BACKGROUND: Maintaining of remission early in the disease course of Crohn's disease (CD) is essential and has major impact on the future prognosis. This study aimed to identify baseline predictors to develop model allowing stratification of patients who will not benefit from long-term azathioprine (AZA) treatment and will require more intensive therapy. METHODS: This study was designed to develop clinical prediction rule using retrospective data analysis of pediatric CD patients included in prospective inception cohort. Clinical relapse was defined as necessity of re-induction of remission. Sequence of Cox models was fitted to predict risk of relapse. RESULTS: Out of 1190 CD patients from 13 European centers, 441 were included, 50.3% patients did not experience clinical relapse within 2 years of AZA treatment initiation. Median time to relapse was 2.11 (CI 1.59-2.46) years. Of all the tested parameters available at diagnosis, six were significant in multivariate analyses: C-reactive protein (p = 0.038), body mass index Z-score >0.8 SD (p = 0.002), abnormal sigmoid imaging (p = 0.039), abnormal esophageal endoscopy (p = 0.005), ileocolonic localization (p = 0.023), AZA dose in specific age category (p = 0.031). CONCLUSIONS: Although the possibility of predicting relapse on AZA treatment appears limited, we developed predictive model based on six baseline parameters potentially helpful in clinical decision. IMPACT: The possibility of predicting relapse on AZA treatment appears to be possible but limited. We identified six independent predictors available at diagnosis of early AZA/6-MP treatment failure in pediatric CD patients. Using combination of these factors, a model applicable to clinical practice was created. A web-based tool, allowing estimation of individual relapse risk in pediatric CD patients on a particular therapeutic regimen, has been developed.
- MeSH
- azathioprin terapeutické užití škodlivé účinky MeSH
- Crohnova nemoc * komplikace diagnóza farmakoterapie MeSH
- dítě MeSH
- imunosupresiva terapeutické užití škodlivé účinky MeSH
- indukce remise MeSH
- lidé MeSH
- prospektivní studie MeSH
- recidiva MeSH
- retrospektivní studie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- azathioprin MeSH
- imunosupresiva MeSH
BACKGROUND & AIMS: We investigated the effects of inducing deep remission in patients with early Crohn's disease (CD). METHODS: We collected follow-up data from 122 patients (mean age, 31.2 ± 11.3 y) with early, moderate to severe CD (median duration, 0.2 years; interquartile range, 0.1-0.5) who participated in the Effect of Tight Control Management on CD (CALM) study, at 31 sites, representing 50% of the original CALM patient population. Fifty percent of patients (n = 61) were randomly assigned to a tight control strategy (increased therapy based on fecal level of calprotectin, serum level of C-reactive protein, and symptoms), and 50% were assigned to conventional management. We categorized patients as those who were vs were not in deep remission (CD endoscopic index of severity scores below 4, with no deep ulcerations or steroid treatment, for 8 or more weeks) at the end of the follow-up period (median, 3.02 years; range, 0.05-6.26 years). The primary outcome was a composite of major adverse outcomes that indicate CD progression during the follow-up period: new internal fistulas or abscesses, strictures, perianal fistulas or abscesses, or hospitalization or surgery for CD. Kaplan-Meier and penalized Cox regression with bootstrapping were used to compare composite rates between patients who achieved or did not achieve remission at the end of the follow-up period. RESULTS: Major adverse outcomes were reported for 34 patients (27.9%) during the follow-up period. Significantly fewer patients in deep remission at the end of the CALM study had major adverse outcomes during the follow-up period (P = .01). When we adjusted for potential confounders, deep remission (adjusted hazard ratio, 0.19; 95% confidence interval, 0.07-0.31) was significantly associated with a lower risk of major adverse outcome. CONCLUSIONS: In an analysis of follow-up data from the CALM study, we associated induction of deep remission in early, moderate to severe CD with decreased risk of disease progression over a median time of 3 years, regardless of tight control or conventional management strategy.
