Primary Non-responders Research Articles

An in vitro study elucidating the synergistic effects of aqueous cinnamon extract and an anti-TNF-α biotherapeutic: implications for a complementary and alternative therapy for non-responders

BackgroundTumor necrosis factor-alpha (TNF-α) is a critical pro-inflammatory cytokine, and its abnormal production is associated with several immune mediated inflammatory diseases (IMID). Biological anti-TNF-α therapy includes treatment with monoclonal antibodies such as infliximab which have proven successful and are well-tolerated in most patients. Unfortunately, some patients may not respond to therapy (primary non-responders) or may lose sensitivity to the biological agent over time (early and late secondary non-responders). Natural products can reduce inflammation and act synergistically with small molecules or biologics, although evidence remains limited. This study aimed to investigate whether complementary and alternative medicine (CAM) could play a role in infliximab non-responders. Reportedly, cinnamon can help manage chronic inflammatory conditions owing to its anti-inflammatory properties.MethodsWe studied the synergistic effects of cinnamon and infliximab in vitro using a two-step approach. First, we investigated whether cinnamon and infliximab act synergistically. Second, we selected conditions that supported statistically significant synergy with infliximab and studied the mRNA expression of several genes involved in non-response to infliximab. We used aqueous cinnamon extract (aCE) from Cinnamomum cassia, Cinnamomum zeylanicum, and Cinnamomum loureiroi and bioactive trans-cinnamaldehyde (TCA), cinnamic acid (CA), and eugenol to study the synergy between infliximab and aCE/bioactive compounds using bioassays in fibroblast (L929) and monocytic (U937) cell lines, followed by qPCR for molecular-level insights. TCA, C. cassia aCE, and C. zeylanicum aCE demonstrated a dose-dependent synergistic effect with infliximab. Moreover, we saw differential gene expression for adhesion molecules, apoptotic factors, signaling molecules, and matrix remodelers in presence and absence of aCE/bioactives.ResultsCAM supplementation was most effective with C. cassia aCE, where a synergistic effect was observed for all the tested genes specifically for MMP-1, BcL-xL, Bax and JAK2, followed by TCA, which affected most of the tested genes except TLR-2, MMP1, MMP3, TIMP-1, and BAX, and C. zeylanicum aCE, which did not affect ICAM-1, VCAM-1, TLR-2, TLR-4, MMP1, MMP3, TIMP-1, and STAT3.ConclusionIn conclusion, cinnamon acted synergistically with infliximab to mitigate inflammation when used as an extract. Purified bioactive TCA also showed synergistic activity. Thus, aCE, or cinnamon bioactive may be used as a CAM to improve patients’ quality of life.

PREDICTORS OF PRIMARY NON-RESPONSE AND DRUG DURABILITY FOR ADALIMUMAB AND INFLIXIMAB IN PEDIATRIC INFLAMMATORY BOWEL DISEASE

Abstract BACKGROUND Anti-tumor necrosis factor (anti-TNF) therapies have become first-line therapy for children with inflammatory bowel disease (IBD). Studies describing drug durability and loss of response to anti-TNF therapies are limited in children with IBD. This study evaluates predictors of primary non-response and long-term durability in children with IBD. METHODS This was a single-center retrospective review of patients with IBD aged 4-17 years that initiated anti-TNF therapy (infliximab or adalimumab) from January 1, 2014 - December 31, 2019. Clinical and laboratory data were recorded at time of anti-TNF initiation, at 14 weeks, 12 months, and 36 months. Kaplan-Meier analysis and log-rank tests evaluated long-term durability of anti-TNF therapy. Predictors of primary non-response (discontinuation of anti-TNF within 14 weeks) and long-term durability were assessed using Cox regression analysis and time-dependent receiver operating characteristic curves identified cut points. RESULTS A total of 456 patients were initiated on anti-TNF therapy (183 adalimumab (86% CD and 14% UC/IC) and 273 infliximab (69% CD and 31% UC/IC)). Eighty one patients were lost to follow up or transferred care. Thirty seven (8%) patients were considered primary non-responders. Seven of these patients received adalimumab (3 CD, 4 UC/IC) and 30 received infliximab (7 CD, 23 UC/IC). In CD, baseline ESR >31 mm/h was predictive of primary non-response (p<0.05). In UC/IC, mono-therapy at diagnosis, baseline albumin <4 g/dL, and age at diagnosis <15.6 years were significant predictors of primary non-response. Eighty patients discontinued anti-TNF therapy between 14 weeks and 36 months. Reasons for drug discontinuation included loss of response (56%), drug reaction (24%), low therapeutic level/antibodies (19%), miscellaneous (1%). Amongst patients with CD that completed induction, week 14 lab values of albumin >3.9 g/dL, hemoglobin >11.8 g/dL, CRP <1.2 mg/dL and calprotectin <650 ug/g were associated with improved drug durability at 1 year. Patients with UC/IC had improved drug durability at 1 year if they received infliximab compared to adalimumab. The three year drug durability for both adalimumab and infliximab was slightly above 70%. Amongst patients with CD the three year drug durability was nearly 80% for both therapies. The three year drug durability with UC/IC was 37% for adalimumab and 56% for infliximab. CONCLUSIONS Less than 10% of patients are primary non-responders to anti-TNF therapies; higher baseline ESR is a predictor in patients with CD, and a lower baseline albumin and younger age are predictors for patients with UC/IC. At 1 year, patients with a lesser inflammatory burden after induction appeared to have improved drug durability. Three-year durability is >75% for patients with CD on either therapy, while the durability is less for patients with UC/IC.

