Diana Mahoney

Low androgen levels may be a risk factor for diabetes in men, a population-based study has shown.

In a sample of 1,413 adult men, concentrations of free and bioavailable testosterone in the low normal range were associated with diabetes independent of adiposity, reported Elizabeth Selvin, Ph.D., of Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues. “To our knowledge, this is the first study to examine the association between sex steroid hormones and diabetes in a large, nationally representative male population,” the authors wrote (Diabetes Care 2007;30:234–8).

The study sample included multiethnic U.S. men aged 20 years or older who participated in the morning session of phase I of the Third National Health and Nutrition Examination Survey (NHANES III), which was conducted between 1988 and 1991. “Morning session participants were chosen for this hormone study to reduce extraneous variation due to diurnal production of sex hormones,” the authors wrote. As part of the survey, all of the study participants underwent an interview, an extensive physical examination, and collection of a blood sample.

Height, weight, and waist and hip circumferences were measured as part of the physical examination, and body mass index was calculated. Information on age, race/ethnicity, and diabetes status was collected by patient self-report. With respect to diabetes specifically, interviewers asked participants if they had ever been told by a health professional that they had diabetes or sugar diabetes, the authors noted.

The main hormone measurements of interest in the investigation included serum total testosterone as well as estimated bioavailable and free testosterone levels, which were calculated from serum total testosterone, sex hormone-binding globulin, and albumin concentrations. “Measurements of free and bioavailable testosterone levels more accurately represent concentrations readily available to tissues and metabolic processes,” the authors stated.

In a multivariate model adjusted for age, race/ethnicity, and adiposity, there was no clear association of total testosterone concentration with diabetes; however, men in the lowest tertile (0.09 ng/mL or below) of free testosterone level were more than four times as likely to have prevalent diabetes, compared with men in the highest tertile (higher than 0.14 ng/mL).

Similarly, men in the lowest tertile of bioavailable testosterone (2.11 ng/mL or below) were nearly four times as likely to have prevalent diabetes as were men in the highest tertile (higher than 3.02 ng/mL), the authors reported, noting that “these associations persisted even after further adjustment for total cholesterol, triglycerides, and systolic blood pressure.” In addition, the association with low free testosterone persisted even after the exclusion of men with clinically low levels of total testosterone (less than 3.25 ng/mL) and/or clinically low levels of free testosterone (less than 0.07 ng/mL), suggesting the observed associations were “not entirely driven by hypogonadal men,” they said.

A sensitivity analysis that included 58 cases of undiagnosed diabetes showed no appreciable alterations in the adjusted models, the authors reported.

“The independent association of low free and bioavailable testosterone levels in our adjusted models suggest[s] that testosterone insufficiency may be a risk factor for diabetes,” the authors wrote. Despite the fact that the directionality of the associations between low androgen levels and adiposity are unclear based on the analysis, “our data are consistent with the hypothesis that androgens may directly influence glucose metabolism and the development of insulin resistance independently of the effects of adiposity,” they stated.

The study reported here is the third from the Hormone Demonstration Program, which is supported by the Maryland Cigarette Restitution Fund Research Grant Program at Johns Hopkins University.

Low androgen levels may be a risk factor for diabetes in men, a population-based study has shown.

In a sample of 1,413 adult men, concentrations of free and bioavailable testosterone in the low normal range were associated with diabetes independent of adiposity, reported Elizabeth Selvin, Ph.D., of Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues. “To our knowledge, this is the first study to examine the association between sex steroid hormones and diabetes in a large, nationally representative male population,” the authors wrote (Diabetes Care 2007;30:234–8).

The study sample included multiethnic U.S. men aged 20 years or older who participated in the morning session of phase I of the Third National Health and Nutrition Examination Survey (NHANES III), which was conducted between 1988 and 1991. “Morning session participants were chosen for this hormone study to reduce extraneous variation due to diurnal production of sex hormones,” the authors wrote. As part of the survey, all of the study participants underwent an interview, an extensive physical examination, and collection of a blood sample.

Height, weight, and waist and hip circumferences were measured as part of the physical examination, and body mass index was calculated. Information on age, race/ethnicity, and diabetes status was collected by patient self-report. With respect to diabetes specifically, interviewers asked participants if they had ever been told by a health professional that they had diabetes or sugar diabetes, the authors noted.

The main hormone measurements of interest in the investigation included serum total testosterone as well as estimated bioavailable and free testosterone levels, which were calculated from serum total testosterone, sex hormone-binding globulin, and albumin concentrations. “Measurements of free and bioavailable testosterone levels more accurately represent concentrations readily available to tissues and metabolic processes,” the authors stated.

In a multivariate model adjusted for age, race/ethnicity, and adiposity, there was no clear association of total testosterone concentration with diabetes; however, men in the lowest tertile (0.09 ng/mL or below) of free testosterone level were more than four times as likely to have prevalent diabetes, compared with men in the highest tertile (higher than 0.14 ng/mL).

Similarly, men in the lowest tertile of bioavailable testosterone (2.11 ng/mL or below) were nearly four times as likely to have prevalent diabetes as were men in the highest tertile (higher than 3.02 ng/mL), the authors reported, noting that “these associations persisted even after further adjustment for total cholesterol, triglycerides, and systolic blood pressure.” In addition, the association with low free testosterone persisted even after the exclusion of men with clinically low levels of total testosterone (less than 3.25 ng/mL) and/or clinically low levels of free testosterone (less than 0.07 ng/mL), suggesting the observed associations were “not entirely driven by hypogonadal men,” they said.

A sensitivity analysis that included 58 cases of undiagnosed diabetes showed no appreciable alterations in the adjusted models, the authors reported.

“The independent association of low free and bioavailable testosterone levels in our adjusted models suggest[s] that testosterone insufficiency may be a risk factor for diabetes,” the authors wrote. Despite the fact that the directionality of the associations between low androgen levels and adiposity are unclear based on the analysis, “our data are consistent with the hypothesis that androgens may directly influence glucose metabolism and the development of insulin resistance independently of the effects of adiposity,” they stated.

The study reported here is the third from the Hormone Demonstration Program, which is supported by the Maryland Cigarette Restitution Fund Research Grant Program at Johns Hopkins University.

Low androgen levels may be a risk factor for diabetes in men, a population-based study has shown.

In a sample of 1,413 adult men, concentrations of free and bioavailable testosterone in the low normal range were associated with diabetes independent of adiposity, reported Elizabeth Selvin, Ph.D., of Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues. “To our knowledge, this is the first study to examine the association between sex steroid hormones and diabetes in a large, nationally representative male population,” the authors wrote (Diabetes Care 2007;30:234–8).

The study sample included multiethnic U.S. men aged 20 years or older who participated in the morning session of phase I of the Third National Health and Nutrition Examination Survey (NHANES III), which was conducted between 1988 and 1991. “Morning session participants were chosen for this hormone study to reduce extraneous variation due to diurnal production of sex hormones,” the authors wrote. As part of the survey, all of the study participants underwent an interview, an extensive physical examination, and collection of a blood sample.

Height, weight, and waist and hip circumferences were measured as part of the physical examination, and body mass index was calculated. Information on age, race/ethnicity, and diabetes status was collected by patient self-report. With respect to diabetes specifically, interviewers asked participants if they had ever been told by a health professional that they had diabetes or sugar diabetes, the authors noted.

The main hormone measurements of interest in the investigation included serum total testosterone as well as estimated bioavailable and free testosterone levels, which were calculated from serum total testosterone, sex hormone-binding globulin, and albumin concentrations. “Measurements of free and bioavailable testosterone levels more accurately represent concentrations readily available to tissues and metabolic processes,” the authors stated.

In a multivariate model adjusted for age, race/ethnicity, and adiposity, there was no clear association of total testosterone concentration with diabetes; however, men in the lowest tertile (0.09 ng/mL or below) of free testosterone level were more than four times as likely to have prevalent diabetes, compared with men in the highest tertile (higher than 0.14 ng/mL).

Similarly, men in the lowest tertile of bioavailable testosterone (2.11 ng/mL or below) were nearly four times as likely to have prevalent diabetes as were men in the highest tertile (higher than 3.02 ng/mL), the authors reported, noting that “these associations persisted even after further adjustment for total cholesterol, triglycerides, and systolic blood pressure.” In addition, the association with low free testosterone persisted even after the exclusion of men with clinically low levels of total testosterone (less than 3.25 ng/mL) and/or clinically low levels of free testosterone (less than 0.07 ng/mL), suggesting the observed associations were “not entirely driven by hypogonadal men,” they said.

A sensitivity analysis that included 58 cases of undiagnosed diabetes showed no appreciable alterations in the adjusted models, the authors reported.

“The independent association of low free and bioavailable testosterone levels in our adjusted models suggest[s] that testosterone insufficiency may be a risk factor for diabetes,” the authors wrote. Despite the fact that the directionality of the associations between low androgen levels and adiposity are unclear based on the analysis, “our data are consistent with the hypothesis that androgens may directly influence glucose metabolism and the development of insulin resistance independently of the effects of adiposity,” they stated.

The study reported here is the third from the Hormone Demonstration Program, which is supported by the Maryland Cigarette Restitution Fund Research Grant Program at Johns Hopkins University.

SAN FRANCISCO— Prepregnancy body mass index and gestational weight gain are more predictive of fetal macrosomia than homeostasis model assessment and glucose load, a study has shown.

Because both of these are modifiable risk factors, “they should be emphasized in order to minimize the risk of macrosomia and associated adverse outcomes,” reported Dr. Chloe A. Zera in a poster presentation at the annual meeting of the Society for Maternal-Fetal Medicine.

In a prospective study designed to investigate whether either early or late gestational insulin resistance predicts infant birth weight and risk of macrosomia-related cesarean delivery, Dr. Zera of Boston's Brigham and Women's Hospital and colleagues collected data from 439 pregnant women enrolled in the Massachusetts General Hospital Obstetrical Maternal Study.

The information included homeostasis model assessment (HOMA) data, glucose load test (GLT) results, and clinical information including prepregnant body mass index (BMI), gestational weight gain, maternal age, delivery information, and infant birth weight.

All of the women had fasting blood samples drawn at 16–18 weeks gestation and all had GLT performed as part of routine care. Prepregnancy BMI was based on weight at first prenatal visit.

The investigators used multivariate analysis to predict infant birth weight as a function of the baseline characteristics of the study population and logistic regression to predict the odds of macrosomia and cesarean section, said Dr. Zera.

An analysis of the study population showed that 37% of the women in the study were overweight or obese prior to pregnancy, 17% of the infants in the cohort were macrosomic (more than 4,000 g), 27% of the deliveries were by cesarean section, and 30% of the cesarean deliveries were for macrosomia or failure to progress, Dr. Zera reported.

In the multivariate linear regression analysis, total gestational weight gain, prepregnancy BMI, and maternal age were significant predictors of birth weight, Dr. Zera said, noting that neither HOMA nor GLT were predictive. Both total weight gain and maternal BMI were significantly associated with risk of macrosomia in the logistical regression model, and maternal BMI alone was significantly associated with risk of cesarean section for macrosomia, she said.

Whereas glucose intolerance during pregnancy is thought to be a risk factor for macrosomia, the findings of this study suggest that “both maternal BMI and gestational weight gain may play more of a role than glucose intolerance in determining infant birth weight and subsequent risk of macrosomia and macrosomia-related cesarean delivery,” according to Dr. Zera.

Given these results, it is conceivable that reducing prepregnancy BMI and decreasing gestational weight gain may reduce the risk of macrosomia and subsequent cesarean delivery, Dr. Zera noted. As such, both should be emphasized clinically in women at risk, she said.

SAN FRANCISCO— Prepregnancy body mass index and gestational weight gain are more predictive of fetal macrosomia than homeostasis model assessment and glucose load, a study has shown.

Because both of these are modifiable risk factors, “they should be emphasized in order to minimize the risk of macrosomia and associated adverse outcomes,” reported Dr. Chloe A. Zera in a poster presentation at the annual meeting of the Society for Maternal-Fetal Medicine.

In a prospective study designed to investigate whether either early or late gestational insulin resistance predicts infant birth weight and risk of macrosomia-related cesarean delivery, Dr. Zera of Boston's Brigham and Women's Hospital and colleagues collected data from 439 pregnant women enrolled in the Massachusetts General Hospital Obstetrical Maternal Study.

The information included homeostasis model assessment (HOMA) data, glucose load test (GLT) results, and clinical information including prepregnant body mass index (BMI), gestational weight gain, maternal age, delivery information, and infant birth weight.

All of the women had fasting blood samples drawn at 16–18 weeks gestation and all had GLT performed as part of routine care. Prepregnancy BMI was based on weight at first prenatal visit.

The investigators used multivariate analysis to predict infant birth weight as a function of the baseline characteristics of the study population and logistic regression to predict the odds of macrosomia and cesarean section, said Dr. Zera.

An analysis of the study population showed that 37% of the women in the study were overweight or obese prior to pregnancy, 17% of the infants in the cohort were macrosomic (more than 4,000 g), 27% of the deliveries were by cesarean section, and 30% of the cesarean deliveries were for macrosomia or failure to progress, Dr. Zera reported.

In the multivariate linear regression analysis, total gestational weight gain, prepregnancy BMI, and maternal age were significant predictors of birth weight, Dr. Zera said, noting that neither HOMA nor GLT were predictive. Both total weight gain and maternal BMI were significantly associated with risk of macrosomia in the logistical regression model, and maternal BMI alone was significantly associated with risk of cesarean section for macrosomia, she said.

Whereas glucose intolerance during pregnancy is thought to be a risk factor for macrosomia, the findings of this study suggest that “both maternal BMI and gestational weight gain may play more of a role than glucose intolerance in determining infant birth weight and subsequent risk of macrosomia and macrosomia-related cesarean delivery,” according to Dr. Zera.

Given these results, it is conceivable that reducing prepregnancy BMI and decreasing gestational weight gain may reduce the risk of macrosomia and subsequent cesarean delivery, Dr. Zera noted. As such, both should be emphasized clinically in women at risk, she said.

SAN FRANCISCO— Prepregnancy body mass index and gestational weight gain are more predictive of fetal macrosomia than homeostasis model assessment and glucose load, a study has shown.

Because both of these are modifiable risk factors, “they should be emphasized in order to minimize the risk of macrosomia and associated adverse outcomes,” reported Dr. Chloe A. Zera in a poster presentation at the annual meeting of the Society for Maternal-Fetal Medicine.

In a prospective study designed to investigate whether either early or late gestational insulin resistance predicts infant birth weight and risk of macrosomia-related cesarean delivery, Dr. Zera of Boston's Brigham and Women's Hospital and colleagues collected data from 439 pregnant women enrolled in the Massachusetts General Hospital Obstetrical Maternal Study.

The information included homeostasis model assessment (HOMA) data, glucose load test (GLT) results, and clinical information including prepregnant body mass index (BMI), gestational weight gain, maternal age, delivery information, and infant birth weight.

