Crohn Disease: Cuffari C

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.

Cuffari C, Dubinsky M, Darbari A, Sena L, Baldassano R. · The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Inflamm Bowel Dis. · Pubmed #15973125 No free full text.

Abstract: Although uncommon, diffuse jejunoilietis is one of the most difficult areas in Crohn's disease (CD) to treat. Although the exact frequency is unknown, most gastroenterologists believe that its prevalence has been underestimated and that it may have an increased incidence among children and young adolescents. The clinical importance of this clinical disease phenotype is the impact diffuse small bowel disease is expected to have on a child's growth and development. Moreover, patients with jejunoileitis are more likely to experience complications, including fistulization, and most commonly, intestinal obstruction. The associated morbidity and frequent need for surgical intervention renders these patients at risk for intestinal insufficiency. Although stricturoplasty has reduced the incidence of short bowel syndrome, most patients with proximal small bowel CD still require repeated surgical intervention. Jejunoileitis represents a distinct clinical phenotype within the heterogenous family of disease phenotypes considered as CD. Whether a specific genotype will be found to associate with jejunoileitis remains to be determined. Through the development of novel diagnostic techniques, including gadolinium enhanced magnetic resonance imaging (GMRI), enteroscopy, and capsule endoscopy, the mean age at diagnosis is expected to decrease. Coupled with an increase in clinical suspicion, early diagnosis may allow physicians to consider implementing aggressive immunomodulatory therapy. Future studies are needed to determine if the early detection and use of immune modulators in patients with proximal small bowel disease will improve overall quality of life and decrease the risk of nutritional and surgical comorbidity.

Carvalho R, Dilworth P, Docimo S, Cuffari C. · Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #19172133 No free full text.

This publication has no abstract.

Oliva-Hemker MM, Abadom V, Cuffari C, Thompson RE. · Department of Pediatrics, Bloomberg School of Public Health, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #17255828 No free full text.

Abstract: OBJECTIVES: To assess the prevalence of adherence to prescribed medications in children with Crohn disease and to identify possible factors associated with nonadherence. PATIENTS AND METHODS: This was a cross-sectional study of 51 pediatric patients with Crohn disease who were prescribed maintenance therapy with a thiopurine immunomodulator (6-mercaptopurine or azathioprine) and/or mesalamine during a 180-day period. Medication adherence rates were calculated from a validated formula using pharmacy records, and nonadherence was defined as a refill rate of <80% of the prescribed medication. Seventy-five percent of patients were prescribed thiopurine immunomodulators and 86% were prescribed mesalamine. RESULTS: The prevalence of nonadherence was 50% for the thiopurine immunomodulators and 66% for mesalamine. The mean number of emergency department visits for patients adherent to mesalamine was significantly greater than the nonadherent group (P < 0.0008). Having an emergency department visit increased the chances of a patient being adherent to mesalamine therapy by >9-fold (odds ratio, 9.6; 95% confidence interval, 1.87-52.17). The mean number of total health care visits was significantly greater for patients adherent to mesalamine (6.1 +/- 0.8) compared with those who were not adherent (3.0 +/- 0.4) (P < 0.001). CONCLUSIONS: These findings suggest that nonadherence to thiopurine immunomodulator or mesalamine therapy in pediatric patients with Crohn disease is common. Having a health care visit was associated with being adherent.

Darbari A, Kalloo AN, Cuffari C. · Department of Pediatrics, Division of Gastroenterology and Nutrition, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. · Gastrointest Endosc. · Pubmed #16860073 No free full text.

Abstract: BACKGROUND: Push enteroscopy has not been compared to standard endoscopy in children. OBJECTIVE: The aim of this study was to determine the feasibility of push enteroscopy in children with suspected proximal small bowel disease, and to compare its diagnostic yield and safety with standard endoscopy. DESIGN/SETTING: Database review. PATIENTS: A database analysis was performed on all children who underwent push enteroscopy at The Johns Hopkins Children's Center from 2001 to 2005. Patient demographics, clinical history, and indication for push enteroscopy were all recorded. Clinical utility was qualified based on the influence of PE on therapy. MAIN OUTCOME MEASUREMENTS: Diagnostic yield and safety of push enteroscopy in children. RESULTS: Push enteroscopy was performed on 44 children (27 M; 17 F) with a median age (range) of 10 (2-18) years. The most common indications for push enteroscopy were suspected proximal small bowel disease based on radiological criteria (21), and bleeding (9). Push enteroscopy confirmed the diagnosis of proximal small bowel Crohn's disease (CD) in 23, polyps in 5, eosinophilic gastroenteritis in 4, celiac disease in 1, microvillous inclusion disease in 1, and lymphoproliferative disease in 1 patient. An isolated non-Crohn's related gastric (1) and jejunal ulcer (1) was also identified. Just 9 of these identifiable lesions were within reach by esophagogastroduodenoscopy (EGD). Seven patients had a normal push enteroscopy. The clinical management was modified in 34 patients. Push enteroscopy was not shown to significantly alter the time of procedure when compared to EGD. CONCLUSIONS: Push enteroscopy is a safe diagnostic tool with proven clinical utility in children with suspected proximal small bowel disease. Larger studies are needed to establish the widespread application of push enteroscopy in pediatrics.

