Andrew B. Grossman

Methotrexate Following Unsuccessful Thiopurine Therapy in Pediatric Crohn's Disease

BACKGROUND:The thiopurines, azathioprine and 6-mercaptopurine, are traditional first-line immunomodulatory agents in adult and pediatric Crohns disease, but the comparative efficacy and safety of methotrexate have seldom been examined. We report outcomes with methotrexate treatment in pediatric patients previously refractory to or intolerant of thiopurines.METHODS:In a four-center, retrospective cohort study, efficacy of methotrexate in maintaining remission was assessed by PCDAI measurements, steroid use, and height velocity. Patients served as their own historical controls. Multivariable analysis controlled for route of methotrexate administration, reason for thiopurine discontinuation, baseline disease activity, and disease duration.RESULTS:Forty-two percent of 60 children treated with methotrexate were in clinical remission without steroids at both 6 and 12 months. A strong steroid sparing effect was observed compared with the year prior to methotrexate (P < 0.001). Success rates were similar in previously thiopurine-intolerant and refractory patients. Height velocity increased from –1.9 SDS to –0.14 SDS (P = 0.004) in the year following therapy. In a median 3-yr follow-up, a third of the patients did not require escalation of therapy; the others required step-up therapy with infliximab or surgery. Eight children (13%) stopped methotrexate due to adverse events, including, most commonly, elevated liver enzymes, and one serious episode of sepsis.CONCLUSION:Methotrexate appears effective in maintaining remission in pediatric Crohns disease, when thiopurines have failed. Consideration should be given to its use earlier in pediatric treatment algorithms.

Outcome following infliximab therapy in children with ulcerative colitis

OBJECTIVES:Infliximab is effective in treating moderate/severe ulcerative colitis (UC) in adults. The aim of this study was to determine the outcome after treatment with infliximab in pediatric UC.METHODS:We performed a multicenter cohort study of 332 pediatric patients with UC enrolled in the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry. Children ≤16 years of age and newly diagnosed with UC are enrolled in the registry. Disease and medication information are collected prospectively from the treating physician at diagnosis, 30 days, and quarterly thereafter. No interventions were specified, per protocol.RESULTS:Of 332 patients, 52 (16%) received infliximab (23% <3 months from diagnosis, 38% 3–12 months, 38% >12 months). Mean age at infliximab initiation was 13.3±2.6 (range 6–17) years; 87% of patients had pancolitis. Median follow-up was 30 months. Continuous maintenance (CM) therapy was given in 65%, episodic in 21%, episodic converted to CM in 6%, and insufficient data in 8% of patients. Sixty-three percent of patients were corticosteroid refractory, and 35% were corticosteroid dependent. Concomitant medications at first infliximab infusion included corticosteroids (87%), thiopurines (63%), and 5-aminosalicylates (51%). Corticosteroid-free inactive disease by physician global assessment was noted in 12/44 (27%), 15/39 (38%), and 6/28 (21%) patients at 6, 12, and 24 months, respectively. Kaplan–Meier analysis showed that the likelihood of remaining colectomy free after treatment with infliximab was 75% at 6 months, 72% at 12 months, and 61% at 2 years.CONCLUSIONS:In this cohort of children with UC receiving infliximab, corticosteroid-free inactive disease was observed in 38 and 21% of patients at 12 and 24 months, respectively. By 24 months, 61% of patients had avoided colectomy.

Outcome Following Thiopurine Use in Children With Ulcerative Colitis: A Prospective Multicenter Registry Study

OBJECTIVES:Despite little supporting data, thiopurine use is common in pediatric ulcerative colitis (UC). Our aim was to determine outcome following thiopurine use in a multicenter inception cohort of children diagnosed with UC.METHODS:Data were obtained from a prospective observational study of newly diagnosed children <16 years of age. Data are recorded at diagnosis, 30 days, and quarterly. Patients are managed by physician dictates not protocol. Disease activity is classified by physician global assessment. The primary outcome was corticosteroid (CS)-free inactive UC at 1 year following thiopurine initiation without the need for rescue therapy (infliximab, calcineurin inhibitors, or colectomy).RESULTS:Of 1,490 patients in our registry, 394 have UC (mean age at diagnosis 11.3±3.7 years); 197 (50%) received thiopurine (49% ≤3 months from diagnosis). Also, 84% were receiving CSs and 60% 5-aminosalicylates at thiopurine start. Of the 197 patients, there was insufficient follow-up (41), previous or concomitant use of infliximab (16), or calcineurin inhibitor (7), leaving 133 patients evaluable at 1 year. Of these, 65 (49%) had CS-free inactive UC without rescue therapy. CS-free inactive disease at 1 year after initiating thiopurine was not affected by starting thiopurine ≤3 months vs. >3 months from diagnosis, gender, age, or concomitant treatment with 5-aminosalicylates. Kaplan–Meier analysis showed that the likelihood of remaining free of rescue therapy in the thiopurine-treated patients was 73% at 1 year.CONCLUSIONS:Approximately 50% of children with UC starting thiopurine without previous or concomitant biologic or calcineurin inhibitor therapy have CS-free inactive disease 1 year later without the need for rescue therapy.

