Serologic response and safety after third dose of the COVID-19 BNT162b2 vaccine in patients with Inflammatory Bowel Diseases

Background: Vaccines are pivotal for control of the ongoing coronavirus disease (COVID-19) pandemic. Patients with inflammatory bowel diseases (IBD) treated with anti-tumor necrosis factor (TNF)-alpha have lower serologic response after two COVID-19 vaccine doses. Data regarding a 3rd vaccine are scarce. Method(s): Aim: To assess immune responses to, and safety of COVID-19 vaccines in patients with IBD, stratified according to therapy, and compared to healthy controls (HC). Subjects were recruited before the 1st vaccine (BNT162b2, Pfizer) and prospectively evaluated after the 2nd and 3rd vaccine doses. Evaluation included: Disease activity, anti-spike (S) and nucleocapsid (N), anti-TNFalpha drug levels and adverse events (AE) Results: Of 198 subjects having the 3rd vaccine dose, 125 had IBD: average age: 39.1+/-14.8 years;40.8% females;82-Crohn's disease (CD), 33 ulcerative colitis (UC), 6 pouch, 3 IBD-U. There were 73 HC: average age 39.4+/-12.5 years, 69.9% females. Among patients with IBD: 51 and 74 (40.8%, 59.2%)) were treated or not with anti-TNFalpha, respectively. A month after the 3rd vaccine dose IBD activity was comparable in all patients regardless of treatment, and no increase in C-reactive protein or white blood cells was observed. Higher but not significant AE rate was registered in all subjects after the 3rd compared to 2nd vaccine dose (81% vs. 76%, respectively). AE rate in IBD and HC was comparable. No serious AE detected. There was a significant increase in anti-S levels one month after compared to pre 3rd vaccine dose in all participants. Furthermore, increase was 2-3 folds higher than that observed one month after the 2nd dose. Importantly, patients treated with anti-TNFalpha compared to non-anti-TNFalpha treated had significantly lower responses: 9219 (6347-13390) vs 16955 (13721-20951) (GMC (95%CI)), p<0.05. Serologic response did not correlate with anti-TNFalpha drug levels, antibodies or interval between drug and vaccine administration. During extended follow-up post 3rd dose, we found that lower serologic response predicts infection over time. Conclusion(s): This prospective study shows that a 3rd dose of BNT162b2 vaccine is effective and safe in patients with IBD. Furthermore, patients treated with anti-TNFalpha had significantly lower serologic responses compared to anti-TNFalpha untreated ones. Lack of correlation between anti-TNFalpha drug levels and immune responses suggests there is no need to modify vaccination timing relatively to anti-TNFalpha administration. The significantly steeper increase in anti-S levels between 2nd and 3rd doses, suggests the 3rd dose is crucial in anti-TNFalpha treated patients, specifically due to the fact that higher serologic response predicts better defense from infection.

SARS-CoV-2 breakthrough infections after COVID-19 vaccination in patients with Inflammatory Bowel Disease: A systematic review and meta-analysis

Background: Patients with inflammatory bowel disease (IBD) have reduced seroconversion rates to COVID-19 vaccination. It is unclear whether an impaired immune response in vaccinated IBD patients impacts the susceptibility to SARS-CoV-2 infection and occurrence of (severe) COVID-19. We evaluated SARS-CoV-2 breakthrough infection rates and the disease course of COVID-19 in vaccinated IBD patients. Method(s): A systematic literature search was performed for studies which reported SARS-CoV-2 breakthrough infection rates and/or the disease course of COVID-19 in patients with IBD after COVID-19 vaccination. Primary outcome was the rates of breakthrough infection per time period. In meta-analyses, the pooled relative risk was calculated with a random effects model for vaccinated patients compared to vaccinated controls, to partially vaccinated and unvaccinated patients with IBD. Result(s): A total of 16 studies were included in analysis. The study period ranged from January 2020 to October 2021, and a follow-up time ranges from 3 weeks to 6 months. The breakthrough infection rates range from 0 to 37.4% in IBD patients within the study follow-up time. Strikingly, only studies with vaccination prior to December 2021 showed a breakthrough infection rate above 2%. (Figure 1). The disease course of a breakthrough infection is generally mild, with mild constitutional and respiratory symptoms in 85% of infected IBD patients. Hospitalization and mortality rates are low (0-8.7% and 0-4.3% respectively). Meta-analyses showed a significantly lower pooled relative risk of breakthrough infection for vaccinated as compared to unvaccinated IBD patients (RR 0.07, 95% CI 0.03;0.18). No difference was observed in risk of breakthrough infections between IBD patients and non-IBD controls (RR 1.01, 95% CI 0.92;1.10), and no difference between vaccinated and partially vaccinated IBD patients (RR 0.67, 95% CI 0.38;1.18). The impact of immunosuppressive therapy on breakthrough infection rates differs between studies. One study reported higher breakthrough infection rates for patients treated with infliximab in comparison to vedolizumab (P<.05). Other studies showed no impact on the breakthrough infection rates for immunosuppressive treatment vs no treatment, anti-TNF-alpha/corticosteroids vs without anti- TNF-alpha/corticosteroids and other biologics vs anti-TNF-alpha. Conclusion(s): Vaccination is effective to prevent COVID-19 infections in patients with IBD. Breakthrough infections do occur, but the disease course is generally mild. Available data seem to suggest a declining trend of breakthrough infections during calendar time. Data on the impact of IBD medication on the rate of breakthrough infections and disease course require further elucidation. (Figure Presented).

What had the greatest impact on the quality of life of IBD patients on intravenous biological therapy in Montenegro during COVID-19?

