Anti-tumor Necrosis Factor-α Treatment Research Articles

Hepatitis B reactivation risk and physician awareness in rheumatological patients receiving anti-tumor necrosis factor-α treatment.

We aimed to evaluate the risk of hepatitis B virus reactivation in rheumatic patients using anti-tumor necrosis factor-alpha drugs and the awareness of physicians about hepatitis B virus reactivation. Demographic characteristics, pre- and post-treatment hepatitis markers, and laboratory parameters of patients receiving anti-tumor necrosis factor-alpha therapy in our rheumatology clinic were retrospectively examined. A total of 448 patients, 240 (53.6%) female and 208 (46.4%) male, were evaluated. Their mean age was 48.02±14.64 years. While HBsAg was examined in 443 (98.9%) patients before treatment, 7 (1.6%) patients were found to be HBsAg positive. While anti-HBc IgG was examined in 405 (90.4%) patients, it was positive in 69 (17%) patients. HBs Ag (total 446-99.6%) test was performed in three patients who were not tested for HBsAg before the treatment, and anti-HBc total (431-96.2% total) test was performed in 26 patients who were not tested for anti-HBc total. All HBsAg positive patients and 17 (24.6%) of those with previous hepatitis B received antiviral treatment. While the median follow-up period of the patients was 24 (6-60) months, no patient developed hepatitis B virus reactivation. The screening rates and awareness of physicians providing anti-tumor necrosis factor-alpha therapy for hepatitis B virus infection were found to be higher compared to similar studies. Hepatitis B virus reactivation did not develop in any patient. Since the risk of hepatitis B virus reactivation is low, especially in patients with previous hepatitis B, it would be more appropriate to follow up the patients without giving antiviral prophylaxis.

Dysbiosis and Associated Stool Features Improve Prediction of Response to Biological Therapy in Inflammatory Bowel Disease

Dysbiosis of the gut microbiota is considered a key contributor to inflammatory bowel disease (IBD) etiology. Here, we investigated potential associations between microbiota composition and the outcomes to biological therapies. The study prospectively recruited 296 patients with active IBD (203 with Crohn's disease, 93 with ulcerative colitis) initiating biological therapy. Quantitative microbiome profiles of pretreatment and posttreatment fecal samples were obtained combining flow cytometry with 16S amplicon sequencing. Therapeutic response was assessed by endoscopy, patient-reported outcomes, and changes in fecal calprotectin. The effect of therapy on microbiome variation was evaluated using constrained ordination methods. Prediction of therapy outcome was performed using logistic regression with 5-fold cross-validation. At baseline, 65.9% of patients carried the dysbiotic Bacteroides2 (Bact2) enterotype, with a significantly higher prevalence among patients with ileal involvement (76.8%). Microbiome variation was associated with the choice of biological therapy rather than with therapeutic outcome. Only anti-tumor necrosis factor-α treatment resulted in a microbiome shift away from Bact2, concomitant with an increase in microbial load and butyrogen abundances and a decrease in potentially opportunistic Veillonella. Remission rates for patients hosting Bact2 at baseline were significantly higher with anti-tumor necrosis factor-α than with vedolizumab (65.1% vs 35.2%). A prediction model, based on anthropometrics and clinical data, stool features (microbial load, moisture, and calprotectin), and Bact2 detection predicted treatment outcome with 73.9% accuracy for specific biological therapies. Fecal characterization based on microbial load, moisture content, calprotectin concentration, and enterotyping may aid in the therapeutic choice of biological therapy in IBD.

Vedolizumab more likely to be discontinued than ustekinumab in anti-TNF-experienced patients with fistulizing Crohn's disease.

Data on the performance of newer biologics in patients with fistulizing Crohn's disease (CD) are limited. Our study's objective was to evaluate the response to ustekinumab (UST) and vedolizumab (VDZ) in patients with fistulizing CD. Retrospective cohort. We used natural language processing of electronic medical record data to identify a retrospective cohort of individuals with fistulizing CD at a single academic tertiary-care referral center and then performed a chart review. Individuals were eligible for inclusion if a fistula was present at the time of UST or VDZ initiation. Outcomes included medication discontinuation, surgical intervention, development of a new fistula, and fistula closure. Groups were compared with unadjusted analyses and competing risk analyses using multi-state survival models. In all, 68 patients were included (48 UST and 20 VDZ). Most patients had one fistula (79%) and had prior anti-tumor necrosis factor-α treatment (98% in UST group, 80% in VDZ group, p = 0.01). VDZ was significantly more likely to be discontinued than UST (p < 0.0001), most frequently due to inadequate clinical response. Those on UST had a longer median time to surgery for CD than those on VDZ (p = 0.008). In those without surgical fistula repair, 79% on UST and 100% on VDZ still had an active fistula at 1 year (p = 0.30). In individuals with fistulizing CD, our data suggest that UST has better clinical utility than VDZ based on lower rates of discontinuation, though the sample size is small. These findings highlight the importance of further research on the treatment of perianal fistulizing Crohn's disease.