All of the women had fasting blood samples drawn at 16–18 weeks gestation and all had GLT performed as part of routine care. Prepregnancy BMI was based on weight at first prenatal visit.

The investigators used multivariate analysis to predict infant birth weight as a function of the baseline characteristics of the study population and logistic regression to predict the odds of macrosomia and cesarean section, said Dr. Zera.

An analysis of the study population showed that 37% of the women in the study were overweight or obese prior to pregnancy, 17% of the infants in the cohort were macrosomic (more than 4,000 g), 27% of the deliveries were by cesarean section, and 30% of the cesarean deliveries were for macrosomia or failure to progress, Dr. Zera reported.

In the multivariate linear regression analysis, total gestational weight gain, prepregnancy BMI, and maternal age were significant predictors of birth weight, Dr. Zera said, noting that neither HOMA nor GLT were predictive. Both total weight gain and maternal BMI were significantly associated with risk of macrosomia in the logistical regression model, and maternal BMI alone was significantly associated with risk of cesarean section for macrosomia, she said.

Whereas glucose intolerance during pregnancy is thought to be a risk factor for macrosomia, the findings of this study suggest that “both maternal BMI and gestational weight gain may play more of a role than glucose intolerance in determining infant birth weight and subsequent risk of macrosomia and macrosomia-related cesarean delivery,” according to Dr. Zera.

Given these results, it is conceivable that reducing prepregnancy BMI and decreasing gestational weight gain may reduce the risk of macrosomia and subsequent cesarean delivery, Dr. Zera noted. As such, both should be emphasized clinically in women at risk, she said.

Intramuscular methylprednisolone can significantly improve symptoms and function in patients with inflammatory hand pain, a proof of concept study has shown.

To test the hypothesis that predominant hand pain with diurnal variation and morning stiffness lasting for at least 30 minutes has an inflammatory etiology and should respond to corticosteroids, Dr. Zunaid Karim of Chapel Allerton Hospital in Leeds, England, and colleagues evaluated the efficacy of intramuscular methylprednisolone treatment in 102 patients who presented to the Leeds Early Arthritis Clinic with more than 3 months of symptoms and who had failed to respond to nonsteroidal anti-inflammatory drugs (Ann. Rheum. Dis. 2007 Jan. 22 [Epub: doi:10.1136/ard.2006.061861]). Patients with clinical synovitis in five or more joints, as well as those with gout, connective tissue disease, or rheumatoid arthritis were excluded, as were those with sensitivity to corticosteroids or hydroxychloroquine.

The presence of two of the following three conditions was considered indicative of clinical synovitis: joint swelling, joint tenderness, and reduced range of movement. Ultrasound was performed on the second to fifth metacarpal, phalangeal, and proximal interphalangeal joints, and synovitis was defined as the presence of abnormally hypoechoic intra-articular tissue that was nondisplaceable and poorly compressible.

At baseline, 21% of the patients were rheumatoid factor positive, 25% had elevated C-reactive protein levels, and 5% tested positive for antinuclear antibodies, the authors reported. Additionally, 23% of the patients had clinical synovitis and 55% had ultrasound-detected synovitis.

Participating patients received an intramuscular injection of 120 mg of methylprednisolone at baseline and were assessed for response (defined as 50% improvement in pain and stiffness symptoms) at 4 weeks, then every 12 weeks for 48 weeks. Patients who responded initially but subsequently relapsed received an additional methylprednisolone injection and were started on 200 mg daily of hydroxychloroquine, with response assessment after 24 weeks.

Of the initial 102 patients, 11 did not complete the 4-week assessment and were excluded from the study. The remaining 91 patients, mean age 51 years, were predominantly female (81%) and had a mean symptom duration of 7 months.

Response at 4 weeks was observed in 66 of the 91 patients (73%), with associated significant reductions in morning stiffness, Health Assessment Questionnaire results, painful and tender joint counts, and patient visual analog scores, the authors wrote. Both ultrasound-detected synovitis and rheumatoid factor were associated significantly with methylprednisolone response, while clinical synovitis and elevated C-reactive protein were not, the investigators reported.

Of the 66 responders, 24 remained well to the end of the study. The remaining 42 patients relapsed within 24 weeks and received a repeat methylprednisolone injection and hydroxychloroquine. Of these patients, 28 remained on the drug long term and 24 of the 28 reported a benefit, the authors noted. The findings may be limited by the lack of sensitivity of the clinical synovitis assessment. Additionally, it is unclear whether the response seen in the hydroxychloroquine group is a function of the repeat methylprednisolone injection or the hydroxychloroquine.

Intramuscular methylprednisolone can significantly improve symptoms and function in patients with inflammatory hand pain, a proof of concept study has shown.

To test the hypothesis that predominant hand pain with diurnal variation and morning stiffness lasting for at least 30 minutes has an inflammatory etiology and should respond to corticosteroids, Dr. Zunaid Karim of Chapel Allerton Hospital in Leeds, England, and colleagues evaluated the efficacy of intramuscular methylprednisolone treatment in 102 patients who presented to the Leeds Early Arthritis Clinic with more than 3 months of symptoms and who had failed to respond to nonsteroidal anti-inflammatory drugs (Ann. Rheum. Dis. 2007 Jan. 22 [Epub: doi:10.1136/ard.2006.061861]). Patients with clinical synovitis in five or more joints, as well as those with gout, connective tissue disease, or rheumatoid arthritis were excluded, as were those with sensitivity to corticosteroids or hydroxychloroquine.

The presence of two of the following three conditions was considered indicative of clinical synovitis: joint swelling, joint tenderness, and reduced range of movement. Ultrasound was performed on the second to fifth metacarpal, phalangeal, and proximal interphalangeal joints, and synovitis was defined as the presence of abnormally hypoechoic intra-articular tissue that was nondisplaceable and poorly compressible.

At baseline, 21% of the patients were rheumatoid factor positive, 25% had elevated C-reactive protein levels, and 5% tested positive for antinuclear antibodies, the authors reported. Additionally, 23% of the patients had clinical synovitis and 55% had ultrasound-detected synovitis.

Participating patients received an intramuscular injection of 120 mg of methylprednisolone at baseline and were assessed for response (defined as 50% improvement in pain and stiffness symptoms) at 4 weeks, then every 12 weeks for 48 weeks. Patients who responded initially but subsequently relapsed received an additional methylprednisolone injection and were started on 200 mg daily of hydroxychloroquine, with response assessment after 24 weeks.

Of the initial 102 patients, 11 did not complete the 4-week assessment and were excluded from the study. The remaining 91 patients, mean age 51 years, were predominantly female (81%) and had a mean symptom duration of 7 months.

Response at 4 weeks was observed in 66 of the 91 patients (73%), with associated significant reductions in morning stiffness, Health Assessment Questionnaire results, painful and tender joint counts, and patient visual analog scores, the authors wrote. Both ultrasound-detected synovitis and rheumatoid factor were associated significantly with methylprednisolone response, while clinical synovitis and elevated C-reactive protein were not, the investigators reported.

Of the 66 responders, 24 remained well to the end of the study. The remaining 42 patients relapsed within 24 weeks and received a repeat methylprednisolone injection and hydroxychloroquine. Of these patients, 28 remained on the drug long term and 24 of the 28 reported a benefit, the authors noted. The findings may be limited by the lack of sensitivity of the clinical synovitis assessment. Additionally, it is unclear whether the response seen in the hydroxychloroquine group is a function of the repeat methylprednisolone injection or the hydroxychloroquine.

Intramuscular methylprednisolone can significantly improve symptoms and function in patients with inflammatory hand pain, a proof of concept study has shown.

To test the hypothesis that predominant hand pain with diurnal variation and morning stiffness lasting for at least 30 minutes has an inflammatory etiology and should respond to corticosteroids, Dr. Zunaid Karim of Chapel Allerton Hospital in Leeds, England, and colleagues evaluated the efficacy of intramuscular methylprednisolone treatment in 102 patients who presented to the Leeds Early Arthritis Clinic with more than 3 months of symptoms and who had failed to respond to nonsteroidal anti-inflammatory drugs (Ann. Rheum. Dis. 2007 Jan. 22 [Epub: doi:10.1136/ard.2006.061861]). Patients with clinical synovitis in five or more joints, as well as those with gout, connective tissue disease, or rheumatoid arthritis were excluded, as were those with sensitivity to corticosteroids or hydroxychloroquine.

The presence of two of the following three conditions was considered indicative of clinical synovitis: joint swelling, joint tenderness, and reduced range of movement. Ultrasound was performed on the second to fifth metacarpal, phalangeal, and proximal interphalangeal joints, and synovitis was defined as the presence of abnormally hypoechoic intra-articular tissue that was nondisplaceable and poorly compressible.

At baseline, 21% of the patients were rheumatoid factor positive, 25% had elevated C-reactive protein levels, and 5% tested positive for antinuclear antibodies, the authors reported. Additionally, 23% of the patients had clinical synovitis and 55% had ultrasound-detected synovitis.

Participating patients received an intramuscular injection of 120 mg of methylprednisolone at baseline and were assessed for response (defined as 50% improvement in pain and stiffness symptoms) at 4 weeks, then every 12 weeks for 48 weeks. Patients who responded initially but subsequently relapsed received an additional methylprednisolone injection and were started on 200 mg daily of hydroxychloroquine, with response assessment after 24 weeks.

Of the initial 102 patients, 11 did not complete the 4-week assessment and were excluded from the study. The remaining 91 patients, mean age 51 years, were predominantly female (81%) and had a mean symptom duration of 7 months.

Response at 4 weeks was observed in 66 of the 91 patients (73%), with associated significant reductions in morning stiffness, Health Assessment Questionnaire results, painful and tender joint counts, and patient visual analog scores, the authors wrote. Both ultrasound-detected synovitis and rheumatoid factor were associated significantly with methylprednisolone response, while clinical synovitis and elevated C-reactive protein were not, the investigators reported.

Of the 66 responders, 24 remained well to the end of the study. The remaining 42 patients relapsed within 24 weeks and received a repeat methylprednisolone injection and hydroxychloroquine. Of these patients, 28 remained on the drug long term and 24 of the 28 reported a benefit, the authors noted. The findings may be limited by the lack of sensitivity of the clinical synovitis assessment. Additionally, it is unclear whether the response seen in the hydroxychloroquine group is a function of the repeat methylprednisolone injection or the hydroxychloroquine.

The absence of large joint involvement, higher serum C-reactive protein levels, and lower disability scores at treatment initiation may be predictors of a good therapeutic response to infliximab in refractory psoriatic polyarthritis, an open-label study has shown.

The efficacy of infliximab in psoriatic arthritis patients has been demonstrated in several placebo controlled and open label trials, but the high cost and potential risks associated with the anti-tumor necrosis factor-α (TNF-α) agent warrants careful selection of patients who are most likely to benefit from this treatment, wrote Dr. Jordi Gratacós of Parc Taulí University Hospital in Barcelona, and colleagues.

To this end, the investigators sought to identify variables associated with a good clinical response in psoriatic arthritis patients being treated with the drug (Ann. Rheum. Dis. 2007 Jan. 25 [Epub doi: 10.1136/ard.2006.060079]).

The multicenter study included 69 patients with active psoriatic arthritis who showed no clinically significant response to at least 8 weeks of treatment with 15 mg of methotrexate weekly. Per study criteria, patients had to have peripheral polyarthritis—defined by the presence of five or more swollen and tender joints—and at least one of the following criteria: morning stiffness lasting more than 45 minutes, an erythrocyte sedimentation rate (ESR) of more than 30 mm per first hour, or a C-reactive protein (CRP) level greater than 15 mg/L. Patients testing positive for rheumatoid factor were excluded from the investigation.

In addition to their stable doses of methotrexate, study participants received 5mg/kg of inifliximab every 8 weeks.

In an intent-to-treat analysis conducted at 38 weeks of active treatment, 30 of the 69 patients (44%) experienced a major clinical response, defined as an improvement of at least 50% of the initial American College of Rheumatology (ACR) composite index, the authors reported. With use of the ACR20 and ACR70 measures, 44 and 18 patients, respectively, were identified as responders.

The results of a univariate analysis based on an ACR50 response at 38 weeks as the main outcome showed that involvement of large joints (hip or knee) and a high level of disability, defined as a score of 2 or higher on the validated Health Assessment Questionnaire (HAQ) at the start of treatment “were both predictors of smaller response to infliximab than in patients with no involvement of the large joints and an HAQ less than 2,” the authors wrote.

When the univariate analysis was performed at 14 weeks, the results were similar except for associations with CRP and age.

In the 14-week analysis, the presence of a CRP of at least 10 mg/L at the start of treatment “was associated with a significantly high rate of response,” reported the authors. And patients who achieved an ACR50 were younger (mean age 39 years), compared with those who did not respond (mean age 45 years), they wrote.

In a multivariate logistic regression model, CRP values and the absence of arthritis in the hip or knee or both were independent predictors of an ACR50 response.

Severe disability was not a significant predictor, but there was a trend toward an association, the authors reported.

While the results of this study suggest that some variables may significantly influence the treatment response to infliximab among patients with psoriatic arthritis, “the data reported here cannot be used as a definitive guide for deciding which patients should be given anti-TNF treatment,” the authors stressed, noting the study's small size and focus on patients with the most severe and refractory disease usually seen in clinical practice. “Large studies supporting our data will be needed in order to prove our statistical model and to establish more accurately the predictive factors for clinical response to infliximab in patients with [psoriatic arthritis],” they concluded.

The absence of large joint involvement, higher serum C-reactive protein levels, and lower disability scores at treatment initiation may be predictors of a good therapeutic response to infliximab in refractory psoriatic polyarthritis, an open-label study has shown.

The efficacy of infliximab in psoriatic arthritis patients has been demonstrated in several placebo controlled and open label trials, but the high cost and potential risks associated with the anti-tumor necrosis factor-α (TNF-α) agent warrants careful selection of patients who are most likely to benefit from this treatment, wrote Dr. Jordi Gratacós of Parc Taulí University Hospital in Barcelona, and colleagues.

To this end, the investigators sought to identify variables associated with a good clinical response in psoriatic arthritis patients being treated with the drug (Ann. Rheum. Dis. 2007 Jan. 25 [Epub doi: 10.1136/ard.2006.060079]).

The multicenter study included 69 patients with active psoriatic arthritis who showed no clinically significant response to at least 8 weeks of treatment with 15 mg of methotrexate weekly. Per study criteria, patients had to have peripheral polyarthritis—defined by the presence of five or more swollen and tender joints—and at least one of the following criteria: morning stiffness lasting more than 45 minutes, an erythrocyte sedimentation rate (ESR) of more than 30 mm per first hour, or a C-reactive protein (CRP) level greater than 15 mg/L. Patients testing positive for rheumatoid factor were excluded from the investigation.

In addition to their stable doses of methotrexate, study participants received 5mg/kg of inifliximab every 8 weeks.