Background: COVID-19 has affected the quality of life (QoL) of patients with chronic diseases, including patients with IBD. The aim of this study is to evaluate the QoL of patients with IBD on intravenous biological therapy (IvBT), through the Short Inflammatory Bowel Disease Questionnaire (sIBDQ), and to correlate the results with sociodemographic data of the patients. Method(s): This study was comprised of patients older than 18 years of age, with a pathohistologically confirmed diagnosis of IBD (Ulcerative Colitis (UC), and Crohn's Disease (CD)). The study was conducted on September and October 2020, during one of the highest incidences period of COVID-19 in our country. Patients completed the sIBDQ, and DASS-21 (Depression, Anxiety and Stress Score-21) questionnaire too, assessing their level of depression, anxiety and stress. For significant symptoms (DASS-21), we used at least moderate DASS-21 subscale score: DASS-21 Depression (>= 14), DASS-21 Anxiety (>= 10) and DASS-21 Stress (>=19). The Simple Clinical Colitis Activity Index was used to assess the disease activity of UC;for CD, the Harvey-Bradshaw Index was used. Patients who scored below 50 on the sIBDQ were those labeled with worse QoL. We also examined demographic data, data on IBD characteristics and COVID-19 data and their impact on quality of life. Result(s): Of the total number of patients (94), there were 40 (42.5%) females, 42 (44.6%) with CD. All patients have been receiving IvBTh (anti TNFalpha: Infliximab-originator and biosimilar (59 patients) and anti-integrins: Vedolizumab (35 patients)) for at least 6 months prior. The results indicated worse QoL in 25 (27%) patients. Multivariate analysis showed that the greatest impact on poor QoL during the COVD-19 pandemic were: active disease (p= 0.002), significant symptoms on the DASS21 score (p= 0.013), patients who did not regularly go to work or were not employed (p=0.017), if they had a patient with COVID-19 in their immediate environment (p=0.024) and those who had a higher degree of health concerns about coming to regular admission to biological therapy at the IBD unit. (p=0.046). Conclusion(s): 27% of IBD patients on IvBT had worse QoL during the COVID 19 pandemic. In addition to disease activity and significant psychological disturbances, other reasons for lower QoL were identified during the pandemic and are directly related to it. (Figure Presented).

Ulcerative Colitis: Rapid Evidence Review

Ulcerative colitis is a relapsing and remitting inflammatory bowel disease of the large intestine. Risk factors include recent Salmonella or Campylobacter infection and a family history of ulcerative colitis. Diagnosis is suspected based on symptoms of urgency, tenesmus, and hematochezia and is confirmed with endoscopic findings of continuous inflammation from the rectum to more proximal colon, depending on the extent of disease. Fecal calprotectin may be used to assess disease activity and relapse. Medications available to treat the inflammation include 5-aminosalicylic acid, corticosteroids, tumor necrosis factor-alpha antibodies, anti-integrin antibodies, anti-interleukin-12 and -23 antibodies, and Janus kinase inhibitors. Choice of medication and method of delivery depend on the location and severity of mucosal inflammation. Other treatments such as fecal microbiota transplantation are considered experimental, and complementary therapies such as probiotics and curcumin have mixed data. Surgical treatment may be needed for fulminant or refractory disease. Increased risk of colorectal cancer and use of immunosuppressive therapies affect the preventive care needs for these patients. (Am Fam Physician. 2022;105(4):406-411. Copyright © 2022 American Academy of Family Physicians.)Copyright © 2022 American Academy of Family Physicians. All rights reserved.

Adalimumab Biosimilar Efficacy and Safety in a 5-Year-Old Patient with Severe Plaque Psoriasis During SARS-CoV-2 Pandemic Outbreak

BACKGROUND: Psoriasis is a chronic inflammatory disease that affects 2% of population. About 0.5–2% of psoriatic cases develop during pediatric age. In most cases, the condition is responsive to topical treatment. However, a small percentage of children require systemic treatment with conventional systemic drugs or biological agents, such as anti-tumor necrosis factor (TNF)-α. Adalimumab (ADA) is an anti-TNF-α recently approved for pediatric psoriasis in the European Union (from 4 years of age, 2015). CASE PRESENTATION: We describe our experience treating a 5-year-old female patient affected by severe plaque psoriasis with ADA biosimilar during SARS-CoV-2 pandemic outbreak also using teledermatology. CONCLUSION: The case reported in this article highlights the safety and the effectiveness of ADA biosimilar MSB11022 (Idacio®) in the treatment of a 5-year-old female affected by plaque psoriasis and paves the way to bigger trials for a more extensive use of TNF-α inhibitor biosimilars for psoriasis in pediatric population.