Clinical Presentation and Five-Year Therapeutic Management of Very Early-Onset Inflammatory Bowel Disease in a Large North American Cohort

OBJECTIVE To evaluate the presentation, therapeutic management, and long-term outcome of children with very early-onset (VEO) (≤ 5 years of age) inflammatory bowel disease (IBD). STUDY DESIGN Data were obtained from an inception cohort of 1928 children with IBD enrolled in a prospective observational registry at multiple centers in North America. RESULTS One hundred twelve children were ≤ 5 years of age with no child enrolled at <1 year of age. Of those, 42.9% had Crohns disease (CD), 46.4% ulcerative colitis (UC), and 10.7% had IBD-unclassified. Among the children with CD, children 1-5 years of age had more isolated colonic disease (39.6%) compared with 6- to 10-year-olds (25.3%, P = .04), and 11- to 16-year-olds (22.3%, P < .01). The change from a presenting colon-only phenotype to ileocolonic began at 6-10 years. Children 1-5 years of age with CD had milder disease activity (45.8%) at diagnosis compared with the oldest group (28%, P = .01). Five years postdiagnosis, there was no difference in disease activity among the 3 groups. However, compared with the oldest group, a greater proportion of 1- to 5-year-olds with CD were receiving corticosteroids (P < .01) and methotrexate (P < .01), and a greater proportion of 1- to 5-year-olds with UC were receiving mesalamine (P < .0001) and thiopurine immunomodulators (P < .0002). CONCLUSIONS Children with VEO-CD are more likely to have mild disease at diagnosis and present with a colonic phenotype with change to an ileocolonic phenotype noted at 6-10 years of age. Five years after diagnosis, children with VEO-CD and VEO-UC are more likely to have been administered corticosteroids and immunomodulators despite similar disease activity in all age groups. This may suggest development of a more aggressive disease phenotype over time.

Concomitant Use of Immunomodulators Affects the Durability of Infliximab Therapy in Children With Crohn's Disease

BACKGROUND & AIMS It is important to determine the effects of immunomodulators on the ability of children to remain on infliximab therapy for Crohns disease (durability of therapy), given the potential benefits and risks of concomitant therapy-especially with thiopurines in male patients. We investigated how immunomodulatory treatment affects the durability of infliximab therapy. METHODS We collected data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, from January 2002 through August 2014, on 502 children with Crohns disease who participated in a prospective multicenter study. Data were collected from patients who received at least a 3-dose induction regimen of infliximab, and their concomitant use of immunomodulators: no thiopurine or methotrexate treatment, treatment for 6 months or less during infliximab therapy, or treatment for more than 6 months during infliximab therapy. RESULTS The probabilities (± standard error) that children remained on infliximab therapy for 1 year, 3 years, and 5 years after the treatment began were 0.84 ± 0.02, 0.69 ± 0.03, and 0.60 ± 0.03, respectively. Age, sex, and disease extent or location did not affect the durability of infliximab therapy. Greater length of concomitant use of immunomodulators was associated with increased time of infliximab therapy. The probability that patients with more than 6 months of immunomodulator use remained on infliximab therapy for 5 years was 0.70 ± 0.04, compared with 0.48 ± 0.08 for patients who did not receive immunomodulators and 0.55 ± 0.06 for patients who received immunomodulators for 6 months or less (P < .001). In boys who received immunomodulators for 6 months or more after starting infliximab, the overall durability of infliximab therapy was greater among patients receiving methotrexate than thiopurine (P < .01); the probabilities that they remained on infliximab therapy for 5 years were 0.97 ± 0.03 vs 0.58 ± 0.08, respectively. CONCLUSIONS In children with Crohns disease, concomitant treatment with an immunomodulator for more than 6 months after starting infliximab therapy increases the chances that patients will remain on infliximab. In boys, methotrexate appears to increase the durability of infliximab therapy compared with thiopurine.

