Osteoarthritis

MINNEAPOLIS – Some day physicians will be able to order detailed vitamin D assay panels much like the lipid panels used today to assess cholesterol.

We’re just not there yet.

“Where we’re at today with 25-hydroxyvitamin D measurement is where we were at 50 or 60 years ago with lipid measurement ... but I believe vitamin D assay panels are coming,” said Dr. Neil C. Binkley of the Institute on Aging at the University of Wisconsin, Madison.

Patrice Wendling/IMNG Medical Media

Part of the problem with 25-hydroxyvitamin D [25(OH)D] measurement is that it has not yet been standardized, and there is no agreement on which cut points should be used by laboratories and assay manufacturers.

In its 2011 report that set for the first time Recommended Dietary Allowances for calcium and vitamin D, the Institute of Medicine declared an “urgent clinical and public health need” to reassess laboratory ranges for 25(OH)D to avoid problems of overtreatment and undertreatment.

The IOM committee concluded that the prevalence of vitamin D deficiency in North Americans has been overestimated by some because of the use of “inappropriate cut points” that greatly exceed levels identified in the report (J. Clin. Endocrinol. Metab. 2011;96:53-8).

Substantial progress has been made in the past decade, thanks in large part to the work of Dr. Graham Carter and DEQAS, the Vitamin D External Quality Assessment Scheme, Dr. Binkley said at the annual meeting of the American Society for Bone and Mineral Research. DEQAS provides serum samples on a quarterly basis to laboratories that wish to check the accuracy of their assays, and statistically trims the data to produce an all-laboratory trimmed mean (ALTM), standard deviation, and coefficient of variation for all major methodologies. Recent DEQAS data show, however, that ALTMs can vary substantially, even among groups striving to improve the quality of their program, he said.

In 2010, the National Institutes of Health Office of Dietary Supplements also launched the international vitamin D standardization program dedicated to standardizing 25(OH)D measurement to the National Institute of Standards and Technology (NIST) reference procedures. The program recently began quantitating DEQAS materials with real values assigned by NIST, and is also working on standardizing measurements for 25(OH)D2 and D3, the C-3 epimer of 25(OH)D2 and D3, and 24,25(OH)2D, he said.

“This, I think, is a substantial positive development; however, despite these efforts some scatter is going to persist in 25(OH)D measurement,” Dr. Binkley said.
The reason for this is that analyses will pick up components of a sample other than the analyte – a phenomenon known as the matrix effect. Given the number of vitamin D metabolites that exist, it’s not surprising that assays have trouble identifying one analyte from other similar analytes, he explained.

One of those confounders is the C-3 epimer (3-epi) of 25(OH)D3, which was previously thought to exist in infants only and, as such, wasn’t of much concern, but is now known to be present at variable, albeit low, levels in virtually all human serum (J. Clin. Endocrinol. Metab. 2012;97:163-8). Since 3-epi has the same molecular structure and molecular weight as 25(OH)D, it’s not surprising that it can add “noise” to your 25(OH)D result, Dr. Binkley said.

Another confounder is 24,25(OH)2D3, which has historically been considered as simply an inactivating step in the 25(OH)D degradation pathway on the way to calcitroic acid. As such, many feel it isn’t worth measuring, he said. Recent studies, however, have found that 24,25(OH)2D3 possesses physiologic effects on cartilage and bone, and that once again, it is present at variable levels in adults up to about 10% of the 25(OH)D level.

“Three of our current immunoassays that I know of have 100% cross-reactivity with 24,25-dihydroxyvitamin D3, so when you’re measuring 25-hydroxyvitamin D, you are also measuring 24,25-dihydroxyvitamin D3,” he said.
A more recent study reports that patients with high levels of serum 24,25-dihydroxyvitamin D3 may have a less robust response to vitamin D3 (J. Steroid. Biochem. Mol. Biol. 2011;126:72-7).

Finally, two additional studies find that vitamin D3 is more potent at increasing 25(OH)D than is vitamin D2, but what may be more important is whether current assays can measure the two equally, Dr. Binkley said. Indeed, unpublished data he presented clearly show that a newer immunoassay was not up to the task.

“By prescribing ergocalciferol, we clinicians are needlessly making life more difficult for our laboratory colleagues” and unnecessarily confounding assay methodologies, he said.

Dr. Binkley reported that he had no relevant financial disclosures.

MINNEAPOLIS – Some day physicians will be able to order detailed vitamin D assay panels much like the lipid panels used today to assess cholesterol.

We’re just not there yet.

“Where we’re at today with 25-hydroxyvitamin D measurement is where we were at 50 or 60 years ago with lipid measurement ... but I believe vitamin D assay panels are coming,” said Dr. Neil C. Binkley of the Institute on Aging at the University of Wisconsin, Madison.

Patrice Wendling/IMNG Medical Media

Part of the problem with 25-hydroxyvitamin D [25(OH)D] measurement is that it has not yet been standardized, and there is no agreement on which cut points should be used by laboratories and assay manufacturers.

In its 2011 report that set for the first time Recommended Dietary Allowances for calcium and vitamin D, the Institute of Medicine declared an “urgent clinical and public health need” to reassess laboratory ranges for 25(OH)D to avoid problems of overtreatment and undertreatment.

The IOM committee concluded that the prevalence of vitamin D deficiency in North Americans has been overestimated by some because of the use of “inappropriate cut points” that greatly exceed levels identified in the report (J. Clin. Endocrinol. Metab. 2011;96:53-8).

Substantial progress has been made in the past decade, thanks in large part to the work of Dr. Graham Carter and DEQAS, the Vitamin D External Quality Assessment Scheme, Dr. Binkley said at the annual meeting of the American Society for Bone and Mineral Research. DEQAS provides serum samples on a quarterly basis to laboratories that wish to check the accuracy of their assays, and statistically trims the data to produce an all-laboratory trimmed mean (ALTM), standard deviation, and coefficient of variation for all major methodologies. Recent DEQAS data show, however, that ALTMs can vary substantially, even among groups striving to improve the quality of their program, he said.

In 2010, the National Institutes of Health Office of Dietary Supplements also launched the international vitamin D standardization program dedicated to standardizing 25(OH)D measurement to the National Institute of Standards and Technology (NIST) reference procedures. The program recently began quantitating DEQAS materials with real values assigned by NIST, and is also working on standardizing measurements for 25(OH)D2 and D3, the C-3 epimer of 25(OH)D2 and D3, and 24,25(OH)2D, he said.

“This, I think, is a substantial positive development; however, despite these efforts some scatter is going to persist in 25(OH)D measurement,” Dr. Binkley said.
The reason for this is that analyses will pick up components of a sample other than the analyte – a phenomenon known as the matrix effect. Given the number of vitamin D metabolites that exist, it’s not surprising that assays have trouble identifying one analyte from other similar analytes, he explained.

One of those confounders is the C-3 epimer (3-epi) of 25(OH)D3, which was previously thought to exist in infants only and, as such, wasn’t of much concern, but is now known to be present at variable, albeit low, levels in virtually all human serum (J. Clin. Endocrinol. Metab. 2012;97:163-8). Since 3-epi has the same molecular structure and molecular weight as 25(OH)D, it’s not surprising that it can add “noise” to your 25(OH)D result, Dr. Binkley said.

Another confounder is 24,25(OH)2D3, which has historically been considered as simply an inactivating step in the 25(OH)D degradation pathway on the way to calcitroic acid. As such, many feel it isn’t worth measuring, he said. Recent studies, however, have found that 24,25(OH)2D3 possesses physiologic effects on cartilage and bone, and that once again, it is present at variable levels in adults up to about 10% of the 25(OH)D level.

“Three of our current immunoassays that I know of have 100% cross-reactivity with 24,25-dihydroxyvitamin D3, so when you’re measuring 25-hydroxyvitamin D, you are also measuring 24,25-dihydroxyvitamin D3,” he said.
A more recent study reports that patients with high levels of serum 24,25-dihydroxyvitamin D3 may have a less robust response to vitamin D3 (J. Steroid. Biochem. Mol. Biol. 2011;126:72-7).

Finally, two additional studies find that vitamin D3 is more potent at increasing 25(OH)D than is vitamin D2, but what may be more important is whether current assays can measure the two equally, Dr. Binkley said. Indeed, unpublished data he presented clearly show that a newer immunoassay was not up to the task.

“By prescribing ergocalciferol, we clinicians are needlessly making life more difficult for our laboratory colleagues” and unnecessarily confounding assay methodologies, he said.

Dr. Binkley reported that he had no relevant financial disclosures.

MINNEAPOLIS – Some day physicians will be able to order detailed vitamin D assay panels much like the lipid panels used today to assess cholesterol.

We’re just not there yet.

“Where we’re at today with 25-hydroxyvitamin D measurement is where we were at 50 or 60 years ago with lipid measurement ... but I believe vitamin D assay panels are coming,” said Dr. Neil C. Binkley of the Institute on Aging at the University of Wisconsin, Madison.

Patrice Wendling/IMNG Medical Media

Part of the problem with 25-hydroxyvitamin D [25(OH)D] measurement is that it has not yet been standardized, and there is no agreement on which cut points should be used by laboratories and assay manufacturers.

In its 2011 report that set for the first time Recommended Dietary Allowances for calcium and vitamin D, the Institute of Medicine declared an “urgent clinical and public health need” to reassess laboratory ranges for 25(OH)D to avoid problems of overtreatment and undertreatment.

The IOM committee concluded that the prevalence of vitamin D deficiency in North Americans has been overestimated by some because of the use of “inappropriate cut points” that greatly exceed levels identified in the report (J. Clin. Endocrinol. Metab. 2011;96:53-8).

Substantial progress has been made in the past decade, thanks in large part to the work of Dr. Graham Carter and DEQAS, the Vitamin D External Quality Assessment Scheme, Dr. Binkley said at the annual meeting of the American Society for Bone and Mineral Research. DEQAS provides serum samples on a quarterly basis to laboratories that wish to check the accuracy of their assays, and statistically trims the data to produce an all-laboratory trimmed mean (ALTM), standard deviation, and coefficient of variation for all major methodologies. Recent DEQAS data show, however, that ALTMs can vary substantially, even among groups striving to improve the quality of their program, he said.

In 2010, the National Institutes of Health Office of Dietary Supplements also launched the international vitamin D standardization program dedicated to standardizing 25(OH)D measurement to the National Institute of Standards and Technology (NIST) reference procedures. The program recently began quantitating DEQAS materials with real values assigned by NIST, and is also working on standardizing measurements for 25(OH)D2 and D3, the C-3 epimer of 25(OH)D2 and D3, and 24,25(OH)2D, he said.

“This, I think, is a substantial positive development; however, despite these efforts some scatter is going to persist in 25(OH)D measurement,” Dr. Binkley said.
The reason for this is that analyses will pick up components of a sample other than the analyte – a phenomenon known as the matrix effect. Given the number of vitamin D metabolites that exist, it’s not surprising that assays have trouble identifying one analyte from other similar analytes, he explained.

One of those confounders is the C-3 epimer (3-epi) of 25(OH)D3, which was previously thought to exist in infants only and, as such, wasn’t of much concern, but is now known to be present at variable, albeit low, levels in virtually all human serum (J. Clin. Endocrinol. Metab. 2012;97:163-8). Since 3-epi has the same molecular structure and molecular weight as 25(OH)D, it’s not surprising that it can add “noise” to your 25(OH)D result, Dr. Binkley said.

Another confounder is 24,25(OH)2D3, which has historically been considered as simply an inactivating step in the 25(OH)D degradation pathway on the way to calcitroic acid. As such, many feel it isn’t worth measuring, he said. Recent studies, however, have found that 24,25(OH)2D3 possesses physiologic effects on cartilage and bone, and that once again, it is present at variable levels in adults up to about 10% of the 25(OH)D level.