TUBERCULOUS PLEURAL EFFUSION MASQUERADING AS DRUG-INDUCED LUPUS

SESSION TITLE: Critical Care Presentations of TB SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 12:25 pm - 01:25 pm INTRODUCTION: TNFα plays a pivotal role in inflammation and maintenance of immune response against tuberculosis. The use of TNF inhibitors (TNFi) is associated with a significant increase in the incidence of tuberculosis (TB). TNFi may cause drug-induced lupus (ATIL) presenting as constitutional symptoms, rashes, pericardial and pleural effusions with positive autoantibodies. We present a case of pleural TB masquerading as drug-induced lupus. CASE PRESENTATION: A 68y/o woman with a history of ulcerative colitis (on infliximab, mesalamine), hypertension, T2DM, CAD, complained of low-grade fever, rashes, left-sided chest pain, dyspnea, and arthralgias for two weeks. Chest pain- worse with inspiration and cough. She emigrated from India to the USA 40 years ago. Six months before infliximab therapy, Quantiferon gold was negative. Exam: faint hyperpigmentation over shins, minimal swelling of MCPs and ankles, dullness to percussion over the left chest with decreased breath sounds. Labs: CRP 101 mg/dL, Hb 10.8 iron deficient, rheumatoid factor and anti-CCP negative, ANA 1:40, dsDNA 1:640, a reminder of ENA negative, anti-histone negative, C3/C4 normal, UA bland, protein/Cr 0.4 mg/gm, negative blood cultures, SPEP and LDH normal. CXR: opacification of the left lung up to midfield. CT chest: moderate left and small right pleural effusions, enlarged mediastinal lymph nodes. COVID and Quantiferon: negative. Thoracentesis: 850 ml of exudative fluid (2 out of 3 Light's criteria), lymphocytic predominance (76% of 4148 nucleated cells), adenosine deaminase (ADA) 42 U/L, gram stain, culture, acid-fast and MTB PCR negative, cytology negative. Thoracoscopy with biopsy of the parietal pleura: necrotizing granulomatous pleuritis with acid-fast bacilli. Sensitivity: pan-sensitive M. tuberculosis. Sputum: negative for TB. She was discharged on RIPE treatment for reactivation of TB. DISCUSSION: The incidence of infliximab-induced lupus is approximately 0.19% and confirming the diagnosis is challenging. The immunogenicity of infliximab is high, 66% of patients develop positive ANA. Anti-histone antibodies are less commonly associated with ATIL as opposed to classic drug-induced lupus and dsDNA is positive in up to 90% of cases of ATIL. Renal involvement is rare. The diagnostic usefulness of ADA (over 40 U/L) in lymphocytic pleural effusions for the diagnosis of tuberculosis in an immunosuppressed individual is demonstrated here. In countries with low TB burden, such as the USA, the positive predictive value of ADA in pleural fluid declines but the negative predictive value remains high. CONCLUSIONS: Tuberculous pleuritis is not always easily diagnosed since AFB smears and sputum may remain negative. When ADA level in lymphocytic pleural fluid is not low thorough search for TB with thoracoscopy and biopsy is justified. Reference #1: Shovman O, Tamar S, Amital H, Watad A, Shoenfeld Y. Diverse patterns of anti-TNF-α-induced lupus: case series and review of the literature. Clin Rheumatol. 2018 Feb;37(2):563-568. Reference #2: Benucci, M., Gobbi, F. L., Fossi, F., Manfredi, M. & Del Rosso, A. (2005). Drug-Induced Lupus After Treatment With Infliximab in Rheumatoid Arthritis. JCR: Journal of Clinical Rheumatology, 11 (1), 47-49. Reference #3: Valdés L, San José ME, Pose A, Gude F, González-Barcala FJ, Alvarez-Dobaño JM, Sahn SA. Diagnosing tuberculous pleural effusion using clinical data and pleural fluid analysis A study of patients less than 40 years-old in an area with a high incidence of tuberculosis. Respir Med. 2010 Aug;104(8):1211-7. DISCLOSURES: No relevant relationships by Adam Adam No relevant relationships by Moses Bachan No relevant relationships by Chen Chao No relevant relationships by Zinobia Khan No relevant relationships by Milena Vukelic

IMMUNE RESPONSE to SARS-COV-2 INFECTION in PATIENTS with RHEUMATIC MUSCULOSKELETAL DISEASES: The MAINSTREAM STUDY

Background: Rheumatic musculoskeletal diseases (RMD) are pathological conditions characterized by an impaired immunological system that is determinant both in the pathogenesis and in the inadequate response to infections. The use of disease-modifying anti-rheumatic drugs (DMARDs), which include conventional synthetic (cs) or biologic and targeted synthetic (b/ts) DMARDs, contribute to compromise immunological reactivity. Objectives: To analyze the immune response to SARS-CoV-2 in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) receiving treatment with DMARDs and to investigate the effect of the different classes of drugs on humoral and cellular response. Methods: Patients were tested for anti-SARS-CoV-2 IgG, IgM and IgA antibodies to nucleoprotein (N) and receptor-binding domain (RBD) through ELISA and neutralization assays. Then, we performed a fow cytometry analysis of monocytes, NK cells, B and T lymphocytes from PBMCs of serologically positive patients. We also included a cohort of non-RMD individuals recovered from COVID-19 as a reference group of non-immunosuppressed subjects. A frst recruitment occurred in May-June 2020 (T1) and a second recruitment, 3-4 months after (T2), allowed to evaluate the persistence of the antibody response over time and to investigate the cellular immune response to SARS-CoV-2 in RMD patients having resolved the infection. Results: During T1, 358 patients with RA (n=200) or SpA (n=158) were recruited. Mean age was 52.8, 64% were female. All patients were treated with DMARDs, 299 with b/tsDMARDs and 59 received csDMARDs alone. One third was also receiving corticosteroids (CS). At T2, 36 subjects were recruited. We found a seroprevalence rate of 18.4%, which did not signifcantly differ between RA and SpA groups, and between patients treated with b/ts-DMARD or csDMARDs, either alone or in combination with CS (Table 1). Antibody levels of RMD patients were lower than non-RMD individuals (Figure 1), with CTLA4-Ig-treated patients having the lowest IgG levels. This difference was less marked in symptomatic RMD patients. 72% of seropositive patients elicited neutralizing sera. Despite an overall decrease in anti-RBD and anti-N titers, more than two-third of patients maintained antibodies titers above positivity threshold at T2. Concerning cellular response, we found that CD8+ T-cells frequency was overall comparable between RMD and non-RMD convalescents, and did not differ in b-or cs-DMARD treated ones. Conversely, CD4+ T-cell frequencies were signifcantly lower in RMD patients, especially those treated with anti-IL6R and CTLA4-Ig. B-cell subpopulations (class-switched, memory, and IgG+ memory B-cells) had sustained frequencies in anti-TNFα treated patients, while they had a trend of reduction in patients treated with anti-IL6R and CTLA4-Ig. Conclusion: Our data provide a comprehensive picture of the humoral and cellular immune responses to SARS-CoV-2 infection in RMD patients. We showed that DMARDs treatments did not alter a successful antibody response to the virus and did not hamper the antibody neutralizing ability. However, the magnitude of antibody response was slightly reduced compared to non-RMD individuals, especially in patients receiving CTLA4-Ig. We did not observe marked differences in the B-and T-cell populations between RMD patients compared to non-RMD individuals. However, in patients receiving anti-TNFα we found a higher relative abundance of effector adaptive population compared to other bDMARDs.

