Introduction

Investigation of SARS-CoV-2 vaccine efficacy in immune-mediated inflammatory disease (IMID) patients receiving immunosuppressives have been restricted to small sized serological studies. We therefore undertook an investigation of immunosuppressants’ impact on real-world effectiveness of vaccines in these patient groups.

Aims & Methods

We performed a nationwide cohort study to assess the risk of COVID-19 infection in vaccinated IMID patients exposed to immunosuppressives compared to propensity score matched unexposed patients in the period from 1 January 2021 to 30 November 2021. Exposure to immunosuppressives 120 days before receiving the second SARS-CoV-2 mRNA vaccination was assessed. Patients were followed from the date of second vaccination, and weighted Cox models were used to estimate the risk of infection associated with immunosuppressives. Secondary outcomes included hospitalisation and death following positive SARS-CoV-2 test. Subgroup analysis for risk of infection by immunosuppressive drug class was also undertaken.

Results

Overall, 152,440 patients were followed over 19,341 person-years. Immunosuppressives were associated with a significantly increased risk of infection in Inflammatory Bowel Disease (IBD; HR: 1.64, 95% CI: 1.42, 1.91), and Arthropathy (HR:1.27, 95% CI: 1.13, 1.43) but not Psoriasis (HR: 1.11, 95% CI: 0.89, 1.38). Meta-analysis of all IMID also showed a significantly increased risk of infection in immunosuppression (HR: 1.35, 95% CI: 1.24, 1.46). Meta-analysis showed no significantly increased risk of either hospitalisation (HR: 1.40, 95% CI: 0.80, 2.46), or death (HR: 0.92, 95% CI: 0.38, 2.23) was identified. Subgroup analysis by immunosuppressive drug class showed increased infection risk in anti-TNF (HR: 1.75, 95% CI: 1.56, 1.96), systemic corticosteroid (HR: 1.24, 95% CI: 1.00, 1.42), and Rituximab and other immunosuppressant (HR: 1.27, 95% CI: 1.14, 1.42) exposure.

Conclusion

Findings suggest reduced effectiveness against infection following two doses of mRNA SARS-CoV-2 vaccination in IBD and arthropathy patients receiving immunosuppressive therapies. Anti-TNF, systemic corticosteroids, and Rituximab and other immunosuppressants were particularly associated with increased infection risk.

Introduction

Patients with immune mediated inflammatory diseases (IMIDs) on immunosuppressive therapies have attenuated vaccine responses (1-3) and are prone to severe infections. Knowledge of COVID-19 outcome following vaccine and hybrid immunity, and identification of protective anti-Spike antibody concentrations are important to further develop vaccine strategies in this vulnerable patient group.

Aims & Methods

In this prospective observational study, adult patients with IMID on immunosuppressive therapies were followed from February 15, 2021, to February 15, 2023. Throughout the study, patients and controls reported data regarding COVID-19, COVID-19 related hospital admissions were recorded from The Norwegian Patient Registry. Anti-Spike antibodies were assessed 2-4 weeks following vaccination and COVID-19. The objectives of this study were to investigate the outcomes of COVID-19 in a large cohort of IMID patients compared to healthy controls, and to identify any associations between anti-Spike antibody concentrations and disease course.