In an intent-to-treat analysis conducted at 38 weeks of active treatment, 30 of the 69 patients (44%) experienced a major clinical response, defined as an improvement of at least 50% of the initial American College of Rheumatology (ACR) composite index, the authors reported. With use of the ACR20 and ACR70 measures, 44 and 18 patients, respectively, were identified as responders.

The results of a univariate analysis based on an ACR50 response at 38 weeks as the main outcome showed that involvement of large joints (hip or knee) and a high level of disability, defined as a score of 2 or higher on the validated Health Assessment Questionnaire (HAQ) at the start of treatment “were both predictors of smaller response to infliximab than in patients with no involvement of the large joints and an HAQ less than 2,” the authors wrote.

When the univariate analysis was performed at 14 weeks, the results were similar except for associations with CRP and age.

In the 14-week analysis, the presence of a CRP of at least 10 mg/L at the start of treatment “was associated with a significantly high rate of response,” reported the authors. And patients who achieved an ACR50 were younger (mean age 39 years), compared with those who did not respond (mean age 45 years), they wrote.

In a multivariate logistic regression model, CRP values and the absence of arthritis in the hip or knee or both were independent predictors of an ACR50 response.

Severe disability was not a significant predictor, but there was a trend toward an association, the authors reported.

While the results of this study suggest that some variables may significantly influence the treatment response to infliximab among patients with psoriatic arthritis, “the data reported here cannot be used as a definitive guide for deciding which patients should be given anti-TNF treatment,” the authors stressed, noting the study's small size and focus on patients with the most severe and refractory disease usually seen in clinical practice. “Large studies supporting our data will be needed in order to prove our statistical model and to establish more accurately the predictive factors for clinical response to infliximab in patients with [psoriatic arthritis],” they concluded.

The absence of large joint involvement, higher serum C-reactive protein levels, and lower disability scores at treatment initiation may be predictors of a good therapeutic response to infliximab in refractory psoriatic polyarthritis, an open-label study has shown.

The efficacy of infliximab in psoriatic arthritis patients has been demonstrated in several placebo controlled and open label trials, but the high cost and potential risks associated with the anti-tumor necrosis factor-α (TNF-α) agent warrants careful selection of patients who are most likely to benefit from this treatment, wrote Dr. Jordi Gratacós of Parc Taulí University Hospital in Barcelona, and colleagues.

To this end, the investigators sought to identify variables associated with a good clinical response in psoriatic arthritis patients being treated with the drug (Ann. Rheum. Dis. 2007 Jan. 25 [Epub doi: 10.1136/ard.2006.060079]).

The multicenter study included 69 patients with active psoriatic arthritis who showed no clinically significant response to at least 8 weeks of treatment with 15 mg of methotrexate weekly. Per study criteria, patients had to have peripheral polyarthritis—defined by the presence of five or more swollen and tender joints—and at least one of the following criteria: morning stiffness lasting more than 45 minutes, an erythrocyte sedimentation rate (ESR) of more than 30 mm per first hour, or a C-reactive protein (CRP) level greater than 15 mg/L. Patients testing positive for rheumatoid factor were excluded from the investigation.

In addition to their stable doses of methotrexate, study participants received 5mg/kg of inifliximab every 8 weeks.

In an intent-to-treat analysis conducted at 38 weeks of active treatment, 30 of the 69 patients (44%) experienced a major clinical response, defined as an improvement of at least 50% of the initial American College of Rheumatology (ACR) composite index, the authors reported. With use of the ACR20 and ACR70 measures, 44 and 18 patients, respectively, were identified as responders.

The results of a univariate analysis based on an ACR50 response at 38 weeks as the main outcome showed that involvement of large joints (hip or knee) and a high level of disability, defined as a score of 2 or higher on the validated Health Assessment Questionnaire (HAQ) at the start of treatment “were both predictors of smaller response to infliximab than in patients with no involvement of the large joints and an HAQ less than 2,” the authors wrote.

When the univariate analysis was performed at 14 weeks, the results were similar except for associations with CRP and age.

In the 14-week analysis, the presence of a CRP of at least 10 mg/L at the start of treatment “was associated with a significantly high rate of response,” reported the authors. And patients who achieved an ACR50 were younger (mean age 39 years), compared with those who did not respond (mean age 45 years), they wrote.

In a multivariate logistic regression model, CRP values and the absence of arthritis in the hip or knee or both were independent predictors of an ACR50 response.

Severe disability was not a significant predictor, but there was a trend toward an association, the authors reported.

While the results of this study suggest that some variables may significantly influence the treatment response to infliximab among patients with psoriatic arthritis, “the data reported here cannot be used as a definitive guide for deciding which patients should be given anti-TNF treatment,” the authors stressed, noting the study's small size and focus on patients with the most severe and refractory disease usually seen in clinical practice. “Large studies supporting our data will be needed in order to prove our statistical model and to establish more accurately the predictive factors for clinical response to infliximab in patients with [psoriatic arthritis],” they concluded.

Cigarette smoking does not appear to negatively influence the progression of radiographic damage in rheumatoid arthritis, a prospective study has shown. In fact, radiographic progression of disease was significantly less among heavy smokers than among moderate smokers and nonsmokers in the longitudinal observational investigation of rheumatoid arthritis patients.

Because smoking is an established risk factor for the development of rheumatoid arthritis (RA), investigators with the Swiss Clinical Quality Management (SCQM) project for RA—a population-based registry designed to monitor disease activity—hypothesized that smoking would exacerbate disease progression. Yet, a comparison of smokers and nonsmokers from the registry showed that radiographic joint damage progressed at an equivalent rate in both groups, reported Dr. Axel Finckh of the Geneva University Hospital and colleagues. “Furthermore, we observed a significant trend for reduced radiographic progression and generally more favorable functional scores among heavy smokers, suggesting that cigarette smoke does not accelerate RA disease progress,” the authors wrote (Ann. Rheum. Dis. 2007 [Epub doi: 10.1136/ard.2006.065060]).

The SCQM system requests at least yearly assessments of disease activity, radiographic damage, antirheumatic therapy, sociodemographic factors, and lifestyle characteristics, including cigarette-smoking history. The cohort for the current study included 2,004 registry patients for whom cigarette smoking history and at least two consecutive sets of radiographs were available.

Progression of radiographic joint damage, as measured by changes from baseline in radiographic damage scores, was the study's primary outcome, and the progression of functional disability as measured by change from baseline in the Stanford Health Assessment Questionnaire (HAQ) disability index was the secondary outcome. The outcome analyses included data collected between March 1996 and November 2005.

Of the 2,004 patients eligible for study inclusion, 545 were current smokers consuming, on average 16 cigarettes per day, with a mean past smoking exposure of 20.6 pack-years. Of the 545 smokers, 55 were characterized as heavy smokers with a reported average intake of 33 cigarettes per day and 27.7 years of smoking and 489 met the criteria for moderate smokers, with an average of 13 cigarettes per day and 24.2 years of smoking.

The smokers were predominantly younger males with shorter disease durations and less joint erosions at baseline, the authors reported. There were no significant differences between smokers and nonsmokers with respect to other important risk factors for disease progression, such as rheumatoid factor seropositivity, antirheumatic therapy, glucocorticoid use, functional status, and educational level.

In both crude and adjusted models of radiographic progression, there was no evidence for more rapid progression among smokers than nonsmokers, according to the authors. “In the fully adjusted model, radiographic damage progressed by 2.79% at 2 years in nonsmokers compared to 2.51% in smokers.”

There was an inverse dose-response effect for heavy smokers, compared with moderate smokers and nonsmokers. “Specifically, radiographic erosions evolved significantly more slowly in heavy smokers [average 1.21% in 2 years] compared to nonsmokers [2.86%], whereas erosive disease in moderate smokers [2.71%] progressed at a rate similar to that in nonsmokers,” the authors reported.

A sensitivity analysis examining current smoking exposure as a continuous variable and with an alternative categorization demonstrated a similar inverse dose-response effect as did analyses restricted to subgroups of patients with rheumatoid factor-positive disease, male patients, and patients treated with tumor necrosis factor inhibitors, according to the authors, who noted that “the strongest predictors of radiographic damage progression were disease duration, baseline radiographic damage, and rheumatoid factor.”

With respect to functional disability, “overall, mean HAQ scores tended to improve somewhat during the first years of the observation,” the authors reported, linking the improvements to the initiation of new antirheumatic therapies at the time of enrollment.

As for functional capacity relative to smoking status, “the evolution of HAQ scores did not differ significantly between smokers and nonsmokers,” the authors wrote, nor was there a significant inverse dose-response effect in heavy smokers, compared with moderate smokers and nonsmokers. High baseline HAQ score, female gender, rheumatoid factor, and lower educational levels were strong predictors for functional disability.

The results of this study suggest, “that smoking may be more important in the initiation of RA than in the perpetuation of the erosive disease process,” the authors noted.

Previous studies have shown some protective effects of smoking in several inflammatory diseases, and nicotine specifically has been shown to have anti-inflammatory properties, which may support the current findings in RA patients, the authors wrote. Smoking or nicotine exposure should not be a therapeutic consideration. “Global health risks associated with smoking are much greater than those potential benefits,” they said.

The exclusion from the study of registry patients with no radiographic follow-up could potentially contribute to a selection bias, although there is no indication that the missing radiographic follow-up was associated with smoking and more severe radiographic progression, the authors wrote.

Cigarette smoking does not appear to negatively influence the progression of radiographic damage in rheumatoid arthritis, a prospective study has shown. In fact, radiographic progression of disease was significantly less among heavy smokers than among moderate smokers and nonsmokers in the longitudinal observational investigation of rheumatoid arthritis patients.

Because smoking is an established risk factor for the development of rheumatoid arthritis (RA), investigators with the Swiss Clinical Quality Management (SCQM) project for RA—a population-based registry designed to monitor disease activity—hypothesized that smoking would exacerbate disease progression. Yet, a comparison of smokers and nonsmokers from the registry showed that radiographic joint damage progressed at an equivalent rate in both groups, reported Dr. Axel Finckh of the Geneva University Hospital and colleagues. “Furthermore, we observed a significant trend for reduced radiographic progression and generally more favorable functional scores among heavy smokers, suggesting that cigarette smoke does not accelerate RA disease progress,” the authors wrote (Ann. Rheum. Dis. 2007 [Epub doi: 10.1136/ard.2006.065060]).

The SCQM system requests at least yearly assessments of disease activity, radiographic damage, antirheumatic therapy, sociodemographic factors, and lifestyle characteristics, including cigarette-smoking history. The cohort for the current study included 2,004 registry patients for whom cigarette smoking history and at least two consecutive sets of radiographs were available.

Progression of radiographic joint damage, as measured by changes from baseline in radiographic damage scores, was the study's primary outcome, and the progression of functional disability as measured by change from baseline in the Stanford Health Assessment Questionnaire (HAQ) disability index was the secondary outcome. The outcome analyses included data collected between March 1996 and November 2005.

Of the 2,004 patients eligible for study inclusion, 545 were current smokers consuming, on average 16 cigarettes per day, with a mean past smoking exposure of 20.6 pack-years. Of the 545 smokers, 55 were characterized as heavy smokers with a reported average intake of 33 cigarettes per day and 27.7 years of smoking and 489 met the criteria for moderate smokers, with an average of 13 cigarettes per day and 24.2 years of smoking.

The smokers were predominantly younger males with shorter disease durations and less joint erosions at baseline, the authors reported. There were no significant differences between smokers and nonsmokers with respect to other important risk factors for disease progression, such as rheumatoid factor seropositivity, antirheumatic therapy, glucocorticoid use, functional status, and educational level.

In both crude and adjusted models of radiographic progression, there was no evidence for more rapid progression among smokers than nonsmokers, according to the authors. “In the fully adjusted model, radiographic damage progressed by 2.79% at 2 years in nonsmokers compared to 2.51% in smokers.”

There was an inverse dose-response effect for heavy smokers, compared with moderate smokers and nonsmokers. “Specifically, radiographic erosions evolved significantly more slowly in heavy smokers [average 1.21% in 2 years] compared to nonsmokers [2.86%], whereas erosive disease in moderate smokers [2.71%] progressed at a rate similar to that in nonsmokers,” the authors reported.

A sensitivity analysis examining current smoking exposure as a continuous variable and with an alternative categorization demonstrated a similar inverse dose-response effect as did analyses restricted to subgroups of patients with rheumatoid factor-positive disease, male patients, and patients treated with tumor necrosis factor inhibitors, according to the authors, who noted that “the strongest predictors of radiographic damage progression were disease duration, baseline radiographic damage, and rheumatoid factor.”

With respect to functional disability, “overall, mean HAQ scores tended to improve somewhat during the first years of the observation,” the authors reported, linking the improvements to the initiation of new antirheumatic therapies at the time of enrollment.

As for functional capacity relative to smoking status, “the evolution of HAQ scores did not differ significantly between smokers and nonsmokers,” the authors wrote, nor was there a significant inverse dose-response effect in heavy smokers, compared with moderate smokers and nonsmokers. High baseline HAQ score, female gender, rheumatoid factor, and lower educational levels were strong predictors for functional disability.

The results of this study suggest, “that smoking may be more important in the initiation of RA than in the perpetuation of the erosive disease process,” the authors noted.

Previous studies have shown some protective effects of smoking in several inflammatory diseases, and nicotine specifically has been shown to have anti-inflammatory properties, which may support the current findings in RA patients, the authors wrote. Smoking or nicotine exposure should not be a therapeutic consideration. “Global health risks associated with smoking are much greater than those potential benefits,” they said.

The exclusion from the study of registry patients with no radiographic follow-up could potentially contribute to a selection bias, although there is no indication that the missing radiographic follow-up was associated with smoking and more severe radiographic progression, the authors wrote.

Cigarette smoking does not appear to negatively influence the progression of radiographic damage in rheumatoid arthritis, a prospective study has shown. In fact, radiographic progression of disease was significantly less among heavy smokers than among moderate smokers and nonsmokers in the longitudinal observational investigation of rheumatoid arthritis patients.

Because smoking is an established risk factor for the development of rheumatoid arthritis (RA), investigators with the Swiss Clinical Quality Management (SCQM) project for RA—a population-based registry designed to monitor disease activity—hypothesized that smoking would exacerbate disease progression. Yet, a comparison of smokers and nonsmokers from the registry showed that radiographic joint damage progressed at an equivalent rate in both groups, reported Dr. Axel Finckh of the Geneva University Hospital and colleagues. “Furthermore, we observed a significant trend for reduced radiographic progression and generally more favorable functional scores among heavy smokers, suggesting that cigarette smoke does not accelerate RA disease progress,” the authors wrote (Ann. Rheum. Dis. 2007 [Epub doi: 10.1136/ard.2006.065060]).

The SCQM system requests at least yearly assessments of disease activity, radiographic damage, antirheumatic therapy, sociodemographic factors, and lifestyle characteristics, including cigarette-smoking history. The cohort for the current study included 2,004 registry patients for whom cigarette smoking history and at least two consecutive sets of radiographs were available.