COMBINATION OF ADVANCED THERAPIES IN PATIENTS WITH COMPLEX INFLAMMATORY BOWEL DISEASE

Background and aim: Dual Targeted Therapy (DTT) is a novel therapeutic strategy proposed for the management of patients with complex inflammatory bowel disease (IBD). Our aim was to evaluate the safety and effectiveness of this approach in a real-life setting Materials and methods: In this single centre retrospective cohort study, we collected data on IBD patients receiving DTT from 2017 to 2022. Baseline characteristics, clinical activity of intestinal and extraintestinal disease, C-reactive protein (CRP) levels, endoscopic assessment and adverse events (AEs) were recorded. Clinical remission, CRP normalization, endoscopic remission and occurrence of AEs were investigated at baseline and during follow up Results: Sixteen patients were identified;indications for DTT were: uncontrolled IBD (11 patients), uncontrolled extraintestinal manifestations (EIMs) (6 patients: 4 spondyloarthritis, 2 psoriatic disease). Patients received vedolizumab (VDZ, 14, 87.5%), ustekinumab (UST, 8, 50%), anti-TNFα (7, 43.8%), sekukinumab (2, 12.5%), tofacitinib (1, 6.3%). The most common combinations were: VDZ+UST (6 patients, 37.5%) and adalimumab+VDZ (3, 18.8%). At baseline, 15/16 (93.8%) and 4/6 (66.6%) patients had active intestinal and EI symptoms, respectively;14 (87.5%) patients had positive CRP and 5 (31.3%) were receiving oral steroids. Median follow-up duration on DTT was 15 months (IQR 11-22). Clinical intestinal remission was reported by 6/16 (37.5%) and 3/11 (27.3%) patients at 6 and 12 months, respectively. Clinical remission of EIMs was reported by 3/7 (42.9%) at 6 and 5/7 (71.4%) patients at 12 months, respectively. CRP normalization was observed in 3/16 (18.8%) and 6/11 (54.5%) patients at 6 and 12 months, respectively. 80% of patients on steroid therapy at baseline discontinued them within 6 months. Endoscopic assessments were available for 8 patients, with endoscopic remission in 2, endoscopic improvement in 3 and no improvement in 3. Four patients (25%) experienced an AE (1 COVID-19 and reactivation of perianal disease;1 mild pneumonitis and reactivation of perianal disease;1 drug-induced pneumonitis;1 arthralgia and COVID-19). Finally, 1 patient underwent colectomy due to uncontrolled disease. Three patients discontinued DTT: 2 because of treatment failure, 1 because of an AE (drug-induced pneumonitis) Conclusions: DTT can be considered a reasonably safe and effective treatment in complex IBD patients, either with uncontrolled intestinal inflammation or with concomitant EIMs, when other therapeutic options have failed

SEROCONVERSION IN INFLAMMATORY BOWEL DISEASE PATIENTS AFTER COVID-19 VACCINATION

Background Data about the effect of different immunosuppressive treatments of IBD patients on seroconversion and to different SARS-CoV-2 vaccinations are scarce. To avoid impaired vaccine responses and worse outcome of COVID-19, factors attenuating protective immunity shoud be shought. Methods Anti SARS-CoV-2S antibody levels of IBD patients in remission were measured by immunoassay (Roche) before vaccination and on the second week. Antibody responses were compared among different treatment groups (biologics, combination, azathioprin, without immunomodulation) and between mRNA and other type of vaccines. Anti TNF alpha levels were also assesed 24 hours before vaccination considering correlation with seroconversion. Results Thirty-eight (31.7%) ulcerative colitis and eightytwo (68,2%) Crohn’s disease patients were included (median age 39.1 years, 53.3% female). No serious comorbidities were present. Eighty-two patients (68.3%) were on biological therapy, fifty-two (43%) were treated with azathioprine alone or in combination. Two doses of mRNA vaccines were administered to ninty-eight patients ((81,7%) Moderna: 20, Pfizer: 78). The other type of vaccines were AstraZeneca (16) Sputnik V (3) and Sinopharm (3). The median anti-SARS-CoV-2S antibody level was 2733 U/mL (IQR: 535-7764) on the 14th day after vaccination (IQR: 14-17). Significant differences were revealed between the groups of patients treated with biological agents or non-biological therapy (median: 1649 U/ml vs. 5711.5 U/ml;p=0.013) and between patients recieving mRNA and non-mRNA vaccine (median: 3367.5 U/ml vs. 392.6 U/ml;p<0.001). Considering the varying effect of immunosupression related to combination therapy, biological drugs, azathioprin and other non-immunomodulating treatments antibody response were assesed in these groups also. The median antibody levels were 850,5 U/ml (IQR: 251.0-4899.5), 1837 U/ml (IQR: 544.5-5902), 3141 U/ml (IQR: 1066-7988), 7764 U/ml (IQR: 5601-13808) demonstrating significant differences among them (p<0.001). No correlation between anti-TNF-alpha serum level and antibody response were found. Discussion Altough all vaccines cause seroconversion in IBD patients who are in remission, the rate of seroconversion is lower in patients treated with immunosupressant, biological agent or combo therapy or recieving non-mRNA vaccines. As the level of anti-TNF-alpha agents do not affect the rate of seroconversion there is probably no need for matching the time of vaccination and anti-TNF therapy.

