anti-TNF Treatment Response Research Articles

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.

Suboptimal response to tumor necrosis factor antagonists in inflammatory bowel disease in Latin America: EXPLORE LATAM study

ObjectiveData on anti-tumor necrosis factor (anti-TNF) treatment and suboptimal response (SOR) among patients with inflammatory bowel diseases (IBD) in Latin America (LATAM) are scarce. This study evaluated the incidence and indicators of SOR to anti-TNF therapy in patients with ulcerative colitis (UC) and Crohn's disease (CD) from Argentina, Colombia and Mexico. Patients and methodsWe performed retrospective analysis of data from LATAM patients of the EXPLORE study (NCT03090139) including adult patients with IBD who initiated anti-TNF therapy between March 2010 to March 2015. The cumulative incidence of SOR to first-line anti-TNF therapy was assessed. A physician survey to assess barriers to anti-TNF therapies was also carried out. ResultsWe included 185 IBD patients (UC/CD: 99/86) treated with first-line anti-TNF from Argentina (38 UC; 40 CD), Colombia (21 UC; 25 CD) and Mexico (40 UC; 21 CD). 36.4% of patients with UC and 46.5% of patients with CD experienced SOR to anti-TNF therapy during the median (interquartile range) observational period: 49.0 months (37.2–60.1) in UC, and 50.0 months (40.9–60.1) in CD. The most common indicator of SOR among patients was augmentation of non-biologic therapy (UC: 41.7%; CD: 35.0%). Affordability and late referral to IBD specialist care centers were the most common barriers to anti-TNF therapies. ConclusionsSOR to anti-TNF therapy was common in LATAM IBD patients, where augmentation with non-biologic therapy represented the most frequent indicator of SOR across indications. Our findings contribute to the current evidence on the unmet needs associated with anti-TNF in LATAM.

ATRPred: A machine learning based tool for clinical decision making of anti-TNF treatment in rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a chronic autoimmune condition, characterised by joint pain, damage and disability, which can be addressed in a high proportion of patients by timely use of targeted biologic treatments. However, the patients, non-responsive to the treatments often suffer from refractoriness of the disease, leading to poor quality of life. Additionally, the biologic treatments are expensive. We obtained plasma samples from N = 144 participants with RA, who were about to commence anti-tumour necrosis factor (anti-TNF) therapy. These samples were sent to Olink Proteomics, Uppsala, Sweden, where proximity extension assays of 4 panels, containing 92 proteins each, were performed. A total of n = 89 samples of patients passed the quality control of anti-TNF treatment response data. The preliminary analysis of plasma protein expression values suggested that the RA population could be divided into two distinct molecular sub-groups (endotypes). However, these broad groups did not predict response to anti-TNF treatment, but were significantly different in terms of gender and their disease activity. We then labelled these patients as responders (n = 60) and non-responders (n = 29) based on the change in disease activity score (DAS) after 6 months of anti-TNF treatment and applied machine learning (ML) with a rigorous 5-fold nested cross-validation scheme to filter 17 proteins that were significantly associated with the treatment response. We have developed a ML based classifier ATRPred (anti-TNF treatment response predictor), which can predict anti-TNF treatment response in RA patients with 81% accuracy, 75% sensitivity and 86% specificity. ATRPred may aid clinicians to direct anti-TNF therapy to patients most likely to receive benefit, thus save cost as well as prevent non-responsive patients from refractory consequences. ATRPred is implemented in R.

Searching for New Genetic Biomarkers of Axial Spondyloarthritis.

