Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965.

High Body Mass Index and Response to Anti-Tumor Necrosis Factor Therapy in Pediatric Crohn's Disease.

INTRODUCTION: Obesity is common among patients with pediatric Crohn's disease (PCD). Some adult studies suggest obese patients respond less well to anti-tumor necrosis factor (TNF) treatment. This study sought compares anti-TNF response and anti-TNF levels between pediatric patients with normal and high body mass index (BMI). METHODS: The COMBINE trial compared anti-TNF monotherapy with combination therapy with methotrexate in patients with PCD. In this secondary analysis, a comparison of time-to-treatment failure among patients with normal BMI vs BMI Z -score >1, adjusting for prescribed anti-TNF (infliximab [IFX] or adalimumab [ADA]), trial treatment assignment (combination vs monotherapy), and relevant covariates. Median anti-TNF levels across BMI category was also examined. RESULTS: Of 224 participants (162 IFX initiators and 62 ADA initiators), 111 (81%) had a normal BMI and 43 (19%) had a high BMI. High BMI was associated with treatment failure among ADA initiators (7/10 [70%] vs 12/52 [23%], hazard ratio 0.29, P = 0.007) but not IFX initiators. In addition, ADA-treated patients with a high BMI had lower ADA levels compared with those with normal BMI (median 5.8 vs 12.8 µg/mL, P = 0.02). IFX trough levels did not differ between BMI groups. DISCUSSION: Overweight and obese patients with PCD are more likely to experience ADA treatment failure than those with normal BMI. Higher BMI was associated with lower drug trough levels. Standard ADA dosing may be insufficient for overweight children with PCD. Among IFX initiators, there was no observed difference in clinical outcomes or drug levels, perhaps due to weight-based dosing and/or greater use of proactive drug monitoring.

Development and Testing of a New Simplified Endoscopic Mucosal Assessment for Crohn's Disease: The SEMA-CD.

OBJECTIVES: Endoscopic mucosal improvement is the gold standard for assessing treatment efficacy in clinical trials of Crohn's disease. Current endoscopic indices are not routinely used in clinical practice. The lack of endoscopic information in large clinical registries limits their use for research. A quick, easy, and accurate method is needed for assessing mucosal improvement for clinicians in real-world practice. We developed and tested a novel simplified endoscopic mucosal assessment for Crohn's disease (SEMA-CD). METHODS: We developed a 5-point scale for ranking endoscopic severity of ileum and colon based on Simple Endoscopic Score for Crohn's disease (SES-CD). Central readers were trained to perform SES-CD and SEMA-CD. Pediatric patients with Crohn's disease undergoing colonoscopy were enrolled. Video recordings of colonoscopies were de-identified and randomly assigned to blinded central readers. The SES-CD and SEMA-CD were scored for each video. The SES-CD was considered the validated standard for comparison. Correlation was assessed with Spearman rho, inter- and intrarater reliability with kappa statistics. RESULTS: Fifty-seven colonoscopies were read a total of 212 times. Correlation between SEMA-CD and SES-CD was strong (rho = 0.98, P < 0.0001). Inter-rater reliability for SEMA-CD was 0.80, and intrarater reliability was 0.83. Central readers rated SEMA-CD as easier than SES-CD. CONCLUSION: The SEMA-CD accurately and reproducibly correlates with the standard SES-CD. Central readers viewed SEMA-CD as easier than SES-CD. Use of SEMA-CD in practice should enable collecting mucosal improvement information in large populations of patients. This will improve the quality of research that can be conducted in clinical registries. External validation is needed.

Variation in care in pediatric Crohn disease.

OBJECTIVES: Variation in medical care can be a barrier to improving clinical outcomes. We aim to describe the variation in care of Crohn disease as provided by a broad sample of pediatric gastroenterologists. METHODS: Two hundred forty-six Crohn disease patients of 93 pediatric gastroenterologists from 48 practice sites starting treatment with either thiopurine or infliximab were studied. We assessed variation in diagnostic testing that had been performed to establish the diagnosis of Crohn disease and to assess the phenotype, extent, and severity of disease. We also assessed variation in initial thiopurine and infliximab dosage and in nutritional therapy. RESULTS: Diagnostic studies in which care was uniform included complete blood count, performed in 100% of patients, erythrocyte sedimentation rate and colonoscopy in 96%, and upper endoscopy in 89%. However, imaging of the small bowel had not been performed in 19%, and a stool test for pathogens had not been performed in 29%. Thiopurine methyltransferase (TPMT) had been measured in 61% of patients before treatment with a thiopurine; in 85%, TPMT was normal. Nonetheless, even when TPMT was normal, 40% of patients received an initial dose of thiopurine that was lower than recommended. Testing for tuberculosis before initiating treatment with infliximab was not performed in 30%. In addition, 36% of severely underweight patients were not receiving a multivitamin supplement, supplemental formula, or tube feeding. CONCLUSIONS: There is variation in diagnostic and therapeutic interventions in the management of pediatric Crohn disease, and gaps exist between recommended and actual care.

