Crohn Disease: Kugathasan S

Sands BE, Cuffari C, Katz J, Kugathasan S, Onken J, Vitek C, Orenstein W. · Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Inflamm Bowel Dis. · Pubmed #15472534 No free full text.

Abstract: During the past 2 decades, medical therapy for Crohn's disease (CD) and ulcerative colitis (UC) has grown to incorporate a variety of immunesuppressing agents. At the same time, basic insights into the aberrant mucosal immune response underlying inflammatory bowel disease (IBD) have expanded dramatically. The interplay of host susceptibility to infection and the safety and efficacy of immunization for vaccine-preventable diseases has been explored in other immune-mediated disease states but only rarely in IBD. The purpose of this review is to formulate best-practice recommendations for immunization in children and adults with IBD by considering the effects of the IBD disease state and its treatments on both the safety and efficacy of immunization. To do so, we first considered the routine recommendations for immunization of children, adults and distinct populations at increased risk for vaccine-preventable disease. Because it was rarely possible to examine direct data on safety and efficacy of immunization in IBD populations, we relied to a large extent upon extrapolation from similar populations and from knowledge of basic mechanisms. The literature suggests that efficacy of immunization may be diminished in some patients whose immune status is compromised by immune suppression. However, except for live agent vaccines, most immunizations may be safely administered to patients with IBD even when immune compromised. Conversely, protection against vaccine-preventable illness may be of even greater benefit to those at risk for morbid or lethal complications of infections because of an immune compromised state. We conclude that for most patients with IBD, recommendations for immunization do not deviate from recommended schedules for the general population.

Binion DG, Kugathasan S, Dwinell MB. · Division of Gastroenterology & Hepatology, Froedtert Memorial Lutheran Hospital, Children's Hospital of Wisconsin, Milwaukee, Wisconsin 53226, USA. · Am J Gastroenterol. · Pubmed #16405541 No free full text.

Abstract: The association of NOD2/CARD15 gene mutations with Crohn's disease (CD) has also provided proof of principle that anatomic location (ileal disease) and stricturing behavior is associated with specific genetic variants. However, the majority of CD patients of Caucasian descent, and essentially all minority CD patients do not possess NOD2/CARD15 mutations. Although these early lessons from NOD2/CARD15 genotype/phenotype correlations are encouraging, much more needs to be done to adequately understand the CD spectrum of subgroups. The study by Brand et al. demonstrates that a chemokine receptor polymorphism (CX3CR1 T280) can also influence disease location and behavior, suggesting yet another genetic variant that can help to subgroup CD patients. Findings similar to the study by Brand and colleagues in this issue of American Journal of Gastroenterology suggest that panels of susceptibility alleles and polymorphisms will ultimately allow an early genetic determination that will correspond with unique clinical patterns of CD: increased expression of the chemokine fractalkine in Crohn's disease and association of the factalkine receptor T280M polymorphism with a fibrostenosing disease phenotype.

Kugathasan S, Fiocchi C. · Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. · Semin Pediatr Surg. · Pubmed #17602969 No free full text.

Abstract: A modern approach to inflammatory bowel disease (IBD) research has been under way for little over one-half century, but only during the last two decades has progress accelerated and finally generated tangible results that have been translated into practical and better therapeutic strategies. The areas where progress has been more evident are those currently believed to be the key components of IBD pathogenesis, and include the environment, genetics, enteric microbiology, and immune reactivity. Progress in these different areas has been somewhat uneven, yielding a better understanding of the mechanisms behind gut inflammation and tissue injury rather than of specific etiological agents or predisposing factors. However, with the rapidly increasing utilization of novel methodological approaches like genetics, genomics, proteomics, and pharmacogenomics, it is reasonable to anticipate that the etiopathogenesis of IBD will be unveiled in the next couple of decades and more definitive, perhaps disease-modifying, approaches will be uncovered and implemented.

Hyams JS, Wilson DC, Thomas A, Heuschkel R, Mitton S, Mitchell B, Daniels R, Libonati MA, Zanker S, Kugathasan S, Anonymous00087. · Division of Digestive Diseases and Nutrition, Connecticut Children's Medical Center, Hartford, CT 06106, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #17255829 No free full text.

Abstract: OBJECTIVES: This study evaluated the safety, tolerability, and efficacy of natalizumab, a humanized monoclonal immunoglobulin-G4 antibody to [alpha]4 integrin, in adolescent patients with moderately to severely active Crohn disease (CD). PATIENTS AND METHODS: In a single-arm study, 38 adolescent patients (ages 12-17 y) with active CD (Pediatric Crohn Disease Activity Index [PCDAI] >30) received 3 intravenous infusions of natalizumab (3 mg/kg) at 0, 4 and 8 weeks. The primary analysis was safety, assessed by adverse events, laboratory results, and vital signs. Pharmacokinetic and pharmacodynamic measurements and formation of anti-natalizumab antibodies also were analyzed. Efficacy outcomes were assessed by changes in PCDAI, quality of life (IMPACT III), and levels of C-reactive protein and serum albumin. RESULTS: Thirty-one patients (82%) received 3 natalizumab infusions. The most common adverse events were headache (26%), pyrexia (21%) and CD exacerbation (24%). Clinical response (> or =15-point decrease from baseline PCDAI) and remission (PCDAI < or =10) rates were greatest at week 10 (55% and 29%, respectively). Three patients (8%) tested positive for anti-natalizumab antibodies. The peak level (61.0 and 66.3 microg/mL) and half-life (92.3 and 96.3 h) of natalizumab were comparable after the first and third infusions. Mean [alpha]4 integrin receptor saturation was 93% at 2 hours and <40% at 4 weeks after the first and third infusions. Increase from baseline in circulating lymphocytes ranged from 106% to 122% at 2 weeks and 45% to 65% at 4 weeks after each infusion. CONCLUSION: Natalizumab (3 mg/kg) was well tolerated in these adolescent patients with active CD, with a safety and efficacy profile similar to that of adult natalizumab-treated CD patients. Future studies should evaluate long-term safety and efficacy.

