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Biomedical subjects

James Markowitz

Publications and source records attributed to James Markowitz.

16 recordsLinked to original sources
PubMed2006

Corticosteroid therapy in the age of infliximab: acute and 1-year outcomes in newly diagnosed children with Crohn's disease.

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.

Adolescent↗
PubMed2006

The natural history of corticosteroid therapy for ulcerative colitis in children.

BACKGROUND & AIMS: The aim of this study was to determine the clinical outcome after corticosteroid therapy in children who are newly diagnosed with ulcerative colitis (UC). METHODS: Data were gathered prospectively from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry database between January 2002 and March 2005. All children who were newly diagnosed with inflammatory bowel disease younger than the age of 16 years were managed according to the dictates of their respective physicians. Demographic, clinical, and laboratory data were collected at diagnosis, at 30 days, and then quarterly. Patients were classified as corticosteroid responsive, corticosteroid dependent, or refractory, and outcomes were determined at 3 months and at 1 year. RESULTS: Ninety-seven patients had a diagnosis of UC and a minimum of 1 year of follow-up evaluation; 77 (79%) received corticosteroids (62 within 30 days of diagnosis [early] and 15 between 31 days and 6 months [late]). At diagnosis, 81% of corticosteroid-treated patients (age, 11.3 +/- 3.5 y) had moderate/severe disease, and 81% had pancolitis. For those treated early with corticosteroids, disease activity at 3 months was inactive in 60%, mild in 27%, and moderate/severe in 11%. At 1 year, 31 of 62 (50%) of the early corticosteroid-treated patients were considered corticosteroid responsive and 28 (45%) were corticosteroid dependent. A total of 4 patients receiving corticosteroids (5%) required colectomy in the first year. Immunomodulators were used in 61% of all corticosteroid-treated patients. CONCLUSIONS: Although short-term clinical response to corticosteroids in children with newly diagnosed UC is excellent, even with the common use of immunomodulators corticosteroid dependence is seen in 45% of patients.

Adolescent↗
PubMed2006

Health-related quality of life in the first year after a diagnosis of pediatric inflammatory bowel disease.

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.

Adolescent↗
PubMed2006

Management of fulminating ulcerative colitis in childhood with chimeric anti-CD25 antibody.

Fulminating acute ulcerative colitis (UC) is a potentially life threatening medical emergency. Up to 30% of individuals respond poorly to corticosteroids alone and second line medical or surgical therapies are indicated. We describe the successful use of chimeric anti-CD25 therapy in 4 such children poorly responsive to combined therapy with intravenous steroids and calcineurin inhibitors with a pretreatment predictive risk of colectomy of 85-100%. Clinical disease activity scores normalized within 72 hours of anti-CD25 administration and colonic histology provided evidence of mucosal healing within 10-14 days. None required emergency colectomy. Anti-CD25 is efficacious in fulminating UC and randomized placebo controlled trials appear indicated.

Acute Disease↗
PubMed2006

Inflammatory bowel diseases.

The inflammatory bowel diseases remain at the forefront of clinical investigation. Immunologic and genetic advances are fueling an explosion of novel diagnostic and therapeutic modalities. With further breakthroughs, there is hope that in the near future, these illnesses will no longer be considered either idiopathic or chronic.

Adult↗
PubMed2005

Evaluation of the pediatric crohn disease activity index: a prospective multicenter experience.