Differential role of tumor necrosis factor receptors in TNBS colitis.

BACKGROUND: Tumor necrosis factor alpha (TNFalpha) plays a central role in the pathology of T helper 1-mediated colitis such as Crohn's disease; however, the role of its 2 receptors in mediating pathology has not been fully explored. METHODS: Trinitrobenzene sulfonic acid colitis was used to induce colitis in mice lacking each of the TNF receptors (TNFRs) and in wild-type mice. TNFR1-/- mice lost more weight, became hypothermic, and had increased mortality compared with wild-type C57Bl/6 mice. TNFR2-/- mice, however, lost less weight, had normal temperatures, and had improved survival. RESULTS: Despite the improved clinical outcomes in TNFR2-/- mice, TNFalpha levels were increased in these mice. CONCLUSIONS: TNFalpha signaling through TNFR1 is protective in the trinitrobenzene sulfonic acid mouse model of inflammatory bowel disease.

Opposing effects of tumor necrosis factor receptor 1 and 2 in sepsis due to cecal ligation and puncture.

Tumor necrosis factor (TNF)-alpha, a cardinal molecule in the cascade of sepsis-induced host injury, binds to two distinct receptors: tumor necrosis factor receptor (TNFR) 1 and TNFR2. We used the cecal ligation and puncture model of polymicrobial sepsis to elucidate the role of these receptors in sepsis pathogenesis. Mice lacking TNFR1 had prolonged survival with less hypothermia, whereas mice lacking TNFR2-/- had shortened survival and more profound hypothermia than wild-type mice. TNFR1-/- and TNFR2-/- mice had increased serum concentrations of interleukin (IL) 1beta and total TNF-alpha (free plus receptor bound) compared with wild-type mice, but there were no differences in IL6 or IL10 concentrations. Furthermore, free TNF-alpha was markedly elevated in the serum and peritoneal fluid of mice lacking TNFR2, supporting a role for this receptor in regulating the concentration of TNF-alpha. Lastly, apoptosis of ileal crypt epithelial cells was increased in mice lacking TNFR1, but there were no differences in lymphocyte apoptosis. These data suggest that in sepsis, TNFR1 mediates much of the TNF-alpha-induced pathology, whereas TNFR2 mediates protective effects.

Lymphocytic esophagitis: a possible manifestation of pediatric upper gastrointestinal Crohn's disease.

BACKGROUND: Lymphocytic esophagitis (LE) is histologically defined by marked esophageal lymphocytosis with no or only rare intraepithelial granulocytes. This study was performed to investigate the association between LE and pediatric Crohn's disease (CD). METHODS: Blinded retrospective morphologic analysis was performed on gastrointestinal biopsies from pediatric patients with an established diagnosis of CD (n = 60) and ulcerative colitis (UC; n = 30), as well as a spectrum of non-inflammatory bowel disease (IBD) patients (n = 38). The highest density of intraepithelial lymphocytes (IEL), neutrophils (IEN), and eosinophils (IEE) per high power field (hpf; 40×) were counted. LE was defined as >50 IEL/hpf and a ratio of >50:1 IEL to intraepithelial granulocytes (IEG). RESULTS: LE was identified in 17/60 patients with CD, and only 2/30 patients with UC and 1/38 non-IBD control patients; P = 0.0263 (CD versus UC) and P = 0.0002 (CD versus non-CD). In all, 6/60 CD patients had esophagitis with granulomas and three of these met the diagnostic criteria for LE. There was no difference in the incidence of upper gastrointestinal (UGI) symptoms between the CD patients with LE (7/17, 41%) and CD patients with esophagitis with granulomas (3/6; P = 1.0). CONCLUSIONS: The histologic diagnosis of LE is associated with pediatric CD and was found in 28% of CD patients. If LE is identified in pediatric CD, it is likely a manifestation of UGI-CD rather than esophagitis due to other etiologies or a variant of normal.