anti-TNF Drugs Research Articles

Discontinuation of anti-tumour necrosis factor alphatreatment owing to blood test abnormalities, and cost-effectiveness of alternate blood monitoring strategies.

There is no evidence base to support the use of 6-monthly monitoring blood tests for the early detection of liver, blood and renal toxicity during established anti-tumour necrosis factor alpha (TNFα) treatment. To evaluate the incidence and risk factors of anti-TNFα treatment cessation owing to liver, blood and renal side-effects, and to estimate the cost-effectiveness of alternate intervals between monitoring blood tests. A secondary care-based retrospective cohort study was performed. Data from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR) were used. Patients with at least moderate psoriasis prescribed their first anti-TNFα treatment were included. Treatment discontinuation due to a monitoring blood test abnormality was the primary outcome. Patients were followed-up from start of treatment to the outcome of interest, drug discontinuation, death, 31 July 2021 or up to 5 years, whichever came first. The incidence rate (IR) and 95% confidence intervals (CIs) of anti-TNFα discontinuation with monitoring blood test abnormality was calculated. Multivariate Cox regression was used to examine the association between risk factors and outcome. A mathematical model evaluated costs and quality-adjusted life years (QALYs) associated with increasing the length of time between monitoring blood tests during anti-TNFα treatment. The cohort included 8819 participants [3710 (42.1%) female, mean (SD) age 44.76 (13.20) years] that contributed 25 058 person-years (PY) of follow-up and experienced 125 treatment discontinuations owing to a monitoring blood test abnormality at an IR of 5.85 (95% CI 4.91-6.97)/1000 PY. Of these, 64 and 61 discontinuations occurred within the first year and after the first year of treatment start, at IRs of 8.62 (95% CI 6.74-11.01) and 3.44 (95% CI 2.67-4.42)/1000 PY, respectively. Increasing age (in years), diabetes and liver disease were associated with anti-TNFα discontinuation after a monitoring blood test abnormality [adjusted hazard ratios of 1.02 (95% CI 1.01-1.04), 1.68 (95% CI 1.00-2.81) and 2.27 (95% CI 1.26-4.07), respectively]. Assuming a threshold of £20 000 per QALY gained, no monitoring was most cost-effective, but all extended periods were cost-effective vs. 3- or 6-monthly monitoring. Anti-TNFα drugs were uncommonly discontinued owing to abnormal monitoring blood tests after the first year of treatment. Extending the duration between monitoring blood tests was cost-effective. Our results produce evidence for specialist society guidance to reduce patient monitoring burden and healthcare costs.

De-escalation of Biologic Treatment in Inflammatory Bowel Disease: A Comprehensive Review.

Biologic therapy is an effective treatment for inflammatory bowel disease [IBD]. However due to cost and safety concerns, dose de-escalation strategies after achieving remission have been suggested. To critically review available data on dose de-escalation of biologics [or other advanced therapies] in IBD. We will focus on studies evaluating de-escalation to standard dosing in patients initially optimised, and also on studies assessing de-escalation from standard dosing. A systematic bibliographic search was performed. The mean frequency of de-escalation after previous dose intensification [12 studies, 1,474 patients] was 34%. The corresponding frequency of de-escalation from standard dosing [five studies, 3,842 patients] was 4.2%. The relapse rate of IBD following anti-tumour necrosis factor [TNF] de-escalation to standard dosing in patients initially dose-escalated [10 studies, 301 patients] was 30%. The corresponding relapse rate following anti-TNF de-escalation from standard dosing [nine studies, 494 patients] was 38%. The risk of relapse was lower for patients in clinical, biologic, and endoscopic/radiological remission at the time of de-escalation. A role of anti-TNF therapeutic drug monitoring in the decision to dose de-escalate has been demonstrated. In patients relapsing after de-escalation, re-escalation is generally effective. De-escalation is not consistently associated with a better safety profile. The cost-effectiveness of the de-escalation strategy remains uncertain. Finally, there is not enough evidence to recommend dose de-escalation of biologics different from anti-TNFs or small molecules. Any consideration for de-escalation of biologic therapy in IBD must be tailored, taking into account the risks and consequences of a flare and patients' preferences.

