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Consider steroids in anti-TNF liver injury
Patients with liver injury secondary to anti–tumor necrosis factor–alpha agents often exhibit histological changes similar to those seen in spontaneous autoimmune hepatitis, wrote Dr. Marwan Ghabril and his colleagues. The report was published in the May issue of Clinical Gastroenterology and Hepatology.
The finding comes from a review seeking to characterize the presentation, injury pattern, course of illness, and treatment of anti-TNF agent–induced liver injury, which Dr. Ghabril, of Indiana University in Indianapolis, said "may be severe and prolonged."
To that end, he and his colleagues studied six patients from the U.S. Drug-Induced Liver Injury Network (DILIN) database who had liver damage that was likely secondary to anti-TNFs, according to DILIN criteria.
Additionally, 28 cases were culled from a literature review of the PubMed database using the search terms "hepatotoxicity," "liver injury," "tumor necrosis factor," and the generic names of all TNF-alpha antagonists.
Among all patients, infliximab was most commonly the offending agent, followed by etanercept and adalimumab; no cases were attributed to natalizumab, golimumab, or certolizumab.
Diseases for which the anti-TNFs were prescribed included ankylosing spondylitis, Crohn’s disease, chronic ulcerative colitis, juvenile inflammatory arthritis, psoriatic arthritis, psoriasis, and rheumatoid arthritis.
First, Dr. Ghabril looked at the six patients from the DILIN database. Among these patients, the median duration of drug use before onset of liver injury was 16 weeks (range, 2-52 weeks).
"At presentation, half had jaundice, half had nausea, but only one had fever and none had immuno-allergic features of skin rash or eosinophilia," wrote the authors.
Only one of these patients developed significantly impaired coagulation, with an INR of 3.5, and none of the DILIN patients developed ascites or other signs of hepatic failure, they added.
The peak ALT ranged from 384 to 1,687 U/L, and the peak bilirubin from 1.5 to 27.7 mg/dL.
"Five of the six patients were treated with corticosteroids. One patient had a protracted illness, but all ultimately recovered and could be withdrawn from corticosteroid therapy without recurrence," they wrote.
Next, the authors turned their attention to the PubMed cases.
"Peak serum ALT ranged from 140 to 2,250 U/L and bilirubin from normal to 27.7 mg/dL," the authors reported.
Most patients (n = 22) had autoimmune serological markers and/or histological features at some point during the clinical course, they found.
Twelve patients stopped the drug and initiated corticosteroid therapy, oral or parenteral; all recovered. The rest improved after discontinuation of the anti-TNF, without steroid treatment, except for one patient who had underlying cirrhosis and required liver transplantation.
Notably, several patients were able to continue anti-TNF treatment with another agent without further incident, the authors wrote. Indeed, "three tolerated treatment with etanercept without recurrence of liver injury after cessation of infliximab or adalimumab. Two did well with adalimumab after [drug-induced liver injury] associated with infliximab, and one was successfully switched from adalimumab to abatacept."
Finally, the investigators contrasted patients with serological or histological autoimmune features with patients who lacked any autoimmune characteristics.
The autoimmune patients tended to have a longer latency period. The median period after the drug was initiated but before liver injury was noted was 16 weeks for the autoimmune patients versus 10 weeks for the nonautoimmune patients (P = .17). The autoimmune patients also had a higher peak ALT (median 784 vs. 528; P = .03).
"The mechanism by which the TNF-alpha antagonists lead to drug-induced liver injury is unknown," the authors wrote.
"Because the injury can occur after only one infusion, dose-dependent toxicity is unlikely. Unpredictable, idiosyncratic drug-induced liver injury seems most likely, as in this series no patients had clinical evidence of a rash or eosinophilia, and only one presented with fever."
"Further studies are needed to ascertain whether genetic or other markers of the hepatotoxicity associated with TNF-alpha antagonists can be identified," they said.
The DILIN database is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors reported having no conflicts of interest.
Patients with liver injury secondary to anti–tumor necrosis factor–alpha agents often exhibit histological changes similar to those seen in spontaneous autoimmune hepatitis, wrote Dr. Marwan Ghabril and his colleagues. The report was published in the May issue of Clinical Gastroenterology and Hepatology.
The finding comes from a review seeking to characterize the presentation, injury pattern, course of illness, and treatment of anti-TNF agent–induced liver injury, which Dr. Ghabril, of Indiana University in Indianapolis, said "may be severe and prolonged."
To that end, he and his colleagues studied six patients from the U.S. Drug-Induced Liver Injury Network (DILIN) database who had liver damage that was likely secondary to anti-TNFs, according to DILIN criteria.
Additionally, 28 cases were culled from a literature review of the PubMed database using the search terms "hepatotoxicity," "liver injury," "tumor necrosis factor," and the generic names of all TNF-alpha antagonists.
Among all patients, infliximab was most commonly the offending agent, followed by etanercept and adalimumab; no cases were attributed to natalizumab, golimumab, or certolizumab.
Diseases for which the anti-TNFs were prescribed included ankylosing spondylitis, Crohn’s disease, chronic ulcerative colitis, juvenile inflammatory arthritis, psoriatic arthritis, psoriasis, and rheumatoid arthritis.
First, Dr. Ghabril looked at the six patients from the DILIN database. Among these patients, the median duration of drug use before onset of liver injury was 16 weeks (range, 2-52 weeks).
"At presentation, half had jaundice, half had nausea, but only one had fever and none had immuno-allergic features of skin rash or eosinophilia," wrote the authors.
Only one of these patients developed significantly impaired coagulation, with an INR of 3.5, and none of the DILIN patients developed ascites or other signs of hepatic failure, they added.
The peak ALT ranged from 384 to 1,687 U/L, and the peak bilirubin from 1.5 to 27.7 mg/dL.
"Five of the six patients were treated with corticosteroids. One patient had a protracted illness, but all ultimately recovered and could be withdrawn from corticosteroid therapy without recurrence," they wrote.
Next, the authors turned their attention to the PubMed cases.
"Peak serum ALT ranged from 140 to 2,250 U/L and bilirubin from normal to 27.7 mg/dL," the authors reported.
Most patients (n = 22) had autoimmune serological markers and/or histological features at some point during the clinical course, they found.
Twelve patients stopped the drug and initiated corticosteroid therapy, oral or parenteral; all recovered. The rest improved after discontinuation of the anti-TNF, without steroid treatment, except for one patient who had underlying cirrhosis and required liver transplantation.
Notably, several patients were able to continue anti-TNF treatment with another agent without further incident, the authors wrote. Indeed, "three tolerated treatment with etanercept without recurrence of liver injury after cessation of infliximab or adalimumab. Two did well with adalimumab after [drug-induced liver injury] associated with infliximab, and one was successfully switched from adalimumab to abatacept."
Finally, the investigators contrasted patients with serological or histological autoimmune features with patients who lacked any autoimmune characteristics.
The autoimmune patients tended to have a longer latency period. The median period after the drug was initiated but before liver injury was noted was 16 weeks for the autoimmune patients versus 10 weeks for the nonautoimmune patients (P = .17). The autoimmune patients also had a higher peak ALT (median 784 vs. 528; P = .03).
"The mechanism by which the TNF-alpha antagonists lead to drug-induced liver injury is unknown," the authors wrote.
"Because the injury can occur after only one infusion, dose-dependent toxicity is unlikely. Unpredictable, idiosyncratic drug-induced liver injury seems most likely, as in this series no patients had clinical evidence of a rash or eosinophilia, and only one presented with fever."
"Further studies are needed to ascertain whether genetic or other markers of the hepatotoxicity associated with TNF-alpha antagonists can be identified," they said.
The DILIN database is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors reported having no conflicts of interest.
Patients with liver injury secondary to anti–tumor necrosis factor–alpha agents often exhibit histological changes similar to those seen in spontaneous autoimmune hepatitis, wrote Dr. Marwan Ghabril and his colleagues. The report was published in the May issue of Clinical Gastroenterology and Hepatology.
The finding comes from a review seeking to characterize the presentation, injury pattern, course of illness, and treatment of anti-TNF agent–induced liver injury, which Dr. Ghabril, of Indiana University in Indianapolis, said "may be severe and prolonged."
To that end, he and his colleagues studied six patients from the U.S. Drug-Induced Liver Injury Network (DILIN) database who had liver damage that was likely secondary to anti-TNFs, according to DILIN criteria.
Additionally, 28 cases were culled from a literature review of the PubMed database using the search terms "hepatotoxicity," "liver injury," "tumor necrosis factor," and the generic names of all TNF-alpha antagonists.
Among all patients, infliximab was most commonly the offending agent, followed by etanercept and adalimumab; no cases were attributed to natalizumab, golimumab, or certolizumab.
Diseases for which the anti-TNFs were prescribed included ankylosing spondylitis, Crohn’s disease, chronic ulcerative colitis, juvenile inflammatory arthritis, psoriatic arthritis, psoriasis, and rheumatoid arthritis.
First, Dr. Ghabril looked at the six patients from the DILIN database. Among these patients, the median duration of drug use before onset of liver injury was 16 weeks (range, 2-52 weeks).
"At presentation, half had jaundice, half had nausea, but only one had fever and none had immuno-allergic features of skin rash or eosinophilia," wrote the authors.
Only one of these patients developed significantly impaired coagulation, with an INR of 3.5, and none of the DILIN patients developed ascites or other signs of hepatic failure, they added.
The peak ALT ranged from 384 to 1,687 U/L, and the peak bilirubin from 1.5 to 27.7 mg/dL.
"Five of the six patients were treated with corticosteroids. One patient had a protracted illness, but all ultimately recovered and could be withdrawn from corticosteroid therapy without recurrence," they wrote.
Next, the authors turned their attention to the PubMed cases.
"Peak serum ALT ranged from 140 to 2,250 U/L and bilirubin from normal to 27.7 mg/dL," the authors reported.
Most patients (n = 22) had autoimmune serological markers and/or histological features at some point during the clinical course, they found.
Twelve patients stopped the drug and initiated corticosteroid therapy, oral or parenteral; all recovered. The rest improved after discontinuation of the anti-TNF, without steroid treatment, except for one patient who had underlying cirrhosis and required liver transplantation.
Notably, several patients were able to continue anti-TNF treatment with another agent without further incident, the authors wrote. Indeed, "three tolerated treatment with etanercept without recurrence of liver injury after cessation of infliximab or adalimumab. Two did well with adalimumab after [drug-induced liver injury] associated with infliximab, and one was successfully switched from adalimumab to abatacept."
Finally, the investigators contrasted patients with serological or histological autoimmune features with patients who lacked any autoimmune characteristics.
The autoimmune patients tended to have a longer latency period. The median period after the drug was initiated but before liver injury was noted was 16 weeks for the autoimmune patients versus 10 weeks for the nonautoimmune patients (P = .17). The autoimmune patients also had a higher peak ALT (median 784 vs. 528; P = .03).
"The mechanism by which the TNF-alpha antagonists lead to drug-induced liver injury is unknown," the authors wrote.
"Because the injury can occur after only one infusion, dose-dependent toxicity is unlikely. Unpredictable, idiosyncratic drug-induced liver injury seems most likely, as in this series no patients had clinical evidence of a rash or eosinophilia, and only one presented with fever."
"Further studies are needed to ascertain whether genetic or other markers of the hepatotoxicity associated with TNF-alpha antagonists can be identified," they said.
The DILIN database is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors reported having no conflicts of interest.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Major finding: Peak ALT levels ranged from 140 to 2,250 U/L among patients with liver injury secondary to tumor necrosis factor–alpha antagonists.
Data source: An analysis of 34 cases of liver injury from the literature and a liver-injury database.
Disclosures: The DILIN database is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors reported having no conflicts of interest.
Celiac disease patients protected from type 2 diabetes
Patients with celiac disease have a significantly lower prevalence of type 2 diabetes than do matched controls without celiac disease and the general population, Dr. Toufic A. Kabbani and his colleagues reported in a study published in the May issue of Gastroenterology.
Moreover, "the possible explanation that the lower rate of NIDDM [non–insulin-dependent diabetes mellitus] in individuals with celiac disease is due to different body mass index distribution is not supported by our study data, as the lower prevalence of NIDDM in celiac disease remains significant after controlling for BMI," they added.
| Source: American Gastroenterological Association |
Dr. Kabbani, of the Celiac Center at the Beth Israel Deaconess Medical Center, Boston, looked at the records of 840 adults with biopsy-proven celiac disease to determine the prevalence of type 2 diabetes or metabolic syndrome. The data were culled from the Celiac Center’s database.
Patients were matched by age, sex, and ethnicity to 840 controls without celiac disease chosen at random from a list of adults presenting to their primary medical provider for an annual checkup.
Patients were also compared with a cohort from the National Health and Nutrition Examination Survey (NHANES) population for reference.
According to the authors, both the celiac disease cohort and their matched counterparts were mainly white (88.9%) and female (72.5%).
Overall, 26 patients in the celiac group had type 2 diabetes (3.1%), compared with 81 controls (9.6%, P less than .0001) (Gastroenterology 2013 Jan. 28 [doi: 10.1053/j.gastro.2013.01.033]).
The prevalence of type 2 diabetes among celiac patients was also significantly lower than the estimated national prevalence derived from NHANES, which was 9.8% (P less than .0001).
Similarly, celiac patients recorded a significantly lower prevalence of metabolic syndrome than did controls (3.5% vs. 12.7%, P less than 0.0001).
Next, the authors conducted a multivariate analysis in which they controlled for BMI and smoking among celiac disease patients. The significantly negative association between celiac disease and type 2 diabetes persisted, with an odds ratio for diabetes among celiac patients of 0.49 (95% confidence interval, 0.29-0.83; P = .008).
"The mechanisms by which individuals with celiac disease are protected from NIDDM and metabolic syndrome are not clear at this time; however, possible explanations include altered pancreatic function, impaired nutrient absorption, and changes in gastrointestinal endocrine function," postulated the authors.
Alternatively, they wrote: "Tissue transglutaminase (tTG) drives inflammation in celiac disease via the down-regulation of peroxisome proliferator–activated receptor gamma (PPARG). On the other hand, PPARG up-regulation has been implicated in [type 2 diabetes] susceptibility.
"Therefore, the down-regulation of PPARG in celiac disease may be implicated in decreased risk of [type 2 diabetes]," the authors said.
Dr. Kabbani conceded that this study had several limitations. For one, most patients did not have an available waist circumference measurement, which is a criterion for metabolic syndrome, according to the International Diabetes Federation. As a proxy, the authors used a BMI of greater than 30 kg/m2. "While this might have affected the prevalence of metabolic syndrome in our study, we expect its impact on our analysis to be minor," they wrote.
Additionally, most celiac patients who started a gluten-free diet did not have endoscopic follow-up to assess intestinal healing.
However, "91.2% of these subjects had clinical improvement as well as normalization of their tTG titers, which increases the likelihood of histological improvement or remission."
None of the authors disclosed any financial conflicts relevant to this study. They disclosed no outside funding.
Patients with celiac disease have a significantly lower prevalence of type 2 diabetes than do matched controls without celiac disease and the general population, Dr. Toufic A. Kabbani and his colleagues reported in a study published in the May issue of Gastroenterology.
Moreover, "the possible explanation that the lower rate of NIDDM [non–insulin-dependent diabetes mellitus] in individuals with celiac disease is due to different body mass index distribution is not supported by our study data, as the lower prevalence of NIDDM in celiac disease remains significant after controlling for BMI," they added.
| Source: American Gastroenterological Association |
Dr. Kabbani, of the Celiac Center at the Beth Israel Deaconess Medical Center, Boston, looked at the records of 840 adults with biopsy-proven celiac disease to determine the prevalence of type 2 diabetes or metabolic syndrome. The data were culled from the Celiac Center’s database.
Patients were matched by age, sex, and ethnicity to 840 controls without celiac disease chosen at random from a list of adults presenting to their primary medical provider for an annual checkup.
Patients were also compared with a cohort from the National Health and Nutrition Examination Survey (NHANES) population for reference.
According to the authors, both the celiac disease cohort and their matched counterparts were mainly white (88.9%) and female (72.5%).
Overall, 26 patients in the celiac group had type 2 diabetes (3.1%), compared with 81 controls (9.6%, P less than .0001) (Gastroenterology 2013 Jan. 28 [doi: 10.1053/j.gastro.2013.01.033]).
The prevalence of type 2 diabetes among celiac patients was also significantly lower than the estimated national prevalence derived from NHANES, which was 9.8% (P less than .0001).