P918 Can we rely on HLA to predict resistance to biological therapy in Inflammatory Bowel Disease patients?

Abstract Background Monoclonal antibodies revolutionized IBD therapy, although some patients do not respond or progressively loose response due to antidrug antibodies. Immunogenicity seems to be related with HLA haplotypes, namely HLA-DQA1*05 allele associated with an increased risk of immunogenicity to anti-TNF therapy in CD. There are no data regarding the association between HLA-DQA1*05 positivity in UC patients and other biological drugs. Objectives We aim to determine HLA-DQA1*05 prevalence in IBD patients and evaluate its association with loss of response to biological therapy. As a secondary endpoint we aim to evaluate the effect of HLA-DQA1*05 genotype in a composite outcome that encompasses clinical, biochemical, and endoscopic remission at week 54. Methods Single center prospective cohort study, including consecutive adult bio-naïve IBD patients followed at IBD consultation, that initiated biological therapy. Data was collected regarding demographic, disease characterization and disease activity at baseline. All patients were screened for HLA-DQA1*05. Pharmacokinetic data was collected, and biological therapy was adjusted based on standardized protocols. Patients were classified as primary non-responders or as secondary non-responders. Response assessment was carried out at week 54 with a composite outcome that encompasses clinical, biochemical, and endoscopic remission. Statistical analysis: Chi-square test; Student’s t-test; Mann Whitney test; Kaplan-Meier survival analysis. Results We included 100 patients (67 CD, 33 UC), of whom 33 primary non-responders, 12 secondary non-responders and 55 achieved w54 of treatment. Patients started anti-TNF (72 patients, 51 Infliximab and 21 Adalimumab), Vedolizumab (18 patients) or Ustekinumab (10 patients), and 26 were on combined therapy. 43 (43%) patients were HLA-DQA1*05 positive. Kaplan-Meier survival analysis revealed no statistically significant differences in therapy persistence between HLA groups in all patients. However, a Kaplan-Meier survival sub analysis revealed patients under Vedolizumab had significant lower therapy persistence if HLA-DQA1*05 positive (p<0.001). UC´s patients revealed tendency to lower therapy persistence if HLA-DQA1*05 positive, although not statistically significant (p=0.051). HLA-DQA1*05 negative patients under Vedolizumab achieved our composite outcome (p<0,001) and patients under anti-TNF revealed a higher response to the composite outcome but without statistical significance. Conclusion HLA-DQA1*05 genotyping demonstrated no impact in therapy persistence, except in the subgroup of patients treated with Vedolizumab. HLA-DQA1*05 negative patients had a higher response to the composite outcome, but with statistical significance only in Vedolizumab subgroup.

P1197 ERAP2 genetic variant rs2248374 is linked to paradoxical skin reactions induced by TNF-alpha inhibitors in Romanian patients with Inflammatory Bowel Diseases

