Misconceptions are common in the care of patients with inflammatory bowel disease(IBD).In this paper,we state the most commonly found misconceptions in clinical practice and deal with the use of 5-aminosalicylates and...Misconceptions are common in the care of patients with inflammatory bowel disease(IBD).In this paper,we state the most commonly found misconceptions in clinical practice and deal with the use of 5-aminosalicylates and thiopurines,to review the related scientificevidence,and make appropriate recommendations.Prevention of errors needs knowledge to avoid making such errors through ignorance.However,the amount of knowledge is increasing so quickly that one new danger is an overabundance of information.IBD is a model of a very complex disease and our goal with this review is to summarize the key evidence for the most common daily clinical problems.With regard to the use of 5-aminosalicylates,the best practice may to be consider abandoning the use of these drugs in patients withsmall bowel Crohn's disease.The combined approach with oral plus topical 5-aminosalicylates should be the first-line therapy in patients with active ulcerative colitis;once-daily treatment should be offered as a first choice regimen due to its better compliance and higher efficacy.With regard to thiopurines,they seem to be as effective in ulcerative colitis as in Crohn's disease.Underdosing of thiopurines is a form of undertreatment.Thiopurines should probably be continued indefinitely because their withdrawal is associated with a high risk of relapse.Mercaptopurine is a safe alternative in patients with digestive intolerance or hepatotoxicity due to azathioprine.Finally,thiopurine methyltransferase(TPMT)screening cannot substitute for regular monitoring because the majority of cases of myelotoxicity are not TPMT-related.展开更多
AIM: To evaluate variation of the concentration of thiopurine metabolites after 5-aminosalicylate(5-ASA) interruption and the role of genetic polymorphisms of N-acetyl transferase(NAT) 1 and 2. METHODS: Concentrations...AIM: To evaluate variation of the concentration of thiopurine metabolites after 5-aminosalicylate(5-ASA) interruption and the role of genetic polymorphisms of N-acetyl transferase(NAT) 1 and 2. METHODS: Concentrations of thioguanine nucleotides(TGN) and methymercaptopurine nucleotides(MMPN), metabolites of thiopurines, were measured by high performance liquid chromatography in 12 young patients(3 females and 9 males, median age 16 years) with inflammatory bowel disease(6 Crohn's disease and 6 ulcerative colitis) treated with thiopurines(7 mercaptopurine and 5 azathioprine) and 5-ASA. Blood samples were collected one month before and one month after the interruption of 5-ASA. DNA was extracted and genotyping of NAT1, NAT2, inosine triphosphate pyrophosphatase(ITPA) and thiopurine methyl transferase(TPMT) genes was performed using PCR assays. RESULTS: Median TGN concentration before 5-ASA interruption was 270 pmol/8 x 108 erythrocytes(range: 145-750); after the interruption of the aminosalicylate, a 35% reduction in TGN mean concentrations(absolutemean reduction 109 pmol/8 × 108 erythrocytes) was observed(median 221 pmol/8 × 108 erythrocytes, range: 96-427, P value linear mixed effects model 0.0011). Demographic and clinical covariates were not related to thiopurine metabolites concentrations. All patients were wild-type for the most relevant ITPA and TPMT variants. For NAT1 genotyping, 7 subjects presented an allele combination corresponding to fast enzymatic activity and 5 to slow activity. NAT1 genotypes corresponding to fast enzymatic activity were associated with reduced TGN concentration(P value linear mixed effects model 0.033), putatively because of increased 5-ASA inactivation and consequent reduced inhibition of thiopurine metabolism. The effect of NAT1 status on TGN seems to be persistent even after one month since the interruption of the aminosalicylate. No effect of NAT1 genotypes was shown on MMPN concentrations. NAT2 genotyping revealed that 6 patients presented a genotype corresponding to fast enzymatic activity and 6 to slow activity; NAT2 genotypes were not related to thiopurine metabolites concentration in this study. CONCLUSION: NAT1 genotype affects TGN levels in patients treated with thiopurines and aminosalicylates and could therefore influence the toxicity and efficacy of these drugs; however the number of patients evaluated is limited and this has to be considered a pilot study.展开更多