Background: Axial spondyloarthritis (axSpA) is a chronic inflammatory condition of the spine. In addition to musculoskeletal symptoms, there are also extra-articular manifestations. The aim of this study was to search for new biomarkers associated with the clinical presentation and treatment response in axSpA patients. Methods: In this study, 106 axSpA patients and 110 healthy controls were enrolled. Six single-nucleotide polymorphisms (SNPs) were selected for genotyping: ERAP1 rs2287987, ERAP2 rs2549782, TNF rs1800629, TNFRSF1A rs767455, TNFRSF1B rs1061622, and FCGR2A rs1801274. Participants were examined at baseline and after 12 and 24 weeks of anti-TNF therapy. Results: SNPs associated with high axSpA initial activity were TNFRSF1A rs767455 and TNFRSF1B rs1061622 (p < 0.008). The ERAP1 rs2287987 AA genotype was more frequently observed in patients with enthesitis (AA vs. G+, p = 0.049), while the TNFRSF1B rs1061622 GG genotype was more common in participants with uveitis (GG vs. TT, p = 0.042). Potential in predicting anti-TNF treatment response was demonstrated by ERAP1 rs2287987, ERAP2 rs2549782, TNFRSF1B rs1061622, and FCGR2A rs1801274. Conclusions: SNPs can be used to identify patients at risk of severe disease to initiate treatment earlier. Genetic testing will allow clinicians to choose the right drug for the patient.

Outcomes of Children with Inflammatory Bowel Disease who Develop Anti-tumour Necrosis Factor-induced Skin Reactions.

Anti-tumour necrosis factor [anti-TNF] induced skin reactions are common adverse events in paediatric inflammatory bowel disease [IBD]. We aimed to report on outcomes of children with anti-TNF induced skin reactions who switched to ustekinumab [UST] vs. continued anti-TNF therapy. Charts were reviewed for paediatric IBD patients with anti-TNF induced skin reactions. Skin reactions, including psoriasiform dermatitis [PD], were classified as mild or severe based on a severity score. Primary outcome was frequency of skin resolution at 6 months. Secondary outcomes were combined clinical remission and skin resolution at 6 months and skin resolution at latest follow-up. A total of 111/638 [17%] children ([85, 21%] infliximab [IFX]; [26, 11%] adalimumab [ADA]) developed skin reactions. Eighty [72%] had PD, 25 [23%] infections, and four [4%] alopecia areata; 71 [64%] continued anti-TNF; and 40 [36%] switched to UST. In all, 73 [66%] had severe reactions and were more likely to switch to UST than if mild (37 [51%] vs. 3 [8%]; p <0.0001). Switching to UST had a higher rate and odds of resolution (29 [73%] vs. 24 [34%]; p <0.0001; odds ratio [OR] = 19.7, 95% confidence interval [CI]: 5.6, 69.5; p <0.0001) and combined remission (21 [52%] vs. 22 [31%]; p = 0.03; OR = 8.5, 95% CI: 2.5, 28.4; p = 0.0005] vs. continuing anti-TNF at 6 months. Children who switched to UST after anti-TNF induced skin reactions were more likely to have improved outcomes than those who continued anti-TNF therapy. Future studies are needed to determine immune mechanisms of anti-TNF induced skin reactions and treatment response.

Pharmacogenomics of Anti-TNF Treatment Response Marks a New Era of Tailored Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is the most commonly occurring chronic inflammatory arthritis, the exact mechanism of which is not fully understood. Tumor Necrosis Factor (TNF)-targeting drugs has been shown to exert high effectiveness for RA, which indicates the key importance of this cytokine in this disease. Nevertheless, the response to TNF inhibitors varies, and approximately one third of RA patients are non-responders, which is explained by the influence of genetic factors. Knowledge in the field of pharmacogenomics of anti-TNF drugs is growing, but has not been applied in the clinical practice so far. Different genome-wide association studies identified a few single nucleotide polymorphisms associated with anti-TNF treatment response, which largely map genes involved in T cell function. Studies of the gene expression profile of RA patients have also indicated specific gene signatures that may be useful to develop novel prognostic tools. In this article, we discuss the significance of TNF in RA and present the current knowledge in pharmacogenomics related to anti-TNF treatment response.