“Three of our current immunoassays that I know of have 100% cross-reactivity with 24,25-dihydroxyvitamin D3, so when you’re measuring 25-hydroxyvitamin D, you are also measuring 24,25-dihydroxyvitamin D3,” he said.
A more recent study reports that patients with high levels of serum 24,25-dihydroxyvitamin D3 may have a less robust response to vitamin D3 (J. Steroid. Biochem. Mol. Biol. 2011;126:72-7).

Finally, two additional studies find that vitamin D3 is more potent at increasing 25(OH)D than is vitamin D2, but what may be more important is whether current assays can measure the two equally, Dr. Binkley said. Indeed, unpublished data he presented clearly show that a newer immunoassay was not up to the task.

“By prescribing ergocalciferol, we clinicians are needlessly making life more difficult for our laboratory colleagues” and unnecessarily confounding assay methodologies, he said.

Dr. Binkley reported that he had no relevant financial disclosures.

WASHINGTON – A daily dose of strontium ranelate was associated with a significant delay in joint space narrowing in adults with symptomatic primary knee osteoarthritis, based on data from the phase III Strontium Ranelate Knee Osteoarthritis Trial (SEKOIA).

Strontium renalate currently is not approved in the United States, but it is approved in more than 100 countries for treating osteoporosis, said Dr. Jean-Yves Reginster, who is head of the Center for Investigation in Bone and Articular Cartilage Metabolism at the University of Liège (Belgium).

Data from nonclinical studies have shown that strontium’s bone-building activity has a positive impact on cartilage as well, he noted at the annual meeting of the American College of Rheumatology.

To examine the effectiveness of strontium ranelate on the progression of knee osteoarthritis (OA), Dr. Reginster and his colleagues randomized 1,683 adults with symptomatic primary knee OA to 1 g of strontium ranelate per day (566 patients), 2 g/day (558 patients), or a placebo (559 patients). Complete data were available for 1,371 patients. The average age of the patients was 63 years, and 69% were women.

Overall, treatment with either dose of strontium was associated with a significant delay in the radiographic progression of knee OA, which was assessed by measuring the radiological joint space narrowing (JSN) of the medial tibiofemoral compartment of the knee joint.

After 1 year, joint space width decreased by 0.27 mm in the 2-g/day group, 0.23 mm in the 1-g/day group, and 0.37 mm in the placebo group. The differences between the 2-g/day and 1-g/day groups and the placebo group were 0.10 mm and 0.14 mm, respectively.

Significantly less radiological progression was noted in both strontium groups, compared with the placebo group. The percentage of patients with radiological progression (defined as joint space narrowing of at least 0.5 mm) was 26% in the 2-g/day group, 22% in the 1-g/day group, and 33% in the placebo group.

"The structural effect is translated clinically into a lower number of patients having a radiological progression over thresholds predictive of OA-related surgery," Dr. Reginster said. The findings suggest that strontium ranelate could reduce the need for knee surgery in OA patients, he added.

In addition, significantly more patients in the 2-g/day group exceeded the minimally perceptible clinical improvement (MCPI) threshold, compared with the placebo patients, on subscores of pain, stiffness, and physical function. The percentage of patients in the 1-g/day group above this threshold was not significantly higher than in the placebo group.

No significant differences in adverse events were observed among the three groups, and the incidence of serious adverse events was 17% in all groups.

The study findings also appeared online on Nov. 9 (Ann. Rheum. Dis. 2012 [doi:10.1136/annrheumdis-2012-202231]).

The study was sponsored by Servier. Dr. Reginster disclosed financial relationships with multiple companies, including Servier.

WASHINGTON – A daily dose of strontium ranelate was associated with a significant delay in joint space narrowing in adults with symptomatic primary knee osteoarthritis, based on data from the phase III Strontium Ranelate Knee Osteoarthritis Trial (SEKOIA).

Strontium renalate currently is not approved in the United States, but it is approved in more than 100 countries for treating osteoporosis, said Dr. Jean-Yves Reginster, who is head of the Center for Investigation in Bone and Articular Cartilage Metabolism at the University of Liège (Belgium).

Data from nonclinical studies have shown that strontium’s bone-building activity has a positive impact on cartilage as well, he noted at the annual meeting of the American College of Rheumatology.

To examine the effectiveness of strontium ranelate on the progression of knee osteoarthritis (OA), Dr. Reginster and his colleagues randomized 1,683 adults with symptomatic primary knee OA to 1 g of strontium ranelate per day (566 patients), 2 g/day (558 patients), or a placebo (559 patients). Complete data were available for 1,371 patients. The average age of the patients was 63 years, and 69% were women.

Overall, treatment with either dose of strontium was associated with a significant delay in the radiographic progression of knee OA, which was assessed by measuring the radiological joint space narrowing (JSN) of the medial tibiofemoral compartment of the knee joint.

After 1 year, joint space width decreased by 0.27 mm in the 2-g/day group, 0.23 mm in the 1-g/day group, and 0.37 mm in the placebo group. The differences between the 2-g/day and 1-g/day groups and the placebo group were 0.10 mm and 0.14 mm, respectively.

Significantly less radiological progression was noted in both strontium groups, compared with the placebo group. The percentage of patients with radiological progression (defined as joint space narrowing of at least 0.5 mm) was 26% in the 2-g/day group, 22% in the 1-g/day group, and 33% in the placebo group.

"The structural effect is translated clinically into a lower number of patients having a radiological progression over thresholds predictive of OA-related surgery," Dr. Reginster said. The findings suggest that strontium ranelate could reduce the need for knee surgery in OA patients, he added.

In addition, significantly more patients in the 2-g/day group exceeded the minimally perceptible clinical improvement (MCPI) threshold, compared with the placebo patients, on subscores of pain, stiffness, and physical function. The percentage of patients in the 1-g/day group above this threshold was not significantly higher than in the placebo group.

No significant differences in adverse events were observed among the three groups, and the incidence of serious adverse events was 17% in all groups.

The study findings also appeared online on Nov. 9 (Ann. Rheum. Dis. 2012 [doi:10.1136/annrheumdis-2012-202231]).

The study was sponsored by Servier. Dr. Reginster disclosed financial relationships with multiple companies, including Servier.

WASHINGTON – A daily dose of strontium ranelate was associated with a significant delay in joint space narrowing in adults with symptomatic primary knee osteoarthritis, based on data from the phase III Strontium Ranelate Knee Osteoarthritis Trial (SEKOIA).

Strontium renalate currently is not approved in the United States, but it is approved in more than 100 countries for treating osteoporosis, said Dr. Jean-Yves Reginster, who is head of the Center for Investigation in Bone and Articular Cartilage Metabolism at the University of Liège (Belgium).

Data from nonclinical studies have shown that strontium’s bone-building activity has a positive impact on cartilage as well, he noted at the annual meeting of the American College of Rheumatology.

To examine the effectiveness of strontium ranelate on the progression of knee osteoarthritis (OA), Dr. Reginster and his colleagues randomized 1,683 adults with symptomatic primary knee OA to 1 g of strontium ranelate per day (566 patients), 2 g/day (558 patients), or a placebo (559 patients). Complete data were available for 1,371 patients. The average age of the patients was 63 years, and 69% were women.

Overall, treatment with either dose of strontium was associated with a significant delay in the radiographic progression of knee OA, which was assessed by measuring the radiological joint space narrowing (JSN) of the medial tibiofemoral compartment of the knee joint.

After 1 year, joint space width decreased by 0.27 mm in the 2-g/day group, 0.23 mm in the 1-g/day group, and 0.37 mm in the placebo group. The differences between the 2-g/day and 1-g/day groups and the placebo group were 0.10 mm and 0.14 mm, respectively.

Significantly less radiological progression was noted in both strontium groups, compared with the placebo group. The percentage of patients with radiological progression (defined as joint space narrowing of at least 0.5 mm) was 26% in the 2-g/day group, 22% in the 1-g/day group, and 33% in the placebo group.

"The structural effect is translated clinically into a lower number of patients having a radiological progression over thresholds predictive of OA-related surgery," Dr. Reginster said. The findings suggest that strontium ranelate could reduce the need for knee surgery in OA patients, he added.

In addition, significantly more patients in the 2-g/day group exceeded the minimally perceptible clinical improvement (MCPI) threshold, compared with the placebo patients, on subscores of pain, stiffness, and physical function. The percentage of patients in the 1-g/day group above this threshold was not significantly higher than in the placebo group.

No significant differences in adverse events were observed among the three groups, and the incidence of serious adverse events was 17% in all groups.

The study findings also appeared online on Nov. 9 (Ann. Rheum. Dis. 2012 [doi:10.1136/annrheumdis-2012-202231]).

The study was sponsored by Servier. Dr. Reginster disclosed financial relationships with multiple companies, including Servier.

The outbreak of fungal meningitis caused by contaminated methylprednisolone has topped 200 patients and is likely to include more, according to a review article on the subject published online in the New England Journal of Medicine. The article was written in an attempt to answer some of the "numerous questions have been raised by physicians, patients who received injections from the implicated lots, and the public."

Despite the fact that the first case reported found the mold Aspergillus fumigatus as the cause of the meningitis, this organism was not been detected in any of the subsequent 200-plus cases and is no longer considered as the basis for appropriate treatment. Instead, the fungal plant pathogen, Exserohilum rostratum, has been cultured or identified using polymerase chain reaction assay from cerebrospinal fluid in at least 25 patients and was detected in at least one unopened vial from the implicated lot of methylprednisolone, according to Dr. Carol A. Kaufman of the Veterans Affairs Ann Arbor (Mich.) Healthcare System, and her colleagues from Alabama and Texas.

E. rostratum is a "black mold" containing melanin in its cell wall. It is rarely infectious to humans and is usually restricted to mild diseases, such as allergic sinusitis, keratitis, and localized soft-tissue infection. In tissues, E. rostratum has the same appearance of irregular, beaded hyphae as seen in many other dematiaceous fungi, and unlike the rarely septate, ribbonlike hyphae of Mucorales fungi or the acutely branching, hyaline hyphae of aspergillus species.

Recommendations for treating this rare infection are based on small case series, individual case reports, and personal experience, according to the authors of the review article (N. Engl. J. Med. 2012 [doi:10.10156/NEJMra1212617]). The Centers for Disease Control and Prevention is providing information on the outbreak with daily updates, along with appropriate diagnostic testing and treatment details on its website, according to the authors.

Initially, when the causative agent was not known and the only detected microorganism was A. fumigatus, high doses of both liposomal amphotericin B and voriconazole were recommended. Once the primary pathogen was determined to be the black mold, however, monotherapy with voriconazole was recommended, except for the sickest patients or those who had substantial side-effects to the drug. For these, amphotericin B could still play a role, the said.

Although exserohilum species are susceptible to available antifungals, for some strains, the minimal inhibitor concentration for the usually recommended agents, including voriconazole, is increased. Thus, susceptibility testing is advised, they added.

Because of the potential toxic effects of voriconazole, especially in the large doses recommended, and the host of drug-drug interactions in which it is involved, prophylactic use is not recommended, the authors said. They noted that side effects included visual hallucinations, which have been noted in patients treated during the outbreak. Other side effects can include photopsia, nausea, and hepatic enzyme elevation.

"Without objective evidence of infection in the cerebrospinal fluid, treatment is not recommended. However, patients who have symptoms should be monitored closely, and if there is even subtle progression of symptoms, a repeat lumbar puncture should be performed immediately. If the number of white cells has increased [reaching 5 mm³or more], then empirical antifungal treatment should be initiated immediately," the authors stated.

"It is encouraging to note that clinically apparent disease has developed in only a small percentage of exposed patients. Management recommendations will almost assuredly change as more information becomes available regarding the pathogenesis of these infections," they concluded.

Dr. Kaufman and the other authors reported having no relevant disclosures for their review paper.

The outbreak of fungal meningitis caused by contaminated methylprednisolone has topped 200 patients and is likely to include more, according to a review article on the subject published online in the New England Journal of Medicine. The article was written in an attempt to answer some of the "numerous questions have been raised by physicians, patients who received injections from the implicated lots, and the public."

