ABSTRACT
Background: The effects of immunosuppressive medications on immune responses to COVID-19 vaccination in patients with inflammatory bowel diseases (IBD) have been reported. However there is little data on immune responses in naturally infected SARS-CoV-2 patients compared with vaccination. We compared in a longitudinal study SARS-CoV-2 antibody and T cell responses in naturally-infected vs. vaccinated IBD patients Methods: 110 IBD patients enrolled at the Icahn School of Medicine at Mount Sinai were prospectively followed with serial blood collection between May 2020, and February 2022. Samples were screened by ELISA to determine seropositivity, and stratified by infection, vaccination status, and IBD medications. Subsequently, ELISA-based inhibition assay and pseudotyped SARS-CoV-2 microneutralization assays were used to determine the inhibition and neutralization capacity of the seropositive individuals for wild type (WT) delta variant (Dv) and Omicron. Cellular responses were measured by IFN-gamma ELIspot using nucleocapsid and spike peptide libraries Results: Overall, 64 patients had Crohn's Disease and 46 had Ulcerative Colitis (UC), 69 were naturally infected. Only Anti-TNF (N=52), Ustekinumab (N=16), and Vedolizumab (VDZ) (N=33) treatment groups were considered. Only US-available vaccinations were included. Double-vaccinated IBD patients showed greater neutralizing responses to SARS-CoV-2 WT and Dv than naturally-infected individuals (p=0.0003, p=0.0025). Moreover, double-vaccinated individuals had greater neutralizing reactions against WT than DV (p 0.017) and Omicron (p 0.001) variants. Following natural infection, there were no differences between treatment groups in neutralization response, however those double-vaccinated on anti-TNF had lower neutralization than VDZ (p=0.008). Neutralization responses were maintained for a period of 8 months following natural infection and double vaccination SARS-CoV-2 spike T cell responses were significantly higher in naturally infected (p=0.009) and double vaccinated individuals (p=0.005) with no significant differences between treatment groups (p<0.999) Conclusion(s): After a second vaccine dose, IBD patients showed stronger neutralizing antibody titers than naturally infected patients. Those on anti-TNF exhibited lower neutralizing responses than VDZ. T-cell responses were similar in infected and double-vaccinated subjects after vaccination or infection. These data imply COVID-19 immunization provides additional serological protection over natural infection.
ABSTRACT
Introduction Treatment of perianal fistulizing Crohn's disease (PFCD) is a major unmet need. Filgotinib (FIL) is a oncedaily, oral, preferential JAK1 inhibitor in development as a CD treatment. The efficacy and safety of FIL for the treatment of PFCD was evaluated in the phase 2, double-blind, randomized, placebo (PBO)-controlled DIVERGENCE2 study (NCT03077412). Methods Patients 18-75years with PFCD (documented diagnosis of CD for >3months and 1-3 external openings [EOs] with drainage [spontaneous or on compression] for ≥4weeks before screening) previously treated with antibiotics, immunomodulators and/or TNFi were randomized (2:2:1) to receive FIL 200mg, 100mg or PBO once daily for <24weeks. Active luminal CD was permitted providing that CDAI score was ≤300 at screening. The primary endpoint was combined fistula response (reduction of ≥1 from baseline in the number of draining EOs determined by investigator assessment and no fluid collections 1cm on centrally read pelvic MRI) at Week24. Combined fistula remission (closure of all draining EOs present at baseline and no fluid collections >1cm) at Week24 was a key secondary endpoint. The study was not powered for statistical comparisons and was prematurely terminated owing to low recruitment rates during the COVID-19 pandemic. Results Baseline characteristics were broadly similar across treatment groups. Overall, 91% (52/57) patients had complex perianal fistulae;TNFi treatment had previously failed in 65% (37/57) patients. A lower proportion of patients randomized to FIL200mg than PBO discontinued the study. The proportion of patients who achieved a combined fistula response at Week24 was numerically higher in the FIL200mg than the PBO group (Figure 1a), with similar results observed for combined fistula remission (Figure 1b). Treatment-emergent severe AEs were highest in the FIL200mg group. AE rates were otherwise similar across groups. Conclusion In this phase 2 study, numerically higher fistula response and remission rates were observed after 24weeks of treatment with FIL200mg vs PBO in patients with active PFCD and a history of multiple medical treatment failures. FIL was well tolerated. Further studies of FIL for PFCD treatment are warranted.
ABSTRACT
Background IBD patients on immune-modulatory therapies are considered high-risk for SARS-CoV-2 infection. Direct comparisons of serological responses to SARS-CoV-2 infection in IBD patients across different continents and medications are lacking. We performed SARS-CoV-2 sero-surveillance of IBD patients prior to vaccination at seven large tertiary centres in Asia, Europe, and North America. Methods Clinical data and sera were collected from, 2,213 IBD patients receiving routine care at institutions in Belgium, Canada, Hong Kong, India, Japan, the United Kingdom, and the United States between, 26 May, 2020 and, 24 September, 2021 (Table, 1). Sera were taken prior to vaccination. Clinical data were collected through patient questionnaires and medical records. Antibody reactivity to the SARS-CoV-2 spike protein was assessed using the Roche SARS-CoV-2 anti-spike total antibody and/or Siemens Healthineers COV2T anti-spike total antibody assays, which showed, 99.4% concordance. Univariate analysis was performed to evaluate association between individual variables and sero-status. Results The pre-vaccination seroprevalence of antibodies to SARS-CoV-2 in IBD patient varied widely according to location from, 0% in Hong Kong to, 57.9% in New Delhi, India (p<0.001). Rates in Europe and North America were similar (range, 3.57%-8.94%). Overall, SARS-CoV-2 seroprevalence appears to be equal to or less than local populations (Table, 2). Seroprevalence rates were associated with IBD type (7.8% CD, 12.4% UC, 15% IBD-U, p<0.001), smoking status (p<0.001), and history of COVID diagnosis (p<0.001) or COVID hospitalization (p=0.001), and any IMM (p<0.001). (Table, 3). Whilst there were no significant differences in seroprevalence between patients receiving infliximab (IFX), vedolizumab (VDZ), and ustekinumab (UST), antibody levels were attenuated in patients on IFX monotherapy and combination therapy (both p=0.002) and VDZ (p=0.02), compared with no medications (Figure 1). Conclusion We confirm in diverse poulations that exposure to biologics or immunomodulators, type of disease, and smoking status are associated with seroprevalence and antibody levels. We show for the first time the dominant influence of geographical location on sero-status in these patients. These observations should be considered as we look towards post-vaccination data to help stratify patients for clinical guidelines on SARS-CoV-2 vaccination.