Abstract Background The endoplasmic reticulum aminopeptidases (ERAPs) are responsible for trimming protein residues to optimal length for major histocompatibility complex class-1 mediated antigen presentation process. Genome-wide association studies have shown the influence of ERAP1 and ERAP2 genetic variants in disease susceptibility for autoimmune disorders. Their role in inflammatory bowel diseases (IBD) however remains obscure due to literature data paucity. The aim of this study was to evaluate the role of a single nucleotide polymorphism (SNP) rs2248374 (G/A) of ERAP2 gene in disease susceptibility and response to treatment in Romanian population with IBD. This SNP is of particular importance because the G allele produces a truncated ERAP2 transcript undergoing nonsense-mediated decay and therefore individuals with GG genotype have no functional ERAP2 enzyme. Methods The study involved 186 IBD patients (87/99 UC/CD, 91M/69F) and 150 healthy controls (77M/73F) all unrelated and of Romanian ethnicity. Extraintestinal manifestations (EIM) were documented in 43 IBD patients (19UC/24BC). Among patients with biological treatment against TNF-alpha (N=113) there were 31 (27.4%) primary non-responders and 13 (11.5%) with paradoxical skin reactions. All subjects were genotyped for ERAP2 rs2248374 (G/A) using TaqMan Allelic Discrimination Assay (C_25649529_10 Real-Time PCR System, Applied Biosystems by Thermo Fisher Scientific, USA). Association tests were performed with OpenEpi online software using Two by Two Table statistics. P-values (2-tail from Mid-P exact test) were considered significant if <0.05. Results Controls and patients were in Hardy-Weinberg equilibrium for the investigated SNP. No significant differences were observed in relation with the risk of disease or with the therapy response. The minor allele A frequency was significantly lower in IBD patients with paradoxical skin reactions (27%) versus patients without these manifestations (50%, p=0.02, OR 0.36). The genotype AA, responsible for full ERAP2 expression, had 0% frequency in the group with adverse skin reactions compared with 23.2% in patients without (p=0.04, OR 0.0). The GG genotype which is related with no ERAP2 protein expression was more frequent in the subgroup of patients with EIM (41.8%) than in patients without EIM (26.7%), showing a marginal association (p=0.06, OR 1.97). Conclusion Our results point to the fact that ERAP2 rs2248374 AA genotype exerts a protective effect over paradoxical skin reaction induced by TNF antagonist agents, and GG genotype shows marginal association with the presence of EIM in Romanian patients with IBD. We consider these results worthy of replication in larger cohorts of patients.

Safety and efficacy of canakinumab treatment for undifferentiated autoinflammatory diseases: the data of a retrospective cohort two-centered study.

The blockade of interleukine-1 (anakinra and canakinumab) is a well-known highly effective tool for monogenic autoinflammatory diseases (AIDs), such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, hyperimmunoglobulinaemia D syndrome, and cryopyrin-associated periodic syndrome, but this treatment has not been assessed for patients with undifferentiated AIDs (uAIDs). Our study aimed to assess the safety and efficacy of canakinumab for patients with uAIDs. Information on 32 patients with uAIDs was retrospectively collected and analyzed. Next-generation sequencing and Federici criteria were used for the exclusion of the known monogenic AID. The median age of the first episode was 2.5 years (IQR: 1.3; 5.5), that of the disease diagnosis was 5.7 years (IQR: 2.5;12.7), and that of diagnostic delay was 1.1 years (IQR: 0.4; 6.1). Patients had variations in the following genes: IL10, NLRP12, STAT2, C8B, LPIN2, NLRC4, PSMB8, PRF1, CARD14, IFIH1, LYST, NFAT5, PLCG2, COPA, IL23R, STXBP2, IL36RN, JAK1, DDX58, LACC1, LRBA, TNFRSF11A, PTHR1, STAT4, TNFRSF1B, TNFAIP3, TREX1, and SLC7A7. The main clinical features were fever (100%), rash (91%; maculopapular predominantly), joint involvement (72%), splenomegaly (66%), hepatomegaly (59%), lymphadenopathy (50%), myalgia (28%), heart involvement (31%), intestinal involvement (19%); eye involvement (9%), pleuritis (16%), ascites (6%), deafness, hydrocephalia (3%), and failure to thrive (25%). Initial treatment before canakinumab consisted of non-biologic therapies: non-steroidal anti-inflammatory drugs (NSAID) (91%), corticosteroids (88%), methotrexate (38%), intravenous immunoglobulin (IVIG) (34%), cyclosporine A (25%), colchicine (6%) cyclophosphamide (6%), sulfasalazine (3%), mycophenolate mofetil (3%), hydroxychloroquine (3%), and biologic drugs: tocilizumab (62%), sarilumab, etanercept, adalimumab, rituximab, and infliximab (all 3%). Canakinumab induced complete remission in 27 patients (84%) and partial remission in one patient (3%). Two patients (6%) were primary non-responders, and two patients (6%) further developed secondary inefficacy. All patients with partial efficacy or inefficacy were switched to tocilizumab (n = 4) and sarilumab (n = 1). The total duration of canakinumab treatment was 3.6 (0.1; 8.7) years. During the study, there were no reported Serious Adverse Events (SAEs). The patients experienced non-frequent mild respiratory infections at a rate that is similar as before canakinumab is administered. Additionally, one patient developed leucopenia, but it was not necessary to stop canakinumab for this patient. The treatment of patients with uAIDs using canakinumab was safe and effective. Further randomized clinical trials are required to confirm the efficacy and safety.

Therapeutic advancement in inflammatory bowel disease by incorporating plant-based diet.

