Expert consensus on vaccination in patients with inflammatory bowel disease in Japan.

Immunosuppressive therapies can affect the immune response to or safety of vaccination in patients with inflammatory bowel disease (IBD). The appropriateness of vaccination should be assessed prior to the initiation of IBD treatment because patients with IBD frequently undergo continuous treatment with immunosuppressive drugs. This consensus was developed to support the decision-making process regarding appropriate vaccination for pediatric and adult patients with IBD and physicians by providing critical information according to the published literature and expert consensus about vaccine-preventable diseases (VPDs) [excluding cervical cancer and coronavirus disease 2019 (COVID-19)] in Japan. This consensus includes 19 important clinical questions (CQs) on the following 4 topics: VPDs (6 CQs), live attenuated vaccines (2 CQs), inactivated vaccines (6 CQs), and vaccination for pregnancy, childbirth, and breastfeeding (5 CQs). These topics and CQs were selected under unified consensus by the members of a committee on intractable diseases with support by a Health and Labour Sciences Research Grant. Physicians should provide necessary information on VPDs to their patients with IBD and carefully manage these patients' IBD if various risk factors for the development or worsening of VPDs are present. This consensus will facilitate informed and shared decision-making in daily IBD clinical practice.

Anxiety and behavioral changes in Japanese patients with inflammatory bowel disease due to COVID-19 pandemic: a national survey.

BACKGROUND: Given the increasing health concerns for patients with inflammatory bowel disease (IBD), amidst the COVID-19 pandemic, we investigated the impact of the pandemic on the anxiety and behavioral changes in Japanese patients with IBD. METHODS: We analyzed 3032 questionnaires from patients with IBD, aged 16 years or older visiting 30 hospitals and 1 clinic between March 2020 and June 2021. The primary outcome was the score of the anxiety experienced by patients with IBD during the pandemic. RESULTS: Participants reported a median age of 44 years; 43.3% of the patients were women. Moreover, 60.6% and 39.4% were diagnosed with ulcerative colitis and Crohn's disease, respectively, with a median disease duration of 10 years. Participants indicated an average of disease-related anxiety score of 5.1 ± 2.5 on a ten-point scale, with a tendency to increase, 1 month after the number of infected persons per population increased. The top three causes for anxiety were the risk of contracting COVID-19 during hospital visits, SARS-CoV-2 infection due to IBD, and infection by IBD medication. Factors associated with anxiety were gender (women), being a homemaker, hospital visit timings, mode of transportation (train), use of immunosuppressive drugs, and nutritional therapy. Most patients continued attending their scheduled hospital visits, taking their medications, experienced the need for a family doctor, and sought guidance and information regarding COVID-19 from primary doctors, television, and Internet news. CONCLUSIONS: Patients with IBD experienced moderate disease-related anxiety due to the pandemic and should be proactively informed about infectious diseases to relieve their anxiety.

The Effect of Guselkumab Induction Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Results at Week 12 by Prior Inadequate Response or Intolerance to Advanced Therapy