Kugathasan S. · Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #11685975 No free full text.

This publication has no abstract.

Kugathasan S, Werlin SL, Martinez A, Rivera MT, Heikenen JB, Binion DG. · Division of Pediatric Gastroenterology and Nutrition, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee 53226, USA. · Am J Gastroenterol. · Pubmed #11095340 No free full text.

Abstract: OBJECTIVES: Tumor necrosis factor-alpha plays a central role in chronic intestinal inflammation of Crohn's disease. Targeting this cytokine with the chimeric monoclonal antibody infliximab has emerged as an effective form of therapy in adult Crohn's disease patients. We sought to determine whether infliximab treatment would benefit pediatric patients with medically refractory Crohn's disease. We also assessed the duration of response, comparing children with early disease to children with long-standing (late) Crohn's disease. METHODS: Fifteen consecutive children (mean age 12.8 +/- 3.2 yr) with medically refractory Crohn's disease were enrolled in a prospective, open-label trial of a single, 5-mg/kg infliximab intravenous infusion. Medically refractory disease was defined as an inability to taper steroids, lack of response to immunomodulator therapy over 4 months, and active disease as measured by the Pediatric Crohn's Disease Activity Index (PCDAI). Primary endpoints included measurements of disease activity (PCDAI), steroid use, and duration of clinical response. RESULTS: In all, 14/15 children (94%) improved after infliximab infusion, with a significant decrease of both PCDAI and daily steroid use by 4 wk. Ten patients (67%) achieved complete remission by 10 wk. Among the 14 patients who responded, three of six children (50%) with early disease maintained clinical response through the 12-month trial period, compared to none of eight children with late disease. There were no serious complications associated with the use of infliximab in any of the patients. CONCLUSIONS: Infliximab is safe and effective in the short-term treatment of medically refractory pediatric Crohn's disease. More importantly, there is a remarkably prolonged duration of response after infliximab therapy in children with early compared to late Crohn's disease.

Wang K, Zhang H, Kugathasan S, Annese V, Bradfield JP, Russell RK, Sleiman PM, Imielinski M, Glessner J, Hou C, Wilson DC, Walters T, Kim C, Frackelton EC, Lionetti P, Barabino A, Van Limbergen J, Guthery S, Denson L, Piccoli D, Li M, Dubinsky M, Silverberg M, Griffiths A, Grant SF, Satsangi J, Baldassano R, Hakonarson H. · Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. · Am J Hum Genet. · Pubmed #19249008 No free full text.

Abstract: Previous genome-wide association (GWA) studies typically focus on single-locus analysis, which may not have the power to detect the majority of genuinely associated loci. Here, we applied pathway analysis using Affymetrix SNP genotype data from the Wellcome Trust Case Control Consortium (WTCCC) and uncovered significant association between Crohn Disease (CD) and the IL12/IL23 pathway, harboring 20 genes (p = 8 x 10(-5)). Interestingly, the pathway contains multiple genes (IL12B and JAK2) or homologs of genes (STAT3 and CCR6) that were recently identified as genuine susceptibility genes only through meta-analysis of several GWA studies. In addition, the pathway contains other susceptibility genes for CD, including IL18R1, JUN, IL12RB1, and TYK2, which do not reach genome-wide significance by single-marker association tests. The observed pathway-specific association signal was subsequently replicated in three additional GWA studies of European and African American ancestry generated on the Illumina HumanHap550 platform. Our study suggests that examination beyond individual SNP hits, by focusing on genetic networks and pathways, is important to unleashing the true power of GWA studies.

Pfefferkorn M, Burke G, Griffiths A, Markowitz J, Rosh J, Mack D, Otley A, Kugathasan S, Evans J, Bousvaros A, Moyer MS, Wyllie R, Oliva-Hemker M, Carvalho R, Crandall W, Keljo D, Walters TD, LeLeiko N, Hyams J. · Riley Hospital for Children, Indianapolis, IN 46202, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #19179878 No free full text.

