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

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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

The response rate to hepatitis B virus (HBV) vaccination in the general population is about 90%. However, the response rate to the vaccine in patients with inflammatory bowel disease (IBD) is significantly lower. IBD is a multifactorial disease so, it is important to study which cell subsets are involved in the failure of the HBV vaccine.

Aims & Methods

Our main objective was to study the differences between the peripheral immune system of responders and not responders to the vaccine. It is an observational clinical practice study on the factors associated with the immunogenicity of the HBV vaccine in patients with IBD. Per clinical practice, 19 IBD patients vaccinated for the first time against HBV were included. Patients were divided according to their vaccination response after three doses of the vaccine at 0, 1, and 6 months as responders (≥ 100 anti-HBV) and non-responders (< 100 anti-HBV). Blood was collected before and after vaccination to characterize the different immune subsets by flow cytometry. Data were analyzed manually and by high dimensional data analysis (UMAP and FlowSOM).

Results

Non-responders displayed a lower percentage of naïve T cells compared with those who responded while responders had a lower percentage of Th2 and CD4 central memory subsets before vaccination. According to the high dimensional data analysis, 22 different T-cell metaclusters were identified. Indeed, the percentage of type 2 conventional dendritic cells was increased following vaccination in both responders and non-responders, allowing us to identify 11 submetacluster. Finally, The percentage of IgG class switch and IgG plasmablasts were increased following vaccination in the responders group, while the percentage of IgM plasmablast was increased in non-responders. Using the high dimensional data analysis 26 different subpopulations, were identified.

Conclusion

The proportion of circulating T cell subsets can be used as predictor markers of the response to the HBV vaccine in IBD patients: while non-responders showed a lower percentage of naïve T cells, responders presented a lower percentage of Th2 T cells compared with their counterparts. The analysis of the data reveals that high-resolution and high-dimensional data, show several clusters containing events that evade the canonical definition.

Introduction

Infections are one of the main side effects faced by patients treated with biological agents.

Aims & Methods

Objective: We aimed to determine the rates of bacterial infections among Inflammatory Bowel Disease (IBD) patients treated with biological agents in a real-life setting.
Methods: Retrospective study based on the Clalit healthcare nationwide database, which included all patients diagnosed with IBD between 1999 and 2022. Data on bacterial infections were collected for patients treated with a biologic agent (Anti_TNF, Vedolizumab and Ustekinumab) and were compared to all other IBD patients during the corresponding timeframe.
Data regarding demographics, bacterial infection events, and mortality were collected. Data were collected using the MdClone platform from the largest Health Maintenance Organization, “Clalit” in Israel.

Results

5523 IBD patients treated with Anti-TNF were compared to 29,598 patients not treated with Anti-TNF. Patients treated with Anti-TNF were younger, age 35.62±14.29 compared to 47.06±19.49 years. Anti-TNF patients had higher rates of respiratory tract infection (36.2% vs 31.2%), genitourinary system infection, 26.7% vs 23.7%, gastrointestinal tract infection (31.8% vs 21.6%), skin infection (22.5% vs 14.3%) and Ear, Nose, throat infection (31.5% vs 24.2%). 2220 patients treated with Vedolizumab compared to 35,100 not treated with Vedolizumab, patients treated with Vedolizumab had higher rates of bacterial infections, respiratory tract infection (13.5 vs 5.1%, p<0.001), genitourinary system infection, (9.7% vs 3.8%, p<0.001) gastrointestinal tract infection (12.6% vs 3.5%, p<0.001), skin infection (8.4% vs 3%, p<0.001) and Ear, Nose, throat infection (11% vs 4.4%, p<0.001). In addition, risk of bacterial infection was higher among 940 patients treated with Ustekinumab than those not treated with Ustekinumab.

Conclusion

Significantly increased risk found among IBD patients treated with biologic agents; clinicians should consider the increased susceptibility to bacterial infections when deciding which biological agent to prescribe to their asthma patients

Introduction

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the digestive tract. The introduction of targeted therapies has significantly improved patient outcomes, although a substantial proportion of patients still do not respond adequately. Genetic factors, including single nucleotide polymorphisms (SNPs), may influence therapeutic efficacy.

Aims & Methods

This study investigated the potential correlation between four SNPs in four cytokine genes and the response to targeted molecular therapies.
This prospective cohort study enrolled 197 patients with IBD (144 with Crohn’s disease CD and 55 with ulcerative colitis UC) receiving molecularly targeted therapies. The following SNPs were analyzed: TGF-β -cod10 T/C (rs1982073), IL-6 -174 G/C (rs1800795), TNF-α -308 G/A (rs1800629), and IL-10 -1082 G/A (rs1800896). These SNPs were assessed in relation to baseline patient characteristics. Therapeutic response to molecularly targeted therapies (adalimumab, infliximab, ustekinumab, vedolizumab and tofacitinib) was evaluated in two cohorts: 134 patients in the per-protocol analysis (who maintained the drug for 12 months) and 155 patients in the intention-to-treat analysis. Response was also assessed in the cohort receiving anti-TNF agents (infliximab and adalimumab), including 73 patients in the per-protocol cohort and 87 in the intention-to-treat cohort. After 12 months, response was defined as biochemical remission (absence of steroid therapy, CRP <5 mg/L, and fecal calprotectin <250 µg/g).