Introduction: QUASAR (NCT04033445) is a phase 2b randomized, double-blind, placebo-controlled study that evaluates guselkumab (GUS), an interleukin-23 p19 subunit antagonist, as induction treatment in patients with moderately to severely active ulcerative colitis (UC) who had an inadequate response or intolerance to conventional (ie, thiopurines or corticosteroids) or advanced therapy (ADT;ie, tumor necrosis factor alpha antagonists, vedolizumab, or tofacitinib). Conclusion: Treatment with GUS resulted in greater improvements compared with placebo across key clinical and endoscopic/histologic outcome measures at Week 12 in patients with moderately to severely active UC with or without a history of inadequate response/intolerance to ADT. Efficacy at Week 12 by prior response/intolerance to ADT Placebo IV (N=105) GUS 200 mg IV (N=101) GUS 400 mg IV (N=107) GUS Combined(N=208) Patients with a history of inadequate response/intolerance to ADT 51 46 51 97  Clinical response a1,b,c,d,e (95% CI) 25.5% (14.3, 39.6) 54.3%* (39.0, 69.1) 47.1%* (32.9, 61.5) 50.5%* (40.2, 60.8)  Clinical remission a2,b,c,d,e (95% CI) 7.8% (2.2, 18.9) 17.4% (7.8, 31.4) 17.6% (8.4, 30.9) 17.5% (10.6, 26.6)  Symptomatic remission a3,b,c,d,e (95% CI) 17.6% (8.4, 30.9) 39.1%* (25.1, 54.6) 37.3%* (24.1, 51.9) 38.1%* (28.5, 48.6)  Endoscopic improvement a4,b,c,d,e (95% CI) 9.8% (3.3, 21.4) 23.9% (12.6, 38.8) 21.6% (11.3, 35.3) 22.7% (14.8, 32.3)  Histo-endoscopic mucosal improvement a5,b,c,d,e (95% CI) 5.9% (1.2, 16.2) 13.0% (4.9, 26.3) 19.6%* (9.8, 33.1) 16.5% (9.7, 25.4)  Endoscopic normalization a6,b,c,d,e (95% CI) 5.9% (1.2, 16.2) 10.9% (3.6, 23.6) 5.9% (1.2, 16.2) 8.2% (3.6, 15.6) Patents with no history of inadequate response/intolerance to ADT 54 55 56 111  Clinical response a1,b,c,d,e (95% CI) 29.6% (18.0, 43.6) 67.3%** (53.3, 79.3) 73.2%** (59.7, 84.2) 70.3%** (60.9, 78.6)  Clinical remission a2,b,c,d,e (95% CI) 11.1% (4.2, 22.6) 32.7%* (20.7, 46.7) 32.1%* (20.3, 46.0) 32.4%* (23.9, 42.0)  Symptomatic remission a3,b,c,d,e (95% CI) 22.2% (12.0, 35.6) 58.2%** (44.1, 71.3) 57.1%** (43.2, 70.3) 57.7%** (47.9, 67.0)  Endoscopic improvement a4,b,c,d,e (95% CI) 14.8% (6.6, 27.1) 36.4%* (23.8, 50.4) 39.3%* (26.5, 53.2) 37.8%* (28.8, 47.5)  Histo-endoscopic mucosal improvement a5,b,c,d,e (95% CI) 11.1% (4.2, 22.6) 27.3%* (16.1, 41.0) 33.9%* (21.8, 47.8) 30.6%* (22.2, 40.1)  Endoscopic normalization a6,b,c,d,e (95% CI) 7.4% (2.1, 17.9) 23.6%* (13.2, 37.0) 21.4%* (11.6, 34.4) 22.5%* (15.1, 31.4) * Nominal p-value < 0.05. ** Nominal p-value < 0.001. a1 Clinical response is defined as decrease from induction baseline in the modified Mayo score by ≥30% and ≥2 points, with either a ≥1-point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. a2 Clinical remission is defined as stool frequency subscore of 0 or 1 with no increase from induction baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability present on the endoscopy. a3 Symptomatic remission is defined as a stool frequency subscore of 0 or 1 with no increase from induction baseline and a rectal bleeding subscore of 0. a4 Endoscopic improvement is defined as an endoscopy subscore of 0 or 1 with no friability present on the endoscopy. a5 Histo-endoscopic mucosal improvement is defined as achieving a combination of histologic improvement (neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system) and endoscopic improvement, a6 Endoscopic normalization is defined as an endoscopy subscore of 0. b Patients who had a prohibited change in UC medication, an ostomy or colectomy, or discontinued study agent due to lack of efficacy or an adverse event of worsening of UC prior to the Week 12 visit were considered not to have achieved the endpoint. c Data after discontinuation of study agent due to COVID-19 related reasons (excluding COVID-19 infection) were considered to be missing. d Patients who were issing one or more components pertaining to a specified endpoint at Week 12 were considered not to have achieved the endpoint. e The p-values were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

52-Week Risankizumab Subcutaneous Maintenance Dosing Is Efficacious and Well Tolerated in Patients With Moderate to Severe Crohn’s Disease Who Had Delayed Response to 12-Weeks IV Risankizumab Induction