Results

Of 2250 IMID patients included in the study, a total of 1729 with a documented COVID-19 history were included in the present analyses (305 Crohn’s disease, 215 ulcerative colitis, 648 rheumatoid arthritis, 272 psoriatic arthritis, and 289 spondyloarthritis) (median age 54 years (IQR 42-64), 971 (56 %) females). Of the patients, 1080 of 1729 (62%) used anti-TNF treatment (65% monotherapy, 35% combination therapy).
1140 (66%) of patients and 236 of 350 (67%) healthy controls (HC) reported COVID-19, the majority (85%) within the Omicron era. COVID-19 reinfection was reported in in 141 (12%) patients and 32 (14%) HC (p=0.66). Compared to hybrid immunity (COVID-19 after three vaccine doses), the risk of COVID-19 was six times higher following vaccine series only (HR 5.9, (95% CI [4.45, 7.80]), p<0.001). Anti-Spike antibody concentrations <8000 BAU/ml were predictive of COVID-19 after three (HR 1.5 (95% CI [1.14, 1.90]), p=0.003) and four vaccine doses (HR 1.4 (95% CI [1.13, 1.83]), p=0.003), and in hybrid immunity (HR 2.6 (95% CI [1.32, 5.13]), p=0.006). In the entire cohort, the median anti-Spike antibody concentration after the 2^nd vaccine dose was 2823 BAU/ml (IQR 999-6199), after the 3^rd dose 6529 BAU/ml (IQR 2325-10140), after the 4^th dose 7624 BAU/ml (3809-12751) and following hybrid immunity 23506 BAU/ml (11423, 37007). Hospitalisation due to COVID-19 (severe disease) occurred in 22 (2%) patients, 9 (41%) before any vaccination, and none of HC. Four patients were admitted to intensive care. Prior to hospitalisation, the median anti-Spike antibody concentration was 444 BAU/ml (IQR 31-1634). Patients with severe disease were older than non-hospitalised (median age 61 years (IQR 48-74) vs. 54 (42-64), p=0.04) and had a higher frequency of comorbidities (19/22 (86%) vs. 474/1118 (42%), p=0.02). No COVID-19 related deaths occurred.
Prolonged COVID-19 (symptoms >14 days) were reported by 201 (18%) patients compared to 29 (12%) HC (p=0.09). The risk of prolonged disease was higher in the vaccine group compared to the hybrid group (HR 8.5 (95 % CI [3.84, 18.90]), p<0.001).

Conclusion

IMID patients and healthy controls had a comparable occurrence of COVID-19, prolonged disease and reinfection. However, severe disease developed only in the patient group. Hybrid immunity protects against COVID-19 and prolonged disease. A high anti-Spike antibody concentration protects against COVID-19, supporting the role of repeated vaccination in IMID patients on immune-suppressive therapy.

References

1. Jorgensen KK, Hoivik ML, Chopra A, Benth JS, Ricanek P, Moum PB, et al. Humoral immune response to SARS-CoV-2 vaccination in patients with inflammatory bowel disease on immunosuppressive medication: association to serum drug levels and disease type. Scand J Gastroenterol. 2023:1-9.
2. Bjorlykke KH, Orbo HS, Tveter AT, Jyssum I, Sexton J, Tran TT, et al. Four SARS-CoV-2 vaccine doses or hybrid immunity in patients on immunosuppressive therapies: a Norwegian cohort study. Lancet Rheumatol. 2023;5(1):e36-e46.
3. Syversen SW, Jyssum I, Tveter AT, Tran TT, Sexton J, Provan SA, et al. Immunogenicity and Safety of Standard and Third-Dose SARS-CoV-2 Vaccination in Patients Receiving Immunosuppressive Therapy. Arthritis Rheumatol. 2022;74(8):1321-32.

Disclosure

Have received speakers bureaus from Bristol-Myers Squibb and Roche

Introduction

Patients with inflammatory bowel disease (IBD) frequently use immunosuppressants and immunobiologicals for maintenance treatment. The humoral responsiveness to COVID-19 vaccines in this group of patients using this drugs is still not fully understood, as the need for more vaccine boosters.

Aims & Methods

Our study aims to evaluate the humoral response to different types of vaccines against SARS-Cov-2 in this population, as well as to compare this response with the healthy population. Patients with IBD enrolled at the Policlinic Piquet Carneiro (UERJ) were prospectively followed with serial blood collection between July 2021 and July 2022. Samples were screened to determine antibody titers, and patients were stratified by demographic and clinical characteristics, naturally occurring infection, vaccination schemes, and IBD medications. Anti-spike IgG antibody titers against the SARS-Cov-2 were determined by ELISA before and one month after the two doses of different vaccination schemes in patients with IBD, regularly followed-up at the outpatient unit. The results were compared with those of a healthy control group during the same period.