Similarly, celiac patients recorded a significantly lower prevalence of metabolic syndrome than did controls (3.5% vs. 12.7%, P less than 0.0001).
Next, the authors conducted a multivariate analysis in which they controlled for BMI and smoking among celiac disease patients. The significantly negative association between celiac disease and type 2 diabetes persisted, with an odds ratio for diabetes among celiac patients of 0.49 (95% confidence interval, 0.29-0.83; P = .008).
"The mechanisms by which individuals with celiac disease are protected from NIDDM and metabolic syndrome are not clear at this time; however, possible explanations include altered pancreatic function, impaired nutrient absorption, and changes in gastrointestinal endocrine function," postulated the authors.
Alternatively, they wrote: "Tissue transglutaminase (tTG) drives inflammation in celiac disease via the down-regulation of peroxisome proliferator–activated receptor gamma (PPARG). On the other hand, PPARG up-regulation has been implicated in [type 2 diabetes] susceptibility.
"Therefore, the down-regulation of PPARG in celiac disease may be implicated in decreased risk of [type 2 diabetes]," the authors said.
Dr. Kabbani conceded that this study had several limitations. For one, most patients did not have an available waist circumference measurement, which is a criterion for metabolic syndrome, according to the International Diabetes Federation. As a proxy, the authors used a BMI of greater than 30 kg/m2. "While this might have affected the prevalence of metabolic syndrome in our study, we expect its impact on our analysis to be minor," they wrote.
Additionally, most celiac patients who started a gluten-free diet did not have endoscopic follow-up to assess intestinal healing.
However, "91.2% of these subjects had clinical improvement as well as normalization of their tTG titers, which increases the likelihood of histological improvement or remission."
None of the authors disclosed any financial conflicts relevant to this study. They disclosed no outside funding.
Patients with celiac disease have a significantly lower prevalence of type 2 diabetes than do matched controls without celiac disease and the general population, Dr. Toufic A. Kabbani and his colleagues reported in a study published in the May issue of Gastroenterology.
Moreover, "the possible explanation that the lower rate of NIDDM [non–insulin-dependent diabetes mellitus] in individuals with celiac disease is due to different body mass index distribution is not supported by our study data, as the lower prevalence of NIDDM in celiac disease remains significant after controlling for BMI," they added.
| Source: American Gastroenterological Association |
Dr. Kabbani, of the Celiac Center at the Beth Israel Deaconess Medical Center, Boston, looked at the records of 840 adults with biopsy-proven celiac disease to determine the prevalence of type 2 diabetes or metabolic syndrome. The data were culled from the Celiac Center’s database.
Patients were matched by age, sex, and ethnicity to 840 controls without celiac disease chosen at random from a list of adults presenting to their primary medical provider for an annual checkup.
Patients were also compared with a cohort from the National Health and Nutrition Examination Survey (NHANES) population for reference.
According to the authors, both the celiac disease cohort and their matched counterparts were mainly white (88.9%) and female (72.5%).
Overall, 26 patients in the celiac group had type 2 diabetes (3.1%), compared with 81 controls (9.6%, P less than .0001) (Gastroenterology 2013 Jan. 28 [doi: 10.1053/j.gastro.2013.01.033]).
The prevalence of type 2 diabetes among celiac patients was also significantly lower than the estimated national prevalence derived from NHANES, which was 9.8% (P less than .0001).
Similarly, celiac patients recorded a significantly lower prevalence of metabolic syndrome than did controls (3.5% vs. 12.7%, P less than 0.0001).
Next, the authors conducted a multivariate analysis in which they controlled for BMI and smoking among celiac disease patients. The significantly negative association between celiac disease and type 2 diabetes persisted, with an odds ratio for diabetes among celiac patients of 0.49 (95% confidence interval, 0.29-0.83; P = .008).
"The mechanisms by which individuals with celiac disease are protected from NIDDM and metabolic syndrome are not clear at this time; however, possible explanations include altered pancreatic function, impaired nutrient absorption, and changes in gastrointestinal endocrine function," postulated the authors.
Alternatively, they wrote: "Tissue transglutaminase (tTG) drives inflammation in celiac disease via the down-regulation of peroxisome proliferator–activated receptor gamma (PPARG). On the other hand, PPARG up-regulation has been implicated in [type 2 diabetes] susceptibility.
"Therefore, the down-regulation of PPARG in celiac disease may be implicated in decreased risk of [type 2 diabetes]," the authors said.
Dr. Kabbani conceded that this study had several limitations. For one, most patients did not have an available waist circumference measurement, which is a criterion for metabolic syndrome, according to the International Diabetes Federation. As a proxy, the authors used a BMI of greater than 30 kg/m2. "While this might have affected the prevalence of metabolic syndrome in our study, we expect its impact on our analysis to be minor," they wrote.
Additionally, most celiac patients who started a gluten-free diet did not have endoscopic follow-up to assess intestinal healing.
However, "91.2% of these subjects had clinical improvement as well as normalization of their tTG titers, which increases the likelihood of histological improvement or remission."
None of the authors disclosed any financial conflicts relevant to this study. They disclosed no outside funding.
FROM GASTROENTEROLOGY
Major finding: The prevalence of type 2 diabetes among celiac disease patients was 3.1%, compared with 9.6% among control patients without celiac disease matched for age, sex, and ethnicity (P less than .0001).
Data source: A prevalence study of 840 patients with celiac disease and 840 matched controls.
Disclosures: None of the authors disclosed any financial conflicts relevant to this study. They disclosed no outside funding.
Concurrent NSAID, PPI use tapers over long term
Among chronic nonsteroidal anti-inflammatory patients at high risk for a gastrointestinal bleeding, only two-thirds continue to be prescribed a proton pump inhibitor after 2 years.
Moreover, patients whose PPI prescriptions were discontinued were significantly more likely to experience a GI adverse event, compared with patients who had continuous NSAID and PPI coprescription, wrote Dr. Isabelle Le Ray and colleagues. The report was published in the May issue of Clinical Gastroenterology and Hepatology (doi:10.1016/j.cgh.2012.12.016).
Dr. Le Ray, of the Centre Hospitalier Universitaire de Dijon, France, and colleagues looked at records from the Longitudinal Patient Database, which collects data from a representative sample of 1,200 general practitioners in France.
Specifically, Dr. Le Ray focused on high-risk patients within the database who received a prescription for an NSAID for more than 7 days in 2007 plus a PPI, who renewed their NSAID within 6 months following the last prescription over a 2-year period.
Patients were considered to be high risk for a GI bleed if they were aged 65 years or older, had a history of upper GI disease, a co-prescription with an anticoagulant or antiplatelet medication, a previous bleed, and other comorbid conditions like rheumatoid arthritis.
A total of 1,856 patients met the criteria; most (74.4%) were over age 65, and 63.8% were female.
Although more than 14 different NSAIDs were prescribed, diclofenac, ketoprofen, piroxicam, and celecoxib accounted for the bulk of prescriptions. The median number of NSAID renewals during the 2-year period was 8, with a median of 30 days duration for each prescription.
According to the authors, at 12 months after initial NSAID/PPI prescription, the persistence probability of still having an active PPI prescription fell to 0.77(95% confidence interval, 0.75-0.79).
By 2 years, that likelihood fell to 0.68 (95% CI, 0.66-0.70).
The authors then looked at the presence of GI adverse events in this cohort. They found that 379 patients experienced an event, with patients who were not persistently prescribed a PPI at significantly higher risk, compared with patients whose PPI prescriptions never lapsed (odds ratio = 1.45; 95% CI, 1.06-2.09, P = .02).
"Absolute risk reduction associated with a continuous prescription of PPI with NSAIDs, in at-risk patients, was 3.2%," wrote the authors.
According to the researchers, factors associated with discontinuing a PPI included change from a given NSAID to a COX-2 inhibitor (multivariate hazard ratio for PPI discontinuation, 2.50; 95% CI, 1.91-3.28), despite the fact that "international guidelines recommend coprescription of a PPI for at-risk patients, even when using a COX-2 selective agent."
Being female also carried a high risk of stopping PPI treatment, (HR 1.25; 95%CI 1.05-1.49), while having multiple prescriptions for other drugs decreased the risk of PPI discontinuation (HR for stopping PPI 0.94 for each additional treatment; 95% CI, 0.91-0.96).
The study represents "the first time that the persistence of a prescription, i.e. systematic renewal of the [gastroprotective agent, the PPI] when the NSAID is being renewed, over time is characterized," the researchers said.
"These data suggest that the optimizing of [gastroprotective agent] coverage, mostly with a PPI, remains a major health issue among chronic NSAID users," they added.
The authors disclosed that this study was funded by the pharmaceutical company Ethypharm, for which one investigator is also an employee and another has served as a paid consultant. They added that this paper discusses no medications manufactured by Ethypharm.
Factors increasing the risk for upper GI complications in NSAID users include older age (>60-75 years); prior upper GI complications or symptomatic ulcers; and concurrent use of aspirin, other antithrombotics, or corticosteroids. If patients cannot be switched to a non-NSAID analgesic, strategies recommended to decrease GI risk include PPI (or misoprostol) cotherapy or substitution of a COX-2 selective NSAID. Patients at very high risk (e.g., recent ulcer bleeding) should receive a COX-2 selective NSAID plus PPI (or misoprostol).
However, multiple observational studies demonstrate that most NSAID users with GI risk factors do not receive protective therapy. Importantly, adherence to a PPI more than 80% of the time is associated with significantly fewer upper GI clinical events than adherence less than 80% and less than 20% of the time.
The study by Le Ray et al looks at a group of NSAID users in whom a decision to provide a PPI prescription has been made. Co-therapy was stopped in 23% of patients at 1 year and 32% at 2 years. The authors correctly indicate that these patients likely are at increased risk. However, the rate of discontinuation was less than might have been anticipated (and less than in another European study), and half those discontinuing PPIs resumed them within 6 months. Furthermore, a number of patients had characteristics for which protective therapy is not generally recommended: e.g., heart disease, rheumatoid arthritis, dyspepsia, and celecoxib use.
Finally, the authors report that lack of PPI prescription was associated with increased GI “adverse events,” “injury,” and “complications.” We should note, however, that these “events” were primarily symptoms rather than complications or clinical events.
Loren Laine, M.D., AGAF, is a professor of medicine (digestive diseases) at Yale University, New Haven, Conn., and the Veterans Affairs Connecticut Healthcare System, West Haven. He also is the current president of the AGA Institute. He reported that he is a member of data safety monitoring boards on studies sponsored by Bayer, Eisai, Merck.
Factors increasing the risk for upper GI complications in NSAID users include older age (>60-75 years); prior upper GI complications or symptomatic ulcers; and concurrent use of aspirin, other antithrombotics, or corticosteroids. If patients cannot be switched to a non-NSAID analgesic, strategies recommended to decrease GI risk include PPI (or misoprostol) cotherapy or substitution of a COX-2 selective NSAID. Patients at very high risk (e.g., recent ulcer bleeding) should receive a COX-2 selective NSAID plus PPI (or misoprostol).
However, multiple observational studies demonstrate that most NSAID users with GI risk factors do not receive protective therapy. Importantly, adherence to a PPI more than 80% of the time is associated with significantly fewer upper GI clinical events than adherence less than 80% and less than 20% of the time.
The study by Le Ray et al looks at a group of NSAID users in whom a decision to provide a PPI prescription has been made. Co-therapy was stopped in 23% of patients at 1 year and 32% at 2 years. The authors correctly indicate that these patients likely are at increased risk. However, the rate of discontinuation was less than might have been anticipated (and less than in another European study), and half those discontinuing PPIs resumed them within 6 months. Furthermore, a number of patients had characteristics for which protective therapy is not generally recommended: e.g., heart disease, rheumatoid arthritis, dyspepsia, and celecoxib use.
Finally, the authors report that lack of PPI prescription was associated with increased GI “adverse events,” “injury,” and “complications.” We should note, however, that these “events” were primarily symptoms rather than complications or clinical events.
Loren Laine, M.D., AGAF, is a professor of medicine (digestive diseases) at Yale University, New Haven, Conn., and the Veterans Affairs Connecticut Healthcare System, West Haven. He also is the current president of the AGA Institute. He reported that he is a member of data safety monitoring boards on studies sponsored by Bayer, Eisai, Merck.
Factors increasing the risk for upper GI complications in NSAID users include older age (>60-75 years); prior upper GI complications or symptomatic ulcers; and concurrent use of aspirin, other antithrombotics, or corticosteroids. If patients cannot be switched to a non-NSAID analgesic, strategies recommended to decrease GI risk include PPI (or misoprostol) cotherapy or substitution of a COX-2 selective NSAID. Patients at very high risk (e.g., recent ulcer bleeding) should receive a COX-2 selective NSAID plus PPI (or misoprostol).
However, multiple observational studies demonstrate that most NSAID users with GI risk factors do not receive protective therapy. Importantly, adherence to a PPI more than 80% of the time is associated with significantly fewer upper GI clinical events than adherence less than 80% and less than 20% of the time.
The study by Le Ray et al looks at a group of NSAID users in whom a decision to provide a PPI prescription has been made. Co-therapy was stopped in 23% of patients at 1 year and 32% at 2 years. The authors correctly indicate that these patients likely are at increased risk. However, the rate of discontinuation was less than might have been anticipated (and less than in another European study), and half those discontinuing PPIs resumed them within 6 months. Furthermore, a number of patients had characteristics for which protective therapy is not generally recommended: e.g., heart disease, rheumatoid arthritis, dyspepsia, and celecoxib use.
Finally, the authors report that lack of PPI prescription was associated with increased GI “adverse events,” “injury,” and “complications.” We should note, however, that these “events” were primarily symptoms rather than complications or clinical events.
Loren Laine, M.D., AGAF, is a professor of medicine (digestive diseases) at Yale University, New Haven, Conn., and the Veterans Affairs Connecticut Healthcare System, West Haven. He also is the current president of the AGA Institute. He reported that he is a member of data safety monitoring boards on studies sponsored by Bayer, Eisai, Merck.
Among chronic nonsteroidal anti-inflammatory patients at high risk for a gastrointestinal bleeding, only two-thirds continue to be prescribed a proton pump inhibitor after 2 years.
Moreover, patients whose PPI prescriptions were discontinued were significantly more likely to experience a GI adverse event, compared with patients who had continuous NSAID and PPI coprescription, wrote Dr. Isabelle Le Ray and colleagues. The report was published in the May issue of Clinical Gastroenterology and Hepatology (doi:10.1016/j.cgh.2012.12.016).
Dr. Le Ray, of the Centre Hospitalier Universitaire de Dijon, France, and colleagues looked at records from the Longitudinal Patient Database, which collects data from a representative sample of 1,200 general practitioners in France.
Specifically, Dr. Le Ray focused on high-risk patients within the database who received a prescription for an NSAID for more than 7 days in 2007 plus a PPI, who renewed their NSAID within 6 months following the last prescription over a 2-year period.
Patients were considered to be high risk for a GI bleed if they were aged 65 years or older, had a history of upper GI disease, a co-prescription with an anticoagulant or antiplatelet medication, a previous bleed, and other comorbid conditions like rheumatoid arthritis.
A total of 1,856 patients met the criteria; most (74.4%) were over age 65, and 63.8% were female.
Although more than 14 different NSAIDs were prescribed, diclofenac, ketoprofen, piroxicam, and celecoxib accounted for the bulk of prescriptions. The median number of NSAID renewals during the 2-year period was 8, with a median of 30 days duration for each prescription.
According to the authors, at 12 months after initial NSAID/PPI prescription, the persistence probability of still having an active PPI prescription fell to 0.77(95% confidence interval, 0.75-0.79).
By 2 years, that likelihood fell to 0.68 (95% CI, 0.66-0.70).
The authors then looked at the presence of GI adverse events in this cohort. They found that 379 patients experienced an event, with patients who were not persistently prescribed a PPI at significantly higher risk, compared with patients whose PPI prescriptions never lapsed (odds ratio = 1.45; 95% CI, 1.06-2.09, P = .02).
"Absolute risk reduction associated with a continuous prescription of PPI with NSAIDs, in at-risk patients, was 3.2%," wrote the authors.
According to the researchers, factors associated with discontinuing a PPI included change from a given NSAID to a COX-2 inhibitor (multivariate hazard ratio for PPI discontinuation, 2.50; 95% CI, 1.91-3.28), despite the fact that "international guidelines recommend coprescription of a PPI for at-risk patients, even when using a COX-2 selective agent."