Despite the fact that the first case reported found the mold Aspergillus fumigatus as the cause of the meningitis, this organism was not been detected in any of the subsequent 200-plus cases and is no longer considered as the basis for appropriate treatment. Instead, the fungal plant pathogen, Exserohilum rostratum, has been cultured or identified using polymerase chain reaction assay from cerebrospinal fluid in at least 25 patients and was detected in at least one unopened vial from the implicated lot of methylprednisolone, according to Dr. Carol A. Kaufman of the Veterans Affairs Ann Arbor (Mich.) Healthcare System, and her colleagues from Alabama and Texas.

E. rostratum is a "black mold" containing melanin in its cell wall. It is rarely infectious to humans and is usually restricted to mild diseases, such as allergic sinusitis, keratitis, and localized soft-tissue infection. In tissues, E. rostratum has the same appearance of irregular, beaded hyphae as seen in many other dematiaceous fungi, and unlike the rarely septate, ribbonlike hyphae of Mucorales fungi or the acutely branching, hyaline hyphae of aspergillus species.

Recommendations for treating this rare infection are based on small case series, individual case reports, and personal experience, according to the authors of the review article (N. Engl. J. Med. 2012 [doi:10.10156/NEJMra1212617]). The Centers for Disease Control and Prevention is providing information on the outbreak with daily updates, along with appropriate diagnostic testing and treatment details on its website, according to the authors.

Initially, when the causative agent was not known and the only detected microorganism was A. fumigatus, high doses of both liposomal amphotericin B and voriconazole were recommended. Once the primary pathogen was determined to be the black mold, however, monotherapy with voriconazole was recommended, except for the sickest patients or those who had substantial side-effects to the drug. For these, amphotericin B could still play a role, the said.

Although exserohilum species are susceptible to available antifungals, for some strains, the minimal inhibitor concentration for the usually recommended agents, including voriconazole, is increased. Thus, susceptibility testing is advised, they added.

Because of the potential toxic effects of voriconazole, especially in the large doses recommended, and the host of drug-drug interactions in which it is involved, prophylactic use is not recommended, the authors said. They noted that side effects included visual hallucinations, which have been noted in patients treated during the outbreak. Other side effects can include photopsia, nausea, and hepatic enzyme elevation.

"Without objective evidence of infection in the cerebrospinal fluid, treatment is not recommended. However, patients who have symptoms should be monitored closely, and if there is even subtle progression of symptoms, a repeat lumbar puncture should be performed immediately. If the number of white cells has increased [reaching 5 mm³or more], then empirical antifungal treatment should be initiated immediately," the authors stated.

"It is encouraging to note that clinically apparent disease has developed in only a small percentage of exposed patients. Management recommendations will almost assuredly change as more information becomes available regarding the pathogenesis of these infections," they concluded.

Dr. Kaufman and the other authors reported having no relevant disclosures for their review paper.

The outbreak of fungal meningitis caused by contaminated methylprednisolone has topped 200 patients and is likely to include more, according to a review article on the subject published online in the New England Journal of Medicine. The article was written in an attempt to answer some of the "numerous questions have been raised by physicians, patients who received injections from the implicated lots, and the public."

Despite the fact that the first case reported found the mold Aspergillus fumigatus as the cause of the meningitis, this organism was not been detected in any of the subsequent 200-plus cases and is no longer considered as the basis for appropriate treatment. Instead, the fungal plant pathogen, Exserohilum rostratum, has been cultured or identified using polymerase chain reaction assay from cerebrospinal fluid in at least 25 patients and was detected in at least one unopened vial from the implicated lot of methylprednisolone, according to Dr. Carol A. Kaufman of the Veterans Affairs Ann Arbor (Mich.) Healthcare System, and her colleagues from Alabama and Texas.

E. rostratum is a "black mold" containing melanin in its cell wall. It is rarely infectious to humans and is usually restricted to mild diseases, such as allergic sinusitis, keratitis, and localized soft-tissue infection. In tissues, E. rostratum has the same appearance of irregular, beaded hyphae as seen in many other dematiaceous fungi, and unlike the rarely septate, ribbonlike hyphae of Mucorales fungi or the acutely branching, hyaline hyphae of aspergillus species.

Recommendations for treating this rare infection are based on small case series, individual case reports, and personal experience, according to the authors of the review article (N. Engl. J. Med. 2012 [doi:10.10156/NEJMra1212617]). The Centers for Disease Control and Prevention is providing information on the outbreak with daily updates, along with appropriate diagnostic testing and treatment details on its website, according to the authors.

Initially, when the causative agent was not known and the only detected microorganism was A. fumigatus, high doses of both liposomal amphotericin B and voriconazole were recommended. Once the primary pathogen was determined to be the black mold, however, monotherapy with voriconazole was recommended, except for the sickest patients or those who had substantial side-effects to the drug. For these, amphotericin B could still play a role, the said.

Although exserohilum species are susceptible to available antifungals, for some strains, the minimal inhibitor concentration for the usually recommended agents, including voriconazole, is increased. Thus, susceptibility testing is advised, they added.

Because of the potential toxic effects of voriconazole, especially in the large doses recommended, and the host of drug-drug interactions in which it is involved, prophylactic use is not recommended, the authors said. They noted that side effects included visual hallucinations, which have been noted in patients treated during the outbreak. Other side effects can include photopsia, nausea, and hepatic enzyme elevation.

"Without objective evidence of infection in the cerebrospinal fluid, treatment is not recommended. However, patients who have symptoms should be monitored closely, and if there is even subtle progression of symptoms, a repeat lumbar puncture should be performed immediately. If the number of white cells has increased [reaching 5 mm³or more], then empirical antifungal treatment should be initiated immediately," the authors stated.

"It is encouraging to note that clinically apparent disease has developed in only a small percentage of exposed patients. Management recommendations will almost assuredly change as more information becomes available regarding the pathogenesis of these infections," they concluded.

Dr. Kaufman and the other authors reported having no relevant disclosures for their review paper.

Infections have developed in one joint each in two individuals who were injected with fungus-contaminated methylprednisolone acetate in the weeks or months preceding the ongoing outbreak, according to a teleconference hosted Oct. 16 by the Food and Drug Administration and the Centers for Disease Control and Prevention.

The indications for those joint injections were not discussed at the briefing, but rheumatologists commonly use methylprednisolone injections in joints affected by rheumatoid arthritis or osteoarthritis to reduce inflammation and ease pain.

Dr. Tom Chiller, a medical epidemiologist at the Division of Foodborne, Waterborne and Environmental Diseases at the CDC, noted that both infected joints were ankles that had been injected with fungus-contaminated methylprednisolone acetate manufactured by the New England Compounding Center (NECC) in Framingham, Mass. That plant has been shut down because inspection by the FDA showed that the conditions were unsterile.

Neither culture nor polymerase chain reaction of synovial fluid aspirated from the infected ankles has grown any fungus. However, because bacteria and crystals have been ruled out as a cause of these two cases of septic arthritic and both patients received intra-articular injections with the contaminated steroid solution, investigators feel certain the patients have fungal joint infections, according to Dr. Chiller.

Three kinds of fungus have been identified in patients with fungal infections associated with the contaminated NECC products. Aspergillus was identified as the cause of the index case of fungal meningitis. Two types of black mold have been cultured from meningitis patients: Exserohilum rostratum and Cladosporium.

In total, as of Oct. 16, there have been 233 confirmed cases of fungal infection in people who received injections, usually epidural, of contaminated steroid in solution, according to Dr. Melissa Schaefer, medical officer in the Division of Healthcare Quality Promotion at the CDC’s National Center for Emerging and Zoonotic Infectious Diseases. Among these people there have been 15 deaths, all from meningitis.

One particularly challenging aspect of this outbreak for rheumatologists is the length of incubation of septic arthritis because of a fungus.

The FDA has advised physicians who used NECC products dated May 21, 2012 or later, to contact their patients to check on their well being. Most of the patients given epidural injections with the contaminated solution are likely to present within 1-2 weeks.

The latency period of a fungus infection in a joint, however, may be months, according to Dr. Peter G. Pappas, professor of medicine in the division of infectious diseases at the University of Alabama at Birmingham, who participated in the CDC teleconference.

Patients with septic arthritis often limp into the office months after the onset of symptoms to seek medical care, he said.

The CDC has revised its treatment guidance for septic arthritis in cases of suspected fungal infection Dr. Chiller said that in cases of suspected fungal septic arthritis, the CDC now recommends empiric treatment with voriconazole (Vfend), beginning with a loading dose of 6 mg/kg every 12 hours for two doses, followed by 4 mg/kg every 12 hours for the duration of treatment. A lipid formulation of amphotericin B at a dose of 5 mg/kg IV daily should be considered in addition to voriconazole in patients with severe joint infection and/or clinical instability. Administration of 1L normal saline prior to infusion may be considered to minimize risk of nephrotoxicity. Providers and patients should be aware of and monitor for potential adverse effects of amphotericin B formulations.

The CDC plans to update the guidance on diagnosing fungal septic arthritis on Oct. 17 or 18.

The source of the outbreak is NECC, a compounding pharmacy that operated in violation of the law on a number of levels.

Infections have developed in one joint each in two individuals who were injected with fungus-contaminated methylprednisolone acetate in the weeks or months preceding the ongoing outbreak, according to a teleconference hosted Oct. 16 by the Food and Drug Administration and the Centers for Disease Control and Prevention.

The indications for those joint injections were not discussed at the briefing, but rheumatologists commonly use methylprednisolone injections in joints affected by rheumatoid arthritis or osteoarthritis to reduce inflammation and ease pain.

Dr. Tom Chiller, a medical epidemiologist at the Division of Foodborne, Waterborne and Environmental Diseases at the CDC, noted that both infected joints were ankles that had been injected with fungus-contaminated methylprednisolone acetate manufactured by the New England Compounding Center (NECC) in Framingham, Mass. That plant has been shut down because inspection by the FDA showed that the conditions were unsterile.

Neither culture nor polymerase chain reaction of synovial fluid aspirated from the infected ankles has grown any fungus. However, because bacteria and crystals have been ruled out as a cause of these two cases of septic arthritic and both patients received intra-articular injections with the contaminated steroid solution, investigators feel certain the patients have fungal joint infections, according to Dr. Chiller.

Three kinds of fungus have been identified in patients with fungal infections associated with the contaminated NECC products. Aspergillus was identified as the cause of the index case of fungal meningitis. Two types of black mold have been cultured from meningitis patients: Exserohilum rostratum and Cladosporium.

In total, as of Oct. 16, there have been 233 confirmed cases of fungal infection in people who received injections, usually epidural, of contaminated steroid in solution, according to Dr. Melissa Schaefer, medical officer in the Division of Healthcare Quality Promotion at the CDC’s National Center for Emerging and Zoonotic Infectious Diseases. Among these people there have been 15 deaths, all from meningitis.

One particularly challenging aspect of this outbreak for rheumatologists is the length of incubation of septic arthritis because of a fungus.

The FDA has advised physicians who used NECC products dated May 21, 2012 or later, to contact their patients to check on their well being. Most of the patients given epidural injections with the contaminated solution are likely to present within 1-2 weeks.

The latency period of a fungus infection in a joint, however, may be months, according to Dr. Peter G. Pappas, professor of medicine in the division of infectious diseases at the University of Alabama at Birmingham, who participated in the CDC teleconference.

Patients with septic arthritis often limp into the office months after the onset of symptoms to seek medical care, he said.

The CDC has revised its treatment guidance for septic arthritis in cases of suspected fungal infection Dr. Chiller said that in cases of suspected fungal septic arthritis, the CDC now recommends empiric treatment with voriconazole (Vfend), beginning with a loading dose of 6 mg/kg every 12 hours for two doses, followed by 4 mg/kg every 12 hours for the duration of treatment. A lipid formulation of amphotericin B at a dose of 5 mg/kg IV daily should be considered in addition to voriconazole in patients with severe joint infection and/or clinical instability. Administration of 1L normal saline prior to infusion may be considered to minimize risk of nephrotoxicity. Providers and patients should be aware of and monitor for potential adverse effects of amphotericin B formulations.