Identification and recognition of the ubiquitous environmental factor are prerequisite for treatment and prevention of the disease. The biggest problem with current practice in inflammatory bowel disease (IBD) is the lack of a widely appreciated ubiquitous environmental factor for the disease. The incidence of IBD is associated with dietary transition from a traditional diet to the current (westernized) diet. Prospective cohort studies and case-control studies indicate that the current diet is a risk factor for IBD. The current diet tends to cause gut microbial dysbiosis resulting in a pro-inflammatory state. Therefore, we regard our current diet as this factor. Even nutritionally balanced meals are unable to suppress relapse, particularly in Crohn's disease (CD). Therefore, we developed a plant-based diet (PBD) (lacto-ovo-semi-vegetarian diet) to counter the current diet. By incorporating the PBD into practice, we achieved far better outcomes in both ulcerative colitis (UC) and CD in both the induction and quiescent phases compared to the current standard therapy. All patients were treated on an inpatient basis and provided with a PBD. CD is far more untenable than UC and is destined to follow a disabling course. Therefore, infliximab was indicated in all patients with CD, but only in severe cases with UC. This infliximab and PBD as first-line (IPF) therapy broke the barrier of primary nonresponders to biologics (around 30%): the remission rate was 96% (44/46) in CD and 76% (13/17) in severe UC. A PBD can induce remission without medication in approximately one-third of mild cases of UC. All patients were advised to adhere PBD after discharge. In CD, a relapse-free outcome was achieved in nearly a half of patients (52%) at 10-year follow-up without biologics or immunosuppressants. Cumulative relapse rates for 51 initial episode cases of UC (18 mild, 30 moderate, 3 severe) at 1 and 5 years were 14% and 27%, respectively. We believe our assertion that the current diet is the ubiquitous environmental factor underlying IBD is correct and a PBD is right diet for the disease.

The Effectiveness and Safety of First-Line Thioguanine in Thiopurine-Naïve Inflammatory Bowel Disease Patients.

Currently thioguanine is solely used as treatment for inflammatory bowel disease after azathioprine and/or mercaptopurine failure. This study aimed to determine the safety, effectiveness, and 12-month drug survival of thioguanine in thiopurine-naïve patients with inflammatory bowel disease. A retrospective cohort study was performed in thiopurine-naïve patients with inflammatory bowel disease treated with thioguanine as first thiopurine derivate. Clinical effectiveness was defined as the continuation of thioguanine without the (re)initiation of concurrent biological therapy, systemic corticosteroids, or a surgical intervention. All adverse events were categorized by the Common Terminology Criteria for Adverse Events. A total of 114 patients (male 39%, Crohn's disease 53%) were included with a median treatment duration of 25 months and a median thioguanine dosage of 20 mg/d. Clinical effectiveness at 12 months was observed in 53% of patients, and 78% of these responding patients remained responsive until the end of follow-up. During the entire follow-up period, 26 patients were primary nonresponders, 8 had a secondary loss of response, and 11 patients were unable to cease therapy with systemic corticosteroids within 6 months and were therefore classified as nonresponders. After 12 months, thioguanine was still used by 86% of patients. Fifty (44%) patients developed adverse events (grade 1 or 2) and 9 (8%) patients ceased therapy due to the occurrence of adverse events. An infection was documented in 3 patients, none of them requiring hospitalization and pancytopenia occurred in 2 other patients. No signs of nodular regenerative hyperplasia or portal hypertension were observed. At 12 months, first-line thioguanine therapy was clinically effective in 53% of thiopurine-naïve inflammatory bowel disease patients with an acceptable safety profile.

Lessons about Botulinum Toxin A Therapy from Cervical Dystonia Patients Drawing the Course of Disease: A Pilot Study.

To compare the course of severity of cervical dystonia (CD) before and after long-term botulinum toxin (BoNT) therapy to detect indicators for a good or poor clinical outcome. A total of 74 outpatients with idiopathic CD who were continuously treated with BoNT and who had received at least three injections were consecutively recruited. Patients had to draw the course of severity of CD from the onset of symptoms until the onset of BoNT therapy (CoDB graph), and from the onset of BoNT therapy until the day of recruitment (CoDA graph) when they received their last BoNT injection. Mean duration of treatment was 9.6 years. Three main types of CoDB and four main types of CoDA graphs could be distinguished. The demographic and treatment-related data of the patients were extracted from the patients' charts. The best outcome was observed in those patients who had experienced a clear, rapid response in the beginning. These patients had been treated with the lowest doses and with a low number of BoNT preparation switches. The worst outcome was observed in those 17 patients who had drawn a good initial improvement, followed by a secondary worsening. These secondary nonresponders had been treated with the highest initial and actual doses and with frequent BoNT preparation switches. A total of 12 patients were primary nonresponders and did not experience any improvement at all. No relation between the CoDB and CoDA graphs could be detected. Primary and secondary nonresponses were observed for all three CoDB types. The use of initial high doses as a relevant risk factor for the later development of a secondary nonresponse was confirmed. Patients' drawings of their course of disease severity helps to easily detect "difficult to treat" primary and secondary nonresponders to BoNT on the one hand, but also to detect "golden responders" on the other hand.