P029 Expression of miR-21 in mucosal biopsies give clues to anti-TNF treatment non-response in IBD children and adults

Abstract Background The use of anti-tumor necrosis factor (TNF) treatment has improved the treatment of IBD patients. However, approximately 30% of patients fail to respond to TNF inhibitors, and up to 50% of the patients who initially benefited from treatment with TNF inhibitors lose the response over time. Thus, identifying predictors of non-response and deciding on a treatment strategy according to biomarker profiles could enhance overall IBD disease management. MicroRNA-21 (miR-21) has been found to confer drug resistance to e.g. trastuzumab, 5-fluorouracil, and cisplatin. In this study, we hypothesized that miR-21 may play a role in anti-TNF drug resistance and therefore, miR-21 levels may be a predictive biomarker of anti TNF response in IBD. Methods Archived formalin-fixed, paraffin-embedded (FFPE) mucosal biopsies of IBD patients (30 adults and 27 children) were used in this study. All biopsies were collected at the time of initiation of biologics. Patients were stratified into three groups according to treatment response: Responders, Primary non-responders (PNR), and Secondary non-responders (SNR). Responders were treated with anti-TNF for a minimum of 3 years and did not experience loss of response thereafter. PNRs lost response during the first year of treatment. SNRs were treated for a minimum of 3 years with subsequent loss of response. MiR-21 expressions were quantified using Quantitative Real-Time PCR (miRCURY LNA RT Kit, Qiagen). Expression of miR-27a was used as the endogenous reference microRNA based on previous studies. Results In adults, responders had less miR-21 expression compared to PNRs and SNRs (relative median of miR-21 expression in folds [IQR]: 3.45[3.36 - 4.2], 5.05 [3.61 - 6.88], and 7.58 [6.21 - 8.2] in responders, PNRs, and SNRs respectively, p=0.04 and p=&amp;lt;0.01). In children, however, responders had an increased miR-21 expression compared to PNRs and SNRs (relative median of miR-21 expression in folds [IQR]: 19.94[15.88–24.59], 9.79[7.69– 14.44], and 10.58[5.66–12.91] in responders, PNRs, and SNRs respectively, p=0.03 and p=0.01). Expression of MiR-21 was found to be higher in children than adults (relative median of miR-21 expression in folds [IQR]: 4.65[3.45–7.21], and 13.6[8.37–19.05], respectively, p=&amp;lt;0.01). Conclusion Higher miR-21 expression indicates a higher response rate in children, whereas higher miR-21 expression could predict resistance to anti-TNF treatment in adults. MiR-21 expression could potentially be used as a predictive biomarker for anti-TNF treatment response in IBD patients with varying measures for children and adults.

RAID Prediction: Pilot Study of Fecal Microbial Signature With Capacity to Predict Response to Anti-TNF Treatment

Crohn's disease and ulcerative colitis evolve with alternate outbreaks and remissions of variable duration in both cases. Despite the advances, about 10-30% of patients do not respond to the treatment after the induction period. Besides, between 20% to 50% further patients need an optimization of the dose to respond the treatment. Recent studies have pointed gut microbiota can play a role in the anti-TNF treatment response. This study aimed to define a bacterial signature that could be used to predict the response of patients to anti-TNF treatment. There were obtained 38 stool samples from 38 IBD patients before starting anti-TNF treatments: Adalimumab, Golimumab or Infliximab. Patients were differentiated in 2 groups: responders and non-responders to biological treatment. From each sample, DNA was purified and used in a qPCR for the quantification of the 8 microbial markers. In this proof of concept, the predictive ability to identify anti-TNF treatment responders was analyzed. An algorithm consisting in the combination of 4 bacterial markers showed a high capacity to discriminate between responders and non- responders. The algorithm proved high sensitivity and specificity reporting values of 93.33% and 100% respectively, with a positive predictive value of 100% and a negative predictive value of 75% for predicting response to biologic treatment. A specific bacterial signature could beneficiate patients with inflammatory bowel disease predicting the therapeutic effectiveness of an anti-TNF treatment, leading to a personalized therapy, improving the patients' quality of life, saving costs and gaining time in patient improvement.