Progression of radiographic joint damage, as measured by changes from baseline in radiographic damage scores, was the study's primary outcome, and the progression of functional disability as measured by change from baseline in the Stanford Health Assessment Questionnaire (HAQ) disability index was the secondary outcome. The outcome analyses included data collected between March 1996 and November 2005.

Of the 2,004 patients eligible for study inclusion, 545 were current smokers consuming, on average 16 cigarettes per day, with a mean past smoking exposure of 20.6 pack-years. Of the 545 smokers, 55 were characterized as heavy smokers with a reported average intake of 33 cigarettes per day and 27.7 years of smoking and 489 met the criteria for moderate smokers, with an average of 13 cigarettes per day and 24.2 years of smoking.

The smokers were predominantly younger males with shorter disease durations and less joint erosions at baseline, the authors reported. There were no significant differences between smokers and nonsmokers with respect to other important risk factors for disease progression, such as rheumatoid factor seropositivity, antirheumatic therapy, glucocorticoid use, functional status, and educational level.

In both crude and adjusted models of radiographic progression, there was no evidence for more rapid progression among smokers than nonsmokers, according to the authors. “In the fully adjusted model, radiographic damage progressed by 2.79% at 2 years in nonsmokers compared to 2.51% in smokers.”

There was an inverse dose-response effect for heavy smokers, compared with moderate smokers and nonsmokers. “Specifically, radiographic erosions evolved significantly more slowly in heavy smokers [average 1.21% in 2 years] compared to nonsmokers [2.86%], whereas erosive disease in moderate smokers [2.71%] progressed at a rate similar to that in nonsmokers,” the authors reported.

A sensitivity analysis examining current smoking exposure as a continuous variable and with an alternative categorization demonstrated a similar inverse dose-response effect as did analyses restricted to subgroups of patients with rheumatoid factor-positive disease, male patients, and patients treated with tumor necrosis factor inhibitors, according to the authors, who noted that “the strongest predictors of radiographic damage progression were disease duration, baseline radiographic damage, and rheumatoid factor.”

With respect to functional disability, “overall, mean HAQ scores tended to improve somewhat during the first years of the observation,” the authors reported, linking the improvements to the initiation of new antirheumatic therapies at the time of enrollment.

As for functional capacity relative to smoking status, “the evolution of HAQ scores did not differ significantly between smokers and nonsmokers,” the authors wrote, nor was there a significant inverse dose-response effect in heavy smokers, compared with moderate smokers and nonsmokers. High baseline HAQ score, female gender, rheumatoid factor, and lower educational levels were strong predictors for functional disability.

The results of this study suggest, “that smoking may be more important in the initiation of RA than in the perpetuation of the erosive disease process,” the authors noted.

Previous studies have shown some protective effects of smoking in several inflammatory diseases, and nicotine specifically has been shown to have anti-inflammatory properties, which may support the current findings in RA patients, the authors wrote. Smoking or nicotine exposure should not be a therapeutic consideration. “Global health risks associated with smoking are much greater than those potential benefits,” they said.

The exclusion from the study of registry patients with no radiographic follow-up could potentially contribute to a selection bias, although there is no indication that the missing radiographic follow-up was associated with smoking and more severe radiographic progression, the authors wrote.

Antimalarial drugs may confer some protection against cancer in lupus patients, according to the results of a prospective cohort study that linked treatment with antimalarials to improved cancer-free survival.

In a study of 235 patients with systemic lupus erythematosus (SLE) from an ongoing, prospective observational study, those who had been treated with antimalarials were significantly less likely to develop cancer over a median 10-year follow-up than those who had never been treated with the drugs, according to Dr. Guillermo Ruiz-Irastorza of the Hospital de Cruces in Bizkaia, Spain, and colleagues.

Previous studies have suggested that individuals with SLE are at increased risk for developing certain types of malignancies, although the causes for this increased susceptibility remain unknown. The possibility that antimalarial agents may have an anticarcinogenic effect might impact treatment decisions in this patient population, the authors wrote (Ann. Rheum. Dis. 2007 Jan. 4 [Epub doi:10.1136/ard.2006.067777]).

Antimalarials such as hydroxychloroquine (Plaquenil), chloroquine, and quinacrine are frequently used to treat both the skin and systemic symptoms of mild to moderate lupus. Recent studies have demonstrated important long-term effects of the drugs in lupus patients, including a reduction in the accrual of disease-related damage and a reduction in long-term mortality, the authors wrote. Antimalarials have also demonstrated potential antineoplastic properties in investigations looking at their use as adjuvant cancer therapy agents.

Based on these collective findings, Dr. Ruiz-Irastorza and colleagues sought to determine the impact of antimalarials on cancer risk in lupus. Of the 235 patients included in the investigation, 156 had ever received antimalarial treatment and 79 had not. Only 2 of the patients in the antimalarial-treated group had developed a radiologically or histologically confirmed neoplasm during the study follow-up, compared with 11 of the 79 patients who had never been treated, the authors reported.

All of the patients in the study fulfilled the updated American College of Rheumatology criteria for the classification of SLE and were included in the cohort at the time of lupus diagnosis. Pediatric lupus patients (younger than 14 years) enrolled in the larger observational study were excluded from the current investigation.

As per study protocol, most of the patients in the cohort underwent clinical and immunologic assessment every 3 months. Patients with long-standing inactive disease required fewer visits, while those with active disease required more frequent visits.

The study criteria for antimalarial exposure included treatment with the agents for any period of 6 months or longer. The median time on antimalarial drugs was 56 months.

To compare the frequencies of cancer in the patients ever treated with antimalarials and those who were never treated with the drugs, the investigators used a chi-square test and created Kaplan-Meier free-of-cancer survival curves. They used a COX proportional hazards model to adjust for variables that could potentially influence the development of neoplasms: age at diagnosis; year of diagnosis; gender; treatment with azathioprine, cyclophosphamide, and methotrexate; smoking history; and SDI at 6 months after lupus diagnosis. “Treatment variables were only counted if patients received the [antimalarial] drug prior to the time of diagnosis of cancer,” the authors wrote.

The COX model showed that, compared with patients who had never received antimalarials, the patients who received them were younger, more likely to have received methotrexate, and less likely to have severe organ damage at 6 months. In addition, patients diagnosed with lupus between 1996 and 2005 were more likely to receive antimalarials than those diagnosed prior to 1996.

With a total observation time of 2,620 patient-years, the incidence of cancer in the full cohort was 4.9/1,000 patient-years, according to the authors. The specific neoplasms observed in the cohort included basal cell carcinoma in three patients and glioblastoma in two, and in one patient each hepatocarcinoma, renal cell carcinoma, endometrial carcinoma, cervical carcinoma, breast cancer, sarcoma, urothelial carcinoma, and Hodgkin's lymphoma. The median time to cancer diagnosis from the time of lupus diagnosis was 3 years.

The cumulative cancer-free survival rates for patients ever treated with antimalarials compared with the never-treated group was 0.98 vs. 0.73, respectively. “The adjusted [hazards ratio] of patients treated with antimalarials was 0.15,” the authors wrote. The only additional variables that showed independent associations with cancer were age at diagnosis and male gender, Dr. Ruiz-Irastorza and colleagues reported.

The limitations of the current investigation included the fact that patients in the cohort who were ever treated with antimalarials were younger and had less severe organ damage at the time of diagnosis, although severity of damage was not associated with cancer in the analysis, the authors stressed. In addition, some patients in the antimalarial group spent some time at risk for malignancy before receiving the drugs, although “a significant association with a lower frequency of cancer is unlikely to be explained by this fact,” they wrote.

Larger, more ethnically diverse cohorts (99% of the current cohort was white) are needed to confirm the hypothesis that antimalarials exert some favorable action against some of the predisposing factors in patients with SLE, according to the authors. Such confirmation “would reinforce the recommendation of universal use of hydroxychloroquine in all patients with SLE,” they concluded.

Antimalarial drugs may confer some protection against cancer in lupus patients, according to the results of a prospective cohort study that linked treatment with antimalarials to improved cancer-free survival.

In a study of 235 patients with systemic lupus erythematosus (SLE) from an ongoing, prospective observational study, those who had been treated with antimalarials were significantly less likely to develop cancer over a median 10-year follow-up than those who had never been treated with the drugs, according to Dr. Guillermo Ruiz-Irastorza of the Hospital de Cruces in Bizkaia, Spain, and colleagues.

Previous studies have suggested that individuals with SLE are at increased risk for developing certain types of malignancies, although the causes for this increased susceptibility remain unknown. The possibility that antimalarial agents may have an anticarcinogenic effect might impact treatment decisions in this patient population, the authors wrote (Ann. Rheum. Dis. 2007 Jan. 4 [Epub doi:10.1136/ard.2006.067777]).

Antimalarials such as hydroxychloroquine (Plaquenil), chloroquine, and quinacrine are frequently used to treat both the skin and systemic symptoms of mild to moderate lupus. Recent studies have demonstrated important long-term effects of the drugs in lupus patients, including a reduction in the accrual of disease-related damage and a reduction in long-term mortality, the authors wrote. Antimalarials have also demonstrated potential antineoplastic properties in investigations looking at their use as adjuvant cancer therapy agents.

Based on these collective findings, Dr. Ruiz-Irastorza and colleagues sought to determine the impact of antimalarials on cancer risk in lupus. Of the 235 patients included in the investigation, 156 had ever received antimalarial treatment and 79 had not. Only 2 of the patients in the antimalarial-treated group had developed a radiologically or histologically confirmed neoplasm during the study follow-up, compared with 11 of the 79 patients who had never been treated, the authors reported.

All of the patients in the study fulfilled the updated American College of Rheumatology criteria for the classification of SLE and were included in the cohort at the time of lupus diagnosis. Pediatric lupus patients (younger than 14 years) enrolled in the larger observational study were excluded from the current investigation.

As per study protocol, most of the patients in the cohort underwent clinical and immunologic assessment every 3 months. Patients with long-standing inactive disease required fewer visits, while those with active disease required more frequent visits.

The study criteria for antimalarial exposure included treatment with the agents for any period of 6 months or longer. The median time on antimalarial drugs was 56 months.

To compare the frequencies of cancer in the patients ever treated with antimalarials and those who were never treated with the drugs, the investigators used a chi-square test and created Kaplan-Meier free-of-cancer survival curves. They used a COX proportional hazards model to adjust for variables that could potentially influence the development of neoplasms: age at diagnosis; year of diagnosis; gender; treatment with azathioprine, cyclophosphamide, and methotrexate; smoking history; and SDI at 6 months after lupus diagnosis. “Treatment variables were only counted if patients received the [antimalarial] drug prior to the time of diagnosis of cancer,” the authors wrote.

The COX model showed that, compared with patients who had never received antimalarials, the patients who received them were younger, more likely to have received methotrexate, and less likely to have severe organ damage at 6 months. In addition, patients diagnosed with lupus between 1996 and 2005 were more likely to receive antimalarials than those diagnosed prior to 1996.

With a total observation time of 2,620 patient-years, the incidence of cancer in the full cohort was 4.9/1,000 patient-years, according to the authors. The specific neoplasms observed in the cohort included basal cell carcinoma in three patients and glioblastoma in two, and in one patient each hepatocarcinoma, renal cell carcinoma, endometrial carcinoma, cervical carcinoma, breast cancer, sarcoma, urothelial carcinoma, and Hodgkin's lymphoma. The median time to cancer diagnosis from the time of lupus diagnosis was 3 years.

The cumulative cancer-free survival rates for patients ever treated with antimalarials compared with the never-treated group was 0.98 vs. 0.73, respectively. “The adjusted [hazards ratio] of patients treated with antimalarials was 0.15,” the authors wrote. The only additional variables that showed independent associations with cancer were age at diagnosis and male gender, Dr. Ruiz-Irastorza and colleagues reported.

The limitations of the current investigation included the fact that patients in the cohort who were ever treated with antimalarials were younger and had less severe organ damage at the time of diagnosis, although severity of damage was not associated with cancer in the analysis, the authors stressed. In addition, some patients in the antimalarial group spent some time at risk for malignancy before receiving the drugs, although “a significant association with a lower frequency of cancer is unlikely to be explained by this fact,” they wrote.

Larger, more ethnically diverse cohorts (99% of the current cohort was white) are needed to confirm the hypothesis that antimalarials exert some favorable action against some of the predisposing factors in patients with SLE, according to the authors. Such confirmation “would reinforce the recommendation of universal use of hydroxychloroquine in all patients with SLE,” they concluded.

Antimalarial drugs may confer some protection against cancer in lupus patients, according to the results of a prospective cohort study that linked treatment with antimalarials to improved cancer-free survival.

In a study of 235 patients with systemic lupus erythematosus (SLE) from an ongoing, prospective observational study, those who had been treated with antimalarials were significantly less likely to develop cancer over a median 10-year follow-up than those who had never been treated with the drugs, according to Dr. Guillermo Ruiz-Irastorza of the Hospital de Cruces in Bizkaia, Spain, and colleagues.

Previous studies have suggested that individuals with SLE are at increased risk for developing certain types of malignancies, although the causes for this increased susceptibility remain unknown. The possibility that antimalarial agents may have an anticarcinogenic effect might impact treatment decisions in this patient population, the authors wrote (Ann. Rheum. Dis. 2007 Jan. 4 [Epub doi:10.1136/ard.2006.067777]).

Antimalarials such as hydroxychloroquine (Plaquenil), chloroquine, and quinacrine are frequently used to treat both the skin and systemic symptoms of mild to moderate lupus. Recent studies have demonstrated important long-term effects of the drugs in lupus patients, including a reduction in the accrual of disease-related damage and a reduction in long-term mortality, the authors wrote. Antimalarials have also demonstrated potential antineoplastic properties in investigations looking at their use as adjuvant cancer therapy agents.

Based on these collective findings, Dr. Ruiz-Irastorza and colleagues sought to determine the impact of antimalarials on cancer risk in lupus. Of the 235 patients included in the investigation, 156 had ever received antimalarial treatment and 79 had not. Only 2 of the patients in the antimalarial-treated group had developed a radiologically or histologically confirmed neoplasm during the study follow-up, compared with 11 of the 79 patients who had never been treated, the authors reported.

All of the patients in the study fulfilled the updated American College of Rheumatology criteria for the classification of SLE and were included in the cohort at the time of lupus diagnosis. Pediatric lupus patients (younger than 14 years) enrolled in the larger observational study were excluded from the current investigation.

As per study protocol, most of the patients in the cohort underwent clinical and immunologic assessment every 3 months. Patients with long-standing inactive disease required fewer visits, while those with active disease required more frequent visits.

The study criteria for antimalarial exposure included treatment with the agents for any period of 6 months or longer. The median time on antimalarial drugs was 56 months.

