Ulcerative Colitis: 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, Lake A. · No affiliation provided · J Pediatr Gastroenterol Nutr. · Pubmed #9890462 No free full text.

This publication has no abstract.

Cuffari C. · Division of Pediatric Gastroenterology, The Johns Hopkins School of Medicine, Baltimore, MD 21287, USA. · Minerva Pediatr. · Pubmed #16835574 No free full text.

Abstract: Crohn's disease (CD) and ulcerative colitis (UC) are common and heterogeneous chronic inflammatory bowel disorders of childhood that account for up to 25% of all patients with inflammatory bowel disease (IBD). In CD, the familial pattern of disease concordance would suggest that genetics contribute to disease etiology. Children are more likely to have proximal small bowel disease complicated by stricture formation, fistulization and the need for surgical intervention. The predisposition for small bowel disease has been associated with mutations of the nucleotide oligomerization domain 2 (NOD2)/Caspase activation and recruitment domain 15 (CARD15) gene on chromosome 16 in 1/3 of patients with CD. Homozygous patients also show an early age at disease onset and a relatively high relative risk for isolated stricturing distal ileal disease. The potential clinical role for NOD2 testing in either the diagnosis or the therapeutic management of patients with CD has yet to be determined. The precise age of onset of CD and UC can be difficult in children. Subclinical phases of disease can be identified through a decrease in weight and height velocity, and a delay in pubertal development. However, a confident distinction between CD and UC also remains a taxonomic dilemma in 25% of pediatric patients with IBD, despite recent technological advances in diagnostic techniques, including gadolinium enhanced magnetic resonance imaging (MRI) and capsule endoscopy, and serological testing. The early introduction of immunomodulators, including azathioprine and 6-mercaptopurine have proven efficacy in maintaining long-term remission without concurrent corticosteroids. The pharmacogenomic of 6-MP metabolism has been shown to be useful in predicting susceptibility to antimetabolite induced toxicity, and possibly allowing physician's to individualize drug therapy to improve clinical response. Novel treatment strategies, including infliximab are being developed in Pediatrics with the aim at improving overall treatment efficacy and potentially avoid surgery.

Cuffari C, Present DH, Bayless TM, Lichtenstein GR. · Johns Hopkins Hospital Division of Gastroenterology and Hepatology Baltimore, Maryland 21287, USA. · Inflamm Bowel Dis. · Pubmed #16189424 No free full text.

Abstract: Pancolitis affects approximately 20% to 40% of the total ulcerative colitis population and remains a therapeutic challenge for clinicians. Practitioners must focus on pancolitis when evaluating a patient for ulcerative colitis, because pancolitis is associated with more severe and fulminant disease and a higher rate of colorectal cancer and colectomy. It is imperative for clinicians to be knowledgeable in the clinical course, medications, and appropriate manner to induce and maintain clinical remission to prevent serious sequelae of the disease. The purpose of this article is to provide a review of the treatment of pancolitis for general gastroenterologists, because medical management decisions have life-long effects for this subgroup of patients.

Eidelwein AP, Cuffari C, Abadom V, Oliva-Hemker M. · Pediatric Gastroenterology and Nutrition, Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Inflamm Bowel Dis. · Pubmed #15735427 No free full text.

Abstract: BACKGROUND: The effects of infliximab, a tumor necrosis factor-alpha (TNF-alpha) antibody, have been well established in adult patients with inflammatory and fistulizing Crohn's disease. This study evaluates short- and long-term efficacy of infliximab in children with ulcerative colitis. METHODS: All pediatric patients with ulcerative colitis who received infliximab between July 2001 and November 2003 at the Johns Hopkins Children's Center were identified. Short- and long-term outcomes and adverse reactions were evaluated. RESULTS: Twelve pediatric patients with ulcerative colitis received infliximab for treatment of fulminant colitis (3 patients), acute exacerbation of colitis (3), steroid-dependent colitis (5), and steroid-refractory colitis (1). Nine patients had a complete short-term response, and 3 had partial improvement. The mean per patient dose of corticosteroid after the first infliximab infusion decreased from 45 mg/day at the first infusion to 22.2 mg/day at 4 weeks (P = 0.02) and 7.8 mg/day at 8 weeks (P = 0.008). Eight patients were classified as long-term responders with a median follow-up time of 10.4 months. Of the 4 long-term nonresponders, 3 underwent colectomy, and the fourth has ongoing chronic symptoms. Three of 4 long-term nonresponders were steroid-refractory compared with 1 of 8 long-term responders. Patients receiving 6-mercaptopurine had a better response to infliximab. CONCLUSION: Infliximab should be considered in the treatment of children with symptoms of acute moderate to severe ulcerative colitis.

Carvalho RS, Wilson L, Cuffari C. · The Johns Hopkins University School of Medicine, Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, Baltimore, Maryland, USA. · J Med Case Reports. · Pubmed #18298838 links to  free full text

Abstract: ABSTRACT: INTRODUCTION: Although respiratory involvement has been described in patients with IBD, well-defined interstitial lung disease has not been reported, especially among children with ulcerative colitis. CASE PRESENTATION: Herein, we present a case of an adolescent female with ulcerative colitis and extra-intestinal complications involving the lungs that were effectively treated with anti-metabolite therapy. CONCLUSION: Children with UC may manifest either interstitial or large airway pulmonary involvement. All children with suspected lung involvement should be screened for tuberculosis prior to starting immunosuppressive therapy.