Anti-TNF Biologicals Enhance the Anti-Inflammatory Properties of IgG N-Glycome in Crohn's Disease.

Crohn's disease (CD) is a chronic inflammation of the digestive tract that significantly impairs patients' quality of life and well-being. Anti-TNF biologicals revolutionised the treatment of CD, yet many patients do not adequately respond to such therapy. Previous studies have demonstrated a pro-inflammatory pattern in the composition of CD patients' immunoglobulin G (IgG) N-glycome compared to healthy individuals. Here, we utilised the high-throughput UHPLC method for N-glycan analysis to explore the longitudinal effect of the anti-TNF drugs infliximab and adalimumab on N-glycome composition of total serum IgG in 198 patients, as well as the predictive potential of IgG N-glycans at baseline to detect primary non-responders to anti-TNF therapy in 1315 patients. We discovered a significant decrease in IgG agalactosylation and an increase in monogalactosylation, digalactosylation and sialylation during the 14 weeks of anti-TNF treatment, regardless of therapy response, all of which suggested a diminished inflammatory environment in CD patients treated with anti-TNF therapy. Furthermore, we observed that IgG N-glycome might contain certain information regarding the anti-TNF therapy outcome before initiating the treatment. However, it is impossible to predict future primary non-responders to anti-TNF therapy based solely on IgG N-glycome composition at baseline.

Estimating tissue-specific TNF mRNA levels prior to anti-TNFα treatment may support therapeutic optimisation in IBD patients

Background and aims Tumour necrosis factor-α (TNF) antagonists have improved the management of inflammatory bowel disease (IBD), however, their usage and administration persist to be suboptimal. Here, we examined the relationship between tissue-specific TNF mRNA expression in mucosal biopsies from IBD patients and anti-TNF treatment response. Methods Archived tissue samples from patients with luminal IBD that had all been or were in treatment with anti-TNF were included (18 adults and 24 paediatric patients). Patients were stratified into three groups according to anti-TNF response: responders, primary non-responders (PNR) and secondary loss of response (SLOR). TNF mRNA was detected using RNAscope in situ hybridisation (ISH) and the expression was quantified using image analysis. Results The ISH analysis showed varying occurrence of TNF mRNA positive cells located in lamina propria and often with increased density in lymphoid follicles (LF). Consequently, expression estimates were obtained in whole tissue areas with and without LF. Significantly higher TNF mRNA expression levels were measured in adults compared to paediatric patients in both the analyses with and without LF (p = .015 and p = .016, respectively). Considering the relation to response, the adult and paediatric patients were evaluated separately. In adults, the TNF expression estimates were higher in PNRs compared to responders with and without LF (p = .017 and p = .024, respectively). Conclusion Our data indicate that adult PNR have significantly higher TNF mRNA levels than responders. This suggests that higher anti-TNF dose may be considered for IBD patients with high TNF mRNA expression estimates from the start of treatment.

Incorporation of Plant-Based Diet Surpasses Current Standards in Therapeutic Outcomes in Inflammatory Bowel Disease

There has been no study of the therapeutic effect of a plant-based diet (PBD) in inflammatory bowel disease (IBD) except for our studies in Japan. In this review, we describe the rationale for the requirement of PBD in IBD and the outcomes of our modality incorporating PBD together with a literature review. The biggest problem in current therapy for IBD is the lack of a widely appreciated ubiquitous environmental factor in IBD. Therefore, a radical strategy against IBD has not been established. Japanese data showed an increased incidence of IBD in association with dietary westernization. Current global consumption consists of an excess of unhealthy foods and a shortage of healthy foods recognized as pro-inflammatory. Patients with IBD are no exception. One of the recommended healthy reference diets is PBD recognized as anti-inflammatory. We assert that IBD occurs in susceptible individuals mainly as a result of our omnivorous (westernized) diet. Therefore, we developed and began to provide a PBD, a lacto-ovo-vegetarian diet, for IBD patients in 2003. Infliximab and PBD as first-line (IPF) therapy was administered for all patients with newly developed Crohn's disease (CD) and for severe ulcerative colitis (UC). Our modality broke the barrier of primary nonresponders to biologics, with a remission rate of 96% in CD, and created a new relapse-free course in slightly over half of the patients (52%) with CD. Based on the rationale derived from available evidence and the clinical outcomes, PBD is highly recommended for IBD.

P510 Comparative effectiveness of Ustekinumab against other biologics in Inflammatory Bowel Disease: a propensity score analysis.