Objective: To evaluate the maintenance effect of probiotics versus that of aminosalicylates on ulcerative colitis. Methods: MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and the Chinese Biomedical Database...Objective: To evaluate the maintenance effect of probiotics versus that of aminosalicylates on ulcerative colitis. Methods: MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and the Chinese Biomedical Database were searched in English or Chinese. Data extracted were selected with strict criteria. Results: In six randomized controlled trials (RCTs), a total of 721 participants were enrolled and the maintenance effect of probiotics (n ? 364) versus that of aminosalicylates (n ? 357) on ulcerative colitis was investigated. No significant difference was observed between probiotics and aminosalicylate groups (relative risk (RR) ? 1.08; 95% confidence interval (CI): 0.91e1.28;P ? 0.40). Three RCTs compared the incidence of adverse events with probiotics versus those with aminosalicylates. No significant difference was observed in the incidence of adverse events between the two groups (RR ? 1.20;95%CI:0.92e1.56;P ? 0.17). Conclusions: Probiotics and aminosalicylates both showed a maintenance effect on ulcerative colitis. However, more well-designed RCTs are required.展开更多
Pelvic cancers are among the most frequently diagnosed cancers worldwide. Treatment of patients requires a multidisciplinary approach that frequently includes radiotherapy. Gastrointestinal(GI) radiation-induced toxic...Pelvic cancers are among the most frequently diagnosed cancers worldwide. Treatment of patients requires a multidisciplinary approach that frequently includes radiotherapy. Gastrointestinal(GI) radiation-induced toxicity is a major complication and the transient or long-term problems, ranging from mild to very severe, arising in non-cancerous tissues resulting from radiation treatment to a tumor of pelvic origin, are actually called as pelvic radiation disease. The incidence of pelvic radiation disease changes according to the radiation technique, the length of follow up, the assessmentmethod, the type and stage of cancer and several other variables. Notably, even with the most recent radiation techniques, i.e., intensity-modulated radiotherapy, the incidence of radiation-induced GI side effects is overall reduced but still not negligible. In addition, radiation-induced GI side effects can develop even after several decades; therefore, the improvement of patient life expectancy will unavoidably increase the risk of developing radiation-induced complications. Once developed, the management of pelvic radiation disease may be challenging. Therefore, the prevention of radiation-induced toxicity represents a reasonable way to avoid a dramatic drop of the quality of life of these patients. In the current manuscript we provide an updated and practical review on the best available evidences in the field of the prevention of pelvic radiation disease.展开更多
The most frequent localization of ulcerative colitis(UC) is the distal colon.In treating patients with active distal UC,efficacy and targeting of the drug to the distal colon are key priorities.Oral and rectal 5-amino...The most frequent localization of ulcerative colitis(UC) is the distal colon.In treating patients with active distal UC,efficacy and targeting of the drug to the distal colon are key priorities.Oral and rectal 5-aminosalicylic acid(5-ASA) preparations represent the first line therapy of mild-to-moderate distal UC for both induction and maintenance treatment.It has been reported that many UC patients are not adherent to therapy and that noncompliant patients had a 5-fold risk of experiencing a relapse.These findings led to the introduction of oncedaily oral regimens of 5-ASA as better therapeutic options in clinical practice due to improved adherence.New formulations of mesalazine,including the multimatrix delivery system,and mesalazine granules,which allow once-daily administration,have been developed.They have been demonstrated to be efficacious in inducing and maintaining remission in mild-to-moderate distal UC in large clinical trials.However,existing data for distal UC are rather insufficient to make a comparison between new and classical 5-ASA formulations.It seems that the new formulations are at least as effective as classical oral 5-ASA formulations.Other treatment options,in the case that 5-ASA therapy is not effective,include systemic corticosteroids,thiopurines(azathioprine or 6-mercaptopurine),cyclosporine,infliximab and surgery.The combination of a prompt diagnostic work-up,a correct therapeutic approach and an appropriate follow-up schedule is important in the management of patients with distal UC.This approach can shorten the duration of symptoms,induce a prolonged remission,improve patient's quality of life,and optimize the use of health resources.展开更多
