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Biomedical subjects

R Modigliani

Publications and source records attributed to R Modigliani.

At least 19 recordsLinked to original sources
PubMed2000

Corticosteroids for maintaining remission of Crohn's disease.

OBJECTIVES: To evaluate the effectiveness and safety of conventional systemic corticosteroid therapy in maintaining clinical remission in Crohn's disease. SEARCH STRATEGY: A computer-assisted search of the on-line bibliographic database MEDLINE of studies published in English, French, Spanish, Italian and German between 1966 and May, 1998. Manual searches of the reference lists from the potentially relevant studies were performed in order to identify additional studies that may have been missed using the computer-assisted search strategy. Proceedings from major gastrointestinal meetings were also manually searched from 1985 to 1997 in order to identify unpublished studies. The Cochrane Controlled Trials Register and the Inflammatory Bowel Disease Review Group Trials Register were also searched. SELECTION CRITERIA: Randomized double-blind placebo-controlled trials involving patients of any age with Crohn's disease in clinical remission as defined by a CDAI < 150 or by the presence of no symptoms or only mild symptoms at the time of entry into the trial. The experimental treatment consisted of oral conventional corticosteroid therapy (excluding budesonide, fluticasone, etc). Clinical disease relapse was used as the outcome measure of interest. DATA COLLECTION AND ANALYSIS: Eligible studies were selected by 4 reviewers and data were extracted onto standardized data extraction forms. Disagreements in eligibility or data extraction were resolved by consensus. Data were converted into individual 2x2 tables for each study. The presence of significant heterogeneity among studies was tested using the chi-square test. The 2x2 tables were synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel (the 'odds ratio' in MetaView). A fixed effects model was used for the pooling of data. MAIN RESULTS: Four studies were initially judged as being eligible for inclusion. After obtaining additional information on one of the studies it was excluded because it was not double-blind. The total number of subjects included in the analysis at the time points of 6, 12 and 24 months were 142, 131 and 95 for the corticosteroid group and 161, 138 and 87 for the control group. The odds ratios for relapse on active treatment and the corresponding 95% confidence intervals were 0.71 (0.39, 1.31), 0.82 (0.47, 1.43) and 0.72 (0.38, 1.35) at 6, 12 and 24 months. The numbers needed to treat with corticosteroids to prevent one additional relapse were 24, 35, 15 respectively. REVIEWER'S CONCLUSIONS: The use of conventional systemic corticosteroids in patients with clinically quiescent Crohn's disease does not appear to reduce the risk of relapse over a 24 month period of follow-up.

Adrenal Cortex Hormones↗
PubMed2000

Azathioprine or 6-mercaptopurine for inducing remission of Crohn's disease.

OBJECTIVES: To determine the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn's disease. SEARCH STRATEGY: Studies were selected using the MEDLINE data base (1966 - December 1997), abstracts from major gastrointestinal meetings and references from published articles and reviews. The Cochrane Controlled Trials Register and the Inflammatory Bowel Disease Review Group Trials Register was also searched. SELECTION CRITERIA: Eight randomized placebo controlled trials of azathioprine and 6-mercaptopurine therapy in adult patients were identified: five dealt with active disease and three had multiple therapeutic arms. DATA COLLECTION AND ANALYSIS: Data were extracted by three independent observers based on the intention to treat principle. Each study was given a quality score based on predetermined criteria. Extracted data were converted to 2X2 tables (response versus no response and antimetabolite versus placebo) and then synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel ('Odds Ratio' in MetaView). MAIN RESULTS: The odds ratio of a response to azathioprine or 6-mercaptopurine therapy compared with placebo in active Crohn's disease was 2.36 (95% CI 1.57-3.53). This corresponded to a number needed to treat of about 5 to observe an effect of therapy in one patient. When the two trials using 6-mercaptopurine in active disease were excluded from the analysis, the odds ratio of response was 2.04 (CI 1.24 - 3.35). Treatment >/= 17 weeks increased the odds ratio of a response to 2.51 (CI 1.63-3. 88). A steroid sparing effect was seen with an odds ratio of 3.86 (CI 2.14 - 6.96), corresponding to a number needed to treat of about 3 to observe steroid sparing in one patient. Adverse events requiring withdrawal from a trial, principally allergy, leukopenia, pancreatitis, and nausea were increased on therapy with an odds ratio of 3.01 (CI 1.30 - 6.96). The number needed to treat to observe one adverse event in one patient treated with azathioprine or 6-mercaptopurine was 14. REVIEWER'S CONCLUSIONS: Azathioprine and 6-mercaptopurine are effective therapy for inducing remission in active Crohn's disease. The odds ratio of response increases after >/= 17 weeks of therapy, suggesting that there is a minimum length of time for a trial of azathioprine or 6-mercaptopurine therapy. Adverse events were more common among patients on therapy.

