key: cord-0753660-tgfrfo8z
authors: Lev-Tzion, Raffi; Focht, Gili; Lujan, Rona; Mendelovici, Adi; Friss, Chagit; Greenfeld, Shira; Kariv, Revital; Ben-Tov, Amir; Matz, Eran; Nevo, Daniel; Barak-Corren, Yuval; Dotan, Iris; Turner, Dan
title: COVID-19 vaccine is effective in inflammatory bowel disease patients and is not associated with disease exacerbation
date: 2021-12-23
journal: Clin Gastroenterol Hepatol
DOI: 10.1016/j.cgh.2021.12.026
sha: 70820d76ad24ab6683258364bf5df534037111c2
doc_id: 753660
cord_uid: tgfrfo8z

Background Studies have shown decreased response to COVID-19 vaccinations in some populations. In addition, it is possible that vaccine-triggered immune activation could trigger immune-dysregulation and thus exacerbate inflammatory bowel diseases (IBD). In this population-based study we used the epi-Israeli IBD Research Nucleus (IIRN) validated cohort to explore the effectiveness of COVID-19 vaccination in IBD and to assess its effect on disease outcomes. Methods We included all IBD patients insured in two of the four Israeli health maintenance organizations (HMOs), covering 35% of the population. Patients receiving two Pfizer-BioNTech BNT162b2 vaccine doses between December 2020 to June 2021 were individually matched to non-IBD controls. To assess IBD outcomes, we matched vaccinated to unvaccinated IBD patients and response was analyzed per medical treatment. Results In total, 12,109 IBD patients received two vaccine doses, of whom 4,946 were matched to non-IBD controls (mean age 51±16 years and median follow-up 22 weeks (interquartile range [IQR], 4-24)). Fifteen patients in each group (0.3%) developed COVID-19 post vaccination (OR=1 [95%CI 0.49-2.05], P=1.0). Patients on tumor necrosis factor (TNF) inhibitors and/or corticosteroids did not have a higher incidence of infection. To explore IBD outcomes, 707 vaccinated IBD patients were compared to unvaccinated IBD patients by stringent matching (median follow-up, 14 weeks [IQR 2.3-20.4]). The risk of exacerbation was 29% in the vaccinated patients compared with 26% in unvaccinated patients (P=.3). Conclusions COVID-19 vaccine effectiveness in IBD patients is comparable to that in non-IBD controls and is not influenced by treatment with TNF inhibitors or corticosteroids. The IBD exacerbation rate did not differ between vaccinated and unvaccinated patients.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus has caused over 200 million confirmed cases of COVID-19 globally as of mid-2021 and more than 4.3 million deaths 1 . Mass vaccination is the most effective strategy for managing the pandemic. Various factors may interfere with host response to vaccination and potentially compromise vaccine effectiveness, including advanced age 2 and various types of immune suppression, such as immunosuppressive medications 3 . Indeed, decreased seroconversion rates to vaccines other than COVID-19 have been demonstrated in inflammatory bowel disease (IBD) patients treated with tumor necrosis factor (TNF) inhibitors [4] [5] [6] . Recent reports have suggested impaired serologic response to COVID-19 infection in patients treated with TNF inhibitors and immunomodulators 7 ; serologic response to vaccination has also been found to be impaired 8,9 . However, as most of these patients do seroconvert 10, 11 it is unclear whether this translates into higher infection rates 8, 12, 13 . Accordingly, concerns have been expressed as to whether the new COVID-19 vaccines are as effective in IBD patients, especially in those treated with immunosuppressive medications. One real-world study from Israel 14 and one prospective cohort study 9 have suggested similar effectiveness of the COVID-19 vaccine as in non-IBD subjects, but follow-up in these studies was short.

An additional concern is that immune activation due to COVID-19 vaccination would trigger IBD exacerbation. It is theoretically plausible that the immune activation initiated by COVID-19 vaccination might trigger IBD exacerbations through an immune-mediated dysregulation of the mucosal immune system. The effect of COVID-19 vaccination on IBD activity has only been assessed thus far for short follow-up periods (up to four weeks) 9, 12 . For routinely administered vaccines other than no vaccine has yet been demonstrated to cause IBD flares, but there are no controlled studies specifically exploring their effect on disease outcomes in IBD.

In the present population-based controlled study, we aimed to explore both the effectiveness of COVID-19 vaccination in preventing SARS-CoV-2 infection, specifically in patients treated with TNF inhibitors and corticosteroids, and its effect on IBD course. A portion of our data was included in the previous study by Ben-Tov et al 14 on vaccine effectiveness in IBD patients. Here, we added a second HMO, utilized more stringent matching, lengthened the follow-up period, and most importantly, explored the novel question of whether the vaccine influences IBD activity.