The CDC plans to update the guidance on diagnosing fungal septic arthritis on Oct. 17 or 18.

The source of the outbreak is NECC, a compounding pharmacy that operated in violation of the law on a number of levels.

Infections have developed in one joint each in two individuals who were injected with fungus-contaminated methylprednisolone acetate in the weeks or months preceding the ongoing outbreak, according to a teleconference hosted Oct. 16 by the Food and Drug Administration and the Centers for Disease Control and Prevention.

The indications for those joint injections were not discussed at the briefing, but rheumatologists commonly use methylprednisolone injections in joints affected by rheumatoid arthritis or osteoarthritis to reduce inflammation and ease pain.

Dr. Tom Chiller, a medical epidemiologist at the Division of Foodborne, Waterborne and Environmental Diseases at the CDC, noted that both infected joints were ankles that had been injected with fungus-contaminated methylprednisolone acetate manufactured by the New England Compounding Center (NECC) in Framingham, Mass. That plant has been shut down because inspection by the FDA showed that the conditions were unsterile.

Neither culture nor polymerase chain reaction of synovial fluid aspirated from the infected ankles has grown any fungus. However, because bacteria and crystals have been ruled out as a cause of these two cases of septic arthritic and both patients received intra-articular injections with the contaminated steroid solution, investigators feel certain the patients have fungal joint infections, according to Dr. Chiller.

Three kinds of fungus have been identified in patients with fungal infections associated with the contaminated NECC products. Aspergillus was identified as the cause of the index case of fungal meningitis. Two types of black mold have been cultured from meningitis patients: Exserohilum rostratum and Cladosporium.

In total, as of Oct. 16, there have been 233 confirmed cases of fungal infection in people who received injections, usually epidural, of contaminated steroid in solution, according to Dr. Melissa Schaefer, medical officer in the Division of Healthcare Quality Promotion at the CDC’s National Center for Emerging and Zoonotic Infectious Diseases. Among these people there have been 15 deaths, all from meningitis.

One particularly challenging aspect of this outbreak for rheumatologists is the length of incubation of septic arthritis because of a fungus.

The FDA has advised physicians who used NECC products dated May 21, 2012 or later, to contact their patients to check on their well being. Most of the patients given epidural injections with the contaminated solution are likely to present within 1-2 weeks.

The latency period of a fungus infection in a joint, however, may be months, according to Dr. Peter G. Pappas, professor of medicine in the division of infectious diseases at the University of Alabama at Birmingham, who participated in the CDC teleconference.

Patients with septic arthritis often limp into the office months after the onset of symptoms to seek medical care, he said.

The CDC has revised its treatment guidance for septic arthritis in cases of suspected fungal infection Dr. Chiller said that in cases of suspected fungal septic arthritis, the CDC now recommends empiric treatment with voriconazole (Vfend), beginning with a loading dose of 6 mg/kg every 12 hours for two doses, followed by 4 mg/kg every 12 hours for the duration of treatment. A lipid formulation of amphotericin B at a dose of 5 mg/kg IV daily should be considered in addition to voriconazole in patients with severe joint infection and/or clinical instability. Administration of 1L normal saline prior to infusion may be considered to minimize risk of nephrotoxicity. Providers and patients should be aware of and monitor for potential adverse effects of amphotericin B formulations.

The CDC plans to update the guidance on diagnosing fungal septic arthritis on Oct. 17 or 18.

The source of the outbreak is NECC, a compounding pharmacy that operated in violation of the law on a number of levels.

SAN FRANCISCO – The addition of rifampin to long-term antibiotic regimens significantly lowers the risk for Clostridium difficile–associated colitis in patients being treated for osteoarticular infections.

The retrospective cohort study comprised 393 treatment episodes – 55% of them for infections subsequent to arthroplasty – among patients admitted to a Swiss orthopedic surgery unit from 1996 to 2012. The ribotype 027 was not endemic in the region.

The 42% of patients who were treated with combination therapy that included oral rifampin (600 mg/day) were significantly less like to develop C. difficile colitis despite being on the antibiotics for a median of 63 days (ranging from 20-294 days), Caroline Landelle, Pharm.D., Ph.D. and her associates reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

Rifampin use was inversely associated with C. difficile colitis, with an adjusted hazard ratio of 0.18, Dr. Landelle reported in a poster presentation.

In general, longer duration of antibiotics treatment was associated with C. difficile colitis, with an adjusted hazard ratio of 1.01, said Dr. Landelle of the University of Geneva.

Factors not associated with colitis risk (either positively or negatively) included the use of antianaerobic antibiotics (in 38% of patients), treatment with intravenous vancomycin (in 45%, for a median of 13 days), age, or sex.

Fourteen patients (4%) developed symptomatic C. difficile colitis after a median of 14 days of antibiotic treatment (ranging from 8-193 days). Of these, six patients were on vancomycin (43%) and two patients were receiving rifampin (14%) prior to development of the colitis, Dr. Landelle reported at the meeting, sponsored by the American Society for Microbiology.

"C. difficile colitis was rare despite long-term antibiotic use among patients with osteoarticular infection. In contrast to intravenous vancomycin, combination antibiotic therapy with oral rifampin might protect against C. difficile–associated colitis," the investigators suggested.

The cohort had a median age of 69 years; 41% was female, and 31% of patients were immunosuppressed.

Of the 401 microorganisms isolated from the osteoarticular infections, 32% were methicillin-sensitive Staphylococcus aureus, 16% were methicillin-resistant S. aureus, 17% each were coagulase-negative Staphylococcus or gram-negative bacilli, and 18% were other organisms.

The investigators hypothesized that combination therapy with rifampin or derivative medications might protect against C. difficile colitis because very few cases have been reported of rifampin-associated pseudomembranous colitis, and patients undergoing treatment with long-term antibiotic combination therapy for osteoarticular infections rarely develop symptomatic C. difficile–associated disease.

Rifaximin and other antibiotics belonging to the macrocyclic family are being investigated as alternative therapies for C. difficile–associated disease, Dr. Landelle said. Some studies have shown high rates of C. difficile resistance to rifampin in Europe, but the rate of resistance at her institution was low. In Switzerland, rifamycin antibiotics have been used for decades, but rifaximin is not licensed for the treatment of hepatic encephalopathy, diarrhea, and traveler’s diarrhea or for prophylaxis in patients undergoing GI surgery, which may explain the low rate of resistance there.

The study excluded patients with prior episodes of C. difficile–associated disease, patients being treated with metronidazole, and patients with septic arthritis.

Dr. Landelle did not provide her financial disclosures.

SAN FRANCISCO – The addition of rifampin to long-term antibiotic regimens significantly lowers the risk for Clostridium difficile–associated colitis in patients being treated for osteoarticular infections.

The retrospective cohort study comprised 393 treatment episodes – 55% of them for infections subsequent to arthroplasty – among patients admitted to a Swiss orthopedic surgery unit from 1996 to 2012. The ribotype 027 was not endemic in the region.

The 42% of patients who were treated with combination therapy that included oral rifampin (600 mg/day) were significantly less like to develop C. difficile colitis despite being on the antibiotics for a median of 63 days (ranging from 20-294 days), Caroline Landelle, Pharm.D., Ph.D. and her associates reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

Rifampin use was inversely associated with C. difficile colitis, with an adjusted hazard ratio of 0.18, Dr. Landelle reported in a poster presentation.

In general, longer duration of antibiotics treatment was associated with C. difficile colitis, with an adjusted hazard ratio of 1.01, said Dr. Landelle of the University of Geneva.

Factors not associated with colitis risk (either positively or negatively) included the use of antianaerobic antibiotics (in 38% of patients), treatment with intravenous vancomycin (in 45%, for a median of 13 days), age, or sex.

Fourteen patients (4%) developed symptomatic C. difficile colitis after a median of 14 days of antibiotic treatment (ranging from 8-193 days). Of these, six patients were on vancomycin (43%) and two patients were receiving rifampin (14%) prior to development of the colitis, Dr. Landelle reported at the meeting, sponsored by the American Society for Microbiology.

"C. difficile colitis was rare despite long-term antibiotic use among patients with osteoarticular infection. In contrast to intravenous vancomycin, combination antibiotic therapy with oral rifampin might protect against C. difficile–associated colitis," the investigators suggested.

The cohort had a median age of 69 years; 41% was female, and 31% of patients were immunosuppressed.

Of the 401 microorganisms isolated from the osteoarticular infections, 32% were methicillin-sensitive Staphylococcus aureus, 16% were methicillin-resistant S. aureus, 17% each were coagulase-negative Staphylococcus or gram-negative bacilli, and 18% were other organisms.

The investigators hypothesized that combination therapy with rifampin or derivative medications might protect against C. difficile colitis because very few cases have been reported of rifampin-associated pseudomembranous colitis, and patients undergoing treatment with long-term antibiotic combination therapy for osteoarticular infections rarely develop symptomatic C. difficile–associated disease.

Rifaximin and other antibiotics belonging to the macrocyclic family are being investigated as alternative therapies for C. difficile–associated disease, Dr. Landelle said. Some studies have shown high rates of C. difficile resistance to rifampin in Europe, but the rate of resistance at her institution was low. In Switzerland, rifamycin antibiotics have been used for decades, but rifaximin is not licensed for the treatment of hepatic encephalopathy, diarrhea, and traveler’s diarrhea or for prophylaxis in patients undergoing GI surgery, which may explain the low rate of resistance there.

The study excluded patients with prior episodes of C. difficile–associated disease, patients being treated with metronidazole, and patients with septic arthritis.

Dr. Landelle did not provide her financial disclosures.

SAN FRANCISCO – The addition of rifampin to long-term antibiotic regimens significantly lowers the risk for Clostridium difficile–associated colitis in patients being treated for osteoarticular infections.

The retrospective cohort study comprised 393 treatment episodes – 55% of them for infections subsequent to arthroplasty – among patients admitted to a Swiss orthopedic surgery unit from 1996 to 2012. The ribotype 027 was not endemic in the region.

The 42% of patients who were treated with combination therapy that included oral rifampin (600 mg/day) were significantly less like to develop C. difficile colitis despite being on the antibiotics for a median of 63 days (ranging from 20-294 days), Caroline Landelle, Pharm.D., Ph.D. and her associates reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

Rifampin use was inversely associated with C. difficile colitis, with an adjusted hazard ratio of 0.18, Dr. Landelle reported in a poster presentation.

In general, longer duration of antibiotics treatment was associated with C. difficile colitis, with an adjusted hazard ratio of 1.01, said Dr. Landelle of the University of Geneva.

Factors not associated with colitis risk (either positively or negatively) included the use of antianaerobic antibiotics (in 38% of patients), treatment with intravenous vancomycin (in 45%, for a median of 13 days), age, or sex.

Fourteen patients (4%) developed symptomatic C. difficile colitis after a median of 14 days of antibiotic treatment (ranging from 8-193 days). Of these, six patients were on vancomycin (43%) and two patients were receiving rifampin (14%) prior to development of the colitis, Dr. Landelle reported at the meeting, sponsored by the American Society for Microbiology.

"C. difficile colitis was rare despite long-term antibiotic use among patients with osteoarticular infection. In contrast to intravenous vancomycin, combination antibiotic therapy with oral rifampin might protect against C. difficile–associated colitis," the investigators suggested.

The cohort had a median age of 69 years; 41% was female, and 31% of patients were immunosuppressed.

Of the 401 microorganisms isolated from the osteoarticular infections, 32% were methicillin-sensitive Staphylococcus aureus, 16% were methicillin-resistant S. aureus, 17% each were coagulase-negative Staphylococcus or gram-negative bacilli, and 18% were other organisms.

