Orofacial granulomatosis in pediatric Crohn's disease: clinical outcomes and genetic background in the era of biologics: a retrospective study in Japan.

Ustekinumab is a human monoclonal antibody targeting the p40 subunit of both interleukin-12 and interleukin-23 with reported efficacy to treat Crohn's disease. However, few studies have reported the use of ustekinumab for pediatric inflammatory bowel disease. This study aimed to assess the clinical efficacy and safety of ustekinumab in children and adolescents with inflammatory bowel disease. Medical records of patients aged under 20years with Crohn's disease or Crohn's disease-like inflammatory bowel disease who had received ustekinumab at a Japanese pediatric inflammatory bowel disease center were retrospectively reviewed for efficacy and safety. The primary outcome was the steroid-free clinical remission rate at weeks 26 and 52. The steroid-free remission rate beyond week 52 was also evaluated. Weighted pediatric Crohn's disease activity index and simple endoscopic score for Crohn's disease were used to assess disease activity. Seventeen patients were included (male:female=8:9, A1a [diagnosed<10years old]:A1b [diagnosed≥10years old]=8:9). All patients were on ustekinumab at week 26, and 9/10 continued treatment over 1year. The steroid-free clinical remission rates were 59% at week 26, 50% at week 52, and 70% over 1year. Three of eight children who underwent endoscopy after ustekinumab introduction achieved endoscopic remission. No serious adverse events were recorded during the study period. Ustekinumab may be an effective and safe treatment option for pediatric and adolescent Crohn's disease and Crohn's disease-like inflammatory bowel disease patients having nonresponse or adverse reactions to anti-tumor necrosis factor agents.

Inflammatory bowel disease in children and adolescents: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

Crohn's disease (CD) is associated with depression. It is unclear if psychosocial interventions offer benefit for depressive symptoms during active CD. In this secondary analysis of a larger study of treating depression in pediatric inflammatory bowel disease, we assessed whether cognitive behavioral therapy (CBT) would differentiate from supportive nondirective therapy in treating depression and disease activity in youth with CD. We also explored whether somatic depressive symptoms showed a different pattern of response in the overall sample and the subset with active inflammatory bowel disease. Youth with depression and CD (n = 161) were randomized to 3 months of CBT (teaching coping skills) or supportive nondirective therapy (supportive listening). Depressive severity was measured using the Children's Depression Rating Scale-Revised (CDRS-R) with the somatic depressive subtype consisting of those CDRS-R items, which significantly correlated with CD activity. Disease activity was measured by the Pediatric Crohn's disease Activity Index. Given the potential confound of higher dose steroids, subanalyses excluded subjects on >20 mg/d prednisone equivalent (n = 34). Total CDRS-R scores in the overall sample significantly decreased over time after both treatments (P < 0.0001). Treatment with CBT was associated with a significantly greater improvement in the Pediatric Crohn's disease Activity Index (P = 0.05) and somatic depressive subtype (P = 0.03) in those with active inflammatory bowel disease (n = 95) compared with supportive nondirective therapy. After excluding those on steroids (n = 34), there was a significant improvement in total CDRS-R (P = 0.03) and in Pediatric Crohn's disease Activity Index (P = 0.03) after CBT. Psychotherapy may be a useful adjunct to treat depression in the context of CD-related inflammation in youth who are not concurrently on higher dose steroids.

The Diagnostic Utility of Lip Biopsy in Paediatric Crohn's Disease: A 10-year Single-centre Retrospective Study