For this analysis, we excluded subjects who had confirmed SARS-CoV-2 infection or positive serology at any time prior to the second vaccine, and those who had received only one vaccine dose. Each vaccinated IBD patient was individually matched to a vaccinated non-IBD subject using the following variables: year of birth, sex, jurisdiction of residence, HMO, and dates of the first vaccination with a caliper of ±3 days.

A biased higher or lower response to vaccination may be a result of a different background infection rate between individuals with and without IBD. In order to explore this potential bias, we individually matched each unvaccinated IBD patient to a non-IBD unvaccinated control by year of birth, sex, jurisdiction of residence, and HMO. Comorbidities that according to the U.S. Centers for Disease Control and Prevention (CDC) may impact COVID-19 severity (Supp. Material -Appendix A) were compared between the matched groups to ensure balanced distribution.

To assess the influence of immunosuppressive medications on vaccine effectiveness, we performed a sub-analysis using propensity score matching to compare the SARS-CoV-2 infection rate among IBD patients treated with TNF inhibitors alone (infliximab, adalimumab, Table 1 ). These sub-groups categorize patients with heterogeneous available data in order to assist in accounting for disease severity.

In order to explore the impact of vaccination on IBD disease course, we matched vaccinated (two doses) to unvaccinated IBD patients by sex, jurisdiction of residence, IBD type (CD or UC), disease severity clusters based on blood work (as defined above), number of disease flares during the preceding two years (defined as any event of medication escalation, all-cause hospitalization, or steroid use), and age at IBD diagnosis (with a caliper of ± one year) (Supp. June 30, 2021. In the event that a control was vaccinated, he/she was converted to a case and was re-matched accordingly.

The outcome of IBD exacerbation was defined as treatment escalation, commencement of corticosteroids or enema, or hospitalization (Appendix C). In addition, a sensitivity analysis was performed using a narrow definition of commencement of corticosteroids only.

Variables are presented as mean ± standard deviation or median (interquartile range) for continuous and categorical variables respectively. Comparisons between groups were made by Student's t-test, Wilcoxon rank sum test, one-way ANOVA and   , as appropriate. Due to the large sample size, p-values are presented along with standardized mean differences (SMD), in which an SMD greater than.1 was considered meaningful. Odds ratios were calculated using the Haldane-Anscombe correction to express the association between the exposure (e.g. IBD patients vs. non-IBD patients) and the outcome (e.g. positive PCR test).

Time to positive SARS-CoV-2 PCR test and to IBD flares are presented using Kaplan-Meier survival curves and compared using the log-rank test with robust variance estimator 18 to account for the individual matching. Analyses were performed using R; p <.05 was considered significant. The study was approved by the local ethics committee. Figure 2 ).

Of the 536 vaccinated IBD patients receiving TNF inhibitors and/or corticosteroids at the time of vaccination, 2 (0.4%) had a positive SARS-CoV-2 PCR during the study period, compared to 36/11,573 (0.3%) vaccinated IBD patients who did not receive these medications (P=1.0).

Propensity score matching was successful for 502 pairs and showed similar infection rates (2/502 [0.4%] for TNF inhibitors/steroids vs. 0/502 for all others; P=.48; Figure 2 ).

In order to further reduce confounding, we compared patients on TNF inhibitors/corticosteroids to patients on any biologics other than TNF inhibitors in order to capture a group with likely greater disease severity, with similar results (2/536 [0.4%] for TNF inhibitors/steroids vs. 0/189 for all other biologics; P=.97; Figure 2 ). Finally, the latter groups were compared by propensity score after more stringent matching by a variety of IBD and demographic variables, including exact matching of IBD severity (Supp. Figure 3) . The 

For this analysis, 2,108 vaccinated IBD patients were matched to unvaccinated IBD patients by sex, jurisdiction of residence, IBD type (CD or UC) and disease severity according to bloodwork clusters. Median follow-up was 12 weeks (IQR 2.4-20.6). No difference in disease outcome was seen during the first 40 days after the second vaccination, but thereafter, time-to flare was shorter in vaccinated compared to unvaccinated IBD patients (Supp. Figure 4) . we found that the overall COVID-19 vaccine effectiveness was similar between IBD patients and matched non-IBD controls. Focusing on medical therapy, we found that patients on TNF inhibitors and/or corticosteroids did not have a higher SARS-CoV-2 infection rate, even after precise matching for demographics, underlying diseases and IBD severity.

Our initial comparison revealed that vaccination was associated with increased risk of IBD exacerbation from 40 days and onward, despite exact matching of demographics, laboratory markers of disease severity and number of exacerbations in the preceding two years.