ABSTRACT
Background: IBD patients on immune-modulatory therapies are considered high-risk for SARS-CoV-2 infection. Direct comparisons of serological responses to SARS-CoV-2 infection in IBD patients across different continents and medications are lacking. We performed SARSCoV- 2 sero-surveillance of IBD patients prior to vaccination at seven large tertiary centres in Asia, Europe, and North America. Methods: Clinical data and sera were collected from 2,241 IBD patients receiving routine care at institutions in Belgium, Canada, Hong Kong, India, Japan, United Kingdom, and the United States between May 2020 and September 2021 (Table 1). Sera were taken prior to vaccination. Clinical data were collected from patient questionnaires and medical records. Antibody reactivity to the SARS-CoV-2 spike protein was assessed using the Roche SARS-CoV-2 anti-spike total antibody and/or Siemens Healthineers COV2T anti-spike total antibody assays, which showed 99.4% concordance. We performed univariate analysis to evaluate association between variables and sero-status. Results: The pre-vaccination seroprevalence of antibodies to SARS-CoV-2 in IBD patient varied widely according to location from 0% in Hong Kong, China, to 57.9% in New Delhi, India. Rates in Europe and North America were similar (range 3.6%-8.9%). Overall, SARSCoV- 2 seroprevalence appears to be equal to or less than local populations (Table 1). Seroprevalence rates were associated with IBD type (Crohn's disease 7.8%, ulcerative colitis 12.4%, IBD-unclassified 15.0%, p<0.001), smoking status (p<0.001), and history of COVID diagnosis (p<0.001) or COVID hospitalization (p=0.001), and any immunomodulator (IMM) (p<0.001) (Table 1). Infection as indicated by seropositivity in the absence of known COVID infection occurred in 7.3% of patients. Whilst there were no significant differences in seroprevalence between patients receiving anti-tumor necrosis factor (anti-TNF) medications, vedolizumab (VDZ), and ustekinumab (UST), antibody levels were attenuated in patients on anti-TNF monotherapy (p=0.002), anti-TNF + IMM combination therapy (p=0.002), and VDZ (p=0.02), compared with no medications (Figure 1). Conclusion: We confirm in diverse populations that exposure to anti-TNFs, vedolizumab and immunomodulators, type of disease, and smoking status are associated with seroprevalence and antibody levels. We show for the first time the dominant influence of geographical location on sero-status in these patients. These observations should be considered as we look towards post-vaccination data to help stratify patients for clinical guidelines on SARS-CoV-2 vaccination. (Table Presented) Table 1. Seroprevalence of total anti-SARS-CoV-2 spike antibodies in IBD patients by ICARUS centre with non-IBD controls noted for New Delhi, India, and publicly reported local seroprevalence and by selected patient characteristics.(Figure Presented) Figure 1. Antibody levels by medication group.
ABSTRACT
Background: An association between shorter disease duration and improved clinical efficacy has been shown in post hoc analyses of clinical trial data with biological therapies in Crohn’s disease (CD). The efficacy and safety of risankizumab (RZB) as induction and maintenance therapy have been recently reported.1,2 Here, the efficacy of RZB stratified by baseline CD duration is reported. Methods: In ADVANCE (NCT03105128) and MOTIVATE (NCT03104413), patients with moderately to severely active CD received intravenous (IV) RZB induction therapy or placebo (PBO) for 12 weeks. Patients with clinical response to RZB IV induction were re-randomised in a 52-week maintenance study (FORTIFY NCT03105102) to receive subcutaneous (SC) RZB or PBO (ie, withdrawal). For this posthoc analysis, patient subgroups were stratified by years of CD duration at baseline (< 2, 2– 5, > 5–10, and > 10 years). Induction analyses focused on patients who received RZB 600 mg IV or PBO for 12 weeks. As all patients who entered maintenance responded to RZB IV induction, maintenance analyses were limited to those patients who responded to induction and then received RZB 360 mg SC for 52 weeks. Clinical and endoscopic outcomes were evaluated using nonresponder imputation incorporating multiple imputation to handle missing data due to impact of the COVID-19 pandemic. Safety was assessed throughout the studies. Results: The induction and maintenance analyses included 527 patients who received RZB 600 mg IV and 141 patients who received RZB 360 mg SC, respectively. At the end of induction (week 12), patients with CD duration of < 2 years achieved higher rates of endoscopic outcomes with IV RZB induction vs patients with longer durations of disease (Figure 1), and regardless of baseline CD duration, greater proportions of RZB-treated patients achieved clinical remission (defined by stool frequency and abdominal pain), endoscopic response, endoscopic remission, and ulcer-free endoscopy vs PBO (P ≤ .05). Clinical remission rates at week 12 were numerically higher in patients with CD duration of < 5 years vs > 5 years (Figure 1). Similar results for improved clinical and endoscopic outcomes associated with shorter disease duration were observed at week 52 with RZB 360 mg SC maintenance treatment (Figure 2). RZB was well tolerated with lower rates of serious adverse events and serious infections vs PBO in induction, across CD duration subgroups. Conclusions: RZB induction and maintenance therapy was effective and well tolerated with a safety profile generally similar across CD duration subgroups. Achievement of clinical and endoscopic endpoints were higher in patients with shorter duration of CD, suggesting that earlier introduction of RZB therapy may lead to improved outcomes.