Premature Subclinical Atherosclerosis in Pediatric Inflammatory Bowel Disease

To the Editor: Thalidomide, which was banned from the market in 1961 because of its teratogenic effects, is currently being rediscovered because of its ability to selectively reduce tumour necrosis factor alpha production by inflammatory cells (1). Several reports have described its effectiveness in treating patients with a variety of ulcerative and immunologic conditions, including aphthous ulcers in human immunodeficiency viral infection (2,3). In this journal, Facchini et al. (4) described their experience with thalidomide use in five patients with Crohn disease who experienced intolerance or resistance to conventional medical treatment. Four of five patients experienced improvement in the Paediatric Crohn's Disease Activity Index and discontinued steroid treatment. However, one patient experienced distal paresthesiae, and treatment had to be discontinued after 6 days. We would like to report the experience of using thalidomide in patients with Crohn disease in the United Kingdom (UK). In Cardiff, we used this drug in two patients with Crohn disease and orofacial granulomatosis (OFG). Both of them experienced the significant side effects of peripheral neuropathy, and this prompted us to survey all the leading UK paediatric gastroenterology centers to determine the experience of thalidomide use in OFG and inflammatory bowel disease (IBD). We distributed a questionnaire to all the members of the IBD working group of the British Society of Paediatric Gastroenterology Hepatology and Nutrition. The responses showed that across the UK, thalidomide had been used in only six children with IBD. The indications were severe OFG and/or perianal Crohn disease refractory to conventional medical therapy. In all six cases, a once-daily dose of thalidomide (50–200 mg) had been used for a period of 3 to 6 months. All centers had requested nerve conduction velocities before starting therapy and repeated them every to 3 to 6 months thereafter. Overall, thalidomide resulted in improvement in symptoms and reduced need for other drugs, including steroids, in three of six cases. However, treatment had to be discontinued in four of six cases because of the development of peripheral neuropathy. These concerns appear to have limited the drug's use in the UK, and we feel that our experience with the frequency of this serious side effect (peripheral neuropathy) is important to take into account. Therefore, we suggest that thalidomide should be considered only in a carefully selected group of patients with severe and resistant OFG when other conventional medical treatments have failed to induce a remission and that extreme caution should be exercised with its use, including verbal and written consent and explanation to parents of potential side effects, in particular the potential for peripheral neuropathy. It is imperative, in our experience, that nerve conduction velocities are undertaken before and during treatment (every 3 months) and careful clinical monitoring done of each patient, looking for signs of neuropathy. M. Ahmed S. El-Hadi H. R. Jenkins

Inflammatory bowel disease (IBD) manifests as a complex disease resulting from gene–environment interactions or as a monogenic disease resulting from deleterious mutations. While monogenic IBD is predominantly pediatric, only one-quarter of complex IBD is pediatric. In this study, we were the first to systematically compare genetic architecture between monogenic and complex pediatric and adult IBD on genetic and molecular pathway levels. Genes reported as causal for monogenic pediatric IBD and related syndromes and as risk factors for pediatric and adult complex IBD were analyzed using CytoScape and ClueGO software tools to elucidate significantly enriched Gene Ontology (GO) terms. Despite the small overlap (seven genes) between monogenic IBD genes (85) and complex IBD loci (240), GO analysis revealed several enriched GO terms shared between subgroups (13.9%). Terms Th17 cell differentiation and Jak/STAT signaling were enriched in both monogenic and complex IBD subgroups. However, primary immunodeficiency and B-cell receptor signaling pathway were specifically enriched only for pediatric subgroups, confirming existing clinical observations and experimental evidence of primary immunodeficiency in pediatric IBD patients. In addition, comparative analysis identified patients below 6 years of age to significantly differ from complex pediatric and adult IBD and could be considered a separate entity.

Reply

Iron deficiency anemia (IDA) is the most common extra-intestinal complication in inflammatory bowel disease (IBD). The persistence of iron deficiency in patients living with quiescent IBD remains poorly understood. Given the extensive body of research linking IBD pathogenesis to microbiome disruptions, it is hypothesized that alterations in the microbiota or immune responses may drive the persistence of IDA in quiescent Crohn's disease. This study aimed to determine whether changes in the gut microbiota or immune phenotypes contribute to IDA, while uncovering potential mechanisms driving IDA in quiescent disease. This cross-sectional, descriptive, and analytical study utilized 141 samples from pediatric Crohn's disease patients with and without iron deficiency as well as healthy controls for initial 16S microbiome analysis and a smaller subset for Shotgun Metagenomics and immunologic analyses. Fecal and peripheral blood samples were obtained from the Jill Roberts Institute Live Cell Bank. While no major differences were observed in the overall gut microbiome composition between pediatric patients with quiescent Crohn's disease, with or without IDA, notable shifts in specific microbial strains were identified. Specifically, levels of Anaerobutyricum soehngenii and Alistipes shahii were significantly altered. Metagenomic analysis revealed an enrichment of pathways related to short-chain fatty acid metabolism and ascorbate degradation, indicative of functional change in these microbes. This is the first comprehensive microbiome analysis of quiescent pediatric Crohn's disease with concomitant IDA. The findings indicate modest but significant microbial strain-level differences and associated functional pathways, potentially implicating microbiota-mediated mechanisms in the persistence of IDA.

