ABSTRACT
Background: With the ongoing SARS-CoV-2 pandemic there is concern for development of Long COVID in patients with immune-mediated diseases treated with immunosuppressive agents. We aimed to determine the incidence of Long COVID among Inflammatory Bowel Disease (IBD) patients and to identify associated risk factors. Our study also aimed at studying the differences in risk of Long COVID among different IBD medication exposures. Method(s): We conducted a retrospective cohort study utilizing a nationwide cohort of patients with IBD in the Veteran Affairs Healthcare System (VAHS). Patients diagnosed with SARS-COV-2 between March 10th, 2020, and January 24th, 2021, were included. All charts were reviewed to determine recent IBD hospitalization, hospitalization for SARS-CoV-2 infection, and stability of IBD control pre and post infection. COVID-19 hospitalizations were also reviewed for intensive care unit requirement (ICU). COVID-19 treatments including remdesivir, monoclonal antibody infusions, and corticosteroids were also ascertained. Primary outcome was development of Long COVID. Cox regression analysis was used to identify variables associated with Long COVID. Result(s): A total of 677 patients with SARS-CoV-2 infection were included, of which 49 (7.3%) were diagnosed with Long COVID (Table 1). No significant differences in IBD medication class between patients with and without Long COVID diagnoses were noted. In multivariable regression analysis, COVID-19 hospitalization (HR 3.56, 95% CI 1.80-7.09, p<0.001), ICU requirement (HR 2.20, 95% CI 1.18-4.08, p=0.01), and COPD (HR 2.41, 95% CI 1.03-5.64, p=0.04) were significantly associated with Long COVID (Table 2). Adjusted survival curves showed that relative to patients who were not hospitalized, patients hospitalized in the ICU had an 8.61-fold increased hazard of Long COVID (HR 8.61, 95% CI 3.98-18.65, p<0.001) (Figure 1). Conclusion(s): Hospitalization and ICU care for COVID-19, as well as pre-existing COPD, were associated with increased risk of developing Long COVID, suggesting that severity of infection with a vulnerable substrate are key drivers of risk. Medications used in the treatment of IBD did not impact the risk of Long COVID. These findings should help reassure and inform IBD patients about the risk of Long COVID.
ABSTRACT
Background: Little is known about the duration of humoral antibody levels after two SARS-CoV-2 mRNA vaccinations in patients with immunosuppression. During this ongoing global epidemic, it is of essential interest to gather information about the time of protection after initial immunization in the vulnerable patients receiving either conventional synthetic disease modifying antirheumatic drugs (csDMARD) or biological/targeted drugs (b/tsDMARDs). Objectives: In this study we compared the antibody level development after vaccination and after six months in patients with infammatory arthritis, infammatory bowel disease (IBD) and healthy controls. Furthermore, we assessed factors affecting the quality and quantity of the humoral response. Methods: We enrolled 85 healthy controls (HC), 75 patients with rheumatoid arthritis and spondyloarthritis and 41 patients suffering from IBD. Patients treated with B-cell depleting therapies were excluded from this study. Binding antibody units were measured after vaccination and 6 or more months. Neutralizing antibodies were measured after 6 months. Multivariate regression analyses analyzing factors associated with low titers after 6 months was performed. Results: We found that patients with infammatory arthritis or IBD showed reduced anti-SARS-CoV-2 S titers compared to HC. When we stratifed for therapies, we found that patients receiving conventional synthetic disease modifying antirheumatic dugs (csDMARDs) had comparable anti-SARS-CoV-2 S titers to HC. In contrast, patients receiving biological or targeted synthetic (b/tsDMARDs) showed reduced anti-SARS-CoV-2 Igs as well as neutralizing antibody titers compared with healthy controls (HC) or patients receiving conventional synthetic (cs)DMARDs. We further show that anti-SARS-CoV-2 titers declined more rapidly in patients receiving b/tsDMARDs compared to HC, leading to a 50 percent reduction in vaccination-associated protection time in patients receiving b/tsD-MARDs when compared to those receiving csDMARDs or even HC. In multi-variate regression analyses, we found that in addition to the type of treatment, also age as well as corticosteroid use were associated with reduced anti-SARS-CoV-2 S titers. Conclusion: Patients under ongoing b/tsDMARDs therapy exposed an accelerated waning of anti-SARS-CoV-2 S titers and therefore decreased immunity and protection against severe Covid-19 infections over time. These results may lead to more personalized approaches for further vaccination strategies in this group of immunosuppressed patients.