ABSTRACT
Background Coronavirus disease 2019 (COVID-19) can increase the risk of thrombosis, cardiovascular events, and kidney injury, but risks among patients with inflammatory bowel disease (IBD) remain unknown. We aimed to characterize risk for these complications among patients with IBD who developed COVID-19. Methods We analyzed complications of COVID-19 in patients reported to the Surveillance Epidemiology of Coronavirus Under Research Exclusion in Inflammatory Bowel Disease (SECURE-IBD) database prior to November 15, 2021. Our primary outcome was a composite of thrombotic complications (peripheral venous thrombosis, pulmonary embolism, thrombotic stroke, and peripheral arterial thrombosis), cardiovascular complications (new arrhythmia, heart failure, myocarditis/pericarditis, and vasculitis), and renal complications (acute kidney injury). Covariates included cardiovascular disease (including stroke), cardiovascular risk factors (diabetes mellitus, hypertension, or smoking), pulmonary disease (asthma, chronic obstructive pulmonary disease, or other chronic lung disease), thrombotic risk conditions (cancer), chronic kidney disease, chronic liver disease, “other” comorbidities, and COVID-19 vaccination with at least one dose. Multivariable analyses assessed the independent effect of variables significant in univariate analyses. Results Among 4,923 patients reported to SECURE-IBD, 79 (1.6%) had thrombotic, cardiovascular, and/or renal complications. There were 45 (0.9%) reports of acute kidney injury, 24 (0.5%) of arrythmias, 8 (0.2%) of peripheral venous thrombosis, 5 (0.1%) each of heart failure, myocarditis/pericarditis, and pulmonary embolism, and 1 (0.02%) each of vasculitis, peripheral atrial thrombosis, and thrombotic stroke. In univariate analyses, complications were more common in patients who were older (p < 0.01), black (p < 0.01), and on corticosteroids (p < 0.01) (Table 1). Patients with severe IBD were more likely to have complications than patients in remission (p < 0.01), as were those with more comorbidities (p < 0.01). Cardiovascular disease, cardiovascular risk factors, pulmonary disease, and chronic renal disease were associated with increased risk (p < 0.01 each). There was no association with vaccination status (p = 1). In multivariate analyses, age (aOR 1.04 [1.03, 1.06]), black race (aOR 4.02 [1.53, 10.55]), severe IBD (aOR 3.21 [1.31, 7.86]), corticosteroid use (aOR 3.63 [1.85, 7.12]), and one (aOR 2.33 [1.10, 4.91]), two (aOR 4.24 [1.42, 12.65]), and three or more (aOR 13.36 [3.48, 51.32]) comorbidities were significant predictors of complications (Table 2). Discussion Thrombotic, cardiovascular, and renal complications from COVID-19 were uncommon among patients with IBD. Patients with older age, black race, corticosteroid use, severe IBD, and greater number of comorbidities may require closer monitoring if they develop COVID-19. (Table Presented)
ABSTRACT
Background: Several SARS-CoV-2 vaccines are highly effective in preventing most infections, serious disease, hospitalization, and death from COVID-19 in the general population, but data regarding their use and efficacy in patients with inflammatory bowel disease (IBD) are limited. In this study we assessed the use patterns and efficacy of SARS-CoV-2 vaccines in patients with IBD. Methods: We established a multicenter matched case-control cohort of patients with IBD [Crohn's disease (CD), ulcerative colitis (UC)] and COVID-19 between February 2020 and December 2020 for the Surveillance of COVID-19 Impact on Long- Term Outcomes in IBD (SCOUT IBD) study. Cases were defined by the presence of COVID- 19-related symptoms and confirmatory SARS-CoV-2 PCR or IgG testing and non-COVID controls were defined as absence of symptoms and both a negative PCR and IgG in 2020. Cases were matched 1:1 to controls based on age, sex and IBD type. Data were collected on vaccine administration in 2021 and incidence of interval COVID-19 (defined as above) between January and September 2021. Results: The total cohort included 502 patients with IBD [UC (n=222, 44%), CD (n=278, 55%), IBD-undefined (n=2, 1%)] of whom 251 had a history of COVID-19 in 2020. The overall vaccination rate was 61% (n=306) with 189 (62%) patients receiving Pfizer-BioNTech, 101 (33%) Moderna, and 12 (4%) Johnson & Johnson. Vaccinated patients were more likely to be older (P=0.02), female (P=0.07), have a co-morbidity (cardiovascular, respiratory, renal) (P=0.04), or currently be on a biologic (P=0.01), and less likely to have had prior COVID-19 (P<0.001) than patients who did not get vaccinated (Table 1). The overall incidence of interval COVID-19 was 1.6% (N=8), with an infection rate of 0.3% (1/311) in vaccinated patients vs. 3.7% (7/184) in unvaccinated patients (P<0.01). Of infections occurring in unvaccinated patients, 1/7 (14.2%) was severe and required hospitalization requiring ICU admission, and the breakthrough infection in the vaccinated patient was mild and self-limited. COVID-19 reinfection occurred in one patient (0.4%) with prior COVID-19 who was unvaccinated. Under multivariable logistic regression, COVID-19 vaccination (aOR 0.05, 95% CI 0.01-0.41) and prior COVID-19 infection (OR 0.07, 95% CI 0.01-0.63) were highly protective against interval COVID-19. Conclusion: COVID-19 vaccines are effective in patients with IBD and markedly reduce the incidence of COVID-19. Prior COVID-19 is also protective against subsequent infection, although re-infections may occur at a very low rate. These results reaffirm the importance of COVID-19 vaccination in patients with IBD.(Table Presented)(Table Presented)