INTERIM ANALYSIS OF A MULTICENTER REGISTRY STUDY OF COVID-19 INFECTED PATIENTS WITH INFLAMMATORY BOWEL DISEASE IN JAPAN (J-COSMOS)

Background: The spread of COVID-19 has had a major impact on the health of people worldwide. The clinical background and clinical course of Japanese inflammatory bowel disease (IBD) patients with COVID-19 remains unclear. Patients with IBD are often on immunosuppressive therapy, and there has been concern about the severity of COVID-19. We conducted the multicenter registry study of Japanese patients with inflammatory bowel disease with COVID-19. Methods: This study is an observational cohort of Japanese IBD patients diagnosed with COVID-19, and was registered in the UMIN Clinical Trials Registry (ID UMIN000040656). Data on age, gender, IBD (classification, treatment, and activity), COVID-19 symptoms and severity, and treatment of COVID-19 were analyzed. Results: From 72 facilities in Japan, one hundred eighty-seven patients were registered from June 2020 to October 2021 (Table1). The estimated incidence ratio of COVID19 in Japanese IBD patients was 0.61%. The median age (±SD) was 42.0±15.6, 4.8% of patients were obese with BMI >30, 7.0% were current smokers, and 31.0% had some complications. Of the patients enrolled, 104 had ulcerative colitis, 74 had Crohn's disease, 3 had IBD-Unclassified, and 6 had intestinal Behcet's disease. The majority of IBD patients with COVID-19 (73%) were in clinical remission. COVID-19 cases were most common in the 20-50 age group, but the COVID-19 severity rate according to WHO classification tended to be higher in the elderly than in middle-aged persons (Figure1). In Japan, the second SARS-CoV-2 vaccination rate jumped from 0% to 90% in just four months from May to September 2021 because the elderly received vaccination preferentially. Therefore, during the fifth wave of the epidemic (July-September 2021), infections among elderly IBD patients were particularly low compared with the younger. According to WHO classification regarding COVID-19 severity, 172 patients (92%) had non-severe, 12 (6%) were severe including serious conditions. Most IBD patients (UC and CD) with COVID-19 had no change in disease activity. A logistic regression analysis stepwise method revealed that older age, higher BMI, and steroid use were risk factors for COVID-19 severity. Six of eight patients who had COVID-19 after vaccination were receiving anti-TNF-alpha antibodies. Conclusion: The estimated incidence ratio of COVID19 in Japanese IBD patients was 0.61%. Age, BMI, and steroid use were associated with COVID-19 severity in Japanese IBD patients. (Table Presented) Table1. Case profile of the registered patients (Figure Presented) Figure1. The Age distribution of patients with COVID-19 and the COVID-19 severity rate

PATIENTS WITH INFLAMMATORY BOWEL DISEASES HAVE IMPAIRED ANTIBODY PRODUCTION AFTER ANTI-SARS-COV-2 VACCINATION, ESPECIALLY THOSE ON ANTI-TNFα OR COMBINATION TREATMENT OF BIOLOGICS PLUS IMMUNOMODULATORS: RESULTS FROM A PANHELLENIC REGISTRY

Background: Patients with inflammatory bowel diseases (IBD) are commonly treated with immunosuppressive agents. Following the novel corona virus (SARS-CoV-2) pandemic, these patients received early the currently EMA approved vaccines. Data on efficacy and safety of SARS-CoV-2 vaccination on this population are lacking. Methods: Greek IBD patients, from 10 tertiary referral centres, who had completed the initial vaccination protocol with the available anti-COVID-19 vaccines (BNT162b2, mRNA-1273, Ad26.CoV2.S, ChAdOx1) at least two weeks before enrolment, were prospectively studied. Demographic and safety data were collected and blood samples were drawn for serum Anti-S1 IgG measurement [Euroimmun Anti-SARS-CoV-2 QuantiVac ELISA (IgG)]. Results: In total 403 IBD patients (59% Crohn's disease, median age 45 years, 53% male) and 124 healthy controls (HC) were included (Table 1). Antibody testing was conducted after a median of 31 (IQR, 23-46) days post-vaccination. Following a full vaccination regimen, 98% of IBD patients seroconverted (anti-S1 IgG³11 RU/ml). In total, IBD patients had lower anti-S1 levels than HC (RU/ ml 108 vs 133 RU/ml, P=0.00009) Administration of mRNA vaccines resulted in higher seroconversion rates and higher antibody titers than viral vector ones (98.6% vs 93.6%, P= 0.02 and 111.2 RU/ml vs 76 RU/ml, P<0.0001, respectively). Treatment with vedolizumab monotherapy was associated with higher antibody levels than anti-TNFα or ustekinumab monotherapy (P=0.02 and P=0.03). Longer timing between vaccination and antibody measurement was independently associated with impaired vaccine response. In multivariable analysis, specifically in mRNA-vaccinated cohort, older age, anti-TNFα treatment and treatment with biologics plus IMMs were significantly associated with lower antibody response (P=0.01, P=0.008, and P=0.02 respectively). Patients with prior COVID-19 infection showed numerically higher levels of antibodies. All vaccines were safe in IBD patients. Conclusions: Patients with IBD have high seroconversion rates to anti-SARS-CoV-2 vaccines. However, they demonstrate impaired antibody responses compared to HC. Patients receiving viral vector vaccines, and those on anti-TNFα or combination treatment may have further response impairment and it is important to consider booster vaccination in those low-response groups. (Table Presented)

WITHIN 6 MONTHS FROM COVID-19 BNT162B2 VACCINE PATIENTS WITH INFLAMMATORY BOWEL DISEASES TREATED WITH ANTI-TNFα HAVE SIGNIFICANTLY LOWER SEROLOGIC RESPONSES