Abstract: OBJECTIVES: We analyzed growth outcomes in children newly diagnosed with Crohn disease and determined whether growth abnormalities persist despite current therapies. PATIENTS AND METHODS: Clinical and growth data were prospectively obtained on an inception cohort younger than 16 years old at diagnosis and Tanner I to III during the study. RESULTS: In all, 176 children (mean age 10.1 years; 65% male) with mild (33%) or moderate/severe (67%) disease at diagnosis were studied. Disease activity at 1 year was inactive/mild (89%) or moderate/severe (11%). First-year treatments included immunomodulators (60%), corticosteroids (77%), 5-aminosalicylates (61%), infliximab (15%), and enteral nutrition (10%). By 2 years, 86% had received immunomodulators and 36% infliximab. Mean height z scores at diagnosis, 1 year, and 2 years were -0.49 +/- 1.2 standard deviations (SDs), -0.50 +/- 1.2, and -0.46 +/- 1.1, respectively. Of the subjects, 10%, 8%, and 6.5% had height z scores less than -2 SD at diagnosis, 1 year, and 2 years. A height velocity z score less than -1SD was seen in 45% of subjects at 1 year and 38% at 2 years. The mean height velocity z score, however, increased between 1 and 2 years from -0.71 to 0.26 (P < 0.03). Corticosteroid use greater than 6 months in the first year was associated with abnormal height velocity at 1 year (adjusted odds ratio = 4.5; 95% confidence interval [CI] = 2.2-9.6). No statistically significant effect on height velocity z scores was noted when comparing those receiving or not receiving infliximab. CONCLUSIONS: Growth delay persists in many children with CD following diagnosis, despite improved disease activity and the frequent use of immunomodulators and biologics. Additional strategies to improve growth outcomes require development.

Thayu M, Leonard MB, Hyams JS, Crandall WV, Kugathasan S, Otley AR, Olson A, Johanns J, Marano CW, Heuschkel RB, Veereman-Wauters G, Griffiths AM, Baldassano RN, Anonymous00065. · Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA 19014, USA. · Clin Gastroenterol Hepatol. · Pubmed #19081527 No free full text.

Abstract: BACKGROUND & AIMS: Crohn's disease (CD) is associated with altered bone metabolism. This study examined changes in bone formation and resorption after infliximab induction and associations between bone biomarkers, linear growth, and disease activity (Pediatric Crohn's Disease Activity Index [PCDAI]) after 54 weeks of infliximab therapy. METHODS: One hundred twelve subjects ages 6-17 years with moderate to severe CD received infliximab induction (5 mg/kg/dose) at weeks 0, 2, and 6; week-10 responders were randomized to infliximab every 8 or every 12 weeks maintenance therapy. Serum bone-specific alkaline phosphatase (BSAP), N-terminal propeptide of type 1 collagen (P1NP), urine C-telopeptide of collagen cross-links (CTX-1), and deoxypyrodinoline (DPD) were collected at baseline and 10 weeks. PCDAI and height z-scores were assessed at baseline and at 10 and 54 weeks. RESULTS: Models were adjusted for bone age, gender, height, and steroid use. Baseline BSAP and P1NP levels were negatively associated with PCDAI (both P = .01). BSAP and P1NP increased during induction (both P < .001) and were associated with 54-week increases in height z-score (P < .05 and P < .001, respectively). Improvements in P1NP were associated with 54-week decreases in PCDAI (P = .01). CTX-1 and DPD also increased during induction (P < .001 and P = .01, respectively) but were not associated with changes in PCDAI. Changes in CTX-1 were associated with improvements in height z-score (P < .002). CONCLUSIONS: Infliximab therapy is associated with dramatic increases in BSAP and P1NP, consistent with inhibition of tumor necrosis factor-alpha effects on osteoblasts. The increases in CTX-1 and DPD likely reflect coupling of bone formation and resorption and increases in linear growth.

Keljo DJ, Markowitz J, Langton C, Lerer T, Bousvaros A, Carvalho R, Crandall W, Evans J, Griffiths A, Kay M, Kugathasan S, LeLeiko N, Mack D, Mamula P, Moyer MS, Oliva-Hemker M, Otley A, Pfefferkorn M, Rosh J, Hyams JS. · Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15213, USA. · Inflamm Bowel Dis. · Pubmed #19023863 No free full text.

Abstract: BACKGROUND: We sought to characterize perianal disease and its treatment in pediatric patients newly diagnosed with Crohn's disease. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Dubinsky MC, Kugathasan S, Mei L, Picornell Y, Nebel J, Wrobel I, Quiros A, Silber G, Wahbeh G, Katzir L, Vasiliauskas E, Bahar R, Otley A, Mack D, Evans J, Rosh J, Hemker MO, Leleiko N, Crandall W, Langton C, Landers C, Taylor KD, Targan SR, Rotter JI, Markowitz J, Hyams J, Anonymous00008, Anonymous00009, Anonymous00010. · Department of Pediatrics, IBD Center, Cedars Sinai Medical Center, Los Angeles, California, USA. · Clin Gastroenterol Hepatol. · Pubmed #18619921 No free full text.

Abstract: BACKGROUND & AIMS: The ability to identify children with CD who are at highest risk for rapid progression from uncomplicated to complicated phenotypes would be invaluable in guiding initial therapy. The aims of this study were to determine whether immune responses and/or CARD15 variants are associated with complicated disease phenotypes and predict disease progression. METHODS: Sera were collected from 796 pediatric CD cases and tested for anti-Cbir1 (flagellin), anti-outer membrane protein C, anti-Saccharomyces cerevisiae, and perinuclear antineutrophil cytoplasmic antibody by using enzyme-linked immunosorbent assay. Genotyping (Taqman MGB) was performed for 3 CARD15 variants (single nucleotide polymorphisms 8, 12, and 13). Associations between immune responses (antibody sum and quartile sum score, CARD15, and clinical phenotype were evaluated. RESULTS: Thirty-two percent of patients developed at least 1 disease complication within a median of 32 months, and 18% underwent surgery. The frequency of internal penetrating, stricturing, and surgery significantly increased (P trend < .0001 for all 3 outcomes) with increasing antibody sum and quartile sum score. Nine percent of seropositive groups had internal penetrating/stricturing versus 2.9% in the seronegative group (P = .01). Twelve percent of seropositive groups underwent surgery versus 2% in the seronegative group (P = .0001). The highest antibody sum group (3) and quartile sum score group (4) demonstrated the most rapid disease progression (P < .0001). Increased hazard ratio was observed for antibody sum group 3 (7.8; confidence interval, 2.2-28.7), P < .002 and quartile sum score group 4 (11.0; confidence interval, 1.5-83.0, P < .02). CONCLUSIONS: The rate of complicated CD increases in children as the number and magnitude of immune reactivity increase. Disease progression is significantly faster in children expressing immune reactivity.

