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Background: The efficacy and safety of risankizumab (RZB) in patients with Crohn's disease (CD) has been demonstrated.1,2 We reported that an additional 12 weeks (ie, induction period 2) of RZB therapy could induce clinical response in patients with CD who did not achieve clinical response after an initial 12-week induction period.3 In this post hoc analysis, we report the proportion of patients who achieved clinical response over 24 weeks (initial and delayed responders to RZB induction therapy). Method(s): Data were pooled from the ADVANCE and MOTIVATE phase 3 RZB studies. Patients who had not achieved stool frequency (SF)/abdominal pain score (APS) clinical response (>= 30% decrease in average daily SF and/or >= 30% decrease in average daily APS and both not worse than baseline) after an initial 12-week induction with intravenous (IV) RZB (600 mg or 1200 mg) at weeks 0, 4, and 8 were rerandomized 1:1:1 in induction period 2 to receive IV RZB 1200 mg (at weeks 12, 16, and 20) or subcutaneous (SC) RZB (180 mg or 360 mg at weeks 12 and 20) in a double-dummy-blinded fashion. In this post hoc analysis, efficacy was analysed in patients treated with either 600 mg RZB IV or placebo (PBO) for 12 weeks in the PBO-controlled induction period and patients who did not achieve clinical response with 600 mg RZB IV for 12 weeks and were rerandomized to 360 mg RZB SC every 8 weeks during induction period 2 (currently marketed RZB doses). SF/ APS clinical response was assessed at week 12 for initial responders and at week 24 for delayed responders in induction period 2. Nonresponder imputation with no special data handling for data missing due to COVID-19 was used. No multiplicity adjustment was performed. Result(s): Of the 889 patients randomised to 600 mg IV RZB or PBO in the induction studies, 70.0% (369/527) in the RZB group compared with 45.6% (165/362) in the PBO group achieved SF/APS clinical response at week 12. Of the 47 patients who did not achieve initial clinical response to 600 mg IV RZB and received 360 mg SC in induction period 2, 32 (68.1%) achieved delayed SF/APS clinical response at week 24. The proportion of patients achieving SF/APS clinical response over 24 weeks (either initial or delayed responders) was 89.1% (401/450). The safety profile of RZB in patients with CD has been reported.1,2 Conclusion(s): In patients with moderate-to-severe CD, RZB treatment leads to approximately 9 of 10 patients achieving either initial (600 mg IV) or delayed (600 mg IV followed by 360 mg SC) clinical response over 24 weeks.
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Background: Vaccines are pivotal for control of the ongoing coronavirus disease (COVID-19) pandemic. Patients with inflammatory bowel diseases (IBD) treated with anti-tumor necrosis factor (TNF)-alpha have lower serologic response after two COVID-19 vaccine doses. Data regarding a 3rd vaccine are scarce. Method(s): Aim: To assess immune responses to, and safety of COVID-19 vaccines in patients with IBD, stratified according to therapy, and compared to healthy controls (HC). Subjects were recruited before the 1st vaccine (BNT162b2, Pfizer) and prospectively evaluated after the 2nd and 3rd vaccine doses. Evaluation included: Disease activity, anti-spike (S) and nucleocapsid (N), anti-TNFalpha drug levels and adverse events (AE) Results: Of 198 subjects having the 3rd vaccine dose, 125 had IBD: average age: 39.1+/-14.8 years;40.8% females;82-Crohn's disease (CD), 33 ulcerative colitis (UC), 6 pouch, 3 IBD-U. There were 73 HC: average age 39.4+/-12.5 years, 69.9% females. Among patients with IBD: 51 and 74 (40.8%, 59.2%)) were treated or not with anti-TNFalpha, respectively. A month after the 3rd vaccine dose IBD activity was comparable in all patients regardless of treatment, and no increase in C-reactive protein or white blood cells was observed. Higher but not significant AE rate was registered in all subjects after the 3rd compared to 2nd vaccine dose (81% vs. 76%, respectively). AE rate in IBD and HC was comparable. No serious AE detected. There was a significant increase in anti-S levels one month after compared to pre 3rd vaccine dose in all participants. Furthermore, increase was 2-3 folds higher than that observed one month after the 2nd dose. Importantly, patients treated with anti-TNFalpha compared to non-anti-TNFalpha treated had significantly lower responses: 9219 (6347-13390) vs 16955 (13721-20951) (GMC (95%CI)), p<0.05. Serologic response did not correlate with anti-TNFalpha drug levels, antibodies or interval between drug and vaccine administration. During extended follow-up post 3rd dose, we found that lower serologic response predicts infection over time. Conclusion(s): This prospective study shows that a 3rd dose of BNT162b2 vaccine is effective and safe in patients with IBD. Furthermore, patients treated with anti-TNFalpha had significantly lower serologic responses compared to anti-TNFalpha untreated ones. Lack of correlation between anti-TNFalpha drug levels and immune responses suggests there is no need to modify vaccination timing relatively to anti-TNFalpha administration. The significantly steeper increase in anti-S levels between 2nd and 3rd doses, suggests the 3rd dose is crucial in anti-TNFalpha treated patients, specifically due to the fact that higher serologic response predicts better defense from infection.