Background: While vaccines against COVID-19 are effective in healthy individuals, we reported significantly lower serologic responses to BNT162b2 in patients with inflammatory bowel diseases (IBD) treated with anti-tumor necrosis factor (TNF) α agents. As this was apparent already 4 weeks post vaccination, vaccine longevity is concerning. Aim: to assess long-term serologic responses to BNT162b2 in patients with IBD stratified according to medical treatment. Methods: A prospective, observational multi-center Israeli study. Patients with IBD (anti-TNFα treated versus non-anti-TNFα treated) and healthy controls (HC) were followed from before the 1st BNT162b2 dose until 6 months after vaccination. COVID-19 spike (S) and nucleocapsid (N) antibodies (Abs) concentrations were analyzed by ELISA, followed by neutralization studies. Specific anti-receptor binding domain (RBD) memory Bcells response, serologic responses against variants of concern (VOCs), Beta, Gamma and Delta, immunoglobulin levels and lymphocyte cell subsets were evaluated as well. Safety was assessed using questionnaires, clinical and laboratory data. Results: Of 193 subjects, 130 had IBD (45 and 85 in the anti-TNFa and non-anti-TNFα groups, respectively), 63 HC. Serologic response assessed 176 (median) days (IQR 166-186) and compared to 4 weeks after 1st dose significantly declined in all three groups, but was lowest in the anti- TNFα group: 6 months anti-S Abs titer geometric means: 193 (95%CI: 128-292), 703 (520- 951), and 1253 (1023-1534) in anti-TNFα, non- anti-TNFα and HC groups, respectively, p<0.001, Figure 1. This was further supported by neutralization and inhibition studies. Importantly, significantly decreased memory B-cell response towards RBD was detected only in the anti-TNFα group, with the most significant reduction in response to Beta VOC (p<0.0008 and p<0.0001, vs. non-anti-TNFα and HC, respectively). Older age was an additional predictor of lower serologic response. Immunoglobulin levels and lymphocyte cell subsets were comparable between the study groups. Infection rate reflected by anti-N Abs was ~1% in all groups. Safety was comparable in all groups. Conclusion: The 6-months serologic response to BNT162b2 vaccine, evaluated prospectively, decreased in all subjects, most prominently in patients with IBD treated with anti-TNFα. Importantly, the latter also had the sharpest decline in serologies, the lowest functional activity and lowest RBD specific memory B-cells. Older age is an additional predictor of decreased serologic response. Altogether, waning of COVID-19 serologic and functional response over 6 months, specifically in patients with IBD treated with anti-TNFα, supports the need for an early third vaccine dose. (Figure Presented)

Ulcerative Colitis: Rapid Evidence Review

Ulcerative colitis is a relapsing and remitting inflammatory bowel disease of the large intestine. Risk factors include recent Salmonella or Campylobacter infection and a family history of ulcerative colitis. Diagnosis is suspected based on symptoms of urgency, tenesmus, and hematochezia and is confirmed with endoscopic findings of continuous inflammation from the rectum to more proximal colon, depending on the extent of disease. Fecal calprotectin may be used to assess disease activity and relapse. Medications available to treat the inflammation include 5-aminosalicylic acid, corticosteroids, tumor necrosis factor-alpha antibodies, anti-integrin antibodies, anti-interleukin-12 and -23 antibodies, and Janus kinase inhibitors. Choice of medication and method of delivery depend on the location and severity of mucosal inflammation. Other treatments such as fecal microbiota transplantation are considered experimental, and complementary therapies such as probiotics and curcumin have mixed data. Surgical treatment may be needed for fulminant or refractory disease. Increased risk of colorectal cancer and use of immunosuppressive therapies affect the preventive care needs for these patients.

COVID-19 AND DERMATOLOGY (PART II): ADVERSE MUCOCUTANEOUS REACTIONS TO MEDICATIONS AND VACCINES USED FOR COVID-19 INFECTION

Background/Aim: There is no proven specific or effective treatment for COVID-19 infection;therefore, many drugs are used empirically to establish control of the infection. Viral infection creates an immunologic environment and facilitate drug sensitization. With the advent of new vaccines, the future holds promise for optimism in establishing control of the pandemic. However, even vaccines are not devoid of side effects. In part II of these review series, we aimed to review the published data on mucocutaneous reactions induced by medications used for COVID-19 infection and vaccines used for COVID-19 prophylaxis. Materials and methods: Literature search was performed in the databases PubMed, Scopus, and Web of Science for the relevant studies, starting from the beginning of COVID-19 pandemic until October 2021. Research on animals, studies utilizing in vitro techniques and publications irrelevant to the study’s framework were excluded. Results: The mucocutaneous side effects liable to medications (antimalarials, azithromycin, lopinavir/ritonavir, remdesivir, ribavirin/interferon, oseltamivir/favipiravir, darunavir, imatinib, tocilizumab, anakinra baricitinib, and other Janus kinase inhibitors, immunoglobulin therapy, colchicine, anti-TNF-α biologics, low molecular weight heparins, camostat mesylate) and vaccines used for COVID-19 infection are reviewed herein. Conclusion: There is a great amount of accumulated data regarding the mucocutaneous side effects of drugs and vaccines used for COVID-19 infection. In the pandemic era, it is a major goal to diagnose drug or vaccine-related mucocutaneous eruptions and distinguish them from pathognomonic, specific, or SARS-CoV-2 virus-related cutaneous eruptions. Timely diagnosis of a mucocutaneous drug/ vaccine reaction will allow for identification of the culprit and appropriate management and protect the patient from forthcoming severe drug/ vaccine reactions. Therefore, it is essential for physicians to update their knowledge regularly on mucocutaneous side effects of COVID-19 therapeutics and vaccines.

Patients with Inflammatory Bowel Diseases on anti-TNF treatment have impaired antibody production after Anti-SARS-CoV-2 vaccination: Results from a Panhellenic registry