Being female also carried a high risk of stopping PPI treatment, (HR 1.25; 95%CI 1.05-1.49), while having multiple prescriptions for other drugs decreased the risk of PPI discontinuation (HR for stopping PPI 0.94 for each additional treatment; 95% CI, 0.91-0.96).
The study represents "the first time that the persistence of a prescription, i.e. systematic renewal of the [gastroprotective agent, the PPI] when the NSAID is being renewed, over time is characterized," the researchers said.
"These data suggest that the optimizing of [gastroprotective agent] coverage, mostly with a PPI, remains a major health issue among chronic NSAID users," they added.
The authors disclosed that this study was funded by the pharmaceutical company Ethypharm, for which one investigator is also an employee and another has served as a paid consultant. They added that this paper discusses no medications manufactured by Ethypharm.
Among chronic nonsteroidal anti-inflammatory patients at high risk for a gastrointestinal bleeding, only two-thirds continue to be prescribed a proton pump inhibitor after 2 years.
Moreover, patients whose PPI prescriptions were discontinued were significantly more likely to experience a GI adverse event, compared with patients who had continuous NSAID and PPI coprescription, wrote Dr. Isabelle Le Ray and colleagues. The report was published in the May issue of Clinical Gastroenterology and Hepatology (doi:10.1016/j.cgh.2012.12.016).
Dr. Le Ray, of the Centre Hospitalier Universitaire de Dijon, France, and colleagues looked at records from the Longitudinal Patient Database, which collects data from a representative sample of 1,200 general practitioners in France.
Specifically, Dr. Le Ray focused on high-risk patients within the database who received a prescription for an NSAID for more than 7 days in 2007 plus a PPI, who renewed their NSAID within 6 months following the last prescription over a 2-year period.
Patients were considered to be high risk for a GI bleed if they were aged 65 years or older, had a history of upper GI disease, a co-prescription with an anticoagulant or antiplatelet medication, a previous bleed, and other comorbid conditions like rheumatoid arthritis.
A total of 1,856 patients met the criteria; most (74.4%) were over age 65, and 63.8% were female.
Although more than 14 different NSAIDs were prescribed, diclofenac, ketoprofen, piroxicam, and celecoxib accounted for the bulk of prescriptions. The median number of NSAID renewals during the 2-year period was 8, with a median of 30 days duration for each prescription.
According to the authors, at 12 months after initial NSAID/PPI prescription, the persistence probability of still having an active PPI prescription fell to 0.77(95% confidence interval, 0.75-0.79).
By 2 years, that likelihood fell to 0.68 (95% CI, 0.66-0.70).
The authors then looked at the presence of GI adverse events in this cohort. They found that 379 patients experienced an event, with patients who were not persistently prescribed a PPI at significantly higher risk, compared with patients whose PPI prescriptions never lapsed (odds ratio = 1.45; 95% CI, 1.06-2.09, P = .02).
"Absolute risk reduction associated with a continuous prescription of PPI with NSAIDs, in at-risk patients, was 3.2%," wrote the authors.
According to the researchers, factors associated with discontinuing a PPI included change from a given NSAID to a COX-2 inhibitor (multivariate hazard ratio for PPI discontinuation, 2.50; 95% CI, 1.91-3.28), despite the fact that "international guidelines recommend coprescription of a PPI for at-risk patients, even when using a COX-2 selective agent."
Being female also carried a high risk of stopping PPI treatment, (HR 1.25; 95%CI 1.05-1.49), while having multiple prescriptions for other drugs decreased the risk of PPI discontinuation (HR for stopping PPI 0.94 for each additional treatment; 95% CI, 0.91-0.96).
The study represents "the first time that the persistence of a prescription, i.e. systematic renewal of the [gastroprotective agent, the PPI] when the NSAID is being renewed, over time is characterized," the researchers said.
"These data suggest that the optimizing of [gastroprotective agent] coverage, mostly with a PPI, remains a major health issue among chronic NSAID users," they added.
The authors disclosed that this study was funded by the pharmaceutical company Ethypharm, for which one investigator is also an employee and another has served as a paid consultant. They added that this paper discusses no medications manufactured by Ethypharm.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Major finding: By 24 months after initial NSAID/PPI coprescription, the persistence probability of still having an active PPI prescription fell to 0.68 (95% CI, 0.66-0.70).
Data source: A retrospective, observational, longitudinal study of 1,856 patients in France at risk for GI events.
Disclosures: The authors disclosed that this study was funded by the pharmaceutical company Ethypharm, for which one investigator is also an employee and another has served as a paid consultant. They added that this paper discusses no medications manufactured by Ethypharm.
MR colonography has utility in high-risk lesions
Magnetic resonance colonography identified asymptomatic adults with adenomas of 6 mm or larger and advanced adenomas with sensitivities of 78.4% and 75%, respectively.
"If primary screening by colonoscopy is not performed, MR colonography appears to be a better option than a one-time fecal occult blood test" for detecting high-risk lesions, without the radiation associated with computed tomography, reported Dr. Anno Graser and his colleagues in the April 1 issue of Gastroenterology (doi: 10.1053/j.gastro.2012.12.041).
Dr. Graser of the University of Munich and his colleagues looked at 286 asymptomatic adults aged 50 years or older with an average risk of colorectal cancer and asymptomatic adults aged 40 years or older with a family history of colorectal cancer (175 men; mean age, 59 years).
Patients were excluded if they had any prior colonoscopy, symptoms or history of bowel disease, significant weight loss, body weight greater than 150 kg, relevant cardiovascular or pulmonary comorbidity, or contraindications to MR scanning.
All patients underwent fecal occult blood testing prior to bowel preparation, and then underwent both colonoscopy and MR colonography on the same day.
Overall, colonoscopy detected 281 luminal lesions, including one adenocarcinoma of the rectum, one squamous cell carcinoma of the anal canal, and 133 adenomas in 85 patients, including 20 advanced adenomas in 17 patients. There were also 129 hyperplastic polyps detected on colonoscopy, as well as 17 other benign lesions.
MR colonography, on the other hand, detected the two cancers, as well as 43 (32.3%) adenomas, including 29 (78.4%) adenomas of 6 mm or greater.
MR colonography also detected 15 (75%) advanced adenomas and 11 (8.5%) hyperplastic polyps.
"There were no complications in either the MR colonographies or the colonoscopies," wrote the authors.
In contrast, fecal occult blood testing found just 3 of 30 patients (10%) with adenomas of 6 mm or greater and 3 of 17 patients (17.6%) with advanced neoplasia.
MR colonography also identified several "potentially important extracolonic findings" in eight (2.8%) patients: three patients with renal masses; two with bulky retroperitoneal lymphadenopathy "representing manifestations of a newly diagnosed diffuse large-cell lymphoma and a chronic lymphatic leukemia, respectively"; one with a serous cystadenoma of the pancreas; and two with aortic aneurysms greater than 5 cm, the authors reported.
In terms of specificity, for adenomas 6 mm or larger, the specificity was 96.9% for colonoscopy, 95.3% for MR colonography, and 91.8% for fecal occult blood testing.
Similarly, for advanced neoplasia the figures were 48.5%, 81.0%, and 92.2% for colonoscopy, MR colonography, and fecal occult blood testing, respectively.
The authors also compared MR colonography in their study to previous studies of CT colonography, which has been shown to have a sensitivity for advanced neoplasia of 96% (Gut 2009;58:241-8).
"Still, the major advantage of MR colonography over CT colonography is that it does not apply ionizing radiation," wrote the authors.
There are several limitations to the technique, the authors said. For one, MR colonography requires gadolinium-based intravenous contrast. However, except for patients with impaired renal function, this is usually well tolerated.
MR colonography has a limited sensitivity for lesions of 5 mm or less, because of the technique’s limited spatial resolution and lack of significant enhancement of diminutive polyps.
However, "as these lesions only carry a low risk of malignancy, this limitation of MR colonography may not impair its potential use as a screening tool."
Finally, "in the light of cost-effectiveness discussions, MR colonography as a relatively expensive test has to be weighed carefully against the cost of colonoscopy," wrote the researchers.
The authors declared that they had no relevant financial conflicts and that the study had no outside funding.
Magnetic resonance colonography identified asymptomatic adults with adenomas of 6 mm or larger and advanced adenomas with sensitivities of 78.4% and 75%, respectively.
"If primary screening by colonoscopy is not performed, MR colonography appears to be a better option than a one-time fecal occult blood test" for detecting high-risk lesions, without the radiation associated with computed tomography, reported Dr. Anno Graser and his colleagues in the April 1 issue of Gastroenterology (doi: 10.1053/j.gastro.2012.12.041).
Dr. Graser of the University of Munich and his colleagues looked at 286 asymptomatic adults aged 50 years or older with an average risk of colorectal cancer and asymptomatic adults aged 40 years or older with a family history of colorectal cancer (175 men; mean age, 59 years).
Patients were excluded if they had any prior colonoscopy, symptoms or history of bowel disease, significant weight loss, body weight greater than 150 kg, relevant cardiovascular or pulmonary comorbidity, or contraindications to MR scanning.
All patients underwent fecal occult blood testing prior to bowel preparation, and then underwent both colonoscopy and MR colonography on the same day.
Overall, colonoscopy detected 281 luminal lesions, including one adenocarcinoma of the rectum, one squamous cell carcinoma of the anal canal, and 133 adenomas in 85 patients, including 20 advanced adenomas in 17 patients. There were also 129 hyperplastic polyps detected on colonoscopy, as well as 17 other benign lesions.
MR colonography, on the other hand, detected the two cancers, as well as 43 (32.3%) adenomas, including 29 (78.4%) adenomas of 6 mm or greater.
MR colonography also detected 15 (75%) advanced adenomas and 11 (8.5%) hyperplastic polyps.
"There were no complications in either the MR colonographies or the colonoscopies," wrote the authors.
In contrast, fecal occult blood testing found just 3 of 30 patients (10%) with adenomas of 6 mm or greater and 3 of 17 patients (17.6%) with advanced neoplasia.
MR colonography also identified several "potentially important extracolonic findings" in eight (2.8%) patients: three patients with renal masses; two with bulky retroperitoneal lymphadenopathy "representing manifestations of a newly diagnosed diffuse large-cell lymphoma and a chronic lymphatic leukemia, respectively"; one with a serous cystadenoma of the pancreas; and two with aortic aneurysms greater than 5 cm, the authors reported.
In terms of specificity, for adenomas 6 mm or larger, the specificity was 96.9% for colonoscopy, 95.3% for MR colonography, and 91.8% for fecal occult blood testing.
Similarly, for advanced neoplasia the figures were 48.5%, 81.0%, and 92.2% for colonoscopy, MR colonography, and fecal occult blood testing, respectively.
The authors also compared MR colonography in their study to previous studies of CT colonography, which has been shown to have a sensitivity for advanced neoplasia of 96% (Gut 2009;58:241-8).
"Still, the major advantage of MR colonography over CT colonography is that it does not apply ionizing radiation," wrote the authors.
There are several limitations to the technique, the authors said. For one, MR colonography requires gadolinium-based intravenous contrast. However, except for patients with impaired renal function, this is usually well tolerated.
MR colonography has a limited sensitivity for lesions of 5 mm or less, because of the technique’s limited spatial resolution and lack of significant enhancement of diminutive polyps.
However, "as these lesions only carry a low risk of malignancy, this limitation of MR colonography may not impair its potential use as a screening tool."
Finally, "in the light of cost-effectiveness discussions, MR colonography as a relatively expensive test has to be weighed carefully against the cost of colonoscopy," wrote the researchers.
The authors declared that they had no relevant financial conflicts and that the study had no outside funding.
Magnetic resonance colonography identified asymptomatic adults with adenomas of 6 mm or larger and advanced adenomas with sensitivities of 78.4% and 75%, respectively.
"If primary screening by colonoscopy is not performed, MR colonography appears to be a better option than a one-time fecal occult blood test" for detecting high-risk lesions, without the radiation associated with computed tomography, reported Dr. Anno Graser and his colleagues in the April 1 issue of Gastroenterology (doi: 10.1053/j.gastro.2012.12.041).
Dr. Graser of the University of Munich and his colleagues looked at 286 asymptomatic adults aged 50 years or older with an average risk of colorectal cancer and asymptomatic adults aged 40 years or older with a family history of colorectal cancer (175 men; mean age, 59 years).
Patients were excluded if they had any prior colonoscopy, symptoms or history of bowel disease, significant weight loss, body weight greater than 150 kg, relevant cardiovascular or pulmonary comorbidity, or contraindications to MR scanning.
All patients underwent fecal occult blood testing prior to bowel preparation, and then underwent both colonoscopy and MR colonography on the same day.
Overall, colonoscopy detected 281 luminal lesions, including one adenocarcinoma of the rectum, one squamous cell carcinoma of the anal canal, and 133 adenomas in 85 patients, including 20 advanced adenomas in 17 patients. There were also 129 hyperplastic polyps detected on colonoscopy, as well as 17 other benign lesions.
MR colonography, on the other hand, detected the two cancers, as well as 43 (32.3%) adenomas, including 29 (78.4%) adenomas of 6 mm or greater.
MR colonography also detected 15 (75%) advanced adenomas and 11 (8.5%) hyperplastic polyps.
"There were no complications in either the MR colonographies or the colonoscopies," wrote the authors.
In contrast, fecal occult blood testing found just 3 of 30 patients (10%) with adenomas of 6 mm or greater and 3 of 17 patients (17.6%) with advanced neoplasia.
MR colonography also identified several "potentially important extracolonic findings" in eight (2.8%) patients: three patients with renal masses; two with bulky retroperitoneal lymphadenopathy "representing manifestations of a newly diagnosed diffuse large-cell lymphoma and a chronic lymphatic leukemia, respectively"; one with a serous cystadenoma of the pancreas; and two with aortic aneurysms greater than 5 cm, the authors reported.
In terms of specificity, for adenomas 6 mm or larger, the specificity was 96.9% for colonoscopy, 95.3% for MR colonography, and 91.8% for fecal occult blood testing.
Similarly, for advanced neoplasia the figures were 48.5%, 81.0%, and 92.2% for colonoscopy, MR colonography, and fecal occult blood testing, respectively.
The authors also compared MR colonography in their study to previous studies of CT colonography, which has been shown to have a sensitivity for advanced neoplasia of 96% (Gut 2009;58:241-8).
"Still, the major advantage of MR colonography over CT colonography is that it does not apply ionizing radiation," wrote the authors.
There are several limitations to the technique, the authors said. For one, MR colonography requires gadolinium-based intravenous contrast. However, except for patients with impaired renal function, this is usually well tolerated.
MR colonography has a limited sensitivity for lesions of 5 mm or less, because of the technique’s limited spatial resolution and lack of significant enhancement of diminutive polyps.
However, "as these lesions only carry a low risk of malignancy, this limitation of MR colonography may not impair its potential use as a screening tool."
Finally, "in the light of cost-effectiveness discussions, MR colonography as a relatively expensive test has to be weighed carefully against the cost of colonoscopy," wrote the researchers.
The authors declared that they had no relevant financial conflicts and that the study had no outside funding.
FROM GASTROENTEROLOGY
Major finding: Magnetic resonance colonography had a sensitivity of 78.4% for detecting adenomas greater than or equal to 6 mm.
Data source: A blinded study of 286 asymptomatic adults undergoing magnetic resonance colonography and colonoscopy on the same day.
Disclosures: The authors declared that they had no relevant financial conflicts and that the study had no outside funding.
PPIs lower progression risk in Barrett's esophagus
Proton pump inhibitor use was associated with a greater than 75% reduction in the risk of neoplastic progression in Barrett’s esophagus.
Indeed, despite the "considerable costs" of these drugs, "prolonged PPI use is ... justified and feasible in Barrett’s patients and should be strongly recommended, in particular in guidelines," concluded Dr. Florine Kastelein in the April 1 issue of Clinical Gastroenterology and Hepatology (doi:10.1016/j.cgh.2012.11.014).
In what they called "the first methodological[ly] sound prospective study which shows that PPIs strongly reduce the risk of neoplastic progression in BE," Dr. Kastelein of Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues looked at 540 patients with known or newly diagnosed endoscopic Barrett’s esophagus (BE) confirmed by intestinal metaplasia.
Patients had a median age of 60.5 years at inclusion and were followed for a median of 5.2 years; 71% were male.
All patients were recruited from multiple academic and regional hospitals across the Netherlands, and patients were excluded if they had Barrett’s esophagus shorter than 2 cm, prior antireflux surgery, or a history of high-grade dysplasia or esophageal adenocarcinoma.