Visceral Adipose Tissue Volumetrics Inform Odds of Treatment Response and Risk of Subsequent Surgery in IBD Patients Starting Antitumor Necrosis Factor Therapy.

Data describing the effect of obesity on antitumor necrosis factor (anti-TNF) treatment response are inconsistent. Visceral adipose tissue (VAT) is a superior marker of adiposity to body mass index. However, its effect on treatment response is unclear. We aimed to evaluate the effect of VAT on anti-TNF treatment response. Inflammatory bowel disease (IBD) patients starting anti-TNF agents between January 1, 2009, and July 31, 2019, were included. 3-dimensional measurements of VAT volume and visceral fat index (visceral:subcutaneous adipose tissue ratio; VFI) were obtained from computed tomography (CT) scans. Subjects were categorized by predefined volume cutoffs (<1500cm3, 1500-2999cm3, ≥3000cm3) and VFI (<0.33, 0.33-0.66, ≥0.67). Primary outcomes included a composite treatment response end point at 6 and 12 months. Secondary outcomes were surgery at 6 and 12 months. Multivariable logistic regression was used to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI). The final cohort included 176 patients. No significant differences in treatment response at 6 months was observed. At 12 months, compared with volume <1500cm3, patients with volume 1500-2999cm3 had higher odds of response (aOR, 3.52; 95% CI, 1.16-10.71; P = .023), whereas volume ≥3000cm3 did not. Compared with VFI<0.33, VFI ≥0.67 had higher odds of surgery at 6 (aOR, 48.22; 95% CI, 4.73-491.57; P = .023) and 12 months (aOR, 20.94; 95% CI, 3.14-139.67; P = .004). Post hoc analysis suggested VAT may affect drug pharmacokinetics. We found VAT volume is associated with anti-TNF treatment response in a nondose dependent manner, and VFI may inform risk of surgery after anti-TNF initiation. If confirmed by prospective studies, VAT volumetrics are potentially useful biomarkers to inform IBD treatment decisions.

IL-33 Gene Polymorphisms as Potential Biomarkers of Disease Susceptibility and Response to TNF Inhibitors in Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients.

ObjectiveRheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) belong to inflammatory rheumatic diseases, the group of conditions of unknown etiology. However, a strong genetic component in their pathogenesis has been well established. A dysregulation of cytokine networks plays an important role in the development of inflammatory arthritis. Interleukin 33 (IL-33) is a recently identified member of the IL-1 family. To date, the significance of IL-33 in inflammatory arthritis has been poorly studied. This research aimed to investigate the potential of IL-33 gene polymorphisms to serve as biomarkers for disease susceptibility and TNF inhibitor response in RA, AS, and PsA patients.Materials and MethodsIn total, 735 patients diagnosed with RA, AS, and PsA and 229 healthy individuals were enrolled in the study. Genotyping for three single nucleotide polymorphisms (SNPs) within the IL-33 gene, namely, rs16924159 (A/G), rs10975519 (T/C), and rs7044343 (C/T), was performed using polymerase chain reaction amplification employing LightSNiP assays.ResultsIn the present study, the IL-33 rs10975519 CC genotype was associated with a decreased risk of developing RA in females, while the IL-33 rs16924159 polymorphism was associated with the efficacy of anti-TNF therapy and clinical parameters for RA and AS patients. The IL-33 rs16924159 AA genotype correlated with higher disease activity and worse clinical outcomes in RA patients treated with TNF inhibitors, and AS patients carrying the IL-33 rs16924159 AA genotype had higher disease activity and a worse response to anti-TNF therapy. That indicates a deleterious role of the IL-33 rs16924159 AA genotype in the context of RA, as well as AS.ConclusionsThe obtained results suggest that IL-33 gene polymorphisms might be potential candidate biomarkers of disease susceptibility and anti-TNF treatment response in patients with inflammatory rheumatic diseases.