Prediction of anti-TNF therapy failure in ulcerative colitis patients by ensemble machine learning: A prospective study

Nowadays, anti-TNF therapy remarkably improves the medical management of ulcerative colitis (UC), but approximately 40 % of patients do not respond to this treatment. In this study, we used 79 anti-TNF-naive patients with moderate-to-severe UC from four cohorts to discover alternative therapeutic targets and develop a personalized medicine approach that can diagnose UC non-responders (UCN) prior to receiving anti-TNF therapy. To this end, two microarray data series were integrated to create a discovery cohort with 35 UC samples. A comprehensive gene expression and functional analysis was performed and identified 313 significantly altered genes, among which IL6 and INHBA were highlighted as overexpressed genes in the baseline mucosal biopsies of UCN, whose cooperation may lead to a decrease in the Tregs population. Besides, screening the abundances of immune cell subpopulations showed neutrophils’ accumulation increasing the inflammation. Furthermore, the correlation of KRAS signaling activation with unresponsiveness to anti-TNF mAb was observed using network analysis. Using 50x repeated 10-fold cross-validation LASSO feature selection and a stack ensemble machine learning algorithm, a five-mRNA prognostic panel including IL13RA2, HCAR3, CSF3, INHBA, and MMP1 was introduced that could predict the response of UC patients to anti-TNF antibodies with an average accuracy of 95.3 %. The predictive capacity of the introduced biomarker panel was also validated in two independent cohorts (44 UC patients). Moreover, we presented a distinct immune cell landscape and gene signature for UCN to anti-TNF drugs and further studies should be considered to make this predictive biomarker panel and therapeutic targets applicable in the clinical setting.

OA19 A complex case of bilateral pneumothoraces due to probable certolizumab driven rheumatoid lung nodules

OA19 A complex case of bilateral pneumothoraces due to probable certolizumab driven rheumatoid lung nodules

Precision Dosing of Anti-TNF Therapy in Pediatric Inflammatory Bowel Disease.

This review focuses on recent advancements in anti-TNF therapeutic drug monitoring (TDM), pharmacogenetics and personalized drug selection for children with inflammatory bowel disease (IBD). Several real-world studies and one clinical trial in children have demonstrated that proactive TDM, targeting higher exposure concentrations (> 5µg/mL), can improve disease remission rates and enhance durability of the anti-TNF biologics. Recent data from both adult and pediatric IBD patients have revealed an association between a genetic polymorphism (HLA-DQA1*05) and the development of auto-drug antibodies. The impact of this association on clinical outcomes, considering more routine use proactive TDM and dose optimization in children, is still under investigation. Additionally, recent studies have identified potential inflammatory signatures and biomarkers that may serve as companion diagnostics for anti-TNF biologics. The effective management of anti-TNF therapies in children with IBD requires evidence-based precision dosing strategies, including routine TDM and proactive pharmacodynamic assessments.

Transcriptomic network analysis reveals key drivers of response to anti-TNF biologics in patients with rheumatoid arthritis.

Anti-TNF biologics have been widely used to ameliorate disease activity in patients with RA. However, a large fraction of patients show a poor response to these agents. Moreover, no clinically applicable predictive biomarkers have been established. This study aimed to identify response-associated biomarkers using longitudinal transcriptomic data in two independent RA cohorts. RNA sequencing data from peripheral blood cell samples of Korean and Caucasian RA cohorts before and after initial treatment with anti-TNF biologics were analysed to assess treatment-induced expression changes that differed between highly reliable excellent responders and null responders. Weighted correlation network, immune cell composition, and key driver analyses were performed to understand response-associated transcriptomic networks and cell types and their correlation with disease activity indices. In total, 305 response-associated genes showed significantly different treatment-induced expression changes between excellent and null responders. Co-expression network construction and subsequent key driver analysis revealed that 41 response-associated genes played a crucial role as key drivers of transcriptomic alteration in four response-associated networks involved in various immune pathways: type I IFN signalling, myeloid leucocyte activation, B cell activation, and NK cell/lymphocyte-mediated cytotoxicity. Transcriptomic response scores that we developed to estimate the individual-level degree of expression changes in the response-associated key driver genes were significantly correlated with the changes in clinical indices in independent patients with moderate or ambiguous response outcomes. This study provides response-specific treatment-induced transcriptomic signatures by comparing the transcriptomic landscape between patients with excellent and null responses to anti-TNF drugs at both gene and network levels.