To compare the frequencies of cancer in the patients ever treated with antimalarials and those who were never treated with the drugs, the investigators used a chi-square test and created Kaplan-Meier free-of-cancer survival curves. They used a COX proportional hazards model to adjust for variables that could potentially influence the development of neoplasms: age at diagnosis; year of diagnosis; gender; treatment with azathioprine, cyclophosphamide, and methotrexate; smoking history; and SDI at 6 months after lupus diagnosis. “Treatment variables were only counted if patients received the [antimalarial] drug prior to the time of diagnosis of cancer,” the authors wrote.

The COX model showed that, compared with patients who had never received antimalarials, the patients who received them were younger, more likely to have received methotrexate, and less likely to have severe organ damage at 6 months. In addition, patients diagnosed with lupus between 1996 and 2005 were more likely to receive antimalarials than those diagnosed prior to 1996.

With a total observation time of 2,620 patient-years, the incidence of cancer in the full cohort was 4.9/1,000 patient-years, according to the authors. The specific neoplasms observed in the cohort included basal cell carcinoma in three patients and glioblastoma in two, and in one patient each hepatocarcinoma, renal cell carcinoma, endometrial carcinoma, cervical carcinoma, breast cancer, sarcoma, urothelial carcinoma, and Hodgkin's lymphoma. The median time to cancer diagnosis from the time of lupus diagnosis was 3 years.

The cumulative cancer-free survival rates for patients ever treated with antimalarials compared with the never-treated group was 0.98 vs. 0.73, respectively. “The adjusted [hazards ratio] of patients treated with antimalarials was 0.15,” the authors wrote. The only additional variables that showed independent associations with cancer were age at diagnosis and male gender, Dr. Ruiz-Irastorza and colleagues reported.

The limitations of the current investigation included the fact that patients in the cohort who were ever treated with antimalarials were younger and had less severe organ damage at the time of diagnosis, although severity of damage was not associated with cancer in the analysis, the authors stressed. In addition, some patients in the antimalarial group spent some time at risk for malignancy before receiving the drugs, although “a significant association with a lower frequency of cancer is unlikely to be explained by this fact,” they wrote.

Larger, more ethnically diverse cohorts (99% of the current cohort was white) are needed to confirm the hypothesis that antimalarials exert some favorable action against some of the predisposing factors in patients with SLE, according to the authors. Such confirmation “would reinforce the recommendation of universal use of hydroxychloroquine in all patients with SLE,” they concluded.

Low levels of androgen may be a risk factor for diabetes in men, according to the findings of a population-based study.

In a sample of 1,413 adult men, concentrations of free and bioavailable testosterone in the low normal range were associated with diabetes independent of adiposity, reported Elizabeth Selvin, Ph.D., of Johns Hopkins Bloomberg School of Public Health, Baltimore, and her colleagues.

“To our knowledge, this is the first study to examine the association between sex steroid hormones and diabetes in a large, nationally representative male population,” the authors wrote (Diabetes Care 2007;30:234–8).

The study sample included multiethnic men aged 20 years or older who participated in the morning session of phase I of the Third National Health and Nutrition Examination Survey (NHANES III), which was conducted between 1988 and 1991.

“Morning session participants were chosen for this hormone study to reduce extraneous variation due to diurnal production of sex hormones,” the authors wrote.

As part of the survey, all of the study participants underwent an interview, an extensive physical examination, and collection of a blood sample.

Height, weight, and waist and hip circumferences were measured as part of the physical examination, and body mass index was calculated.

The information on age, race and ethnicity, and diabetes status was collected by patient self-report. With respect to diabetes specifically, the interviewers asked the participants if they had ever been told by a health professional that they had diabetes or sugar diabetes, the authors noted.

The main hormone measurements of interest in the investigation included serum total testosterone as well as estimated bioavailable and free testosterone levels, which were calculated from serum total testosterone, sex hormone-binding globulin, and albumin concentrations. “Measurements of free and bioavailable testosterone levels more accurately represent concentrations readily available to tissues and metabolic processes,” the authors stated.

In a multivariate model adjusted for age, race/ethnicity, and adiposity, there was no clear association of total testosterone concentration with diabetes; however, men in the lowest tertile (0.09 ng/mL or below) of free testosterone level were more than four times as likely to have prevalent diabetes, compared with men in the highest tertile (higher than 0.14 ng/mL).

Similarly, men in the lowest tertile of bioavailable testosterone (2.11 ng/mL or below) were nearly four times as likely to have prevalent diabetes as were men in the highest tertile (higher than 3.02 ng/mL), the authors reported. They also noted that “these associations persisted even after further adjustment for total cholesterol, triglycerides, and systolic blood pressure.”

In addition, the association with low free testosterone persisted even after the exclusion of men with clinically low levels of total testosterone (less than 3.25 ng/mL) and/or clinically low levels of free testosterone (less than 0.07 ng/mL), suggesting the observed associations were “not entirely driven by hypogonadal men,” the authors wrote.

A sensitivity analysis that included 58 cases of undiagnosed diabetes showed no appreciable alterations in the adjusted models, the authors reported.

“The independent association of low free and bioavailable testosterone levels in our adjusted models suggest[s] that testosterone insufficiency may be a risk factor for diabetes,” the authors wrote.

Despite the fact that the directionality of the associations between low androgen levels and adiposity are unclear based on the analysis, “our data are consistent with the hypothesis that androgens may directly influence glucose metabolism and the development of insulin resistance independently of the effects of adiposity,” they stated.

The study is limited by its cross-sectional design, which precludes evaluation of the temporality of the observed associations between androgen levels and diabetes, the authors wrote.

“However, several previous prospective analyses suggest that decreases in testosterone level may precede the development of diabetes, lending support to a temporal if not causal relation,” they said. “Additionally, including individuals with undiagnosed diabetes, a population at an earlier point in the progression of diabetes, did not change our results.”

Additional studies are needed to investigate the mechanisms by which sex steroid hormones contribute to diabetes as well as other chronic diseases, the authors concluded.

The study is the third from the Hormone Demonstration Program, which is supported by the Maryland Cigarette Restitution Fund Research Grant Program that is based at Johns Hopkins University.

Low levels of androgen may be a risk factor for diabetes in men, according to the findings of a population-based study.

In a sample of 1,413 adult men, concentrations of free and bioavailable testosterone in the low normal range were associated with diabetes independent of adiposity, reported Elizabeth Selvin, Ph.D., of Johns Hopkins Bloomberg School of Public Health, Baltimore, and her colleagues.

“To our knowledge, this is the first study to examine the association between sex steroid hormones and diabetes in a large, nationally representative male population,” the authors wrote (Diabetes Care 2007;30:234–8).

The study sample included multiethnic men aged 20 years or older who participated in the morning session of phase I of the Third National Health and Nutrition Examination Survey (NHANES III), which was conducted between 1988 and 1991.

“Morning session participants were chosen for this hormone study to reduce extraneous variation due to diurnal production of sex hormones,” the authors wrote.

As part of the survey, all of the study participants underwent an interview, an extensive physical examination, and collection of a blood sample.

Height, weight, and waist and hip circumferences were measured as part of the physical examination, and body mass index was calculated.

The information on age, race and ethnicity, and diabetes status was collected by patient self-report. With respect to diabetes specifically, the interviewers asked the participants if they had ever been told by a health professional that they had diabetes or sugar diabetes, the authors noted.

The main hormone measurements of interest in the investigation included serum total testosterone as well as estimated bioavailable and free testosterone levels, which were calculated from serum total testosterone, sex hormone-binding globulin, and albumin concentrations. “Measurements of free and bioavailable testosterone levels more accurately represent concentrations readily available to tissues and metabolic processes,” the authors stated.

In a multivariate model adjusted for age, race/ethnicity, and adiposity, there was no clear association of total testosterone concentration with diabetes; however, men in the lowest tertile (0.09 ng/mL or below) of free testosterone level were more than four times as likely to have prevalent diabetes, compared with men in the highest tertile (higher than 0.14 ng/mL).

Similarly, men in the lowest tertile of bioavailable testosterone (2.11 ng/mL or below) were nearly four times as likely to have prevalent diabetes as were men in the highest tertile (higher than 3.02 ng/mL), the authors reported. They also noted that “these associations persisted even after further adjustment for total cholesterol, triglycerides, and systolic blood pressure.”

In addition, the association with low free testosterone persisted even after the exclusion of men with clinically low levels of total testosterone (less than 3.25 ng/mL) and/or clinically low levels of free testosterone (less than 0.07 ng/mL), suggesting the observed associations were “not entirely driven by hypogonadal men,” the authors wrote.

A sensitivity analysis that included 58 cases of undiagnosed diabetes showed no appreciable alterations in the adjusted models, the authors reported.

“The independent association of low free and bioavailable testosterone levels in our adjusted models suggest[s] that testosterone insufficiency may be a risk factor for diabetes,” the authors wrote.

Despite the fact that the directionality of the associations between low androgen levels and adiposity are unclear based on the analysis, “our data are consistent with the hypothesis that androgens may directly influence glucose metabolism and the development of insulin resistance independently of the effects of adiposity,” they stated.

The study is limited by its cross-sectional design, which precludes evaluation of the temporality of the observed associations between androgen levels and diabetes, the authors wrote.

“However, several previous prospective analyses suggest that decreases in testosterone level may precede the development of diabetes, lending support to a temporal if not causal relation,” they said. “Additionally, including individuals with undiagnosed diabetes, a population at an earlier point in the progression of diabetes, did not change our results.”

Additional studies are needed to investigate the mechanisms by which sex steroid hormones contribute to diabetes as well as other chronic diseases, the authors concluded.

The study is the third from the Hormone Demonstration Program, which is supported by the Maryland Cigarette Restitution Fund Research Grant Program that is based at Johns Hopkins University.

Low levels of androgen may be a risk factor for diabetes in men, according to the findings of a population-based study.

In a sample of 1,413 adult men, concentrations of free and bioavailable testosterone in the low normal range were associated with diabetes independent of adiposity, reported Elizabeth Selvin, Ph.D., of Johns Hopkins Bloomberg School of Public Health, Baltimore, and her colleagues.

“To our knowledge, this is the first study to examine the association between sex steroid hormones and diabetes in a large, nationally representative male population,” the authors wrote (Diabetes Care 2007;30:234–8).

The study sample included multiethnic men aged 20 years or older who participated in the morning session of phase I of the Third National Health and Nutrition Examination Survey (NHANES III), which was conducted between 1988 and 1991.

“Morning session participants were chosen for this hormone study to reduce extraneous variation due to diurnal production of sex hormones,” the authors wrote.

As part of the survey, all of the study participants underwent an interview, an extensive physical examination, and collection of a blood sample.

Height, weight, and waist and hip circumferences were measured as part of the physical examination, and body mass index was calculated.

The information on age, race and ethnicity, and diabetes status was collected by patient self-report. With respect to diabetes specifically, the interviewers asked the participants if they had ever been told by a health professional that they had diabetes or sugar diabetes, the authors noted.

The main hormone measurements of interest in the investigation included serum total testosterone as well as estimated bioavailable and free testosterone levels, which were calculated from serum total testosterone, sex hormone-binding globulin, and albumin concentrations. “Measurements of free and bioavailable testosterone levels more accurately represent concentrations readily available to tissues and metabolic processes,” the authors stated.

In a multivariate model adjusted for age, race/ethnicity, and adiposity, there was no clear association of total testosterone concentration with diabetes; however, men in the lowest tertile (0.09 ng/mL or below) of free testosterone level were more than four times as likely to have prevalent diabetes, compared with men in the highest tertile (higher than 0.14 ng/mL).

Similarly, men in the lowest tertile of bioavailable testosterone (2.11 ng/mL or below) were nearly four times as likely to have prevalent diabetes as were men in the highest tertile (higher than 3.02 ng/mL), the authors reported. They also noted that “these associations persisted even after further adjustment for total cholesterol, triglycerides, and systolic blood pressure.”

In addition, the association with low free testosterone persisted even after the exclusion of men with clinically low levels of total testosterone (less than 3.25 ng/mL) and/or clinically low levels of free testosterone (less than 0.07 ng/mL), suggesting the observed associations were “not entirely driven by hypogonadal men,” the authors wrote.

A sensitivity analysis that included 58 cases of undiagnosed diabetes showed no appreciable alterations in the adjusted models, the authors reported.

“The independent association of low free and bioavailable testosterone levels in our adjusted models suggest[s] that testosterone insufficiency may be a risk factor for diabetes,” the authors wrote.

Despite the fact that the directionality of the associations between low androgen levels and adiposity are unclear based on the analysis, “our data are consistent with the hypothesis that androgens may directly influence glucose metabolism and the development of insulin resistance independently of the effects of adiposity,” they stated.

The study is limited by its cross-sectional design, which precludes evaluation of the temporality of the observed associations between androgen levels and diabetes, the authors wrote.

“However, several previous prospective analyses suggest that decreases in testosterone level may precede the development of diabetes, lending support to a temporal if not causal relation,” they said. “Additionally, including individuals with undiagnosed diabetes, a population at an earlier point in the progression of diabetes, did not change our results.”

Additional studies are needed to investigate the mechanisms by which sex steroid hormones contribute to diabetes as well as other chronic diseases, the authors concluded.

The study is the third from the Hormone Demonstration Program, which is supported by the Maryland Cigarette Restitution Fund Research Grant Program that is based at Johns Hopkins University.

New venous thromboembolism guidelines aimed at primary care providers emphasize the need for swift diagnosis and initial treatment with low-molecular-weight heparin over the unfractionated formulation.

Issued jointly by the American College of Physicians and the American Academy of Family Physicians, the guidelines represent an acknowledgement that diagnosis of venous thromboembolism (VTE) is first and foremost a primary care challenge.

Risk factors for the condition, such as recent hospitalization, surgery, trauma, and immobilization, are well known, but early diagnosis—which is critical to a successful outcome—is difficult because thromboembolic events are often “clinically silent,” said Dr. B. Gail Macik, of the division of hematology and oncology at the University of Virginia, Charlottesville.

Advances in therapy are poised to reduce VTE-associated mortality, but they can only do so if they are well disseminated through the primary care ranks, which, historically, they have not been, Dr. Macik added.

In fact, most management guidelines to date have been geared toward patients with difficult or complicated disease in inpatient health care settings, such as intensive care units. In contrast, the new guidelines offer “clinically relevant screening and treatment recommendations specifically for primary care physicians who are the most likely to have front-line contact with [undiagnosed] VTE,” she said. “As with most guidelines, these leave wiggle room for individual application, but the concise review and recommendation for care is very welcome,” said Dr. Macik, who was not involved in writing the recommendations.

The diagnostic and management guidelines, published separately, are based on findings of a comprehensive systematic literature review published in 2003 and recently updated by Dr. Jodi B. Segal and colleagues at the Johns Hopkins University Evidence-Based Practice Center in Baltimore (Ann. Intern. Med. 2007;146:211-22).

Diagnosis

The importance of early diagnosis of VTE “cannot be overstressed,” wrote guideline coauthor Dr. Amir Qaseem, senior medical associate in the Clinical Programs and Quality of Care Division at the ACP.