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 Immunosuppressive and biological medications are a mainstay in the treatment of immune-mediated diseases, such as inflammatory bowel diseases (IBD), rheumatic diseases, and psoriasis. However, the COVID-19 pandemic caused concerns over the safety of these drugs pertaining to risk and severity of infection with SARS-CoV2. Moreover, pandemic mitigation strategies may negatively impacted treatment start with immunosuppressive and biological treatment fostering worse long-term disease outcomes. The aim of this study was to examine the impact of the COVID-19 pandemic on new starts of immunosuppressive and biological treatment in Austria. Methods We conducted a retrospective analysis with a 4-year observation period from 2017 to 2020 on real-world data on prescriptions for immune-mediated diseases of the Austrian health insurance funds covering 98% of the Austrian population. Data from all patients with incident biologic or conventional immunosuppressive treatment (Table 1) were included. Incidence of biologic (including small molecules) and immunosuppressive therapy was defined as all first prescriptions of one of the listed substances from 2017. The incidence rate for biologic and immunosuppressive treatments was recorded monthly in 2020 and compared with the three previous years (2017 – 2019). Results During the first lockdown in Austria in spring 2020 (week 12 – week 20), there was a significant decrease in the overall starts of biologic (including small molecules) and immunosuppressive treatments (both p<0.0001), especially in April (Figure 1 and 2). After that lockdown, new starts of immunosuppressive and biological treatments rapidly re-achieved pre-lockdown levels despite higher infection rates with SARS-CoV-2 and subsequent lockdown periods (Figure 3). Independent from the COVID-19 pandemic, we observed a continuous increase of biological medication (bDMARDs) and small molecules (p<0.0001) and a decrease of conventional immunosuppressive medications (cDMARDS) (p<0.0120) during all observed years (Figure 1 and 2) Conclusion In patients with immune-mediated diseases in Austria the COVID-19 pandemic led to a significant decrease of newly started immunosuppressive and biological treatments only during the first lock-down. Over the last four years, we can observe a continuous increase of small molecules and biological medication as well as a continuous decrease of conventional immunosuppressive medication.
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.
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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: Cases of Coronavirus disease 2019 (COVID-19) have emerged in discrete waves across different regions in the world. We explored temporal trends in the reporting of COVID-19 in patients with inflammatory bowel disease (IBD), in a large global database. Methods: The Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) is an international registry to study the character-istics and outcomes of patients with IBD diagnosed with COVID-19. Joinpoint regression models calculated the average percent change (APC) with 95% confidence intervals (CI) in weekly reported cases of COVID-19 in patients in the registry stratified by geographic regions (Asia, Europe, Latin America, and North America) during two time periods: March 22 to September 12 and September 13 to November 14, 2020. We also determined the APC in US regions (Midwest, Northeast, South and West) during the two time periods. Results: Across 63 countries and dependencies, 3,195 cases of COVID-19 in people with IBD were reported over an 8-month period. Overall, COVID-19 reporting steadily decreased throughout the world by 4.5% per week (95% CI: −5.7, −3.2) from March 22 to September 12, 2020 but then steadily climbed by 12.4% per week (95% CI: 6.8, 18.3) from September 13 to November 14, 2020. After stratification by geographic region, weekly reporting declined before September 13 in North America (APC = −2.0%;95% CI: −3.7, −0.4), Asia (APC =− 4.4%;95% CI: −7.8, −0.9), and Europe (APC = −8.6%;95% CI: −10.6, −6.6), but escalated in Latin America (APC = 3.4%;95% CI: 0.7, 6.1) (Figure 1). After September 12, the rate of weekly cases decreased in Latin America (APC = −19.0%;95% CI: −33.3, −1.7) and Asia (APC = −19.3%;95% CI: −34.6, −0.5), while increased in North America (APC = 10.7%;95% CI: 4.3, 17.4) and Europe (APC = 28.0%;95% CI: 17.3, 39.6) (Figure 1). Within the US, temporal trends differed by region: Midwest (stable APC: −0.8%;95% CI: −3.5, 1.9 then increase APC: 27.3%;95%: 16.1, 39.6), Northeast (decrease APC: −9.1%;95% CI:− 11.8, −6.2 then stable APC: 2.4%;95% CI: −9.9, 16.5), South (increase APC: 5.3%;95%CI: 2.5, 8.3 then decrease APC: −12.0;95% CI: −18.4, −5.0), and West (stable APC: 0.2%;95% CI: −3.0, 3.5 then stable APC: 9.0%;95% CI: −13.8, 37.9) (Figure 2). Conclusion: COVID-19 reporting to SECURE-IBD declined steadily during the first wave of the pandemic throughout the world except Latin America. Starting in September, reports to SECURE-IBD rose in both Europe and North America, consistent with the second wave of the pandemic in these countries.(Figure presented)Figure 1. Global regional temporal trends in reporting of COVID-19 in patients with IBD from the SECURE-IBD registry: A. Asia, B. Europe, C. Latin America, and D. North America: March 22–28 to September 6-12 and September 13-19 to November 8–14, 2020(Figure presented)Figure 2. United States regional temporal trends in reporting of COVID-19 in patients with IBD from the SECURE-IBD registry: A. Midwest, B. Northeast, C. South, and D. West: March 22–28 to September 6-12 and September 13-19 to November 8–14, 2020