Whole Blood DNA Methylation Changes Are Associated with Anti-TNF Drug Concentration in Patients with Crohn's Disease.

Anti-tumour necrosis factor [TNF] treatment failure in patients with inflammatory bowel disease [IBD] is common and frequently related to low drug concentrations. In order to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy, we sought to define epigenetic biomarkers in whole blood at baseline associated with anti-TNF drug concentrations at week 14. DNA methylation from 1104 whole blood samples from 385 patients in the Personalised Anti-TNF Therapy in Crohn's disease [PANTS] study were assessed using the Illumina EPIC Beadchip [v1.0] at baseline and weeks 14, 30, and 54. We compared DNA methylation profiles in anti-TNF-treated patients who experienced primary non-response at week 14 if they were assessed at subsequent time points and were not in remission at week 30 or 54 [infliximab n = 99, adalimumab n = 94], with patients who responded at week 14 and when assessed at subsequent time points were in remission at week 30 or 54 [infliximab n = 99, adalimumab n = 93]. Overall, between baseline and week 14, we observed 4999 differentially methylated positions [DMPs] annotated to 2376 genes following anti-TNF treatment. Pathway analysis identified 108 significant gene ontology terms enriched in biological processes related to immune system processes and responses. Epigenome-wide association [EWAS] analysis identified 323 DMPs annotated to 210 genes at baseline associated with higher anti-TNF drug concentrations at Week 14. Of these, 125 DMPs demonstrated shared associations with other common traits [proportion of shared CpGs compared with DMPs] including body mass index [23.2%], followed by C-reactive protein [CRP] [11.5%], smoking [7.4%], alcohol consumption per day [7.1%], and IBD type [6.8%]. EWAS of primary non-response to anti-TNF identified 20 DMPs that were associated with both anti-TNF drug concentration and primary non-response to anti-TNF with a strong correlation of the coefficients [Spearman's rho = -0.94, p <0.001]. Baseline DNA methylation profiles may be used as a predictor for anti-TNF drug concentration at week 14 to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy.

Predictors and optimal management of tumor necrosis factor antagonist nonresponse in inflammatory bowel disease: A literature review.

Tumor necrosis factor-α (TNF-α) antagonists, the first biologics approved for treating patients with inflammatory bowel disease (IBD), are effective for the induction and maintenance of remission and significantly improving prognosis. However, up to one-third of treated patients show primary nonresponse (PNR) to anti-TNF-α therapies, and 23%-50% of IBD patients experience loss of response (LOR) to these biologics during subsequent treatment. There is still no recognized predictor for evaluating the efficacy of anti-TNF drugs. This review summarizes the existing predictors of PNR and LOR to anti-TNF in IBD patients. Most predictors remain controversial, and only previous surgical history, disease manifestations, drug concentrations, antidrug antibodies, serum albumin, some biologic markers, and some genetic markers may be potentially predictive. In addition, we also discuss the next steps of treatment for patients with PNR or LOR to TNF antagonists. Therapeutic drug monitoring plays an important role in treatment selection. Dose escalation, combination therapy, switching to a different anti-TNF drug, or switching to a biologic with a different mechanism of action can be selected based on the concentration of the drug and/or antidrug antibodies.

Apoptosis and inflammatory genes variants in primary non-response to anti-TNF therapy in Crohn's disease patients.