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Introduction: Vaccines are pivotal for control of the ongoing coronavirus disease (COVID-19) pandemic. Patients with inflammatory bowel diseases (IBD) treated with anti-tumor necrosis factor (TNF)-alpha have significantly lower serologic response after two COVID-19 vaccine doses. Data regarding a 3rd vaccine are scarce. Aims & Methods: We conducted a prospective observational multi-center Israeli study aiming to assess immune responses to, and safety of mRNAbased COVID-19 vaccines in patients with IBD, stratified according to therapy, and compared to healthy controls (HC). Subjects were recruited before the 1st vaccine (BNT162b2, Pfizer) and were prospectively evaluated one and six months after the 2nd vaccine dose, as well as one month after the 3rd vaccine dose. Disease activity was assessed using accepted clinical scores and biomarkers. COVID-19 spike (S) and nucleocapsid (N) antibodies concentrations were analyzed using ELISA. Anti- TNFalpha drug levels were measured using ELISA. Adverse events (AE) were registered. Result(s): Of 198 subjects having the 3rd vaccine dose, 125 had IBD: average age: 39.1+/-14.8 years;40.8% females;82- Crohn's disease (CD), 33 ulcerative colitis (UC), 6 pouch, 3 IBD-U. There were 73 HC: average age 39.4+/-12.5 years, 69.9% females. IBD treatment: 51 (40.8%) patients were treated with anti-TNFalpha: monotherapy 35, concomitant immunomodulators 7, 5ASA 5, steroids 3 and ustekinumab 1. In 74 non-TNFalpha treated patients 5ASA were received by 19, vedolizumab 18, ustekinumab 9, immunomodulators 2, steroids 2, tofacitinib 4, no medication 19 patients. The 3rd vaccine dose was administered 201 (187-216) (median [IQR]) days after the 2nddose and 267 (250-278) days after the 1st dose. A month after the 3rd vaccine dose IBD activity was comparable in all patients regardless of treatment, and no increase in C-reactive protein or white blood cells was observed. Higher but not significant AE rate was registered in all subjects after the 3rd compared to 2nd vaccine dose (81% vs. 76%, respectively). AE proportion in IBD and HC was comparable, mostly local pain. No serious AE detected. Significant increase in anti-S levels one month after compared to pre 3rd vaccine dose was observed in IBD and HC. Furthermore, increase was 2-3 folds higher than that observed one month after the 2nd dose. Importantly, patients treated with anti-TNFalpha compared to non-anti-TNFalpha treated had significantly lower responses: 9219 (6347-13390) vs 16955 (13721- 20951) (GMC (95%CI)), p<0.05. Anti-N levels reflecting infection were positive in only 4 subjects- all with IBD, 2 treated with anti-TNFalpha, 1 ustekinumab, 1 untreated. Serologic response did not correlate with anti-TNFalpha drug levels, antibodies or interval between drug and vaccine administration (p=0.616, p=0.697 and p=0.6, respectively). Conclusion(s): In this prospective study we show that a 3rd dose of BNT162b2 vaccine is effective and safe in patients with IBD, however, patients treated with anti-TNFalpha had significantly lower serologic responses compared to anti-TNFalpha untreated ones. Lack of correlation between anti-TNFalpha drug levels and immune responses suggests there is no need to modify vaccination timing relatively to anti-TNFalpha administration. The significantly steeper increase in anti-S levels between 2nd and 3rd doses, suggests the 3rd dose is crucial in anti-TNFalpha treated patients. Their significantly lower anti-S levels compared to anti-TNFalpha untreated ones may suggest the advantage of a 4th vaccine dose.