Introduction: In patients with moderate to severe Crohn's disease (CD), the ADVANCE and MOTIVATE phase 3 induction studies showed intravenous (IV) risankizumab (RZB), an anti-p19 interleukin-23 inhibitor, to be superior to placebo (PBO) for achieving clinical and endoscopic endpoints at Week (Wk) 12.1 Here, we evaluated the long-term efficacy and safety of RZB during the FORTIFY maintenance study in patients with delayed clinical response to IV RZB induction. [...]patients receiving RZB SC (180 mg or 360 mg) also achieved endoscopic response (36.7%, 45.5%), endoscopic remission (40.0%, 42.4%), deep remission (40.0%, 39.4%), ulcer free endoscopy (27.6%, 24.2%), and the combined endpoint of SF/APS clinical remission + endoscopic response (23.3%, 36.4%). [...]a dose-response trend was observed, with numerically higher response rates observed with RZB 360 mg SC relative to 180 mg SC for most outcomes, including clinical remission (CDAI and SF/APS), CDAI clinical response, enhanced clinical response, endoscopic response, endoscopic remission, and the composite endpoint of SF/APS clinical remission + endoscopic response. Efficacy and Safety after 52-Weeks Maintenance SC RZB Dosing in Delayed Responders (NRI-NCa) Responder Group Treatment Group, n (%) [95% CI] CDAI Clinical Response Enhanced Clinical Response CDAI Clinical Remission SF/APS Clinical Remission Endoscopic Response Ulcer Free Endoscopy Endoscopic Remission SF/APS Clinical Remission and Endoscopic Response Deep Remission RZB 180 mg SC delayed responders, Wk 24 53.3 (6/30) [35.5, 71.2] 56.7 (17/30) [38.9, 74.4] 53.3 (16/30) [35.5, 71.2] 43.3 (13/30) [25.6, 61.1] 36.7 (11/30) [19.4, 53.9] 27.6 (8/29) [11.3, 43.9] 40.0 (12/30) [22.5, 57.5] 23.3 (7/30) [8.2, 38.5] 40.0 (12/30) [22.5, 57.5] RZB 360 mg SC delayed responders, Wk 24 75.8 (25/33) [61.1, 90.4] 66.7 (22/33) [50.6, 82.8] 66.7 (22/33) [50.6, 82.8] 54.5 (18/33) [37.6, 71.5] 45.5 (15/33) [28.5, 62.4] 24.2 (8/33) [9.6, 38.9] 42.4 (14/33) [25.6, 59.3] 36.4 (12/33) [20.0, 52.8] 39.4 (13/33) [22.7, 56.1] Responder Group Treatment Group, (E/100PYs) Deaths Serious infections All treatment emergent adverse events AE related to COVID-19 Serious AE Hepatic events Injection site reactions AE leading to discontinuation of study drug Crohn's Disease RZB 180 mg SC (N=31) (PYs=27.5) delayed responders, Wk 24 0 0 132 (479.8) 0 6 (21.8) 0 6 (21.8) 2 (7.3) 7 (25.4) RZB 360 mg SC (N=33) (PYs=32.1) delayed responders, Wk 24 0 1 (3.1) 83 (258.9) 0 4 (12.5) 1 (3.1) 2 (6.2) 0 7 (21.8)

Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials.

BACKGROUND: Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease. METHODS: ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete. FINDINGS: Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12-29; 152/336) with risankizumab 600 mg and 42% (17%, 8-25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14-30; 146/336) with risankizumab 600 mg and 41% (19%, 11-27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21-35; 135/336) with risankizumab 600 mg and 32% (20%, 14-27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13-31; 80/191) with risankizumab 600 mg and 40% (21%, 12-29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6-24; 66/191) with risankizumab 600 mg and 40% (20%, 12-29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10-25; 55/191) with risankizumab 600 mg and 34% (23%, 15-31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug. INTERPRETATION: Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease. FUNDING: AbbVie.

Safety evaluation of ustekinumab for moderate-to-severe ulcerative colitis.