Retrospective cohort study of Methotrexate use in the treatment of pediatric Crohn's disease

Background:Methotrexate (MTX) use as an alternative to thiopurines in the treatment of Crohns disease (CD) in children is increasing. This study was undertaken to assess safety and efficacy of MTX in children with CD. Methods:Patients treated with MTX with a minimum of 1-year follow-up were identified in the Pediatric IBD Collaborative Research Group Registry, a prospective inception cohort study started in 2002. The clinical efficacy and safety of MTX were analyzed retrospectively. Results:Two hundred ninety patients treated with MTX were identified. One hundred seventy-two patients received at least 3 months of MTX without thiopurine or biologicals and had ≥1 year of follow-up. Eighty-one of 172 patients (47%) received MTX as first immunomodulator (IMM), of which 22 (27%) achieved ≥12 months of sustained clinical remission without surgery, thiopurine, biologicals, or corticosteroids. Those receiving MTX as second IMM achieved similar remission rate (35%, P = not significant). Fourteen percent received MTX as first IMM in 2002 and 60% in 2010 (P = 0.005). Disease location did not affect outcomes. MTX doses were equivalent in both groups. Fifteen percent of patients developed an alanine aminotransferase >60 international units/liter and 12% developed a white blood cell <4000 cells per microliter while on MTX. Only 4% of these discontinued MTX completely. A small group of 6 centers, which contributed only about one-third of patients with CD in the registry, contributed nearly two-thirds of the patients receiving MTX (P < 0.001). Conclusions:MTX use as first choice IMM is increasing in pediatric CD. MTX provided sustained clinical remission in nearly one-third of patients with minimal toxicity. There is large center-to-center variability in its use.

Increased dosing requirements for 6‐mercaptopurine and azathioprine in inflammatory bowel disease patients six years and younger

Background: 6‐Mercaptopurine (6‐MP) and its prodrug azathioprine (AZA) are effective for the induction and maintenance of remission and reduction of corticosteroid exposure for pediatric inflammatory bowel disease (IBD). The standard dose of 6‐MP is 1.0–1.5 mg/kg/day and for AZA is 2.0–2.5 mg/kg/day. The aim of this study was to determine whether IBD patients 6 years of age and younger require higher than standard doses of 6‐MP/AZA to achieve clinical remission. Methods: Clinical data was collected retrospectively for all IBD patients 6 years of age or younger treated with 6‐MP/AZA at The Childrens Hospital of Philadelphia. Results: Thirty patients met the inclusion criteria. IBD was diagnosed at a median age of 3.3 years (25–75th %ile 2.3–4.6 years) and 6‐MP/AZA was initiated at a median age of 3.9 years (range 0.8–6.8 years). After dose escalation, the median AZA‐equivalent dose was 3.1 mg/kg/day (25–75th %ile 2.5–3.5, max. dose 5.1 mg/kg/day). At the final recorded dose, 8/13 (62%) patients receiving AZA >3.0 mg/kg/day achieved clinical remission, compared to 2/12 (17%) receiving 2–3 mg/kg/day (P = 0.02). The risk of having active disease was on average 85% lower if the AZA‐equivalent dose was >3.0 mg/kg/day (95% confidence interval [CI] 72%–93%). Adverse events were experienced by 4/30 patients (hepatitis, n = 2; leukopenia, n = 2). No patients had to discontinue 6‐MP/AZA, and all laboratory abnormalities improved spontaneously or with dose reduction. Conclusions: The standard dose of 6‐MP/AZA may not be adequate for IBD patients 6 years of age and younger. Closely monitored dose escalation beyond the standard dosing range is effective and well‐tolerated.

A novel enteral nutrition protocol for the treatment of pediatric Crohn's disease.