VISCERAL ADIPOSE TISSUE INFLUENCES ANTI-TUMOR NECROSIS FACTOR (TNF) TREATMENT RESPONSE IN IBD

Data describing the effect of obesity on anti-TNF treatment response in inflammatory bowel disease (IBD) are conflicting. This likely reflects the shortcomings of using body mass index (BMI) to capture an individual’s adipose stores. Recent studies have found visceral adipose tissue (VAT), not BMI, is associated with IBD-related complications and post-operative recurrence. However, the relationship between VAT and treatment response is unclear. We aim to evaluate the effect of VAT on anti-TNF treatment response.

VISCERAL ADIPOSE TISSUE INFLUENCES ANTI-TUMOR NECROSIS FACTOR (TNF) TREATMENT RESPONSE IN IBD

Abstract Background Data describing the effect of obesity on anti-TNF treatment response in inflammatory bowel disease (IBD) are conflicting. This likely reflects the shortcomings of using body mass index (BMI) to capture an individual’s adipose stores. Recent studies have found visceral adipose tissue (VAT), not BMI, is associated with IBD-related complications and post-operative recurrence. However, the relationship between VAT and treatment response is unclear. We aim to evaluate the effect of VAT on anti-TNF treatment response. Methods IBD patients starting anti-TNF agents between 1/1/2009 to 7/31/2019 at two academic medical centers were included. Three-dimensional VAT volume was measured from CT scans with Aquarius (iNtuition, Foster City, CA). Patients were categorized by predefined volume cutoffs: &amp;lt;1500cm3, 1500-2999cm3, &amp;gt;3000cm3. Primary outcomes included composite endpoint of corticosteroid-free response (CFR) at 6 and 12 months defined by meeting one of the following: a) clinical response based on Harvey Bradshaw Index for Crohn’s disease (CD) or Lichtiger score for ulcerative colitis (UC) b) endoscopic improvement based on ulcer healing for CD and Mayo score for UC compared to baseline or c) 50% improvement or normalization of CRP or fecal calprotectin. Secondary outcomes included IBD-related surgery at 6 and 12 months. We performed a multivariable logistic regression on CFR and surgery, adjusting for age, gender, IBD diagnosis, disease duration, active tobacco use, and immunomodulator exposure, to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI). Results We included 182 patients. Table 1 summarizes differences in baseline characteristics. There were no differences in CFR at 6 months. Compared to those with VAT volume &amp;lt;1500cm3, patients with VAT volume 1500-2999cm3 were significantly more likely to achieve CFR at 12 months (aOR 3.27, [95%CI 1.26–8.5]), but not for those with VAT volume &amp;gt;3000cm3 (aOR 0.45, [95%CI 0.13–1.50], Figure 1b). With respect to surgery within 6 months, patients with volume &amp;gt;3000cm3 were significantly more likely to undergo surgery than those with VAT volume &amp;lt;1500cm3 (aOR: 7.99 [95%CI 1.49–2.94]), while there was no significant difference with patients with VAT volume 1500-2999cm3 (aOR: 0.63 [95%CI 0.14–2.78]). While not statistically significant, a similar trend was observed at 12 months with those with VAT volume &amp;gt;3000cm3 having the highest risk of surgery (aOR: 3.55 [95%CI 0.87–14.61], Figure 1c and d). Conclusion In this retrospective, multicenter, cohort study, we found VAT influences treatment response but not in a dose-dependent manner as previously hypothesized. If confirmed by future prospective studies, VAT may be employed as a biomarker to better inform treatment decisions and improve outcomes, especially considering the growth of artificial intelligence in medical imaging.