Anti-TNF therapy has indeed revolutionized the treatment of Crohn's disease, leading to higher rates of response and remission in patients. However, a significant proportion of 20-40% of patients do not respond to the initial therapy, others experience a secondary loss of response with ongoing treatment. Adverse drug reactions also occur in some patients. The effectiveness of anti-TNF treatment may be influenced by genetic variability, including FCGR3A, ADAM17, TNFRSF1A, TNFRSF1B, FAS, FASL, IL1B, CASP9 , and MIF genes. In this article, we provide an overview of the current knowledge and findings in the pharmacogenetics of anti-TNF drugs in CD focusing on the aspect of apoptosis and inflammatory genes variants in primary non-response. Pharmacogenetic investigations have been conducted to identify genetic markers that can predict response to anti-TNF therapy. However, large multi-center validation studies and multi-loci algorithms development are required to effectively prognose the treatment effect. The identification of predictive markers of response to anti-TNF therapy can help clinicians make informed decisions about treatment options and minimize adverse drug reactions in patients.

Preclinical Characterization of Pharmacologic NAD+ Boosting as a Promising Therapeutic Approach in Rheumatoid Arthritis.

We analyzed NAD+ metabolism in patients with rheumatoid arthritis (RA), its association with disease activity and clinical outcomes of RA, and the therapeutic potential of pharmacologic NAD+ boosting. Our study included 253 participants. In the first cohort, comprising 153 RA patients and 56 healthy donors, we assessed NAD+ levels and NAD+ -related gene pathways. We analyzed 92 inflammatory molecules by proximity extension assay. In the second cohort, comprising 44 RA patients starting anti-tumor necrosis factor (anti-TNF) drugs, we evaluated changes in NAD+ levels and their association with clinical response after 3 months. Mechanistic studies were performed ex vivo on peripheral blood mononuclear cells (PBMCs) from patients with RA to test the beneficial effects of NAD+ boosters, such as nicotinamide and nicotinamide riboside. Reduced NAD+ levels were found in RA samples, in line with altered activity and expression of genes involved in NAD+ consumption (sirtuins, poly[ADP-ribose] polymerase, CD38), transport (connexin 43), and biosynthesis (NAMPT, NMNATs). Unsupervised clustering analysis identified a group of RA patients with the highest inflammatory profile, the lowest NAD+ levels, and the highest disease activity (as shown by the Disease Activity Score in 28 joints). NAD+ levels were modulated by anti-TNF therapy in parallel with the clinical response. In vitro studies using PBMCs from RA patients showed that nicotinamide riboside and nicotinamide increased NAD+ levels via NAMPT and NMNAT and reduced their prooxidative, proapoptotic, and proinflammatory status. RA patients display altered NAD+ metabolism, directly linked to their inflammatory and disease activity status, which was reverted by anti-TNF therapy. The preclinical beneficial effects of NAD+ boosters, as shown in leukocytes from RA patients, along with their proven clinical safety, might pave the way for the development of clinical trials using these compounds.

Characteristic analysis of adverse reactions of five anti-TNFɑ agents: a descriptive analysis from WHO-VigiAccess.

Introduction: Tumor necrosis factor (TNF) inhibitors (adalimumab, infliximab, etanercept, golimumab, and certolizumab pegol) have revolutionized the treatment of severe immune-mediated inflammatory diseases, including rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis. This study assessed adverse drug reactions (ADRs) after the use of TNFα inhibitors in VigiAccess of the World Health Organization (WHO) and compared the adverse reaction characteristics of five inhibitors to select the drug with the least risk for individualized patient use. Methods: The study was a retrospective descriptive analysis method in design. We sorted out five marketed anti-TNFα drugs, and their ADR reports were obtained from WHO-VigiAccess. Data collection included data on the age groups, sex, and regions of patients worldwide covered by ADR reports, as well as data on disease systems and symptoms caused by ADRs recorded in annual ADR reports and reports received by the WHO. By calculating the proportion of adverse reactions reported for each drug, we compared the similarities and differences in adverse reactions for the five drugs. Results: Overall, 1,403,273 adverse events (AEs) related to the five anti-TNFα agents had been reported in VigiAccess at the time of the search. The results show that the 10 most commonly reported AE manifestations were rash, arthralgia, rheumatoid arthritis, headache, pneumonia, psoriasis, nausea, diarrhea, pruritus, and dyspnea. The top five commonly reported AE types of anti-TNFα drugs were as follows: infections and infestations (184,909, 23.0%), musculoskeletal and connective tissue disorders (704,657, 28.6%), gastrointestinal disorders (122,373, 15.3%), skin and subcutaneous tissue disorders (108,259, 13.5%), and nervous system disorders (88,498, 11.0%). The preferred terms of myelosuppression and acromegaly were obvious in golimumab. Infliximab showed a significantly higher ADR report ratio in the infusion-related reaction compared to the other four inhibitors. The rate of ADR reports for lower respiratory tract infection and other infections was the highest for golimumab. Conclusion: No causal associations could be established between the TNFα inhibitors and the ADRs. Current comparative observational studies of these inhibitors revealed common and specific adverse reactions in the ADR reports of the WHO received for these drugs. Clinicians should improve the rational use of these high-priced drugs according to the characteristics of ADRs.