Punati J, Markowitz J, Lerer T, Hyams J, Kugathasan S, Griffiths A, Otley A, Rosh J, Pfefferkorn M, Mack D, Evans J, Bousvaros A, Moyer MS, Wyllie R, Oliva-Hemker M, Mezoff A, Leleiko N, Keljo D, Crandall W, Anonymous00311. · Nationwide Children's Hospital, Ohio State University, Columbus, Ohio 43210, USA. · Inflamm Bowel Dis. · Pubmed #18306311 links to  free full text

Abstract: BACKGROUND: The immunomodulators (IMs) 6-mercaptopurine and azathioprine decrease corticosteroid dependence and maintain remission in Crohn's disease (CD). We describe IM use in newly diagnosed pediatric CD, comparing outcomes of "early" versus "late" initiation of therapy. METHODS: Data were obtained from pediatric CD patients enrolled in a prospective, multicenter observational study. Moderate/severe disease patients treated with IM were compared for outcomes of remission, corticosteroid use, infliximab therapy, hospitalizations, and CD-related surgery based on timing of initiation of IM therapy. RESULTS: In all, 247 children met the criteria (60% male, mean age 11.9 years); 199 were treated with IM within 1 year of diagnosis; 150 between 0-3 months (early), 49 between 3-12 months (late). Both groups showed a decrease in corticosteroid use by 12 months, at which time proportionately fewer early group patients had received corticosteroids in the preceding quarter (22%) than late groups patients (41%)(P = 0.013). The number of hospitalizations per patient was also noted to be significantly lower in the early group over the 2-year follow-up (P = 0.03). No difference was noted in the rates of remission, infliximab use over time, or surgery. CONCLUSIONS: 80% of children with newly diagnosed moderate to severe CD are treated with IM within 1 year. Early IM use is associated with reduced corticosteroid exposure and possibly fewer hospitalizations per patient.

Baptista ML, Amarante H, Picheth G, Sdepanian VL, Peterson N, Babasukumar U, Lima HC, Kugathasan S. · Department of Internal Medicine, Federal University of Paraná, Curitiba, PR. · Inflamm Bowel Dis. · Pubmed #18200510 links to  free full text

Abstract: BACKGROUND: Although many genetic variants are identified in association with Crohn's disease (CD), CARD15, IL23R, and ATG16L1 association with CD have been firmly confirmed in Caucasians of European ancestry. The prevalence of CD is rapidly rising in Brazil, where European ancestry is firmly admixed with natives and Africans, resulting in a heterogeneous population. We investigated the contribution of CARD15, IL23R, and ATG16L1 with CD risk in a heterogeneous Brazilian population. METHODS: Genotyping for CARD15 (R702W, G908R, 3020insC), IL23R (rs1004819, rs7517847, rs11209026, rs10889677, rs1495965), and ATG16L1 (rs2241880) was performed in 187 children and adults with CD and 255 healthy ethnically matched controls. Clinical records were systematically reviewed and detailed phenotypic information was obtained. RESULTS: At least 1 CARD15 risk allele was present in 30% of the CD patients compared with 10% of controls. Variants of CARD15 (3020insC and R702W) and IL23R (rs1004819, rs11209026, and rs1088967) were associated with CD. However, no genotype-phenotype correlations were found among the Brazilian CD population with CARD15 or IL23R variants. No significant association was achieved with ATG16L1. CONCLUSIONS: CARD15 and IL23R confer susceptibility to CD in the Brazilian population. However, the presence of these variants did not influence disease phenotype. Further research should be focused on larger sample sizes with population admixture analysis to better understand the risks and genotype-phenotype correlation in populations like Brazil where the prevalence of CD is rapidly rising.

Turner D, Grossman AB, Rosh J, Kugathasan S, Gilman AR, Baldassano R, Griffiths AM. · Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Canada. · Am J Gastroenterol. · Pubmed #18042110 No free full text.

Abstract: BACKGROUND: The thiopurines, azathioprine and 6-mercaptopurine, are traditional first-line immunomodulatory agents in adult and pediatric Crohn's 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 Crohn's disease, when thiopurines have failed. Consideration should be given to its use earlier in pediatric treatment algorithms.