BACKGROUND AND OBJECTIVES: Longitudinal assessment of disease activity is necessary for studies of therapeutic intervention in children with Crohn disease. The Pediatric Crohn Disease Activity Index (PCDAI) was developed a decade ago for such a purpose, but it function has only been examined in a small number of studies with a limited number of patients. The primary objectives of the present study were to develop cut scores reflecting disease activity as determined by physician global assessment (PGA) and to evaluate the responsiveness of the PCDAI to changes in patient condition after therapeutic interventions. METHODS: Data were derived from a prospective database of newly diagnosed children with inflammatory bowel disease established in 2002 at 18 pediatric gastroenterology centers in the United States and Canada. At diagnosis, at 30 days and 3 months after diagnosis, and quarterly thereafter, children (<16 years of age) with Crohn disease had disease assessment performed by PGA and PCDAI. Disease management was provided according to the dictates of the attending gastroenterologist and not by predetermined protocol. RESULTS: 181 patients had concomitant PGA and PCDAI performed at diagnosis, and 95 of these had similar assessment at short-term follow up. Mean +/- SD PCDAI scores for mild, moderate, and severe disease by PGA at diagnosis were 19.5 +/- 10.4, 32.2 +/- 12.7, and 47.8 +/- 14.9, respectively (P < 0.001 for all comparisons). Mean +/- SD PCDAI for inactive disease after treatment was 5.2 +/- 5.4. Receiver operating characteristic (ROC) curve analysis suggested that: 1) activity of moderate/severe disease was best reflected by a PCDAI of > or = 30 points, 2) clinical response (moderate/severe disease improving to mild/inactive) was best reflected by a decrease in PCDAI of > or = 12.5 points, and 3) a PCDAI < 10 best reflected inactive disease. CONCLUSIONS: PCDAI scores accurately reflect disease activity as assessed by physician global assessment. A PCDAI score of > or = 30 has acceptable sensitivity and specificity to indicate disease of moderate/severe activity. A PCDAI decrease of 12.5 points or greater following therapeutic intervention accurately reflects a clinically significant response. The PCDAI is an appropriate tool for intervention trials in Crohn disease in children.

Child↗
PubMed2004

Effects of infliximab on apoptosis and reverse signaling of monocytes from healthy individuals and patients with Crohn's disease.

OBJECTIVES: Infliximab, an anti-tumor necrosis factor (TNF) monoclonal antibody, might exert some of its long-term therapeutic effects in Crohn's disease (CD) by interacting directly with cells of the immune system such as monocytes and T lymphocytes via membrane TNF and by inducing apoptosis. Accordingly, the effects of inflix-imab on monocyte apoptosis and down-regulation of proinflammatory cytokines (reverse signaling) were assessed. METHODS: To assess apoptosis, monocytes from healthy individuals (controls) and CD patients were incubated in the presence or absence of infliximab or the apoptotic agent gliotoxin for 24 hours. Annexin V staining and the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-FITC nick end labeling assay were used to measure early and late apoptosis. To measure the effects of infliximab on reverse signaling, monocytes from healthy individuals pretreated in vitro with infliximab were stimulated with lipopolysaccharide or staphylococcal enterotoxin A, and the induction of the proinflammatory cytokines, TNF-alpha, interleukin (IL)-1beta, IL-6, and IL-8 was measured by reverse transcription polymerase chain reaction. The effect of in vivo infliximab treatment of monocytes was similarly determined by comparing the responses of monocytes from CD patients before and immediately after infliximab infusion. RESULTS: Infliximab did not induce apoptosis of monocytes from either healthy individuals or CD patients but rather stabilized them. However, monocytes from healthy individuals treated with infliximab in vitro, or from CD patients infused with infliximab, produced significantly less TNF and other proinflammatory cytokines when stimulated with the bacterial products lipopolysaccharide and staphylococcal enterotoxin A. CONCLUSIONS: Apoptosis of monocytes is not responsible for the therapeutic effects of infliximab. However, some of the therapeutic effects of infliximab may be caused by its ability to down-regulate proinflammatory cytokines production by monocytes exposed to bacterial antigens.

Antibodies, Monoclonal↗
PubMed2004

Risk factors for carcinoma of the pelvic ileal pouch/anal canal in ulcerative colitis.