ABSTRACT
Background: Inflammatory bowel disease (IBD) and IBD-related biologic therapies are not associated with worse outcomes of Coronavirus Disease 2019 (COVID-19), however, data are lacking regarding the long-term impact of COVID-19 and its inflammatory sequelae on the disease course of IBD. We aimed to investigate the long-term outcomes of patients with IBD and COVID-19. Methods: We performed a multicenter matched case-control study of patients with IBD [Crohn's disease (CD), ulcerative colitis (UC)] and COVID-19 between February 2020 and December 2020 at 5 large health systems. Cases were defined by the presence of COVID-19-related symptoms and confirmatory SARS-CoV-2 PCR or IgG testing. Non-COVID controls were defined as absence of symptoms and both a negative PCR and IgG during the study entry period. Cases were matched 1:1 to controls based on age, sex and IBD type. The primary composite outcome was IBD-related hospitalization or surgery, and outcomes were sub-stratified by COVID-19 severity. Results: We identified 251 cases with IBD [UC (n=111, 44%), CD (n=139, 55%)] and confirmed COVID-19, matched with 251 non-COVID-19 IBD controls, with a median follow-up of 394 days. COVID-19 patients had higher rates of prior IBD-related hospitalizations (36% vs. 27%;P=0.03), corticosteroid use (75% vs. 65%;P=0.06), and biologic exposure (73% vs. 64%;P=0.04) than controls. There were no differences in UC extent or CD phenotype between groups. In COVID-19 positive patients, the most common symptoms were fever (61%), cough (48%), fatigue (30%) and diarrhea (28%). Severe COVID-19 (defined as hospitalization, ICU requirement or mechanical ventilation) occurred in 16% (n=39) of cases. The primary composite outcome of IBD-related hospitalization or surgery occurred in 12% (n=38) of cases vs. 15% (n=29) of controls (P=0.24;Table 1). When further stratified by COVID-19 severity, the incidence of the primary composite outcome was highest in patients with severe COVID-19, followed by controls and non-severe COVID-19 (Figure 1). Under multivariate Cox regression, severe COVID-19 remained a predictor of worse IBD outcomes (aHR 2.09, 95% CI 0.91-4.86) whereas non-severe COVID-19 was associated with decreased risk (aHR 0.52, 95% CI 0.28- 0.99). Prior IBD-related hospitalization or surgery (aHR 3.10, 95% CI 1.70-6.57) and current steroid use (aHR 2.17, 95% CI 0.95-4.94) were also predictive of worse IBD outcomes. Conclusion: In this matched case-control study, a history of any COVID-19 infection did not appear to exacerbate the course of IBD, however, severe COVID-19 was associated with worse IBD outcomes. These data suggest that the inflammatory sequelae of COVID-19 may adversely impact the subsequent disease course of IBD. Further studies are required to confirm these associations, which underscore the importance of COVID-19 mitigation measures.(Table Presented) (Figure Presented)
ABSTRACT
Introduction: Ozanimod, a sphingosine 1-phosphate (S1P) receptor S1P1 and S1P5 modulator, is approved in the United States for moderately to severely active ulcerative colitis (UC) and in multiple countries for relapsing multiple sclerosis (MS). We describe COVID-19 outcomes in ozanimod-treated UC or MS patients in active phase 3 open-label extension studies. Methods: A database search identified COVID-19 infection reports in ozanimodtreated patients with UC in the True North open-label extension and MS in the DAYBREAK open-label extension. The analysis period was November 1, 2019 to either August 31, 2021 (UC) or May 10, 2021 (MS). The last COVID-19 event from all patients with ³1 event was analyzed. Results: Among 2792 ozanimod-treated patients with UC or MS, 258 developed COVID-19 (confirmed: 215);thus, the incidence in these clinical trial settings was 9.2% during the analysis periods. Most patients with confirmed cases (193/215 [89.8%]) had nonserious infections not requiring hospitalization or meeting other International Conference on Harmonisation criteria for a serious event. Of 611 ozanimod-treated patients with UC, 68 (11.1%) developed COVID-19 (confirmed: 55;Figure 1). A majority of UC patients with confirmed cases (45/55 [81.8%]) had nonserious COVID-19;most (54/55 [98.2%]) recovered (2 with sequalae) and 1 was recovering at data cutoff. One UC patient with confirmed COVID-19 discontinued ozanimod (1.8%), 23 temporarily interrupted it (41.8%), and 31 had no change to treatment (56.4%). No COVID-19-related deaths were reported in UC patients. Of 2181 ozanimod-treated pts with MS, 190 (8.7%) developed COVID-19 (confirmed: 160;Figure 2). Most MS patients with confirmed COVID-19 (148/160 [92.5%]) had nonserious cases;most (158/160 [98.8%]) recovered (5 with sequelae) (Figure 1). No MS patients with confirmed cases discontinued ozanimod, 61 temporarily interrupted it (38.1%), and 99 had no change to treatment (61.9%). Outcomes in 13 additional UC patients (Figure 1) and 30 additional MS patients (Figure 2) with suspected COVID-19 were similar to those with confirmed cases. There were 3 COVID-19-related deaths in the MS program. Conclusion: In the UC and MS open-label extension studies, most patients with confirmed COVID-19 had nonserious infections, recovered, and did not require ozanimod discontinuation. There were 3 deaths in MS patients (case-fatality rate 1.6% in MS, 1.2% overall). (Figure Presented)(Figure Presented)
ABSTRACT