Serologic Response and Safety after a Third Dose of the COVID-19 BNT162b2 Vaccine in Patients with Inflammatory Bowel Diseases.

Vaccines are pivotal for control of the coronavirus disease (COVID-19) pandemic. Patients with inflammatory bowel diseases (IBDs) treated with antitumor necrosis factor (TNF)-α have lower serologic response after two COVID-19 vaccine doses. Data regarding a third vaccine dose are scarce. An Israeli multicenter prospective observational study recruited 319 subjects: 220 with IBD (79 treated with anti-TNFα) and 99 healthy control (HC) participants. All patients received two mRNA-BNT162b2 vaccines (Pfizer/BioNTech), 80% of whom received a third vaccine dose. Evaluation included disease activity, anti-spike (S) and nucleocapsid (N) antibody levels, anti-TNFα drug levels, and adverse events (AEs). All participants showed significant serologic response one month after receiving a third dose. However, three months later, the anti-S levels decreased significantly in patients treated with anti-TNFα compared with the non-anti-TNFα and HC groups. A correlation between serologic response to the third vaccine dose and anti-TNF drug levels was not found. No significant AE or IBD exacerbation was observed. Importantly, lower serologic response after the third vaccine dose predicted infection. A third dose of BNT162b2 is effective and safe in patients with IBD. Lower serologic response predicted infection, even in seropositive subjects. Lower serologic responses and their rapid decline suggest a fourth vaccine dose in this patient population.

Polymorphisms indicating risk of inflammatory bowel disease or antigenicity to anti-TNF drugs as biomarkers of response in children

Few genetic polymorphisms predict early response to anti-TNF drugs in inflammatory bowel disease (IBD), and even fewer have been identified in the pediatric population. However, it would be of considerable clinical interest to identify and validate genetic biomarkers of long-term response. Therefore, the aim of the study was to analyze the usefulness of biomarkers of response to anti-TNFs in pediatric IBD (pIBD) as long-term biomarkers and to find differences by type of IBD and type of anti-TNF drug. The study population comprised 340 children diagnosed with IBD who were treated with infliximab or adalimumab. Genotyping of 9 selected SNPs for their association with early response and/or immunogenicity to anti-TNFs was performed using real-time PCR. Variants C rs10508884 (CXCL12), A rs2241880 (ATG16L1), and T rs6100556 (PHACTR3) (p value 0.049; p value 0.03; p value 0.031) were associated with worse long-term response to anti-TNFs in pIBD. DNA variants specific to disease type and anti-TNF type were identified in the pediatric population. Genotyping of these genetic variants before initiation of anti-TNFs would enable, if validated in a prospective cohort, the identification of pediatric patients who are long-term responders to this therapy.

Frequency of latent tuberculosis in patients receiving Anti-TNF-Alpha therapy.