Perianal manifestations are frequent in patients with Crohn disease. The incidence in the pediatric age group has been estimated between 13.6 and 62% (1). Perianal disease may be mild and require no treatment, but may also be severe, debilitating, and recalcitrant to therapy. Markowitz et al. (2), described a severe and mutilating form of perianal Crohn disease called highly destructive perianal disease (HDPD). This condition is rare and is characterized by progressive ulceration of the perianal skin with involvement of the perineum and surrounding areas. We have recently treated three patients with this devastating condition. These children have not only severe pain and disability resulting from the perineal disease but are also limited in social interaction and school attendance by constant anal leakage of stool and exudate. The condition poses a challenge in terms of appropriate medical management as well as rehabilitation and limitation of disability. Because our patients failed conservative treatment they underwent diversion of fecal stream which provided relief from pain and stool leakage. CASE SUMMARIES Case 1 A three year old boy presented with rectal bleeding and an anal fissure. Crohn disease was not suspected. He was treated initially with laxatives. The fissure healed but subsequently recurred. At 7 years, he developed a chronic fistula-in-ano and a large perianal abscess. The fistula was excised and the abscess deroofed leaving a large cavity. Histology of the excised tissue revealed a chronic granulomatous process, and Crohn disease was suspected. Colonoscopy showed grossly normal findings but biopsies from the terminal ileum revealed a granuloma suggestive of Crohn disease. Barium meal and follow-through was normal. At 10 years, despite the absence of active intestinal disease, he developed a large painful perianal ulcer. The ulcer grew in the next 2 years producing a deep, discharging crater around the anterior 270 degrees of the anus, with a radius of 7 cm (Fig. 1). The edges were overhanging and surrounding skin thinned out. The ulcer did not involve the anal sphincters or urethra. He was treated initially with systemic steroids and later with steroids and azathioprine. Progression occurred despite sequential treatment with systemic steroids, azathioprine, intralesional steroid, topical tacrolimus, colchicine, salazopyrin, infliximab (chimeric monoclonal antibody to human tumour necrosis factor), thalidomide, and hyperbaric oxygen. Persistently painful defecation prompted a defunctioning sigmoid colostomy, after which he underwent unsuccessful split skin grafting of the ulcer site. Three years later, he developed active colonic disease, which failed to respond to three infusions of infliximab. He underwent left hemicolectomy. An ileostomy was formed to maintain diversion of the fecal stream. After further skin grafting, significant ulcer healing was apparent on recent review.FIG. 1: Extensive perianal ulceration as a result of highly destructive perianal disease. Arrow indicates anal orifice.Case 2 The patient is a 12-year-old boy who first presented at 6 years of age with orofacial granulomatosis. No other features of Crohn disease were apparent. He developed perianal fissures at 11 years and underwent upper and lower gastrointestinal endoscopy. The left colon was inflamed and edematous. Biopsies confirmed the diagnosis of Crohn disease. In the next 12 months, despite intensive medical therapy and significant improvement in colonic disease, he developed ulceration around the entire circumference of the anus with a radius of 5 cm. The ulcer was painful and continuously discharged purulent material. He underwent end-sigmoid colostomy for symptom relief. Postoperatively, he developed an intra-abdominal abscess that required percutaneous drainage. His midline abdominal wound was slow to heal. The peristomal skin ulcerated creating problems with stoma appliances. Healing of the skin occurred gradually over 6 months. Despite the postoperative complications, the patient believes surgery was worthwhile because he is now free of his previous severe pain on defecation. Six months after the operation, there has been no reduction in the size of the perianal lesion. Skin grafting is contemplated. Case 3 The patient is an 11-year-old boy who developed diarrhea, vomiting, and weight loss at the age of 3 years. Colonoscopy revealed an inflamed left colon, and a diagnosis of ulcerative colitis was made. He underwent treatment with mesalamine systemic steroid, steroid enemas, and elemental diet. Six months later, he developed an acute exacerbation and was referred to our center. Colonoscopy revealed extensively diseased rectum and left colon. Histology showed features of Crohn disease. He was treated accordingly, and the disease remained in remission until he had episodes of rectal bleeding at age 9. Perforation of the severely diseased sigmoid occurred during endoscopy and an emergency defunctioning ileostomy was performed. One year later, despite the ileostomy and treatment with infliximab, he developed a rapidly enlarging perianal ulcer that was refractory to medical treatment. He recently