Results

In the IBD group (46 individuals), mean antibody titers were 430.3 AU/ml pre-vaccination and 8038.4 AU/ml after the two vaccine doses. In comparison, in the control group (92 individuals), mean antibody titers were 90.5 AU/ml pre-vaccination and 7697.5 AU/ml after the two doses. In both groups, there was a significant increase in the titer of antibodies after the two vaccine doses (p<0.001). When comparing antibody titers one month after the 2nd dose, there was no difference between the two groups (p=0.731). On the other hand, in the IBD group, there was a difference between the vaccination schemes, with higher titers in those who received Pfizer, as well as in younger patients (p<0.005) and in those with previous natural COVID-19 infection (p<0.012). Diagnosis of Crohn’s disease or ulcerative colitis, sex, race, smoking status, clinical variables related to disease localization, extension, behavior, clinical activity, and type of medical therapy did not significantly affect the immune response to vaccines.

Conclusion

The use of immunosuppressants and immunobiologicals does not affect the overall humoral response to the COVID-19 vaccination among patients with IBD. Nevertheless, specific vaccine schemes, age, and previous COVID-19 infection significantly affect antibody titers.

References

1. Ministério da Saúde. Painel Coronavírus. Accessed 01/2023. https://covid.saude.gov.br.
2. Tsang HF, Chan LWC, Cho WCS et al. An update on COVID-19 pandemic: the epidemiology, pathogenesis, prevention and treatment strategies. Expert Rev Anti Infect Ther 2021;19(7):877-888.https://doi.org/10.1080/14787210.2021.1863146.
3. Rahman S, Montero MTV, Rowe K et al. Epidemiology, pathogenesis, clinical presentations, diagnosis and treatment of COVID-19: a review of current evidence. Expert Rev Clin Pharmacol. 2021;14(5):601-621. https://doi.org/10.1080/17512433.2021.1902303.
4. Chenchula S, Karunakaran P, Sharma S et al. Current evidence on efficacy of COVID-19 booster dose vaccination against the Omicron variant: A systematic review. J Med Virol. 2022;94(7):2969-2976. https://doi.org/10.1002/jmv.27697.
5. Hunt RH, East JE, Lanas A et al. COVID-19 and Gastrointestinal Disease: Implications for the Gastroenterologist. Dig Dis 2021;39(2):119-139. https://doi.org/10.1159/000512152.
6. Neurath MF. COVID-19 and immunomodulation in IBD. Gut 2020;69(7):1335-1342. https://doi.org/10.1136/gutjnl-2020-321269.
7. Quaresma AB, Kaplan GG, Kotze PG, The globalization of inflammatory bowel disease: the incidence and prevalence of inflammatory bowel disease in Brazil. Curr Opin Gastroenterol 2019;35(4):259-264. https://doi.org/10.1097/MOG.0000000000000534.
8. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009;361(21):2066-78. https://doi.org/10.1056/NEJMra0804647.
9. Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019;68(Suppl 3):s1-s106. https://doi.org/10.1136/gutjnl-2019-318484.

Introduction

There is evidence linking inflammatory bowel disease (IBD) and cardiovascular diseases. However, the roles of histologic and clinical activity of IBD in the development of arrhythmias remain unknown.

Aims & Methods

In this nationwide cohort study in Sweden, we included IBD patients with histologic data (n = 61,383; diagnosed 1969–2017; classified as histologic inflammation vs. remission based on the Swedish version of the Systematized Nomenclature of Medicine codes) and clinical activity data (n = 96,154; diagnosed 1969–2020; classified as clinically active vs. quiescent IBD based on IBD-related hospitalization, surgery, and treatment escalation) and followed them through December 31, 2021. The primary outcome was incident arrhythmias (including atrial fibrillation/flutter, bradyarrhythmias, other supraventricular arrhythmias, and ventricular arrhythmias/cardiac arrest) within 2 years after documented histologic inflammation (vs. remission) or clinically active IBD (vs. quiescent IBD). Poisson regression models estimated incidence rates (IRs) of arrhythmias, while Cox proportional hazards models estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). We adjusted for age at IBD diagnosis, sex, calendar year at index date, county of residence, educational attainment, country of birth, number of health care visits, and history of CVD-related comorbidities in the model.