In this study, it was aimed to reveal the incidence of tuberculosis development in patients receiving tumor necrosis factor-alpha (TNF-α) blocker therapy, despite tuberculosis chemoprophylaxis. 520 patients who were receiving anti TNF-α treatment in the last 3 years were evaluated retrospectively. Radiological imaging tuberculin skin test (TST), history of tuberculosis, BCG vaccine, chemoprophylaxis administration, used anti TNF-α drugs were recorded. There were 265(51.0%) of the patients with ankylosing spondylitis (AS), 175(33.7%) with rheumatoid arthritis, 35(6.7%) with Crohn's, 10(1.9%) with ulcerative colitis (UC), 21(4.0%) with psoriatic arthritis, 14(2.7%) with psoriasis vulgaris. In total, 455 (79.6%) patients were given INH prophylaxis. Active tuberculosis development was observed in five patients (4: pulmonary,1: extrapulmonary; 3: UC, 2:AS) who all received anti TNF-α treatment (0.96%), infliximab. Three patients had tuberculosis disease in the 6th month, and the other 2 patients in the 5th and 24th month of their anti TNF-α treatments, and two had 9-month, and 1 had 6-month chemoprophylaxis history. The incidence of tuberculosis development in patients treated with anti TNF-α was found to be higher than the general population. In our country, where tuberculosis is still prevalent, patients receiving Anti TNF-α treatment (especially infliximab) should be carefully questioned and examined about tuberculosis.

Refractory multisystemic sarcoidosis, a diagnosis and treatment challenge: a case report

BackgroundSarcoidosis is a multisystemic granulomatous disease of unknown origin. It is characterized by abnormal activation of lymphocytes and macrophages with the formation of granulomas. Most cases have asymptomatic pulmonary involvement. In case of symptoms, they have an excellent response to glucocorticoid therapy. We present a case of sarcoidosis with multi-organ involvement, refractory to multiple treatments including biological. Partial remission was achieved in it.Case presentationWe report an interesting case of a 38-years-old Spanish woman treated by Heerfordt’s syndrome (uveitis, parotiditis, fever and facial palsy) plus pulmonary hiliar adenopathy. A sarcoidosis diagnosis was confirmed by lung biopsy. She was initially treated with an 8 weeks course of medium dose oral glucocorticoids and tapered over 8 weeks with improvement. After the suspension of glucocorticoids a relapse occurs with severe ocular involvement and suspicion of neurological involvement. The patient received multiple lines of treatment with poor response. Finally, after the combination of cyclophosphamide with infliximab, the uveitis resolved, improving the neurological symptoms.ConclusionsSarcoidosis is a benign disease in most cases. In a small percentage of cases behaves aggressively, requiring early diagnosis and immunosuppressive treatment to avoid sequelae. An adequate immunosuppressive therapy based on Anti TNF drugs should be started to minimize damage and improve the quality of life.The choice of treatment depends on the type and severity of the disease.

The Role of Low-Dose Oral Methotrexate in Increasing Anti-TNF Drug Levels and Reducing Immunogenicity in IBD

Concomitant immunomodulation is utilised in combination with anti-TNF therapy for IBD primarily to increase drug levels and prevent anti-drug antibody formation. Whilst thiopurines have traditionally been the immunomodulator of choice in IBD populations, there are concerns regarding the long-term safety of the prolonged use of these agents: particularly an association with lymphoproliferative disorders. Given this, we have explored the existing literature on the use of low-dose oral methotrexate as an alternative immunomodulator for this indication. Although there is a lack of data directly comparing the efficacies of methotrexate and thiopurines as concomitant immunomodulators, the available literature supports the use of methotrexate in improving the pharmacokinetics of anti-TNF agents. Furthermore, low-dose oral methotrexate regimens appear to have comparable efficacies to higher-dose parenteral administration and are better tolerated. We suggest that clinicians should consider the use of low-dose oral methotrexate as an alternative to thiopurines when the primary purpose of concomitant immunomodulation is to improve anti-TNF pharmacokinetics.

Self-reported treatment effectiveness for Crohn's disease using a novel crowdsourcing web-based platform.