Abstract Background Background: Increasing evidence supports the use of Ustekinumab (USTK) in patients with moderate to severe Crohn’s disease (CD) and Ulcerative colitis (UC). Comparison of USTK against other biologics is still lacking. Methods AIMS: to perform a propensity score analysis (PSA) for comparison of USTK against conventional Infliximab (IFX), proactive IFX and vedolizumab in CD and UC Methods retrospective study including patients under Ustekinumab (n=71), Vedolizumab (n=98), conventional IFX (n=70) and proactive IFX (n=148). PSA correcting for age, gender, IBD subtype, previous biologic exposure was performed for each comparison. We compared the rates of fecal calprotectin (Fc) remission (<150 µg/g), treatment discontinuation, hospitalization, and surgery at 52 weeks of treatment. Primary non-responders were excluded. Results Results: after PSP, ustekinumab showed lower rates of treatment discontinuation compared to vedolizumab (7.4% vs 37%, P< 0.001) with a trend for higher rates of Fc remission (42.6% vs 25.9%, P=0.104). Ustekinumab showed higher rates of Fc remission compared to conventional IFX (53.8% vs 19.2%, P= 0.020) with a trend for lower rates of hospitalization (7.7% vs 30.8%, P= 0.075). There were no differences between ustekinumab and proactive IFX in any of the clinical outcomes. Conclusion Conclusion: taking into account the potential limitations of PSP, our results suggest that ustekinumab may be as effective as proactive IFX with some benefits compared to vedolizumab and conventional IFX.

P591 Negative impact of high body mass index on the efficacy of anti-TNFα agents in patients with Inflammatory Bowel Disease

Abstract Background Anti-tumor necrosis factor (TNF)-α agents are a therapy of choice in the induction and maintenance treatment of inflammatory bowel disease (IBD). Unfortunately, their efficacy varies. Some IBD patients are primary non-responders and many will experience a secondary loss of response. However, we do not yet have good predictors of their efficacy. Obesity, which prevalence increases worldwide, is also increasingly found in IBD population. Some studies suggest an association between obesity and poorer response to anti-TNFα therapy in IBD patients, although with conflicting results. The aim of this study is to assess the impact of patients’ body mass index (BMI) on the efficacy of anti-TNFα agents in IBD and if there is difference according to the route of administration (intravenous (IV) vs subcutaneous (SC)) or the type of disease (Crohn’s disease (CD) vs ulcerative colitis (UC)). Methods We retrospectively collected data from 188 patients with IBD, aged ≥ 18 years, treated with a first anti-TNFα agent started in our center between January 2002 and December 2020 to avoid missing data. A lack or loss of response to anti-TNFα therapy was defined by the need to optimize or change the treatment or by the initiation of any intercurrent treatment (steroid therapy, hospitalization, or surgery). Frequency of the event and time to its occurrence were analyzed and compared according to BMI using uni- and multivariate logistic regression models and survival curves (Kaplan-Meier), represented by BMI categories (<18.5; 18.5-25; 25-30 and ≥ 30 kg/m²). Results In this cohort of 188 patients (143 CD, 43 UC, 2 Indeterminate Colitis), 8% were obese. We observed that the higher the patient’s BMI, the earlier the risk of optimization or change of treatment (HR=1.043, p=0.045). Association was even stronger for obese patients (HR=2.13, p=0.018). After adjustment for IBD type and administration route, association with obesity persisted. Two other characteristics - female gender (HR=1.56, p=0.012) and higher CRP (HR=1.14, p=0.021) – were associated with earlier optimization or treatment change. Similarly, analysis of survival curves showed a significant difference in time to optimization or change of treatment between BMI categories in patients with CD (p=0.02) but not in those with UC (p=0.87). No association was found between BMI and need for intercurrent treatment. Conclusion This study confirms an association between higher BMI – specifically obesity - and an earlier loss of efficacy of a first anti-TNFα treatment, regardless of IBD type or route of drug administration. Prospective studies with analysis of trough levels are required for a better understanding of the mechanisms involved in the response to anti-TNFα therapy in IBD obese patient.

Predictive factors of response to infliximab therapy in Brazilian inflammatory bowel disease patients.