Lichtenstein GR, Cuffari C, Kane SV, Hanauer S, Present DH. · University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · Inflamm Bowel Dis. · Pubmed #15475769 No free full text.

This publication has no abstract.

Attard TM, Horton KM, DeVito K, Darbari A, Oliva-Hemker M, Thompson R, Cuffari C. · Departments of Pediatrics, Division of Gastroenterology and Nutrition, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21287, USA. · Inflamm Bowel Dis. · Pubmed #15475743 No free full text.

Abstract: BACKGROUND: Jejunoileitis (JI) is an unusual manifestation of Crohn's disease (CD) that has been associated with high morbidity and the frequent need for surgical intervention. Although the disease has been well-described in adults, the true prevalence and clinical phenotype in children is unknown. AIM: To compare the clinical course and nutritional impact of CD in children with and without proximal small bowel involvement. METHODS: Patients with either Crohn's jejunitis or JI with or without colonic involvement were identified through a clinical database (1996--2002). All radiologic studies were reviewed by an experienced radiologist blinded to the clinical diagnosis. Thirty-six patients with CD without histologic or radiologic signs of proximal small bowel involvement were used for comparison. All medical, surgical, and hematologic parameters were compared in both disease groups. RESULTS: Among the 134 patients with CD, 23 (17%) had radiologic signs of JI, including intestinal fold thickening (57%), luminal narrowing (31%), and skip lesions (13%). Enteric fistula (6%) and strictures (6%) were less common. Patients with JI were likely to be stunted at the time of diagnosis, require surgical intervention (P < 0.03) and nutritional therapy in the form of nasogastric tube feeds (P < 0.03). Nutritional therapy was also associated with an improvement in height in patients with proximal small bowel disease (OR:5.87). DISCUSSION: JI is a relatively common disease phenotype in children with CD that requires aggressive nutritional and surgical intervention. Future studies are required to determine if the early detection and use of immune modulators may lessen the morbidity associated with proximal small bowel disease.

Darbari A, Sena L, Argani P, Oliva-Hemker JM, Thompson R, Cuffari C. · Department of Pediatrics, The Johns Hopkins University, Baltimore, MD 21287, USA. · Inflamm Bowel Dis. · Pubmed #15168803 No free full text.

Abstract: BACKGROUND: Recent advances in gadolinium-enhanced magnetic resonance imaging (G-MRI) have been developed to enhance the resolution of the intestinal mucosa and facilitate the differentiation of ulcerative colitis (UC) from Crohn's disease (CD). The objective of this study is to apply this technology in Pediatrics. METHODS: A G-MRI was performed on 58 consecutive children with suspected IBD between 1999 and 2002 using intravenous gadolinium, fat suppression, and respiration-suspended sequences to enhance the resolution of the intestinal wall. The sensitivity and specificity in diagnosing either UC or CD was determined by comparing the G-MRI to the established histologic diagnosis. RESULTS: G-MRI confirmed the diagnosis of either CD (21) or UC (7) with a sensitivity and specificity of 96% and 92%, respectively. Among the 21 patients with CD, 14 showed proximal small bowel involvement by G-MRI. In total, 17 patients were diagnosed with indeterminate colitis (IC) based on histologic criteria alone, and among these patients, G-MRI had a significantly lower non-classification rate (P < 0.02). In comparison, endoscopy was less sensitive (57%), but more specific (100%) than either histology or G-MRI in diagnosing IBD. G-MRI also showed a strong concordance with computed tomography in diagnosing CD (P = 0.001). CONCLUSION: G-MRI is a both a sensitive and specific radiologic tool in diagnosing pediatric IBD. In patients with CD, G-MRI may be useful in identifying proximal small bowel involvement. Longitudinal follow-up studies are needed in those patients diagnosed with IC to determine the predictive value of G-MRI testing.

Cuffari C, Dassopoulos T, Turnbough L, Thompson RE, Bayless TM. · Department of Pediatrics, The Johns Hopkins University and the Meyerhoff IBD Center at the Johns Hopkins Hospital, Baltimore, Maryland, USA. · Clin Gastroenterol Hepatol. · Pubmed #15118980 No free full text.