Background:Enteral nutritional therapy (EN) is an effective modality for inducing and maintaining remission in pediatric patients with Crohn’s disease (CD). The standard protocol for EN provides patients with 100% of their caloric needs for induction of remission. The aim of this study was to determine the efficacy of delivering 80% to 90% of patient’s caloric needs through EN, to induce remission in pediatric patients with CD. This approach allows patients to consume remaining calories from a normal diet. Methods:A retrospective review of charts from 1998 to 2010 was conducted at The Children’s Hospital of Philadelphia. Remission (Pediatric Crohn’s Disease Activity Index <10) and response (decrease in Pediatric Crohn’s Disease Activity Index score of ≥12.5 points) were calculated before and after treatment with EN. Weight z scores and laboratory parameters were evaluated in all participants. Results:Forty-three charts were evaluated. Mean age of participants was 12.8 years (5.1–17.4), 67% were male and 33% female patients. Remission and response were evaluated in a group of 23 participants, with no missing data. There were reductions in erythrocyte sedimentation rate (P < 0.0001) and C-reactive protein (P < 0.02), and increases in albumin (P < 0.03). Mean Pediatric Crohn’s Disease Activity Index score at baseline was 26.9 and was reduced to a score of 10.2 at follow-up (P < 0.0001). Induction of remission was achieved in 65% and response in 87% at a mean follow-up of 2 months (1–4 months). Conclusions:This novel EN protocol seems to be effective for the induction of remission in pediatric patients with CD and contributes to increasing weight and improving laboratory markers. This protocol may result in improved EN acceptance and compliance and will be evaluated prospectively.

Outcome following aminosalicylate therapy in children newly diagnosed as having ulcerative colitis

Objectives: Despite a paucity of published supporting data, 5-aminosalicylate (5-ASA) use in pediatric ulcerative colitis (UC) is common. The present study describes the use and outcome of a large multicenter inception cohort of children with UC treated with 5-ASA. Methods: Data were obtained from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, a prospective North American observational study of children newly diagnosed as having inflammatory bowel disease ages 16 years or younger. Patient data are recorded at diagnosis, 30 days, and then quarterly. Patients are managed by physician dictate, not protocol. Disease activity is classified by physician global assessment. The primary outcome examined was corticosteroid (CS) free, inactive UC at 1 year following initiation of 5-ASA within 30 days of diagnosis (with or without concomitant CS use) without the need for rescue therapy (immunomodulators, biologics, or colectomy). Results: Study subjects included 213 patients newly diagnosed as having UC who received oral 5-ASA compounds (115 of whom also received CS) during the first 30 days after diagnosis, and no other oral therapies for the treatment of UC. Of these 213 patients, 86 (40%) were CS free and physician global assessment inactive at 1 year without rescue. Outcome was not associated with disease severity at diagnosis, demographic or laboratory factors examined, or initial dose of 5-ASA used. Conclusions: Forty percent of children taking 5-ASA as primary maintenance therapy at diagnosis are in CS-free remission after 1 year of treatment. Further pediatric studies will be needed to address whether increased adherence and/or higher dosing schedules will improve outcomes.

Vedolizumab Therapy in Severe Pediatric Inflammatory Bowel Disease.

Background:Vedolizumab is effective for inducing and maintaining remission in adults with inflammatory bowel disease (IBD); however, there is limited pediatric data. This study aimed to describe the adverse events and clinical response to vedolizumab in refractory pediatric IBD. Methods:Disease activity indices, clinical response, concomitant medication use, and adverse events were measured over 22 weeks in an observational prospective cohort study of children with refractory IBD who had failed anti–tumor necrosis factor therapy and subsequently initiated vedolizumab therapy. Results:Twenty-one subjects, 16 with Crohn disease, received vedolizumab. Clinical response was observed in 6/19 (31.6%) of the evaluable subjects at week 6 and in 11/19 (57.9%) by week 22. Before induction, 15/21 (71.4%) participants were treated with systemic corticosteroids, as compared with 7/21 (33.3%) subjects at 22 weeks. Steroid-free remission was seen in 1/20 (5.0%) subjects at 6 weeks, 3/20 (15.0%) at 14 weeks, and 4/20 (20.0%) at 22 weeks. There was statistically significant improvement in serum albumin and hematocrit; however, C-reactive protein increased by week 22 (P < 0.05). There were no infusion reactions. Vedolizumab was discontinued in 2 patients because of severe colitis, requiring surgical intervention. Conclusions:There is limited experience with vedolizumab therapy in pediatric IBD. There seems to be a marked number of subjects with clinical response in the first 6 weeks that increases further by week 22 despite the severity of disease in this cohort. Adverse events may not be directly related to vedolizumab. This study is limited by small sample size, and larger prospective studies are warranted.