Levine A, Kugathasan S, Annese V, Biank V, Leshinsky-Silver E, Davidovich O, Kimmel G, Shamir R, Palmieri O, Orazio P, Karban A, Broeckel U, Cucchiara S. · Pediatric Gastroenterology Unit, Wolfson Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. · Inflamm Bowel Dis. · Pubmed #17763471 links to  free full text

Abstract: BACKGROUND: Pediatric onset Crohn's disease (CD) is associated with more colitis and less ileitis compared with adult onset CD. Differences in disease site by age may suggest a different genotype, or different host responses such as decreased ileal susceptibility or increased susceptibility of the colon. METHODS: We evaluated 721 pediatric onset CD patients from 3 cohorts with a high allele frequency of NOD2/CARD15 mutations. Children with isolated upper intestinal disease were excluded. The remaining 678 patients were evaluated for interactions between age of onset, NOD2/CARD15, and disease location. RESULTS: We found an age-related tendency for isolated colitis. Among pediatric onset patients without NOD2/CARD15 mutations, colitis without ileal involvement was significantly more common in first-decade onset patients (P = 4.57 x 10(-5), odds ratio [OR] 2.76, 95% confidence interval [CI] 1.72-4.43). This was not true for colonic disease with ileal involvement (P = 0.35), or for isolated colitis in patients with NOD2/CARD15 mutations (P = 0.61). Analysis of 229 patients with ileal or ileocolonic disease and a NOD2/CARD15 mutation disclosed that ileocolitis was more prevalent through age 10, while isolated ileitis was more prevalent above age 10 (P = 0.016). NOD2/CARD15 mutations were not associated with age of onset. CONCLUSIONS: In early-onset pediatric CD, children with NOD2/CARD15 mutations demonstrate more ileocolitis and less isolated ileitis. Young children without NOD2/CARD15 mutations have an isolated colonic disease distribution, suggesting that this phenotype is associated with genes that lead to a specific phenotype of early-onset disease.

Kugathasan S, Saubermann LJ, Smith L, Kou D, Itoh J, Binion DG, Levine AD, Blumberg RS, Fiocchi C. · Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. · Gut. · Pubmed #17682002 No free full text.

Abstract: BACKGROUND AND AIMS: Crohn's disease is a life-long form of inflammatory bowel disease (IBD) mediated by mucosal immune abnormalities. Understanding of the pathogenesis is limited because it is based on data from adults with chronic Crohn's disease. We investigated mucosal T-cell immunoregulatory events in children with early Crohn's disease. METHODS: Mucosal biopsies and T-cell clones were derived from children experiencing the first attack of Crohn's disease, children with long-standing Crohn's disease, infectious colitis, and children without gut inflammation. RESULTS: As in acute infectious colitis, interleukin (IL) 12 induced T cells from early Crohn's disease to acquire a strongly polarised T helper (Th) type 1 response characterised by high IFN-gamma production and IL12Rbeta2 chain expression. Th1 polarisation was not induced in clones from late Crohn's disease. Mucosal levels of IL12p40 and IL12Rbeta2 messenger RNA were significantly higher in children with early than late Crohn's disease. These results demonstrate that susceptibility to IL12-mediated modulation is strongly dependent on the stage of Crohn's disease. CONCLUSIONS: At the onset of Crohn's disease mucosal T cells appear to mount a typical Th1 response that resembles an acute infectious process, and is lost with progression to late Crohn's disease. This suggests that mucosal T-cell immunoregulation varies with the course of human IBD. Patients with the initial manifestations of IBD may represent an ideal population in which immunomodulation may have optimal therapeutic efficacy.

Mack DR, Langton C, Markowitz J, LeLeiko N, Griffiths A, Bousvaros A, Evans J, Kugathasan S, Otley A, Pfefferkorn M, Rosh J, Mezoff A, Moyer S, Oliva-Hemker M, Rothbaum R, Wyllie R, delRosario JF, Keljo D, Lerer T, Hyams J, Anonymous00371. · Department of Pediatrics, Children's Hospital of Eastern Ontario, 401 Smyth Rd, Ottawa, Ontario, Canada K1H 8L1. · Pediatrics. · Pubmed #17545378 links to  free full text

Abstract: OBJECTIVE: The goal was to determine how often common laboratory tests yield normal results at the time of diagnosis for children with inflammatory bowel disease. METHODS: Data were obtained from a registry of children with newly diagnosed inflammatory bowel disease who were enrolled prospectively in 18 US/Canadian centers. Laboratory values investigated included hemoglobin level, platelet count, albumin level, and erythrocyte sedimentation rate. Disease severity was categorized by physician global assessment. RESULTS: A total of 526 children (mean age: 11.6 years; 58% male; 392 with Crohn disease and 134 with ulcerative colitis) were studied. All 4 values were normal for 21% of patients with mild Crohn disease and 54% with mild ulcerative colitis. In contrast, only 3.8% of children with moderate/severe Crohn disease and 4.3% with moderate/severe ulcerative colitis had normal results for all 4 tests. The erythrocyte sedimentation rate was least likely to be normal; overall, 26% of patients with inflammatory bowel disease had a normal erythrocyte sedimentation rate, including 18% with moderate/severe disease. Hemoglobin levels were normal for 32%, platelet counts for 50%, and albumin levels for 60%. There was no clear association between Crohn disease location and either severity or number of normal laboratory values. In contrast, there were direct correlations between ulcerative colitis disease severity and both the extent of bowel inflammation and the number of abnormal laboratory tests. CONCLUSION: The presence of normal screening laboratory studies should not dissuade clinicians from considering a diagnosis of inflammatory bowel disease.

Anonymous00166, Anonymous00167, Bousvaros A, Antonioli DA, Colletti RB, Dubinsky MC, Glickman JN, Gold BD, Griffiths AM, Jevon GP, Higuchi LM, Hyams JS, Kirschner BS, Kugathasan S, Baldassano RN, Russo PA. · No affiliation provided · J Pediatr Gastroenterol Nutr. · Pubmed #17460505 No free full text.