The investigators hypothesized that combination therapy with rifampin or derivative medications might protect against C. difficile colitis because very few cases have been reported of rifampin-associated pseudomembranous colitis, and patients undergoing treatment with long-term antibiotic combination therapy for osteoarticular infections rarely develop symptomatic C. difficile–associated disease.

Rifaximin and other antibiotics belonging to the macrocyclic family are being investigated as alternative therapies for C. difficile–associated disease, Dr. Landelle said. Some studies have shown high rates of C. difficile resistance to rifampin in Europe, but the rate of resistance at her institution was low. In Switzerland, rifamycin antibiotics have been used for decades, but rifaximin is not licensed for the treatment of hepatic encephalopathy, diarrhea, and traveler’s diarrhea or for prophylaxis in patients undergoing GI surgery, which may explain the low rate of resistance there.

The study excluded patients with prior episodes of C. difficile–associated disease, patients being treated with metronidazole, and patients with septic arthritis.

Dr. Landelle did not provide her financial disclosures.

ESTES PARK, COLO. – S-adenosyl-l-methionine doesn’t crack the annual top-10 lists of the most widely used nutritional supplements in complementary and alternative medicine surveys. But unlike other far more popular products, SAMe is supported by randomized trial evidence of efficacy for osteoarthritis, depression, and fibromyalgia.

Indeed, S-adenosyl-l-methionine (SAMe) is "buzz-worthy," Dr. Lisa Corbin declared at a conference on internal medicine sponsored by the University of Colorado.

The Natural Medicines Comprehensive Database, which she considers the best available source of physician information on supplements, rates SAMe as "likely effective" for depression and osteoarthritis and "possibly effective" for fibromyalgia, noted Dr. Corbin, medical director of the Center for Integrative Medicine and a general internist at the University of Colorado in Denver.

The Natural Medicines Comprehensive Database is subscription funded and eschews financial support from industry. The organization is famously tough in its efficacy ratings. "Likely effective" is about as good as it gets. Take, for example, hypertension. Nothing included in the natural medicines database has earned the coveted "effective" rating for treatment of hypertension, and only a single item is listed as "likely effective," namely the National Institutes of Health–backed DASH (Dietary Approaches to Stop Hypertension) diet.

SAMe is a naturally occurring homocysteine derivative present in all living human cells. Its synthesis is related to vitamin B₁₂/folate metabolism, and SAMe serves as an essential methyl donor in cellular metabolism.

Osteoarthritis

SAMe appears to increase proteoglycan synthesis and has analgesic and anti-inflammatory effects. Numerous small studies of varying quality have demonstrated a benefit similar to that of non-cyclooxygenase-2 (non-COX2) inhibitor selective nonsteroidal anti-inflammatory drugs (NSAIDs), but with fewer side effects.

And in a University of California, Irvine, 16-week, double-blind, crossover trial of 61 patients with knee osteoarthritis, SAMe dosed at 400 mg t.i.d. and celecoxib at 200 mg/day demonstrated comparable pain reduction and improvement over time in functional health scores and isometric joint function tests.

SAMe was slower acting, taking almost a month to catch up to the COX-2 inhibitor in terms of analgesic effect. On the other hand, it appeared that the benefits of SAMe lasted after the medication was stopped.

Fibromyalgia

Danish rheumatologists randomized 43 patients with fibromyalgia to 800 mg/day of SAMe or placebo double-blind for 6 weeks. The SAMe group showed significant improvement compared with controls in fatigue, clinical disease activity, pain during the past week, mood, and morning stiffness, but not in tender point score or isokinetic muscle strength. Side effects in the SAMe group were no different from those with placebo (Scand. J. Rheumatol. 1991;20:294-302).

Another Danish double-blind randomized trial compared intravenous SAMe – a route of administration almost never used today – to placebo in 34 fibromyalgia patients. Ten days of IV SAMe at 600 mg/day showed nonsignificant trends toward better outcomes compared with placebo (Scand. J. Rheumatol. 1997; 26: 206-11).

Dr. Corbin said there have been no major safety issues with SAMe. At higher doses it has been associated with gastrointestinal side effects, headache, and loss of appetite.

"I think the financial toxicity is a potential issue," she quipped.

She urges her patients who are interested in trying dietary supplements to seek out those with "USP Verified" displayed prominently on the label. That designation signals that the product meets rigorous United States Pharmacopeia quality standards. However, SAMe is not a big seller, and no USP standards have been set for it. So she recommends that patients scan the shelves and select a SAMe product marketed by a company with USP labels on plenty of their other, more common supplements.

"That way you know that in general this manufacturer is making decent products, so that’s where I’d spend my money," Dr. Corbin said.

She reported having no financial interests relevant to her presentation.

ESTES PARK, COLO. – S-adenosyl-l-methionine doesn’t crack the annual top-10 lists of the most widely used nutritional supplements in complementary and alternative medicine surveys. But unlike other far more popular products, SAMe is supported by randomized trial evidence of efficacy for osteoarthritis, depression, and fibromyalgia.

Indeed, S-adenosyl-l-methionine (SAMe) is "buzz-worthy," Dr. Lisa Corbin declared at a conference on internal medicine sponsored by the University of Colorado.

The Natural Medicines Comprehensive Database, which she considers the best available source of physician information on supplements, rates SAMe as "likely effective" for depression and osteoarthritis and "possibly effective" for fibromyalgia, noted Dr. Corbin, medical director of the Center for Integrative Medicine and a general internist at the University of Colorado in Denver.

The Natural Medicines Comprehensive Database is subscription funded and eschews financial support from industry. The organization is famously tough in its efficacy ratings. "Likely effective" is about as good as it gets. Take, for example, hypertension. Nothing included in the natural medicines database has earned the coveted "effective" rating for treatment of hypertension, and only a single item is listed as "likely effective," namely the National Institutes of Health–backed DASH (Dietary Approaches to Stop Hypertension) diet.

SAMe is a naturally occurring homocysteine derivative present in all living human cells. Its synthesis is related to vitamin B₁₂/folate metabolism, and SAMe serves as an essential methyl donor in cellular metabolism.

Osteoarthritis

SAMe appears to increase proteoglycan synthesis and has analgesic and anti-inflammatory effects. Numerous small studies of varying quality have demonstrated a benefit similar to that of non-cyclooxygenase-2 (non-COX2) inhibitor selective nonsteroidal anti-inflammatory drugs (NSAIDs), but with fewer side effects.

And in a University of California, Irvine, 16-week, double-blind, crossover trial of 61 patients with knee osteoarthritis, SAMe dosed at 400 mg t.i.d. and celecoxib at 200 mg/day demonstrated comparable pain reduction and improvement over time in functional health scores and isometric joint function tests.

SAMe was slower acting, taking almost a month to catch up to the COX-2 inhibitor in terms of analgesic effect. On the other hand, it appeared that the benefits of SAMe lasted after the medication was stopped.

Fibromyalgia

Danish rheumatologists randomized 43 patients with fibromyalgia to 800 mg/day of SAMe or placebo double-blind for 6 weeks. The SAMe group showed significant improvement compared with controls in fatigue, clinical disease activity, pain during the past week, mood, and morning stiffness, but not in tender point score or isokinetic muscle strength. Side effects in the SAMe group were no different from those with placebo (Scand. J. Rheumatol. 1991;20:294-302).

Another Danish double-blind randomized trial compared intravenous SAMe – a route of administration almost never used today – to placebo in 34 fibromyalgia patients. Ten days of IV SAMe at 600 mg/day showed nonsignificant trends toward better outcomes compared with placebo (Scand. J. Rheumatol. 1997; 26: 206-11).

Dr. Corbin said there have been no major safety issues with SAMe. At higher doses it has been associated with gastrointestinal side effects, headache, and loss of appetite.

"I think the financial toxicity is a potential issue," she quipped.

She urges her patients who are interested in trying dietary supplements to seek out those with "USP Verified" displayed prominently on the label. That designation signals that the product meets rigorous United States Pharmacopeia quality standards. However, SAMe is not a big seller, and no USP standards have been set for it. So she recommends that patients scan the shelves and select a SAMe product marketed by a company with USP labels on plenty of their other, more common supplements.

"That way you know that in general this manufacturer is making decent products, so that’s where I’d spend my money," Dr. Corbin said.

She reported having no financial interests relevant to her presentation.

ESTES PARK, COLO. – S-adenosyl-l-methionine doesn’t crack the annual top-10 lists of the most widely used nutritional supplements in complementary and alternative medicine surveys. But unlike other far more popular products, SAMe is supported by randomized trial evidence of efficacy for osteoarthritis, depression, and fibromyalgia.

Indeed, S-adenosyl-l-methionine (SAMe) is "buzz-worthy," Dr. Lisa Corbin declared at a conference on internal medicine sponsored by the University of Colorado.

The Natural Medicines Comprehensive Database, which she considers the best available source of physician information on supplements, rates SAMe as "likely effective" for depression and osteoarthritis and "possibly effective" for fibromyalgia, noted Dr. Corbin, medical director of the Center for Integrative Medicine and a general internist at the University of Colorado in Denver.

The Natural Medicines Comprehensive Database is subscription funded and eschews financial support from industry. The organization is famously tough in its efficacy ratings. "Likely effective" is about as good as it gets. Take, for example, hypertension. Nothing included in the natural medicines database has earned the coveted "effective" rating for treatment of hypertension, and only a single item is listed as "likely effective," namely the National Institutes of Health–backed DASH (Dietary Approaches to Stop Hypertension) diet.

SAMe is a naturally occurring homocysteine derivative present in all living human cells. Its synthesis is related to vitamin B₁₂/folate metabolism, and SAMe serves as an essential methyl donor in cellular metabolism.

Osteoarthritis

SAMe appears to increase proteoglycan synthesis and has analgesic and anti-inflammatory effects. Numerous small studies of varying quality have demonstrated a benefit similar to that of non-cyclooxygenase-2 (non-COX2) inhibitor selective nonsteroidal anti-inflammatory drugs (NSAIDs), but with fewer side effects.

And in a University of California, Irvine, 16-week, double-blind, crossover trial of 61 patients with knee osteoarthritis, SAMe dosed at 400 mg t.i.d. and celecoxib at 200 mg/day demonstrated comparable pain reduction and improvement over time in functional health scores and isometric joint function tests.

SAMe was slower acting, taking almost a month to catch up to the COX-2 inhibitor in terms of analgesic effect. On the other hand, it appeared that the benefits of SAMe lasted after the medication was stopped.

Fibromyalgia

Danish rheumatologists randomized 43 patients with fibromyalgia to 800 mg/day of SAMe or placebo double-blind for 6 weeks. The SAMe group showed significant improvement compared with controls in fatigue, clinical disease activity, pain during the past week, mood, and morning stiffness, but not in tender point score or isokinetic muscle strength. Side effects in the SAMe group were no different from those with placebo (Scand. J. Rheumatol. 1991;20:294-302).

Another Danish double-blind randomized trial compared intravenous SAMe – a route of administration almost never used today – to placebo in 34 fibromyalgia patients. Ten days of IV SAMe at 600 mg/day showed nonsignificant trends toward better outcomes compared with placebo (Scand. J. Rheumatol. 1997; 26: 206-11).

Dr. Corbin said there have been no major safety issues with SAMe. At higher doses it has been associated with gastrointestinal side effects, headache, and loss of appetite.

"I think the financial toxicity is a potential issue," she quipped.

She urges her patients who are interested in trying dietary supplements to seek out those with "USP Verified" displayed prominently on the label. That designation signals that the product meets rigorous United States Pharmacopeia quality standards. However, SAMe is not a big seller, and no USP standards have been set for it. So she recommends that patients scan the shelves and select a SAMe product marketed by a company with USP labels on plenty of their other, more common supplements.

"That way you know that in general this manufacturer is making decent products, so that’s where I’d spend my money," Dr. Corbin said.

She reported having no financial interests relevant to her presentation.

Measures that take into account the effects of weight loss on specific areas of "feeling and function" should be included in the evaluation of drugs being developed to treat obesity, according to a report on obesity drug outcome measures, released by the George Washington University School of Public Health and Health Services.