Introduction: More adverse clinical outcomes following SARS-CoV-2 infection are reported in patients treated with infliximab/thiopurines (IFX/THIO), compared with biological monotherapy with anti-TNF or vedolizumab (VDZ). VDZ has been associated with a heightened and more durable serological response after infection and vaccination, compared to IFX. However, whether IBD patients on VDZ have a fully intact systemic response to SARS- CoV2 remains unknown. We explored the serological and functional neutralizing response after SARS-CoV-2 infection in IBD patients treated with VDZ, IFX or IFX/THIO compared to true healthy controls to guide treatment decisions and vaccination strategies. Methods: Serum from 640 IBD patients attending routine infusions in Oxford and London (May to December 2020) was screened by the Abbott assay for SARS-CoV-2 nucleocapsid (N) antibodies. Serum from seropositive patients was compared to seropositive health care workers (Table 1). Antibody reactivity to the SARS-CoV-2 wild type (WT) strain receptor-binding domain (RBD), full-length spike, and N was assayed by IgG/IgA ELISA over time as well as by IgG MSD V-PLEX ELISA at the time of seropositivity. A pseudotyped SARS-CoV-2 virus microneutralization assay was used to detect neutralizing antibodies to the WT, and an ELISA-based inhibition assay to compare differential inhibition of the WT vs. delta variant (DV) SARS-CoV-2 RBD-ACE2 interaction. Results: All IBD patients showed significantly reduced IgG antibody responses compared to healthy controls to all SARS-CoV-2 antigens, using MSD V-PLEX (Figure 1A-C). The greatest reduction in IgG response by ELISA was observed in patients treated with IFX/THIO (p=0.00019), whereas IgG response over time declined significantly faster in the IFX treated group (p=0.019). IgA responses were significantly reduced in the IFX/THIO group compared to healthy controls (p=0.009), but not in the IFX or VDZ group. The rate of decline in these monotherapy groups was not significantly different to healthy controls. Compared to healthy controls, functional SARS-CoV-2 neutralization was reduced in each treatment group (Figure 1D), with the greatest effect in patients receiving IFX/THIO (p=0.00000091). Neutralizing capacity to the DV was significantly reduced in 68.1% of IBD patients (30/44, p=0.0005). Conclusion: Both IFX and VDZ are associated with significantly reduced IgG responses to multiple SARS-CoV-2 antigens, and with impaired functional SARS-CoV-2 neutralizing antibody capacity, compared to healthy individuals. However, whilst IgG and neutralization responses are reduced in IBD patients on biological monotherapy, these findings were most pronounced in the combination treatment group. As neutralizing antibody responses are associated with protection, these observations may impact on decision-making regarding treatment and vaccination strategies.(Table Presented)(Figure Presented)
ABSTRACT
Background: Coronavirus disease 2019 (COVID-19) tends to cause mild disease in children, although severe disease occurs rarely. Children with inflammatory bowel disease (IBD) often receive immunosuppressive medications that may increase risk of infectious complications. Little is known about the severity of breakthrough infection after COVID-19 vaccination in children with IBD. We describe COVID-19 outcomes among children with IBD, including those with breakthrough infection. Methods: The Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) is a database created to evaluate COVID-19 outcomes in IBD patients. We included children (age ≤18) from the SECURE-IBD database through November 17th, 2021. We used descriptive statistics to summarize demographic/disease characteristics of the study population, both overall and stratified by hospitalization status, and performed bivariate comparisons. We reported demographic and clinical details of patients requiring an intensive care unit stay and those with breakthrough infection (defined as ≥1 COVID-19 vaccination prior to infection), respectively. Results: We analyzed 606 pediatric IBD COVID-19 cases from 37 countries. The most common IBD medications were tumor necrosis factor (TNF) antagonist monotherapy (48%) and sulfasalazine/ mesalamine (20%). Most patients (85%) had no non-IBD comorbidities. No patients died, and 28 children (5%) were hospitalized. Factors associated with hospitalization included non-IBD comorbid conditions (43% hospitalized vs 13% not;p <0.01), moderate/severe IBD disease activity (61% vs 15%;p <0.01 overall), gastrointestinal symptoms (68% vs 16%, p <0.01), and steroid use (29% vs 6%, p <0.01). TNF antagonist monotherapy was associated with a decreased likelihood of hospitalization (29% vs 49%;p value 0.03) (Table 1). Seven patients needed intensive care, and three (0.5%) required mechanical ventilation (Table 2). There were nine fully vaccinated and five partially vaccinated patients who developed breakthrough infection, of whom only one required hospitalization but did not need a ventilator (Table 3). The majority of patients with breakthrough infection (13/14) were on systemic immunosuppressants at the time of COVID-19 infection (10/14 on TNF antagonists). Conclusion: We found that children with IBD have a relatively low risk of severe COVID-19 outcomes. Among children with IBD who developed COVID-19 after vaccination, the majority were on immunosuppressants and had mild disease that did not require hospitalization. These data may reassure families and providers of children with IBD during the COVID-19 pandemic and support public health recommendations for COVID-19 vaccination among eligible children with IBD.