INTRODUCTION: Ustekinumab is a human IgG1 kappa monoclonal antibody that targets the p40 subunit of interleukin (IL)-12 and IL-23 and blocks the binding of these cytokines to the IL-12Rß1 chain of their receptors. Ustekinumab is approved for treating moderate-to-severe ulcerative colitis (UC). AREAS COVERED: We reviewed the mechanism of action, pharmacokinetics, efficacy, and safety of ustekinumab. Future challenges for optimizing UC treatment with ustekinumab are discussed. EXPERT OPINION: Ustekinumab has favorable clinical efficacy and safety profiles for moderately-to-severely active UC. Ustekinumab is the first biologic for targeting IL-12/IL-23 pathways. Therefore, ustekinumab can be a therapeutic option following the failure of other biologics, including anti-tumor necrosis factor-α antagonists and anti-α4ß7 integrin antagonists. However, the positioning of ustekinumab in the therapeutic strategy for UC remains unclear. The efficacy of combinations of ustekinumab and immunomodulators over ustekinumab monotherapy has not been supported in studies. Ustekinumab is a human immunoglobulin G monoclonal antibody with low immunogenicity. Therefore, ustekinumab monotherapy, which should be safe, could be sufficient for treating UC. Further studies are required to understand the efficacy and safety of ustekinumab in patients with UC, particularly in special situations, and to optimize UC treatment with ustekinumab.

Interim analysis of a multicenter registry study of COVID-19 patients with inflammatory bowel disease in Japan (J-COSMOS).

BACKGROUND: The spread of coronavirus disease 2019 (COVID-19) had a major impact on the health of people worldwide. The clinical background and clinical course of inflammatory bowel disease (IBD) among Japanese patients with COVID-19 remains unclear. METHODS: This study is an observational cohort of Japanese IBD patients diagnosed with COVID-19. Data on age, sex, IBD (classification, treatment, and activity), COVID-19 symptoms and severity, and treatment of COVID-19 were analyzed. RESULTS: From 72 participating facilities in Japan, 187 patients were registered from June 2020 to October 2021. The estimated incidence of COVID19 in Japanese IBD patients was 0.61%. The majority of IBD patients with COVID-19 (73%) were in clinical remission. According to the WHO classification regarding COVID-19 severity, 93% (172/184) of IBD patients had non-severe episodes, while 7% (12/184) were severe cases including serious conditions. 90.9% (165/187) of IBD patients with COVID-19 had no change in IBD disease activity. A logistic regression analysis stepwise method revealed that older age, higher body mass index (BMI), and steroid use were independent risk factors for COVID-19 severity. Six of nine patients who had COVID-19 after vaccination were receiving anti-tumor necrosis factor (TNF)-α antibodies. CONCLUSION: Age, BMI and steroid use were associated with COVID-19 severity in Japanese IBD patients.

Development of algorithms for identifying patients with Crohn's disease in the Japanese health insurance claims database.

BACKGROUND: Real-world big data studies using health insurance claims databases require extraction algorithms to accurately identify target population and outcome. However, no algorithm for Crohn's disease (CD) has yet been validated. In this study we aim to develop an algorithm for identifying CD using the claims data of the insurance system. METHODS: A single-center retrospective study to develop a CD extraction algorithm from insurance claims data was conducted. Patients visiting the Kitasato University Kitasato Institute Hospital between January 2015-February 2019 were enrolled, and data were extracted according to inclusion criteria combining the Tenth Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) diagnosis codes with or without prescription or surgical codes. Hundred cases that met each inclusion criterion were randomly sampled and positive predictive values (PPVs) were calculated according to the diagnosis in the medical chart. Of all cases, 20% were reviewed in duplicate, and the inter-observer agreement (Kappa) was also calculated. RESULTS: From the 82,898 enrolled, 255 cases were extracted by diagnosis code alone, 197 by the combination of diagnosis and prescription codes, and 197 by the combination of diagnosis codes and prescription or surgical codes. The PPV for confirmed CD cases was 83% by diagnosis codes alone, but improved to 97% by combining with prescription codes. The inter-observer agreement was 0.9903. CONCLUSIONS: Single ICD-code alone was insufficient to define CD; however, the algorithm that combined diagnosis codes with prescription codes indicated a sufficiently high PPV and will enable outcome-based research on CD using the Japanese claims database.