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Background: While vaccines against COVID-19 are effective in healthy individuals, we reported significantly lower serologic responses to BNT162b2 in patients with inflammatory bowel diseases (IBD) treated with anti-tumor necrosis factor (TNF) α agents. As this was apparent already 4 weeks post vaccination, vaccine longevity is concerning. Aim: to assess long-term serologic responses to BNT162b2 in patients with IBD stratified according to medical treatment. Methods: A prospective, observational multi-center Israeli study. Patients with IBD (anti-TNFα treated versus non-anti-TNFα treated) and healthy controls (HC) were followed from before the 1st BNT162b2 dose until 6 months after vaccination. COVID-19 spike (S) and nucleocapsid (N) antibodies (Abs) concentrations were analyzed by ELISA, followed by neutralization studies. Specific anti-receptor binding domain (RBD) memory Bcells response, serologic responses against variants of concern (VOCs), Beta, Gamma and Delta, immunoglobulin levels and lymphocyte cell subsets were evaluated as well. Safety was assessed using questionnaires, clinical and laboratory data. Results: Of 193 subjects, 130 had IBD (45 and 85 in the anti-TNFa and non-anti-TNFα groups, respectively), 63 HC. Serologic response assessed 176 (median) days (IQR 166-186) and compared to 4 weeks after 1st dose significantly declined in all three groups, but was lowest in the anti- TNFα group: 6 months anti-S Abs titer geometric means: 193 (95%CI: 128-292), 703 (520- 951), and 1253 (1023-1534) in anti-TNFα, non- anti-TNFα and HC groups, respectively, p<0.001, Figure 1. This was further supported by neutralization and inhibition studies. Importantly, significantly decreased memory B-cell response towards RBD was detected only in the anti-TNFα group, with the most significant reduction in response to Beta VOC (p<0.0008 and p<0.0001, vs. non-anti-TNFα and HC, respectively). Older age was an additional predictor of lower serologic response. Immunoglobulin levels and lymphocyte cell subsets were comparable between the study groups. Infection rate reflected by anti-N Abs was ~1% in all groups. Safety was comparable in all groups. Conclusion: The 6-months serologic response to BNT162b2 vaccine, evaluated prospectively, decreased in all subjects, most prominently in patients with IBD treated with anti-TNFα. Importantly, the latter also had the sharpest decline in serologies, the lowest functional activity and lowest RBD specific memory B-cells. Older age is an additional predictor of decreased serologic response. Altogether, waning of COVID-19 serologic and functional response over 6 months, specifically in patients with IBD treated with anti-TNFα, supports the need for an early third vaccine dose. (Figure Presented)
ABSTRACT
Background: While vaccines against COVID-19 are effective in healthy individuals, we reported significantly lower serologic responses to BNT162b2 in patients with inflammatory bowel diseases (IBD) treated with anti-tumor necrosis factor (TNF) α agents. As this was apparent already, 4 weeks post vaccination, vaccine longevity is concerning. Aim: to assess long-term serologic responses to BNT162b2 in patients with IBD stratified according to medical treatment. Methods: A prospective, observational multi-center Israeli study. Patients with IBD (anti-TNFα treated versus non-anti-TNFα treated) and healthy controls (HC) were followed from before the, 1st BNT162b2 dose until, 6 months after vaccination. COVID-19 spike (S) and nucleocapsid (N) antibodies (Abs) concentrations were analyzed by ELISA, followed by neutralization studies. Specific anti-receptor binding domain (RBD) memory B-cells response, serologic responses against variants of concern (VOCs), Beta, Gamma and Delta, immunoglobulin levels and lymphocyte cell subsets were evaluated as well. Safety was assessed using questionnaires, clinical and laboratory data. Results: Of, 193 subjects, 130 had IBD (45 and, 85 in the anti-TNFα and non-anti-TNFα groups, respectively), 63 HC. Serologic response assessed, 176 (median) days (IQR, 166-186) and compared to, 4 weeks after, 1st dose significantly declined in all three groups, but was lowest in the anti- TNFα group:, 6 months anti-S Abs titer geometric means:, 193 (95%CI:, 128-292), 703 (520-951), and, 1253 (1023-1534) in anti-TNFα, nonanti- TNFα and HC groups, respectively, p<0.001, Figure, 1. This was further supported by neutralization and inhibition studies. Importantly, significantly decreased memory B-cell response towards RBD was detected only in the anti-TNFα group, with the most significant reduction in response to Beta VOC (p<0.0008 and p<0.0001, vs. non-anti-TNFα and HC, respectively). Older age was an additional predictor of lower serologic response. Immunoglobulin levels and lymphocyte cell subsets were comparable between the study groups. Infection rate reflected by anti-N Abs was ∼1% in all groups. Safety was comparable in all groups. Conclusion: The, 6-months serologic response to BNT162b2 vaccine, evaluated prospectively, decreased in all subjects, most prominently in patients with IBD treated with anti-TNFα. Importantly, the latter also had the sharpest decline in serologies, the lowest functional activity and lowest RBD specific memory B-cells. Older age is an additional predictor of decreased serologic response. Altogether, waning of COVID- 19 serologic and functional response over, 6 months, specifically in patients with IBD treated with anti-TNFα, supports the need for an early third vaccine dose. (Figure Presented).