The Simplified MR Index of Activity Score in Pediatric Small-Bowel Crohn Disease: An Interreader Agreement and Responsiveness Study.

BACKGROUND. The simplified MR index of activity (MaRIA) score is used to assess the severity of small-bowel inflammation without use of IV contrast material. OBJECTIVE. The purposes of this study were to assess interreader agreement on the use of simplified MaRIA scores for evaluation of the inflammatory activity of terminal ileal Crohn disease in children and young adults and to assess whether simplified MaRIA scores change after biologic medical therapy. METHODS. This analysis was ancillary to a previously reported primary prospective research investigation. The study included 20 children and young adults with newly diagnosed ileal Crohn disease and 15 healthy control participants who underwent research small-bowel MRI examinations between December 2018 and October 2021. The participants with Crohn disease underwent baseline MRI and MRI 6 weeks and 6 months after beginning anti-tumor necrosis factor α-treatment as well as weighted pediatric Crohn disease activity index (wPCDAI) and C-reactive protein (CRP) assessment on the day of each examination. Control participants underwent one MRI examination. Four pediatric radiologists independently assigned simplified MaRIA scores using axial and coronal T2-weighted SSFSE images. Median simplified MaRIA score among readers was computed. Interreader agreement was assessed with Fleiss kappa coefficients and intra-class correlation coefficient (ICC). Analysis included the Mann-Whitney U test, Friedman test, and Spearman rank correlation. RESULTS. Simplified MaRIA scores (across time points and study groups) had substantial interreader agreement (κ = 0.65 [95% CI, 0.56-0.74]; ICC, 0.71 [95% CI, 0.63-0.78]). Median scores were higher in participants with Crohn disease at baseline than in healthy control participants (3.5 [IQR, 2.5-4.9] vs 0.5 [IQR, 0-2.0]; p < .001). Scores decreased after medical treatment in participants with Crohn disease (p = .005). The median score was 3.5 (IQR, 2.5-4.9) at baseline, 2.3 (IQR, 1.6-3.9) at 6 weeks, and 2.0 (IQR, 0.5-2.5) at 6 months. In participants with Crohn disease, median scores had significant correlations with wPCDAI (ρ = 0.46 [95% CI, 0.18-0.64]; p < .001) and CRP level (ρ = 0.48 [95% CI, 0.27-0.65]; p < .001). CONCLUSION. Radiologists had substantial agreement in use of simplified MaRIA scores to assess intestinal inflammation in ileal Crohn disease. Scores changed over time after medical therapy. CLINICAL IMPACT. The results support the simplified MaRIA score as an objective MRI-based clinical measure of intestinal inflammation in children and young adults with Crohn disease.

Complete Endoscopic Healing Is Associated With Lower Relapse Risk After Anti-TNF Withdrawal in Inflammatory Bowel Disease

Discontinuation of anti-tumor necrosis factor-α treatment (anti-TNF) (infliximab and adalimumab) in patients with inflammatory bowel disease (IBD) is associated with a high relapse risk that may be influenced by endoscopic activity at the time of stopping. We assessed the relapse rate after anti-TNF withdrawal in patients with endoscopic healing and studied predictors of relapse including the depth of endoscopic healing. This was a multicenter, prospective study in adult patients with Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU), with ≥6 months of corticosteroid-free clinical remission (confirmed at baseline) and endoscopic healing (Mayo <2/SES-CD <5 without large ulcers), who discontinued anti-TNF between 2018 and 2020 in the Netherlands. We performed Kaplan-Meier and Cox regression analyses to assess the relapse rate and evaluate potential predictors: partial (Mayo 1/SES-CD 3-4) versus complete (Mayo 0/SES-CD 0-2) endoscopic healing, anti-TNF trough levels, and immunomodulator and/or mesalamine use. Among 81 patients (CD: n= 41, 51%) with a median follow-up of 2.0 years (interquartile range, 1.6-2.1), 40 patients (49%) relapsed. Relapse rates in CD and UC/IBDU patients were comparable. At 12 months, 70% versus 35% of patients with partial versus complete endoscopic healing relapsed, respectively (adjusted hazard rate [aHR], 3.28; 95% confidence interval [CI], 1.43-7.50). Mesalamine use was associated with fewer relapses in UC/IBDU patients (aHR, 0.08; 95% CI, 0.01-0.67). Thirty patients restarted anti-TNF, and clinical remission was regained in 73% at 3 months. The relapse risk was high after anti-TNF withdrawal in IBD patients with endoscopic healing, but remission was regained in most cases after anti-TNF reintroduction. Complete endoscopic healing and mesalamine treatment in UC/IBDU patients decreased the risk of relapse.