Biological therapies have revolutionized the treatment of patients with inflammatory bowel disease (IBD). Infliximab (IFX) has been shown to be effective in inducing and maintaining remission in patients with Crohn's disease and ulcerative colitis. However, about one-third of the patients are primary non-responders, and up to half can lose response over time. Hence, it is important to assess which factors are related to treatment failure. We aimed to identify factors predicting clinical and endoscopic remission with IFX treatment during maintenance therapy in a Brazilian IBD referral center. We conducted a cross-sectional study to describe demographic, clinical, and IBD therapy-related characteristics of IBD patients treated with IFX for at least 6 months in a Brazilian referral center. Subsequently, we evaluated factors associated with clinical and endoscopic remission (primary and secondary outcomes, respectively). We used descriptive statistics to summarize the essential demographic and clinical characteristics of the population. The association of sociodemographic and clinical variables with outcomes was analyzed using multivariable logistic regression. A total of 131 IBD patients (the mean age 41.7 years) were enrolled in this study. Clinical and endoscopic remission were observed in 79.4% and 58.2% of the patients, respectively. In the multivariable analysis, IFX therapy duration and higher albumin levels increased the likelihood of clinical remission, while previous surgery decreased its chance. Prior use of adalimumab and higher C-reactive protein levels reduced the likelihood of endoscopic remission. In summary, this study has enhanced our understanding of the predictive factors of treatment response to IFX in a well-characterized Brazilian IBD population. 4.254.501 and 2.903.748.

Pharmacodynamic mechanisms behind a refractory state in inflammatory bowel disease

Background and aimsBiological therapy for inflammatory bowel disease is efficient in many cases but not all. The underlying molecular mechanisms behind non-response to biological therapy in inflammatory bowel disease are poorly described. Therefore, we aimed to characterize the mucosal cytokine transcript profile in non-immunogenic, non-responder patients with adequate trough level.Material and methodsPatients with ulcerative colitis (UC) (n = 21) and Crohn’s disease (CD) (n = 12) with non-response to biological therapy (anti-tumor necrosis factor (TNF) or vedolizumab) were included. Reference groups were A: untreated patients with UC or CD at debut of disease who had severe 1-year outcome, B: patients with UC or CD treated to endoscopic remission with biological agents, and C: healthy normal controls. Mucosal transcripts of TNF, interleukin (IL)17 and IL23 were measured by reverse transcription real-time quantitative polymerase chain reaction.ResultsOf the non-responders, 2 out of 12 CD and 1 out of 21 UC patients needed surgery during follow-up. Of the remaining non-responding patients, 8 out of 10 CD and 12 out of 20 UC patients switched biologic treatment. The remaining 2 CD and 8 UC patients continued treatment with the same biological agent with the addition of steroids, immunomodulators (AZA/MTX) and /or local steroids/5ASA. Twelve (8 UC/4 CD) out of 20 IBD patients were still non-responders after changing biological therapy to either anti-TNF (2), vedolizumab (9) or ustekinumab (1).The transcripts of IL17, IL23 and TNF were significantly upregulated in the non-response group compared to normal controls and patients in remission. In UC, 24% of the non-responders had normal mucosal TNF transcript indicating a non-TNF mediated inflammation. No obvious differences in gene expression were observed between primary and secondary non-responders, nor between anti-TNF and vedolizumab non-responders.ConclusionsMucosal transcripts of IL17 and IL23 are highly associated with non-response to biological therapy, whereas some UC patients may also have a non-TNF mediated inflammatory pathway.

S1052 Characterization of Crohn’s Patients That Are Multiple Primary Non-Responders to Biologic Therapies

S1052 Characterization of Crohn’s Patients That Are Multiple Primary Non-Responders to Biologic Therapies

Mucosal Eosinophil Abundance in Non-Inflamed Colonic Tissue Is Associated with Response to Vedolizumab Induction Therapy in Inflammatory Bowel Disease.

Vedolizumab is used as a treatment for patients with inflammatory bowel disease (IBD), but induction therapy leads to clinical response and remission in approximately 55% and 30% of patients with IBD, respectively. In this study, we aimed to explore the predictive value of mucosal eosinophils and serum eotaxin-1 regarding response to vedolizumab induction therapy. Eighty-four (84) patients with IBD (37 Crohn’s disease [CD], 47 ulcerative colitis [UC]) were included. For 24 patients with IBD, histopathology was assessed for eosinophil counts in non-inflamed colonic tissue prior to vedolizumab treatment. For 64 patients with IBD, serum eotaxin-1 levels were quantified prior to (baseline) and during vedolizumab treatment. Serum samples of 100 patients with IBD (34 CD, 66 UC) from the GEMINI 1 and 2 trials were used for external validation. Baseline mucosal eosinophil numbers in non-inflamed colonic tissue were significantly higher in responders to vedolizumab induction therapy when compared to primary non-responders (69 [34–138] vs. 24 [18–28] eosinophils/high-power field, respectively, p < 0.01). Baseline serum eotaxin-1 levels in the discovery cohort were significantly elevated in responders, compared to primary non-responders (0.33 [0.23–0.44] vs. 0.20 [0.16–0.29] ng/mL, p < 0.01). Prediction models based on mucosal eosinophil counts and serum eotaxin-1 showed an area under the curve (AUC) of 0.90 and 0.79, respectively. However, the predictive capacity of baseline serum eotaxin-1 levels could not be validated in the GEMINI cohort. Mucosal eosinophil abundance in non-inflamed colonic tissue was associated with response to vedolizumab induction therapy in patients with IBD. Future studies are warranted to further validate the potential value of mucosal eosinophils and serum eotaxin-1 as biomarkers for response to vedolizumab therapy.