Crohn's disease is a chronic inflammatory condition that may involve any segment of the gastrointestinal tract. Although several drugs have proven efficacy in inducing and maintaining disease in remission, resecti...Crohn's disease is a chronic inflammatory condition that may involve any segment of the gastrointestinal tract. Although several drugs have proven efficacy in inducing and maintaining disease in remission, resectional surgery remains as a cornerstone in the management of the disease, mainly for the treatment of its stenosing and penetrating complications. However, the occurrence of new mucosal (endoscopic) lesions in the neoterminal ileum early after surgery is almost constant, it is followed in the mid-term by clinical symptoms and, in a proportion of patients, repeated intestinal resections are required. Pathogenesis of postoperative recurrence (POR) is not fully understood, but luminal factors (commensal microbes, dietary antigens) seem to play an important role, and environmental and genetic factors may also have a relevant influence. Many studies tried to identify clinical predictors for POR with heterogeneous results, and only smoking has repeatedly been associated with a higher risk of POR. Ileocolonoscopy remains as the gold standard for the assessment of appearance and severity of POR, although the real usefulness of the available endoscopic score needs to be revisited and alternative techniques are emerging. Several drugs have been evaluated to prevent POR with limited success. Smoking cessation seems to be one of the more beneficial therapeutic measures. Aminosalicylates have only proved to be of marginal benefit, and they are only used in low-risk patients. Nitroimidazolic antibiotics, although efficient, are associated with a high rate of intolerance and might induce irreversible side effects when used for a long-term. Thiopurines are not widely used after ileocecal resection, maybe because some concerns in giving immunomodulators in asymptomatic patients still remain. In the era of biological agents and genetic testing, a well-established preventive strategy for POR is still lacking, and larger studies to identify good clinical, serological, and genetic predictors of early POR as well as more effective drugs (or drug combinations) are needed.展开更多
BACKGROUND There is a small and poorly studied population of patients with mild and limited Crohn’s disease(CD),who either spontaneously enter remission and can discontinue therapy,or be maintained on milder anti-inf...BACKGROUND There is a small and poorly studied population of patients with mild and limited Crohn’s disease(CD),who either spontaneously enter remission and can discontinue therapy,or be maintained on milder anti-inflammatory treatment.AIM To identify a group of children with mild CD who were not escalated to immunomodulators(azathioprine,mercaptopurine,or methotrexate)or biologics(infliximab or adalimumab)within the first two years after their Crohn’s diagnosis and outline the natural history and phenotypic features of these patients.METHODS In a retrospective chart review of the inflammatory bowel disease database at Boston Children’s Hospital we reviewed all the mild CD patient’s clinic visits,laboratory studies,and procedures for the duration of time they were followed at the center.Patients were included if they had clear diagnosis of Crohn’s disease,and they were not escalated to immunosuppressive therapies for at least 2 years after the date of diagnosis.These mild CD patients were compared to controls diagnosed at a similar time,that were treated with immunomodulators or biologics.Data that was abstracted included:Age at diagnosis,sex,disease location utilizing the Paris classification,medical treatment,surgical treatment,endoscopic findings,histology,and hospitalizations.We also analyzed differences in the phenotypic features between those with mild CD and those with moderate to severe disease.RESULTS Out of 1205 patients with CD diagnosed between 1990 and 2013,we identified 29 patients that met the inclusion criteria,and they were matched with 58 controls.There were no significant differences between the disease behaviors at presentation,with approximately 90%of patients in each group having inflammatory disease.However,patients with mild disease were more likely to have disease limited to the colon(31%vs 12%,P=0.03).In contrast,patients with moderate to severe disease(aka control group)were more likely to have ileocolonic disease(70%vs 45%in the mild group,P=0.02).Of the 29 patients,only 8 required medication escalation to immunomodulators during the period of follow-up.The primary indication for escalation to immune suppressive therapies was corticosteroid dependence.We also found that patients treated without immunomodulators or biologics for mild CD continue to exhibit histologic intestinal inflammation.Of the 29 patients,three developed significant complications of ileal disease,though only one required surgical intervention during the period of follow-up.CONCLUSION We identified a cohort of children with mild CD,who were able to avoid the institution of immune suppressive therapies for several years,and generally had good outcomes during the period of follow-up.While a subset of these patients will eventually require either immunosuppression or surgery,the majority of them have a good quality of life despite having low-grade intestinal inflammation.Importantly,this subset of patients has managed to avoid the potential toxicities of immune suppression for several years.The majority of these patients have either colonic disease with minimal small bowel involvement or limited ileal disease.展开更多