Abstract: Background & Aims: Genetic polymorphism in thiopurine methyltransferase (TPMT) activity may influence clinical responsiveness to azathioprine (AZA) therapy. Our aim was to determine if the measurement of erythrocyte TPMT enzyme activity could be used to optimize clinical responsiveness to AZA therapy in patients with inflammatory bowel disease (IBD). Methods: A total of 142 consecutive patients were studied. Forty-one patients (32 with Crohn's disease [CD] and 9 with ulcerative colitis [UC]) were enrolled in a 4-month prospective nonrandomized study with AZA, and 101 (65 with CD and 36 with UC) were on either maintenance AZA or 6-mercaptopurine (6-MP). Erythrocyte TPMT activity and AZA metabolite levels were measured blinded to the clinical response. Results: The response rate after 4 months of continuous AZA therapy was 69% (9/13) in those patients with below-average (</=12 U/mL blood) TPMT activity, and 29% (8/27) in patients with enzyme activity levels >12 U/mL blood (P < 0.001). Patients with TPMT activity </=12 achieved a mean (SEM) erythrocyte 6-thioguanine ribonucleotide (6-TGn) level of 394 +/- 29 pmol/8 x 10(8) red blood cells (RBCs); higher than in patients with TPMT activity >12 (218 +/- 28), despite similar mean (1.6 mg/kg/day) dosages of AZA (P < 0.001). By multivariate logistic regression analysis, patients with a TPMT level <15.3 U/mL blood were 6.2 times more likely to respond to AZA therapy. A 6-TGn level of >292 pmol/8 x 10(8) RBCs was associated with a positive predictive value of clinical response of 85.7%. Conclusions: Patients with higher than average TPMT activity (>12) may remain refractory to conventional dosages of AZA, and may require high (>292) 6-TGn levels. Prospective, randomized, controlled trials are needed to determine whether prior TPMT phenotype testing can be used to adjust the dose of AZA effectively to improve clinical response time and rate.

Cuffari C, Li DY, Mahoney J, Barnes Y, Bayless TM. · Department of Pediatrics, Division of Gastroenterology and Nutrition, The Johns Hopkins University, Baltimore, Maryland, USA. · Dig Dis Sci. · Pubmed #14992447 No free full text.

Abstract: 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are well known for their lymphocytotoxic and bone marrow suppressive effects in the management of patients with leukemia. Although their immunosuppressive properties are mediated by the active AZA antimetabolite 6-thioguanine (6-TG), its mechanism of action is largely unknown. In IBD, a significant inverse correlation has been shown between erythrocyte 6-TG metabolite levels and disease activity, further supporting the proposed immunosuppressive role for 6-TG. Since leukocytes possess quantitatively different purine metabolic pathways compared to erythrocytes, this study aims to measure lymphocyte DNA 6-TG metabolites and correlate levels with the INF-gamma and IL-10 cytokine profile in patients with Crohn's disease (CD). Forty-six adult patients with CD, either naive (17) or on long-term (>4-month) AZA therapy (29), had erythrocyte and lymphocyte DNA 6-TG levels measured by reverse-phase HPLC under UV detection (6-TG, 340 nm). Lymphocyte DNA 6-TG was expressed as picomoles per milligram of DNA. Lymphocyte DNA 6-TG metabolite levels were correlated with INF-gamma and IL-10 cytokine profiles using the OptEIA kit (Pharmigen). Lymphocyte DNA 6-TG metabolite levels correlate with erythrocyte 6-TG levels (P < 0.03) but not total patient leukocyte levels. Erythrocyte 6-TG metabolite levels correlated (P < 0.01) inversely with INF-gamma but not IL-10 cytokine levels. This study suggests a preferential dampening of the TH1 response on exposure to 6-TG and a possible immunosuppressive mechanism of action for AZA. Future studies are needed to determine if cytokine profiles can be used to predict recalcitrant CD to AZA therapy.

Cuffari C, Lichtenstein GR. · No affiliation provided · Gastroenterology. · Pubmed #12806638 No free full text.

This publication has no abstract.

Cuffari C, Hunt S, Bayless TM. · Department of Paediatrics, The Johns Hopkins Hospital, Baltimore, MD 21287, USA. · Aliment Pharmacol Ther. · Pubmed #10930894 links to  free full text

Abstract: BACKGROUND: Azathioprine and 6-mercaptopurine have proven efficacy in the treatment of Crohn's disease. Immunosuppression is mediated by their intracellular metabolism into active 6-thioguanine metabolites, and clinical responsiveness to therapy in patients with inflammatory bowel disease has been correlated with the measure of erythrocyte 6-thioguanine levels. AIMS AND METHODS: To perform a dosing equivalency analysis and comparison of clinical efficacy in 82 patients with inflammatory bowel disease on long-term (> 2 months) therapy with either branded azathioprine (Imuran) (n=26), generic azathioprine (n=38), or 6-mercaptopurine (n=18), based on the measurement of erythrocyte 6-thioguanine metabolite levels. RESULTS: Disease remission was achieved in 51% (42 out of 82) of patients treated with either azathioprine or 6-mercaptopurine therapy, and correlated well with high erythrocyte 6-thioguanine levels (> 250 pmoles/8 x 108 RBCs). Patients treated with either branded azathioprine or 6-mercaptopurine achieved significantly higher erythrocyte 6-thioguanine levels than patients treated with generic azathioprine, thereby suggesting that branded azathioprine has improved oral bioavailability compared to generic azathioprine. These data are consistent with the putative immunosuppressive role of 6-thioguanine metabolites in the treatment of inflammatory bowel disease, and provides a basis for developing a therapeutic index of clinical efficacy based on the measurement of erythrocyte 6-thioguanine metabolite levels. CONCLUSIONS: Our results suggest that differences in bioavailability may have clinical relevance when considering the need to optimize erythrocyte 6-thioguanine metabolite levels in patients deemed unresponsive to treatment on conventional drug dosages.