ABSTRACT
Background: Ozanimod, a sphingosine 1-phosphate (S1P) receptor S1P1 and S1P5 modulator, is approved in the United States for moderately to severely active ulcerative colitis (UC) and in multiple countries for relapsing multiple sclerosis (MS). We describe COVID-19 outcomes in ozanimod-treated UC or MS patients (pts) in active phase 3 openlabel extension (OLE) studies. Methods: A database search identified COVID-19 infection reports in ozanimod-treated pts with UC in the True North OLE and MS in the DAYBREAK OLE. The analysis period was November 1, 2019 to either August 31, 2021 (UC) or May 10, 2021 (MS). The last COVID-19 event from all pts with ≥1 event was analyzed. Results: Among 2792 ozanimod-treated pts with UC or MS, 258 developed COVID-19 (confirmed: 215);thus, the incidence in these clinical trial settings was 9.2% during the analysis periods. Most pts with confirmed cases (193/215 [89.8%]) had nonserious infections not requiring hospitalization or meeting other International Conference on Harmonisation criteria for a serious event. Of 611 ozanimod-treated pts with UC, 68 (11.1%) developed COVID-19 (confirmed: 55;Fig 1). A majority of UC pts with confirmed cases (45/55 [81.8%]) had nonserious COVID-19;most (54/55 [98.2%]) recovered (2 with sequalae) and 1 was recovering at data cutoff. One UC pt with confirmed COVID-19 discontinued ozanimod (1.8%), 23 temporarily interrupted it (41.8%), and 31 had no change to treatment (56.4%). No COVID-19-related deaths were reported in UC pts. Of 2181 ozanimod-treated pts with MS, 190 (8.7%) developed COVID-19 (confirmed: 160;Fig 2). Most MS pts with confirmed COVID-19 (148/160 [92.5%]) had nonserious cases;most (158/160 [98.8%]) recovered (5 with sequelae) (Fig 1). No MS pts with confirmed cases discontinued ozanimod, 61 temporarily interrupted it (38.1%), and 99 had no change to treatment (61.9%). Outcomes in 13 additional UC pts (Fig 1) and 30 additional MS pts (Fig 2) with suspected COVID-19 were similar to those with confirmed cases. There were 3 COVID-19-related deaths in the MS program. One pt died from a presumed pulmonary embolism;this pt had received high-dose corticosteroids for MS relapse immediately before COVID-19 symptom onset. Another pt died from suspected COVID-19-related respiratory failure. One tetraplegic, cachectic pt died from a lung abscess following COVID-19 infection. Conclusion: In the UC and MS OLE studies, most pts with confirmed COVID-19 had nonserious infections, recovered, and did not require ozanimod discontinuation. There were 3 deaths in MS patients (casefatality rate 1.6% in MS, 1.2% overall).
ABSTRACT
Background: Recent data have highlighted adverse clinical outcomes in IBD patients treated with infliximab/thiopurines (IFX/ THIO) upon infection with SARS-CoV-2, as well as attenuated serological responses after infection and vaccination in patients treated with IFX. To provide mechanistic insight, we explored the serological and functional anti-viral response after infection in IBD patients treated with VDZ, IFX or IFX/THIO compared to healthy controls to guide clinical decision-making regarding treatment and vaccination strategies. Methods: Serum from 640 IBD patients attending routine infusions in Oxford and London in May to December 2020 was screened for anti-SARS-CoV-2 antibody responses by the Abbott assay. Serum from seropositive patients was compared to seropositive health care workers (Table 1). Antibody reactivity to the SARS-CoV-2 wild type strain receptor-binding domain (RBD), full-length spike, and nucleocapsid was assayed by IgG/IgA ELISA over time as well as by IgG high-throughput MSD V-PLEX ELISA at the time of seropositivity. A pseudotyped SARS-CoV-2 virus microneutralization assay was used to detect neutralising antibodies to the wild type, and an ELISA-based inhibition assay to compare differential inhibition of the wild type vs. delta variant SARS-CoV-2 RBD-ACE2 interaction. Results: All IBD patients showed significantly reduced IgG antibody responses compared to healthy controls for all SARS-CoV-2 antigens, using MSD V-PLEX ELISA (Figure 1). The greatest reduction in IgG response by ELISA was observed in individuals treated with IFX/THIO (p=0.00019), whereas IgG response over time declined significantly faster in the IFX treated group (p=0.019). IgA responses were significantly reduced in the IFX/THIO group compared to healthy controls (p=0.009), but not in the IFX or VDZ monotherapy group. The rate of decline in these monotherapy groups was also not significantly different to healthy controls. Functional SARS-CoV-2 neutralisation was significantly lower in all IBD patients compared to healthy controls, with the greatest reduction in patients receiving IFX/THIO (Figure 2A;p=0.00000091). The delta variant inhibition capacity was significantly reduced in 68.1% of IBD patients (30/44, Figure 2B;p=0.0005). Conclusion: IFX/THIO is associated with significantly lower IgA and IgG responses, and with impaired functional SARS-CoV-2 neutralising antibody capacity, compared to healthy individuals. Whilst IgG and neutralisation responses are reduced in each group of IBD patients, these findings were most pronounced in the combination treatment group. As neutralising antibody responses are associated with protection, this observation may impact on decision-making regarding treatment and vaccination/antiviral strategies.