Carvalho RS, Abadom V, Dilworth HP, Thompson R, Oliva-Hemker M, Cuffari C. · Johns Hopkins University School of Medicine, Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, Baltimore, MD 21287, USA. · Inflamm Bowel Dis. · Pubmed #16633047 links to  free full text

Abstract: BACKGROUND: Indeterminate colitis (IC) is a subgroup of inflammatory bowel disease (IBD) that cannot be characterized as either ulcerative colitis (UC) or Crohn's disease (CD). Our aims are to determine the prevalence of IC in our pediatric patient population and to describe its clinical presentation, natural history,and disease distribution. METHODS: We performed a retrospective database analysis of all children diagnosed with IBD at the Johns Hopkins Children's IBD Center between 1996 and 2001. Patient demographics, including age, sex, and age at disease onset, were tallied. Disease distribution was identified on the basis of a review of all endoscopic, colonoscopic, histopathological, and radiological records. All of the patients were followed up clinically to determine the extent of disease progression on the basis of the initial diagnosis of IC. RESULTS: Among 250 children registered in the database, 127 (50.8%) had a diagnosis of CD, 49 (19.6%) had UC, and 74(29.6%) had IC. Patients with IC had a significantly younger mean +/- SEM age (9.53 +/- 4.8 years) at diagnosis compared with patients with CD (12.4 +/- 3.8 years; P < 0.001) but not compared with patients with UC (7.41 +/- 3.5 years). Among the patients with IC, 59 (79.7%) had a pancolitis at diagnosis, and the remaining 15 had left-sided disease that progressed to a pancolitis within a mean of 6 years. Twenty-five patients (33.7%) with an initial diagnosis of IC were reclassified to either CD or UC after a median follow-up of 1.9 years (range 0.6-4.5 years). Forty-nine patients (66.2%) maintained their diagnosis of IC after a mean follow-up of 7 years (SEM 2.5 years). CONCLUSIONS: IC is a distinct pediatric subgroup of IBD with a prevalence that is higher than that observed in adults. Children with IC have an early age of disease onset and a disease that rapidly progresses to pancolitis. Longitudinal studies are needed to determine the clinical implications of this pediatric IBD subgroup.

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, Hunt S, Bayless T. · Division of Gastroenterology, Department of Paediatrics, The Johns Hopkins Hospital, Baltimore, MD 21287, USA. · Gut. · Pubmed #11302961 links to  free full text

Abstract: BACKGROUND AND AIM: The immunosuppressive properties of 6-mercaptopurine and its parent compound azathioprine are mediated by their intracellular metabolism into active 6-thioguanine (6-TG) metabolites. Measurement of erythrocyte 6-TG metabolite levels has been proposed as a useful clinical tool for assessing treatment efficacy in patients with inflammatory bowel disease (IBD). AIM: The purpose of the study was to establish a therapeutic index of treatment efficacy based on measurement of erythrocyte 6-TG metabolite levels, and apply it clinically to guide therapy. METHODS: Heparinised blood was obtained from 82 adult patients with IBD on long term (more than three months) antimetabolite therapy (63 Crohn's disease; 19 ulcerative colitis). Erythrocyte 6-TG metabolite levels were measured using reverse phase high performance chromatography, and correlated with treatment efficacy. In 22 patients with refractory Crohn's disease despite long term azathioprine therapy, their dosage was increased by 25 mg/day at eight week intervals as needed. Serial erythrocyte 6-TG metabolite levels were measured at each clinic visit and correlated with treatment efficacy. RESULTS: Clinical remission, as defined by a low disease index score in patients weaned off or on a low alternate day dose (<20 mg on alternate days) of corticosteroid, was achieved in 68% of patients on long term antimetabolite therapy. Treatment efficacy correlated with erythrocyte 6-TG levels greater than 250 pmol/8x10(8) red blood cells in patients with colonic and fistulising Crohn's disease (p<0.01) but not in patients with ileocolonic disease. Eighteen of 22 patients with incompletely responsive Crohn's disease achieved disease remission by optimising their dose of azathioprine therapy. Median (range) erythrocyte 6-TG metabolite levels increased from 194 (67-688) to 303 (67-737) pmol/8x10(8) red blood cells (p<0.05). Clinical response associated well with a reduction in corticosteroid requirements. Mean (SEM) white blood cell count decreased from 8.6 (0.9) to 6.9 (0.6) x10(3)/microl with adjustment in azathioprine dosage. No patient incurred azathioprine induced leucopenia. CONCLUSION: Measurement of erythrocyte 6-TG metabolite levels is helpful in determining the adequacy of azathioprine dosage and can be used to optimise the dose of antimetabolite therapy to achieve an improved clinical response without inducing leucopenia. Patients who are clinically refractory to azathioprine therapy despite achieving high erythrocyte 6-TG levels (>250) should be considered for adjunct or alternative forms of immunosuppressive therapy or surgery.