To that end, diagnostic guidelines encourage using validated clinical prediction tools, such as the Wells prediction rule, to determine the probability of deep-vein thrombosis (DVT) and pulmonary embolism before performing more definitive testing (Ann. Fam. Med. 2007;5:57-62).

Because the Wells prediction rule performs better in younger patients without comorbidities or VTE history, “physicians should use their clinical judgment in cases where a patient is older or presents with comorbidities,” according to the guidelines.

Obtaining a high-sensitivity D-dimer assay is a reasonable option in appropriately selected patients with low pretest probability of DVT or pulmonary embolism, including younger patients without associated comorbidity or history of VTE and with short duration of symptoms. “In older patients, those with associated comorbidity, and long duration of symptoms, a D-dimer alone may not be sufficient to rule out VTE,” according to the authors.

Obtain an ultrasound in patients with intermediate to high pretest probability of DVT in the lower extremities. “Ultrasound is less sensitive in patients who have DVT limited to the calf, therefore a negative ultrasound does not rule out DVT in these patients,” the authors stressed. Additionally, “repeat ultrasound or venography may be required for patients who have suspected calf-vein DVT and a negative ultrasound,” as well as for those patients with suspected proximal DVT and an inadequate ultrasound.

Imaging is essential for patients with intermediate or high pretest probability of pulmonary embolism. Ventilation-perfusion, multidetector helical computed axial tomography, and pulmonary angiography are among the potential imaging options.

Treatment and Prevention

Compared with unfractionated heparin, low-molecular-weight heparin (LMWH) is associated with a reduced risk of major bleeding and mortality in the treatment of DVT, and as such “should be used whenever possible for the initial inpatient treatment” of these patients, according to the treatment guidelines (Ann. Intern. Med. 2007;146:204-10).

Other recommendations regarding management include:

▸ Home-based therapy. Patients who have adequate support at home can receive LMWH treatment on an outpatient basis. Data on the risks among inpatients versus outpatients demonstrate only slight differences in the rates of recurrent VTE, major bleeding, and death. However, most studies relevant to this question “excluded patients with previous VTE, thrombophilic conditions, or significant comorbidity, pregnant patients, and patients unlikely to adhere to outpatient therapy,” the authors wrote. Also, several of the studies allowed for brief inpatient admissions for stabilization prior to randomization to outpatient treatment.

▸ Compression stockings. On the basis of evidence demonstrating a marked reduction in the incidence of postthrombotic syndrome among patients with DVT who wear compression stockings, the guidelines recommend the routine use of either over-the-counter or custom-fit stockings beginning 1 month after diagnosis of proximal DVT, and continuing for a minimum of 1 year. Of three randomized, controlled trials that studied the use of compression stockings, the two that enrolled patients within 1 month of developing proximal DVT showed a significant reduction in postthrombotic syndrome, while no such benefit was seen in the one trial that enrolled patients 1 year after the DVT event, the authors reported.

▸ Pregnancy. Anticoagulation management during pregnancy is particularly important, as the risk of VTE in pregnant women is five times greater than in nonpregnant women, the authors stated. However, the available data are insufficient to recommend specific therapies in pregnant women. The guideline recommends avoiding vitamin K antagonists because they can cross the placenta and have been associated with fetal bleeding and embryopathy at 6-12 weeks' gestation. “Neither LMWH nor unfractionated heparin crosses the placenta, and neither is associated with embryopathy or fetal bleeding,” they wrote.

▸ Secondary and idiopathic VTE. For VTE secondary to transient risk factors, such as surgery, trauma, or immobilization, the available evidence indicates that patients may be well served with 3-6 months of oral anticoagulation therapy.

With respect to idiopathic VTE, available data suggest that extended-duration anticoagulation therapy is associated with a reduced relative risk of recurrence, although the optimal duration is not known as the length of therapy in the trials varied substantially, and the results reflect follow-up only to 4 years. Consequently, the guideline advises continuing anticoagulant therapy for more than 12 months for recurrent VTE.

▸ Long-term treatment. In comparing long-term treatment with LMWH versus vitamin K antagonists, the former is “safe and efficacious for the long-term treatment of VTE in selected patients, and may be preferable for patients with cancer,” as studies have linked LMWH to a survival advantage in this population. Specifically, the data suggest that “LMWH may be a useful treatment for patients in whom INR [international normalized ratio] control is difficult.”

▸ Pulmonary embolism. Regarding pulmonary embolism treatment, “LMWH is at least as effective as unfractionated heparin,” according to a review of the available evidence; thus, either drug is appropriate for initial treatment, said Dr. Vincenza Snow, director of clinical programs and quality of care for the ACP. The authors did note, however, that additional trials are needed to more rigorously examine the efficacy of LMWH for pulmonary embolism.

New venous thromboembolism guidelines aimed at primary care providers emphasize the need for swift diagnosis and initial treatment with low-molecular-weight heparin over the unfractionated formulation.

Issued jointly by the American College of Physicians and the American Academy of Family Physicians, the guidelines represent an acknowledgement that diagnosis of venous thromboembolism (VTE) is first and foremost a primary care challenge.

Risk factors for the condition, such as recent hospitalization, surgery, trauma, and immobilization, are well known, but early diagnosis—which is critical to a successful outcome—is difficult because thromboembolic events are often “clinically silent,” said Dr. B. Gail Macik, of the division of hematology and oncology at the University of Virginia, Charlottesville.

Advances in therapy are poised to reduce VTE-associated mortality, but they can only do so if they are well disseminated through the primary care ranks, which, historically, they have not been, Dr. Macik added.

In fact, most management guidelines to date have been geared toward patients with difficult or complicated disease in inpatient health care settings, such as intensive care units. In contrast, the new guidelines offer “clinically relevant screening and treatment recommendations specifically for primary care physicians who are the most likely to have front-line contact with [undiagnosed] VTE,” she said. “As with most guidelines, these leave wiggle room for individual application, but the concise review and recommendation for care is very welcome,” said Dr. Macik, who was not involved in writing the recommendations.

The diagnostic and management guidelines, published separately, are based on findings of a comprehensive systematic literature review published in 2003 and recently updated by Dr. Jodi B. Segal and colleagues at the Johns Hopkins University Evidence-Based Practice Center in Baltimore (Ann. Intern. Med. 2007;146:211-22).

Diagnosis

The importance of early diagnosis of VTE “cannot be overstressed,” wrote guideline coauthor Dr. Amir Qaseem, senior medical associate in the Clinical Programs and Quality of Care Division at the ACP.

To that end, diagnostic guidelines encourage using validated clinical prediction tools, such as the Wells prediction rule, to determine the probability of deep-vein thrombosis (DVT) and pulmonary embolism before performing more definitive testing (Ann. Fam. Med. 2007;5:57-62).

Because the Wells prediction rule performs better in younger patients without comorbidities or VTE history, “physicians should use their clinical judgment in cases where a patient is older or presents with comorbidities,” according to the guidelines.

Obtaining a high-sensitivity D-dimer assay is a reasonable option in appropriately selected patients with low pretest probability of DVT or pulmonary embolism, including younger patients without associated comorbidity or history of VTE and with short duration of symptoms. “In older patients, those with associated comorbidity, and long duration of symptoms, a D-dimer alone may not be sufficient to rule out VTE,” according to the authors.

Obtain an ultrasound in patients with intermediate to high pretest probability of DVT in the lower extremities. “Ultrasound is less sensitive in patients who have DVT limited to the calf, therefore a negative ultrasound does not rule out DVT in these patients,” the authors stressed. Additionally, “repeat ultrasound or venography may be required for patients who have suspected calf-vein DVT and a negative ultrasound,” as well as for those patients with suspected proximal DVT and an inadequate ultrasound.

Imaging is essential for patients with intermediate or high pretest probability of pulmonary embolism. Ventilation-perfusion, multidetector helical computed axial tomography, and pulmonary angiography are among the potential imaging options.

Treatment and Prevention

Compared with unfractionated heparin, low-molecular-weight heparin (LMWH) is associated with a reduced risk of major bleeding and mortality in the treatment of DVT, and as such “should be used whenever possible for the initial inpatient treatment” of these patients, according to the treatment guidelines (Ann. Intern. Med. 2007;146:204-10).

Other recommendations regarding management include:

▸ Home-based therapy. Patients who have adequate support at home can receive LMWH treatment on an outpatient basis. Data on the risks among inpatients versus outpatients demonstrate only slight differences in the rates of recurrent VTE, major bleeding, and death. However, most studies relevant to this question “excluded patients with previous VTE, thrombophilic conditions, or significant comorbidity, pregnant patients, and patients unlikely to adhere to outpatient therapy,” the authors wrote. Also, several of the studies allowed for brief inpatient admissions for stabilization prior to randomization to outpatient treatment.

▸ Compression stockings. On the basis of evidence demonstrating a marked reduction in the incidence of postthrombotic syndrome among patients with DVT who wear compression stockings, the guidelines recommend the routine use of either over-the-counter or custom-fit stockings beginning 1 month after diagnosis of proximal DVT, and continuing for a minimum of 1 year. Of three randomized, controlled trials that studied the use of compression stockings, the two that enrolled patients within 1 month of developing proximal DVT showed a significant reduction in postthrombotic syndrome, while no such benefit was seen in the one trial that enrolled patients 1 year after the DVT event, the authors reported.

▸ Pregnancy. Anticoagulation management during pregnancy is particularly important, as the risk of VTE in pregnant women is five times greater than in nonpregnant women, the authors stated. However, the available data are insufficient to recommend specific therapies in pregnant women. The guideline recommends avoiding vitamin K antagonists because they can cross the placenta and have been associated with fetal bleeding and embryopathy at 6-12 weeks' gestation. “Neither LMWH nor unfractionated heparin crosses the placenta, and neither is associated with embryopathy or fetal bleeding,” they wrote.

▸ Secondary and idiopathic VTE. For VTE secondary to transient risk factors, such as surgery, trauma, or immobilization, the available evidence indicates that patients may be well served with 3-6 months of oral anticoagulation therapy.

With respect to idiopathic VTE, available data suggest that extended-duration anticoagulation therapy is associated with a reduced relative risk of recurrence, although the optimal duration is not known as the length of therapy in the trials varied substantially, and the results reflect follow-up only to 4 years. Consequently, the guideline advises continuing anticoagulant therapy for more than 12 months for recurrent VTE.

▸ Long-term treatment. In comparing long-term treatment with LMWH versus vitamin K antagonists, the former is “safe and efficacious for the long-term treatment of VTE in selected patients, and may be preferable for patients with cancer,” as studies have linked LMWH to a survival advantage in this population. Specifically, the data suggest that “LMWH may be a useful treatment for patients in whom INR [international normalized ratio] control is difficult.”

▸ Pulmonary embolism. Regarding pulmonary embolism treatment, “LMWH is at least as effective as unfractionated heparin,” according to a review of the available evidence; thus, either drug is appropriate for initial treatment, said Dr. Vincenza Snow, director of clinical programs and quality of care for the ACP. The authors did note, however, that additional trials are needed to more rigorously examine the efficacy of LMWH for pulmonary embolism.

New venous thromboembolism guidelines aimed at primary care providers emphasize the need for swift diagnosis and initial treatment with low-molecular-weight heparin over the unfractionated formulation.

Issued jointly by the American College of Physicians and the American Academy of Family Physicians, the guidelines represent an acknowledgement that diagnosis of venous thromboembolism (VTE) is first and foremost a primary care challenge.

Risk factors for the condition, such as recent hospitalization, surgery, trauma, and immobilization, are well known, but early diagnosis—which is critical to a successful outcome—is difficult because thromboembolic events are often “clinically silent,” said Dr. B. Gail Macik, of the division of hematology and oncology at the University of Virginia, Charlottesville.

Advances in therapy are poised to reduce VTE-associated mortality, but they can only do so if they are well disseminated through the primary care ranks, which, historically, they have not been, Dr. Macik added.

In fact, most management guidelines to date have been geared toward patients with difficult or complicated disease in inpatient health care settings, such as intensive care units. In contrast, the new guidelines offer “clinically relevant screening and treatment recommendations specifically for primary care physicians who are the most likely to have front-line contact with [undiagnosed] VTE,” she said. “As with most guidelines, these leave wiggle room for individual application, but the concise review and recommendation for care is very welcome,” said Dr. Macik, who was not involved in writing the recommendations.

The diagnostic and management guidelines, published separately, are based on findings of a comprehensive systematic literature review published in 2003 and recently updated by Dr. Jodi B. Segal and colleagues at the Johns Hopkins University Evidence-Based Practice Center in Baltimore (Ann. Intern. Med. 2007;146:211-22).

Diagnosis

The importance of early diagnosis of VTE “cannot be overstressed,” wrote guideline coauthor Dr. Amir Qaseem, senior medical associate in the Clinical Programs and Quality of Care Division at the ACP.

To that end, diagnostic guidelines encourage using validated clinical prediction tools, such as the Wells prediction rule, to determine the probability of deep-vein thrombosis (DVT) and pulmonary embolism before performing more definitive testing (Ann. Fam. Med. 2007;5:57-62).

Because the Wells prediction rule performs better in younger patients without comorbidities or VTE history, “physicians should use their clinical judgment in cases where a patient is older or presents with comorbidities,” according to the guidelines.

Obtaining a high-sensitivity D-dimer assay is a reasonable option in appropriately selected patients with low pretest probability of DVT or pulmonary embolism, including younger patients without associated comorbidity or history of VTE and with short duration of symptoms. “In older patients, those with associated comorbidity, and long duration of symptoms, a D-dimer alone may not be sufficient to rule out VTE,” according to the authors.

Obtain an ultrasound in patients with intermediate to high pretest probability of DVT in the lower extremities. “Ultrasound is less sensitive in patients who have DVT limited to the calf, therefore a negative ultrasound does not rule out DVT in these patients,” the authors stressed. Additionally, “repeat ultrasound or venography may be required for patients who have suspected calf-vein DVT and a negative ultrasound,” as well as for those patients with suspected proximal DVT and an inadequate ultrasound.

Imaging is essential for patients with intermediate or high pretest probability of pulmonary embolism. Ventilation-perfusion, multidetector helical computed axial tomography, and pulmonary angiography are among the potential imaging options.

Treatment and Prevention

Compared with unfractionated heparin, low-molecular-weight heparin (LMWH) is associated with a reduced risk of major bleeding and mortality in the treatment of DVT, and as such “should be used whenever possible for the initial inpatient treatment” of these patients, according to the treatment guidelines (Ann. Intern. Med. 2007;146:204-10).

Other recommendations regarding management include:

▸ Home-based therapy. Patients who have adequate support at home can receive LMWH treatment on an outpatient basis. Data on the risks among inpatients versus outpatients demonstrate only slight differences in the rates of recurrent VTE, major bleeding, and death. However, most studies relevant to this question “excluded patients with previous VTE, thrombophilic conditions, or significant comorbidity, pregnant patients, and patients unlikely to adhere to outpatient therapy,” the authors wrote. Also, several of the studies allowed for brief inpatient admissions for stabilization prior to randomization to outpatient treatment.