Pharmacogenetic analysis of canonical versus noncanonical pathway of NF-kB in Crohn's disease patients under anti-tumor necrosis factor-α treatment.

This study explores the potential of gene polymorphisms in the canonical and noncanonical NF-kB signaling pathway as a prediction biomarker of anti-tumor necrosis factor (TNF)α response in Crohn's patients. A total of 109 Greek patients with Crohn's disease (CD) were recruited, and the genotype of TLR2 rs3804099, LTA rs909253, TLR4 rs5030728, and MAP3K14/NIK rs7222094 single nucleotide polymorphisms was investigated for association with response to anti-TNFα therapy. Patient's response to therapy was based on the Crohn's Disease Activity Index, depicting the maximum response within 24 months after initiation of treatment. Seventy-three patients (66.7%) were classified as responders while 36 as nonresponders (33.3%). Comparing allelic frequencies between responders and nonresponders, the presence of TLR2 rs3804099 T allele was associated with nonresponse (P = 0.003), even after stratification by anti-TNFα drugs (infliximab: P = 0.032, adalimumab: P = 0.026). No other association was identified for the rest of the polymorphisms under study. Haplotype analysis further enhanced the association of rs3804099 T allele with loss of response, even though the results were NS (P = 0.073). Our results suggest that polymorphisms in the canonical NF-kB pathway genes could potentially act as a predictive biomarker of anti-TNFα response in CD.

DOP67 First-line infliximab is cost-effective compared to conventional treatment in paediatric Crohn’s Disease – Results from the TISKids study

Abstract Background First-line infliximab (FL-IFX) induction treatment combined with azathioprine (AZA) is more effective to achieve clinical remission without treatment escalation at week 52 compared to conventional induction treatment (CONV) (Exclusive Enteral Nutrition or prednisone) combined with AZA in children with moderate-to-severe Crohn’s disease (CD). FL-IFX may lead to higher treatment costs compared to conventional treatment. However, data on cost-effectiveness of FL-IFX in children with CD is still limited. Therefore, our aim is to investigate the cost-effectiveness of FL-IFX in comparison with CONV. We hypothesized that cost effectiveness of FL-IFX is comparable to CONV in children with newly diagnosed moderate-to-severe CD in the first two years after treatment. Methods We included patients from the TISKids international randomized controlled trial in which children with moderate-to-severe CD were treated with either FL-IFX (Inflectra, biosimilar of IFX) or CONV.(1) Patients included outside of the Netherlands (n=6) or patients with serious comorbidity besides CD were excluded from this analysis (n=2). Data on healthcare consumption and costs were obtained per hospital for all included patients until week 104. Direct health-related costs were collected, including hospital visits, drug costs, laboratory tests, endoscopies and surgeries. The effectiveness of treatment was assessed by mean weighted paediatric CD activity index (wPCDAI) and faecal calprotectin (fcal) levels (µg/g) measured over time until week 104. This analysis was performed by a mixed model. Moreover, time to additional anti-tumor necrosis factor-α (anti-TNF) treatment up to 104 weeks after inclusion was assessed. Results In this analysis, 89 patients were included, 44 in the FL-IFX group and 45 in the conventional treatment group. There were no significant differences between the two groups at baseline. Interestingly, the mean costs were similar for FL-IFX (€34,783) and CONV (€34,923) after two years, p=0.97 (Figure 1). Mean fcal levels were lower for FL-IFX compared to CONV over two years (416 vs. 625, p=0.03). The mean wPCDAI scores over two years were numerically lower for FL-IFX compared to CONV (5.95 vs. 10.34, p=0.01), but this difference became smaller over time. Furthermore, the time to (re)start anti-TNF treatment was significantly longer in the FL-IFX group (median 68 weeks) compared to the conventional treatment group (median 32 weeks) (p=0.02) (Figure 2). Conclusion Treatment with FL-IFX is cost-effective compared to conventional treatment in the first two years after diagnosis in children with moderate-to-severe CD. Reference 1. Jongsma MME et al. Gut. 2020 Dec 31; DOI: 10.1136/gutjnl-2020–322339. / PMID: 33384335

