Sherry Boschert

Two imaging modalities independently predicted progressive joint erosion in patients with early rheumatoid arthritis as a group, but the tests performed only slightly better than did clinical and demographic variables for individual prognoses, judging from findings of a 1-year study.

Among 79 patients who completed quarterly follow-ups with a battery of imaging and nonimaging measures, 53 (67%) showed erosive progression. On a group level, results of ultrasound gray-scale (USGS) findings of inflammation and magnetic resonance images showing bone marrow edema each were significant predictors that erosive disease progression would be detected by MRI.

Patients with USGS inflammation in the dominant wrist were twice as likely to develop erosive progression and patients with MRI bone marrow edema in the dominant wrist were 28% more likely to develop erosive progression compared with patients without these imaging findings, Dr. Pernille Bøyesen and associates reported (Ann. Rheum. Dis. 2011;70:176-9 [doi: 10.1136/ard.2009. 126953]).

On an individual level, however, the imaging modalities were not dramatically better than clinical and demographic variables to predict erosive progression of early RA. USGS inflammation, synovitis on MRI, and bone marrow edema that was visible on MRI performed slightly better than using antibody to cyclic citrullinated protein, rheumatoid factor, and disease activity score based on a 28-joint count, reported Dr. Bøyesen of Diakonhjemmet Hospital, Oslo.

USGS inflammation was the best of 12 imaging modalities and measures of disease severity in identifying patients at risk of developing erosions on MRI, with a sensitivity of 78%, a specificity of 55%, a positive likelihood ration of 1.75, and accuracy of 70%.

Future studies are needed using composite indices of disease progression, including modern imaging modalities, to determine their value as predictors of an individual patient's likelihood of disease progression, the investigators concluded.

The study appears to be the first to confirm previous data suggesting that measuring inflammation by ultrasound can help predict subsequent joint damage, they noted. The findings also confirmed previous data identifying bone marrow edema on MRI as an independent predictor of joint damage.

Other imaging modalities in the study included digital x-ray radiogrammetry (DXR) of cortical bone mineral density in the hand. Results showed only trends toward higher levels of synovitis on MRI and bone density loss on DXR in patients with erosive progression of disease at 1 year. The findings did not support previous studies that reported cortical hand bone mineral density to be independently predictive of erosive progression, perhaps due to the small size of the study, Dr. Bøyesen added.

Given the comprehensive comparison of imaging modalities in the study, however, 84 patients can be considered a large number, the investigators noted.

The multivariate analyses controlled for the effects of age, sex, and other independent variables.

The investigators declared having no conflicts of interest. The study was funded by the Eastern Norway Regional Health Authority, the Research Council of Norway, the Norwegian Rheumatism Association, the Norwegian Women Public Health Association, the Grethe Harbitz Legacy, and the Marie and Else Mustad Legacy.

Baseline USGS (A) and 1-year MRI (B-D) of the radio-carpal joint are shown in a patient without erosive progression and in a patient with erosions (arrows) (E-H).

Source Courtesy Dr. Pernille Bøyesen

Two imaging modalities independently predicted progressive joint erosion in patients with early rheumatoid arthritis as a group, but the tests performed only slightly better than did clinical and demographic variables for individual prognoses, judging from findings of a 1-year study.

Among 79 patients who completed quarterly follow-ups with a battery of imaging and nonimaging measures, 53 (67%) showed erosive progression. On a group level, results of ultrasound gray-scale (USGS) findings of inflammation and magnetic resonance images showing bone marrow edema each were significant predictors that erosive disease progression would be detected by MRI.

Patients with USGS inflammation in the dominant wrist were twice as likely to develop erosive progression and patients with MRI bone marrow edema in the dominant wrist were 28% more likely to develop erosive progression compared with patients without these imaging findings, Dr. Pernille Bøyesen and associates reported (Ann. Rheum. Dis. 2011;70:176-9 [doi: 10.1136/ard.2009. 126953]).

On an individual level, however, the imaging modalities were not dramatically better than clinical and demographic variables to predict erosive progression of early RA. USGS inflammation, synovitis on MRI, and bone marrow edema that was visible on MRI performed slightly better than using antibody to cyclic citrullinated protein, rheumatoid factor, and disease activity score based on a 28-joint count, reported Dr. Bøyesen of Diakonhjemmet Hospital, Oslo.

USGS inflammation was the best of 12 imaging modalities and measures of disease severity in identifying patients at risk of developing erosions on MRI, with a sensitivity of 78%, a specificity of 55%, a positive likelihood ration of 1.75, and accuracy of 70%.

