodulator use, history of intestinal resection, infliximab dose) and Mayo Score and Crohn’s Disease Activity Index (CDAI) were obtained for each participant.

Τhere were 147 and 889 patients on infliximab with and without PPI therapy, respectively. Patients on PPI were older, more likely to be Caucasian and less likely to be on immunomodulator therapy. To reduce the bias introduced by the differences in baseline characteristics, patients on infliximab and PPI therapy were matched with those without PPI therapy in a 1:3 ratio based on the above baseline characteristics.

The primary outcome was week 30 remission rates as this was a clinical endpoint available in all the trials. Clinical remission was defined as CDAI <150 for patients with Crohn’s Disease (CD) and as partial Mayo Score <3 for those with Ulcerative Colitis (UC).

Additionally, week 54 remission rates were assessed, alongside the week 14 remission rates for CD patients and week 8 remission rates for UC patients, whenever these data were available in the database. Hospitalisation rates for all IBD patients and endoscopy Mayo Score for week 30 in UC patients were also included when available.

Multivariable analysis and propensity score-matched analysis were performed to assess the above outcomes.


Patients on PPI were significantly less likely to achieve week 30 remission on multivariable analysis (OR 0.45, p<0.001). After propensity score matching adjusting for baseline differences in patient characteristics, patients on infliximab and PPI therapy continued to be significantly less likely to achieve week 30 remission compared with those without PPI use (30% vs 49%, p<0.001).

Analysing separately for disease, the findings remained statistically significant in CD but did not reach significance in UC. Similar results were seen with week 54 remission rates. Patients on PPI were also more likely to be hospitalised (15% vs 8%, p=0.007). Rates of adverse events such as gastroenteritis were not different between the two groups.


The investigators found that patients with IBD taking PPI were less likely to achieve remission while on infliximab therapy. The results of the study warrant further investigation into the effect of PPI on IBD outcomes and therapies.

Potential mechanisms for the decreased remission rates could include the alteration of the immune cell function and the gut dysbiosis mediated by the PPI treatment [7, 8]. It also remains unclear whether PPI use could be a risk factor for patients on a different class of biologic therapy such as anti-integrin therapy. This would be another area of further investigation.

The authors have admitted that their study has several limitations, such as the differences in the patients’ age, race and immunomodulator use at baseline, although this was addressed by performing multivariable analysis and baseline characteristic matching of the patients. Second, only a small subset of patients had indications for PPI prescription available and the most common indication for PPI prescription was GORD. The possibility that a small proportion of patients taking PPI may have had overlapping drug-induced microscopic colitis, which could in turn affect their clinical scores, cannot be excluded. Third, there is the inherent bias associated with analysing a different hypothesis than the original hypothesis of the clinical trials.


In conclusion, in this patient-level meta-analysis of randomised controlled studies, PPI use appeared as a risk factor for patients with IBD treated with infliximab. This association remained significant after controlling for confounders and was independent of the gastroenteritis risk. Further prospective studies are needed to validate these findings and explore potential underlying mechanisms.


  1. Lichtenstein GR, Loftus EV, Isaacs KL, et al. ACG clinical guideline: management of Crohn’s disease in adults. Am J Gastroenterol. 2018;113:481–517.
  2. Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG clinical guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019;114:384–413.
  3. Lu TX, Cohen RD. Maneuvering clinical pathways for Crohn’s disease. Curr Gastroenterol Rep. 2019;21:20.
  4. Ben-Horin S, Chowers Y. Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nat Rev Gastroenterol Hepatol. 2014;11:243–55.
  5. Strand DS, Kim D, Peura DA. 25 years of proton pump inhibitors: a comprehensive review. Gut Liver. 2017;11:27–37.
  6. Gawron AJ, Feinglass J, Pandolfino JE, et al. Brand name and generic proton pump inhibitor prescriptions in the United States: insights from the National ambulatory medical care survey (2006-2010). Gastroenterol Res Pract. 2015;2015:1–7.
  7. Alkim H, Unal S, Okur H, et al. Omeprazole inhibits natural killer cell functions. Dig Dis Sci. 2008;53:347–51.
  8. Bruno G, Zaccari P, Rocco G, et al. Proton pump inhibitors and dysbiosis: current knowledge and aspects to be clarified. World J Gastroenterol. 2019;25:2706–19.

Panagiotis Markopoulos - Short Biography

Panagiotis Markopoulos is a specialty doctor in gastroenterology, and currently a Senior Clinical Fellow in Inflammatory Bowel Disease at Guy's and St Thomas' Hospital in London. His areas of interest are IBD and endoscopy.

Posted in ECCO News, Y-ECCO Literature Reviews, Committee News, Y-ECCO, Volume 17, Issue 1