Patients with neoplastic progression found within the first 9 months after study inclusion also were ultimately excluded "since high-grade dysplasia or esophageal adenocarcinoma may be missed at index endoscopy in these patients," the investigators said.
Surveillance was performed according to the guidelines of the American College of Gastroenterology, such that patients without dysplasia underwent gastroscopy with biopsy sampling every 3 years and patients with low-grade dysplasia underwent it every year.
Overall, at inclusion in the study, 462 (85%) patients had used a PPI for a median duration of 4.0 years.
Dr. Kastelien and her associates found that, during follow-up, 28 patients developed high-grade dysplasia and another 12 developed esophageal adenocarcinoma, for a combined annual incidence of 1.6%.
"PPI use at inclusion was associated with a reduced risk of neoplastic progression (hazard ratio, 0.43; 95% confidence interval: 0.21-0.88) and remained associated with a trend toward a protective effect after adjusting for age, gender, time of BE diagnosis, BE length, esophagitis histology, and use of other medications (HR, 0.47; 95% CI: 0.19-1.18)," the researchers wrote.
Moreover, among the 99% of patients who used a PPI at any time during follow-up (median, 5.1 years), time-dependent analysis revealed that PPI use was associated with a reduced risk of neoplastic progression (HR, 0.15; 95% CI: 0.06-0.40) and remained so after adjusting for age, gender, BE length, histology, baseline PPI use, and use of other medications (HR, 0.21; 95% CI: 0.07-0.66).
The authors found no significant difference between neoplastic progression and the various PPIs assessed in this study (including esomeprazole and pantoprazole as well as omeprazole, rabeprazole, and lansoprazole).
According to Dr. Kastelein and her associates, the study is actually limited by the incredibly high rate of compliance among its population.
"Despite the large sample size, only eight (2%) patients never used a PPI and 18 (3%) patients used a PPI during [only] a part of their follow-up period," they wrote.
"Although this reflects clinical practice in Western countries and is representative for a disease in which patients seek to avoid reflux symptoms, it limits the options for investigating the effect of PPIs," they added.
However, "because not all patients used PPIs throughout their entire follow-up period, we were able to perform time-dependent analyses."
|
| Dr. Nicholas J. Shaheen |
Kastelein and colleagues provide the best data yet in support of this approach. PPI use in their observational study was associated with a substantial risk reduction in cancer and high-grade dysplasia, both at study enrollment and in follow-up.
This is far-from-perfect evidence of a protective effect of PPIs in Barrett’s. As the authors recognize, there are several substantial issues limiting the study’s generalizability. The few patients who were not on a PPI may differ substantially from the rest in multiple unmeasurable ways. Also, to the credit of the Dutch health care system, 99% of Barrett’s patients were on PPIs for at least part of the follow-up, and 97% of total follow-up time was spent on PPIs. Therefore, the investigators had few non-PPI years to assess. In fact, the entire study really hinges on 12 years of non-PPI follow-up in subjects destined to go on to high-grade dysplasia/cancer.
Despite these limitations, this prospective study is the best to date, and may be the best we see on this topic. Given the weight of the observational data supporting PPI use in Barrett’s, a randomized controlled trial of PPIs versus placebo as an antineoplastic measure in Barrett’s will not likely be undertaken. Given the risk-benefit ratio, we should continue to promote PPI use in our Barrett’s patients, while acknowledging the less-than-perfect evidence underpinning this recommendation.
Nicholas J. Shaheen, M.D., MPH, AGAF, is professor of medicine and epidemiology, director of the Center for Esophageal Diseases and Swallowing, at the University of North Carolina School of Medicine, Chapel Hill. He receives or has received research funding from Takeda Pharmaceuticals, AstraZeneca, and Shire.
|
|
| Dr. Nicholas J. Shaheen |
Kastelein and colleagues provide the best data yet in support of this approach. PPI use in their observational study was associated with a substantial risk reduction in cancer and high-grade dysplasia, both at study enrollment and in follow-up.
This is far-from-perfect evidence of a protective effect of PPIs in Barrett’s. As the authors recognize, there are several substantial issues limiting the study’s generalizability. The few patients who were not on a PPI may differ substantially from the rest in multiple unmeasurable ways. Also, to the credit of the Dutch health care system, 99% of Barrett’s patients were on PPIs for at least part of the follow-up, and 97% of total follow-up time was spent on PPIs. Therefore, the investigators had few non-PPI years to assess. In fact, the entire study really hinges on 12 years of non-PPI follow-up in subjects destined to go on to high-grade dysplasia/cancer.
Despite these limitations, this prospective study is the best to date, and may be the best we see on this topic. Given the weight of the observational data supporting PPI use in Barrett’s, a randomized controlled trial of PPIs versus placebo as an antineoplastic measure in Barrett’s will not likely be undertaken. Given the risk-benefit ratio, we should continue to promote PPI use in our Barrett’s patients, while acknowledging the less-than-perfect evidence underpinning this recommendation.
Nicholas J. Shaheen, M.D., MPH, AGAF, is professor of medicine and epidemiology, director of the Center for Esophageal Diseases and Swallowing, at the University of North Carolina School of Medicine, Chapel Hill. He receives or has received research funding from Takeda Pharmaceuticals, AstraZeneca, and Shire.
|
|
| Dr. Nicholas J. Shaheen |
Kastelein and colleagues provide the best data yet in support of this approach. PPI use in their observational study was associated with a substantial risk reduction in cancer and high-grade dysplasia, both at study enrollment and in follow-up.
This is far-from-perfect evidence of a protective effect of PPIs in Barrett’s. As the authors recognize, there are several substantial issues limiting the study’s generalizability. The few patients who were not on a PPI may differ substantially from the rest in multiple unmeasurable ways. Also, to the credit of the Dutch health care system, 99% of Barrett’s patients were on PPIs for at least part of the follow-up, and 97% of total follow-up time was spent on PPIs. Therefore, the investigators had few non-PPI years to assess. In fact, the entire study really hinges on 12 years of non-PPI follow-up in subjects destined to go on to high-grade dysplasia/cancer.
Despite these limitations, this prospective study is the best to date, and may be the best we see on this topic. Given the weight of the observational data supporting PPI use in Barrett’s, a randomized controlled trial of PPIs versus placebo as an antineoplastic measure in Barrett’s will not likely be undertaken. Given the risk-benefit ratio, we should continue to promote PPI use in our Barrett’s patients, while acknowledging the less-than-perfect evidence underpinning this recommendation.
Nicholas J. Shaheen, M.D., MPH, AGAF, is professor of medicine and epidemiology, director of the Center for Esophageal Diseases and Swallowing, at the University of North Carolina School of Medicine, Chapel Hill. He receives or has received research funding from Takeda Pharmaceuticals, AstraZeneca, and Shire.
Proton pump inhibitor use was associated with a greater than 75% reduction in the risk of neoplastic progression in Barrett’s esophagus.
Indeed, despite the "considerable costs" of these drugs, "prolonged PPI use is ... justified and feasible in Barrett’s patients and should be strongly recommended, in particular in guidelines," concluded Dr. Florine Kastelein in the April 1 issue of Clinical Gastroenterology and Hepatology (doi:10.1016/j.cgh.2012.11.014).
In what they called "the first methodological[ly] sound prospective study which shows that PPIs strongly reduce the risk of neoplastic progression in BE," Dr. Kastelein of Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues looked at 540 patients with known or newly diagnosed endoscopic Barrett’s esophagus (BE) confirmed by intestinal metaplasia.
Patients had a median age of 60.5 years at inclusion and were followed for a median of 5.2 years; 71% were male.
All patients were recruited from multiple academic and regional hospitals across the Netherlands, and patients were excluded if they had Barrett’s esophagus shorter than 2 cm, prior antireflux surgery, or a history of high-grade dysplasia or esophageal adenocarcinoma.
Patients with neoplastic progression found within the first 9 months after study inclusion also were ultimately excluded "since high-grade dysplasia or esophageal adenocarcinoma may be missed at index endoscopy in these patients," the investigators said.
Surveillance was performed according to the guidelines of the American College of Gastroenterology, such that patients without dysplasia underwent gastroscopy with biopsy sampling every 3 years and patients with low-grade dysplasia underwent it every year.
Overall, at inclusion in the study, 462 (85%) patients had used a PPI for a median duration of 4.0 years.
Dr. Kastelien and her associates found that, during follow-up, 28 patients developed high-grade dysplasia and another 12 developed esophageal adenocarcinoma, for a combined annual incidence of 1.6%.
"PPI use at inclusion was associated with a reduced risk of neoplastic progression (hazard ratio, 0.43; 95% confidence interval: 0.21-0.88) and remained associated with a trend toward a protective effect after adjusting for age, gender, time of BE diagnosis, BE length, esophagitis histology, and use of other medications (HR, 0.47; 95% CI: 0.19-1.18)," the researchers wrote.
Moreover, among the 99% of patients who used a PPI at any time during follow-up (median, 5.1 years), time-dependent analysis revealed that PPI use was associated with a reduced risk of neoplastic progression (HR, 0.15; 95% CI: 0.06-0.40) and remained so after adjusting for age, gender, BE length, histology, baseline PPI use, and use of other medications (HR, 0.21; 95% CI: 0.07-0.66).
The authors found no significant difference between neoplastic progression and the various PPIs assessed in this study (including esomeprazole and pantoprazole as well as omeprazole, rabeprazole, and lansoprazole).
According to Dr. Kastelein and her associates, the study is actually limited by the incredibly high rate of compliance among its population.
"Despite the large sample size, only eight (2%) patients never used a PPI and 18 (3%) patients used a PPI during [only] a part of their follow-up period," they wrote.
"Although this reflects clinical practice in Western countries and is representative for a disease in which patients seek to avoid reflux symptoms, it limits the options for investigating the effect of PPIs," they added.
However, "because not all patients used PPIs throughout their entire follow-up period, we were able to perform time-dependent analyses."
Proton pump inhibitor use was associated with a greater than 75% reduction in the risk of neoplastic progression in Barrett’s esophagus.
Indeed, despite the "considerable costs" of these drugs, "prolonged PPI use is ... justified and feasible in Barrett’s patients and should be strongly recommended, in particular in guidelines," concluded Dr. Florine Kastelein in the April 1 issue of Clinical Gastroenterology and Hepatology (doi:10.1016/j.cgh.2012.11.014).
In what they called "the first methodological[ly] sound prospective study which shows that PPIs strongly reduce the risk of neoplastic progression in BE," Dr. Kastelein of Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues looked at 540 patients with known or newly diagnosed endoscopic Barrett’s esophagus (BE) confirmed by intestinal metaplasia.
Patients had a median age of 60.5 years at inclusion and were followed for a median of 5.2 years; 71% were male.
All patients were recruited from multiple academic and regional hospitals across the Netherlands, and patients were excluded if they had Barrett’s esophagus shorter than 2 cm, prior antireflux surgery, or a history of high-grade dysplasia or esophageal adenocarcinoma.
Patients with neoplastic progression found within the first 9 months after study inclusion also were ultimately excluded "since high-grade dysplasia or esophageal adenocarcinoma may be missed at index endoscopy in these patients," the investigators said.
Surveillance was performed according to the guidelines of the American College of Gastroenterology, such that patients without dysplasia underwent gastroscopy with biopsy sampling every 3 years and patients with low-grade dysplasia underwent it every year.
Overall, at inclusion in the study, 462 (85%) patients had used a PPI for a median duration of 4.0 years.
Dr. Kastelien and her associates found that, during follow-up, 28 patients developed high-grade dysplasia and another 12 developed esophageal adenocarcinoma, for a combined annual incidence of 1.6%.
"PPI use at inclusion was associated with a reduced risk of neoplastic progression (hazard ratio, 0.43; 95% confidence interval: 0.21-0.88) and remained associated with a trend toward a protective effect after adjusting for age, gender, time of BE diagnosis, BE length, esophagitis histology, and use of other medications (HR, 0.47; 95% CI: 0.19-1.18)," the researchers wrote.
Moreover, among the 99% of patients who used a PPI at any time during follow-up (median, 5.1 years), time-dependent analysis revealed that PPI use was associated with a reduced risk of neoplastic progression (HR, 0.15; 95% CI: 0.06-0.40) and remained so after adjusting for age, gender, BE length, histology, baseline PPI use, and use of other medications (HR, 0.21; 95% CI: 0.07-0.66).
The authors found no significant difference between neoplastic progression and the various PPIs assessed in this study (including esomeprazole and pantoprazole as well as omeprazole, rabeprazole, and lansoprazole).
According to Dr. Kastelein and her associates, the study is actually limited by the incredibly high rate of compliance among its population.
"Despite the large sample size, only eight (2%) patients never used a PPI and 18 (3%) patients used a PPI during [only] a part of their follow-up period," they wrote.
"Although this reflects clinical practice in Western countries and is representative for a disease in which patients seek to avoid reflux symptoms, it limits the options for investigating the effect of PPIs," they added.
However, "because not all patients used PPIs throughout their entire follow-up period, we were able to perform time-dependent analyses."
Major finding: In Barrett’s esophagus, use of proton pump inhibitors was associated with a hazard ratio of 0.21 for neoplastic progression.
Data source: A multicenter, prospective cohort study of 540 patients with known or newly diagnosed Barrett’s esophagus.
Disclosures: None of the authors disclosed any conflicts of interest related to this article. No funding was reported.
Alpha-fetoprotein useful marker in HCC
Changes in serum alpha-fetoprotein levels over time correlated with the development of hepatocellular carcinoma in hepatitis C patients, wrote Dr. Elliot Lee and his colleagues in the April 1 issue of Clinical Gastroenterology and Hepatology.*
"If confirmed in future studies, these findings could be used to develop individualized risk assessments for clinical use, which could then influence the frequency and type of further testing" in this population, added the researchers (doi:10.1016/j.cgh.2012.11.029).
In what he called "the first large study to demonstrate that patterns of AFP [alpha-fetoprotein] over time are independently associated with HCC [hepatocellular carcinoma] development," Dr. Lee of the University of Michigan, Ann Arbor, looked at patients enrolled in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) trial, in which hepatitis C patients who were nonresponders to prior antiviral therapy were randomized to receive maintenance pegylated interferon or placebo.
According to the trial protocol, patients were screened every 3 months for the first 3.5 years, then every 6 months thereafter on a voluntary basis, with levels of serum alpha-fetoprotein measured at each visit.
Patients who developed hepatocellular carcinoma were matched to controls without HCC in a 1:3 ratio according to the length of follow-up "in order to exclude bias caused by subjects with longer follow-up time having higher cumulative probability of HCC development, as well as more AFP values available," wrote the authors.
Overall, among 967 subjects with hepatitis C, 82 developed HCC during the study period, with a median of 18 (range, 5-22) AFP tests performed.
Dr. Lee then analyzed the association between the development of HCC and three AFP patterns.
First, the researchers assessed the rate of rise, defined as the patient’s final alpha-fetoprotein level (before study conclusion or HCC development, whichever came first) minus the AFP baseline value (on study entry), all over the follow-up duration divided by 90 days.
He found that this metric was associated with an odds ratio for developing HCC of 1.178 (P less than .001) in a simple logistic regression analysis that accounted for baseline risk factors only, with an area under the receiver-operating characteristic (AUROC) of 0.69.
Next, Dr. Lee calculated the standard deviation of AFP, defined as the standard deviation of all AFP values recorded within each patient.
In the same simple logistic regression, the standard deviation calculation was associated with an odds ratio of 1.026 for HCC per unit increase in standard deviation (P less than .001) and an AUROC of 0.76.
Third, Dr. Lee looked at the most recent AFP value on record. In this case, the odds ratio for developing HCC was 1.012 (also with P less than .001) and an AUROC of 0.76.
Finally, the researchers incorporated both standard deviation and rate of rise of AFP along with baseline age, platelet count, and smoking history to create a "history" model, which had an AUROC of 0.81 – an even better predictor than the models that looked only at one of those factors.
In an attempt to explain their findings, the researchers wrote, "it is intuitively evident why the rate of rise of AFP might be associated with risk of HCC development, but what might explain the association with standard deviation?"
They added, "The biologic basis is unknown, but we theorize that fluctuations in AFP may reflect cycles of damage and regeneration within the liver, and that growth factors involved in regeneration could stimulate hepatocarcinogenesis."
The authors acknowledged that the study had several limitations. "From a practical perspective, these metrics will only be useful once a patient has been followed for at least 2 years in order for the patterns to emerge," they wrote.
Additionally, "this study included only patients with hepatitis C; it is unknown whether these associations would be present among patients with other chronic liver diseases."