Imputing missing patient-level data and propensity score matching in cost-effectiveness analysis in Crohn's disease

ABSTRACT Objectives The effect of imputing missing data followed by propensity score analysis on the incremental cost-effectiveness ratio (ICER) in a cost-effectiveness analysis is unknown. The objective was to compare alternative approaches in grouping data following imputation and prior to calculating propensity scores for use in economic evaluation. Methods Patient-level data from an observational study of 573 children with Crohn’s disease were used in a microsimulation model to determine the incremental cost of early anti-tumor necrosis factor-α treatment compared to standard care per remission week gained. Multiple imputation of a missing covariate followed by propensity score matching to create comparator groups was approached in two ways. The Within approach calculated propensity scores on each imputed dataset separately, while the Across method averaged propensity scores to create one matched population resulting in multiple sets of health state transition probabilities. Results The incremental cost per remission week gained ranged from CAD$2,236 to CAD$12,464 (mean CAD$4,266) with Within datasets and was CAD$4,679 per remission week gained with the Across dataset. Conclusion Imputation of missing patient-level data and propensity score analysis increases methodological uncertainty in cost-effectiveness analysis. The present study indicated that the Across approach may be less cumbersome, and slightly reduce bias and variance.

Effect of Anti-Rheumatic Treatment on the Periodontal Condition of Rheumatoid Arthritis Patients.

Periodontitis, a bacterial-induced infection of the supporting soft and hard tissues of the teeth (the periodontium), is common in patients with rheumatoid arthritis (RA). As RA and periodontitis underlie common inflammatory pathways, targeting the progression of RA might mediate both periodontitis and RA. On the other hand, patients with RA on immunosuppressive medication have an increased risk of infection. Therefore, the objective of this longitudinal observation study was to assess the effect of methotrexate (MTX) and anti-tumor necrosis factor-α (anti-TNF, etanercept) treatment on the periodontal condition of RA patients. Overall, 14 dentate treatment-naive RA patients starting with MTX and 12 dentate RA patients starting with anti-TNF therapy in addition to MTX were included. Follow-up was scheduled matching the routine protocol for the respective treatments. Prior to the anti-rheumatic treatment with MTX or the anti-TNF therapy in addition to MTX, and during follow-up, i.e., 2 months for MTX, and 3 and 6 months for the anti-TNF therapy in addition to MTX, the periodontal inflamed surface area (PISA) was measured. The efficacy of the anti-rheumatic treatment was assessed by determining the change in RA disease activity (DAS28-ESR). Furthermore, the erythrocyte sedimentation rates were determined and the levels of C-reactive protein, IgM-rheumatoid factor, anti-cyclic citrullinated protein antibodies, and antibodies to the periodontal pathogen Porphyromonas gingivalis, were measured. Subgingival sampling and microbiological characterization of the subgingival microflora was done at baseline. MTX or anti-TNF treatment did not result in an improvement of the periodontal condition, while both treatments significantly improved DAS28 scores (both p < 0.01), and reduced C-reactive protein levels and erythrocyte sedimentation rates (both p < 0.05). It is concluded that anti-rheumatic treatment (MTX and anti-TNF) has negligible influence on the periodontal condition of RA patients.

Systematic Review and Meta-Analysis: Preoperative Vedolizumab and Postoperative Complications in Patients with IBD.