Immune Response after mRNA COVID-19 Vaccination in Lung Transplant Recipients: A 6-Month Follow-Up.

Background and objective: This prospective cohort study analyzed the immune response to COVID-19 mRNA vaccines in lung transplant recipients (LuTRs) compared to healthy controls (HCs) at a 6-month follow-up. Methods: After the first two doses of either BNT162b2 or mRNA-1273, SARS-CoV-2 antibodies were measured in LuTRs (n = 57) and sex- and age-matched HCs (n = 57). Antibody kinetics during a 6-month follow-up and the effect of a third vaccine dose were evaluated. Humoral responses were assessed using the Elecsys® Anti-SARS-CoV-2 S immunoassay. In 16 LuTRs, SARS-CoV-2-specific T cell responses were quantified using IFN-γ ELISpot assays. Results: Seroconversion rates were 94% and 100% after the first and second vaccine dose, respectively, in HCs, while only 19% and 56% of LuTRs developed antibodies. Furthermore, 22 of 24 LuTRs who received the third vaccine dose showed seroconversion (five of seven primary non-responders and 17 of 17 primary responders). A T cell response against SARS-CoV-2-spike S1 and/or S2 was detected in 100% (16/16) of HCs and 50% (8/16) of LuTRs. Conclusions: The data suggest that LuTRs have reduced humoral and cellular immune responses after two doses of COVID-19 mRNA vaccination when compared to HCs. A third dose may be of substantial benefit.

Reference Values for Weight Loss During 1 Year After Sleeve Gastrectomy: a Multicenter Retrospective Study in Japan.

This study aimed to provide reference values for the percentage total weight loss during 1year after laparoscopic sleeve gastrectomy associated with primary response in Japan. This multicenter retrospective study comprised 248 patients with severe obesity who underwent laparoscopic sleeve gastrectomy at five institutions in Japan. A percentage total weight loss < 20% at 1year was defined as primary non-response. Parsimonious predictive models were developed based on the results of multiple regression analyses. A receiver operating characteristic curve analysis was used to assess the discriminative performance for primary non-response. The median age, initial body mass index, and percentage total weight loss at 1year were 41years, 41.4kg/m2, and 30.1%, respectively. There were 28 (11.3%) primary non-responders. For discriminating primary non-responders, the areas under the receiver operating characteristic curve of the parsimonious model and actual percentage of total weight loss at 3months after laparoscopic sleeve gastrectomy were 0.846 and 0.803, respectively. Cutoffs for the predicted percentage total weight loss using the model and actual value of percentage total weight loss at 3months attaining 80% sensitivity were 30% and 22%, and those attaining 98% specificity were 22% and 15%, respectively. Reference values for the percentage total weight loss at 3months were obtained using the predictive model and actual value of percentage total weight loss at 3months. Patients at risk for primary non-response can be determined at 3months with these values, which can help in considering earlier interventions.

Booster COVID-19 Vaccines for Immune-Mediated Inflammatory Disease Patients: A Systematic Review and Meta-Analysis of Efficacy and Safety.

Background: Seroconversion and longevity of vaccine-induced immune response is blunted in immune-mediated inflammatory disease (IMID) patients owing to immunosuppressive regimens. COVID-19 booster vaccines after a primary series have been proposed with inconclusive evidence on efficacy to date. Methods: This PROSPERO-registered systematic review (CRD42022302534) was conducted according to PRISMA guidelines. PubMed, EMBASE, CENTRAL, Web of Science, CORD-19, WHO ICTRP, and medRxiv were searched up to 28 February 2022 for eligible studies. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal tools. Results: From 6647 records, 17 prospective studies were included for systematic review and 12 in meta-analysis of primary series non-responders. The risk of bias was low. Pooling 340 non-responders, a booster dose proved effective with 0.47 seroconverting (95% CI: 0.32–0.63, I2 = 82%). Rituximab therapy was associated with significant impairment, with risks of 0.25 (95% CI: 0.17–0.36, I2 = 50.7%) versus 0.81 (95% CI: 0.72–0.87, I2 = 0.0%) for those without rituximab therapy. A systematic review of antibody levels against COVID-19 showed several-fold increases across studies. Incidence of local and systemic adverse events, including disease flares, were either comparable or slightly increased after the booster dose compared to primary series. No major events such as myocarditis or death were reported. Conclusion: Our results show that booster doses are effective in eliciting seroconversion in non-responders, bolstering immunity to COVID-19. It has also not been associated with major adverse events.