Abstract: BACKGROUND: Studies of pediatric inflammatory bowel disease (IBD) have varied in the criteria used to classify patients as having Crohn disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). Patients undergoing an initial evaluation for IBD will often undergo a series of diagnostic tests, including barium upper gastrointestinal series with small bowel follow-through, abdominal CT, upper endoscopy, and colonoscopy with biopsies. Other tests performed less frequently include magnetic resonance imaging scans, serological testing, and capsule endoscopy. The large amount of clinical information obtained may make a physician uncertain as to whether to label a patient as having CD or UC. Nevertheless, to facilitate the conduct of epidemiological studies in children, to allow the entry of children into clinical trials, and to allow physicians to more clearly discuss diagnosis with their patients, it is important that clinicians be able to differentiate between CD and UC. METHODS: A consensus conference regarding the diagnosis and classification of pediatric IBD was organized by the Crohn's and Colitis Foundation of America. The meeting included 10 pediatric gastroenterologists and 4 pediatric pathologists. The primary aim was to determine the utility of endoscopy and histology in establishing the diagnosis of CD and UC. Each member of the group was assigned a topic for review. Topics evaluated included differentiating inflammatory bowel disease from acute self-limited colitis, endoscopic and histological features that allow differentiation between CD and UC, upper endoscopic features seen in both CD and UC, ileal inflammation and "backwash ileitis" in UC, patchiness and rectal sparing in pediatric IBD, periappendiceal inflammation in CD and UC, and definitions of IC. RESULTS: Patients with UC may have histological features such as microscopic inflammation of the ileum, histological gastritis, periappendiceal inflammation, patchiness, and relative rectal sparing at the time of diagnosis. These findings should not prompt the clinician to change the diagnosis from UC to CD. Other endoscopic findings, such as macroscopic cobblestoning, segmental colitis, ileal stenosis and ulceration, perianal disease, and multiple granulomas in the small bowel or colon more strongly suggest a diagnosis of CD. An algorithm is provided to enable the clinician to differentiate more reliably between these 2 entities. CONCLUSIONS: The recommendations and algorithm presented here aim to assist the clinician in differentiating childhood UC from CD. We hope the recommendations in this report will reduce variability among practitioners in how they use the terms "ulcerative colitis," "Crohn disease," and "indeterminate colitis." The authors hope that progress being made in genetic, serological, and imaging studies leads to more reliable phenotyping.

Hyams J, Crandall W, Kugathasan S, Griffiths A, Olson A, Johanns J, Liu G, Travers S, Heuschkel R, Markowitz J, Cohen S, Winter H, Veereman-Wauters G, Ferry G, Baldassano R, Anonymous00151. · Connecticut Children's Medical Center, Hartford, Conneticut 06106, USA. · Gastroenterology. · Pubmed #17324398 No free full text.

Abstract: BACKGROUND AND AIMS: The REACH study evaluated the safety and efficacy of infliximab in children with moderately to severely active Crohn's disease. METHODS: Patients (n = 112) with a Pediatric Crohn's Disease Activity Index (PCDAI) score >30 received infliximab 5 mg/kg at weeks 0, 2, and 6. Patients responding to treatment at week 10 were randomized to infliximab 5 mg/kg every 8 or 12 weeks through week 46. A concurrent immunomodulator was required. Clinical response (decrease from baseline in the PCDAI score > or =15 points; total score < or =30) and clinical remission (PCDAI score < or =10 points) were evaluated at weeks 10, 30, and 54. RESULTS: At week 10, 99 of 112 (88.4%) patients responded to infliximab (95% confidence interval: [82.5%, 94.3%]) and 66 of 112 (58.9%) patients achieved clinical remission (95% confidence interval: [49.8%, 68.0%]). At week 54, 33 of 52 (63.5%) and 29 of 52 (55.8%) patients receiving infliximab every 8 weeks did not require dose adjustment and were in clinical response and clinical remission, respectively, compared with 17 of 51 (33.3%) and 12 of 51 (23.5%) patients receiving treatment every 12 weeks (P = .002 and P < .001, respectively). CONCLUSIONS: Pediatric patients responding to an induction regimen of infliximab were more likely to be in clinical response and remission at week 54 without dose adjustment when their maintenance therapy was given every 8 weeks rather than every 12 weeks. Allowing for dose intensification in the case of relapse, remission rates, but not response rates, at week 54 were superior with every 8-week dosing compared with every 12-week dosing.