Patients with ulcerative colitis who undergo proctocolectomy and an ileal anal anastomosis (IPAA) require surveillance; dysplasia and carcinoma occur in both the small intestinal mucosa of the ileal pouch and the retained rectal mucosa as early as 2 yr after ileostomy closure. This study evaluated risk factors for carcinoma (eg, dysplasia, p53 overexpression, labeling index, and aneuploidy) in the small intestinal and rectal mucosa. Thirty patients (age 14-64 yr) with ulcerative colitis and IPAA were studied. The mean duration of ulcerative colitis prior to IPAA was 3 yr (range 6 mo-21 yr). Patients were followed by annual endoscopy and biopsies of the ileal pouch and rectal mucosa. Sections of small intestine and rectal mucosa were evaluated for inflammation and dysplasia, and by immunohistochemical stains Ki-67 (MIB-1) for a labeling index and for p53. Ploidy determination was performed by flow cytometry. Active inflammation of the small intestinal mucosa and the rectal mucosa was frequent and the labeling index of both the pouch and rectal mucosa was abnormal. Two patients had changes indefinite for dysplasia, one involving the small bowel mucosa of the pouch and the other the retained rectal mucosa. Fifteen of the 30 patients had overexpression of p53, 9 from the pouch, and 6 from the rectal mucosa. Overexpression of p53 was seen in both of the patients with indefinite dysplasia. Aneuploidy was noted in 3 patients: two from the pouch and one from the rectal mucosa. All aneuploidic specimens were p53-positive, but negative for dysplasia. In conclusion, most biopsies of the ileal pouch and rectal mucosa were inflamed. The labeling indexes of the small bowel and rectal mucosa were higher than normal. The risk factors for carcinoma (dysplasia, overexpression of p53, and aneuploidy) occurred in the small intestinal and the rectal mucosa. Overexpression of p53 was noted in 16 patients, dysplasia only in 2. Therefore, p53 overexpression and aneuploidy should be considered in the evaluation of surveillance biopsies of patients with ulcerative colitis with IPAA, whereas dysplasia is an insensitive marker.

Adolescent↗
PubMed2003

Consensus and controversy in the management of pediatric Crohn disease: an international survey.

OBJECTIVES: Treatment options for patients with Crohn disease (CD) have expanded, but the use of some of these options in pediatric patients remains controversial. The authors evaluate current trends in treatment and areas of consensus or controversy. METHODS: An international survey of certified pediatric gastroenterologists was conducted using an e-mail questionnaire in an attempt to evaluate management of active Crohn disease, attitudes toward four types of therapy, and prevalence of testing for osteopenia and 6-thioguanine levels. RESULTS: One hundred sixty-seven physicians from the United States, Canada, Western Europe, and Israel were included. The majority of North American physicians (71%) prefer to use conventional steroids and azathioprine (AZA) before nutritional therapy or budesonide for patients with mild to moderately active disease, versus 21% of Western Europeans (P < 0.001). Western Europeans prefer nutritional therapy followed by budesonide or steroids for those with mild or moderate disease. Only 4% of North American gastroenterologists use nutritional therapy frequently versus 62% of their Western European colleagues (P < 0.001). Infliximab was thought to be effective for steroid-unresponsive disease by almost all physicians surveyed, although its efficacy as a maintenance therapy was rated higher by North American physicians than by their Western European and Israeli colleagues (P < 0.01). Bone mineral density is routinely evaluated by about 45% of physicians in Western Europe and North America. CONCLUSIONS: Attitudes toward current therapies vary significantly by region, with North Americans strongly favoring corticosteroids followed by immunomodulatory therapy, and Western Europeans favoring nutritional therapy or budesonide and the avoidance of conventional corticosteroids.

Adrenal Cortex Hormones↗
PubMed2002

Inflammatory Bowel Disease in Children.