underwent total colectomy because of intractable colon disease. His perianal disease precluded ileostomy closure at this time. The perianal disease had improved considerably at last review. DISCUSSION Perianal manifestations of Crohn disease include perianal skin lesions (anal skin tags), anal canal lesions (anal fissures, anal ulcers, anorectal strictures), perianal fistulas and abscesses, rectovaginal fistulas and cancer (3-5). HDPD is a severe, mutilating form characterized by deep, cavitating ulceration of the perianal skin involving the adjoining perineum ± the vulva with marked undermining of the skin edges and copious exudate. It was described in 1995 by Markowitz et al. (2) in 6 (9%) of 67 patients with perianal Crohn disease. Tolia (1) alluded to a similar condition in her classification of pediatric perianal Crohn disease in 1996. In addition to pain and discomfort, leakage of feces and exudate caused embarrassment and problems with social interaction in our three school aged patients. HDPD has a major negative impact on lifestyle in these young adolescents, with a serious effect on school attendance, which demands effective management. Various modalities of medical therapy effective in inflammatory bowel disease have been used in HDPD including local and systemic steroid, metronidazole, cyclosporine, 6-mercaptopurine, elemental and semi-elemental diets, colchicine, thalidomide, infliximab, local application of tacrolimus (FK506), and hyperbaric oxygen therapy. The results have been disappointing, with only two of six patients in Markowitz's series (2) responding to medical treatment alone and none of our patients showing any improvement from the modalities used. When surgery is considered, local measures have little to offer. Abrasion of the surface and debridement failing to hasten healing in our experience. The possibility of controlling perianal disease by diversion of the fecal stream or resection of primary intestinal disease has been considered in children and adults for many years. In 1980, Zelas and Jagelman (6) reported improvement in severe perianal disease in 22 of 23 (95%) patients after fecal diversion, but the relapse rate was high (72%), with only 6 remaining well. Harper et al. (7) demonstrated improvement in 11 of 19 (58%) patients after ileostomy, 4 (36%) of whom relapsed while diverted. In 1991, Palder et al. (4) reported four patients who underwent resection of primary disease in an attempt to control perianal disease in two of whom a diverting stoma was formed. All had an improvement in their perianal disease. But Orkin and Telander (8) found improvement in perianal disease in only 5 of 17 (29%) children undergoing resection and primary anastomosis and in only 2 of 10 (20%) children after fecal diversion. Of Markowitz's (2) patients with HDPD, two underwent defunctioning colostomy, and one healed. Failure of aggressive medical treatment, severe pain during defecation and inability to achieve perineal hygiene because of anal discharge were the indications for diversion in two of our patients. These two obtained excellent symptomatic relief despite little change in the perianal disease. The third had already been defunctioned for a year when he developed HDPD that has not been very troublesome in the absence of defecation. A more radical approach to HDPD has been suggested by Orkin and Telander (8), who recommended proctocolectomy when there was associated rectosigmoid disease. The 35% incidence of delayed perineal healing in this study is worrying because of the earlier quoted nonhealing rate of 50% reported by Lockhart-Mummery (9) in 1972 for adults undergoing proctocolectomy for Crohn disease. Also, the indication for proctocolectomy is less clear in the absence of severe rectosigmoid disease. Proctocolectomy resulted in resolution of HDPD in an 18-year-old girl with long-standing colonic involvement in Markowitz's (2) series. We have been reluctant to recommend proctocolectomy for our patients because they are all very young, have acceptable symptom relief at present, and would like to preserve the anorectum in the hope of future restoration of bowel continuity. One of our patients has responded to a partial thickness skin graft, and we are considering this option in another. The third patient has recently shown some evidence of healing after total colectomy for failure to grow and active colonic disease, although the long-term outcome is uncertain in all three. CONCLUSIONS HDPD is a devastating and mutilating complication of perianal Crohn disease characterized by deep, excavating ulceration of the perianal skin and copious exudate. No race or sex predilection has been consistently demonstrated. Colonic involvement especially of the left side is an associated feature. The lesion is refractory to medical and surgical management. Diversion of the fecal stream is of value in amelioration of pain associated with defecation and in prevention of constant leakage of feces and exudate and may lead to ulcer healing in some patients. HDPD is an entity with poor prognosis, and early recognition is important to limit social isolation and enable school attendance.