The authors said they had no relevant financial disclosures. They disclosed grant support from the National Science Foundation Graduate Research Fellowship.
*Correction, 3/25/2013: An earlier version of this story misstated the name of Clinical Gastroenterology and Hepatology.
Changes in serum alpha-fetoprotein levels over time correlated with the development of hepatocellular carcinoma in hepatitis C patients, wrote Dr. Elliot Lee and his colleagues in the April 1 issue of Clinical Gastroenterology and Hepatology.*
"If confirmed in future studies, these findings could be used to develop individualized risk assessments for clinical use, which could then influence the frequency and type of further testing" in this population, added the researchers (doi:10.1016/j.cgh.2012.11.029).
In what he called "the first large study to demonstrate that patterns of AFP [alpha-fetoprotein] over time are independently associated with HCC [hepatocellular carcinoma] development," Dr. Lee of the University of Michigan, Ann Arbor, looked at patients enrolled in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) trial, in which hepatitis C patients who were nonresponders to prior antiviral therapy were randomized to receive maintenance pegylated interferon or placebo.
According to the trial protocol, patients were screened every 3 months for the first 3.5 years, then every 6 months thereafter on a voluntary basis, with levels of serum alpha-fetoprotein measured at each visit.
Patients who developed hepatocellular carcinoma were matched to controls without HCC in a 1:3 ratio according to the length of follow-up "in order to exclude bias caused by subjects with longer follow-up time having higher cumulative probability of HCC development, as well as more AFP values available," wrote the authors.
Overall, among 967 subjects with hepatitis C, 82 developed HCC during the study period, with a median of 18 (range, 5-22) AFP tests performed.
Dr. Lee then analyzed the association between the development of HCC and three AFP patterns.
First, the researchers assessed the rate of rise, defined as the patient’s final alpha-fetoprotein level (before study conclusion or HCC development, whichever came first) minus the AFP baseline value (on study entry), all over the follow-up duration divided by 90 days.
He found that this metric was associated with an odds ratio for developing HCC of 1.178 (P less than .001) in a simple logistic regression analysis that accounted for baseline risk factors only, with an area under the receiver-operating characteristic (AUROC) of 0.69.
Next, Dr. Lee calculated the standard deviation of AFP, defined as the standard deviation of all AFP values recorded within each patient.
In the same simple logistic regression, the standard deviation calculation was associated with an odds ratio of 1.026 for HCC per unit increase in standard deviation (P less than .001) and an AUROC of 0.76.
Third, Dr. Lee looked at the most recent AFP value on record. In this case, the odds ratio for developing HCC was 1.012 (also with P less than .001) and an AUROC of 0.76.
Finally, the researchers incorporated both standard deviation and rate of rise of AFP along with baseline age, platelet count, and smoking history to create a "history" model, which had an AUROC of 0.81 – an even better predictor than the models that looked only at one of those factors.
In an attempt to explain their findings, the researchers wrote, "it is intuitively evident why the rate of rise of AFP might be associated with risk of HCC development, but what might explain the association with standard deviation?"
They added, "The biologic basis is unknown, but we theorize that fluctuations in AFP may reflect cycles of damage and regeneration within the liver, and that growth factors involved in regeneration could stimulate hepatocarcinogenesis."
The authors acknowledged that the study had several limitations. "From a practical perspective, these metrics will only be useful once a patient has been followed for at least 2 years in order for the patterns to emerge," they wrote.
Additionally, "this study included only patients with hepatitis C; it is unknown whether these associations would be present among patients with other chronic liver diseases."
The authors said they had no relevant financial disclosures. They disclosed grant support from the National Science Foundation Graduate Research Fellowship.
*Correction, 3/25/2013: An earlier version of this story misstated the name of Clinical Gastroenterology and Hepatology.
Changes in serum alpha-fetoprotein levels over time correlated with the development of hepatocellular carcinoma in hepatitis C patients, wrote Dr. Elliot Lee and his colleagues in the April 1 issue of Clinical Gastroenterology and Hepatology.*
"If confirmed in future studies, these findings could be used to develop individualized risk assessments for clinical use, which could then influence the frequency and type of further testing" in this population, added the researchers (doi:10.1016/j.cgh.2012.11.029).
In what he called "the first large study to demonstrate that patterns of AFP [alpha-fetoprotein] over time are independently associated with HCC [hepatocellular carcinoma] development," Dr. Lee of the University of Michigan, Ann Arbor, looked at patients enrolled in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) trial, in which hepatitis C patients who were nonresponders to prior antiviral therapy were randomized to receive maintenance pegylated interferon or placebo.
According to the trial protocol, patients were screened every 3 months for the first 3.5 years, then every 6 months thereafter on a voluntary basis, with levels of serum alpha-fetoprotein measured at each visit.
Patients who developed hepatocellular carcinoma were matched to controls without HCC in a 1:3 ratio according to the length of follow-up "in order to exclude bias caused by subjects with longer follow-up time having higher cumulative probability of HCC development, as well as more AFP values available," wrote the authors.
Overall, among 967 subjects with hepatitis C, 82 developed HCC during the study period, with a median of 18 (range, 5-22) AFP tests performed.
Dr. Lee then analyzed the association between the development of HCC and three AFP patterns.
First, the researchers assessed the rate of rise, defined as the patient’s final alpha-fetoprotein level (before study conclusion or HCC development, whichever came first) minus the AFP baseline value (on study entry), all over the follow-up duration divided by 90 days.
He found that this metric was associated with an odds ratio for developing HCC of 1.178 (P less than .001) in a simple logistic regression analysis that accounted for baseline risk factors only, with an area under the receiver-operating characteristic (AUROC) of 0.69.
Next, Dr. Lee calculated the standard deviation of AFP, defined as the standard deviation of all AFP values recorded within each patient.
In the same simple logistic regression, the standard deviation calculation was associated with an odds ratio of 1.026 for HCC per unit increase in standard deviation (P less than .001) and an AUROC of 0.76.
Third, Dr. Lee looked at the most recent AFP value on record. In this case, the odds ratio for developing HCC was 1.012 (also with P less than .001) and an AUROC of 0.76.
Finally, the researchers incorporated both standard deviation and rate of rise of AFP along with baseline age, platelet count, and smoking history to create a "history" model, which had an AUROC of 0.81 – an even better predictor than the models that looked only at one of those factors.
In an attempt to explain their findings, the researchers wrote, "it is intuitively evident why the rate of rise of AFP might be associated with risk of HCC development, but what might explain the association with standard deviation?"
They added, "The biologic basis is unknown, but we theorize that fluctuations in AFP may reflect cycles of damage and regeneration within the liver, and that growth factors involved in regeneration could stimulate hepatocarcinogenesis."
The authors acknowledged that the study had several limitations. "From a practical perspective, these metrics will only be useful once a patient has been followed for at least 2 years in order for the patterns to emerge," they wrote.
Additionally, "this study included only patients with hepatitis C; it is unknown whether these associations would be present among patients with other chronic liver diseases."
The authors said they had no relevant financial disclosures. They disclosed grant support from the National Science Foundation Graduate Research Fellowship.
*Correction, 3/25/2013: An earlier version of this story misstated the name of Clinical Gastroenterology and Hepatology.
FROM GASTROENTEROLOGY AND HEPATOLOGY NEWS
Major finding: Each standard deviation unit increase in serum alpha-fetoprotein carried a 1.026 odds ratio for hepatocellular carcinoma.
Data source: A nested case-control study of subjects enrolled in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis trial.
Disclosures: The authors said they had no relevant financial disclosures. They received grant support from the National Science Foundation Graduate Research Fellowship.
Older women with primary biliary cirrhosis responders to UDCA
The age and sex of the patient at the onset of primary biliary cirrhosis predict the severity of disease and the likelihood of response to treatment with ursodeoxycholic acid, Dr. Marco Carbone and his associates reported in Gastroenterology.
In what they described as the first study large enough to permit examination of meaningful numbers of patient subgroups, the researchers found that among women, older age at diagnosis correlated with a better chance of responding to UDCA and with a less severe disease phenotype. These findings are reassuring because women with primary biliary cirrhosis outnumber men by approximately 10 to 1, and most are older than 50 years at disease onset.
Source: American Gastroenterological Association
But the other side of the coin is that the minority of patients who do present at an earlier age, or are men, are more likely to have a severe disease phenotype and less likely to respond to therapy.
"Collectively our findings highlight that primary biliary cirrhosis is not a uniform disease with uniform risks and impact, but one with high- and low-risk patients," said Dr. Carbone of the department of hepatology, Cambridge (England) University Hospitals National Health Service Foundation Trust, and his associates (doi:10.1053/j.gastro.2012.12.005).
The researchers analyzed data from the United Kingdom–Primary Biliary Cirrhosis cohort, an ongoing national genetic study of the disease that enrolled patients from every hospital in the country during a recent 3-year period. This patient population represents 25% of all primary biliary cirrhosis patients in the United Kingdom.
Dr. Carbone and his colleagues assessed the records of 2,353 participants in the UK-PBC, including a subgroup of 1,379 who supplied extra detailed clinical information. The cohort included 221 men.
More than 80% of the study subjects were managed outside of specialist liver transplant centers. These patients were just as likely as were those managed at specialty centers to be offered therapy with UDCA.
Women who presented at age 50 or older were significantly more likely than were younger women or men to have less severe disease and to respond to UDCA. In particular, women aged 70 and older at presentation had a greater than 90% chance of responding.
One possible explanation for this finding is that hormones, particularly high estrogen levels, may raise resistance to treatment. "There certainly are plausible biologic mechanisms for such an endocrine effect, as female sex hormones modulate immune regulation and biliary epithelial cell turnover. Furthermore, case reports show that tamoxifen, an antiestrogen, improves liver biochemistry in primary biliary cirrhosis," the investigators said.
This finding suggests that a clinical trial of antiestrogens as adjunctive therapy should be considered for high-risk patients who don’t respond to UDCA, they noted.
Men typically presented at an older age but with more severe disease, as evidenced by their reduced platelet counts and higher frequency of splenomegaly.
"This is likely to represent delayed diagnosis resulting from the misperception that primary biliary cirrhosis is ‘a female disease,’ with the presence of features such as elevated [liver enzymes] being falsely ascribed to conditions or etiologies that are common in the male population, such as increased alcohol consumption," Dr. Carbone and his associates said.
Men were just as likely as were women to be offered UDCA therapy, but were significantly less likely to respond adequately.
Autonomic symptoms were more marked among women than men. In a substudy in which male subjects were matched with female subjects, the difference in autonomic symptoms closely correlated with differences in fatigue severity, "raising the obvious question as to whether reduction in autonomic dysfunction might reduce fatigue," the investigators said.
One possible reason that men have fewer autonomic symptoms may be that they tend to have higher underlying blood pressure than women, they added.
Overall, it appears that most patients with primary biliary cirrhosis present at an older age, have few symptoms, and respond well to UDCA – a "benign picture" that should guide planning and delivery of care.
In contrast, younger patients tend to have a more complex course, with more symptoms that interfere with daily life and a higher risk of treatment failure. "Such patients should be the focus for novel therapy to improve outcomes."
Men have a lower chance of responding to therapy, but fortunately they have a lower symptom burden and their age at disease onset doesn’t affect prognosis.
No financial conflicts were reported.
This large study of primary biliary cirrhosis demonstrates convincingly that PBC is a heterogeneous disease. The finding that the disease appears to be less responsive to UDCA and thus more aggressive in young women and in men is intriguing and clinically relevant. At present, there is no good pathophysiologic explanation for this observation, and it is more likely that this difference is due to diagnostic bias: Because PBC is considered to be a disease of older women it is less likely to be diagnosed in younger women and in men unless it is more active and symptomatic.
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In addition, in mild disease, laboratory values may remain normal until older age, while in aggressive disease with features of secondary autoimmune hepatitis, elevated liver enzymes can be found already early in the disease process. Whether hormonal factors play a role needs further study, and this large patient cohort may help in such an analysis as patients who received contraceptives or hormonal replacements could be compared with patients without hormonal exposure.
What does the study mean for the practicing clinician? The heterogeneity of PBC, the more aggressive course in some patients, and the benefit from additional immunosuppressive therapy require identification of patients at risk. Liver biopsy is the most sensitive test to detect an aggressive course of PBC by showing features of lobular and interface hepatitis, and seems to be indicated particularly in young women, in men, and in insufficient response to initial UDCA treatment.
Ansgar W. Lohse, M.D., is professor of medicine at University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. He has no financial disclosures.
This large study of primary biliary cirrhosis demonstrates convincingly that PBC is a heterogeneous disease. The finding that the disease appears to be less responsive to UDCA and thus more aggressive in young women and in men is intriguing and clinically relevant. At present, there is no good pathophysiologic explanation for this observation, and it is more likely that this difference is due to diagnostic bias: Because PBC is considered to be a disease of older women it is less likely to be diagnosed in younger women and in men unless it is more active and symptomatic.
|
|
|
In addition, in mild disease, laboratory values may remain normal until older age, while in aggressive disease with features of secondary autoimmune hepatitis, elevated liver enzymes can be found already early in the disease process. Whether hormonal factors play a role needs further study, and this large patient cohort may help in such an analysis as patients who received contraceptives or hormonal replacements could be compared with patients without hormonal exposure.
What does the study mean for the practicing clinician? The heterogeneity of PBC, the more aggressive course in some patients, and the benefit from additional immunosuppressive therapy require identification of patients at risk. Liver biopsy is the most sensitive test to detect an aggressive course of PBC by showing features of lobular and interface hepatitis, and seems to be indicated particularly in young women, in men, and in insufficient response to initial UDCA treatment.
Ansgar W. Lohse, M.D., is professor of medicine at University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. He has no financial disclosures.
This large study of primary biliary cirrhosis demonstrates convincingly that PBC is a heterogeneous disease. The finding that the disease appears to be less responsive to UDCA and thus more aggressive in young women and in men is intriguing and clinically relevant. At present, there is no good pathophysiologic explanation for this observation, and it is more likely that this difference is due to diagnostic bias: Because PBC is considered to be a disease of older women it is less likely to be diagnosed in younger women and in men unless it is more active and symptomatic.
|
|
|
In addition, in mild disease, laboratory values may remain normal until older age, while in aggressive disease with features of secondary autoimmune hepatitis, elevated liver enzymes can be found already early in the disease process. Whether hormonal factors play a role needs further study, and this large patient cohort may help in such an analysis as patients who received contraceptives or hormonal replacements could be compared with patients without hormonal exposure.
What does the study mean for the practicing clinician? The heterogeneity of PBC, the more aggressive course in some patients, and the benefit from additional immunosuppressive therapy require identification of patients at risk. Liver biopsy is the most sensitive test to detect an aggressive course of PBC by showing features of lobular and interface hepatitis, and seems to be indicated particularly in young women, in men, and in insufficient response to initial UDCA treatment.
Ansgar W. Lohse, M.D., is professor of medicine at University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. He has no financial disclosures.
The age and sex of the patient at the onset of primary biliary cirrhosis predict the severity of disease and the likelihood of response to treatment with ursodeoxycholic acid, Dr. Marco Carbone and his associates reported in Gastroenterology.
In what they described as the first study large enough to permit examination of meaningful numbers of patient subgroups, the researchers found that among women, older age at diagnosis correlated with a better chance of responding to UDCA and with a less severe disease phenotype. These findings are reassuring because women with primary biliary cirrhosis outnumber men by approximately 10 to 1, and most are older than 50 years at disease onset.
Source: American Gastroenterological Association
But the other side of the coin is that the minority of patients who do present at an earlier age, or are men, are more likely to have a severe disease phenotype and less likely to respond to therapy.
"Collectively our findings highlight that primary biliary cirrhosis is not a uniform disease with uniform risks and impact, but one with high- and low-risk patients," said Dr. Carbone of the department of hepatology, Cambridge (England) University Hospitals National Health Service Foundation Trust, and his associates (doi:10.1053/j.gastro.2012.12.005).
The researchers analyzed data from the United Kingdom–Primary Biliary Cirrhosis cohort, an ongoing national genetic study of the disease that enrolled patients from every hospital in the country during a recent 3-year period. This patient population represents 25% of all primary biliary cirrhosis patients in the United Kingdom.
Dr. Carbone and his colleagues assessed the records of 2,353 participants in the UK-PBC, including a subgroup of 1,379 who supplied extra detailed clinical information. The cohort included 221 men.
More than 80% of the study subjects were managed outside of specialist liver transplant centers. These patients were just as likely as were those managed at specialty centers to be offered therapy with UDCA.