Results

Histologic inflammation was associated with an increased risk of developing any arrhythmias compared to histologic remission (IR: 62.0 vs. 47.2 per 10,000 person-years; aHR = 1.35, 95%CI: 1.18–1.54), corresponding to one additional event of arrhythmia per 338 IBD patients over 2 years after histologic inflammation. We found an excess risk for atrial fibrillation/flutter (aHR = 1.38, 95%CI: 1.18–1.62) and ventricular arrhythmias/cardiac arrest (aHR = 1.73, 95%CI: 1.22–2.44), but not for bradyarrhythmias or other supraventricular arrhythmias. Compared to clinically quiescent IBD, active IBD was also related to a higher risk of arrhythmias (IR: 67.4 vs. 108.4; aHR = 1.77, 95%CI: 1.66–1.88), affecting all subtypes except bradyarrhythmias. In patients with clinically quiescent IBD, histologic inflammation was also associated with an increased risk of arrhythmias (aHR = 1.16, 95%CI: 1.00–1.36, P=0.054).

Conclusion

Histologic and clinical activity were associated with a slightly increased risk of arrhythmias in patients with IBD.

Disclosure

All authors have completed the ICMJE uniform disclosure form and declare:
OO has been PI on projects at Karolinska Institutet financed by grants from Janssen, Pfizer, AbbVie, Takeda, Galapagos/Alfasigma, Ferring, and Bristol Myer Squibb. JH served as speaker or advisory board member for AbbVie, BMS, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Index Pharma, Janssen, Medtronic, Merck, MSD, Novartis, Pfizer, Sandoz, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma, and Vifor Pharma and received grant support from Takeda, Janssen, and MSD. FE has served as an advisory board member for Boehringer Ingelheim. JFL has coordinated a study for the Swedish IBD Quality Register (SWIBREG), which received funding from Janssen Corporation. JFL has also received financial support from MSD to develop a paper reviewing national healthcare registers in China. JFL has a research collaboration on celiac disease with Takeda and has a research collaboration on fibrosis in IBD with MSD. The other authors report no disclosures relevant to the manuscript.

Introduction

Prior research has established an association between inflammatory bowel disease (IBD) and obstructive lung diseases (OLD), such as asthma, bronchitis, COPD (chronic obstructive pulmonary disease), and bronchiectasis. Studies have suggested that there may be a bidirectional relationship between IBD and OLD, with patients diagnosed with either condition being more likely to develop the other.¹ While previous studies have mainly examined the prevalence of this association,^2–4 only two incidence studies have been conducted, both of which focused on the risk of IBD in individuals who were already diagnosed with asthma or COPD.^5,6 Consequently, there is a need for further investigation to determine the risk of disease development in people with IBD.

Aims & Methods

The aim was twofold: firstly, to determine the likelihood of OLD prior to the onset of IBD; and secondly, to evaluate the risk of OLD after the onset of IBD.
The present study employed data from the Danish National Patient Registry and the Danish National Prescription Registry, from January 1, 1999, to December 31, 2018.^7,8 Incident cases of IBD in Denmark from 2003 to 2013 were identified based on relevant International Classification of Diseases, 10^th revision (ICD-10) diagnosis codes.⁹ A matched population without IBD was included for comparison in a 1:10 ratio. Individuals with OLD were identified based on relevant ICD-10 codes or ATC codes (two on different dates within a year). Additionally, a sensitivity analysis was performed using only ICD-10 codes to estimate the risk of obstructive lung disease.
Logistic regression was applied to estimate the prevalence odds ratio for OLD up to four years before IBD diagnosis/index date. Time-to-event analysis (Cox proportional regression) was then used to explore the risk of OLD. In the sensitivity analyses, the time-to-event analysis was repeated based solely on ICD-10 diagnosis codes.