Investigation of genetically regulated gene expression and response to treatment in rheumatoid arthritis highlights an association between IL18RAP expression and treatment response

ObjectivesIn this study, we sought to investigate whether there was any association between genetically regulated gene expression (as predicted using various reference panels) and anti-tumour necrosis factor (anti-TNF) treatment response...

P824 Molecular predictors of anti-TNF treatment response in patients with Crohn’s disease

Abstract Background Anti-tumour necrosis factor (anti-TNF) therapy has revolutionised the treatment of Crohn’s disease (CD). These drugs induce clinical and mucosal remission with high effectiveness, however almost 20–40% of patients do not respond to initial treatment. The exact mechanism of primary non-response is still unknown. The aim of the study was to investigate the impact of genetic interindividual differences on patients’ response. This will allow to identify molecular predictors of variable reaction to anti-TNF treatment. Methods DNA samples were obtained from 107 diagnosed and clinically characterised CD patients following anti-TNF therapy, where 12 of patients were classified as nonresponders. Based on long-range PCR libraries and next-generation sequencing (NGS), a panel of 23 genes belonging to TNF superfamily, proinflammatory factors, apoptosis-related proteins, signal transmission factors and receptors was analysed. After NGS, bioinformatical and statistical analysis were performed. Results In total, 598 single-nucleotide variants (SNP) for all analysed targets were identified. Patients’ nonresponse was associated with genotypes in 12 following loci (p ≤ 0.05): rs1061624 (OR: 4.22; 95% CI: 1.33–13.34) in TNFRSF1B gene, rs7896789 (OR: 0.27; 95% CI: 0.09–0.78) in FAS gene, rs2041747 (OR: 0.17; 95% CI: 0.04–0.80) in IL1R gene, rs373184583 (OR: 0.29; 95% CI: 0.09–0.82), rs12128686 (OR: 0.29; 95% CI: 0.09–0.82), rs7539036 (OR: 0.31; 95% CI: 0.11–0.87) and rs6672453 (OR: 0.31; 95% CI: 0.11–0.87) in FCGR3A gene, rs1071676 (OR: 2.47; 95% CI: 1.04–5.85), rs1143639 (OR: 2.47; 95% CI: 1.04–5.85), rs1143637 (OR: 2.47; 95% CI: 1.04–5.85) and rs1143634 (OR: 2.47; 95% CI: 1.04–5.85) in IL1B gene as well as rs55790676 (OR: 2.64; 95% CI: 1.02–6.83) in ADAM17 gene. Conclusion Obtained results suggest that molecular changes in genes involved in TNF activity may play an important role in response to anti-TNF treatment and be useful as molecular markers indicating potential patients’ response. Additionally, these results may contribute to better understanding the mechanism of monoclonal antibodies action in IBD treatment.

745 Developing Precision Medicine in IBD: Peripheral Blood Eosinophilia Identifies Individuals With Worse Outcomes Following Initiation of Anti-TNF Biologic Agents