Women who presented at age 50 or older were significantly more likely than were younger women or men to have less severe disease and to respond to UDCA. In particular, women aged 70 and older at presentation had a greater than 90% chance of responding.
One possible explanation for this finding is that hormones, particularly high estrogen levels, may raise resistance to treatment. "There certainly are plausible biologic mechanisms for such an endocrine effect, as female sex hormones modulate immune regulation and biliary epithelial cell turnover. Furthermore, case reports show that tamoxifen, an antiestrogen, improves liver biochemistry in primary biliary cirrhosis," the investigators said.
This finding suggests that a clinical trial of antiestrogens as adjunctive therapy should be considered for high-risk patients who don’t respond to UDCA, they noted.
Men typically presented at an older age but with more severe disease, as evidenced by their reduced platelet counts and higher frequency of splenomegaly.
"This is likely to represent delayed diagnosis resulting from the misperception that primary biliary cirrhosis is ‘a female disease,’ with the presence of features such as elevated [liver enzymes] being falsely ascribed to conditions or etiologies that are common in the male population, such as increased alcohol consumption," Dr. Carbone and his associates said.
Men were just as likely as were women to be offered UDCA therapy, but were significantly less likely to respond adequately.
Autonomic symptoms were more marked among women than men. In a substudy in which male subjects were matched with female subjects, the difference in autonomic symptoms closely correlated with differences in fatigue severity, "raising the obvious question as to whether reduction in autonomic dysfunction might reduce fatigue," the investigators said.
One possible reason that men have fewer autonomic symptoms may be that they tend to have higher underlying blood pressure than women, they added.
Overall, it appears that most patients with primary biliary cirrhosis present at an older age, have few symptoms, and respond well to UDCA – a "benign picture" that should guide planning and delivery of care.
In contrast, younger patients tend to have a more complex course, with more symptoms that interfere with daily life and a higher risk of treatment failure. "Such patients should be the focus for novel therapy to improve outcomes."
Men have a lower chance of responding to therapy, but fortunately they have a lower symptom burden and their age at disease onset doesn’t affect prognosis.
No financial conflicts were reported.
The age and sex of the patient at the onset of primary biliary cirrhosis predict the severity of disease and the likelihood of response to treatment with ursodeoxycholic acid, Dr. Marco Carbone and his associates reported in Gastroenterology.
In what they described as the first study large enough to permit examination of meaningful numbers of patient subgroups, the researchers found that among women, older age at diagnosis correlated with a better chance of responding to UDCA and with a less severe disease phenotype. These findings are reassuring because women with primary biliary cirrhosis outnumber men by approximately 10 to 1, and most are older than 50 years at disease onset.
Source: American Gastroenterological Association
But the other side of the coin is that the minority of patients who do present at an earlier age, or are men, are more likely to have a severe disease phenotype and less likely to respond to therapy.
"Collectively our findings highlight that primary biliary cirrhosis is not a uniform disease with uniform risks and impact, but one with high- and low-risk patients," said Dr. Carbone of the department of hepatology, Cambridge (England) University Hospitals National Health Service Foundation Trust, and his associates (doi:10.1053/j.gastro.2012.12.005).
The researchers analyzed data from the United Kingdom–Primary Biliary Cirrhosis cohort, an ongoing national genetic study of the disease that enrolled patients from every hospital in the country during a recent 3-year period. This patient population represents 25% of all primary biliary cirrhosis patients in the United Kingdom.
Dr. Carbone and his colleagues assessed the records of 2,353 participants in the UK-PBC, including a subgroup of 1,379 who supplied extra detailed clinical information. The cohort included 221 men.
More than 80% of the study subjects were managed outside of specialist liver transplant centers. These patients were just as likely as were those managed at specialty centers to be offered therapy with UDCA.
Women who presented at age 50 or older were significantly more likely than were younger women or men to have less severe disease and to respond to UDCA. In particular, women aged 70 and older at presentation had a greater than 90% chance of responding.
One possible explanation for this finding is that hormones, particularly high estrogen levels, may raise resistance to treatment. "There certainly are plausible biologic mechanisms for such an endocrine effect, as female sex hormones modulate immune regulation and biliary epithelial cell turnover. Furthermore, case reports show that tamoxifen, an antiestrogen, improves liver biochemistry in primary biliary cirrhosis," the investigators said.
This finding suggests that a clinical trial of antiestrogens as adjunctive therapy should be considered for high-risk patients who don’t respond to UDCA, they noted.
Men typically presented at an older age but with more severe disease, as evidenced by their reduced platelet counts and higher frequency of splenomegaly.
"This is likely to represent delayed diagnosis resulting from the misperception that primary biliary cirrhosis is ‘a female disease,’ with the presence of features such as elevated [liver enzymes] being falsely ascribed to conditions or etiologies that are common in the male population, such as increased alcohol consumption," Dr. Carbone and his associates said.
Men were just as likely as were women to be offered UDCA therapy, but were significantly less likely to respond adequately.
Autonomic symptoms were more marked among women than men. In a substudy in which male subjects were matched with female subjects, the difference in autonomic symptoms closely correlated with differences in fatigue severity, "raising the obvious question as to whether reduction in autonomic dysfunction might reduce fatigue," the investigators said.
One possible reason that men have fewer autonomic symptoms may be that they tend to have higher underlying blood pressure than women, they added.
Overall, it appears that most patients with primary biliary cirrhosis present at an older age, have few symptoms, and respond well to UDCA – a "benign picture" that should guide planning and delivery of care.
In contrast, younger patients tend to have a more complex course, with more symptoms that interfere with daily life and a higher risk of treatment failure. "Such patients should be the focus for novel therapy to improve outcomes."
Men have a lower chance of responding to therapy, but fortunately they have a lower symptom burden and their age at disease onset doesn’t affect prognosis.
No financial conflicts were reported.
FROM GASTROENTEROLOGY
Major Finding: Women aged 70 and older at presentation for primary biliary cirrhosis had a greater than 90% chance of responding to ursodeoxycholic acid therapy.
Data Source: An observational cross-sectional study describing the phenotype of primary biliary cirrhosis, using data from a UK cohort of 2,353 adults with the autoimmune disease.
Disclosures: No financial conflicts of interest were reported.
Anti-TNF agents vary in ability to cross placenta
Two small studies now add to the very sparse clinical experience with the use of anti-TNF-alpha agents in women who have inflammatory bowel disease and become pregnant, according to separate groups of researchers writing in the March issue of Clinical Gastroenterology and Hepatology.
Both studies confirm that two TNF antagonists do cross the placenta to the fetus at high levels and persist in the infant for months after birth. Discontinuing the drugs during the second trimester lessens but does not eliminate this exposure.
"At this time, we do not know what a safe or harmful level of drug in the newborn is, and what the full consequences of neonatal anti-TNF-alpha exposure to newborn development will be. The risks and benefits of therapy should be individualized, and pediatricians should be cautioned to monitor for potential infections and other abnormalities," said Dr. Uma Mahadevan of the University of California, San Francisco, and her associates (Clin. Gastroenterol. Hepatol. 2012 [doi:10.1016/j.cgh.2012.11.011]).
In their study, Dr. Mahadevan and her colleagues identified 31 pregnant women in their practice or in the Crohn’s Colitis Foundation of America’s Pregnancy IBD and Neonatal Outcomes registry who had Crohn’s disease and were taking infliximab (11 women), adalimumab (10 women), or certolizumab (10 women).
The first two of these anti-TNF-alpha agents are both of the IgG1 subclass and thus should, in theory, cross the placenta at high rates during the third trimester. Certolizumab, a pegylated fragment of an anti-TNF-alpha monoclonal antibody, in theory should not be transported across the placenta. To test these theories, the researchers determined the concentrations of each medication in samples of cord blood, infant serum, and the mother’s plasma taken on the day of birth. None of the infants had birth defects or required neonatal ICU care.
In the infliximab group, the median interval between the last dose of the agent and delivery was 35 days (range, 2-91 days). In every case, cord blood and infant serum samples showed much higher levels of the TNF-alpha antagonist than did maternal plasma samples, at a median ratio of 160:100. The drug persisted in the infants’ circulation for 2-7 months postpartum.
In the adalimumab group, the median interval between the last dose of the agent and delivery was 5.5 weeks. Again, in every case, cord blood and infant serum samples showed much higher levels of the TNF-alpha antagonist than did maternal plasma samples, at a median ratio of 179:100. The drug persisted in the infants’ circulation for at least 11 weeks.
In contrast, no certolizumab was detected in any of the infant samples.
"Based on the results of this study and available safety data, infliximab, adalimumab, and certolizumab can be used through conception and the first and second trimester of pregnancy on schedule. However, the significant placental transfer and subsequent slow postpartum clearance of infliximab and adalimumab raise concerns about their use during the third trimester," Dr. Mahadevan and her associates said.
Such concerns must be balanced against the risk of a flare of IBD, "which has far more consequences to neonatal development," impairing nutritional status of mother and fetus; raising the risk of preterm delivery; and possibly requiring harmful diagnostic testing, medication, and even surgery on the pregnant patient.
Physicians may consider switching patients to certolizumab during pregnancy because of its lack of transfer to the fetus, but "if a pregnant patient is doing well on infliximab or adalimumab, there is no indication, and even a potential risk, of switching ... as the primary goal remains to maintain a quiescent disease state that is critical for a successful pregnancy," they noted.
In the other study, Dr. Zuzana Zelinkova of Erasmus Medical Center, Rotterdam, the Netherlands, and her associates assessed 28 pregnant women who had Crohn’s disease or ulcerative colitis for which they were taking TNF-alpha antagonists.
Of the 17 taking infliximab, 12 had IBD in remission and discontinued the drug at a mean of 23 weeks’ gestation. Three others had perianal fistulas but discontinued early in the second trimester, while two had perianal fistulas and active luminal disease and didn’t discontinue the drug until weeks 30 and 34. None developed IBD relapses.
All 11 study subjects who were taking adalimumab had quiescent disease in the second trimester and discontinued the drug at a mean gestation of 22 weeks (range, 21-27 weeks). Two of them (18%) developed relapses of IBD.
There were three spontaneous miscarriages during the first trimester, and one child was born with polydactyly.
Levels of TNF-alpha antagonists in cord blood samples were significantly lower in the group who discontinued the drugs early, compared with the group who continued taking them until 10 or fewer weeks before delivery. "We recommend considering the discontinuation of anti-TNF-alpha treatment in patients who have quiescent disease at the beginning of the second trimester," to decrease but not completely eliminate the child’s exposure to these agents, Dr. Zelinkova and her associates said.
Dr. Mahadevan’s study was supported by Abbott (marketer of adalimumab), UCB (marketer of certolizumab), Prometheus Labs, and the Crohn’s Colitis Foundation of America. Dr. Mahadevan and her associates reported ties to Janssen (marketer of infliximab), UCB, and Abbott. Dr. Zelinkova and her associates reported ties to Abbott; Merck, Sharp & Dohme; and Shire.
These two studies firm up our knowledge regarding anti-TNF therapy during pregnancy. They confirm that the IgG1 monoclonal antibodies infliximab and adalimumab have substantial transplacental transfer that increases during the third trimester. Infants born to women who continue these medications during the third trimester will have detectable drug concentrations that persist for 2-7 months.
No serious infectious events occurred in these studies. However, there is a previous report of an infant whose mother took infliximab during the third trimester who was vaccinated with the live organism BCG [Bacille Calmette Guerin] and developed disseminated BCG, which ultimately led to death (J. Am. Acad. Dermatol. 2011;65:870). This case report demonstrates that infants who are born with detectable infliximab or adalimumab levels are at risk for opportunistic infections. In contrast, certolizumab pegol does not cross the placenta.
The studies also show that interruption of infliximab or adalimumab at the end of the second trimester substantially reduces the amount of antibody transferred to the infant and shortens the time required for the infant to clear the antibody. Finally, discontinuation of infliximab and adalimumab during the third trimester appears to be associated with a low risk of relapse.
Altogether, these findings would appear to support the discontinuation of infliximab and adalimumab during the third trimester. Discontinuation of certolizumab pegol is not necessary.
William J. Sandborn, M.D., AGAF, is chief of the division of gastroenterology and director of the UCSD IBD Center in the University of California San Diego Health System. He has consulted for and received research grants from Janssen and consulted for AbbVie (previously Abbott Laboratories) and UCB Pharma.
These two studies firm up our knowledge regarding anti-TNF therapy during pregnancy. They confirm that the IgG1 monoclonal antibodies infliximab and adalimumab have substantial transplacental transfer that increases during the third trimester. Infants born to women who continue these medications during the third trimester will have detectable drug concentrations that persist for 2-7 months.
No serious infectious events occurred in these studies. However, there is a previous report of an infant whose mother took infliximab during the third trimester who was vaccinated with the live organism BCG [Bacille Calmette Guerin] and developed disseminated BCG, which ultimately led to death (J. Am. Acad. Dermatol. 2011;65:870). This case report demonstrates that infants who are born with detectable infliximab or adalimumab levels are at risk for opportunistic infections. In contrast, certolizumab pegol does not cross the placenta.
The studies also show that interruption of infliximab or adalimumab at the end of the second trimester substantially reduces the amount of antibody transferred to the infant and shortens the time required for the infant to clear the antibody. Finally, discontinuation of infliximab and adalimumab during the third trimester appears to be associated with a low risk of relapse.
Altogether, these findings would appear to support the discontinuation of infliximab and adalimumab during the third trimester. Discontinuation of certolizumab pegol is not necessary.
William J. Sandborn, M.D., AGAF, is chief of the division of gastroenterology and director of the UCSD IBD Center in the University of California San Diego Health System. He has consulted for and received research grants from Janssen and consulted for AbbVie (previously Abbott Laboratories) and UCB Pharma.
These two studies firm up our knowledge regarding anti-TNF therapy during pregnancy. They confirm that the IgG1 monoclonal antibodies infliximab and adalimumab have substantial transplacental transfer that increases during the third trimester. Infants born to women who continue these medications during the third trimester will have detectable drug concentrations that persist for 2-7 months.
No serious infectious events occurred in these studies. However, there is a previous report of an infant whose mother took infliximab during the third trimester who was vaccinated with the live organism BCG [Bacille Calmette Guerin] and developed disseminated BCG, which ultimately led to death (J. Am. Acad. Dermatol. 2011;65:870). This case report demonstrates that infants who are born with detectable infliximab or adalimumab levels are at risk for opportunistic infections. In contrast, certolizumab pegol does not cross the placenta.
The studies also show that interruption of infliximab or adalimumab at the end of the second trimester substantially reduces the amount of antibody transferred to the infant and shortens the time required for the infant to clear the antibody. Finally, discontinuation of infliximab and adalimumab during the third trimester appears to be associated with a low risk of relapse.
Altogether, these findings would appear to support the discontinuation of infliximab and adalimumab during the third trimester. Discontinuation of certolizumab pegol is not necessary.
William J. Sandborn, M.D., AGAF, is chief of the division of gastroenterology and director of the UCSD IBD Center in the University of California San Diego Health System. He has consulted for and received research grants from Janssen and consulted for AbbVie (previously Abbott Laboratories) and UCB Pharma.
Two small studies now add to the very sparse clinical experience with the use of anti-TNF-alpha agents in women who have inflammatory bowel disease and become pregnant, according to separate groups of researchers writing in the March issue of Clinical Gastroenterology and Hepatology.
Both studies confirm that two TNF antagonists do cross the placenta to the fetus at high levels and persist in the infant for months after birth. Discontinuing the drugs during the second trimester lessens but does not eliminate this exposure.
"At this time, we do not know what a safe or harmful level of drug in the newborn is, and what the full consequences of neonatal anti-TNF-alpha exposure to newborn development will be. The risks and benefits of therapy should be individualized, and pediatricians should be cautioned to monitor for potential infections and other abnormalities," said Dr. Uma Mahadevan of the University of California, San Francisco, and her associates (Clin. Gastroenterol. Hepatol. 2012 [doi:10.1016/j.cgh.2012.11.011]).
In their study, Dr. Mahadevan and her colleagues identified 31 pregnant women in their practice or in the Crohn’s Colitis Foundation of America’s Pregnancy IBD and Neonatal Outcomes registry who had Crohn’s disease and were taking infliximab (11 women), adalimumab (10 women), or certolizumab (10 women).