Results

The total study population consisted of 266,618 individuals: 24,238 with IBD and 242,380 without IBD. Individuals with IBD had a 60% higher likelihood (adjusted odds ratio [aOR]: 1.60, 95% CI: 1.53-1.67) of OLD before diagnosis compared to non-IBD individuals, whereas the risk was over 40% higher after IBD diagnosis. A sensitivity analysis confirmed the elevated risk after IBD diagnosis, with a higher adjusted hazard ratio (aHR) of 1.63 (95% CI: 1.53-1.73).

Conclusion

Our findings suggest a significant bidirectional association between IBD and OLD. We demonstrate in an unprecedented nationwide cohort study, an increased risk of OLD among individuals diagnosed with IBD. Further studies concerning the gut-lung axis are warranted to explore the mechanisms underlying this association.^​

References

1. Vutcovici M, Brassard P, Bitton A. Inflammatory bowel disease and airway diseases. World J Gastroenterol 2016;22:7735-7741.
2. Raj AA, Birring SS, Green R, et al. Prevalence of inflammatory bowel disease in patients with airways disease. Respir Med 2008;102:780-785.
3. Bernstein CN, Wajda A, Blanchard JF. The clustering of other chronic inflammatory diseases in inflammatory bowel disease: A population-based study. Gastroenterology 2005;129:827-836.
4. Ekbom A, Brandt L, Granath F, et al. Increased risk of both ulcerative colitis and Crohn’s disease in a population suffering from COPD. Lung 2008;186:167-172.
5. Hemminki K, Li X, Sundquist J, et al. Subsequent Autoimmune or Related Disease in Asthma Patients: Clustering of Diseases or Medical Care? Ann Epidemiol 2010;20:217-222.
6. Brassard P, Vutcovici M, Ernst P, et al. Increased incidence of inflammatory bowel disease in Québec residents with airway diseases. Eur Respir J 2015;45:962-968.
7. Schmidt M, Schmidt SAJ, Sandegaard JL, et al. The Danish National patient registry: A review of content, data quality, and research potential. Clin Epidemiol 2015;7:449-490.
8. Wallach Kildemoes H, Toft Sørensen H, Hallas J. The Danish national prescription registry. Scand J Public Health 2011;39:38-41.
9. World Health Organization. International Statistical Classification of Diseases and Related Health Problems (ICD). ICD-10.

Introduction

Thiopurine therapy is a cornerstone in the treatment of patients with inflammatory bowel disease (IBD).

Aims & Methods

We aimed to assess the effect of thiopurines on the risk of cancer in IBD according to drug exposure and age. Danish national registers were used to identify incident IBD patients, exposure to drugs and status of cancers, in 1996-2018. Cox regressions were used to i) compare IBD to non-IBD reference individuals, ii) analyse IBD according to drug exposure status, and iii) assess patients’ cumulative drug exposure and the association to first reported cancer, excluding non-melanoma skin cancer.

Results

In total, 43,419 IBD patients were followed for a median of 8.2 years (IQR:3.7-14.2) after IBD diagnosis. Cancer was reported in 3,128 (7.2%) IBD patients. Both monotherapy and combination therapy were associated with developing cancer (aHR:1.36 (95%CI:1.17-1.58) and (aHR:2.48 (95%CI:1.64-3.76), respectively) compared to unexposed IBD patients. Among the elderly (>65 years), the risk was especially high in those receiving combination therapy. In patients who discontinued thiopurines, the aHR returned to the level of unexposed patients (aHR:0.89 (95%CI:0.78-1.01)). The aHR was positively associated with cumulative thiopurine exposure and in patients with more than five years of exposure, reaching aHR of 1.36 (95%CI:1.14-1.61).

Conclusion

Thiopurines were associated with increased risk of cancer, especially when used in combination therapy in the elderly. The risk increased by 36% when patients were exposed to thiopurines for more than five years. Reassuringly, the risk returned to baseline after discontinuation of thiopurines. This study suggests avoiding combination therapy in the elderly and not treating patients with thiopurines for longer than five years, regardless of age.

Disclosure

This study was funded by an unrestricted grant from Aage og Johanne Louis-Hansens Fond.