▸ Compression stockings. On the basis of evidence demonstrating a marked reduction in the incidence of postthrombotic syndrome among patients with DVT who wear compression stockings, the guidelines recommend the routine use of either over-the-counter or custom-fit stockings beginning 1 month after diagnosis of proximal DVT, and continuing for a minimum of 1 year. Of three randomized, controlled trials that studied the use of compression stockings, the two that enrolled patients within 1 month of developing proximal DVT showed a significant reduction in postthrombotic syndrome, while no such benefit was seen in the one trial that enrolled patients 1 year after the DVT event, the authors reported.

▸ Pregnancy. Anticoagulation management during pregnancy is particularly important, as the risk of VTE in pregnant women is five times greater than in nonpregnant women, the authors stated. However, the available data are insufficient to recommend specific therapies in pregnant women. The guideline recommends avoiding vitamin K antagonists because they can cross the placenta and have been associated with fetal bleeding and embryopathy at 6-12 weeks' gestation. “Neither LMWH nor unfractionated heparin crosses the placenta, and neither is associated with embryopathy or fetal bleeding,” they wrote.

▸ Secondary and idiopathic VTE. For VTE secondary to transient risk factors, such as surgery, trauma, or immobilization, the available evidence indicates that patients may be well served with 3-6 months of oral anticoagulation therapy.

With respect to idiopathic VTE, available data suggest that extended-duration anticoagulation therapy is associated with a reduced relative risk of recurrence, although the optimal duration is not known as the length of therapy in the trials varied substantially, and the results reflect follow-up only to 4 years. Consequently, the guideline advises continuing anticoagulant therapy for more than 12 months for recurrent VTE.

▸ Long-term treatment. In comparing long-term treatment with LMWH versus vitamin K antagonists, the former is “safe and efficacious for the long-term treatment of VTE in selected patients, and may be preferable for patients with cancer,” as studies have linked LMWH to a survival advantage in this population. Specifically, the data suggest that “LMWH may be a useful treatment for patients in whom INR [international normalized ratio] control is difficult.”

▸ Pulmonary embolism. Regarding pulmonary embolism treatment, “LMWH is at least as effective as unfractionated heparin,” according to a review of the available evidence; thus, either drug is appropriate for initial treatment, said Dr. Vincenza Snow, director of clinical programs and quality of care for the ACP. The authors did note, however, that additional trials are needed to more rigorously examine the efficacy of LMWH for pulmonary embolism.

BOSTON — Telbivudine showed greater efficacy than lamivudine did during 2 years of treatment for chronic hepatitis B infection, according to the most recent results from the international GLOBE trial.

In the phase III trial, telbivudine (Tyzeka), which recently received Food and Drug Administration approval for the treatment of hepatitis B virus (HBV) infection, surpassed the older antiviral on all key measures of virologic and clinical efficacy.

These results were found in both HBV e-antigen (HBeAg)-positive and HBeAg-negative patients enrolled in the study of 1,367 patients, Dr. Ching-Lung Lai said at the annual meeting of the American Association for the Study of Liver Diseases.

The international, multicenter investigation was partially funded by Idenix Pharmaceuticals, the manufacturer—with Novartis Pharma AG—of telbivudine. The trial was designed to compare the efficacy of telbivudine at 600 mg/day to that of lamivudine (Epivir) at 100 mg/day in patients who were HB s-antigen positive at enrollment and had baseline HBV DNA greater than 6 log10 copies/mL, alanine aminotransferase (ALT) levels between 1.3 and 10 times the upper limit of normal, and compensated liver disease.

The study's primary efficacy end point was therapeutic response, based on a combination of viral suppression (serum HBV DNA below 100,000 copies/mL) and either improved liver disease markers (ALT normalization) or loss of detectable HBeAg.

The first-year results from the trial, presented last year, “demonstrated that telbivudine was superior to lamivudine on all measures of direct antiviral efficacy and on several key clinical efficacy measures,” said Dr. Lai, professor of medicine and hepatology at the University of Hong Kong. “The new data indicate the efficacy levels were sustained over 104 weeks.”

After 2 years of treatment, analysis showed that HBeAG-positive and -negative patients randomized to telbivudine therapy had significantly greater HBV DNA reductions (-5.7 log10 and -5.0 log10, respectively) than did HBeAG-positive and -negative patients on lamivudine (-4.4 log10 and -4.2 log10, respectively).

Similarly, significantly more patients receiving telbivudine achieved clearance of detectable HBV DNA. In HBeAg-positive patients, “telbivudine treatment led to loss of detectable HBV DNA in 56% of patients, compared to 39% with lamivudine,” said Dr. Lai. Among HBeAg-negative patients, 82% of telbivudine patients achieved undetectable HBV DNA levels, compared with 57% of lamivudine patients, he said.

Patients who had achieved HBV DNA clearance by study week 24 had the best overall response rates in terms of seroconversion, ALT normalization, and reduced therapeutic resistance, Dr. Lai noted.

Treatment failure was significantly less common with telbivudine than with lamivudine in both HBeAg-positive and -negative patients. Among HBeAg-positive patients, antiviral treatment failed in 4% of telbivudine patients, compared with 12% of lamivudine patients. In HBeAg-negative patients, there were no treatment failures in telbivudine patients, compared with 3% of patients taking lamivudine, he said.

Drug resistance occurred in 17.8% of HBeAg-positive patients on telbivudine and 30.1% of HBeAg-positive lamivudine patients during the 2-year study period; resistance was defined in the GLOBE study as HBV DNA return to greater than 5 log10 or to within 1 log10 of baseline. Among the HBeAg-negative patients, 7.3% of those on telbivudine and 16.6% of those on lamivudine developed resistance, Dr. Lai said.

Viral resistance, defined as rebound of HBV DNA after initial suppression to 1 log10 increase above nadir, was found in 21.6% of telbivudine patients and 35.0% of lamivudine patients in the HBeAg-positive group, as well as 8.6% of telbivudine patients and 21.9% of lamivudine patients in the HBeAg-negative group, he said.

Telbivudine was associated with fewer and less severe resistance-associated elevations of serum ALT levels, which occurred in 2.8% of patients, compared with 8.4% of the lamivudine group, Dr. Lai reported.

Both study drugs were generally well tolerated and had similar patterns of clinical adverse events, Dr. Lai said. Grade 3/4 creatine kinase elevations were more commonly associated with telbivudine, occurring in 13% of patients, compared with 4% of lamivudine patients, he noted.

Dr. Lai said he is a scientific adviser to Idenix Pharmaceuticals.

BOSTON — Telbivudine showed greater efficacy than lamivudine did during 2 years of treatment for chronic hepatitis B infection, according to the most recent results from the international GLOBE trial.

In the phase III trial, telbivudine (Tyzeka), which recently received Food and Drug Administration approval for the treatment of hepatitis B virus (HBV) infection, surpassed the older antiviral on all key measures of virologic and clinical efficacy.

These results were found in both HBV e-antigen (HBeAg)-positive and HBeAg-negative patients enrolled in the study of 1,367 patients, Dr. Ching-Lung Lai said at the annual meeting of the American Association for the Study of Liver Diseases.

The international, multicenter investigation was partially funded by Idenix Pharmaceuticals, the manufacturer—with Novartis Pharma AG—of telbivudine. The trial was designed to compare the efficacy of telbivudine at 600 mg/day to that of lamivudine (Epivir) at 100 mg/day in patients who were HB s-antigen positive at enrollment and had baseline HBV DNA greater than 6 log10 copies/mL, alanine aminotransferase (ALT) levels between 1.3 and 10 times the upper limit of normal, and compensated liver disease.

The study's primary efficacy end point was therapeutic response, based on a combination of viral suppression (serum HBV DNA below 100,000 copies/mL) and either improved liver disease markers (ALT normalization) or loss of detectable HBeAg.

The first-year results from the trial, presented last year, “demonstrated that telbivudine was superior to lamivudine on all measures of direct antiviral efficacy and on several key clinical efficacy measures,” said Dr. Lai, professor of medicine and hepatology at the University of Hong Kong. “The new data indicate the efficacy levels were sustained over 104 weeks.”

After 2 years of treatment, analysis showed that HBeAG-positive and -negative patients randomized to telbivudine therapy had significantly greater HBV DNA reductions (-5.7 log10 and -5.0 log10, respectively) than did HBeAG-positive and -negative patients on lamivudine (-4.4 log10 and -4.2 log10, respectively).

Similarly, significantly more patients receiving telbivudine achieved clearance of detectable HBV DNA. In HBeAg-positive patients, “telbivudine treatment led to loss of detectable HBV DNA in 56% of patients, compared to 39% with lamivudine,” said Dr. Lai. Among HBeAg-negative patients, 82% of telbivudine patients achieved undetectable HBV DNA levels, compared with 57% of lamivudine patients, he said.

Patients who had achieved HBV DNA clearance by study week 24 had the best overall response rates in terms of seroconversion, ALT normalization, and reduced therapeutic resistance, Dr. Lai noted.

Treatment failure was significantly less common with telbivudine than with lamivudine in both HBeAg-positive and -negative patients. Among HBeAg-positive patients, antiviral treatment failed in 4% of telbivudine patients, compared with 12% of lamivudine patients. In HBeAg-negative patients, there were no treatment failures in telbivudine patients, compared with 3% of patients taking lamivudine, he said.

Drug resistance occurred in 17.8% of HBeAg-positive patients on telbivudine and 30.1% of HBeAg-positive lamivudine patients during the 2-year study period; resistance was defined in the GLOBE study as HBV DNA return to greater than 5 log10 or to within 1 log10 of baseline. Among the HBeAg-negative patients, 7.3% of those on telbivudine and 16.6% of those on lamivudine developed resistance, Dr. Lai said.

Viral resistance, defined as rebound of HBV DNA after initial suppression to 1 log10 increase above nadir, was found in 21.6% of telbivudine patients and 35.0% of lamivudine patients in the HBeAg-positive group, as well as 8.6% of telbivudine patients and 21.9% of lamivudine patients in the HBeAg-negative group, he said.

Telbivudine was associated with fewer and less severe resistance-associated elevations of serum ALT levels, which occurred in 2.8% of patients, compared with 8.4% of the lamivudine group, Dr. Lai reported.

Both study drugs were generally well tolerated and had similar patterns of clinical adverse events, Dr. Lai said. Grade 3/4 creatine kinase elevations were more commonly associated with telbivudine, occurring in 13% of patients, compared with 4% of lamivudine patients, he noted.

Dr. Lai said he is a scientific adviser to Idenix Pharmaceuticals.

BOSTON — Telbivudine showed greater efficacy than lamivudine did during 2 years of treatment for chronic hepatitis B infection, according to the most recent results from the international GLOBE trial.

In the phase III trial, telbivudine (Tyzeka), which recently received Food and Drug Administration approval for the treatment of hepatitis B virus (HBV) infection, surpassed the older antiviral on all key measures of virologic and clinical efficacy.

These results were found in both HBV e-antigen (HBeAg)-positive and HBeAg-negative patients enrolled in the study of 1,367 patients, Dr. Ching-Lung Lai said at the annual meeting of the American Association for the Study of Liver Diseases.

The international, multicenter investigation was partially funded by Idenix Pharmaceuticals, the manufacturer—with Novartis Pharma AG—of telbivudine. The trial was designed to compare the efficacy of telbivudine at 600 mg/day to that of lamivudine (Epivir) at 100 mg/day in patients who were HB s-antigen positive at enrollment and had baseline HBV DNA greater than 6 log10 copies/mL, alanine aminotransferase (ALT) levels between 1.3 and 10 times the upper limit of normal, and compensated liver disease.

The study's primary efficacy end point was therapeutic response, based on a combination of viral suppression (serum HBV DNA below 100,000 copies/mL) and either improved liver disease markers (ALT normalization) or loss of detectable HBeAg.

The first-year results from the trial, presented last year, “demonstrated that telbivudine was superior to lamivudine on all measures of direct antiviral efficacy and on several key clinical efficacy measures,” said Dr. Lai, professor of medicine and hepatology at the University of Hong Kong. “The new data indicate the efficacy levels were sustained over 104 weeks.”

After 2 years of treatment, analysis showed that HBeAG-positive and -negative patients randomized to telbivudine therapy had significantly greater HBV DNA reductions (-5.7 log10 and -5.0 log10, respectively) than did HBeAG-positive and -negative patients on lamivudine (-4.4 log10 and -4.2 log10, respectively).

Similarly, significantly more patients receiving telbivudine achieved clearance of detectable HBV DNA. In HBeAg-positive patients, “telbivudine treatment led to loss of detectable HBV DNA in 56% of patients, compared to 39% with lamivudine,” said Dr. Lai. Among HBeAg-negative patients, 82% of telbivudine patients achieved undetectable HBV DNA levels, compared with 57% of lamivudine patients, he said.

Patients who had achieved HBV DNA clearance by study week 24 had the best overall response rates in terms of seroconversion, ALT normalization, and reduced therapeutic resistance, Dr. Lai noted.

Treatment failure was significantly less common with telbivudine than with lamivudine in both HBeAg-positive and -negative patients. Among HBeAg-positive patients, antiviral treatment failed in 4% of telbivudine patients, compared with 12% of lamivudine patients. In HBeAg-negative patients, there were no treatment failures in telbivudine patients, compared with 3% of patients taking lamivudine, he said.

Drug resistance occurred in 17.8% of HBeAg-positive patients on telbivudine and 30.1% of HBeAg-positive lamivudine patients during the 2-year study period; resistance was defined in the GLOBE study as HBV DNA return to greater than 5 log10 or to within 1 log10 of baseline. Among the HBeAg-negative patients, 7.3% of those on telbivudine and 16.6% of those on lamivudine developed resistance, Dr. Lai said.

Viral resistance, defined as rebound of HBV DNA after initial suppression to 1 log10 increase above nadir, was found in 21.6% of telbivudine patients and 35.0% of lamivudine patients in the HBeAg-positive group, as well as 8.6% of telbivudine patients and 21.9% of lamivudine patients in the HBeAg-negative group, he said.

Telbivudine was associated with fewer and less severe resistance-associated elevations of serum ALT levels, which occurred in 2.8% of patients, compared with 8.4% of the lamivudine group, Dr. Lai reported.

Both study drugs were generally well tolerated and had similar patterns of clinical adverse events, Dr. Lai said. Grade 3/4 creatine kinase elevations were more commonly associated with telbivudine, occurring in 13% of patients, compared with 4% of lamivudine patients, he noted.

Dr. Lai said he is a scientific adviser to Idenix Pharmaceuticals.

Combination therapy with disease-modifying antirheumatic drugs in early rheumatoid arthritis is more effective than monotherapy in producing sustained remission, which in turn is associated with better radiographic outcomes, a Finnish study has found.