However, when we included in the analysis the recentness of the last exacerbation prior to baseline, the difference was attenuated and was no longer significant. This underscores the challenge of accounting for disease severity in administrative databases and the importance of prospectively followed a group of 185 IBD patients after two doses of BNT162b2 vaccine and found that while all patients on anti-TNF medication seroconverted, antibody levels were significantly lower and neutralizing and inhibitory functions were similarly lower in this patient group. These studies raise concern for reduced durability of vaccine efficacy. Two recent serological studies, the PREVENT-COVID study and the CORALE-IBD study found that the large majority of IBD patients seroconverted, though levels in TNF-inhibitor patients were somewhat lower 10, 11 . Our findings support the notion that while post-vaccine antibody levels and function are both reduced in anti-TNF-treated patients, they are nonetheless sufficient to protect from infection for at least a 22-week median follow-up period.

Our findings support those of the two previous studies that addressed real-world COVID-19

vaccine effectiveness for preventing infection in patients on anti-TNF medication; neither study found increased COVID-19 incidence in these patients. However, Hadi et al 12 did not J o u r n a l P r e -p r o o f specify length of follow-up and Ben-Tov et al 14 followed the cohort for a median of 10 weeks.

In the current study, we have shown that vaccine effectiveness in IBD patients on TNF inhibitors and corticosteroids continues to be unimpaired for up to 22 weeks.

The strengths of our study include a large population-based cohort, as well as rigorous individual and propensity score matching in order to reduce the inevitable confounders inherent in retrospective research using observational data. As COVID-19 prevalence Our finding of higher COVID-19 incidence in unvaccinated IBD patients compared to unvaccinated individuals without IBD may stem from the fact that the IBD patients had a higher prevalence of a variety of underlying medical conditions than the non-IBD groupamong both unvaccinated as well as vaccinated individuals (Supp. Table 2 ). This finding serves to increase certainty that the low infection rate in vaccinated IBD patients was not biased by a lower background rate, and strengthens the significance of our finding that the vaccine protected IBD patients equally as well as those without IBD.

The main limitations of the study relate to its retrospective analysis of data obtained from an administrative database. It is possible that some hidden confounding variables were still not properly addressed and that some of the data were biased by misclassification. Nonetheless, J o u r n a l P r e -p r o o f case ascertainment of IBD in the epi-IIRN database is one of the most accurate globally and registration of medications and COVID-19-related data are very accurate by virtue of the function of the Israeli health care system. The low infection rates in vaccinated subjects limits our statistical power to prove equivalent effectiveness, but the fact that the infection rate was so low in a very large cohort clearly shows that the vaccine was highly effective in both groups, including those on anti-TNF therapy.

While the number of matched patients available for analysis was inevitably much lower than the number in the total cohort due to rigorous matching, comparison of the group that participated in the effectiveness analysis to the entire cohort revealed minimal differences in most demographic parameters (Supp. Table 4 ).

In conclusion, we found that COVID-19 BNT162b2 vaccine was equally effective in IBD patients and in the non-IBD population, including those on TNF inhibitors and corticosteroids, and likely did not increase the risk of IBD exacerbation. The former finding supports previous short-term follow-up data. The present study is the first large controlled study to address the latter conclusion using a broad definition of exacerbation and provides further reassurance regarding safety of the COVID-19 vaccine in IBD patients. J o u r n a l P r e -p r o o f + + + + + ++ + + + + + + + + + + + + + + ++ + + + + + + + + + + + + + + ++ ++ +++ ++ + +++ ++ + +++ ++ ++ ++ + + + ++ ++ + ++ + + ++ + + + + + + + + + + + + + + + + ++ ++ + + + ++ + + + + + + + + ++ ++ + + + + + + + + + + + ++ + + + + + + + + + + + + +++ + + + + + + + + ++ + + + + + + + + + + + + + + ++ + + + + + + + + + + + + + + ++ ++ +++ ++ + +++ ++ + +++ ++ ++ ++ + + + ++ ++ + ++ + + + + + + + + + + + + + + + + + + + ++ ++ + + + ++ + + + + + + + + ++ ++ + + + + + + + + + + + ++ + + + + + + + + + + + + +++ + + + While Pfizer COVID-19 vaccine is extremely effective at preventing infection, questions have arisen regarding its effectiveness in inflammatory bowel disease (IBD) patients on immunosuppressive medications. Additionally, its effect on IBD outcomes has not been assessed.

In a large population-based study, Pfizer COVID-19 vaccine was equally effective at preventing infection in IBD patients, including those on immunosuppressive medication, as in non-IBD subjects. Vaccinated IBD patients had no more disease exacerbations after vaccination than unvaccinated IBD patients.

The study is the first to demonstrate that the Pfizer COVID-19 vaccine provided excellent protection for IBD patients on immunosuppression for as long as 22 weeks, and that no worsening of IBD outcomes occurred after vaccination.

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