文摘Misconceptions are common in the care of patients with inflammatory bowel disease(IBD).In this paper,we state the most commonly found misconceptions in clinical practice and deal with the use of 5-aminosalicylates and thiopurines,to review the related scientificevidence,and make appropriate recommendations.Prevention of errors needs knowledge to avoid making such errors through ignorance.However,the amount of knowledge is increasing so quickly that one new danger is an overabundance of information.IBD is a model of a very complex disease and our goal with this review is to summarize the key evidence for the most common daily clinical problems.With regard to the use of 5-aminosalicylates,the best practice may to be consider abandoning the use of these drugs in patients withsmall bowel Crohn's disease.The combined approach with oral plus topical 5-aminosalicylates should be the first-line therapy in patients with active ulcerative colitis;once-daily treatment should be offered as a first choice regimen due to its better compliance and higher efficacy.With regard to thiopurines,they seem to be as effective in ulcerative colitis as in Crohn's disease.Underdosing of thiopurines is a form of undertreatment.Thiopurines should probably be continued indefinitely because their withdrawal is associated with a high risk of relapse.Mercaptopurine is a safe alternative in patients with digestive intolerance or hepatotoxicity due to azathioprine.Finally,thiopurine methyltransferase(TPMT)screening cannot substitute for regular monitoring because the majority of cases of myelotoxicity are not TPMT-related.
基金Supported by Italian Ministry of Health,and Fondazione Benefica Alberto e Kathleen Casali
文摘AIM: To evaluate variation of the concentration of thiopurine metabolites after 5-aminosalicylate(5-ASA) interruption and the role of genetic polymorphisms of N-acetyl transferase(NAT) 1 and 2. METHODS: Concentrations of thioguanine nucleotides(TGN) and methymercaptopurine nucleotides(MMPN), metabolites of thiopurines, were measured by high performance liquid chromatography in 12 young patients(3 females and 9 males, median age 16 years) with inflammatory bowel disease(6 Crohn's disease and 6 ulcerative colitis) treated with thiopurines(7 mercaptopurine and 5 azathioprine) and 5-ASA. Blood samples were collected one month before and one month after the interruption of 5-ASA. DNA was extracted and genotyping of NAT1, NAT2, inosine triphosphate pyrophosphatase(ITPA) and thiopurine methyl transferase(TPMT) genes was performed using PCR assays. RESULTS: Median TGN concentration before 5-ASA interruption was 270 pmol/8 x 108 erythrocytes(range: 145-750); after the interruption of the aminosalicylate, a 35% reduction in TGN mean concentrations(absolutemean reduction 109 pmol/8 × 108 erythrocytes) was observed(median 221 pmol/8 × 108 erythrocytes, range: 96-427, P value linear mixed effects model 0.0011). Demographic and clinical covariates were not related to thiopurine metabolites concentrations. All patients were wild-type for the most relevant ITPA and TPMT variants. For NAT1 genotyping, 7 subjects presented an allele combination corresponding to fast enzymatic activity and 5 to slow activity. NAT1 genotypes corresponding to fast enzymatic activity were associated with reduced TGN concentration(P value linear mixed effects model 0.033), putatively because of increased 5-ASA inactivation and consequent reduced inhibition of thiopurine metabolism. The effect of NAT1 status on TGN seems to be persistent even after one month since the interruption of the aminosalicylate. No effect of NAT1 genotypes was shown on MMPN concentrations. NAT2 genotyping revealed that 6 patients presented a genotype corresponding to fast enzymatic activity and 6 to slow activity; NAT2 genotypes were not related to thiopurine metabolites concentration in this study. CONCLUSION: NAT1 genotype affects TGN levels in patients treated with thiopurines and aminosalicylates and could therefore influence the toxicity and efficacy of these drugs; however the number of patients evaluated is limited and this has to be considered a pilot study.