Kappelman MD, Bousvaros A, Hyams J, Markowitz J, Pfefferkorn M, Kugathasan S, Rosh J, Otley A, Mack D, Griffiths A, Evans J, Grand R, Langton C, Kleinman K, Finkelstein JA. · Center for Inflammatory Bowel Disease, Division of Gastroenterology and Nutrition, Children's Hospital Boston, Massachusetts 02115, USA. · Inflamm Bowel Dis. · Pubmed #17286275 links to  free full text

Abstract: BACKGROUND: Variation in care is a ubiquitous feature of medical practice and may lead to significant differences in health care costs, quality, and outcomes. We undertook this study to determine the extent of intercenter variation in the initial management of children newly diagnosed with Crohn's disease. METHODS: We analyzed the utilization of 5 classes of medication (immunomodulators, prednisone, antibiotics, 5-aminosalicylates, and infliximab) among 311 children with newly diagnosed Crohn's disease followed at 10 North American pediatric gastroenterology centers. Multivariate logistic regression was used to compare the utilization rate of each class of medication at each of the 10 centers, adjusting for potential confounders including patient age, sex, race, disease severity, and anatomic location of disease. RESULTS: Median utilization of each class of medication was: immunomodulators, 56% (range 29%-97%); prednisone, 78% (range 32%-88%); antibiotics, 29% (range 11%-68%); 5-aminosalicylates, 63.5% (range 18%-92%); and infliximab, 7.5% (range 3%-21%). Each of these treatments showed statistically significant intercenter variation in utilization (P < 0.001 for immunomodulators, prednisone, antibiotics, and 5-ASA; P = 0.02 for infliximab). After adjusting for the demographic and clinical factors listed above, intercenter variation remained significant; however, the low utilization of infliximab precluded multivariate analysis. CONCLUSIONS: Widespread intercenter variation in the medical management of newly diagnosed children with Crohn's disease was observed, even after adjusting for possible differences in case mix between institutions. This variation may lead to unintended differences in health care costs and outcomes.

Biank V, Friedrichs F, Babusukumar U, Wang T, Stoll M, Broeckel U, Kugathasan S. · Department of Pediatrics, Medical College Wisconsin, Milwaukee, Wisconsin 53226, USA. · Am J Gastroenterol. · Pubmed #17156146 No free full text.

Abstract: OBJECTIVE: A significant association between the DLG5 variant (R30Q) and inflammatory bowel disease (IBD) has been confirmed in several independent adult IBD cohorts. There is growing evidence that gender significantly influences R30Q susceptibility in Crohn's disease (CD). Pediatric onset CD features a significantly lower incidence for female children compared with male children. We, therefore, studied the influence of gender on R30Q susceptibility in an exclusively pediatric onset IBD cohort. DESIGN: A total of 281 CD (181 trios) and 479 population-based controls were genotyped for DLG5 R30Q using Taqman assay. Association was tested by case-control and transmission disequilibrium testing analysis. Multivariate logistic regression was performed to investigate gene-gene and gene-gender interactions, as well as genotype-phenotype correlations. RESULTS: Overall allele frequency for R30Q was 8.5% in CD and 10.3% in controls. Logistic regression showed R30Q had no association with CD (OR 0.81, 95% CI 0.55-1.20, P= 0.3) when the cohort was analyzed as a whole. Stratified by gender, a significant negative association was detected for R30Q in female children (OR 0.39, 95% CI 0.2-0.77, P= 0.006), but not in male children. Gender was found to be an effect modifier of the association between R30Q and CD as the odds ratios in female children and male children differed significantly. The gender-specific association of R30Q and CD was independent of additional CD risk factors such as CARD15 and IBD5. CONCLUSIONS: DLG5 has a gender-specific role in the susceptibility of pediatric CD. Specifically, the significant negative association found between DLG5 R30Q and CD in female children suggests DLG5 may have a protective effect in CD susceptibility for female children.

Kugathasan S. · Department of Pediatrics, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. · Curr Opin Gastroenterol. · Pubmed #17031182 No free full text.

Abstract: Epidemiologic data suggest that the incidences of pediatric ulcerative colitis and Crohn disease continue to evolve with geographic variations. One study suggests that children with autism have a unique inflammatory bowel disorder that is associated with gastrointestinal symptoms. The appropriate use of new diagnostic tests and novel treatments for inflammatory bowel disease (IBD) needs to be clarified in the pediatric population. Because of concerns regarding sensitivity and specificity, serologic markers measuring anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies cannot yet replace conventional diagnostic testing for screening or diagnosis of pediatric IBD. Large, prospective, pediatric population-based studies still need to be performed to ascertain their use as a noninvasive screening tool. Genetic studies using thiopurine methyl transferase and measurement of 6-mercaptopurine metabolites appear to be valuable for management of pediatric patients with IBD, in assisting clinicians in optimizing therapeutic response to 6-mercaptopurine, and in identifying individuals at increased risk for drug-induced toxicity. Newer immunomodulatory agents also are being explored in pediatric IBD. Open pilot trials of infliximab (Remicade; Centocor, Malvern, PA) for the treatment of children with Crohn disease that does not respond to conventional management have demonstrated short-term efficacy and safety. Trials of tacrolimus for treatment of fulminant colitis in children have been disappointing.

Otley AR, Griffiths AM, Hale S, Kugathasan S, Pfefferkorn M, Mezoff A, Rosh J, Tolia V, Markowitz J, Mack D, Oliva-Hemker M, Wyllie R, Rothbaum R, Bousvaros A, Del Rosario JF, Evans J, Blanchard W, Hyams J, Anonymous00277. · FRCPC, Division of Gastroenterology & Nutrition, IWK Health Centre, Halifax, Nova Scotia, Canada. · Inflamm Bowel Dis. · Pubmed #16917222 No free full text.