- Klíčová slova
- Adalimumab, CDEIS, IBD, Inflammatory Bowel Diseases,
- MeSH
- adalimumab aplikace a dávkování škodlivé účinky MeSH
- antiflogistika aplikace a dávkování škodlivé účinky MeSH
- azathioprin aplikace a dávkování škodlivé účinky MeSH
- časové faktory MeSH
- Crohnova nemoc diagnóza farmakoterapie imunologie patologie MeSH
- dospělí MeSH
- hospitalizace statistika a číselné údaje MeSH
- indukce remise metody MeSH
- kombinovaná farmakoterapie škodlivé účinky metody MeSH
- lidé MeSH
- mladý dospělý MeSH
- následné studie MeSH
- prednison aplikace a dávkování škodlivé účinky MeSH
- progrese nemoci MeSH
- retrospektivní studie MeSH
- stupeň závažnosti nemoci MeSH
- TNF-alfa antagonisté a inhibitory imunologie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- adalimumab MeSH
- antiflogistika MeSH
- azathioprin MeSH
- prednison MeSH
- TNF protein, human MeSH Prohlížeč
- TNF-alfa MeSH
BACKGROUND: Young age and thiopurine therapy are risk factors for lymphoproliferative disease among patients with inflammatory bowel disease (IBD). AIMS: The aims of this study were to evaluate the prevalence of seropositivity for the Epstein-Barr virus (EBV) and human cytomegalovirus (CMV) among children and adolescents with IBD, to assess the viral load of EBV, CMV, and BK and JC polyomaviruses (BKV, JCV) in these patients, and to assess the influence of different therapeutic regimens on seroprevalence and viral load. METHODS: Children who had been followed in our center were tested for EBV, CMV, BKV, and JCV in a cross-sectional study. One hundred and six children were included who had Crohn's disease (68%), ulcerative colitis (29%), and unclassified IBD (3%). RESULTS: We found that 64% of patients were EBV seropositive. The proportion of EBV seropositive patients increased during childhood. Azathioprine therapy (p = 0.003) was associated with EBV seropositivity in a multiple logistic regression model, after adjusting for gender, age, and disease activity at determination. We found a significant association between the number of polymerase chain reaction copies and infliximab dose (p = 0.023). We did not find any significant association between CMV serology and CMV, BKV, or JCV viral load, or any other therapeutic regimen or clinical characteristics. CONCLUSIONS: Treatment with azathioprine appears to be a risk factor for early EBV seropositivity in children with IBD, and the infliximab dose was associated with a higher EBV viral load.
- Klíčová slova
- Azathioprine, Cytomegalovirus, Epstein–Barr virus, Immunosuppressive therapy, Inflammatory bowel disease, Infliximab,
- MeSH
- azathioprin škodlivé účinky MeSH
- Crohnova nemoc diagnóza farmakoterapie epidemiologie imunologie MeSH
- cytomegalovirové infekce diagnóza epidemiologie imunologie virologie MeSH
- dítě MeSH
- imunokompromitovaný pacient MeSH
- imunosupresiva škodlivé účinky MeSH
- infekce virem Epsteina-Barrové diagnóza epidemiologie imunologie virologie MeSH
- infliximab škodlivé účinky MeSH
- lidé MeSH
- logistické modely MeSH
- mladiství MeSH
- multivariační analýza MeSH
- odds ratio MeSH
- oportunní infekce diagnóza epidemiologie imunologie virologie MeSH
- polyomavirové infekce diagnóza epidemiologie imunologie virologie MeSH
- předškolní dítě MeSH
- prevalence MeSH
- průřezové studie MeSH
- rizikové faktory MeSH
- séroepidemiologické studie MeSH
- sérologické testy MeSH
- ulcerózní kolitida diagnóza farmakoterapie epidemiologie imunologie MeSH
- věkové faktory MeSH
- virová nálož MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika epidemiologie MeSH
- Názvy látek
- azathioprin MeSH
- imunosupresiva MeSH
- infliximab MeSH
BACKGROUND: Azathioprine [AZA] and mercaptopurine [MP] are recommended for maintenance of steroid-free remission in children with Crohn`s disease [CD]. Azathioprine-induced pancreatitis, an idiosyncratic and major side effect, has been considered as an absolute contraindication for the use of a second thiopurine in IBD patients. MATERIALS AND METHODS: We describe two children with CD in whom MP were successfully trialled after a confirmed azathioprine-induced pancreatitis, being well tolerated in both cases. RESULTS: Two boys [13 and 10 years old] started exclusive enteral nutrition after diagnosis of moderate (Pediatric Crohn's Disease Activity Index [wPCDAI] = 45) and mild [wPCDAI = 35] CD. Both developed an acute mild to moderate pancreatitis after 2 and 3 weeks, respectively, of AZA treatment but recovered fully in hospital after AZA withdrawal. They started on MP treatment without any adverse effect. They were tested for the presence of polymorphisms 238G>C, 460G>A, and 719A>G in the TPMT gene and 94C>A and 21>C in the ITPase. Both patients were wild-type for all tested polymorphisms. CONCLUSIONS: Azathioprine-induced acute pancreatitis should not be considered as an absolute contraindication for the use of MP. Further investigation is required to create a better understanding of the mechanism underlying the adverse events and to allow more possibilities for personalised therapy.