文摘Objective: To evaluate the maintenance effect of probiotics versus that of aminosalicylates on ulcerative colitis. Methods: MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and the Chinese Biomedical Database were searched in English or Chinese. Data extracted were selected with strict criteria. Results: In six randomized controlled trials (RCTs), a total of 721 participants were enrolled and the maintenance effect of probiotics (n ? 364) versus that of aminosalicylates (n ? 357) on ulcerative colitis was investigated. No significant difference was observed between probiotics and aminosalicylate groups (relative risk (RR) ? 1.08; 95% confidence interval (CI): 0.91e1.28;P ? 0.40). Three RCTs compared the incidence of adverse events with probiotics versus those with aminosalicylates. No significant difference was observed in the incidence of adverse events between the two groups (RR ? 1.20;95%CI:0.92e1.56;P ? 0.17). Conclusions: Probiotics and aminosalicylates both showed a maintenance effect on ulcerative colitis. However, more well-designed RCTs are required.
文摘Pelvic cancers are among the most frequently diagnosed cancers worldwide. Treatment of patients requires a multidisciplinary approach that frequently includes radiotherapy. Gastrointestinal(GI) radiation-induced toxicity is a major complication and the transient or long-term problems, ranging from mild to very severe, arising in non-cancerous tissues resulting from radiation treatment to a tumor of pelvic origin, are actually called as pelvic radiation disease. The incidence of pelvic radiation disease changes according to the radiation technique, the length of follow up, the assessmentmethod, the type and stage of cancer and several other variables. Notably, even with the most recent radiation techniques, i.e., intensity-modulated radiotherapy, the incidence of radiation-induced GI side effects is overall reduced but still not negligible. In addition, radiation-induced GI side effects can develop even after several decades; therefore, the improvement of patient life expectancy will unavoidably increase the risk of developing radiation-induced complications. Once developed, the management of pelvic radiation disease may be challenging. Therefore, the prevention of radiation-induced toxicity represents a reasonable way to avoid a dramatic drop of the quality of life of these patients. In the current manuscript we provide an updated and practical review on the best available evidences in the field of the prevention of pelvic radiation disease.
文摘The most frequent localization of ulcerative colitis(UC) is the distal colon.In treating patients with active distal UC,efficacy and targeting of the drug to the distal colon are key priorities.Oral and rectal 5-aminosalicylic acid(5-ASA) preparations represent the first line therapy of mild-to-moderate distal UC for both induction and maintenance treatment.It has been reported that many UC patients are not adherent to therapy and that noncompliant patients had a 5-fold risk of experiencing a relapse.These findings led to the introduction of oncedaily oral regimens of 5-ASA as better therapeutic options in clinical practice due to improved adherence.New formulations of mesalazine,including the multimatrix delivery system,and mesalazine granules,which allow once-daily administration,have been developed.They have been demonstrated to be efficacious in inducing and maintaining remission in mild-to-moderate distal UC in large clinical trials.However,existing data for distal UC are rather insufficient to make a comparison between new and classical 5-ASA formulations.It seems that the new formulations are at least as effective as classical oral 5-ASA formulations.Other treatment options,in the case that 5-ASA therapy is not effective,include systemic corticosteroids,thiopurines(azathioprine or 6-mercaptopurine),cyclosporine,infliximab and surgery.The combination of a prompt diagnostic work-up,a correct therapeutic approach and an appropriate follow-up schedule is important in the management of patients with distal UC.This approach can shorten the duration of symptoms,induce a prolonged remission,improve patient's quality of life,and optimize the use of health resources.