Background: The novel corona virus (SARS-CoV-2) outbreak was declared as a pandemic in March 2020;this prompted the need for rapid vaccine development. Currently four EMA approved vaccines exist but their efficacy and safety data on patients with Inflammatory Bowel diseases are limited. Methods: Greek IBD patients, from 10 tertiary referral centres, who had completed the initial vaccination protocol with the available anti-COVID-19 vaccines at least two weeks before enrolment, were prospectively studied. Demographic and safety data were collected and blood samples were drawn for serum Anti-S1 IgG measurement [Euroimmun Anti-SARS-CoV-2 QuantiVac ELISA (IgG)]. Results: In total 403 IBD patients (59% Crohn's disease, median age 45 years, 53% male) and 124 healthy controls (HC) were included (Table 1). Antibody testing was conducted after a median of 31 (IQR, 23-46) days post-vaccination. Following a full vaccination regimen, 98% of IBD patients seroconverted (anti-S1 IgG≥11 RU/ ml). Administration of mRNA vaccines resulted in higher seroconversion rates and higher antibody titers than viral vector ones (98.6% vs 93.6%, P=0.02 and 111.2 RU/ml vs 76 RU/ml, P<0.0001, respectively). In total, IBD patients had lower anti-S1 levels than HC (RU/ ml 108 vs 133 RU/ml, P=0.00009). IBD patients without immunosuppression had higher antibody titers than immunocompromised patients (P=0.012). In univariable analysis, older age, longer time since vaccination, and treatment with corticosteroids, immunomodulators, anti-TNFα or combination therapy were associated with lower anti- S1 titers. In contrast, higher anti-S1 levels were detected in patients on vedolizumab monotherapy or non-immunosuppressive treatment. In multivariable analysis, only age, time since vaccination, and anti- TNFα therapy remained significant (P=0.011, P=0.002, and P=0.013 respectively). Treatment with vedolizumab monotherapy was associated with higher antibody levels than anti-TNFα or ustekinumab monotherapy (P=0.023 and P=0.032). Patients with prior COVID-19 infection showed numerically higher levels of Abs. All vaccines were safe in IBD patients. Conclusion: Patients with IBD have high seroconversion rates to anti- SARS-CoV-2 vaccines, with mRNA vaccines being more efficacious. However, IBD patients have impaired response to vaccination comparing to HC. Lower antibody responses were observed in patients who received viral vector vaccines, in older patients, and in those on anti- TNFα treatment. It is important to consider booster vaccination in those low-response groups.

Seroconversion after COVID-19 vaccination in inflammatory bowel disease patients

Background: Data about the effect of different immunosuppressive treatments of IBD patients on seroconversion and on different SARSCoV- 2 vaccinations are scarce. To avoid impaired vaccine responses and worse outcome of COVID-19, factors attenuating protective immunity shoud be shought. Methods: Anti SARS-CoV-2S antibody levels of IBD patients in remission were measured by immunoassay (Roche) before vaccination and on the second week. Antibody responses were compared among different treatment groups (biologics, combination, azathioprin, without immunomodulation) and between mRNA and other type of vaccines. Anti TNF alpha levels were also assesed, 24 hours before vaccination considering correlation with seroconversion. Results: Thirty-eight (31.7%) ulcerative colitis and eighty-two (68,2%) Crohn's disease patients were included (median age, 39.1 years, 53.3% female). No serious comorbidities were present. Eighty-two patients (68.3%) were on biological therapy, fifty-two (43%) were treated with azathioprine alone or in combination. Two doses of mRNA vaccines were administered to ninty-eight patients ((81,7%) Moderna:, 20, Pfizer:, 78). The other type of vaccines were AstraZeneca (16) Sputnik V (3) and Sinopharm (3). The median anti-SARS-CoV-2S antibody level was, 2733 U/mL (IQR:, 535-7764) on the, 14th day after vaccination (IQR:, 14-17). Significant differences were revealed between the groups of patients treated with biological agents or non-biological therapy (median:, 1649 U/ml vs., 5711.5 U/ml;p=0.013) and between patients recieving mRNA and non-mRNA vaccine (median:, 3367.5 U/ml vs., 392.6 U/ml;p<0.001). Considering the varying effect of immunosupression related to combination therapy, biological drugs, azathioprin and other non-immunomodulating treatments antibody response were assesed in these groups also. The median antibody levels were, 850,5 U/ ml (IQR:, 251.0-4899.5), 1837 U/ml (IQR:, 544.5-5902), 3141 U/ml (IQR:, 1066-7988), 7764 U/ml (IQR:, 5601-13808) demonstrating significant differences among them (p<0.001). No correlation between anti-TNF-alpha serum level and antibody response were found. Conclusion: Altough all vaccines cause seroconversion in IBD patients who are in remission, the rate of seroconversion is lower in patients treated with immunosupressant, biological agent or combo therapy or recieving non-mRNA vaccines. As the level of anti-TNF-alpha agents do not affect the rate of seroconversion there is probably no need for matching the time of vaccination and anti-TNF therapy.

Within, 6 months from COVID-19 BNT162b2 vaccine patients with Inflammatory Bowel Diseases treated with Anti-TNFα have significantly lower serologic responses

Background: While vaccines against COVID-19 are effective in healthy individuals, we reported significantly lower serologic responses to BNT162b2 in patients with inflammatory bowel diseases (IBD) treated with anti-tumor necrosis factor (TNF) α agents. As this was apparent already, 4 weeks post vaccination, vaccine longevity is concerning. Aim: to assess long-term serologic responses to BNT162b2 in patients with IBD stratified according to medical treatment. Methods: A prospective, observational multi-center Israeli study. Patients with IBD (anti-TNFα treated versus non-anti-TNFα treated) and healthy controls (HC) were followed from before the, 1st BNT162b2 dose until, 6 months after vaccination. COVID-19 spike (S) and nucleocapsid (N) antibodies (Abs) concentrations were analyzed by ELISA, followed by neutralization studies. Specific anti-receptor binding domain (RBD) memory B-cells response, serologic responses against variants of concern (VOCs), Beta, Gamma and Delta, immunoglobulin levels and lymphocyte cell subsets were evaluated as well. Safety was assessed using questionnaires, clinical and laboratory data. Results: Of, 193 subjects, 130 had IBD (45 and, 85 in the anti-TNFα and non-anti-TNFα groups, respectively), 63 HC. Serologic response assessed, 176 (median) days (IQR, 166-186) and compared to, 4 weeks after, 1st dose significantly declined in all three groups, but was lowest in the anti- TNFα group:, 6 months anti-S Abs titer geometric means:, 193 (95%CI:, 128-292), 703 (520-951), and, 1253 (1023-1534) in anti-TNFα, nonanti- TNFα and HC groups, respectively, p<0.001, Figure, 1. This was further supported by neutralization and inhibition studies. Importantly, significantly decreased memory B-cell response towards RBD was detected only in the anti-TNFα group, with the most significant reduction in response to Beta VOC (p<0.0008 and p<0.0001, vs. non-anti-TNFα and HC, respectively). Older age was an additional predictor of lower serologic response. Immunoglobulin levels and lymphocyte cell subsets were comparable between the study groups. Infection rate reflected by anti-N Abs was ∼1% in all groups. Safety was comparable in all groups. Conclusion: The, 6-months serologic response to BNT162b2 vaccine, evaluated prospectively, decreased in all subjects, most prominently in patients with IBD treated with anti-TNFα. Importantly, the latter also had the sharpest decline in serologies, the lowest functional activity and lowest RBD specific memory B-cells. Older age is an additional predictor of decreased serologic response. Altogether, waning of COVID- 19 serologic and functional response over, 6 months, specifically in patients with IBD treated with anti-TNFα, supports the need for an early third vaccine dose. (Figure Presented).