Crohn's disease and ulcerative colitis remain medically incurable conditions with potentially significant morbidity. The treatment of children with these conditions therefore should seek to reduce or eliminate symptoms, optimize nutritional status, promote normal growth and development, prevent complications, and minimize the potential psychologic effects of chronic illness. Treatment strategies must seek to both induce and maintain clinical remission. For all but the most mildly affected children with Crohn's disease, a combination of nutritional and pharmacologic approaches is optimal. For those with ulcerative colitis, anti-inflammatory medication is necessary. Moderate to severe Crohn's disease acutely responds best to potent immunomodulatory therapy, eg, corticosteroids and infliximab. Either agent must be coupled with 6-mercaptopurine or azathioprine to maintain long-term remission and to minimize toxicity. Particular attention must be paid to limit the growth suppression and other toxic effects of corticosteroids. Elemental or semielemental enteral nutrition also can induce remission effectively, but relapse is common after primary nutritional therapy is discontinued, mandating concomitant pharmacologic therapy with either 6-mercaptopurine or azathioprine. The availability of 6-mercaptopurine/azathioprine metabolite testing allows optimization of immunomodulatory therapy, detection of noncompliance, and avoidance of potentially dangerous toxicity. Mild ulcerative colitis acutely responds to treatment with a 5-aminosalicylate medication. Long-term remission frequently can be maintained with the same medication. Moderate to severe disease activity requires potent immunomodulatory therapy if colectomy is to be avoided. Surgery is a potential cure for patients with ulcerative colitis, although the development of pouchitis after ileal pouch anal anastomosis is common and frequently requires long-term medical management. Surgery provides only palliative relief of complications in those with Crohn's disease. Emerging therapies, especially evolving biologic and probiotic agents, offer hope for better treatments in the years ahead.

Journal Article↗
PubMed2002

Atypical morphologic presentation of biliary atresia and value of serial liver biopsies.

BACKGROUND: Liver biopsy findings are important in diagnosing extrahepatic biliary atresia. Diffuse ductular proliferation is a characteristic finding. We describe four patients with conjugated hyperbilirubinemia in whom the initial liver biopsy findings showed a lack of ductular proliferation, despite subsequent development of biliary atresia. RESULTS: On initial biopsy, paucity of intrahepatic bile ducts was present in three of four patients, with a bile duct to portal space ratio of 0.3 to 0.4 (normal, 0.9-1.8). A normal bile duct to portal space ratio of 1.0 was observed in the fourth patient. Ductular proliferation became apparent in three subjects between 9 and 12 weeks of age, and biliary atresia was noted at the time of a Kasai portoenterostomy. The fourth child had well-developed biliary cirrhosis at liver transplantation. CONCLUSIONS: Changes characteristic of biliary atresia may appear even after 9 weeks of age. Bile duct paucity and normal bile duct to portal space ratio do not preclude the subsequent development of biliary atresia. Infants with unexplained conjugated hyperbilirubinemia and acholic stools should undergo sequential liver biopsies until clinical improvement occurs or until biliary atresia can be excluded from the differential diagnosis.

Bile Duct Diseases↗
PubMed2002

Immunomodulatory therapy for pediatric inflammatory bowel disease: changing patterns of use, 1990-2000.

OBJECTIVE: To identify changes over the past decade in physicians' attitudes regarding the use of immunomodulatory agents for the treatment of children with inflammatory bowel disease (IBD), we surveyed the membership of the North American Society for Pediatric Gastroenterology and Nutrition and compared the responses to those from an identical survey performed in 1990. METHODS: Surveys were mailed to 718 physicians in January, 2000. All surveys returned by mid-February were analyzed, and results compared to those obtained in the 1990 survey. RESULTS: Thirty-nine percent (278/718) of surveys were returned, compared to 27% (105/385) in 1990. Overall, 93% of the current survey's respondents agreed with the statement "immunomodulatory agents are effective in the treatment of children and adolescents with IBD." Compared to 1990, significant increases (p < 0.0001) were noted in the percentage of respondents who prescribe immunomodulatory agents to children with all forms of IBD. Indications for immunomodulation that showed significant increases (p < 0.001) since 1990 included treatment of perianal and non-perianal fistulae; growth failure; use as initial, primary therapy; and use as prophylaxis against postoperative recurrence. 6-Mercaptopurine and azathioprine continue to be the agents prescribed by the greatest percentage of respondents. More physicians are willing to use immunomodulatory agents in children younger than 5 yr, and duration of use is longer than in 1990. Currently, physicians seem to favor the use of immunomodulatory agents over colectomy for children with either intractable ulcerative or Crohn's colitis. Most respondents remain concerned about potential bone marrow and immune suppression, but concerns regarding malignancy, teratogenicity, and infertility have lessened. CONCLUSION: These survey findings document that pediatric gastroenterologists have widely accepted the use of immunomodulators in the treatment of children and adolescents with IBD.

Adjuvants, Immunologic↗