"The FDA should consider patient improvements in feeling and function associated with weight loss as part of the risk-benefit calculus in its evaluation of drugs for the treatment of obesity where data are provided demonstrating benefit in a drug-specific clinical trial," concludes the report, called "Obesity Drug Outcome Measures."

The specific areas that can be measured using validated tools include osteoarthritis, mobility, and urinary incontinence, and could be considered secondary end points for obesity drug trials, the report pointed out.

The report is a result of the discussions and recommendations made by stakeholders convened by GWU – which included clinicians who treat obesity, Food and Drug Administration officials who review these drugs, patient advocates, and pharmaceutical companies – to evaluate the issues and challenges related to FDA approval of drugs for obesity and the appropriate use of obesity drugs, including the need for more treatments to help fill the void between lifestyle interventions and bariatric surgery.

Copyright George Washington University

The risks associated with a drug treatment may be more acceptable to an obese patient with "feeling and function abnormalities," Dr. Donna Ryan said during a webinar to discuss the report. Dr. Ryan, who is involved in clinical trials and research of obesity at the Pennington Biomedical Research Center, Baton Rouge, La., noted that one of the main focuses of the panel was on the various conditions that can be improved with modest weight loss, and cited a study that found a modest amount of weight loss at 1 year was associated with improvements in urinary incontinence. The effect of weight loss on improvements in sleep apnea was also mentioned during the webinar.

Among the other recommendations in the report were considering the drugs for chronic weight management as obesity treatments, not weight loss drugs, and limiting the availability of these drugs to people "for whom they are medically appropriate," and studying obesity drugs in pediatric patients.

Currently, the FDA’s draft guidance for industry for developing products for weight management are based on changes in body weight, as a primary end point, and changes in cardiometabolic parameters, as a secondary end point. The guidance, used since 2007, states that a drug can be considered effective if after 1 year of treatment, the difference in mean weight loss between patients treated with the product and those treated with placebo is at least 5% and the difference is statistically significant; or the proportion of subjects who lose at least 5% of their baseline body weight on the active product is at least 35%, is about double the proportion in the placebo-treated group – and the difference between the groups is statistically significant.

The FDA does not accept any quality of life or patient-reported outcome measurements when considering obesity drugs for approval, because the tools that measure these outcomes do not meet the agency’s standards.

The research project was supported by unrestricted gifts from Eisai Co.; Novo Nordisk Worldwide; Obesity Action Coalition; Orexigen Therapeutics; Takeda Pharmaceuticals, USA; and Vivus.

Measures that take into account the effects of weight loss on specific areas of "feeling and function" should be included in the evaluation of drugs being developed to treat obesity, according to a report on obesity drug outcome measures, released by the George Washington University School of Public Health and Health Services.

"The FDA should consider patient improvements in feeling and function associated with weight loss as part of the risk-benefit calculus in its evaluation of drugs for the treatment of obesity where data are provided demonstrating benefit in a drug-specific clinical trial," concludes the report, called "Obesity Drug Outcome Measures."

The specific areas that can be measured using validated tools include osteoarthritis, mobility, and urinary incontinence, and could be considered secondary end points for obesity drug trials, the report pointed out.

The report is a result of the discussions and recommendations made by stakeholders convened by GWU – which included clinicians who treat obesity, Food and Drug Administration officials who review these drugs, patient advocates, and pharmaceutical companies – to evaluate the issues and challenges related to FDA approval of drugs for obesity and the appropriate use of obesity drugs, including the need for more treatments to help fill the void between lifestyle interventions and bariatric surgery.

Copyright George Washington University

The risks associated with a drug treatment may be more acceptable to an obese patient with "feeling and function abnormalities," Dr. Donna Ryan said during a webinar to discuss the report. Dr. Ryan, who is involved in clinical trials and research of obesity at the Pennington Biomedical Research Center, Baton Rouge, La., noted that one of the main focuses of the panel was on the various conditions that can be improved with modest weight loss, and cited a study that found a modest amount of weight loss at 1 year was associated with improvements in urinary incontinence. The effect of weight loss on improvements in sleep apnea was also mentioned during the webinar.

Among the other recommendations in the report were considering the drugs for chronic weight management as obesity treatments, not weight loss drugs, and limiting the availability of these drugs to people "for whom they are medically appropriate," and studying obesity drugs in pediatric patients.

Currently, the FDA’s draft guidance for industry for developing products for weight management are based on changes in body weight, as a primary end point, and changes in cardiometabolic parameters, as a secondary end point. The guidance, used since 2007, states that a drug can be considered effective if after 1 year of treatment, the difference in mean weight loss between patients treated with the product and those treated with placebo is at least 5% and the difference is statistically significant; or the proportion of subjects who lose at least 5% of their baseline body weight on the active product is at least 35%, is about double the proportion in the placebo-treated group – and the difference between the groups is statistically significant.

The FDA does not accept any quality of life or patient-reported outcome measurements when considering obesity drugs for approval, because the tools that measure these outcomes do not meet the agency’s standards.

The research project was supported by unrestricted gifts from Eisai Co.; Novo Nordisk Worldwide; Obesity Action Coalition; Orexigen Therapeutics; Takeda Pharmaceuticals, USA; and Vivus.

Measures that take into account the effects of weight loss on specific areas of "feeling and function" should be included in the evaluation of drugs being developed to treat obesity, according to a report on obesity drug outcome measures, released by the George Washington University School of Public Health and Health Services.

"The FDA should consider patient improvements in feeling and function associated with weight loss as part of the risk-benefit calculus in its evaluation of drugs for the treatment of obesity where data are provided demonstrating benefit in a drug-specific clinical trial," concludes the report, called "Obesity Drug Outcome Measures."

The specific areas that can be measured using validated tools include osteoarthritis, mobility, and urinary incontinence, and could be considered secondary end points for obesity drug trials, the report pointed out.

The report is a result of the discussions and recommendations made by stakeholders convened by GWU – which included clinicians who treat obesity, Food and Drug Administration officials who review these drugs, patient advocates, and pharmaceutical companies – to evaluate the issues and challenges related to FDA approval of drugs for obesity and the appropriate use of obesity drugs, including the need for more treatments to help fill the void between lifestyle interventions and bariatric surgery.

Copyright George Washington University

The risks associated with a drug treatment may be more acceptable to an obese patient with "feeling and function abnormalities," Dr. Donna Ryan said during a webinar to discuss the report. Dr. Ryan, who is involved in clinical trials and research of obesity at the Pennington Biomedical Research Center, Baton Rouge, La., noted that one of the main focuses of the panel was on the various conditions that can be improved with modest weight loss, and cited a study that found a modest amount of weight loss at 1 year was associated with improvements in urinary incontinence. The effect of weight loss on improvements in sleep apnea was also mentioned during the webinar.

Among the other recommendations in the report were considering the drugs for chronic weight management as obesity treatments, not weight loss drugs, and limiting the availability of these drugs to people "for whom they are medically appropriate," and studying obesity drugs in pediatric patients.

Currently, the FDA’s draft guidance for industry for developing products for weight management are based on changes in body weight, as a primary end point, and changes in cardiometabolic parameters, as a secondary end point. The guidance, used since 2007, states that a drug can be considered effective if after 1 year of treatment, the difference in mean weight loss between patients treated with the product and those treated with placebo is at least 5% and the difference is statistically significant; or the proportion of subjects who lose at least 5% of their baseline body weight on the active product is at least 35%, is about double the proportion in the placebo-treated group – and the difference between the groups is statistically significant.

The FDA does not accept any quality of life or patient-reported outcome measurements when considering obesity drugs for approval, because the tools that measure these outcomes do not meet the agency’s standards.

The research project was supported by unrestricted gifts from Eisai Co.; Novo Nordisk Worldwide; Obesity Action Coalition; Orexigen Therapeutics; Takeda Pharmaceuticals, USA; and Vivus.

BERLIN – The observed initial improvement in functional ability seen with treat-to-target strategies for rheumatoid arthritis patients in the BeSt trial was maintained at 8-year follow-up, according to findings presented at the annual European Congress of Rheumatology.

"At year 8, we found stable good functional ability for all treatment groups, and low disease activity in 79% of patients. And even though treatment was aimed at low disease activity, we found a stable remission percentage of 52%," said Dr. Marianne van den Broek of Leiden University Medical Centre, the Netherlands.

Participants in the multicenter, randomized, single-blind Behandel Strategieën trial (BeSt) included 508 adults with recent onset RA. They were randomized to one of four treatment strategies, including sequential monotherapy, step-up combination therapy, initial combination therapy with prednisone, or initial combination with infliximab. All treatment arms aimed for a disease activity score smaller than or equal to 2.4, indicating low disease activity. Behandel Strategieën is Dutch for treatment strategies, she said.

"After 1 year, we found that patients from the two initial combination therapy groups showed earlier improvement of disease activity and functional ability and less radiological damage progression than the two initial monotherapy groups," Dr. van den Broek explained.

From year 3, patients who had been in remission – defined as a DAS of less than 1.6 – for at least 6 months on a maintenance dose of either methotrexate or sulfasalazine monotherapy could taper their disease-modifying antirheumatic drug until they were drug free, she added.

In the follow-up phase, between 15% and 18% of the 347 patients who remained in the study were in drug-free remission at 8 years, depending on their treatment arm, with a median remission duration of 45 months and a mean duration of 39 months, she said.

Radiological damage progression was minimal in the entire follow-up study population.

Also, despite differences in outcomes between the four treatment arms at the end of the initial BeSt study period, those differences were no longer significant at the end of follow-up.

"The fact that the initial differences between the initial treatment groups are no longer found at 8-year follow-up confirms the importance of treatment to target, which is now the mainstay of EULAR recommendations for the management of patients with RA," Dr. van den Broek said.

Furthermore, BeSt is one of few studies in which tapering to drug free was incorporated in the protocol, she added.

"We have shown that, with early initiation of targeted treatment, almost 20% of patients can maintain remission without using any DMARD, for a prolonged period [median duration, 45 months]," she said.

The findings are also important because they demonstrate the overall long-term benefits of treat-to-target strategies.

"With our 8-year follow-up data in this large treat-to-target cohort, we show that long-term treating to target is possible. It is beneficial not only in the early stages of RA when disease is usually most active, but also during follow-up," she said.

Dr. van den Broek reported that she had no relevant financial conflicts of interest.

BERLIN – The observed initial improvement in functional ability seen with treat-to-target strategies for rheumatoid arthritis patients in the BeSt trial was maintained at 8-year follow-up, according to findings presented at the annual European Congress of Rheumatology.

"At year 8, we found stable good functional ability for all treatment groups, and low disease activity in 79% of patients. And even though treatment was aimed at low disease activity, we found a stable remission percentage of 52%," said Dr. Marianne van den Broek of Leiden University Medical Centre, the Netherlands.

Participants in the multicenter, randomized, single-blind Behandel Strategieën trial (BeSt) included 508 adults with recent onset RA. They were randomized to one of four treatment strategies, including sequential monotherapy, step-up combination therapy, initial combination therapy with prednisone, or initial combination with infliximab. All treatment arms aimed for a disease activity score smaller than or equal to 2.4, indicating low disease activity. Behandel Strategieën is Dutch for treatment strategies, she said.

"After 1 year, we found that patients from the two initial combination therapy groups showed earlier improvement of disease activity and functional ability and less radiological damage progression than the two initial monotherapy groups," Dr. van den Broek explained.

From year 3, patients who had been in remission – defined as a DAS of less than 1.6 – for at least 6 months on a maintenance dose of either methotrexate or sulfasalazine monotherapy could taper their disease-modifying antirheumatic drug until they were drug free, she added.

In the follow-up phase, between 15% and 18% of the 347 patients who remained in the study were in drug-free remission at 8 years, depending on their treatment arm, with a median remission duration of 45 months and a mean duration of 39 months, she said.

Radiological damage progression was minimal in the entire follow-up study population.