IBD and COVID-19 in Italy: Comparisons between first and second pandemic wave

Background: Coronavirus disease 2019 (COVID-19), had two pandemic waves in 2020, respectively in April and November. In the general population, the first wave has been characterized by a higher prevalence in Northern Italy and a higher mortality rate compared to the second one. The aim of this study was to compare the characteristics of IBD patients and negative outcomes of COVID-19 (pneumonia, hospitalization, ventilatory support, death) between the two pandemic waves in Italy. Methods: Prospective observational cohort study. Patients with diagnosis of IBD and confirmed SARS-CoV-2 infection were enrolled. Differences between first and second wave were tested for significance using the Student's t test and Fisher's test, as appropriate. A two-tailed p value <0.05 was indicative of statistical significance. Results: We enrolled 937 IBD patients from 47 participating IBD centres across Italy (219 in the first wave, 718 in the second wave). There were no significant differences between the first and the second wave in terms of age (46.3 ± 16.0 vs. 44.1 ± 15.5 years, p=0.06) and gender (female 45.7% vs. 48.2%, p= 0.54). In the first wave, a lower percentage of patients was affected by Crohn's disease (CD): 92 (42.0%) vs. 399 (55.6%) (p<0.001) while no differences were observed for disease clinical activity: 97/219 (44.3%) vs. 280/718 (38.9%) in the first and second wave, respectively (p=0.18). Regarding biologic therapy, the percentage of patients on biologics in the two waves was similar: 119/219 (54.3%) vs. 393/718 (54.7%) (p=0.94), without differences in anti-TNFalpha, anti-integrins and anti-IL12/23 distribution. During the first wave, a significantly higher percentage of patients were from Northern Italy compared to Central-Southern Italy: 171/219 (78.1%) vs. 387/718 (53.9%), respectively (p<0.001). Overall, COVID-19 negative outcomes were significantly higher in the first wave compared to the second one: 110 (50.2%) vs. 95 (13.2%), respectively (p<0.001). Also the single negative outcomes were significantly higher in the first wave: 61/219 (27.8%) vs. 84/718 (11.7%) had pneumonia, 62/219 (28.3%) vs. 76/718 (10.6%) required hospitalization, 26/219 (11.9%) vs. 39/718 (5.4%) required ventilatory support, and 12/219 (5.5%) vs. 13/718 (1.8%) died (Figure 1). Conclusion: IBD patients had higher number of COVID-19 negative outcomes in the first wave than in second wave. In the first wave, a significantly higher percentage of patients were from Northern Italy, but no significant differences in negative outcomes were observed in comparison with those from Central- Southern Italy. Overall, findings in IBD population are coherent with those observed in the general population. (Table Presented).

IMPROVING INFLUENZA VACCINATION IN PEDIATRIC INFLAMMATORY BOWEL DISEASE: A QUALITY IMPROVEMENT INITIATIVE

Background: Vaccination rates remain low among patients with inflammatory bowel disease (IBD) despite guideline recommendations and evidence-based publications. Reported barriers include perceived lack of benefit, fear of side effects, and inconvenience. At our IBD center we follow approximately 1700 patients. During the 2019-2020 influenza season, our vaccination rate for the entire IBD population was 40.3% and 45.5% for those receiving biologic therapies at our infusion center (n=772). We developed a quality improvement initiative to evaluate vaccination practices and to determine effective strategies to increase vaccine uptake. As a first-step, we targeted our most vulnerable and accessible population: patients receiving biologic infusions. Methods: Our initiative began in August 2020. Plan-do-study-act cycles included creation of a multi-disciplinary team to review vaccination barriers and distribution of a survey to caregivers or IBD patients >=18 years to explore vaccination decision making process, awareness of recommendations, and impact of vaccine availability in the infusion center on uptake. The next phase was optimizing access among patients receiving biologic therapies at our infusion center. The strategies we implemented included educational sessions with the division providers and infusion center nurses, creation of an Epic EMR order set, active phone screening of our population prior to infusion visits, at which point unvaccinated patients were offered the vaccine during the appointment. Chi squared analysis compared survey responses between caregivers and patients. Two proportion sample test identified differences in vaccination rates between the two influenza seasons. Results: The survey was answered by 14.4% (n=269 caregivers and n=60 patients), with 71.3% on either anti-TNF alpha (infliximab, adalimumab) or vedolizumab. Of respondents, 13.4% were unvaccinated in 2019-2020. Top reasons for non-vaccination included “unsure of safety” (31.8%), “unsure of benefit” (29.5%), and “forgot to schedule” (13.6%). Patients and caregivers had similar vaccine impressions, with no statistically significant differences (Figure 1). For the 2020-2021 season, 88.75% plan to get vaccinated and 51.7% expressed interest in receiving the vaccine during their infusion appointment. Since implementing our initiative, the vaccination rate has already increased to 59.2% compared to 45.5% (p=0.001). Conclusions: Our initiative increased vaccination rates in patients receiving biologic infusions by 13.7% thus far. Particularly during the COVID-19 pandemic, the influenza vaccine is essential to protect this vulnerable population and decrease the burden on the healthcare system. We have identified pre-screening prior to appointments and providing access in conjunction to scheduled appointments as the most effective strategies to optimize vaccination uptake.(figure presented)