Disease course and efficacy of medical therapy in stricturing paediatric Crohn's disease

Modifications in endoscopic practice for pediatric patients

Our pilot study aimed to determine the effect of tumor necrosis factor-alpha (TNF-alpha) 308 G-->A promoter single-nucleotide polymorphism in pediatric inflammatory bowel disease (IBD), its influence on inflammatory activity and the clinical manifestations. We obtained genomic DNA from 164 subjects, 82 with long-standing IBD aged 8 to 18 years: 46 with Crohn disease (CD) and 36 with ulcerative colitis (UC). Eighty-two healthy children served as the control population. Genotyping was determined by using a restriction enzyme-based assay. TNF-alpha 308 G-->A polymorphism was assessed in terms of inflammatory (C-reactive protein [CRP]) and disease activity. The latter was assessed by the Pediatric Crohn's Disease Activity Index (PCDAI) and the Truelove index for CD and UC, respectively. Significant differences in TNF-alpha 308 A polymorphism were found between the IBD group and controls (P < 0.05) and the UC group and controls (P < 0.001). No differences were noted between TNF-alpha 308 A polymorphism and clinical characteristics in UC. The frequency of the -308 A allele of TNF was not different in CD compared with that in the control group. The frequency of TNF-alpha 308 A genotype was significantly higher in CD patients with predominantly stenosing/penetrating disease compared with patients without complications (P < 0.001) and healthy controls (P < 0.01). In CD patients, those carrying TNF -308 A had a significant increase in CRP (P < 0.05) and the PCDAI (P < 0.05). In CD, CRP levels strongly correlated with the PCDAI (r = 0.6150, P < 0.001). In UC, significant differences among the mean levels of CRP (P < 0.05) and disease activity (P < 0.001) related to TNF-alpha 308 A polymorphism were found. Allele distribution (odds ratio, 12.9; CI, 1.18-140.81, P < 0.001) and CRP serum levels (odds ratio, 1.020; CI, 1.00-1.04, P < 0.001) were independently associated with CD complications. Although not necessarily dictating IBD initiation, the TNF-alpha 308 A polymorphism may play a role in modifying the CD phenotype. The polymorphism may influence disease activity as well as more intense inflammatory activity in both forms of IBD and may modify the progression of chronic digestive tract inflammation.

We sought to characterize perianal disease and its treatment in pediatric patients newly diagnosed with Crohn's disease. Data were obtained from the Pediatric Inflammatory Bowel Disease (IBD) Collaborative Group Registry, a prospective, multicenter observational registry recording clinical and laboratory outcomes in children under 16 years of age newly diagnosed with IBD. Patients with Crohn's disease were selected who had data on perianal disease and at least 24 months of follow-up. The records of patients with a Pediatric Crohn's Disease Activity Index perianal subscore greater than 0 were reviewed, and patients with abscesses or fistulas were selected. The therapies used and the course of their perianal disease were then assessed. Of the 276 patients identified, 41 had perianal lesions within 30 days of diagnosis. Thirteen of these had skin tags and fissures only, whereas 28 had fistulas and/or abscesses. The latter lesions resolved by 1 year in 20 patients, and 8 had chronic/recurrent perianal disease persisting for more than 1 year following diagnosis. Patients with fistulizing disease were much more likely to be treated and were treated earlier with antibiotics, infliximab, and immunomodulators than were nonfistulizing patients. Patients who developed chronic perianal disease were more likely to have low body mass indices and required more perianal surgery than did patients whose perianal disease resolved. Approximately 10% of newly diagnosed pediatric patients with Crohn's disease will have perianal fistulas and/or abscesses at the time of diagnosis. Most of these will resolve within a year with medical therapy alone.

Pediatric inflammatory bowel disease is associated with growth failure due to chronic inflammation, nutrient disorder, and the side effects of drugs, such as corticosteroids. Biological agents are therapeutic drugs that significantly improve the prognosis of patients with inflammatory bowel disease. The effectiveness of ustekinumab has been reported in the management of adult patients with inflammatory bowel disease. There are very few reports regarding the effectiveness and safety of ustekinumab in pediatric patients with inflammatory bowel disease, especially those who are biologically naive. A 10-year-old girl presented with chronic abdominal pain, diarrhea, and weight loss. Colonoscopy showed a longitudinal ulcer and cobblestone appearance in the ileum and discontinuous inflammation of the colon; therefore, she was diagnosed with Crohn's disease. She was prescribed a fat-restricted diet, elemental diet, 5-aminosalicylic acid, transient prednisolone, and ustekinumab. She achieved clinical and endoscopic remission based on the weighted Pediatric Crohn's Disease Activity Index, fecal calprotectin, and colonoscopy findings at week 75. This patient developed no adverse events, such as infusion reaction or susceptibility to infection over the 75 weeks. The use of ustekinumab as the first biological agent may be an effective and safe treatment for pediatric Crohn's disease.