Antimetabolites↗
PubMed2000

Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy.

BACKGROUND & AIMS: Myelosuppression in patients with Crohn's disease (CD) treated with azathioprine has been attributed to low activity of thiopurine S-methyltransferase (TPMT). Allelic variants of the TPMT gene responsible for changes in the enzyme activity have been characterized. We investigated the distribution of mutant alleles associated with TPMT deficiency in patients with CD and myelosuppression during azathioprine/6-mercaptopurine therapy. METHODS: Forty-one patients with CD were included. They developed leukopenia or thrombocytopenia during azathioprine or 6-mercaptopurine treatment. Polymerase chain reaction-based methods were used to search for mutations associated with TPMT deficiency. RESULTS: Four patients (10%) had 2 mutant alleles associated with TPMT deficiency, 7 (17%) had 1 mutant allele, and 30 (73%) had no known TPMT mutation. The delay between administration of the drug and occurrence of bone marrow toxicity was less than 1.5 months in the 4 patients with 2 mutant alleles, and ranged from 1 to 18 months in patients with 1 mutant allele and from 0.5 to 87 months in patients with normal genotype. CONCLUSIONS: Twenty-seven percent of patients with CD and myelosuppression during azathioprine therapy had mutant alleles of the TPMT gene associated with enzyme deficiency. Myelosuppression is more often caused by other factors. Continued monitoring of blood cell counts remains mandatory in patients treated with azathioprine.

Adolescent↗
PubMed2000

Recurrent cholestatic jaundice associated with generalized pustular psoriasis: evidence for a neutrophilic cholangitis.

Generalized pustular psoriasis can result in systemic complications. We report the case of a woman with relapsing generalized pustular psoriasis and recurring episodes of cholestatic jaundice. Liver biopsy performed during an attack showed a neutrophilic infiltrate surrounding and invading portal triad bile ducts. Ultrasonographic exams and retrograde cholangiography ruled out biliary tract disease. This observation suggests that recurring cholestatic jaundice in pustular psoriasis is related to a neutrophilic cholangitis.

Adult↗
PubMed2000

Distinction between coeliac disease and refractory sprue: a simple immunohistochemical method.

AIMS: We recently showed that refractory sprue is distinct from coeliac disease, the former being characterized by abnormal intraepithelial T-lymphocytes expressing a cytoplasmic CD3 chain (CD3c), lacking CD3 and CD8 surface expression, and showing TCRgamma gene rearrangements. To take advantage of the abnormal phenotype of CD3c + CD8 - intraepithelial lymphocytes (IEL) in refractory sprue we developed a simple method to distinguish coeliac disease from refractory sprue. METHODS AND RESULTS: Comparative immunohistochemical studies using anti-CD3 and anti-CD8 antibodies were applied on paraffin-embedded and frozen biopsy specimens in refractory sprue (n = 6), coeliac disease (n = 10), healthy controls (n = 5) and suspected refractory sprue (n = 6). Comparable results were obtained on fixed and frozen biopsy specimens. In four of the six patients with suspected refractory sprue, abnormal CD3c + CD8 - IEL and TCRgamma gene rearrangements were found, as in refractory sprue; the remaining two patients had normal (CD3 + CD8 +) IEL and no TCRgamma gene rearrangements. Both patients had coeliac disease, as one failed to comply with a gluten-free diet, while the other was a slow responder. CONCLUSION: This simplified immunostaining method using anti-CD3 and anti-CD8 antibodies on paraffin sections can distinguish active coeliac disease from refractory sprue and should prove useful in clinical practice.