ABSTRACT
Background: An association between shorter disease duration and improved clinical efficacy has been shown in post hoc analyses of clinical trial data with biological therapies in Crohn's disease (CD). The efficacy and safety of risankizumab (RZB) as induction and maintenance therapy have been recently reported. Here, the efficacy of RZB stratified by baseline CD duration is reported. Methods: In ADVANCE (NCT03105128) and MOTIVATE (NCT03104413), patients with moderately to severely active CD received intravenous (IV) RZB induction therapy or placebo (PBO) for 12 weeks. Patients with clinical response to RZB IV induction were re-randomised in a 52-week maintenance study (FORTIFY, NCT03105102) to receive subcutaneous (SC) RZB or PBO (ie, withdrawal). For this post-hoc analysis, patient subgroups were stratified by years of CD duration at baseline (< 2, 2-5, > 5-10, and > 10 years). Induction analyses focused on patients who received RZB 600 mg IV or PBO for 12 weeks. As all patients who entered maintenance responded to RZB IV induction, maintenance analyses were limited to those patients who responded to induction and then received RZB 360 mg SC for 52 weeks. Clinical and endoscopic outcomes were evaluated using nonresponder imputation incorporating multiple imputation to handle missing data due to impact of the COVID-19 pandemic. Safety was assessed throughout the studies. Results: The induction and maintenance analyses included 527 patients who received RZB 600 mg IV and 141 patients who received RZB 360 mg SC, respectively. At the end of induction (week 12), patients with CD duration of < 2 years achieved higher rates of endoscopic outcomes with IV RZB induction vs patients with longer durations of disease (Figure 1), and regardless of baseline CD duration, greater proportions of RZB-treated patients achieved clinical remission (defined by stool frequency and abdominal pain), endoscopic response, endoscopic remission, and ulcer-free endoscopy vs PBO (P ≤ .05). Clinical remission rates at week 12 were numerically higher in patients with CD duration of < 5 years vs > 5 years (Figure 1). Similar results for improved clinical and endoscopic outcomes associated with shorter disease duration were observed at week 52 with RZB 360 mg SC maintenance treatment (Figure 2). RZB was well tolerated with lower rates of serious adverse events and serious infections vs PBO in induction, across CD duration subgroups. Conclusion: RZB induction and maintenance therapy was effective and well tolerated with a safety profile generally similar across CD duration subgroups. Achievement of clinical and endoscopic endpoints were higher in patients with shorter duration of CD, suggesting that earlier introduction of RZB therapy may lead to improved outcomes.
ABSTRACT
Background: Treatment of perianal fistulizing Crohn's disease (PFCD) is a major unmet need. Filgotinib (FIL) is a once-daily, oral, preferential Janus kinase 1 inhibitor in development for the treatment of inflammatory bowel diseases. The efficacy and safety of FIL for the treatment of PFCD was evaluated in the phase 2, double-blind, randomized, placebo (PBO)-controlled DIVERGENCE 2 study (NCT03077412). Methods: Patients (18-75 years old) with PFCD (documented diagnosis of CD for at least 3 months and 1-3 external openings [EOs] with drainage [spontaneous or on compression] for ≥ 4 weeks before screening) previously treated with antibiotics, immunomodulators and/or tumour necrosis factor inhibitors (TNFi) were randomized (2:2:1) to receive FIL 200 mg, FIL 100 mg or PBO once daily for up to 24 weeks. Active luminal CD was permitted providing that the Crohn's Disease Activity Index score was ≤ 300 at screening. The primary endpoint was combined fistula response (reduction of ≥ 1 from baseline in the number of draining EOs determined by investigator assessment and no fluid collections > 1 cm on centrally read pelvic magnetic resonance imaging [MRI]) at Week 24. Combined fistula remission (closure of all draining EOs present at baseline and no fluid collections > 1 cm) at Week 24 was a key secondary endpoint. The study was not powered for statistical comparisons and was prematurely terminated owing to low recruitment rates during the COVID-19 pandemic. Results: Baseline characteristics were broadly similar across the treatment groups (Table 1). Overall, 91.2% of patients had complex perianal fistulae and TNFi treatment had previously failed in 64.9% of patients. A lower proportion of patients randomized to receive FIL 200 mg discontinued the study compared with those who received PBO (Table 2). The proportion of patients who achieved a combined fistula response at Week 24 was numerically higher in the FIL 200 mg group (47.1%;90% confidence interval [CI]: 26.0-68.9) than in the PBO group (25.0%;90% CI: 7.2-52.7) (Figure 1), with similar results observed for combined fistula remission (FIL 200 mg [47.1%;CI: 26.0-68.9] versus PBO [16.7%;CI: 3.0-43.8]) (Figure 2). Treatment-emergent severe adverse events were highest in the FIL 200 mg group (Table 2). Adverse event rates were otherwise similar across treatment groups. Conclusion: In this phase 2 study, numerically higher fistula response and remission rates were observed after 24 weeks of treatment with FIL 200 mg versus PBO in patients with active PFCD and a history of multiple medical treatment failures. FIL was well tolerated overall. Further studies of FIL for the treatment of PFCD are warranted.