The effect of vedolizumab on postoperative outcomes in patients with inflammatory bowel disease (IBD) remains unclear. We aimed to determine the relation between preoperative vedolizumab and early postoperative complications in patients with IBD undergoing abdominal surgery. A search of databases and abstracts from gastroenterology conferences was performed. Primary outcomes included overall and infectious postoperative complication rates as well as surgical site infections. Studies that compared Crohn disease, ulcerative colitis, or patients with IBD-undefined with preoperative vedolizumab treatment undergoing abdominal surgery with controls with preoperative antitumor necrosis factor-α (anti-TNF-α) treatment or no preoperative biologic treatment were included. A meta-analysis was completed using the Mantel-Haenszel and DerSimonian and Laird models. Six studies totaling 1201 patients were included; 281 patients were treated preoperatively with vedolizumab, 327 patients were treated preoperatively with anti-TNF-α agents, and 593 patients were not treated preoperatively with any biologics. There was no significant difference in overall complications (odds ratio [OR] 1.04, 95% confidence interval [CI] 0.48-2.24, P = 0.92, I2 =77%) between the vedolizumab and no-biologic groups. There also was no significant difference in infectious complications (OR 1.00, 95% CI 0.37-2.69, P = 1.00, I2 = 78%), which persisted after sensitivity analysis (OR 0.71, 95% CI 0.31-1.60, P = 0.41, I2 = 46%). Furthermore, there was no significant difference in overall complications (OR 0.77, 95% CI 0.24-2.46, P = 0.66, I2 = 85%) and infectious complications (OR 0.89, 95% CI 0.20-3.94, P = 0.87, I2 = 86%) between the vedolizumab and anti-TNF-α groups. After sensitivity analysis, differences in overall and infectious complications remained insignificant (OR 0.54 and 0.50, 95% CI 0.24-1.17 and 0.22-1.15, P = 0.12 and 0.10, I2 = 39% and 18%, respectively). Vedolizumab was also not associated with a significant increase in surgical site infections compared with the no-biologic (OR 1.45, 95% CI 0.33-6.32, P = 0.62, I2 = 75%) and anti-TNF (OR 1.30, 95% CI 0.22-7.60, P = 0.77, I2 = 81%) groups. Preoperative treatment with vedolizumab in patients with IBD undergoing abdominal surgery is not associated with increases in overall or infectious postoperative complications compared with preoperative anti-TNF-α treatment and no preoperative biologic treatment. Large, prospective studies are needed to further assess the impact of preoperative vedolizumab treatment on postoperative complications, particularly with respect to IBD subtype.

Pulmonary nocardiosis: Life-threatening complications of antitumor necrosis factor-α treatment for Crohn's disease

Nocardia is an emerging infection in the era of biological therapy with a fatal outcome without treatment. Risk of dissemination and multisystem involvement demands an early diagnosis from the treating physician. We share our experience of such opportunistic infection (pulmonary nocardiosis) in a young male with Crohn's disease on injection adalimumab. The patient was managed with appropriate antibiotics and after therapy, prophylaxis with cotrimoxazole was initiated. Adalimumab was re-introduced, as he developed flare-up of the perianal disease on follow-up. Atypical opportunistic infection requires a meticulous approach to reach early diagnosis to prevent poor outcomes.

The Citrullinated and MMP-degraded Vimentin Biomarker (VICM) Predicts Early Response to Anti-TNFα Treatment in Crohn's Disease.

In Crohn's disease (CD), 10% to 40% of patients do not respond to anti-tumor necrosis factor-α (TNFα) treatment. Currently, there are no biomarkers with adequate sensitivity to separate responders from nonresponders at an early stage. The aim of this study was to investigated whether early changes in the VICM (citrullinated and matrix metalloproteinase-degraded vimentin) biomarker were associated with response to anti-TNFα treatment in patients with CD. Serum VICM levels were measured by ELISA in 2 independent cohorts of CD patients (n=42) treated with anti-TNFα (infliximab or adalimumab). Response was determined by achieving clinical remission (Harvey Bradshaw Index<5). Compared with baseline, VICM serum levels were reduced by anti-TNFα in the infliximab cohort (week 6 and 14) and in the adalimumab cohort (week 8). VICM was lower in the responders compared with the nonresponders [infliximab: week 6, P<0.05; area under the curve (AUC)=0.90; adalimumab: week 1, P<0.01 (AUC=0.91), and week 8, P<0.05 (AUC=0.86)], and were able to predict response to treatment after 1 week of treatment with an odds ratio of 42.5. The VICM biomarker was time dependently reduced in CD patients responding to anti-TNFα treatment. We suggest that VICM may be used as a marker for monitoring early response to anti-TNFα in patients with CD.

Associations Between Obesity and the Effectiveness of Anti-Tumor Necrosis Factor-α Agents in Inflammatory Bowel Disease Patients: A Literature Review and Meta-analysis.