Management of inflammatory bowel disease during the COVID-19 pandemic.

The COVID-19 pandemic, caused by novel coronavirus SARS-CoV-2, has had an enormous impact on public health, medical systems, economies, and social conditions. The pandemic has also greatly influenced medical care systems for patients with inflammatory bowel disease (IBD). Establishment of a global registry system and accumulated experiences have led to consensus for IBD management under the COVID-19 pandemic. IBD itself does not pose an increased risk of SARS-CoV-2 infection or aggravation of COVID-19, and immune-control treatments other than systemic steroids, such as biologics, are unlikely to increase this risk. The importance of suppressing disease activity has not changed since before the pandemic. The effects of the COVID-19 pandemic on behavioral changes and psychological states among patients have various results and differ by country or region as well as between adult and pediatric patients. In future, information-sharing tools that can widely and correctly disseminate the views of experts will be very important. Vaccination remains in its infancy, but the impact of immunoregulatory therapy on antibody titers must be investigated. Information about COVID-19 is constantly being updated, and new and accurate medical care updates are needed. In Japan, the Japan COVID-19 Taskforce contributes to information dissemination, patient registries, and clinical research.

Expert Opinions on the Current Therapeutic Management of Inflammatory Bowel Disease during the COVID-19 Pandemic: Japan IBD COVID-19 Taskforce, Intractable Diseases, the Health and Labor Sciences Research.

BACKGROUND: The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a dramatic challenge for all healthcare systems worldwide. This outbreak immediately affected gastroenterologists as well as global physicians worldwide because COVID-19 can be associated with not only triggering respiratory inflammation but also gastrointestinal (GI) inflammation based on the mechanism by which SARS-CoV-2 enters cells via its receptor the angiotensin-converting enzyme 2, which is expressed on GI cells. However, the comorbidity spectrum of digestive system in patients with COVID-19 remains unknown. Because the inflammatory bowel disease (IBD) management involves treating uncontrolled inflammation with immune-based therapies, physicians, and patients have great concern about whether IBD patients are more susceptible to SARS-CoV-2 infection and have worsened disease courses. SUMMARY: It is necessary to precisely ascertain the risk of SARS-CoV-2 infection and the COVID-19 severity in IBD patients and to acknowledge the IBD management during the COVID-19 pandemic with clinically reliable information from COVID-19 cohorts and IBD experts' opinions. In this review, we highlight clinical questions regarding IBD management during the COVID-19 pandemic and make comments corresponding to each question based on recent publications. Key Messages: We propose that there is (1) no evidence that IBD itself increases the risk of SARS-CoV-2 infection, (2) to basically prioritize the control of disease activity of IBD, (3) no need for physicians to suddenly discontinue immunomodulatory or biologic therapy in patients with quiescent IBD, and (4) a need for careful observation of elderly (>60 years old) and IBD patients receiving corticosteroid treatment during the COVID-19 pandemic.

Asian Pacific Association of Gastroenterology (APAGE) Inflammatory Bowel Disease (IBD) Working Party guidelines on IBD management during the COVID-19 pandemic.

The COVID-19 pandemic, secondary to SARS-CoV-2, has resulted in high mortality and morbidity worldwide. As inflammatory bowel disease (IBD) is a chronic disease, and most patients are on long-term immunosuppressive agents, there is understandable concern, particularly in terms of therapy. In view of this, experts in IBD across the Asia Pacific region were invited to put together recommendations based on their experience and the currently available data. In general, most IBD therapies (with a few exceptions) can be continued safely, and the general consensus is that maintaining disease control should remain the main principle of management. In addition, social distancing measures and the appropriate use of personal protective equipment should be strictly adhered to. During the current pandemic, face-to-face clinic follow ups and non-urgent procedures should be kept to a minimum.