Internet and social media platforms have become an unprecedented source for sharing self-experience, potentially allowing the collection and integration of health data with patient experience. StuffThatWorks (STW) is an online open platform that applies machine learning and the power of crowdsourcing, where patients with chronic medical conditions can self-report and compare their individual outcomes using a structured online questionnaire. We aimed to conduct a cross-sectional, international, crowdsourcing, artificial-intelligence (AI) web-based study of patients with Crohn's disease (CD) self-reporting their outcomes. A proprietary STW Bayesian inference model was built to measure improvement in CD severity (on scale of 1-5) for each treatment and ranked treatments using effectiveness. The effectiveness of first-line biological treatments was analyzed by multiple comparisons and by calculating odds ratios and 95% confidence intervals for each treatment pair. We included 7593 self-reported CD patients for the analysis. Most of the participants were female (75.8%) and from English-speaking countries (95.7%). Overall, anti-TNF drugs were the most reported tried treatment (52.8%). Infliximab (IFX) was ranked as the most effective treatment by the STW effectiveness model followed by bowel surgery (second), adalimumab (ADA, third), ustekinumab (UST, 4rd), and vedolizumab (VDZ, fifth). In paired comparison analyses, IFX was most effective, ADA had similar effectiveness compared to UST and all three were more effective than VDZ. We present the first online crowdsourcing AI platform-based study of self-reported treatment effectiveness in CD. Net-based crowdsourcing patient-reported outcome platforms can potentially help both clinicians and patients select the best treatment for their condition.

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.

Infections in inflammatory bowel disease patients on immunomodulator and biologic therapy are not associated with high serum drug levels.

Inflammatory bowel disease (IBD) therapies now utilise higher doses of immunomodulatory and biologic therapies, predisposing patients to an increased risk of infections. We aimed to determine whether infections were associated with high anti-tumour necrosis factor (TNF) drug levels in IBD and to quantify the risk and consequences of infections. Two retrospective studies were performed, a descriptive cohort study and a matched case-control study. For the matched case-control study, cases of infection occurring on anti-TNF agents were matched in a 1:2 ratio to controls of anti-TNF treated patients without infections. In the descriptive study, 76 infections occurred in 60 patients, including 49 bacterial, 24 viral, four fungal and four parasitic. Of these, 61 (80.3%) were on biologics, 49 (64.5%) on immunomodulators and 11 (14.5%) on corticosteroids. Thirty-four (44.7%) were on combination therapy, 27 (35.5%) on biologic monotherapy and 15 (19.7%) on immunomodulator monotherapy. Median anti-TNF drug levels in infection cases were 3.9 μg/mL for infliximab and 6.0 μg/mL for adalimumab. In the case-control study, 32 cases of infection in 27 anti-TNF treated patients were matched with 64 anti-TNF treated controls without infections. Among infection cases, 59.5% were on combination therapy versus 40.6% on biologic monotherapy (P = 0.59). Median drug levels for cases and controls respectively were 3.9 μg/mL versus 5.5 μg/mL for infliximab (P = 0.72) and 6.0 μg/mL versus 9.9 μg/mL for adalimumab (P = 0.34). Infections in patients with IBD were common, and the risk was highest with combination therapy. Infections were not associated with high serum anti-TNF levels.

Development of a Prediction Model for Short-Term Remission of Patients with Crohn's Disease Treated with Anti-TNF Drugs.

Therapy with anti-tumor necrosis factor (TNF) has dramatically changed the natural history of Crohn's disease (CD). However, these drugs are not without adverse events, and up to 40% of patients could lose efficacy in the long term. We aimed to identify reliable markers of response to anti-TNF drugs in patients with CD. A consecutive cohort of 113 anti-TNF naive patients with CD was stratified according to clinical response as short-term remission (STR) or non-STR (NSTR) at 12 weeks of treatment. We compared the protein expression profiles of plasma samples in a subset of patients from both groups prior to anti-TNF therapy by SWATH proteomics. We identified 18 differentially expressed proteins (p ≤ 0.01, fold change ≥ 2.4) involved in the organization of the cytoskeleton and cell junction, hemostasis/platelet function, carbohydrate metabolism, and immune response as candidate biomarkers of STR. Among them, vinculin was one of the most deregulated proteins (p < 0.001), whose differential expression was confirmed by ELISA (p = 0.054). In the multivariate analysis, plasma vinculin levels along with basal CD Activity Index, corticosteroids induction, and bowel resection were factors predicting NSTR.