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Use of proton pump inhibitors increases the risk of calcium pyrophosphate deposition (CPPD) in a population-based study


Tuhina Neogi, Christine Peloquin, Robert Terkeltaub, David Felson



Boston University School of Medicine, University of California - San Diego



Background : The most commonly recognized clinical presentation of calcium pyrophosphate deposition (CPPD) is that of acute CPP crystal arthritis, previously known as pseudogout. CPPD is also the most common cause of chondrocalcinosis. There are no therapies available that specifically target CPPD, with treatment primarily limited to symptomatic management. Identifying and optimizing key risk factors may offer a means of lessening the burden of CPPD. Hypomagnesemia has been recognized as one such risk factor for CPPD, and its treatment has been advocated by EULAR for CPPD management. Proton pump inhibitors (PPIs) are an under-appreciated cause of hypomagnesemia, and therefore PPIs may be an important under-recognized risk factor for CPPD. We examined the relation of PPI use to the development of CPPD in older adults.

Methods: We conducted a nested case-control study in The Health Improvement Network (THIN), a general practitioner (GP) electronic medical records database representative of the general UK population. We identified incident cases of individuals diagnosed with pseudogout or chondrocalcinosis (hereafter referred to as the EULAR-preferred umbrella term of CPPD) using READ codes from the years 2000-2015 among those aged 50-89 who were enrolled in a GP practice in the year prior to study entry, and matched them by age, sex, and study entry year with 4 controls using risk-set sampling. We identified incident use of PPIs among the cases at any time prior to their diagnosis date (index date) as well as within one year prior to their index date, and did the same for controls, who were randomly assigned the index date of their matched case. We excluded subjects with a diagnosis of gout. We examined the relation of incident PPI use to the risk of incident CPPD using conditional logistic regression, stratified by the age- and sex-matched set, adjusting for BMI, alcohol use, chronic kidney disease, congestive heart failure, hypertension, diabetes, hyperparathyroidism, and diuretics (loop, thiazide, potassium-sparing). To examine what is more likely to be clinically relevant, we also conducted a sensitivity analysis limited to cases of incident pseudogout (i.e., excluding those with chondrocalcinosis only).

Results: We identified 2036 incident cases of CPPD who were matched to 8144 controls.
The mean age of the cases and controls was 72.5, mean BMI was 26.7, and 55% were female. Incident PPI use at any time prior to the index date was associated with a 1.9-times higher odds of incident CPPD than no PPI use (adjusted OR 1.89, 95% CI 1.69-2.11). When we examined incident PPI use restricted to within one year prior to the index date, the results were similar (adjusted OR 1.87, 95% CI 1.66-2.10). When limited to incident cases of pseudogout, the results were similar: for incident PPI use any time prior to the index date, the adjusted OR was 1.91 (95% CI 1.64-2.22); for incident PPI use within one year prior to the index date, the adjusted OR was 1.99 (95% CI 1.69-2.33).

Conclusions: In this population-based study of physician-recorded CPPD, incident use of PPIs was associated with an increased risk of developing CPPD, including the clinically relevant diagnosis of “pseudogout”. Since there are very few treatment and preventive options available for CPPD and the use of PPIs is common and widespread, avoiding unnecessary use of PPIs may be of clinical benefit to patients with CPPD.