Abstract: BACKGROUND AND AIMS: Assessment of health-related quality of life (HRQOL) is of increasing importance in the evaluation of new therapies for inflammatory bowel disease (IBD). Available data concerning HRQOL in pediatric patients are sparse and uniformly cross-sectional. The aim of this study was to describe HRQOL and influential factors in newly diagnosed pediatric patients with Crohn's disease and ulcerative colitis during the first 12 months after diagnosis. MATERIALS AND METHODS: Participants were drawn from a large, prospectively derived observational IBD registry of pediatric patients studied through 18 U.S. and Canadian centers. Patients who had completed a baseline IMPACT questionnaire and for whom there were 12 months of follow-up data available were included. In addition to description of cohort, factors that were believed to influence HLQOL were assessed during the course of the year from diagnosis. RESULTS: Two hundred eighteen children met inclusion criteria (77% Crohn's disease, 23 % ulcerative colitis, mean age 12.7 +/- 1.9 years). Mean total IMPACT score at baseline was 154, 181 at 6 months, and 191 at 1 year (possible range 0-238, with increasing scores representing better quality of life). Repeated measures analysis showed that age and disease severity significantly negatively affected the IMPACT scores during the course of the year. CONCLUSIONS: In this large prospective pediatric IBD cohort, significant improvement in HRQOL is noted during the year from diagnosis. Mean IMPACT scores varied significantly depending on the disease severity and also decreased with increasing age.

Markowitz J, Hyams J, Mack D, Leleiko N, Evans J, Kugathasan S, Pfefferkorn M, Mezoff A, Rosh J, Tolia V, Otley A, Griffiths A, Moyer MS, Oliva-Hemker M, Wyllie R, Rothbaum R, Bousvaros A, Del Rosario JF, Hale S, Lerer T, Anonymous00070. · North Shore-Long Island Jewish Health System, New Hyde Park, New York, USA. · Clin Gastroenterol Hepatol. · Pubmed #16861053 No free full text.

Abstract: BACKGROUND & AIMS: The aim of this study was to describe 3-month and 1-year outcomes of children with Crohn's disease (CD) treated with corticosteroids within 30 days of diagnosis, with particular emphasis on the influence of infliximab on these outcomes. We also aimed to determine whether there are clinical or laboratory characteristics associated with corticosteroid therapy outcomes. METHODS: Data from 109 children were drawn from a multicenter observational registry that was started in 2002. Clinical characteristics and data on corticosteroid and other therapies were recorded prospectively. Corticosteroid therapy outcomes at 3 months were defined as complete acute response, partial response, or corticosteroid resistance. At 1 year, corticosteroid responsiveness, dependence, and surgical rates were determined. Infliximab's influence on short- and long-term outcomes also was investigated. RESULTS: At 3 months, 65 of 109 (60%) patients had a complete acute response to corticosteroids, 26 (24%) had a partial response, and 18 (17%) were corticosteroid resistant. At 1 year, 61% were corticosteroid responsive, 31% were corticosteroid dependent, and 8% required surgery. Irrespective of the duration of corticosteroid treatment, 16 of 24 of corticosteroid-dependent/resistant patients rapidly discontinued corticosteroids after starting infliximab. No clinical or laboratory characteristics at diagnosis predicted short-term outcome. Growth impairment at diagnosis increased risk for corticosteroid dependence or surgery at 1 year. CONCLUSIONS: At 3 months, 84% of children had a complete or partial response to corticosteroids. However, despite concomitant immunomodulators, at 1 year 31% were corticosteroid dependent and 8% required surgery. Infliximab improves outcomes of corticosteroid-dependent/resistant patients because the duration of corticosteroid use can be controlled by initiating treatment with infliximab.

Babusukumar U, Wang T, McGuire E, Broeckel U, Kugathasan S. · Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. · Am J Gastroenterol. · Pubmed #16771961 No free full text.

Abstract: BACKGROUND & AIMS: The IBD5 locus on chromosome 5q31 is a confirmed Crohn's disease (CD) susceptibility locus in adults. Recently, two polymorphisms in the organic cation transporter (OCTN) gene cluster within the IBD5 locus have been found to be associated with CD. Although the original report of significant linkage to IBD5 was in families with at least one case of early age at onset CD, there are no published reports on the role of OCTN genes in pediatric onset CD. We performed a comprehensive analysis of OCTN variants in an independent, exclusively pediatric onset CD cohort and examined the genotype/phenotype correlations. METHODS: 264 Caucasian CD children (172 of them were trios) were genotyped along with 527 controls for OCTN1 (SLC22A4 C1672T), OCTN2 (SLC22A5 G-207C), and two haplotype-tagging SNPs (IGR2230 and IGR2198). RESULTS: TDT confirmed the association of SLC22A4 and SLC22A5. Case-control analysis of the SLC22A4 1672T, SLC22A5-207C diplotype showed significant association (p=0.04) with CD susceptibility compared with controls. Little correlation was seen with regard to clinical phenotype and the SLC22A4/SLC22A5 diplotype. There was no significant interaction between the SLC22A4/SLC22A5 diplotype and the three CD-associated CARD15 SNPs. CONCLUSIONS: We confirm the association of the OCTN variants (SLC22A4 and SLC22A5) in pediatric onset CD as seen in adult CD cohorts. However, when an extended IBD5 haplotype was examined, no independent association between OCTN variants and pediatric onset CD can be demonstrated. Compared with adults, a relatively weak association of the OCTN variants was observed in our CD cohort. No definitive genotype-phenotype correlation or gene-gene interactions with CARD15 were observed. Although the IBD5 locus is associated with pediatric onset CD, no definitive conclusions can be drawn about OCTN variants as causative genes in pediatric CD at this point.