Also, despite differences in outcomes between the four treatment arms at the end of the initial BeSt study period, those differences were no longer significant at the end of follow-up.

"The fact that the initial differences between the initial treatment groups are no longer found at 8-year follow-up confirms the importance of treatment to target, which is now the mainstay of EULAR recommendations for the management of patients with RA," Dr. van den Broek said.

Furthermore, BeSt is one of few studies in which tapering to drug free was incorporated in the protocol, she added.

"We have shown that, with early initiation of targeted treatment, almost 20% of patients can maintain remission without using any DMARD, for a prolonged period [median duration, 45 months]," she said.

The findings are also important because they demonstrate the overall long-term benefits of treat-to-target strategies.

"With our 8-year follow-up data in this large treat-to-target cohort, we show that long-term treating to target is possible. It is beneficial not only in the early stages of RA when disease is usually most active, but also during follow-up," she said.

Dr. van den Broek reported that she had no relevant financial conflicts of interest.

BERLIN – The observed initial improvement in functional ability seen with treat-to-target strategies for rheumatoid arthritis patients in the BeSt trial was maintained at 8-year follow-up, according to findings presented at the annual European Congress of Rheumatology.

"At year 8, we found stable good functional ability for all treatment groups, and low disease activity in 79% of patients. And even though treatment was aimed at low disease activity, we found a stable remission percentage of 52%," said Dr. Marianne van den Broek of Leiden University Medical Centre, the Netherlands.

Participants in the multicenter, randomized, single-blind Behandel Strategieën trial (BeSt) included 508 adults with recent onset RA. They were randomized to one of four treatment strategies, including sequential monotherapy, step-up combination therapy, initial combination therapy with prednisone, or initial combination with infliximab. All treatment arms aimed for a disease activity score smaller than or equal to 2.4, indicating low disease activity. Behandel Strategieën is Dutch for treatment strategies, she said.

"After 1 year, we found that patients from the two initial combination therapy groups showed earlier improvement of disease activity and functional ability and less radiological damage progression than the two initial monotherapy groups," Dr. van den Broek explained.

From year 3, patients who had been in remission – defined as a DAS of less than 1.6 – for at least 6 months on a maintenance dose of either methotrexate or sulfasalazine monotherapy could taper their disease-modifying antirheumatic drug until they were drug free, she added.

In the follow-up phase, between 15% and 18% of the 347 patients who remained in the study were in drug-free remission at 8 years, depending on their treatment arm, with a median remission duration of 45 months and a mean duration of 39 months, she said.

Radiological damage progression was minimal in the entire follow-up study population.

Also, despite differences in outcomes between the four treatment arms at the end of the initial BeSt study period, those differences were no longer significant at the end of follow-up.

"The fact that the initial differences between the initial treatment groups are no longer found at 8-year follow-up confirms the importance of treatment to target, which is now the mainstay of EULAR recommendations for the management of patients with RA," Dr. van den Broek said.

Furthermore, BeSt is one of few studies in which tapering to drug free was incorporated in the protocol, she added.

"We have shown that, with early initiation of targeted treatment, almost 20% of patients can maintain remission without using any DMARD, for a prolonged period [median duration, 45 months]," she said.

The findings are also important because they demonstrate the overall long-term benefits of treat-to-target strategies.

"With our 8-year follow-up data in this large treat-to-target cohort, we show that long-term treating to target is possible. It is beneficial not only in the early stages of RA when disease is usually most active, but also during follow-up," she said.

Dr. van den Broek reported that she had no relevant financial conflicts of interest.

A risk evaluation and mitigation strategy for extended-release and long-acting opioid medications has received Food and Drug Administration approval.

The move has been anticipated as an important element in an attempt to stem the swelling tide of abuse, misuse, and overdose of these prescription drugs while assuring continued access to the highly potent analgesics for patients with moderate to severe persistent pain, Dr. Margaret A. Hamburg said in a media briefing.

The new safety measures, which pertain to approximately 30 currently available medications, will require the manufacturers of the drugs to make FDA-approved education materials available to prescribers no later than March 1, 2013, via development grants to continuing education providers who will develop and deliver the training, said Dr. Hamburg, commissioner of the FDA. In addition, the risk evaluation and mitigation strategy (REMS) will include the distribution of a patient counseling leaflet to prescribers regarding the safe and effective use of the drugs; an updated, single-page medication guide for consumers, an implementation plan, and periodic assessments to evaluate the impact of the program on the safe use of these products, which the FDA will review and use to tweak the program as needed, she said.

"It is important to note that we are focusing on extended-release and long-acting opioid medications ... because these have very specific safety problems that have to be addressed very carefully," according to Dr. John Jenkins, director of the Office of New Drugs within the FDA’s Center for Drug Evaluation and Research. These drugs, including hydromorphone, oxycodone, morphine, oxymorphone, methadone, transdermal fentanyl, and transdermal buprenorphine, "can cause problems even when prescribed appropriately."

The prescriber education component of the REMS will include information regarding the risks and benefits of opioid therapy for individual patients, choosing patients appropriately, patient management and monitoring, and patient counseling, Dr. Jenkins explained. It will also include guidance on the potential for misuse, abuse, and addition, as well as recognizing evidence for these outcomes. The updated medication guide and patient counseling document will include information on how to safely use, store, and dispose of these analgesics, specific instructions for recognizing the signs of potential overdose and advice for preventing accidental exposure to family and household visitors, he said.

With respect to the assessment and auditing component of the program, the FDA has established goals, which the manufacturers are expected to achieve, for the percentage of prescribers who complete the training and for assessing prescribers’ understanding of the risk information. Participation in the educational programs is not mandatory for prescribers, Dr. Hamburg stated. The assessments are also required to evaluate whether the [REMS] adversely affect patient access to these drugs, she said. "Patients in pain must have continued assess to medications they need," she added.

The new REMS program is one component of a multiagency, national strategy unveiled by the White House in 2011 to address prescription drug abuse, "which is this country’s fastest-growing drug problem," said Dr. Hamburg, noting that opioid overdoses in particular were the cause of approximately 15,000 deaths among Americans in 2008 and nearly 16,000 in 2009. Called Epidemic: Responding to America's Prescription Drug Abuse Crisis, the national plan suggests expansion of state-based prescription drug-monitoring programs; seeks creation of recommendations for convenient and environmentally responsible ways to dispose of unused medications; and calls for legislative action to reduce "doctor shopping" and "pill mills."

In the absence of the legislative changes needed to fulfill the comprehensive White House plan, the REMS "is an important and timely step by FDA to supplement prescriber training and consumer information," R. Gil Kerlikowske, director of the White House Office of National Drug Control Policy, said during the telebriefing.

A risk evaluation and mitigation strategy for extended-release and long-acting opioid medications has received Food and Drug Administration approval.

The move has been anticipated as an important element in an attempt to stem the swelling tide of abuse, misuse, and overdose of these prescription drugs while assuring continued access to the highly potent analgesics for patients with moderate to severe persistent pain, Dr. Margaret A. Hamburg said in a media briefing.

The new safety measures, which pertain to approximately 30 currently available medications, will require the manufacturers of the drugs to make FDA-approved education materials available to prescribers no later than March 1, 2013, via development grants to continuing education providers who will develop and deliver the training, said Dr. Hamburg, commissioner of the FDA. In addition, the risk evaluation and mitigation strategy (REMS) will include the distribution of a patient counseling leaflet to prescribers regarding the safe and effective use of the drugs; an updated, single-page medication guide for consumers, an implementation plan, and periodic assessments to evaluate the impact of the program on the safe use of these products, which the FDA will review and use to tweak the program as needed, she said.

"It is important to note that we are focusing on extended-release and long-acting opioid medications ... because these have very specific safety problems that have to be addressed very carefully," according to Dr. John Jenkins, director of the Office of New Drugs within the FDA’s Center for Drug Evaluation and Research. These drugs, including hydromorphone, oxycodone, morphine, oxymorphone, methadone, transdermal fentanyl, and transdermal buprenorphine, "can cause problems even when prescribed appropriately."

The prescriber education component of the REMS will include information regarding the risks and benefits of opioid therapy for individual patients, choosing patients appropriately, patient management and monitoring, and patient counseling, Dr. Jenkins explained. It will also include guidance on the potential for misuse, abuse, and addition, as well as recognizing evidence for these outcomes. The updated medication guide and patient counseling document will include information on how to safely use, store, and dispose of these analgesics, specific instructions for recognizing the signs of potential overdose and advice for preventing accidental exposure to family and household visitors, he said.

With respect to the assessment and auditing component of the program, the FDA has established goals, which the manufacturers are expected to achieve, for the percentage of prescribers who complete the training and for assessing prescribers’ understanding of the risk information. Participation in the educational programs is not mandatory for prescribers, Dr. Hamburg stated. The assessments are also required to evaluate whether the [REMS] adversely affect patient access to these drugs, she said. "Patients in pain must have continued assess to medications they need," she added.

The new REMS program is one component of a multiagency, national strategy unveiled by the White House in 2011 to address prescription drug abuse, "which is this country’s fastest-growing drug problem," said Dr. Hamburg, noting that opioid overdoses in particular were the cause of approximately 15,000 deaths among Americans in 2008 and nearly 16,000 in 2009. Called Epidemic: Responding to America's Prescription Drug Abuse Crisis, the national plan suggests expansion of state-based prescription drug-monitoring programs; seeks creation of recommendations for convenient and environmentally responsible ways to dispose of unused medications; and calls for legislative action to reduce "doctor shopping" and "pill mills."

In the absence of the legislative changes needed to fulfill the comprehensive White House plan, the REMS "is an important and timely step by FDA to supplement prescriber training and consumer information," R. Gil Kerlikowske, director of the White House Office of National Drug Control Policy, said during the telebriefing.

A risk evaluation and mitigation strategy for extended-release and long-acting opioid medications has received Food and Drug Administration approval.

The move has been anticipated as an important element in an attempt to stem the swelling tide of abuse, misuse, and overdose of these prescription drugs while assuring continued access to the highly potent analgesics for patients with moderate to severe persistent pain, Dr. Margaret A. Hamburg said in a media briefing.

The new safety measures, which pertain to approximately 30 currently available medications, will require the manufacturers of the drugs to make FDA-approved education materials available to prescribers no later than March 1, 2013, via development grants to continuing education providers who will develop and deliver the training, said Dr. Hamburg, commissioner of the FDA. In addition, the risk evaluation and mitigation strategy (REMS) will include the distribution of a patient counseling leaflet to prescribers regarding the safe and effective use of the drugs; an updated, single-page medication guide for consumers, an implementation plan, and periodic assessments to evaluate the impact of the program on the safe use of these products, which the FDA will review and use to tweak the program as needed, she said.

"It is important to note that we are focusing on extended-release and long-acting opioid medications ... because these have very specific safety problems that have to be addressed very carefully," according to Dr. John Jenkins, director of the Office of New Drugs within the FDA’s Center for Drug Evaluation and Research. These drugs, including hydromorphone, oxycodone, morphine, oxymorphone, methadone, transdermal fentanyl, and transdermal buprenorphine, "can cause problems even when prescribed appropriately."

The prescriber education component of the REMS will include information regarding the risks and benefits of opioid therapy for individual patients, choosing patients appropriately, patient management and monitoring, and patient counseling, Dr. Jenkins explained. It will also include guidance on the potential for misuse, abuse, and addition, as well as recognizing evidence for these outcomes. The updated medication guide and patient counseling document will include information on how to safely use, store, and dispose of these analgesics, specific instructions for recognizing the signs of potential overdose and advice for preventing accidental exposure to family and household visitors, he said.

With respect to the assessment and auditing component of the program, the FDA has established goals, which the manufacturers are expected to achieve, for the percentage of prescribers who complete the training and for assessing prescribers’ understanding of the risk information. Participation in the educational programs is not mandatory for prescribers, Dr. Hamburg stated. The assessments are also required to evaluate whether the [REMS] adversely affect patient access to these drugs, she said. "Patients in pain must have continued assess to medications they need," she added.