Adult↗
PubMed2000

Immunosuppressors for inflammatory bowel disease: how long is long enough?

Immunosuppressors used in inflammatory bowel disease (IBD) are useful in refractory, chronic, active, steroid-dependent, or steroid-resistant IBD, but do not provide a permanent cure for IBD, their effect being only temporary. Only azathioprine and methotrexate are currently prescribed in the long term for IBD. The question of how long immunosuppressors should be given once remission has been induced and steroids discontinued has not yet been answered.

Azathioprine↗
PubMed2000

Methotrexate in Crohn's disease: long-term efficacy and toxicity.

OBJECTIVE: A 16-wk, placebo-controlled trial has recently shown weekly low-dose methotrexate to be an effective treatment for patients with chronically active Crohn's disease. The long-term efficacy and safety of this antimetabolite drug, however, are not yet well established and are assessed in this study. METHODS: A total of 49 patients with Crohn's disease who were treated with methotrexate for > or =6 months were studied. All patients had been chronically treated with steroids; but at the time of initiation, only 27 were still on steroids. Of the 49 patients, 42 had previously taken azathioprine but were no longer on this drug because of intolerance or failure. Clinical remission was defined as a Harvey-Bradshaw index of <4. RESULTS: In all, 41 patients achieved complete clinical remission and were maintained on methotrexate for a median of 18 months (range, 7-59 months). In these patients the probabilities of relapse were 29%, 41%, and 48% at 1, 2, and 3 yr, respectively. A higher rate of relapse was observed in women and in patients with ileocolitis. Adverse reactions were recorded in 24 patients, requiring discontinuation of methotrexate in five. A liver biopsy was performed in 11 patients; a mild steatosis was found in five, a slight dilation of the sinusoids in one, a granulomatous hepatitis with a mild portal fibrosis in one, and a slight periportal fibrosis in one patient. CONCLUSIONS: This study suggests a long-term benefit of maintenance treatment with methotrexate in patients with chronically active Crohn's disease, with side effects that are usually only moderate.

Adolescent↗
PubMed1999

[Pregnancy outcome in inflammatory bowel diseases].

OBJECTIVE: To assess pregnancy outcome in relation to disease activity and maintenance therapy in patients with inflammatory bowel disease. METHODS: A postal questionnaire was sent to every woman of child-bearing age followed for inflammatory bowel disease in three referral centers (Rothschild, Saint-Lazare, Saint-Louis). Response rate was 65%. RESULTS: One hundred and forty-four pregnancies (153 fetuses) in 138 women (122 had Crohn's disease) were reported. Outcome of pregnancy was normal (baby > 2500 g, without malformation) in 115 cases (77%). There were 17 cases of preterm birth (11.5%), 3 cases of hypotrophy, and 14 pregnancy losses (9 miscarriages (6%), 4 therapeutic abortions for major malformation (2.8%)). Percentages of normal pregnancy outcome were not different between patients who continued maintenance therapy and those who stopped: respective percentages were 75 vs 73% in patients receiving mesalamine or olsalazine (n = 30), and 60 vs 75% in patients receiving azathioprine (n = 22). CONCLUSION: In a selected series of women with inflammatory bowel disease, pregnancy outcome is approaching that observed in a normal population, except for an elevated rate of preterm births. There is no need to stop maintenance therapy with 5-aminosalicylates or azathioprine during pregnancy.

Aminosalicylic Acids↗
PubMed1998

Abnormal intestinal intraepithelial lymphocytes in refractory sprue.