- Klíčová slova
- Crohn′s disease, Thiopurines, azathioprine, children, mercaptopurine, pancreatitis,
- MeSH
- azathioprin škodlivé účinky terapeutické užití MeSH
- Crohnova nemoc komplikace farmakoterapie MeSH
- dítě MeSH
- imunosupresiva terapeutické užití MeSH
- lidé MeSH
- merkaptopurin terapeutické užití MeSH
- mladiství MeSH
- pankreatitida chemicky indukované MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Názvy látek
- azathioprin MeSH
- imunosupresiva MeSH
- merkaptopurin MeSH
Severe forms of pemphigus vulgaris (PV) that are resistant to standard treatment present a life-threatening disease with a mortality of 5-10%. The treatment is usually individualized. The most popular procedures used today include intravenous applications of immunoglobulins and rituximab. Currently the common use of pulse corticosteroids, often in first-line treatment, is being neglected. This particular case documented the severity of the disease and also the need for combined and comprehensive care, in which corticosteroid pulse therapy still plays an important role.
- Klíčová slova
- own experience, resistant form of pemphigus vulgaris, therapeutic possibilities,
- MeSH
- antibakteriální látky terapeutické užití MeSH
- antifungální látky terapeutické užití MeSH
- azathioprin škodlivé účinky MeSH
- biopsie MeSH
- časové faktory MeSH
- hormony kůry nadledvin aplikace a dávkování MeSH
- imunosupresiva škodlivé účinky MeSH
- intravenózní imunoglobuliny terapeutické užití MeSH
- kombinovaná farmakoterapie MeSH
- kůže účinky léků patologie MeSH
- leukopenie chemicky indukované diagnóza terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- pemfigus diagnóza farmakoterapie MeSH
- pulzní dávkování léků MeSH
- recidiva MeSH
- sepse chemicky indukované diagnóza terapie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Názvy látek
- antibakteriální látky MeSH
- antifungální látky MeSH
- azathioprin MeSH
- hormony kůry nadledvin MeSH
- imunosupresiva MeSH
- intravenózní imunoglobuliny MeSH
BACKGROUND: Approximately 10-28 % of patients experience adverse drug reactions related to treatment with thiopurines. The most serious reaction is myelosuppression, typically manifested as leucopenia, which occurs in approximately 2-5 % of patients. Other adverse drug reactions that often accompany thiopurine therapy are pancreatitis, hepatotoxicity, allergic reactions, digestive intolerance, arthralgia, febrile conditions, and rash. OBJECTIVE: The objective of this study was to assess the relationship between variant alleles of thiopurine S-methyltransferase (SNPs 238G > C, 460G > A and 719A > G), inosine triphosphate diphosphatase (SNPs 94C > A and IVS2 + 21A > C), and xanthine dehydrogenase (837C > T) and the occurrence of adverse drug reactions to azathioprine therapy. METHODS: Genotype was determined for 188 Caucasians diagnosed with inflammatory bowel disease treated with a standard dose of azathioprine (1.4-2.0 mg/kg/day). Allelic variants were determined by PCR-REA and real-time PCR methods. Results were statistically evaluated by use of Fisher's test and by odds ratio calculation. RESULTS: Variant genotype thiopurine S-methyltransferase predisposes to development of leucopenia (P = 0.003, OR = 5, CI 95 %, 1.8058-13.8444). Although not statistically significant, we observed a trend that suggested correlation between the occurrence of digestive intolerance and the variant genotype inosine triphosphate diphosphatase (P = 0.1102; OR 15.63, CI 95 %, 1.162-210.1094), and between the occurrence of pancreatitis and the variant allele xanthine dehydrogenase 837T (P = 0.1124; OR 12,1, CI 95 %, 1.15-126.37). CONCLUSION: The variant genotype thiopurine S-methyltransferase has been associated with the occurrence of leucopenia. The involvement of polymorphisms in inosine triphosphate diphosphatase and xanthine dehydrogenase genes in the development of digestive intolerance and pancreatitis will require further verification.