The new REMS program is one component of a multiagency, national strategy unveiled by the White House in 2011 to address prescription drug abuse, "which is this country’s fastest-growing drug problem," said Dr. Hamburg, noting that opioid overdoses in particular were the cause of approximately 15,000 deaths among Americans in 2008 and nearly 16,000 in 2009. Called Epidemic: Responding to America's Prescription Drug Abuse Crisis, the national plan suggests expansion of state-based prescription drug-monitoring programs; seeks creation of recommendations for convenient and environmentally responsible ways to dispose of unused medications; and calls for legislative action to reduce "doctor shopping" and "pill mills."

In the absence of the legislative changes needed to fulfill the comprehensive White House plan, the REMS "is an important and timely step by FDA to supplement prescriber training and consumer information," R. Gil Kerlikowske, director of the White House Office of National Drug Control Policy, said during the telebriefing.

BERLIN – Prednisolone improves pain scores in patients with moderate to severe knee osteoarthritis by nearly one-third, according to the WOMAC pain scale, compared with patients on placebo, according to a new study presented at the annual European Congress of Rheumatology.

"Given the limitations of current nonspecific symptom-relieving drugs such as NSAIDs, we need medications that control pain in the medium to long term as well as short term," said Dr. Anna Abou-Raya of the University of Alexandria (Egypt).

Dr. Abou-Raya conducted a randomized, double-blind, controlled trial to assess whether 6 weeks of daily, low-dose oral prednisolone would lessen pain, improve mobility, and ease systemic low-grade inflammation, as well as be sustained over 12 weeks in older adults with moderate to severe knee osteoarthritis (OA).

In all, 125 adults older than 65 years were recruited from among OA patients who attended her institution’s outpatient clinic. Patients met ACR (American College of Rheumatology) clinical and radiographic criteria of primary knee OA and had a mean pain score greater than 4 on a scale of 0-10 in the week prior to treatment that had occurred for at least 14 days a month for 3 months prior to randomization.

Oral prednisolone (7.5 mg/day) was given to 63 patients, and placebo was given to 62; all completers were followed up at 6 and 12 weeks. All patients received physical examination and were reviewed for their pain levels, flares, and analgesic use.

The primary outcome was pain reduction, with secondary outcomes of systemic inflammation and improvement in physical functioning score. Dr. Abou-Raya assessed knee OA using the Kellgren-Lawrence scale; clinical function on a 0-100 VAS (Visual Analogue Scale); self-reported physical function, pain, and stiffness as reported by the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index; and a 6-minute walk distance test. Blood levels of interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF)–alpha, and high-sensitivity C-reactive protein (hsCRP) were also measured.

"There was a significantly greater absolute change from baseline in all three subscale scores – function, pain, and stiffness – [at both] 6 and 12 weeks in the prednisolone group," compared with the placebo group.

WOMAC pain scores showed a change of –3.4 (95% confidence interval, –5.15 to –2.99) over 12 weeks on prednisolone, compared with –0.4 (95% CI, –0.193 to –0.41) for patients on placebo (P = .001). WOMAC function scores also showed improvement in the prednisolone group, with a change from baseline of –10.9 (95% CI, –4.46 to –2.31) over 12 weeks, compared with –0.4 (95% CI, –0.196 to –0.29) in the placebo group (P = .005).

"The mean number of analgesic users decreased significantly in the intervention group" compared with the placebo group at both 6 and 12 weeks when compared with baseline, added Dr. Abou-Raya.

The researcher also found that mean levels of inflammatory markers IL-1, IL-6, TNF-alpha, and hsCRP were all reduced in the prednisolone group vs. the placebo group. For example, IL-1 levels at 6 weeks were 18.7 pg/mL vs. 25 pg/mL in the prednisolone and placebo groups, respectively (P = .005), and this was maintained at 12 weeks. The hsCRP levels were 2.3 mg/L vs. 3.6 mg/L at 6 weeks for the prednisolone and placebo groups, respectively (P = .005), and these were also maintained at 12 weeks.

"There was a significant improvement in the 6-minute walk distance test at 6 and 12 weeks," reported Dr. Abou-Raya, with an absolute change from baseline of 7.6 m in the prednisolone group compared with 0 m in the placebo arm.

Treatment-related adverse effects were similar in both groups, with no serious events recorded.

"The findings may provide evidence of efficacy and tolerability of low-dose oral prednisolone in reducing pain and subsequently improving function in older adults with knee OA; however, we need larger scale longitudinal studies to further verify this information," concluded Dr. Abou-Raya.

Dr. Abou-Raya reported that she had no relevant conflicts of interest.

BERLIN – Prednisolone improves pain scores in patients with moderate to severe knee osteoarthritis by nearly one-third, according to the WOMAC pain scale, compared with patients on placebo, according to a new study presented at the annual European Congress of Rheumatology.

"Given the limitations of current nonspecific symptom-relieving drugs such as NSAIDs, we need medications that control pain in the medium to long term as well as short term," said Dr. Anna Abou-Raya of the University of Alexandria (Egypt).

Dr. Abou-Raya conducted a randomized, double-blind, controlled trial to assess whether 6 weeks of daily, low-dose oral prednisolone would lessen pain, improve mobility, and ease systemic low-grade inflammation, as well as be sustained over 12 weeks in older adults with moderate to severe knee osteoarthritis (OA).

In all, 125 adults older than 65 years were recruited from among OA patients who attended her institution’s outpatient clinic. Patients met ACR (American College of Rheumatology) clinical and radiographic criteria of primary knee OA and had a mean pain score greater than 4 on a scale of 0-10 in the week prior to treatment that had occurred for at least 14 days a month for 3 months prior to randomization.

Oral prednisolone (7.5 mg/day) was given to 63 patients, and placebo was given to 62; all completers were followed up at 6 and 12 weeks. All patients received physical examination and were reviewed for their pain levels, flares, and analgesic use.

The primary outcome was pain reduction, with secondary outcomes of systemic inflammation and improvement in physical functioning score. Dr. Abou-Raya assessed knee OA using the Kellgren-Lawrence scale; clinical function on a 0-100 VAS (Visual Analogue Scale); self-reported physical function, pain, and stiffness as reported by the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index; and a 6-minute walk distance test. Blood levels of interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF)–alpha, and high-sensitivity C-reactive protein (hsCRP) were also measured.

"There was a significantly greater absolute change from baseline in all three subscale scores – function, pain, and stiffness – [at both] 6 and 12 weeks in the prednisolone group," compared with the placebo group.

WOMAC pain scores showed a change of –3.4 (95% confidence interval, –5.15 to –2.99) over 12 weeks on prednisolone, compared with –0.4 (95% CI, –0.193 to –0.41) for patients on placebo (P = .001). WOMAC function scores also showed improvement in the prednisolone group, with a change from baseline of –10.9 (95% CI, –4.46 to –2.31) over 12 weeks, compared with –0.4 (95% CI, –0.196 to –0.29) in the placebo group (P = .005).

"The mean number of analgesic users decreased significantly in the intervention group" compared with the placebo group at both 6 and 12 weeks when compared with baseline, added Dr. Abou-Raya.

The researcher also found that mean levels of inflammatory markers IL-1, IL-6, TNF-alpha, and hsCRP were all reduced in the prednisolone group vs. the placebo group. For example, IL-1 levels at 6 weeks were 18.7 pg/mL vs. 25 pg/mL in the prednisolone and placebo groups, respectively (P = .005), and this was maintained at 12 weeks. The hsCRP levels were 2.3 mg/L vs. 3.6 mg/L at 6 weeks for the prednisolone and placebo groups, respectively (P = .005), and these were also maintained at 12 weeks.

"There was a significant improvement in the 6-minute walk distance test at 6 and 12 weeks," reported Dr. Abou-Raya, with an absolute change from baseline of 7.6 m in the prednisolone group compared with 0 m in the placebo arm.

Treatment-related adverse effects were similar in both groups, with no serious events recorded.

"The findings may provide evidence of efficacy and tolerability of low-dose oral prednisolone in reducing pain and subsequently improving function in older adults with knee OA; however, we need larger scale longitudinal studies to further verify this information," concluded Dr. Abou-Raya.

Dr. Abou-Raya reported that she had no relevant conflicts of interest.

BERLIN – Prednisolone improves pain scores in patients with moderate to severe knee osteoarthritis by nearly one-third, according to the WOMAC pain scale, compared with patients on placebo, according to a new study presented at the annual European Congress of Rheumatology.

"Given the limitations of current nonspecific symptom-relieving drugs such as NSAIDs, we need medications that control pain in the medium to long term as well as short term," said Dr. Anna Abou-Raya of the University of Alexandria (Egypt).

Dr. Abou-Raya conducted a randomized, double-blind, controlled trial to assess whether 6 weeks of daily, low-dose oral prednisolone would lessen pain, improve mobility, and ease systemic low-grade inflammation, as well as be sustained over 12 weeks in older adults with moderate to severe knee osteoarthritis (OA).

In all, 125 adults older than 65 years were recruited from among OA patients who attended her institution’s outpatient clinic. Patients met ACR (American College of Rheumatology) clinical and radiographic criteria of primary knee OA and had a mean pain score greater than 4 on a scale of 0-10 in the week prior to treatment that had occurred for at least 14 days a month for 3 months prior to randomization.

Oral prednisolone (7.5 mg/day) was given to 63 patients, and placebo was given to 62; all completers were followed up at 6 and 12 weeks. All patients received physical examination and were reviewed for their pain levels, flares, and analgesic use.

The primary outcome was pain reduction, with secondary outcomes of systemic inflammation and improvement in physical functioning score. Dr. Abou-Raya assessed knee OA using the Kellgren-Lawrence scale; clinical function on a 0-100 VAS (Visual Analogue Scale); self-reported physical function, pain, and stiffness as reported by the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index; and a 6-minute walk distance test. Blood levels of interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF)–alpha, and high-sensitivity C-reactive protein (hsCRP) were also measured.

"There was a significantly greater absolute change from baseline in all three subscale scores – function, pain, and stiffness – [at both] 6 and 12 weeks in the prednisolone group," compared with the placebo group.

WOMAC pain scores showed a change of –3.4 (95% confidence interval, –5.15 to –2.99) over 12 weeks on prednisolone, compared with –0.4 (95% CI, –0.193 to –0.41) for patients on placebo (P = .001). WOMAC function scores also showed improvement in the prednisolone group, with a change from baseline of –10.9 (95% CI, –4.46 to –2.31) over 12 weeks, compared with –0.4 (95% CI, –0.196 to –0.29) in the placebo group (P = .005).

"The mean number of analgesic users decreased significantly in the intervention group" compared with the placebo group at both 6 and 12 weeks when compared with baseline, added Dr. Abou-Raya.

The researcher also found that mean levels of inflammatory markers IL-1, IL-6, TNF-alpha, and hsCRP were all reduced in the prednisolone group vs. the placebo group. For example, IL-1 levels at 6 weeks were 18.7 pg/mL vs. 25 pg/mL in the prednisolone and placebo groups, respectively (P = .005), and this was maintained at 12 weeks. The hsCRP levels were 2.3 mg/L vs. 3.6 mg/L at 6 weeks for the prednisolone and placebo groups, respectively (P = .005), and these were also maintained at 12 weeks.

"There was a significant improvement in the 6-minute walk distance test at 6 and 12 weeks," reported Dr. Abou-Raya, with an absolute change from baseline of 7.6 m in the prednisolone group compared with 0 m in the placebo arm.

Treatment-related adverse effects were similar in both groups, with no serious events recorded.

"The findings may provide evidence of efficacy and tolerability of low-dose oral prednisolone in reducing pain and subsequently improving function in older adults with knee OA; however, we need larger scale longitudinal studies to further verify this information," concluded Dr. Abou-Raya.

Dr. Abou-Raya reported that she had no relevant conflicts of interest.