ABSTRACT
Background: While short-term safety data of COVID-19 vaccination has been reassuring, it is theoretically possible that the vaccineassociated immune activation could trigger immune dysregulation and thus exacerbation of IBD. We used the epi-Israeli IBD Research Nucleus (IIRN) database to perform a population-based study exploring the effect of COVID-19 vaccination on disease course in IBD patients. Methods: We included all IBD patients insured in two of the four Israeli HMOs, covering 35% of the population, by validated algorithms, and selected those who received two doses of Pfizer BNT162b2 vaccine. These were matched to unvaccinated IBD patients by demographics, parameters of disease severity at baseline generated by hierarchical clustering of laboratory data, and length of time from previous exacerbation to baseline. The primary outcome was rate of IBD exacerbation as defined by proxies of hospitalizations, treatment escalation, and commencement of corticosteroid or enema. The study period was December, 2020 to June, 2021 Results: 707 pairs of vaccinated and unvaccinated IBD patients were compared. The pairs matched exactly for gender, district, IBD type and disease severity, and ±1 year for age at IBD diagnosis and at vaccination. Mean age was 38.5±13.5 years and median follow-up was 98 days (IQR 16-143). No difference in the outcome was found between the groups from the 2nd vaccination to the end of follow-up, with risk of exacerbation in vaccinated patients of 29% and risk in unvaccinated patients 26% (p=0.3). Conclusion: COVID-19 vaccinated IBD patients demonstrated a rate of IBD exacerbation following vaccination that was no different from that of unvaccinated patients. The multifaceted immune activation induced by the vaccine did not result in worsening IBD disease course. These results provide further reassurance for IBD patients receiving the vaccine.
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Background: Some studies have shown decreased serological response to vaccination in patients on anti-tumor necrosis factor (TNF) medications. While the large majority of these patients do seroconvert after vaccination, titers have generally been lower and one study showed reduced neutralizing and inhibitory functions. One real-world population- based study compared found no increased infection rate in anti- TNF treated patients, but infection rates were low. The low event rate mandates exploration in longer-term population-based data. We used the epi-Israeli IBD Research Nucleus (IIRN) database to explore the effectiveness of COVID-19 vaccination in IBD patients in Israel. Methods: We included all IBD patients insured in two of the four Israeli HMOs, covering 35% of the population, by validated algorithms, and selected those who received two doses of Pfizer BNT162b2 vaccine. These were matched by date of vaccination ±3 days and demographic variables to non-IBD controls. The primary outcome was incidence of positive COVID-19 PCR following vaccination between December, 2020 to June, 2021. Results: 12,640 IBD patients received two vaccine doses;the matched cohort included 4,946 matched pairs (total 9,892 subjects). Mean age was 50.5±16.1 years and median follow-up was 22 weeks (range 4.1-24.4). Fifteen (0.3%) vaccinated IBD patients tested positive compared with 15 (0.3%) vaccinated non-IBD controls (OR=1 [95%CI 0.49-2.05], p=1.0). Patients on anti-TNF and/or corticosteroids did not have a higher incidence of positivity - neither compared to the entire group nor to IBD patients treated with vedolizumab/ustekinumab, even after precise matching for demographics, underlying diseases and IBD severity. Conclusion: In a large population-based cohort of IBD patients in Israel, vaccine effectiveness was equivalent to non-IBD controls and was not influenced by treatment with anti-TNF or corticosteroids. Notwithstanding previous findings of impaired serological response in anti-TNF treated IBD patients, this real-world large-scale study shows that vaccine protection is robust in IBD patients, including those on immunosuppressive medications.