In a comparison of the rates of achieved and sustained remission and good treatment response among a cohort of early rheumatoid arthritis (RA) patients receiving either combination or single DMARD therapy, patients randomized to combination therapy were more than twice as likely to meet modified American College of Rheumatology (ACR) remission criteria at 2 years and were more than four times as likely to demonstrate sustained remission at each visit, compared with patients on monotherapy, reported Dr. Heidi Makinen of Jyväskylä Central Hospital (Finland) and colleagues in the Finnish RA Combination Therapy Trial (FIN-RACo).

The trial included 169 patients out of 195 included in the original FIN-RACo study for whom complete data were available. Patients were aged 18-65 years and had recent-onset RA, defined as less than 2 years' duration of active disease with 3 or more swollen joints and three of the following: erythrocyte sedimentation rate (ESR) of at least 28 mm/hr or C-reactive protein (CRP) greater than 19 mg/L; morning stiffness lasting a minimum of 29 minutes; more than 5 swollen joints; or more than 10 tender joints.

The 79 patients randomized to combination therapy initially received 500 mg of sulfasalazine twice daily, 7.5 mg methotrexate per week, 300 mg of hydroxychloroquine daily, and 5 mg of prednisolone daily. Dose adjustments were made for patients who did not achieve at least 50% improvement in two of the following three criteria: swollen joint count, tender joint count, and ESR or CRP, and drug replacements were made (auranofin for sulfasalazine or hydroxychloroquine, and azathioprine for methotrexate) if the original agents were discontinued for lack of efficacy or adverse events.

The 90 patients randomized to monotherapy initially received 2 g of sulfasalazine daily, which could be increased up to 3 g per day and, at the discretion of the treating rheumatologist, up to 10 mg of prednisolone daily. In the case of adverse events or lack of efficacy, sulfasalazine could be replaced with methotrexate or another single DMARD. Intra-articular glucocorticoid injections were allowed in all patients at the treating physicians' discretion.

Patient evaluations at baseline, 6, 12, and 24 months included assessments of tender joint count, swollen joint count, duration of morning stiffness, physician and patient overall assessment and pain on visual analog scales, physical function on patient self-report Health Assessment Questionnaire, ESR, and CRP. Radiographs of hands and feet were obtained at 6 and 24 months and were scored by radiologists blinded to the treatments according to the Larsen method.

Remission was defined based on modified ACR criteria, including no joint swelling or soft tissue swelling of tendon sheaths, no joint tenderness or pain on motion, normal ESR, and morning stiffness lasting no longer than 15 minutes. Remission based on Disease Activity Score 28 (DAS28) was defined as a DAS28 score of less than 2.6. Sustained remission was defined as the presence of remission at 6, 12, and 24 months. Good treatment response was defined according to the European League Against Rheumatism (EULAR) treatment response criteria as a DAS28 score less than 3.2 and a decreased DAS28 score of more than 1.2 from baseline.

Of the full study population, 62% were female, 70% were rheumatoid-factor positive, and 48% had evidence of erosions on baseline hand and/or foot radiographs.

Based on the modified ACR criteria, 20 of the combination-therapy patients and 11 of the single-therapy patients were in remission at 6 months. At 12 months, 13 of the combination patients and 3 of the single-therapy patients were still in remission, and at 24 months, 11 of the combination patients and 3 of the single-therapy patients remained in remission. The odds ratio for sustained remission in the combination versus single-therapy group, adjusted for baseline DAS28 values, was 4.61, the authors reported (J. Rheumatol. 2007;34:1–6).

With respect to the duration of DAS28 remission, 52 of the combination patients were in DAS28 remission at 6 months, and 45 and 40 were still in DAS28 remission at 12 and 24 months, respectively. In the single-therapy group, 33 patients were in DAS28 remission at 6 months, and 21 and 14 remained in DAS28 remission at months 12 and 24, respectively. As such, the odds ratio for sustained DAS28 remission in the combination-therapy group, compared with the single-therapy group was 5.58, the authors wrote.

Treatment responses were good based on the EULAR criteria in 59 of the combination patients and 47 of the single-therapy patients at 6 months. Approximately 67% of the combination patients and 27% of the single-therapy patients demonstrated sustained good responses at 24 months, they stated.

A review of the association between radiographic progression and the sustained remission and good treatment response showed markedly less deterioration in Larson score among patients in sustained remission, compared with those who achieved remission at the 6-month visit but did not sustain it, according to the investigators. Because sustained remissions were more common in the combination-therapy patients, it follows that such treatment would be associated with better radiographic outcomes, they said.

While the study was limited by its assessment of remission only at the 6-, 12-, and 24-month time points—leaving open the possibility that patients in remission at those time points could have experienced active disease flares between visits—previous studies have shown that such flares are often linked to discontinuation of therapy while in remission. “In our study, combination therapy was continued successfully for 2 years, and half the patients remained in sustained DAS28 remission,” the authors wrote.

The findings of this study suggest that sustained remission, rather than remission, should be the goal of DMARD therapy, the authors concluded.

Combination therapy with disease-modifying antirheumatic drugs in early rheumatoid arthritis is more effective than monotherapy in producing sustained remission, which in turn is associated with better radiographic outcomes, a Finnish study has found.

In a comparison of the rates of achieved and sustained remission and good treatment response among a cohort of early rheumatoid arthritis (RA) patients receiving either combination or single DMARD therapy, patients randomized to combination therapy were more than twice as likely to meet modified American College of Rheumatology (ACR) remission criteria at 2 years and were more than four times as likely to demonstrate sustained remission at each visit, compared with patients on monotherapy, reported Dr. Heidi Makinen of Jyväskylä Central Hospital (Finland) and colleagues in the Finnish RA Combination Therapy Trial (FIN-RACo).

The trial included 169 patients out of 195 included in the original FIN-RACo study for whom complete data were available. Patients were aged 18-65 years and had recent-onset RA, defined as less than 2 years' duration of active disease with 3 or more swollen joints and three of the following: erythrocyte sedimentation rate (ESR) of at least 28 mm/hr or C-reactive protein (CRP) greater than 19 mg/L; morning stiffness lasting a minimum of 29 minutes; more than 5 swollen joints; or more than 10 tender joints.

The 79 patients randomized to combination therapy initially received 500 mg of sulfasalazine twice daily, 7.5 mg methotrexate per week, 300 mg of hydroxychloroquine daily, and 5 mg of prednisolone daily. Dose adjustments were made for patients who did not achieve at least 50% improvement in two of the following three criteria: swollen joint count, tender joint count, and ESR or CRP, and drug replacements were made (auranofin for sulfasalazine or hydroxychloroquine, and azathioprine for methotrexate) if the original agents were discontinued for lack of efficacy or adverse events.

The 90 patients randomized to monotherapy initially received 2 g of sulfasalazine daily, which could be increased up to 3 g per day and, at the discretion of the treating rheumatologist, up to 10 mg of prednisolone daily. In the case of adverse events or lack of efficacy, sulfasalazine could be replaced with methotrexate or another single DMARD. Intra-articular glucocorticoid injections were allowed in all patients at the treating physicians' discretion.

Patient evaluations at baseline, 6, 12, and 24 months included assessments of tender joint count, swollen joint count, duration of morning stiffness, physician and patient overall assessment and pain on visual analog scales, physical function on patient self-report Health Assessment Questionnaire, ESR, and CRP. Radiographs of hands and feet were obtained at 6 and 24 months and were scored by radiologists blinded to the treatments according to the Larsen method.

Remission was defined based on modified ACR criteria, including no joint swelling or soft tissue swelling of tendon sheaths, no joint tenderness or pain on motion, normal ESR, and morning stiffness lasting no longer than 15 minutes. Remission based on Disease Activity Score 28 (DAS28) was defined as a DAS28 score of less than 2.6. Sustained remission was defined as the presence of remission at 6, 12, and 24 months. Good treatment response was defined according to the European League Against Rheumatism (EULAR) treatment response criteria as a DAS28 score less than 3.2 and a decreased DAS28 score of more than 1.2 from baseline.

Of the full study population, 62% were female, 70% were rheumatoid-factor positive, and 48% had evidence of erosions on baseline hand and/or foot radiographs.

Based on the modified ACR criteria, 20 of the combination-therapy patients and 11 of the single-therapy patients were in remission at 6 months. At 12 months, 13 of the combination patients and 3 of the single-therapy patients were still in remission, and at 24 months, 11 of the combination patients and 3 of the single-therapy patients remained in remission. The odds ratio for sustained remission in the combination versus single-therapy group, adjusted for baseline DAS28 values, was 4.61, the authors reported (J. Rheumatol. 2007;34:1–6).

With respect to the duration of DAS28 remission, 52 of the combination patients were in DAS28 remission at 6 months, and 45 and 40 were still in DAS28 remission at 12 and 24 months, respectively. In the single-therapy group, 33 patients were in DAS28 remission at 6 months, and 21 and 14 remained in DAS28 remission at months 12 and 24, respectively. As such, the odds ratio for sustained DAS28 remission in the combination-therapy group, compared with the single-therapy group was 5.58, the authors wrote.

Treatment responses were good based on the EULAR criteria in 59 of the combination patients and 47 of the single-therapy patients at 6 months. Approximately 67% of the combination patients and 27% of the single-therapy patients demonstrated sustained good responses at 24 months, they stated.

A review of the association between radiographic progression and the sustained remission and good treatment response showed markedly less deterioration in Larson score among patients in sustained remission, compared with those who achieved remission at the 6-month visit but did not sustain it, according to the investigators. Because sustained remissions were more common in the combination-therapy patients, it follows that such treatment would be associated with better radiographic outcomes, they said.

While the study was limited by its assessment of remission only at the 6-, 12-, and 24-month time points—leaving open the possibility that patients in remission at those time points could have experienced active disease flares between visits—previous studies have shown that such flares are often linked to discontinuation of therapy while in remission. “In our study, combination therapy was continued successfully for 2 years, and half the patients remained in sustained DAS28 remission,” the authors wrote.

The findings of this study suggest that sustained remission, rather than remission, should be the goal of DMARD therapy, the authors concluded.

Combination therapy with disease-modifying antirheumatic drugs in early rheumatoid arthritis is more effective than monotherapy in producing sustained remission, which in turn is associated with better radiographic outcomes, a Finnish study has found.

In a comparison of the rates of achieved and sustained remission and good treatment response among a cohort of early rheumatoid arthritis (RA) patients receiving either combination or single DMARD therapy, patients randomized to combination therapy were more than twice as likely to meet modified American College of Rheumatology (ACR) remission criteria at 2 years and were more than four times as likely to demonstrate sustained remission at each visit, compared with patients on monotherapy, reported Dr. Heidi Makinen of Jyväskylä Central Hospital (Finland) and colleagues in the Finnish RA Combination Therapy Trial (FIN-RACo).

The trial included 169 patients out of 195 included in the original FIN-RACo study for whom complete data were available. Patients were aged 18-65 years and had recent-onset RA, defined as less than 2 years' duration of active disease with 3 or more swollen joints and three of the following: erythrocyte sedimentation rate (ESR) of at least 28 mm/hr or C-reactive protein (CRP) greater than 19 mg/L; morning stiffness lasting a minimum of 29 minutes; more than 5 swollen joints; or more than 10 tender joints.

The 79 patients randomized to combination therapy initially received 500 mg of sulfasalazine twice daily, 7.5 mg methotrexate per week, 300 mg of hydroxychloroquine daily, and 5 mg of prednisolone daily. Dose adjustments were made for patients who did not achieve at least 50% improvement in two of the following three criteria: swollen joint count, tender joint count, and ESR or CRP, and drug replacements were made (auranofin for sulfasalazine or hydroxychloroquine, and azathioprine for methotrexate) if the original agents were discontinued for lack of efficacy or adverse events.

The 90 patients randomized to monotherapy initially received 2 g of sulfasalazine daily, which could be increased up to 3 g per day and, at the discretion of the treating rheumatologist, up to 10 mg of prednisolone daily. In the case of adverse events or lack of efficacy, sulfasalazine could be replaced with methotrexate or another single DMARD. Intra-articular glucocorticoid injections were allowed in all patients at the treating physicians' discretion.

Patient evaluations at baseline, 6, 12, and 24 months included assessments of tender joint count, swollen joint count, duration of morning stiffness, physician and patient overall assessment and pain on visual analog scales, physical function on patient self-report Health Assessment Questionnaire, ESR, and CRP. Radiographs of hands and feet were obtained at 6 and 24 months and were scored by radiologists blinded to the treatments according to the Larsen method.

Remission was defined based on modified ACR criteria, including no joint swelling or soft tissue swelling of tendon sheaths, no joint tenderness or pain on motion, normal ESR, and morning stiffness lasting no longer than 15 minutes. Remission based on Disease Activity Score 28 (DAS28) was defined as a DAS28 score of less than 2.6. Sustained remission was defined as the presence of remission at 6, 12, and 24 months. Good treatment response was defined according to the European League Against Rheumatism (EULAR) treatment response criteria as a DAS28 score less than 3.2 and a decreased DAS28 score of more than 1.2 from baseline.

Of the full study population, 62% were female, 70% were rheumatoid-factor positive, and 48% had evidence of erosions on baseline hand and/or foot radiographs.

Based on the modified ACR criteria, 20 of the combination-therapy patients and 11 of the single-therapy patients were in remission at 6 months. At 12 months, 13 of the combination patients and 3 of the single-therapy patients were still in remission, and at 24 months, 11 of the combination patients and 3 of the single-therapy patients remained in remission. The odds ratio for sustained remission in the combination versus single-therapy group, adjusted for baseline DAS28 values, was 4.61, the authors reported (J. Rheumatol. 2007;34:1–6).

With respect to the duration of DAS28 remission, 52 of the combination patients were in DAS28 remission at 6 months, and 45 and 40 were still in DAS28 remission at 12 and 24 months, respectively. In the single-therapy group, 33 patients were in DAS28 remission at 6 months, and 21 and 14 remained in DAS28 remission at months 12 and 24, respectively. As such, the odds ratio for sustained DAS28 remission in the combination-therapy group, compared with the single-therapy group was 5.58, the authors wrote.

Treatment responses were good based on the EULAR criteria in 59 of the combination patients and 47 of the single-therapy patients at 6 months. Approximately 67% of the combination patients and 27% of the single-therapy patients demonstrated sustained good responses at 24 months, they stated.

A review of the association between radiographic progression and the sustained remission and good treatment response showed markedly less deterioration in Larson score among patients in sustained remission, compared with those who achieved remission at the 6-month visit but did not sustain it, according to the investigators. Because sustained remissions were more common in the combination-therapy patients, it follows that such treatment would be associated with better radiographic outcomes, they said.

While the study was limited by its assessment of remission only at the 6-, 12-, and 24-month time points—leaving open the possibility that patients in remission at those time points could have experienced active disease flares between visits—previous studies have shown that such flares are often linked to discontinuation of therapy while in remission. “In our study, combination therapy was continued successfully for 2 years, and half the patients remained in sustained DAS28 remission,” the authors wrote.

The findings of this study suggest that sustained remission, rather than remission, should be the goal of DMARD therapy, the authors concluded.