BACKGROUND & AIMS: The etiology of refractory sprue is unclear. To gain insight into its pathogenesis, the phenotype and T-cell receptor (TCR) gene rearrangement status of intestinal lymphocytes were analyzed in a group of patients with clinical or biological features of celiac disease but either initially or subsequently refractory to a gluten-free diet. METHODS: Intestinal biopsy specimens were obtained from 26 adults: 6 patients with refractory sprue, 7 patients with active celiac disease, and 13 normal controls. The phenotype of intestinal lymphocytes was studied by immunohistochemistry and, in 3 patients with refractory sprue, by cytometry of lymphocytes purified from intestinal biopsy specimens. TCR rearrangements were assessed by studying TCRgammaV-J junctional regions from DNA extracted from intestinal biopsy specimens and purified intestinal lymphocytes. RESULTS: In the 6 patients with refractory sprue, but not in normal controls or patients with active celiac disease, the intestinal epithelium was massively infiltrated by small lymphocytes that lacked CD8, CD4, and TCR, contained intracytoplasmic but not surface CD3epsilon chains, and exhibited restricted TCRgamma gene rearrangements. CONCLUSIONS: Refractory sprue is associated with an abnormal subset of intraepithelial lymphocytes containing CD3epsilon and restricted rearrangements of the TCRgamma chain but lacking surface expression of T-cell receptors.

Adult↗
PubMed1998

Granulocytic sarcoma of the jejunum: a rare cause of small bowel obstruction.

We report the case of a 40-yr-old man presenting with symptoms of small bowel obstruction. Small bowel x-rays revealed a stricture of the mid-jejunum. Push enteroscopy found a polypoid mass at 1 meter of the ligament of Treitz. Histopathological examination of the biopsy and surgical specimens showed a diffuse infiltrate of the mucosa made of medium to large cells, which were stained on immunohistochemistry by the leucocyte marker CD45 and the histiocyte/monocyte marker CD68 but were negative for the B and T cell markers. Cytological examination of the ascitic fluid revealed many myelobasts with cytoplasmic Auer rods and positive myeloperoxidase staining. There was no evidence of blood or bone marrow involvement suggestive of acute leukemia or myeloproliferative disorders. These findings were consistent with the diagnosis of preleukemic granulocytic sarcoma (or chloroma). Chemotherapy led to complete remission, but 21 months later the patient developed an acute myeloid leukemia. He died from aspergillus pneumonitis, 10 months after bone marrow allograft. Preleukemic granulocytic sarcoma of the small bowel is a rare condition and its diagnosis is usually not easy, requiring histochemical or immunohistochemical studies. Most cases have progressed to acute myeloid leukemia.

Adult↗
PubMed1998

[6-mercaptopurine levels and study of blood lymphocyte subsets during azathioprine treatment of Crohn's disease].

OBJECTIVES: Our aim was to study the relationships between clinical efficacy of azathioprine, 6-mercaptopurine pharmacokinetics and changes in peripheral blood lymphocyte subpopulations induced by azathioprine treatment in Crohn's disease. METHODS: Twenty-three patients were prospectively followed up for 1 year. Peripheral blood counts, total lymphocytes, CD3+, CD4+, CD8+, CD25+, CD16+CD56+, CD57+ and CD19+ lymphocyte subpopulations were carried out, using flow cytometry, during azathioprine treatment. Pharmacokinetic studies were performed at day 8 and month 3 by measuring 6-mercaptopurine plasma concentration after an oral dose of azathioprine (2 mg/kg). Results were compared in responders (no activity and no steroids) and non-responders. RESULTS: The decrease in peripheral blood leukocytes and neutrophils was significant after 1 month, reaching 49% and 48% of the pre-treatment values at 1 year; the one of lymphocytes was significant after 6 months and reached 41% at 1 year. Percentages of CD3+, CD4+, CD8+, CD57+, CD16+CD56+ and CD19+ lymphocytes remained unchanged whereas percentage of CD25+ lymphocytes increased from 10% to 28% (P < 0.01). There was a high inter and intraindividual variability of 6-mercaptopurine peak plasma concentration and area under the curve. No significant difference was found between responders (n = 14) and non responders (n = 7) for pharmacokinetic parameters and lymphocyte subpopulations; there was no correlation between lymphocyte subpopulation changes and 6-mercaptopurine pharmacokinetics. CONCLUSION: Monitoring of 6-mercaptopurine plasma concentration and blood lymphocyte subpopulations is of little value in Crohn's disease patients treated with azathioprine.