Background: A total of 15% to 40% of adult inflammatory bowel disease (IBD) patients are obese. The influence of obesity on anti-tumor necrosis factor-α (anti-TNF-α) treatment in IBD patients is not consistent. Objective: To determine the association between obesity and the efficacy of anti-TNF treatment in IBD patients. Methods: We performed a systematic search from January 1990 through November 2019 on MEDLINE, Web of Science, Google Scholar, ClinicalTrials.gov, and Cochrane library. We included randomized controlled trials and observational cohort studies that investigated the outcome of anti-TNF treatment in IBD patients with stratification according to body mass index or body weight. The odds ratio (OR) and its 95% CI were calculated. Results: In this pooled meta-analysis, we observed that obesity increased the odds of failure of anti-TNF therapy (OR = 1.195; 95% CI = 1.034-1.380; P = 0.015; I2 = 47.8%). After performing subgroup analyses, obesity was associated with higher odds of anti-TNF treatment failure in ulcerative colitis (UC) patients (OR = 1.413; 95% CI = 1.008-1.980; P = 0.045; I2 = 20.0%) but not in Crohn's disease patients (OR = 1.099; 95% CI = 0.928-1.300). Obesity significantly increased the odds of treatment failure of both dose-fixed and weight-based anti-TNF agents (OR = 1.121, 95% CI = 1.027-1.224, P = 0.011, and OR = 1.449, 95% CI = 1.006-2.087, P = 0.046, respectively). Conclusion and Relevance: In our meta-analysis, obesity was associated with the inferior response of anti-TNF treatments in UC patients. Clinicians should be aware that obese UC patients may require higher doses in anti-TNF treatment.

Quiescence and Subsequent Anterior Chamber Inflammation in Adalimumab-treated Pediatric Noninfectious Uveitis.

PurposeTo evaluate the effect of adalimumab in pediatric uveitis and subsequent changes in anterior chamber inflammation following the inactivation of uveitis.MethodsIn this retrospective study, patients with noninfectious uveitis younger than 18 years of age who were treated with adalimumab for more than 12 months were included. The rate of complete suppression and the relapse in anterior chamber inflammation following the initiation of adalimumab therapy were evaluated using anterior chamber cell score and laser flare photometry (LFP) values, if available. Changes in visual acuity and the sparing effect of topical steroid agents were also evaluated.ResultsAmong 22 eyes of 12 pediatric uveitis patients enrolled, 13 eyes were associated with juvenile idiopathic arthritis and nine eyes had idiopathic uveitis. The mean ± standard deviation age was 10.2 ± 3.6 years. Types of uveitis included anterior uveitis (n = 17) and panuveitis (n = 5). Quiescence was observed in 14 eyes (63.6%) at 3 months and in 21 eyes (95.5%) at 12 months after initiation, respectively. After achieving inactive uveitis, uveitis relapsed in two eyes at 6 months, even with adalimumab treatment. In 11 eyes, anterior chamber showed 0.5+ cell scores during the rest of the follow-up period and one of those eyes met the criteria for the relapse based on LFP values. The dosage of topical steroids decreased significantly at 3, 9, and 12 months after the initiation of therapy (p ≤ 0.05). Visual acuity did not show improvement. There were no severe adverse effects of anti-tumor necrosis factor-α treatment reported.ConclusionsIn this study, adalimumab achieved a quiescent state in most eyes with pediatric noninfectious uveitis for 12 months with a relapse rate of 9.5%. LFP values together with the anterior chamber cell score can be utilized to monitor the improvement or relapse in anterior chamber inflammation in pediatric noninfectious uveitis.

Lack of Increased Risk of Lymphoma by Thiopurines or Biologics in Japanese Patients with Inflammatory Bowel Disease: A Large-Scale Administrative Database Analysis.

Background and AimsPatients with inflammatory bowel diseases may have higher incidences of non-melanoma skin cancers and non-Hodgkin lymphoma, potentially linked to underlying disease and treatments. This analysis assessed incidence rates of these malignancies in Japanese patients with ulcerative colitis or Crohn’s disease, and their association with thiopurine and/or anti-tumor necrosis factor-α treatment, using data from a nationwide administrative database in Japan.MethodsPatients diagnosed with inflammatory bowel disease without malignancy were identified from the Medical Data Vision database. Incident cases of non-melanoma skin cancers and non-Hodgkin lymphoma diagnosed after prescription of thiopurine and/or anti-tumor necrosis factor-α were identified between April 2008 and January 2018. Age- and sex-adjusted incidence rate ratios were calculated relative to the total treated patient population.ResultsA total of 75 673 eligible patients were identified at the index date. Thiopurine prescription with or without anti-tumor necrosis factor-α agents increased incidence rate ratios for non-melanoma skin cancers relative to the overall population (3.39 and 4.03, respectively). There were no notable differences in non-Hodgkin lymphoma incidence relative to the total population in any treatment subgroup, regardless of prescription of thiopurine and/or anti-tumor necrosis factor-α (all incidence rate ratios, ~1).ConclusionsThere is no evidence for an increased incidence of non-Hodgkin lymphoma attributable to thiopurine or anti-tumor necrosis factor-α treatment in Japanese patients with inflammatory bowel disease. The impact of racial differences on non-Hodgkin lymphoma incidences should be considered. Thiopurine therapy may be a risk factor for non-melanoma skin cancers in Japanese patients.

