Letter to the editor - Letter to the editor regarding Influence of proton pump inhibitor use on clinical outcomes of patients with inflammatory bowel disease

Sep 30, 2026

Uploaded by Bulrr

Letter to the editor responding to an Annals of Medicine study on proton pump inhibitor (PPI) use and adverse clinical outcomes in patients with inflammatory bowel disease (IBD). The authors raise methodological concerns: PPI exposure derived only from outpatient prescription claims (missing OTC purchases), unclear temporal relationship between PPI initiation and IBD flare, and likely residual confounding from unmeasured lifestyle factors. They further note limitations of claims-based exposure, lack of inflammation markers, and constraints of dose-response assessment, urging validation with granular medication histories, objective disease-activity measures, and prospective follow-up before changing prescribing policies.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages2

Reading Time5 min

AccessFree to download

Letter to the editor

Key methodological concerns

PPI exposure definition and OTC omission

Temporal ambiguity between PPI initiation and flares

Residual confounding by lifestyle factors

Limitations of claims-based exposure measures

Dose–response assessment constraints

Summary and recommendations

Authors’ contributions and disclosures

AnnAls of Medicine 2026, Vol. 58, no. 1, 2607234 [https://doi.org/10.1080/07853890.2025.2607234](https://doi.org/10.1080/07853890.2025.2607234) LETTER TO THE EDITOR Letter to the editor regarding: “influence of proton pump inhibitor use on clinical outcomes of patients with inflammatory bowel disease” We read with interest the article by Choden et al. [1] . titled “Influence of proton pump inhibitor use on clinical outcomes of patients with inflammatory bowel disease”. The authors leveraged a large U.S. administrative database to show that concomitant proton-pump inhibitor (PPI) therapy is associated with treatment escalation (new biologic starts), IBD-related hospitalisation, and surgery. While the study adds useful real-world evidence, we would like to highlight several methodological issues that merit attention before these findings are translated into clinical practice. First, the definition of “PPI exposure” is based solely on outpatient prescription claims. Over-the-counter (OTC) PPI purchases are common in the United States and cannot be captured by MarketScan. OTC omeprazole or esomeprazole purchases would misclassify users as non-users, attenuating the true effect. Validation through patient interview or pharmacy reconciliation would be necessary to quantify this bias. Second, the temporal relation between PPI initiation and IBD flare remains ambiguous. The 2017–2018 MarketScan files document dispensing dates but not exact start/stop times, indication, or adherence. It is plausible—though not yet corroborated by prospective data—that at least a proportion of PPI prescriptions may have been written for prodromal upper-GI symptoms or for gastro-protection during corticosteroid courses. Without a time-varying exposure model that accounts for PPI starts in relation to disease activity, the observed associations may reflect confounding by indication rather than a causal harmful effect. Third, residual confounding by unmeasured lifestyle factors is likely. Smoking, obesity, and NSAID use are only partially captured via claims codes, and data on diet, alcohol, non-prescription NSAIDs, and disease phenotype (e.g. perianal Crohn’s, disease extent by Montreal classification) are absent. These variables simultaneously influence both PPI prescribing and IBD outcomes. Fourth, claims-based exposure definitions are intrinsically limited. MarketScan records outpatient pharmacy dispensings but not over-the-counter purchases, exact start/stop dates, pill consumption, or the clinical indication for each prescription. Consequently, some patients classified as “non-users” may have taken OTComeprazole, whereas dispensings recorded as “use” may represent brief, intermittent, or prophylactic courses. Similarly, the database lacks endoscopy scores, faecal calprotectin, C-reactive protein, or other markers of mucosal inflammation. Without these surrogates, we cannot tell whether PPI dispensing precedes true inflammation worsening. It may simply flag patients whose severe disease already prompts acid-suppressant prescribing and later escalation or hospitalisation These inherent constraints suggest that the observed associations may be attributable to confounding by indication rather than to a causal harmful effect of PPIson IBD activity. Finally, the dose–response analysis counts dispensed prescriptions only; dose (mg) and continuous duration were unavailable. One 30-day supply could reflect daily long-term use or brief intermittent courses. In the absence of cumulative DDD or PDC, the incremental risk attributed to ‘higher exposure’ warrants cautious interpretation. In summary, the study provides an important signal that PPI therapy may be associated with adverse IBD outcomes. We encourage the authors to validate their findings in cohorts with granular medication histories, objective disease-activity markers, and prospective follow-up before recommending restrictive PPI prescribing policies for patients with IBD. Ack

FAQs

How was PPI exposure defined in the referenced study, and what is the main concern?

PPI exposure was based on outpatient prescription claims only. The concern is that OTC PPI purchases common in the U.S. could lead to misclassification of users as non-users, biasing the effect estimate.

Why is the timing between PPI initiation and IBD flare considered problematic?

The available data capture dispensing dates but not exact start/stop times, indication, or adherence. The letter notes that PPI prescriptions may reflect prodromal symptoms or gastro-protection, so associations could reflect confounding by indication rather than causality.

What residual confounders might distort the observed associations?

Smoking, obesity, NSAID use, and other lifestyle and disease-phenotype variables are only partially captured by claims and key data such as diet, alcohol, non-prescription NSAIDs, and phenotype details are absent.

What additional evidence does the letter request before restricting PPI prescribing in IBD?

It encourages validation using cohorts with detailed medication histories, objective disease-activity and inflammation markers, and prospective follow-up rather than relying solely on claims-based proxies.

Sep 30, 2026

Uploaded by Bulrr