- MeSH
- azathioprin škodlivé účinky terapeutické užití MeSH
- gastrointestinální nemoci chemicky indukované genetika MeSH
- genetická predispozice k nemoci MeSH
- genotyp MeSH
- idiopatické střevní záněty farmakoterapie MeSH
- imunosupresiva škodlivé účinky terapeutické užití MeSH
- leukopenie chemicky indukované genetika MeSH
- lidé MeSH
- methyltransferasy genetika metabolismus MeSH
- pankreatitida chemicky indukované genetika MeSH
- polymerázová řetězová reakce metody MeSH
- polymorfismus genetický * MeSH
- prohibitiny MeSH
- regulace genové exprese MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- azathioprin MeSH
- imunosupresiva MeSH
- methyltransferasy MeSH
- PHB2 protein, human MeSH Prohlížeč
- prohibitiny MeSH
- thiopurine methyltransferase MeSH Prohlížeč
INTRODUCTION: Drug-induced acute pancreatitis is considered to be a rare diagnosis. The incidence of drug-induced acute pancreatitis is usually estimated from case reports. AIM: The aim of this study was to determine the incidence, etiology, and severity of drug-induced pancreatitis during a 2-year period in a tertiary hospital. METHODS: The study was conducted as a retrospective analysis of all cases of pancreatitis in the University Hospital in Olomouc (1,432 beds) in 2006-2007. All cases of acute pancreatitis were re-evaluated and divided according to the causative factor. In drug-induced cases, the WHO Probability Scale for the evaluation of causality relationship was used. RESULTS: The inclusion criteria were met by 170 medical files. There were 91 (53%) cases in men and 79 (47%) in women, and mean age was 57 years old (5-91 years old). The etiology was in 53% biliary, 31% alcohol-induced, 12% other determined, and in 4% the cause could not be established. The proportion of drug-induced acute pancreatitis was 5.3% and it was the third most frequent cause of the AP. Azathioprine was the most frequent causative factor (three cases in two patients); all the other causative drugs were documented only in single cases: mesalazine, dexamethasone, ramipril, mycophenolate mofetil, cytarabine, and valproate. CONCLUSIONS: The diagnosis of drug-induced acute pancreatitis seems to be underestimated because of the difficulties in determining the causative agent and the need for a retrospective re-evaluation of the suspected causative factors. The disease is more probable in younger persons, women, and patients suffering from Crohn's disease.
- MeSH
- akutní nemoc MeSH
- azathioprin škodlivé účinky MeSH
- Crohnova nemoc farmakoterapie epidemiologie MeSH
- cytarabin škodlivé účinky MeSH
- dexamethason škodlivé účinky MeSH
- dítě MeSH
- dospělí MeSH
- imunosupresiva škodlivé účinky MeSH
- incidence MeSH
- kyselina mykofenolová škodlivé účinky analogy a deriváty MeSH
- kyselina valproová škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- mesalamin škodlivé účinky MeSH
- mladiství MeSH
- mladý dospělý MeSH
- pankreatitida chemicky indukované epidemiologie MeSH
- předškolní dítě MeSH
- ramipril škodlivé účinky MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- stupeň závažnosti nemoci * MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- azathioprin MeSH
- cytarabin MeSH
- dexamethason MeSH
- imunosupresiva MeSH
- kyselina mykofenolová MeSH
- kyselina valproová MeSH
- mesalamin MeSH
- ramipril MeSH
OBJECTIVES: Our study aims to find the relationship between metabolic enzyme thiopurine S-methyltransferase (TPMT) gene polymorphisms and clinical output of the therapy with azathioprine. We focused on patients who experienced leucopenia caused by high blood levels of active azathioprine metabolites. DESIGN: Our group consists of 87 patients who have been treated by azathioprine. 21 individuals experienced leucopenia during treatment with standard dose of azathioprine. We have used PCR-REA and "real-time" PCR methods for genotype detection G238C, G460G and A719G substitutions in TPMT gene. RESULTS: We have found statistical association between the presence of non-standard TPMT alleles and adverse event associated with azathioprine treatment - leucopenia (p=0.0033). CONCLUSION: Our results confirm that TPMT genotyping prior to the treatment with azathioprine could predict patients with genetic predisposition for serious leucopenia and seems to be a useful genetic marker for individualisation of the therapy.