Ulcerative intestinal tuberculosis case as a complication of treatment by infliximab for intestinal Behçet's disease

Rationale:Intestinal Behçet's disease (BD) is characterized by intestinal ulcerations and gastrointestinal symptoms. Ulcerative intestinal tuberculosis (TB) is usually with dyspepsia, abdominal pain, vomiting, and weight loss. The 2 diseases exhibit similar clinical manifestations, but the most critical aspects of their clinical courses and required treatments are not at all similar.Patient concerns:We present a case in which a patient with intestinal Behçet's disease developed a de novo ulcerative intestinal TB infection after the start of anti-tumor necrosis factor-α treatment. This was despite histopathologic examination without caseous necrosis granuloma and negative for acid-fast staining and latent TB screen.Diagnoses:Intestinal Behçet's disease and intestinal TB.Interventions:The patient was treated with quadruple antituberculous chemotherapy, comprising rifapentine, isoniazid, ethambutol, and pyrazinamide.Outcomes:At follow-up about 3 months, the therapy of oral antituberculous drugs and thalidomide was continued and the patient's condition had stabilized.Lessons:This case illustrates the importance of closely monitoring patients who are on infliximab for possible onset of TB, even without abdominal symptoms, and with negative screening results for latent TB.

Current Pharmacologic Approaches in Painful Bladder Research: An Update.

The symptoms of interstitial cystitis (IC)/bladder pain syndrome (BPS) may have multiple causes and involve many contributing factors. Traditional treatments (intravesical instillations) have had a primary focus on the bladder as origin of symptoms without adequately considering the potential influence of other local (pelvic) or systemic factors. Systemic pharmacological treatments have had modest success. A contributing factor to the low efficacy is the lack of phenotyping the patients. Individualized treatment based on is desirable, but further phenotype categorization is needed. There seems to be general agreement that IC is a unique disease and that BPS is a syndrome with multiple pathophysiologies, but this has so far not been not been well reflected in preclinical research with the aim of finding new pharmacological treatments. Current research approaches, including anti-nerve growth factor treatment, anti-tumor necrosis factor-α treatment, activation of SHIP1 (AQX-1125), and P2X3 receptor antagonists, and α1-adrenoceptor antagonists are potential systemic treatments, implying that not only the bladder is exposed to the administered drug, which may be beneficial if the IC/BPS is a bladder manifestation of a systemic disease, or negative (adverse effects) if it is a local bladder condition. Local treatment approaches such as the antagonism of Toll-like receptors (which still is only experimental) and intravesical liposomes (with positive proof-of-concept), may have the advantages of a low number of systemic adverse effects, but cannot be expected to have effects on symptoms generated outside the bladder. Assessment of which of the treatment approaches discussed in this review that can be developed into useful therapies requires further studies.

Predictors of Relapse after Discontinuing Systemic Treatment in Childhood Autoimmune Chronic Uveitis

To identify clinical predictors of relapse in childhood autoimmune chronic uveitis after stopping systemic treatment. A retrospective, multicenter, cohort study. Ninety-four children in remission, receiving no treatments and with at least a 6-month followup, were enrolled. A higher probability of maintaining remission after discontinuing treatment was shown in idiopathic compared with juvenile idiopathic arthritis uveitis (Mantel-Cox chi-square = 23.21) if inactivity had been obtained within 6 months from starting systemic treatment (Mantel-Cox chi-square = 24.17) and by antitumor necrosis factor-α treatment (Mantel-Cox chi-square = 6.43). Type of disease, time, and type of systemic therapy to achieve inactivity predict different duration of uveitis remission after treatment withdrawal.

Interleukin-27 as a Novel Therapy for Inflammatory Bowel Disease: A Critical Review of the Literature.