INTRODUCTION: Peripheral blood eosinophilia (PBE) has been recognized as a biomarker, identifying a subgroup of inflammatory bowel disease (IBD) patients with worse clinical outcomes. With more severe disease, anti-TNF therapy is often employed, with varied rates of success. The aim of this study was to determine whether the presence of pre-treatment PBE identifies IBD patients at risk for diminished anti-TNF treatment response. METHODS: We performed a registry analysis of IBD patients starting anti-TNF therapy who were enrolled in a consented, prospective, natural history IBD cohort at a tertiary center. Metadata was collected in the 2 years preceding and 2 years following anti-TNF initiation. The presence of PBE before and after anti-TNF initiation was recorded and treatment response was assessed for those with/without PBE using disease activity scores [Harvey Bradshaw Index (HBI) and Ulcerative Colitis Activity Index (UCAI)], quality of life measures [Short Inflammatory Bowel Disease Questionnaire (SIBDQ)], inflammatory markers (ESR, CRP), steroid use (prednisone or methylprednisolone), IBD-related hospitalizations, and IBD-related surgeries. Outcomes were assessed via linear mixed-effects and Cox proportional-hazards models for Crohn's disease (CD) and ulcerative colitis (UC). RESULTS: A total of 580 IBD patients (CD 430, UC 150) were included with 111 (19%) demonstrating pre-treatment PBE (CD 66, UC 45). Table 1 summarizes demographic and clinical data. Following anti-TNF therapy, CD patients with pre-treatment PBE were more likely to have an IBD-related hospitalization [adjusted hazard ratio (AHR) 1.88, 95% CI 1.22-2.90, P = 0.004] and require anal fistula repair (AHR 3.88, 95% CI 1.09-13.8, P = 0.04) than CD patients without PBE. UC patients with pre-treatment PBE were more likely to have an elevated CRP following anti-TNF therapy (OR 2.77, 95% CI 1.50-5.10, P = 0.001) with a non-significant trend towards increased IBD-related admissions and surgeries. CD patients with pre-treatment PBE were less likely to require steroids following anti-TNF therapy than CD patients without PBE (AHR 0.40, 95% CI 0.18-0.86, P = 0.019). There was no significant difference in HBI, UCAI, or SIBDQ scores in patients with/without PBE undergoing anti-TNF therapy. CONCLUSION: Pre-treatment PBE identifies IBD patients at risk for worse outcomes following anti-TNF therapy, particularly in CD. Further studies are warranted to determine if alternate mechanism of action biologics will function optimally in the PBE IBD population.

Regulatory T cells as a biomarker for response to adalimumab in rheumatoid arthritis

Regulatory T cells as a biomarker for response to adalimumab in rheumatoid arthritis

Association of miR-146 rs2910164, miR-196a rs11614913, miR-221 rs113054794 and miR-224 rs188519172 polymorphisms with anti-TNF treatment response in a Greek population with Crohn's disease.

AIMTo investigate the correlation between rs2910164, rs11 614913, rs113054794, and rs188519172 polymorphisms and response to anti-TNF treatment in patients with Crohn’s disease (CD).METHODSOne hundred seven patients with CD based on standard clinical, endoscopic, radiological, and pathological criteria were included in the study. They all received infliximab or adalimumab intravenously or subcutaneously at standard induction doses as per international guidelines. Clinical and biochemical response was assessed using the Harvey-Bradshaw index and CRP levels respectively. Endoscopic response was evaluated by ileocolonoscopy at week 12-20 of therapy. The changes in endoscopic appearance compared to baseline were classified into four categories, and patients were classified as responders and non-responders. Whole peripheral blood was extracted and genotyping was performed by PCR.RESULTSOne hundred and seven patients were included in the study. Seventy two (67.3%) patients were classified as complete responders, 22 (20.5%) as partial while 13 (12.1%) were primary non-responders. No correlation was detected between response to anti-TNF agents and patients’ characteristics such as gender, age and disease duration while clinical and biochemical indexes used were associated with endoscopic response. Concerning prevalence of rs2910164, rs11614913, and rs188519172 polymorphisms of miR-146, miR-196a and miR-224 respectively no statistically important difference was found between complete, partial, and non-responders to anti-TNF treatment. Actually CC genotype of rs2910164 was not detected in any patient. Regarding rs113054794 of miR-221, normal CC genotype was the only one detected in all studied patients, suggesting this polymorphism is highly rare in the studied population.CONCLUSIONNo correlation is detected between studied polymorphisms and patients’ response to anti-TNF treatment. Polymorphism rs113054794 is not detected in our population.

Brief Report: The Role of Rare Protein-Coding Variants in Anti-Tumor Necrosis Factor Treatment Response in Rheumatoid Arthritis.