The first two of these anti-TNF-alpha agents are both of the IgG1 subclass and thus should, in theory, cross the placenta at high rates during the third trimester. Certolizumab, a pegylated fragment of an anti-TNF-alpha monoclonal antibody, in theory should not be transported across the placenta. To test these theories, the researchers determined the concentrations of each medication in samples of cord blood, infant serum, and the mother’s plasma taken on the day of birth. None of the infants had birth defects or required neonatal ICU care.
In the infliximab group, the median interval between the last dose of the agent and delivery was 35 days (range, 2-91 days). In every case, cord blood and infant serum samples showed much higher levels of the TNF-alpha antagonist than did maternal plasma samples, at a median ratio of 160:100. The drug persisted in the infants’ circulation for 2-7 months postpartum.
In the adalimumab group, the median interval between the last dose of the agent and delivery was 5.5 weeks. Again, in every case, cord blood and infant serum samples showed much higher levels of the TNF-alpha antagonist than did maternal plasma samples, at a median ratio of 179:100. The drug persisted in the infants’ circulation for at least 11 weeks.
In contrast, no certolizumab was detected in any of the infant samples.
"Based on the results of this study and available safety data, infliximab, adalimumab, and certolizumab can be used through conception and the first and second trimester of pregnancy on schedule. However, the significant placental transfer and subsequent slow postpartum clearance of infliximab and adalimumab raise concerns about their use during the third trimester," Dr. Mahadevan and her associates said.
Such concerns must be balanced against the risk of a flare of IBD, "which has far more consequences to neonatal development," impairing nutritional status of mother and fetus; raising the risk of preterm delivery; and possibly requiring harmful diagnostic testing, medication, and even surgery on the pregnant patient.
Physicians may consider switching patients to certolizumab during pregnancy because of its lack of transfer to the fetus, but "if a pregnant patient is doing well on infliximab or adalimumab, there is no indication, and even a potential risk, of switching ... as the primary goal remains to maintain a quiescent disease state that is critical for a successful pregnancy," they noted.
In the other study, Dr. Zuzana Zelinkova of Erasmus Medical Center, Rotterdam, the Netherlands, and her associates assessed 28 pregnant women who had Crohn’s disease or ulcerative colitis for which they were taking TNF-alpha antagonists.
Of the 17 taking infliximab, 12 had IBD in remission and discontinued the drug at a mean of 23 weeks’ gestation. Three others had perianal fistulas but discontinued early in the second trimester, while two had perianal fistulas and active luminal disease and didn’t discontinue the drug until weeks 30 and 34. None developed IBD relapses.
All 11 study subjects who were taking adalimumab had quiescent disease in the second trimester and discontinued the drug at a mean gestation of 22 weeks (range, 21-27 weeks). Two of them (18%) developed relapses of IBD.
There were three spontaneous miscarriages during the first trimester, and one child was born with polydactyly.
Levels of TNF-alpha antagonists in cord blood samples were significantly lower in the group who discontinued the drugs early, compared with the group who continued taking them until 10 or fewer weeks before delivery. "We recommend considering the discontinuation of anti-TNF-alpha treatment in patients who have quiescent disease at the beginning of the second trimester," to decrease but not completely eliminate the child’s exposure to these agents, Dr. Zelinkova and her associates said.
Dr. Mahadevan’s study was supported by Abbott (marketer of adalimumab), UCB (marketer of certolizumab), Prometheus Labs, and the Crohn’s Colitis Foundation of America. Dr. Mahadevan and her associates reported ties to Janssen (marketer of infliximab), UCB, and Abbott. Dr. Zelinkova and her associates reported ties to Abbott; Merck, Sharp & Dohme; and Shire.
Two small studies now add to the very sparse clinical experience with the use of anti-TNF-alpha agents in women who have inflammatory bowel disease and become pregnant, according to separate groups of researchers writing in the March issue of Clinical Gastroenterology and Hepatology.
Both studies confirm that two TNF antagonists do cross the placenta to the fetus at high levels and persist in the infant for months after birth. Discontinuing the drugs during the second trimester lessens but does not eliminate this exposure.
"At this time, we do not know what a safe or harmful level of drug in the newborn is, and what the full consequences of neonatal anti-TNF-alpha exposure to newborn development will be. The risks and benefits of therapy should be individualized, and pediatricians should be cautioned to monitor for potential infections and other abnormalities," said Dr. Uma Mahadevan of the University of California, San Francisco, and her associates (Clin. Gastroenterol. Hepatol. 2012 [doi:10.1016/j.cgh.2012.11.011]).
In their study, Dr. Mahadevan and her colleagues identified 31 pregnant women in their practice or in the Crohn’s Colitis Foundation of America’s Pregnancy IBD and Neonatal Outcomes registry who had Crohn’s disease and were taking infliximab (11 women), adalimumab (10 women), or certolizumab (10 women).
The first two of these anti-TNF-alpha agents are both of the IgG1 subclass and thus should, in theory, cross the placenta at high rates during the third trimester. Certolizumab, a pegylated fragment of an anti-TNF-alpha monoclonal antibody, in theory should not be transported across the placenta. To test these theories, the researchers determined the concentrations of each medication in samples of cord blood, infant serum, and the mother’s plasma taken on the day of birth. None of the infants had birth defects or required neonatal ICU care.
In the infliximab group, the median interval between the last dose of the agent and delivery was 35 days (range, 2-91 days). In every case, cord blood and infant serum samples showed much higher levels of the TNF-alpha antagonist than did maternal plasma samples, at a median ratio of 160:100. The drug persisted in the infants’ circulation for 2-7 months postpartum.
In the adalimumab group, the median interval between the last dose of the agent and delivery was 5.5 weeks. Again, in every case, cord blood and infant serum samples showed much higher levels of the TNF-alpha antagonist than did maternal plasma samples, at a median ratio of 179:100. The drug persisted in the infants’ circulation for at least 11 weeks.
In contrast, no certolizumab was detected in any of the infant samples.
"Based on the results of this study and available safety data, infliximab, adalimumab, and certolizumab can be used through conception and the first and second trimester of pregnancy on schedule. However, the significant placental transfer and subsequent slow postpartum clearance of infliximab and adalimumab raise concerns about their use during the third trimester," Dr. Mahadevan and her associates said.
Such concerns must be balanced against the risk of a flare of IBD, "which has far more consequences to neonatal development," impairing nutritional status of mother and fetus; raising the risk of preterm delivery; and possibly requiring harmful diagnostic testing, medication, and even surgery on the pregnant patient.
Physicians may consider switching patients to certolizumab during pregnancy because of its lack of transfer to the fetus, but "if a pregnant patient is doing well on infliximab or adalimumab, there is no indication, and even a potential risk, of switching ... as the primary goal remains to maintain a quiescent disease state that is critical for a successful pregnancy," they noted.
In the other study, Dr. Zuzana Zelinkova of Erasmus Medical Center, Rotterdam, the Netherlands, and her associates assessed 28 pregnant women who had Crohn’s disease or ulcerative colitis for which they were taking TNF-alpha antagonists.
Of the 17 taking infliximab, 12 had IBD in remission and discontinued the drug at a mean of 23 weeks’ gestation. Three others had perianal fistulas but discontinued early in the second trimester, while two had perianal fistulas and active luminal disease and didn’t discontinue the drug until weeks 30 and 34. None developed IBD relapses.
All 11 study subjects who were taking adalimumab had quiescent disease in the second trimester and discontinued the drug at a mean gestation of 22 weeks (range, 21-27 weeks). Two of them (18%) developed relapses of IBD.
There were three spontaneous miscarriages during the first trimester, and one child was born with polydactyly.
Levels of TNF-alpha antagonists in cord blood samples were significantly lower in the group who discontinued the drugs early, compared with the group who continued taking them until 10 or fewer weeks before delivery. "We recommend considering the discontinuation of anti-TNF-alpha treatment in patients who have quiescent disease at the beginning of the second trimester," to decrease but not completely eliminate the child’s exposure to these agents, Dr. Zelinkova and her associates said.
Dr. Mahadevan’s study was supported by Abbott (marketer of adalimumab), UCB (marketer of certolizumab), Prometheus Labs, and the Crohn’s Colitis Foundation of America. Dr. Mahadevan and her associates reported ties to Janssen (marketer of infliximab), UCB, and Abbott. Dr. Zelinkova and her associates reported ties to Abbott; Merck, Sharp & Dohme; and Shire.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Major Finding: Ratios of infliximab and adalimumab in samples of cord blood and infant serum to maternal plasma occurred at a median of 160:100 and 179:100, respectively, despite discontinuing the drugs a median of 35 days and 5.5 weeks, respectively, before delivery.
Data Source: Two observational studies involving a total of 59 pregnant women in which the levels of anti-TNF-alpha agents were measured in cord blood, infant serum, and maternal plasma on the day of birth.
Disclosures: Dr. Mahadevan’s study was supported by Abbott (marketer of adalimumab), UCB (marketer of certolizumab), Prometheus Labs, and the Crohn’s Colitis Foundation of America. Dr. Mahadevan and her associates reported ties to Janssen (marketer of infliximab), UCB, and Abbott. Dr. Zelinkova and her associates reported ties to Abbott; Merck Sharp & Dohme; and Shire.
Intractable vomiting may signal brainstem autoinflammatory disorder
Intractable nausea and vomiting can be the isolated presenting symptom of neuromyelitis optica spectrum disorder, and gastroenterologists as well as internists need to be more aware of this possibility, even though it is rare, Dr. Raffaele Iorio and his colleagues said in the March issue of Clinical Gastroenterology and Hepatology.
Neuromyelitis optica spectrum disorder is a relapsing inflammatory demyelinating disease of the CNS similar to multiple sclerosis, which progresses to optic neuritis and/or longitudinally extensive transverse myelitis. If untreated, it often results in blindness and confinement to a wheelchair. It is especially important to recognize this disorder as early as possible, so that immunosuppressant therapy can be initiated and progression to such devastating outcomes can be averted, said Dr. Iorio, of the department of laboratory medicine and pathology, Mayo Clinic, Rochester, Minn., and his associates.
Source: American Gastroenterological Association
The cause of neuromyelitis optica spectrum disorder is thought to be autoantibodies that target the astrocytic aquaporin-4 (AQP4) water channel, the principal water channel in the central nervous system. The fourth ventricular floor, which contains the chemosensitive nausea and vomiting center (the area postrema), is a particularly AQP4-enriched region of the brain.
For some patients who develop the disorder, intractable nausea and vomiting may be the only presenting symptom. "These patients commonly undergo extensive, but nonrevealing evaluations on presentation to internists and gastroenterologists, who are largely unaware of this emerging neurological entity." Consequently, many patients are subjected to unnecessary gastroscopy, biopsy, x-rays, ultrasound, CTs, and even surgery, the investigators noted.
They previously reported that a retrospective chart review identified 69 patients diagnosed at the Mayo Clinic as having neuromyelitis optica spectrum disorder. Eight of them (12%) presented with intractable nausea and vomiting as the sole initial symptom.
The researchers have since reviewed an additional 70 charts in their database and now report an additional 10 patients (14% of the 70) in whom intractable nausea and vomiting was the only presenting symptom.
Nine of these 10 patients were women. Mean age of symptom onset was 47 years (range, 26-72 years).
Nausea and vomiting were continuous rather than cyclic, and both occurred day and night. Patients did not report headache or other CNS symptoms, but three had intractable hiccups concomitant with their vomiting.
All 10 patients initially presented to a gastroenterologist or internist. Seven required immediate inpatient IV hydration. Treatment with antiemetics "yielded only partial benefit."
Inflammatory markers, including erythrocyte sedimentation rate and C-reactive protein level, were within normal limits.
A total of 6 of the 10 patients underwent extensive GI evaluation, which included abdominal CT, abdominal ultrasound, small bowel x-ray, upper gastroscopy with biopsy, pelvic and liver CT and ultrasound, gastric-emptying studies, and wireless capsule endoscopy.
One patient underwent cholecystectomy when imaging studies detected a "tiny" gallbladder polyp. Her vomiting worsened after the procedure.
A total of 5 of the 10 patients eventually underwent brain MRI. Three of them showed abnormalities in the area postrema, another showed abnormalities in the deep white matter, and the fifth patient showed no abnormalities on this exam. "With timely MRI imaging ... discrete lesions in the area postrema, the AQP4-rich emetic reflex center of the medulla," usually can be visualized, Dr. Iorio and his associates said.
The mean interval between the onset of vomiting and the development of a classic symptom of neuromyelitis optica spectrum disorder was 111 weeks.
When the disorder was finally suspected, testing revealed AQP4-IgG in serum or cerebrospinal fluid samples in all 10 patients.
During a mean follow-up of 57 months, eight patients progressed to classic neuromyelitis optica and two to neuromyelitis optica spectrum disorder.
The typical disease course included the development of optic neuritis followed by paresthesias of the lower limbs that gradually ascended to the torso. Urinary retention, constipation, and weakness of the extremities accompanied by dysesthesias and ataxia soon ensued.
Treatment with plasmapheresis and methylprednisolone generally relieved gait and sensory complaints and improved bladder and bowel function as well as the nausea and vomiting.
This study was supported by the Guthy-Jackson Charitable Foundation, the National Institutes of Health, the Mayo Foundation for Medical Education and Research, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Iorio reported no financial conflicts of interest. His associates reported holding numerous patents and having ties to Alexion Pharmaceuticals, Novartis, Biogen Idec, Genzyme Corporation, and RSR Ltd.
Intractable nausea and vomiting can be the isolated presenting symptom of neuromyelitis optica spectrum disorder, and gastroenterologists as well as internists need to be more aware of this possibility, even though it is rare, Dr. Raffaele Iorio and his colleagues said in the March issue of Clinical Gastroenterology and Hepatology.
Neuromyelitis optica spectrum disorder is a relapsing inflammatory demyelinating disease of the CNS similar to multiple sclerosis, which progresses to optic neuritis and/or longitudinally extensive transverse myelitis. If untreated, it often results in blindness and confinement to a wheelchair. It is especially important to recognize this disorder as early as possible, so that immunosuppressant therapy can be initiated and progression to such devastating outcomes can be averted, said Dr. Iorio, of the department of laboratory medicine and pathology, Mayo Clinic, Rochester, Minn., and his associates.
Source: American Gastroenterological Association
The cause of neuromyelitis optica spectrum disorder is thought to be autoantibodies that target the astrocytic aquaporin-4 (AQP4) water channel, the principal water channel in the central nervous system. The fourth ventricular floor, which contains the chemosensitive nausea and vomiting center (the area postrema), is a particularly AQP4-enriched region of the brain.
For some patients who develop the disorder, intractable nausea and vomiting may be the only presenting symptom. "These patients commonly undergo extensive, but nonrevealing evaluations on presentation to internists and gastroenterologists, who are largely unaware of this emerging neurological entity." Consequently, many patients are subjected to unnecessary gastroscopy, biopsy, x-rays, ultrasound, CTs, and even surgery, the investigators noted.
They previously reported that a retrospective chart review identified 69 patients diagnosed at the Mayo Clinic as having neuromyelitis optica spectrum disorder. Eight of them (12%) presented with intractable nausea and vomiting as the sole initial symptom.
The researchers have since reviewed an additional 70 charts in their database and now report an additional 10 patients (14% of the 70) in whom intractable nausea and vomiting was the only presenting symptom.
Nine of these 10 patients were women. Mean age of symptom onset was 47 years (range, 26-72 years).
Nausea and vomiting were continuous rather than cyclic, and both occurred day and night. Patients did not report headache or other CNS symptoms, but three had intractable hiccups concomitant with their vomiting.
All 10 patients initially presented to a gastroenterologist or internist. Seven required immediate inpatient IV hydration. Treatment with antiemetics "yielded only partial benefit."
Inflammatory markers, including erythrocyte sedimentation rate and C-reactive protein level, were within normal limits.
A total of 6 of the 10 patients underwent extensive GI evaluation, which included abdominal CT, abdominal ultrasound, small bowel x-ray, upper gastroscopy with biopsy, pelvic and liver CT and ultrasound, gastric-emptying studies, and wireless capsule endoscopy.
One patient underwent cholecystectomy when imaging studies detected a "tiny" gallbladder polyp. Her vomiting worsened after the procedure.
A total of 5 of the 10 patients eventually underwent brain MRI. Three of them showed abnormalities in the area postrema, another showed abnormalities in the deep white matter, and the fifth patient showed no abnormalities on this exam. "With timely MRI imaging ... discrete lesions in the area postrema, the AQP4-rich emetic reflex center of the medulla," usually can be visualized, Dr. Iorio and his associates said.
The mean interval between the onset of vomiting and the development of a classic symptom of neuromyelitis optica spectrum disorder was 111 weeks.