Inflammatory bowel disease (IBD) is an inflammatory disorder of the intestine that affects an estimated 329 per 100,000 people in the United States and is increasing in incidence within a number of cultures worldwide. Likely due to its incompletely understood pathophysiology and etiology, the standard treatments for IBD are only efficacious in subsets of patients and often do not induce lasting remission. As a result, novel therapies are needed. The success of anti-tumor necrosis factor-α treatment in a subset of patients with IBD demonstrated that therapy targeting a single cytokine could be efficacious in IBD, and clinical trials investigating the blockade of a variety of cytokines have commenced. Interleukin (IL) 27 is a relatively recently discovered type I cytokine with established roles in infectious disease, autoimmunity, and cancer in a variety of organs. IL-27 was identified as a candidate gene for IBD, and a number of studies in mouse models of IBD have demonstrated that IL-27 therapy is protective. However, in contrast to these investigations, genetic deletion of the IL-27 receptor has been shown to be protective in some mouse models of IBD. The purpose of this review is to highlight the recent literature investigating the role of IL-27 in IBD and to discuss the possible explanations for the sometimes conflicting results of these studies. Evidence supporting IL-27 therapy as a treatment for IBD will also be discussed.

Development of Rheumatoid Nodules after Anti-Tumor Necrosis Factor-α Treatment with Adalimumab for Rheumatoid Arthritis.

Dear Editor: A 40-year-old male presented with 4 months history of multiple various sized erythematous to violaceous subcutaneous nodules on both extensor surfaces of elbows, which was partially movable and showed no symptoms (Fig. 1A). He was diagnosed as rheumatoid arthritis (RA) 7 years ago. A variety of therapeutic options, such as systemic corticosteroid, antimalarial drug, nonsteroidal anti-inflammatory drugs (NSAIDs), and methotrexate, were prescribed to control RA activity. However, they all failed to show symptomatic improvement. After that, the patient started adalimumab, a human monoclonal antibody to tumor necrosis factor (TNF)-α, 40 mg injection every other week with concomitant systemic corticosteroid, methotrexate and a NSAID. Adalimumab injection improved signs and symptoms of RA gradually. However, the multiple subcutaneous nodules occurred in the extensor sides of the elbows two months after adalimumab injection. A skin biopsy was performed and it showed dense fibrinoid deposits in deep dermis. At high magnification, large palisading granulomas surrounding degenerated connective tissue and fibrin were noticed and infiltrating inflammatory cells were mostly composed of lymphocytes and histiocytes. Mucin deposition was rarely observed. Overall, it was consistent with rheumatoid nodule (Fig. 1B, C). The patient didn't receive any treatment, and there was no change in the lesion at the follow-up visit. Fig. 1 (A) Multiple various sized erythematous to violaceous subcutaneous nodules on both extensor surfaces of elbows. (B) Biopsy showed dense fibrinoid deposits in deep dermis (H&E, ×100). (C) Biopsy showed palisading granulomas surrounding ... Rheumatoid nodule development is extremely rare side effect of TNF-α antagonists and only two cases after etanercept and adalimumab injection have reported so far. However, in the previous report caused by adalimumab injection, rheumatoid nodule was diagnosed by only ultrasonogram1. Thus, to our knowledge, this is the first report of rheumatoid nodules confirmed by histopathologic diagnosis following the treatment with adalimumab. Rheumatoid nodules are one of the most common extra-articular manifestations of RA, usually associated with severe disease activity. Macrophage is the main infiltrating inflammatory cell in both rheumatoid nodule and synovial membrane of RA and they show similar expressions of proinflammatory cytokines such as TNF-α, and interleukin-1 receptor antagonist (IL-1Ra)2. However, in this case, rheumatoid nodules were developed when the signs and symptoms of RA had been gradually improving by the adalimumab. There are several differences between rheumatoid nodule and synovial membrane of RA. Rheumatoid nodules lack infiltrating B cells, plasma cells, and organized lymphoid structures. In addition, E-selectin expression, IL-1 level are higher and TNF-α concentration is significantly lower in the rheumatoid nodule compared to the synovial membrane of RA3, which suggests that development of rheumatoid nodules might be less influenced by TNF-α. One study with TNF-α knockout mice demonstrated abnormally low TNF-α level might induce an exaggeration of the effects driven by other inflammatory mediators4. Therefore, it could be considered that excessive TNF-α suppression could induce the development of rheumatoid nodules. Furthermore, anti-TNF-α treatments increase peripheral blood counts which are thought to be related to reduced cell traffic to the inflamed joint in RA5. Thus it is conceivable that these migratory cells infiltrate other inflamed tissues and form rheumatoid nodules. So herein, we report a case with great interest which could be one of the example and supporting clinical evidence of the paradoxical effects of anti-TNF-α treatment.