文摘Crohn's disease is a chronic inflammatory condition that may involve any segment of the gastrointestinal tract. Although several drugs have proven efficacy in inducing and maintaining disease in remission, resectional surgery remains as a cornerstone in the management of the disease, mainly for the treatment of its stenosing and penetrating complications. However, the occurrence of new mucosal (endoscopic) lesions in the neoterminal ileum early after surgery is almost constant, it is followed in the mid-term by clinical symptoms and, in a proportion of patients, repeated intestinal resections are required. Pathogenesis of postoperative recurrence (POR) is not fully understood, but luminal factors (commensal microbes, dietary antigens) seem to play an important role, and environmental and genetic factors may also have a relevant influence. Many studies tried to identify clinical predictors for POR with heterogeneous results, and only smoking has repeatedly been associated with a higher risk of POR. Ileocolonoscopy remains as the gold standard for the assessment of appearance and severity of POR, although the real usefulness of the available endoscopic score needs to be revisited and alternative techniques are emerging. Several drugs have been evaluated to prevent POR with limited success. Smoking cessation seems to be one of the more beneficial therapeutic measures. Aminosalicylates have only proved to be of marginal benefit, and they are only used in low-risk patients. Nitroimidazolic antibiotics, although efficient, are associated with a high rate of intolerance and might induce irreversible side effects when used for a long-term. Thiopurines are not widely used after ileocecal resection, maybe because some concerns in giving immunomodulators in asymptomatic patients still remain. In the era of biological agents and genetic testing, a well-established preventive strategy for POR is still lacking, and larger studies to identify good clinical, serological, and genetic predictors of early POR as well as more effective drugs (or drug combinations) are needed.
文摘BACKGROUND There is a small and poorly studied population of patients with mild and limited Crohn’s disease(CD),who either spontaneously enter remission and can discontinue therapy,or be maintained on milder anti-inflammatory treatment.AIM To identify a group of children with mild CD who were not escalated to immunomodulators(azathioprine,mercaptopurine,or methotrexate)or biologics(infliximab or adalimumab)within the first two years after their Crohn’s diagnosis and outline the natural history and phenotypic features of these patients.METHODS In a retrospective chart review of the inflammatory bowel disease database at Boston Children’s Hospital we reviewed all the mild CD patient’s clinic visits,laboratory studies,and procedures for the duration of time they were followed at the center.Patients were included if they had clear diagnosis of Crohn’s disease,and they were not escalated to immunosuppressive therapies for at least 2 years after the date of diagnosis.These mild CD patients were compared to controls diagnosed at a similar time,that were treated with immunomodulators or biologics.Data that was abstracted included:Age at diagnosis,sex,disease location utilizing the Paris classification,medical treatment,surgical treatment,endoscopic findings,histology,and hospitalizations.We also analyzed differences in the phenotypic features between those with mild CD and those with moderate to severe disease.RESULTS Out of 1205 patients with CD diagnosed between 1990 and 2013,we identified 29 patients that met the inclusion criteria,and they were matched with 58 controls.There were no significant differences between the disease behaviors at presentation,with approximately 90%of patients in each group having inflammatory disease.However,patients with mild disease were more likely to have disease limited to the colon(31%vs 12%,P=0.03).In contrast,patients with moderate to severe disease(aka control group)were more likely to have ileocolonic disease(70%vs 45%in the mild group,P=0.02).Of the 29 patients,only 8 required medication escalation to immunomodulators during the period of follow-up.The primary indication for escalation to immune suppressive therapies was corticosteroid dependence.We also found that patients treated without immunomodulators or biologics for mild CD continue to exhibit histologic intestinal inflammation.Of the 29 patients,three developed significant complications of ileal disease,though only one required surgical intervention during the period of follow-up.CONCLUSION We identified a cohort of children with mild CD,who were able to avoid the institution of immune suppressive therapies for several years,and generally had good outcomes during the period of follow-up.While a subset of these patients will eventually require either immunosuppression or surgery,the majority of them have a good quality of life despite having low-grade intestinal inflammation.Importantly,this subset of patients has managed to avoid the potential toxicities of immune suppression for several years.The majority of these patients have either colonic disease with minimal small bowel involvement or limited ileal disease.