Results

The TNF-α -308 mutated allele was more frequently associated with CD than UC (the GA polymorphism was present in 33% of patients with CD and in 21% of patients with UC, while the AA polymorphism was present only in patients with CD, at 4.3%; p = 0.020). The wild-type IL-6 -174 SNP was associated with an older age at diagnosis, with a median age of 30y (22-41) vs 25y (19-36) (p = 0.049) and showed a partial association with a lower history of surgical interventions (p = 0.076). In the cohort of patients who had calprotectin and CRP values at T12, only the mutated IL-10 -1082 SNP was significantly associated with response in the per-protocol cohort (73.4% of patients who did not respond to therapy had the wild-type genotype; p = 0.041) [OR = 2.14 (95% CI 1.03–4.44)] and showed a trend toward significance in the intention-to-treat cohort (p = 0.053). Regarding anti-TNF therapy response, the mutated IL-10 -1082 SNP was associated with better therapeutic outcomes in the per-protocol cohort (84.8% of patients who did not respond to therapy had the wild-type genotype; p = 0.034) [OR = 3.36 (95% CI 1.07–10.58)], but not in the intention-to-treat cohort (p = 0.103). Additionally, a statistically significant correlation was found between TNF-α -308 SNP genotypes (wild-type, heterozygous mutated, and homozygous mutated) and response to anti-TNF therapy in the per-protocol cohort (p = 0.040) [OR = 2.82 (95% CI 1.01–7.85)].

Conclusion

Although four cytokine SNPs were analyzed, the most significant associations were observed with the IL-6 polymorphism, where the mutation was linked to a more aggressive disease course, and the IL-10 cytokine SNP, where the CC+GC genotypes appeared to be associated with a better response to target therapies.

Introduction

The therapeutic goal in inflammatory bowel disease (IBD), which includes Crohn´s disease (CD) and ulcerative colitis (UC), is the control of the inflammatory process frequently through biologic and JAK-inhibitor therapies, which are generally expensive and can cause adverse effects. Unfortunately, only about one-third of patients respond to these treatments, and there are no markers that accurately predict this response.

Aims & Methods

The aim of this study was to identify potential serum and urinary metabolic biomarkers predictive of IBD response to different drugs at baseline (before treatment), which could facilitate the selection of the most appropriate therapy for each patient. For this purpose, a prospective multicenter study was conducted including CD and UC patients who initiated biologic (anti-TNF, ustekinumab or vedolizumab) or JAK-inhibitor (tofacitinib) therapies. Patients were assessed at 14 weeks to determine if they had achieved an endoscopic response, based on the SES-CD and on the endoscopic subscore of the Partial Mayo Score. The analyses of the serum and urine metabolome, along with the deconvolution of the serum lipoprotein profile, were performed using nuclear magnetic resonance for a quantitative differential analysis comparing the baseline serum samples of responders and non-responders.

Results

A total of 150 patients were included (30 CD anti-TNF, 30 UC anti-TNF, 30 CD ustekinumab, 30 UC vedolizumab and 30 UC tofacitinib). Metabolomic analysis identified 55 potential predictive biomarkers of IBD treatment response with significantly altered levels (p<0.05) in the baseline urine and serum samples of subsequent responders compared to non-responders. Among them, 44 were drug-specific and none were shared between serum and urine. Moreover, based on ROC curve analysis, some of these biomarkers showed good sensitivity and specificity for distinguishing between responders and non-responders before treatment (Table 1). Finally, the integrated metabolite set enrichment analysis of urine and serum samples identified distinct biological pathways associated with the response to each treatment for IBD, with common pathways highlighted, including the metabolism of short-chain fatty acids, the citrate cycle and the metabolism of amino acids such as alanine, aspartate, glutamate, and arginine.

Conclusion

The present study represents a step towards personalized medicine in the selection of targeted therapies for IBD patients, addressing an important unmet need. Although further validation is needed, we have identified serum and urinary metabolic biomarkers with the potential to predict response to biologic and JAK-inhibitor therapies.

Table 1. Summary of potential metabolic biomarkers identified as predictive of endoscopic response before each IBD treatment.

*Biomarkers with significantly altered levels (p<0.05) in baseline serum or urine samples of responders vs non-responders. **AUC corresponding to the biomarkers with the best sensitivity and specificity for distinguishing between responder and non-responder patients before treatment. AUC: Area Under the Curve calculated using the Metabolanalyst software in univariate analysis; CD: Crohn's disease; IBD: Inflammatory bowel disease; UC: Ulcerative colitis.