ABSTRACT
Introduction: U-ACCOMPLISH is one of two phase 3 induction trials evaluating safety and efficacy of upadacitinib-45 mg once daily (UPA) in adults with ulcerative colitis (UC). Methods: U-ACCOMPLISH, a multicentre, randomized, double-blind, placebo-controlled trial (NCT03653026), enrolled patients (pts) with moderate-to-severe UC (defined as adapted Mayo score 5-9 with centrally read endoscopic score of 2-3) who had inadequate response, loss of response, or intolerance to aminosalicylates, immunosuppressants, corticosteroids and/or biologics. Pts were randomized 2:1 to UPA or placebo (PBO) for 8 weeks (wks). At wk 8, responders entered the maintenance phase and non-responders entered the extended treatment period to receive open-label UPA for additional 8 wks. Primary endpoint (clinical remission per adapted Mayo Score) and ranked secondary endpoints including symptomatic, endoscopic-histologic evaluations from 8-wk PBO-controlled period are reported here. Non-responder imputation incorporating multiple imputation for missing data due to COVID-19 are reported. Results: 522 pts were randomized (UPA, n = 345;PBO, n = 177);intent-to-treat population included 341 pts in UPA and 174 pts in PBO group. Baseline demographics and disease characteristics were similar between groups;50.7% and 51.1% were biologic inadequate responders in UPA and PBO groups, respectively (Table 1). A significantly higher proportion of pts receiving UPA (33.5%) versus PBO (4.1%) achieved primary endpoint (adjusted treatment difference: 29.0% [23.2, 34.7];P<0.001). A significantly higher proportion of pts receiving UPA versus PBO also achieved all ranked secondary endpoints (all P<0.001;Figure 1).Serious adverse events were reported by 3.2% and 4.5% of pts in UPA and PBO groups, respectively (Table 1). Similar rates of serious infection were observed in both groups (0.6%);2 events each of herpes zoster and opportunistic infection were reported in UPA group. No active tuberculosis, malignancy, adjudicated major adverse cardiovascular events, or deaths were reported. One pt with venous thromboembolism (deep vein thrombosis and pulmonary embolism) and 1 pt with gastrointestinal perforation were reported in the placebo group. Conclusion: UPA 45 mg QD induction treatment led to statistically significant improvements in clinical, endoscopic, and combined endoscopic-histologic endpoints. Treatment was well tolerated, and safety profile and AE prevalence were comparable with previous studies of UPA with no new safety signals identified.
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Introduction: A subcutaneous (SC) infliximab (IFX), CT-P13 SC, has received regulatory approval from the European Medicines Agency for indications including inflammatory bowel disease.1 In response to the coronavirus disease 2019 (COVID-19) pandemic, clinical guidance has recommended considering switching from intravenous (IV) treatment to SC alternatives to minimise hospital visits.2 Aims & Methods: In this analysis, data from the pivotal randomised controlled trial (NCT02883452) of CT-P13 SC in patients with active Crohn's disease (CD) and ulcerative colitis (UC) were analysed to investigate the clinical impact of switching from IV to SC IFX.3 Patients in the CT-P13 IV arm of the pivotal trial received CT-P13 5 mg/kg IV every 8 weeks from Week (W) 6 until W22. At W30, patients switched to receive CT-P13 SC every 2 weeks up to W54 (dose 120 mg or 240 mg for patients <80 kg or ≥80 kg, respectively).3 This post hoc analysis compared per-patient pairwise data at W30 (pre-switch) and W54 (post-switch) from the CT-P13 IV arm for the following outcomes: trough serum concentration (Ctrough;5 μg/mL was considered to be the target exposure level), clinical response (for CD patients, ≥100-point decrease in Crohn's Disease Activity Index score;for UC patients, ≥2-point decrease in partial Mayo score with accompanying ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding subscore of 0 or 1) and immunogenicity (anti-drug antibody [ADA] and neutralising antibody [NAb] positivity;as measured by a drug tolerant assay;ADA negative was regarded as NAb negative). For pairwise comparisons, patients with missing data at either W30 or W54 were excluded from the analysis. Statistical comparisons used Fisher's exact test. The differences are reported in a descriptive manner. Results: Overall, 65 patients (25 CD;40 UC) were included in the CT-P13 IV arm. The proportion of patients with a Ctrough level exceeding target exposure was significantly higher post-switch (36/41, 87.8%) than pre-switch (8/41, 19.5%;p<0.00001) (Table). Clinical response rates were comparable at both pre- and post-switch timepoints (40/49 [81.6%] vs 44/49 [89.8%], respectively;p=0.3873). Positive ADA and NAb rates at pre-switch and post-switch were also comparable, in which some changes were regarded from patients with marginal value (Table). Conclusion: Switching from IV to SC IFX did not detrimentally affect the clinical outcomes of patients with active CD or UC. Further, switching from IV to SC IFX might confer more favourable pharmacokinetic outcomes, although larger comparative studies are warranted. (Table Presented).