Among commercially-insured RA patients, we found a low rate of hospitalized GIP, which occurred at a rate of 1.12 (95% CI 0.50–2.49) per 1,000 patient-years among individuals who were current users of biologics and oral glucocorticoids. Oral glucocorticoid use was an independently-associated risk factor for GIP, as was diverticulitis (recognized prior to the event). Indeed, 70% of GIP cases had one or both of these two risk factors.
Our results are informative in comparison with the recently reported rates of GIP in the tocilizumab development program, which occurred at a rate of 2.8 (95% CI 1.9–4.1) per 1,000 person-years (1
). Similar to our findings, a majority of the tocilizumab-associated GIP cases (24 of 26, or 91%) occurred in the lower GI tract. Little data regarding GIP is available from other clinical trials of other biologics, although this outcome has been observed in patients on anti-TNF therapies(8
)and from observational studies of RA patients not on biologics (9
). The clinical importance of events that are in the range of 1–3 per 1,000 person-years is debatable; by way of comparison, the rates of hospitalized infections is in the range of 5 per 100 years in most RA cohorts and registries (10
). However, prior research suggests that in counseling patients regarding the side effect profile of new medications, fear regarding even very rare events is often judged as important and may impact treatment decisions if the events are serious and unfamiliar (11
Several observational studies provide additional context for our results. A synthesis of 12 studies conducted both in the U.S. and internationally found that, compared to our rates for RA patients, the incidence of GIP was lower in the general population and occurred at a rate of 0.1 (95% CI 0.04–0.23) per 1,000 person years (13
). The rate of diverticular perforations is even lower (14
). Another co-occurring event that sometimes accompanies GIP is GI bleeding; studies that have estimated both bleeding and perforation have found one case of GIP for every six to nine cases of GI bleeding (13
). In fact, many studies do not report rates of GIP separately and instead group perforation with the more common GI bleeding events (15
). NSAIDs appear to be more strongly related to upper GI events compared to lower GI events (16
). We found that a majority of the perforation events in our RA population were of the lower GI tract rather than the upper GI tract. A decreasing trend for upper GI bleeding and perforation and an increasing trend for lower GI events has been previously observed and hypothesized to be related to changing patterns of NSAID use, GI prophylaxis with agents such as proton pump inhibitors, eradication of H. pylori infection, and other factors (16
). Also concordant with our findings, a prior study that evaluated a combined endpoint of hospitalization for GI bleeding or perforation found that the strongest risk factors for these outcomes were glucocorticoid use (incidence rate ratio [IRR] = 3.1, 95% CI 2.1 – 4.8) and age (IRR = 1.4 per 10 years, 95% CI 1.2–1.8) (17
The strengths of our study include a large cohort of RA patients treated in real world settings, and the size of the database allowed us to study this relatively uncommon adverse event. Our GIP case definition has been previously-validated against medical record review and has been shown to have very high validity, with a PPV of 94%. Despite these strengths, a few limitations must be recognized. Despite the fact that all outcome events occurred during a hospitalization, commercial administrative data sources typically do not allow for ascertainment of out-of-hospital deaths, which limits understanding of mortality associated with GIP. Previous studies have suggested it is high, up to 24% (14
). Because of small numbers of events, we were not able to quantify risk associated with individual biologic agents or non-biologic DMARDs other than MTX. We also did not include in our case definition for GI perforation surgeries for diverticulitis (unless also accompanied by a perforation diagnosis); some of these might have been for acute GI perforation events. Finally, medical records were not available for this analysis. Our claims-based algorithm for GI perforations was supported by a validation study, but we recognize that administrative data provides limited clinical information and thus may misclassify events. Our sensitivity analysis that added inpatient physician diagnoses suggests that the event rates reported in our primary results are conservative, and the actual event rates may be up to 20–30% higher.
In conclusion, our results provide context in evaluating the rates and risk factors for GIP in future safety studies of RA medications. Patients who are not glucocorticoid users nor who have diverticulitis appear to be at very low risk for this event.