- MeSH
- alely MeSH
- azathioprin škodlivé účinky krev MeSH
- dospělí MeSH
- genetická predispozice k nemoci MeSH
- genotyp MeSH
- jednonukleotidový polymorfismus MeSH
- leukopenie chemicky indukované MeSH
- lidé MeSH
- methyltransferasy genetika MeSH
- polymerázová řetězová reakce MeSH
- polymorfismus genetický * MeSH
- prohibitiny MeSH
- sekvenční analýza DNA MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- azathioprin MeSH
- methyltransferasy MeSH
- PHB2 protein, human MeSH Prohlížeč
- prohibitiny MeSH
- thiopurine methyltransferase MeSH Prohlížeč
BACKGROUND: Studies evaluating interferon beta (IFNbeta) for multiple sclerosis (MS) showed only partial efficacy. In many patients, IFNbeta does not halt relapses or disability progression. One strategy to potentially enhance efficacy is to combine IFNbeta with classical immunosuppressive agents, such as azathioprine (AZA) or corticosteroids, commonly used for other autoimmune disorders. OBJECTIVE: The Avonex-Steroids-Azathioprine study was placebo-controlled trial and evaluated efficacy of IFNbeta-1a alone and combined with low-dose AZA alone or low-dose AZA and low-dose corticosteroids as initial therapy. METHODS: A total of 181 patients with relapsing-remitting MS (RRMS) were randomized to receive IFNbeta-1a 30 microg intramuscularly (IM) once weekly, IFNbeta-1a 30 microg IM once weekly plus AZA 50 mg orally once daily, or IFNbeta-1a 30 microg IM once weekly plus AZA 50 mg orally once daily plus prednisone 10 mg orally every other day. The primary end point was annualized relapse rate (ARR) at 2 years. Patients were eligible for enrollment in a 3-year extension. RESULTS: At 2 years, adjusted ARR was 1.05 for IFNbeta-1a, 0.91 for IFNbeta-1a plus AZA, and 0.73 for combination. The cumulative probability of sustained disability progression was 16.8% for IFNbeta-1a, 20.7% for IFNbeta-1a plus AZA, and 17.5% for combination. There were no statistically significant differences among groups for either measure at 2 and 5 years. Percent T2 lesion volume change at 2 years was significantly lower for combination (+14.5%) versus IFNbeta-1a alone (+30.3%, P < 0.05). Groups had similar safety profiles. CONCLUSION: In IFNbeta-naïve patients with early active RRMS, combination treatment did not show superiority over IFNbeta-1a monotherapy.
- MeSH
- aplikace orální MeSH
- atrofie MeSH
- azathioprin aplikace a dávkování škodlivé účinky MeSH
- časové faktory MeSH
- dvojitá slepá metoda MeSH
- hormony kůry nadledvin aplikace a dávkování škodlivé účinky MeSH
- imunologické faktory aplikace a dávkování škodlivé účinky MeSH
- imunosupresiva aplikace a dávkování škodlivé účinky MeSH
- injekce intramuskulární MeSH
- interferon beta 1a MeSH
- interferon beta aplikace a dávkování škodlivé účinky MeSH
- kombinovaná farmakoterapie MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mozek patologie MeSH
- posuzování pracovní neschopnosti MeSH
- prednison aplikace a dávkování škodlivé účinky MeSH
- progrese nemoci MeSH
- prospektivní studie MeSH
- recidiva MeSH
- relabující-remitující roztroušená skleróza diagnóza farmakoterapie MeSH
- rozvrh dávkování léků MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- azathioprin MeSH
- hormony kůry nadledvin MeSH
- imunologické faktory MeSH
- imunosupresiva MeSH
- interferon beta 1a MeSH
- interferon beta MeSH
- prednison MeSH
Azathioprine and 6-mercaptopurine have been used for many years in the treatment of inflammatory bowel disease. Approximately 0.3% of the population are homozygous for variant alleles associated with extremely low thiopurine S-methyltransferase enzyme activity. We describe the case of a young patient with ulcerative colitis, homozygous for TPMT*3A alleles, who suffered fatal azathioprine-induced myelotoxicity after standard dosing with azathioprine. Screening for decreased activity of TPMT in patients prior to azathioprine treatment is advised to minimize the risk of drug-induced toxicity.
- MeSH
- azathioprin škodlivé účinky terapeutické užití MeSH
- dospělí MeSH
- fatální výsledek MeSH
- gangréna plynatá komplikace farmakoterapie enzymologie imunologie MeSH
- homozygot MeSH
- kostní dřeň účinky léků MeSH
- lidé MeSH
- methyltransferasy nedostatek genetika MeSH
- nežádoucí účinky léčiv MeSH
- pancytopenie komplikace farmakoterapie imunologie patologie MeSH
- ulcerózní kolitida komplikace farmakoterapie imunologie patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- azathioprin MeSH
- methyltransferasy MeSH
- thiopurine methyltransferase MeSH Prohlížeč