When the disorder was finally suspected, testing revealed AQP4-IgG in serum or cerebrospinal fluid samples in all 10 patients.
During a mean follow-up of 57 months, eight patients progressed to classic neuromyelitis optica and two to neuromyelitis optica spectrum disorder.
The typical disease course included the development of optic neuritis followed by paresthesias of the lower limbs that gradually ascended to the torso. Urinary retention, constipation, and weakness of the extremities accompanied by dysesthesias and ataxia soon ensued.
Treatment with plasmapheresis and methylprednisolone generally relieved gait and sensory complaints and improved bladder and bowel function as well as the nausea and vomiting.
This study was supported by the Guthy-Jackson Charitable Foundation, the National Institutes of Health, the Mayo Foundation for Medical Education and Research, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Iorio reported no financial conflicts of interest. His associates reported holding numerous patents and having ties to Alexion Pharmaceuticals, Novartis, Biogen Idec, Genzyme Corporation, and RSR Ltd.
Intractable nausea and vomiting can be the isolated presenting symptom of neuromyelitis optica spectrum disorder, and gastroenterologists as well as internists need to be more aware of this possibility, even though it is rare, Dr. Raffaele Iorio and his colleagues said in the March issue of Clinical Gastroenterology and Hepatology.
Neuromyelitis optica spectrum disorder is a relapsing inflammatory demyelinating disease of the CNS similar to multiple sclerosis, which progresses to optic neuritis and/or longitudinally extensive transverse myelitis. If untreated, it often results in blindness and confinement to a wheelchair. It is especially important to recognize this disorder as early as possible, so that immunosuppressant therapy can be initiated and progression to such devastating outcomes can be averted, said Dr. Iorio, of the department of laboratory medicine and pathology, Mayo Clinic, Rochester, Minn., and his associates.
Source: American Gastroenterological Association
The cause of neuromyelitis optica spectrum disorder is thought to be autoantibodies that target the astrocytic aquaporin-4 (AQP4) water channel, the principal water channel in the central nervous system. The fourth ventricular floor, which contains the chemosensitive nausea and vomiting center (the area postrema), is a particularly AQP4-enriched region of the brain.
For some patients who develop the disorder, intractable nausea and vomiting may be the only presenting symptom. "These patients commonly undergo extensive, but nonrevealing evaluations on presentation to internists and gastroenterologists, who are largely unaware of this emerging neurological entity." Consequently, many patients are subjected to unnecessary gastroscopy, biopsy, x-rays, ultrasound, CTs, and even surgery, the investigators noted.
They previously reported that a retrospective chart review identified 69 patients diagnosed at the Mayo Clinic as having neuromyelitis optica spectrum disorder. Eight of them (12%) presented with intractable nausea and vomiting as the sole initial symptom.
The researchers have since reviewed an additional 70 charts in their database and now report an additional 10 patients (14% of the 70) in whom intractable nausea and vomiting was the only presenting symptom.
Nine of these 10 patients were women. Mean age of symptom onset was 47 years (range, 26-72 years).
Nausea and vomiting were continuous rather than cyclic, and both occurred day and night. Patients did not report headache or other CNS symptoms, but three had intractable hiccups concomitant with their vomiting.
All 10 patients initially presented to a gastroenterologist or internist. Seven required immediate inpatient IV hydration. Treatment with antiemetics "yielded only partial benefit."
Inflammatory markers, including erythrocyte sedimentation rate and C-reactive protein level, were within normal limits.
A total of 6 of the 10 patients underwent extensive GI evaluation, which included abdominal CT, abdominal ultrasound, small bowel x-ray, upper gastroscopy with biopsy, pelvic and liver CT and ultrasound, gastric-emptying studies, and wireless capsule endoscopy.
One patient underwent cholecystectomy when imaging studies detected a "tiny" gallbladder polyp. Her vomiting worsened after the procedure.
A total of 5 of the 10 patients eventually underwent brain MRI. Three of them showed abnormalities in the area postrema, another showed abnormalities in the deep white matter, and the fifth patient showed no abnormalities on this exam. "With timely MRI imaging ... discrete lesions in the area postrema, the AQP4-rich emetic reflex center of the medulla," usually can be visualized, Dr. Iorio and his associates said.
The mean interval between the onset of vomiting and the development of a classic symptom of neuromyelitis optica spectrum disorder was 111 weeks.
When the disorder was finally suspected, testing revealed AQP4-IgG in serum or cerebrospinal fluid samples in all 10 patients.
During a mean follow-up of 57 months, eight patients progressed to classic neuromyelitis optica and two to neuromyelitis optica spectrum disorder.
The typical disease course included the development of optic neuritis followed by paresthesias of the lower limbs that gradually ascended to the torso. Urinary retention, constipation, and weakness of the extremities accompanied by dysesthesias and ataxia soon ensued.
Treatment with plasmapheresis and methylprednisolone generally relieved gait and sensory complaints and improved bladder and bowel function as well as the nausea and vomiting.
This study was supported by the Guthy-Jackson Charitable Foundation, the National Institutes of Health, the Mayo Foundation for Medical Education and Research, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Iorio reported no financial conflicts of interest. His associates reported holding numerous patents and having ties to Alexion Pharmaceuticals, Novartis, Biogen Idec, Genzyme Corporation, and RSR Ltd.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Major Finding: Ten of 70 patients (14%) with neuromyelitis optica spectrum disorder initially presented to gastroenterologists or internists with intractable nausea and vomiting as their only symptom; in the mean of 111 weeks before the CNS cause of these symptoms was identified, they underwent extensive unnecessary GI evaluation including radiographic imaging, gastroscopies, biopsies, and surgery.
Data Source: A single-center retrospective chart review of 70 cases of neuromyelitis optica spectrum disorder.
Disclosures: This study was supported by the Guthy-Jackson Charitable Foundation, the National Institutes of Health, the Mayo Foundation for Medical Education and Research, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Iorio reported no financial conflicts of interest. His associates reported holding numerous patents and having ties to Alexion Pharmaceuticals, Novartis, Biogen Idec, Genzyme Corp., and RSR Ltd.
Screen asymptomatic siblings of CRC patients
Asymptomatic siblings of Chinese colorectal cancer patients are at threefold higher risk for advanced colorectal neoplasms and at twofold higher risk for any colorectal adenoma, compared with siblings of healthy Chinese adults, Dr. Siew C. Ng and her colleagues reported in the March issue of Gastroenterology (doi:10.1053/j.gastro.2012.11.011).
Given these findings from a large prospective cross-sectional study, colorectal screening, with the removal of any premalignant lesions that are found, is warranted in this high-risk group, said Dr. Ng of the Prince of Wales Hospital and the Chinese University of Hong Kong and her associates.
Source: American Gastroenterological Association
Current guidelines recommend earlier and more frequent screening of close relatives of patients who have colorectal cancer, but what to expect on these screenings is unclear because "data from well-conducted prospective studies are lacking," they said.
Dr. Ng and her colleagues compared the prevalence of advanced neoplasms in such siblings against the prevalence in siblings of patients who underwent colorectal screening but had normal results. "The use of such a control group avoids a biased estimate of the association with family history, and removes the acquired or environmental component to this association," the investigators wrote.
All the screenings used a conventional white-light colonocope without high definition and were performed with patients under conscious sedation with intravenous midazolam and pethidine.
During a period of 10 years, 374 siblings (mean age, 53 years) of CRC patients aged 40-70 years participated in the study, as did 374 age- and sex-matched control subjects. The quality of bowel preparation was similar between the two groups.
All three study endoscopists were experienced, and they had comparable rates of adenoma detection.
The primary outcome was the prevalence of advanced neoplasms, defined as cancers or adenomas at least 10 mm in diameter that had high-grade dysplasia or villous/tubovillous histologic traits. This prevalence was approximately three times higher in the siblings of CRC patients (7.5%) as in the siblings of healthy controls (2.9%), with an odds ratio of 3.07.
Adenocarcinomas were detected in six siblings of CRC patients, but in none of the control subjects. These included two stage I cancers, two stage II cancers, and two stage III cancers.
Similarly, the prevalence of large adenomas was approximately three times as high in siblings of CRC patients (5.9%) as in controls (2.1%).
Siblings of CRC patients also had a higher prevalence of smaller adenomas (31%) than did control subjects (18.2%).
When the data were analyzed by lesion location, the siblings of CRC patients had a higher prevalence of every type: distal adenomas (13.1% vs. 8.3%), proximal adenomas (12.0% vs. 6.2%), and synchronous adenomas (5.9% vs. 2.7%).
The prevalence of hyperplastic polyps was comparable between the two groups (27.3% and 21.4%).
When the data were analyzed by subject age, siblings of CRC patients had a higher prevalence of all colorectal adenomas whether they were younger than 50 years (21.0% vs. 9.8%), 50-60 years old (34.4% vs. 23.9%), or older than 60 years (41.0% vs. 20.5%).
The study findings remained robust in two further sensitivity analyses.
Among the siblings of CRC patients, the risk of detecting an advanced adenoma was higher if the affected sibling’s cancer was located in the distal colon than if it was located in the proximal colon. This risk also was higher if the affected sibling was a woman than a man; however, this finding must be interpreted with caution because the number of subjects in these subgroups was small.
These study results can be used to "provide a background against which screening strategies can be formulated." More important, the strong, significantly increased risk of advanced neoplasms means that siblings of CRC patients should be screened carefully, Dr. Ng and her associates said.
Asymptomatic siblings of Chinese colorectal cancer patients are at threefold higher risk for advanced colorectal neoplasms and at twofold higher risk for any colorectal adenoma, compared with siblings of healthy Chinese adults, Dr. Siew C. Ng and her colleagues reported in the March issue of Gastroenterology (doi:10.1053/j.gastro.2012.11.011).
Given these findings from a large prospective cross-sectional study, colorectal screening, with the removal of any premalignant lesions that are found, is warranted in this high-risk group, said Dr. Ng of the Prince of Wales Hospital and the Chinese University of Hong Kong and her associates.
Source: American Gastroenterological Association
Current guidelines recommend earlier and more frequent screening of close relatives of patients who have colorectal cancer, but what to expect on these screenings is unclear because "data from well-conducted prospective studies are lacking," they said.
Dr. Ng and her colleagues compared the prevalence of advanced neoplasms in such siblings against the prevalence in siblings of patients who underwent colorectal screening but had normal results. "The use of such a control group avoids a biased estimate of the association with family history, and removes the acquired or environmental component to this association," the investigators wrote.
All the screenings used a conventional white-light colonocope without high definition and were performed with patients under conscious sedation with intravenous midazolam and pethidine.
During a period of 10 years, 374 siblings (mean age, 53 years) of CRC patients aged 40-70 years participated in the study, as did 374 age- and sex-matched control subjects. The quality of bowel preparation was similar between the two groups.
All three study endoscopists were experienced, and they had comparable rates of adenoma detection.
The primary outcome was the prevalence of advanced neoplasms, defined as cancers or adenomas at least 10 mm in diameter that had high-grade dysplasia or villous/tubovillous histologic traits. This prevalence was approximately three times higher in the siblings of CRC patients (7.5%) as in the siblings of healthy controls (2.9%), with an odds ratio of 3.07.
Adenocarcinomas were detected in six siblings of CRC patients, but in none of the control subjects. These included two stage I cancers, two stage II cancers, and two stage III cancers.
Similarly, the prevalence of large adenomas was approximately three times as high in siblings of CRC patients (5.9%) as in controls (2.1%).
Siblings of CRC patients also had a higher prevalence of smaller adenomas (31%) than did control subjects (18.2%).
When the data were analyzed by lesion location, the siblings of CRC patients had a higher prevalence of every type: distal adenomas (13.1% vs. 8.3%), proximal adenomas (12.0% vs. 6.2%), and synchronous adenomas (5.9% vs. 2.7%).
The prevalence of hyperplastic polyps was comparable between the two groups (27.3% and 21.4%).
When the data were analyzed by subject age, siblings of CRC patients had a higher prevalence of all colorectal adenomas whether they were younger than 50 years (21.0% vs. 9.8%), 50-60 years old (34.4% vs. 23.9%), or older than 60 years (41.0% vs. 20.5%).
The study findings remained robust in two further sensitivity analyses.
Among the siblings of CRC patients, the risk of detecting an advanced adenoma was higher if the affected sibling’s cancer was located in the distal colon than if it was located in the proximal colon. This risk also was higher if the affected sibling was a woman than a man; however, this finding must be interpreted with caution because the number of subjects in these subgroups was small.
These study results can be used to "provide a background against which screening strategies can be formulated." More important, the strong, significantly increased risk of advanced neoplasms means that siblings of CRC patients should be screened carefully, Dr. Ng and her associates said.
Asymptomatic siblings of Chinese colorectal cancer patients are at threefold higher risk for advanced colorectal neoplasms and at twofold higher risk for any colorectal adenoma, compared with siblings of healthy Chinese adults, Dr. Siew C. Ng and her colleagues reported in the March issue of Gastroenterology (doi:10.1053/j.gastro.2012.11.011).
Given these findings from a large prospective cross-sectional study, colorectal screening, with the removal of any premalignant lesions that are found, is warranted in this high-risk group, said Dr. Ng of the Prince of Wales Hospital and the Chinese University of Hong Kong and her associates.
Source: American Gastroenterological Association
Current guidelines recommend earlier and more frequent screening of close relatives of patients who have colorectal cancer, but what to expect on these screenings is unclear because "data from well-conducted prospective studies are lacking," they said.
Dr. Ng and her colleagues compared the prevalence of advanced neoplasms in such siblings against the prevalence in siblings of patients who underwent colorectal screening but had normal results. "The use of such a control group avoids a biased estimate of the association with family history, and removes the acquired or environmental component to this association," the investigators wrote.
All the screenings used a conventional white-light colonocope without high definition and were performed with patients under conscious sedation with intravenous midazolam and pethidine.
During a period of 10 years, 374 siblings (mean age, 53 years) of CRC patients aged 40-70 years participated in the study, as did 374 age- and sex-matched control subjects. The quality of bowel preparation was similar between the two groups.
All three study endoscopists were experienced, and they had comparable rates of adenoma detection.
The primary outcome was the prevalence of advanced neoplasms, defined as cancers or adenomas at least 10 mm in diameter that had high-grade dysplasia or villous/tubovillous histologic traits. This prevalence was approximately three times higher in the siblings of CRC patients (7.5%) as in the siblings of healthy controls (2.9%), with an odds ratio of 3.07.
Adenocarcinomas were detected in six siblings of CRC patients, but in none of the control subjects. These included two stage I cancers, two stage II cancers, and two stage III cancers.
Similarly, the prevalence of large adenomas was approximately three times as high in siblings of CRC patients (5.9%) as in controls (2.1%).
Siblings of CRC patients also had a higher prevalence of smaller adenomas (31%) than did control subjects (18.2%).
When the data were analyzed by lesion location, the siblings of CRC patients had a higher prevalence of every type: distal adenomas (13.1% vs. 8.3%), proximal adenomas (12.0% vs. 6.2%), and synchronous adenomas (5.9% vs. 2.7%).
The prevalence of hyperplastic polyps was comparable between the two groups (27.3% and 21.4%).
When the data were analyzed by subject age, siblings of CRC patients had a higher prevalence of all colorectal adenomas whether they were younger than 50 years (21.0% vs. 9.8%), 50-60 years old (34.4% vs. 23.9%), or older than 60 years (41.0% vs. 20.5%).
The study findings remained robust in two further sensitivity analyses.
Among the siblings of CRC patients, the risk of detecting an advanced adenoma was higher if the affected sibling’s cancer was located in the distal colon than if it was located in the proximal colon. This risk also was higher if the affected sibling was a woman than a man; however, this finding must be interpreted with caution because the number of subjects in these subgroups was small.
These study results can be used to "provide a background against which screening strategies can be formulated." More important, the strong, significantly increased risk of advanced neoplasms means that siblings of CRC patients should be screened carefully, Dr. Ng and her associates said.
GASTROENTEROLOGY
Major Finding: The prevalence of advanced colorectal neoplasms was approximately three times higher among siblings of colorectal cancer patients (7.5%) as among siblings of adults who had normal colonoscopy results (2.9%).
Data Source: A prospective cross-sectional study of advanced colorectal neoplasms in 374 siblings of Chinese colorectal cancer patients and 374 age- and sex-matched siblings of Chinese volunteers who had negative colonoscopy results.
Disclosures: This study was supported by the Hong Kong Society of Gastroenterology and the Chinese University of Hong Kong. No financial conflicts of interest were reported.