In many rheumatoid arthritis (RA) patients, disease is controlled with anti-tumor necrosis factor (anti-TNF) biologic therapies. However, in a significant number of patients, the disease fails to respond to anti-TNF therapy. We undertook the present study to examine the hypothesis that rare and low-frequency genetic variants might influence response to anti-TNF treatment. We sequenced the coding region of 750 genes in 1,094 RA patients of European ancestry who were treated with anti-TNF. After quality control, 690 genes were included in the analysis. We applied single-variant association and gene-based association tests to identify variants associated with anti-TNF treatment response. In addition, given the key mechanistic role of TNF, we performed gene set analyses of 27 TNF pathway genes. We identified 14,420 functional variants, of which 6,934 were predicted as nonsynonymous 2,136 of which were further predicted to be "damaging." Despite the fact that the study was well powered, no single variant or gene showed study-wide significant association with change in the outcome measures disease activity or European League Against Rheumatism response. Intriguingly, we observed 3 genes, of 27 with nominal signals of association (P < 0.05), that were involved in the TNF signaling pathway. However, when we performed a rigorous gene set enrichment analysis based on association P value ranking, we observed no evidence of enrichment of association at genes involved in the TNF pathway (Penrichment = 0.15, based on phenotype permutations). Our findings suggest that rare and low-frequency protein-coding variants in TNF signaling pathway genes or other genes do not contribute substantially to anti-TNF treatment response in patients with RA.

Potential Impact of Diet on Treatment Effect from Anti-TNF Drugs in Inflammatory Bowel Disease.

We wanted to investigate the current knowledge on the impact of diet on anti-TNF response in inflammatory bowel diseases (IBD), to identify dietary factors that warrant further investigations in relation to anti-TNF treatment response, and, finally, to discuss potential strategies for such investigations. PubMed was searched using specified search terms. One small prospective study on diet and anti-TNF treatment in 56 patients with CD found similar remission rates after 56 weeks among 32 patients with good compliance that received concomitant enteral nutrition and 24 with poor compliance that had no dietary restrictions (78% versus 67%, p = 0.51). A meta-analysis of 295 patients found higher odds of achieving clinical remission and remaining in clinical remission among patients on combination therapy with specialised enteral nutrition and Infliximab (IFX) compared with IFX monotherapy (OR 2.73; 95% CI: 1.73–4.31, p < 0.01, OR 2.93; 95% CI: 1.66–5.17, p < 0.01, respectively). In conclusion, evidence-based knowledge on impact of diet on anti-TNF treatment response for clinical use is scarce. Here we propose a mechanism by which Western style diet high in meat and low in fibre may promote colonic inflammation and potentially impact treatment response to anti-TNF drugs. Further studies using hypothesis-driven and data-driven strategies in prospective observational, animal and interventional studies are warranted.

Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn's disease.

AIMTo investigate genetic factors that might help define which Crohn’s disease (CD) patients are likely to benefit from anti-tumor necrosis factor (TNF) therapy.METHODSThis was a prospective cohort study. Patients were recruited from a university digestive disease practice database. We included CD patients who received anti-TNF therapy, had available medical records (with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood, and 7 single nucleotide polymorphisms (SNPs) were assessed. The main outcome measure (following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age, gender, race, and socioeconomic status disease, as well as disease characteristics (such as Montreal criteria).RESULTS121 patients were included. Twenty-one were non-responders, and 100 were ever-responders. Fas ligand SNP (rs763110) genotype frequencies, TNF gene -308 SNP (rs1800629) genotype frequencies, and their combination, were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype (P = 0.009, OR = 4.30, 95%CI: 1.45-12.80). The presence of the A (minor) TNF gene -308 allele correlated with three-fold higher odds of being a non-responder (P = 0.049, OR = 2.88, 95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF -308 A allele had nearly five-fold higher odds of being a non-responder (P = 0.015, OR = 4.76, 95%CI: 1.35-16.77). No difference was seen for the remaining SNPs.CONCLUSIONThe Fas-ligand SNP and TNF gene -308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.