ABSTRACT
Background: Coronavirus disease 2019 (COVID-19) can cause gastrointestinal (GI) symp-toms, which may be associated with improved outcomes. There are limited data on COVID-19 and GI symptoms among inflammatory bowel disease (IBD) patients. We aimed to describe new GI symptoms and their association with clinical outcomes in IBD patients with COVID-19.Methods: We utilized data from the Surveillance of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD), an international, collaborative registry of IBD patients with confirmed COVID-19. Any new GI symptoms during the time of COVID-19 infection were recorded. We performed descriptive statistics and bivariate analyses to characterize patients with and without new GI symptoms. We also performed a sensitivity analysis of new GI symptoms comparing patients in remission versus those not in remission by physician global assessment. Multivariable logistic regression assessed independent associ-ation of any new GI symptoms with the odds of death due to COVID-19 adjusting for age, sex, race, number of comorbidities, baseline corticosteroid use, and tumor necrosis factor (TNF) antagonist use.Results: Of 2,917 IBD patients with COVID-19, 764 (26.2%) experienced new GI symptoms. The most commonly reported new GI symptom was diarrhea (Table 1). IBD was noted to be in remission in 382 (50%) patients at time of COVID-19 infection. New GI symptoms were common (23.3%) among IBD patients in remission though were more frequently observed in patients with active disease (29.4%). Patients with new GI symptoms were more likely to be older, female, have active disease, of Asian race, and have at least one co-morbidity (Table 2). Patients on any medication, in particular TNF antagonist monotherapy, were less likely to report new GI symptoms. On bivariate analyses, IBD patients with new GI symptoms were more likely to be hospitalized (31.4% vs. 19.2%, p<0.001) but were not more likely to require intensive care/ventilator (5.8% vs. 4.6%, p=0.18) or die due to COVID-19 (2.0% vs 2.5%, p=0.39). On multivariable analysis, new GI symptoms were not significanlty associated with risk of death due to COVID-19 (adjusted OR 0.72, 95% CI 0.38-1.36).Conclusion: New GI symptoms are common among IBD patients with COVID-19. Diarrhea was the most predominant symptom. Patients in remission and those with active disease both frequently reported new GI symptoms. While IBD patients with new GI symptoms were more likely to be hospitalized, they were not more likely to die due to COVID-19.(Table Presented)Table 1. Description of Gastrointestinal (GI) Symptoms Among IBD Patients with COVID-19. New GI symptoms reported among all patients and stratified by disease activity at time of COVID-19 infection.(Table Presented)
ABSTRACT
Background: Risk calculators can be an important tool for enabling shared decision making between patients and their health care providers. Demographics, comorbidities, medication use, geographic region, and other factors may increase the risk for complications from COVID-patients with inflammatory bowel disease (IBD). We developed a prognostic risk prediction tool for estimating the probability of hospitalization, intensive care unit (ICU) admission, and death due to COVID-19 in patients with IBD. Methods: Based on reports to Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) from March to October 2020, we modeled the probability of Hospitalization+ (a composite outcome of hospitalization, ICU and/or death), ICU+ (a composite outcome of ICU admission, intubation, and/or death) and Death separately using the Least Absolute Shrinkage and Selection set consisting of a random sample of cases reported between March 2020 and a pre-set cutoff date. Model validation was conducted using a test data set consisting of the remaining cases not in the training data plus all additional cases from one month past the cutoff date. We assessed the resulting models' discrimination using the area under the curve (AUC) of the receiver-operator characteristic (ROC) curves and corresponding 95% confidence intervals. Results: Overall, 2709 cases from 59 countries were included (mean age 41.3 years (s.d. 633 (24%) were hospitalized, 137 (5%) were admitted to ICU or intubated, and 69 (3%) died. The models have excellent discrimination, with an AUC and associated 95% confidence interval estimated on the test data set of 0.79 (0.75, 0.83) for Hospitalization+, 0.88 (0.82, 0.95) for ICU+, and 0.95 (0.91, 0.99) for Death. Age, comorbidities, corticosteroid use, and male sex were associated with higher risk of death while use of biologic therapies was associated with a lower risk of death (Figure 1). The online risk calculator is free and publicly available at https://covidibd.org/covid-19-riskcalculator/ for health care providers to facilitate discussion of the risk from COVID-19 with their IBD patients (Figure 2). After the physician inputs patient information, the prediction tool numerically and visually summarizes the patient’s probabilities of adverse outcomes intervals. Conclusion: Prognostic models can effectively predict who is at higher risk for COVID-19-related adverse outcomes in a population of IBD patients. The risk calculator could provide a basis for distinguishing between high and low-risk patients to aid in personalizing clinical guidance.
ABSTRACT
Background: Comorbidities Increase The Risk Covid-19 Morbidity And Mortality. As Comorbidities Are Common In Patients With Inflammatory Bowel Diseases (Ibd), We Sought To Evaluate The Effect Of Comorbidities On Covid-19 Outcomes Among Ibd Patients. Methods: Data Were Obtained From Surveillance Epidemiology Of Coronavirus Under Research Exclusion For Inflammatory Bowel Disease (Secure-Ibd), An International Registry To Determine Characteristics And Outcomes Of Covid-19 In Ibd Patients. We Used Multivariable Regression To Analyze Associations Between Eleven Non-Ibd Comorbidities And Covid-19-Related Hospitalization Or Death. We First Modeled Each Comorbidity Individually, Adjusting Potential Confounders Such As Age, Gender, Race, Ethnicity And Medication Use. Then, To Determine The Independent Effects Of Each Comorbidity, We Fit A Model Including All Comorbidities As Covariates. Results: 2,035 Patients From 58 Countries Were Included (Mean Age Was 42.7 Years, 50.6% Male). A Total Of 538 Patients (26.4%) Experienced Covid-19-Related Hospitalization Or Death. Of Eleven Comorbidities Analyzed, All But A History Of Stroke And Obesity Were Associated With Hospitalization Or Death In Our Initial Analysis, With Adjusted Odds Ratio (Aor) Ranging From 1.9 (Asthma And Cardiovascular Disease) To 3.7 (Chronic Kidney Disease). After Adjusting For Age, Sex, Medications, And Comorbidites Found To Significantly Influence Severe Covid-19 In The Initial Analysis, The Independent Associations For Most Comorbidities Remained Significant And Were Strongest For Chronic Kidney Disease (Aor 3.02, 95% Ci 1.45-6.31) And Chronic Obstructive Pulmonary Disease (Copd) (Aor 2.92, 95% Ci 1.32-6.48) (Table 1). Conclusion: Comorbidities Are Associated With Covid-19 Hospitalization And Death Among Ibd Patients. These Data Can Be Used To Risk-Stratify Ibd Patients And Guide Treatment And Lifestyle Decisions During The Ongoing Pandemic. (Table Presented) Independent Effects Of Individual Comorbidities On The Risk Of Hospitalization Or Death From Covid-19 In Patients With Inflammatory Bowel Diseases