Adult↗
PubMed1997

Drug therapy for ulcerative colitis during pregnancy.

Women with ulcerative colitis (UC) are usually young and thus likely to undergo pregnancy. They should be advised to conceive when the disease is quiescent. Steroids and salicylates may be used normally during pregnancy, possibly without exceeding a dose of 2g/day for mesalazine. Azathioprine can be maintained if its indication is clear cut. Cyclosporin seems to be without additional risk in the pregnant woman, its use being limited to acute steroid-refractory disease, as an alternative to surgery.

Adrenal Cortex Hormones↗
PubMed1997

[Severe colitis in mucoviscidosis].

We report the association of severe indeterminate colitis with cystic fibrosis in a 21 year old woman, with mild pulmonary involvement, and without digestive or pancreatic symptoms or pancreatic enzyme preparation. Ten cases of inflammatory bowel disease associated with a cystic fibrosis have been reported. Most fit with the diagnostic criteria of Crohn's disease. Although this case was compatible with this diagnosis, we have retained the diagnosis of "severe indeterminate colitis" because of the lack of specific histological features of Crohn's disease. The association between inflammatory bowel disease and cystic fibrosis is probably not fortuitous, although the pathophysiological link between the two diseases is unknown.

Adolescent↗
PubMed1996

Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine.

BACKGROUND: Crohn's ulcerative gastrointestinal disease is presently managed through a variety of medical interventions, including-according to severity of illness-anti-inflammatory, immunosuppressive, and corticosteroid agents; and with remedial surgery to correct anatomical abnormalities caused by disease processes. The immunosuppressant azathioprine (or its metabolite, 6-mercaptopurine) is considered an efficient maintenance therapy for Crohn's, but there is always concern about bone-marrow suppression, liver damage, and other adverse effects. For how long persons with this disease should be given these drugs has not been determined. METHODS: Patients who were treated with azathioprine or 6-mercaptopurine for more than 6 months, and who were in prolonged clinical remission (> 6 months without steroids) were followed. The time-to-relapse was analysed in those on treatment, in those who stopped treatment for reasons other than a relapse, and in the whole sample, taking into account that they could be treated with the drugs or not, as a function of time. The influence of concomitant variables on time-to-relapse rate was examined using the Cox proportional hazard model. FINDINGS: In the 157 patients who continued to take the therapy, cumulative probabilities of relapse at 1 and 5 years were 11% and 32% respectively. Female gender, younger age, and a time for achieving remission more than 6 months were associated with a higher risk of relapse. In 42 patients who stopped therapy, probabilities of relapse at 1 and 5 years were 38% and 75%, respectively. Male gender, younger age and duration of remission less than 4 years were associated with a higher risk of relapse. After 4 years of remission on these drugs, the risk of relapse appeared to be similar, whether the therapy was maintained or stopped. INTERPRETATION: Taking into account the potential risks of long-term immunosuppressive therapy, the usefulness of maintaining azathioprine or 6-mercaptopurine in patients who have been in remission for more than 4 years is questionable.

Adolescent↗
PubMed1996

Enhanced CD3 monoclonal antibody induced proliferation of colonic mucosal T lymphocytes in Crohn's disease patients free of corticosteroid or immunosuppressor treatment.

Mucosal lymphocytes are increasingly activated in Crohn's disease. In order to investigate this phenomenon we tested the response of cultured colonic mucosal T lymphocytes to CD3 activation. These lymphocytes were obtained by biopsy from control subjects and Crohn's disease patients. T cells from mucosa involved in Crohn's disease showed a higher CD3-induced proliferative response compared to control T lymphocytes (P < 0.01). T cells from uninvolved areas showed a wide range of response, ranging from normal to very high proliferative indices. Our results suggest that the exaggerated response of mucosal T lymphocytes, due to the impairment of the downregulation of the CD3-dependent signaling process, may contribute to the pathogenesis of Crohn's disease.

Adult↗