Response to Medical Treatment in Patients with Crohn’s Disease: The Role of NOD2/CRAD15, Disease Phenotype, and Age of Diagnosis

Weiss, Batia; Lebowitz, O.; Fidder, Herma H.; Maza, Itay; Levine, Arie; Shaoul, Ron; Reif, Shimon; Bujanover, Yoram; Karban, Amir

doi:10.1007/s10620-009-0936-8

Cited by 15 publications

(6 citation statements)

References 30 publications

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“…This was in contrast to another study that could not find an association between NOD2 carrier status or age of onset of disease and response to steroids [43]. We speculated that treatment response might vary analyzing pediatric and adult CD patient study cohorts regarding NOD2 genotype.…”

Section: Discussioncontrasting

confidence: 80%

“…To corroborate this hypothesis we now included a pediatric CD cohort and reclassified all CD patients in our adult cohort according to the onset of disease in pediatric and adult onset. Using this approach we found a significant association for steroid failure in CD patients with NOD2 variant alleles and younger age of onset in contrast to Weiss et al [43]. In addition, the need for long-term immunosuppressive therapy and second line therapy with anti-TNF-alpha agents was also only associated with younger age of onset and the presence of any NOD2 variant allele.…”

Section: Discussionmentioning

confidence: 50%

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Age-of-onset-dependent influence of NOD2 gene variants on disease behaviour and treatment in Crohn’s disease

et al. 2013

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BackgroundInfluence of genetic variants in the NOD2 gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn’s disease (CD).Methods85 pediatric- and 117 adult-onset CD patients were tested for the three main NOD2 CD-associated variants (p.R702W, p.G908R and p.10007fs) and clinical data of at least two years of follow-up were compared regarding disease behaviour and activity, response to therapy and bone mineral density (BMD).ResultsChronic active and moderate to severe course of CD is associated in patients with pediatric-onset (p=0.0001) and NOD2 variant alleles (p=0.0001). In pediatric-onset CD the average PCDAI-Score was significantly higher in patients carrying NOD2 variants (p=0.0008). In addition, underweight during course of the disease (p=0.012) was associated with NOD2 variants. Interestingly, osteoporosis was found more frequently in patients carrying NOD2 variant alleles (p=0.033), especially in pediatric-onset CD patients with homozygous NOD2 variants (p=0.037). Accordingly, low BMD in pediatric-onset CD is associated with a higher PCDAI (p=0.0092), chronic active disease (p=0.0148), underweight at diagnosis (p=0.0271) and during follow-up (p=0.0109). Furthermore, pediatric-onset CD patients with NOD2 variants are more frequently steroid-dependent or refractory (p=0.048) and need long-term immunosuppressive therapy (p=0.0213).ConclusionsThese data suggests that the presence of any of the main NOD2 variants in CD is associated with osteoporosis and an age of onset dependent influence towards underweight, higher disease activity and a more intensive immunosuppressive therapy. This observation supports the idea for an early intensive treatment strategy in children and adolescent CD patients with NOD2 gene variants.

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Section: Discussioncontrasting

confidence: 80%

Section: Discussionmentioning

confidence: 50%

Age-of-onset-dependent influence of NOD2 gene variants on disease behaviour and treatment in Crohn’s disease

et al. 2013

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“…In a multivariate logistic regression model, treatment success with prednisolone was independent of disease localization (ileal site), stricturing or internal fistulizing disease behavior, and the need for surgery . Another study could not find an association of NOD2 carrier status and response to steroids [29]. In contrast to the study of Weiss et al .…”

Section: Discussionmentioning

confidence: 90%

NOD2 Polymorphism Predicts Response to Treatment in Crohn’s Disease—First Steps to a Personalized Therapy

et al. 2011

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Background and AimsGreat efforts have been made to predict disease behavior over time and the response to treatment in Crohn’s disease (CD). Such understanding could personalize therapy. Early introduction of more aggressive therapies to patients at high risk and no introduction of predictable refractory treatments could become possible. We hence tested the influence of the NOD2 carrier status on treatment response.Patients and MethodsIn 185 CD patients (age 45 ± 9.8 years, female n = 108, minimum disease duration 10 years), the three most common polymorphisms (p.Arg702Trp, p.Gly908Arg, p.Leu1007fsX1008) of NOD2 were tested by polymerase chain reaction and sequencing. Detailed clinical and medical history were obtained with a standardized questionnaire and by reviewing the medical charts. Treatments introduced were chosen by physicians blinded to genotype data.ResultsThe frequency of the NOD2 variant allele was about one-third (67, 30.2%) of CD patients. NOD2 carriers were more often treated with systemic and locally active steroids and with an immunosuppressant (Azathioprine/6-MP). NOD2 mutation carrier status was more often associated with systemic steroid [8.9% vs. wild-type (WT) 1.2%, P = 0.0086] and local-steroid refractory (14.9% vs. WT 3.5%; P = 0.001). The WT patients were significantly higher refractory to immunosuppressant (12.8% vs. NOD2 carriers, 0.5%, P = 0.03). Most WT patients were treated with TNF-α antagonists and remission rates were significantly higher in this group after 1 year of treatment (84% vs. NOD2 carriers, 33%, P = 0.07).ConclusionsThe study presents first hints for the NOD2 carrier status to be predictive for response to therapy. A higher percentage of CD patients with NOD2 mutation carrier status was steroid refractory but could be treated well with immunosuppressants. The WT status showed a higher response to steroids and remission rates within 1 year of anti-TNF-α therapy. On the way to personalized medicine, this approach should be further investigated in larger studies.

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“…Most of the patients in our cohort were diagnosed prior to the introduction of anti‐TNF and thus notably the rate of anti‐TNF therapy was low in our patient population (∼6%). In previous adult population‐ and hospital‐based studies13, 21, 22, 33, 34 using similar definitions of response to corticosteroids, rates of resistance and dependency ranged from 16%–20% and 20%–38%, respectively. It is interesting to note that overall slightly higher rates of resistance have been reported in adults than in pediatric studies, with the exception of a Chinese study in adult‐CD that reported low rates of nonresponse (6%) 33.…”

Section: Discussionmentioning

confidence: 90%

Immediate and long-term outcomes of corticosteroid therapy in pediatric crohnʼs disease patients

Krupoves

Mack

Seidman

et al. 2011

Inflammatory Bowel Diseases

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Response to Medical Treatment in Patients with Crohn’s Disease: The Role of NOD2/CRAD15, Disease Phenotype, and Age of Diagnosis

Abstract: Response to treatment with systemic steroids, AZA/6-MP and infliximab are not related to NOD2/CARD15 mutations, age of diagnosis and disease behavior. Patients with colonic disease have higher rates of steroid dependency.

Cited by 15 publications

References 30 publications

Age-of-onset-dependent influence of NOD2 gene variants on disease behaviour and treatment in Crohn’s disease

Age-of-onset-dependent influence of NOD2 gene variants on disease behaviour and treatment in Crohn’s disease

NOD2 Polymorphism Predicts Response to Treatment in Crohn’s Disease—First Steps to a Personalized Therapy

Immediate and long-term outcomes of corticosteroid therapy in pediatric crohnʼs disease patients

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