Future studies are needed using composite indices of disease progression, including modern imaging modalities, to determine their value as predictors of an individual patient's likelihood of disease progression, the investigators concluded.

The study appears to be the first to confirm previous data suggesting that measuring inflammation by ultrasound can help predict subsequent joint damage, they noted. The findings also confirmed previous data identifying bone marrow edema on MRI as an independent predictor of joint damage.

Other imaging modalities in the study included digital x-ray radiogrammetry (DXR) of cortical bone mineral density in the hand. Results showed only trends toward higher levels of synovitis on MRI and bone density loss on DXR in patients with erosive progression of disease at 1 year. The findings did not support previous studies that reported cortical hand bone mineral density to be independently predictive of erosive progression, perhaps due to the small size of the study, Dr. Bøyesen added.

Given the comprehensive comparison of imaging modalities in the study, however, 84 patients can be considered a large number, the investigators noted.

The multivariate analyses controlled for the effects of age, sex, and other independent variables.

The investigators declared having no conflicts of interest. The study was funded by the Eastern Norway Regional Health Authority, the Research Council of Norway, the Norwegian Rheumatism Association, the Norwegian Women Public Health Association, the Grethe Harbitz Legacy, and the Marie and Else Mustad Legacy.

Baseline USGS (A) and 1-year MRI (B-D) of the radio-carpal joint are shown in a patient without erosive progression and in a patient with erosions (arrows) (E-H).

Source Courtesy Dr. Pernille Bøyesen

Two imaging modalities independently predicted progressive joint erosion in patients with early rheumatoid arthritis as a group, but the tests performed only slightly better than did clinical and demographic variables for individual prognoses, judging from findings of a 1-year study.

Among 79 patients who completed quarterly follow-ups with a battery of imaging and nonimaging measures, 53 (67%) showed erosive progression. On a group level, results of ultrasound gray-scale (USGS) findings of inflammation and magnetic resonance images showing bone marrow edema each were significant predictors that erosive disease progression would be detected by MRI.

Patients with USGS inflammation in the dominant wrist were twice as likely to develop erosive progression and patients with MRI bone marrow edema in the dominant wrist were 28% more likely to develop erosive progression compared with patients without these imaging findings, Dr. Pernille Bøyesen and associates reported (Ann. Rheum. Dis. 2011;70:176-9 [doi: 10.1136/ard.2009. 126953]).

On an individual level, however, the imaging modalities were not dramatically better than clinical and demographic variables to predict erosive progression of early RA. USGS inflammation, synovitis on MRI, and bone marrow edema that was visible on MRI performed slightly better than using antibody to cyclic citrullinated protein, rheumatoid factor, and disease activity score based on a 28-joint count, reported Dr. Bøyesen of Diakonhjemmet Hospital, Oslo.

USGS inflammation was the best of 12 imaging modalities and measures of disease severity in identifying patients at risk of developing erosions on MRI, with a sensitivity of 78%, a specificity of 55%, a positive likelihood ration of 1.75, and accuracy of 70%.

Future studies are needed using composite indices of disease progression, including modern imaging modalities, to determine their value as predictors of an individual patient's likelihood of disease progression, the investigators concluded.

The study appears to be the first to confirm previous data suggesting that measuring inflammation by ultrasound can help predict subsequent joint damage, they noted. The findings also confirmed previous data identifying bone marrow edema on MRI as an independent predictor of joint damage.

Other imaging modalities in the study included digital x-ray radiogrammetry (DXR) of cortical bone mineral density in the hand. Results showed only trends toward higher levels of synovitis on MRI and bone density loss on DXR in patients with erosive progression of disease at 1 year. The findings did not support previous studies that reported cortical hand bone mineral density to be independently predictive of erosive progression, perhaps due to the small size of the study, Dr. Bøyesen added.

Given the comprehensive comparison of imaging modalities in the study, however, 84 patients can be considered a large number, the investigators noted.

The multivariate analyses controlled for the effects of age, sex, and other independent variables.

The investigators declared having no conflicts of interest. The study was funded by the Eastern Norway Regional Health Authority, the Research Council of Norway, the Norwegian Rheumatism Association, the Norwegian Women Public Health Association, the Grethe Harbitz Legacy, and the Marie and Else Mustad Legacy.

Baseline USGS (A) and 1-year MRI (B-D) of the radio-carpal joint are shown in a patient without erosive progression and in a patient with erosions (arrows) (E-H).

Source Courtesy Dr. Pernille Bøyesen

Major Finding: Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo.

Data Source: Network meta-analysis of 31 large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo in 116,429 patients with 117,218 patient-years of follow-up.

Disclosures: The Swiss National Science Foundation funded the study. The investigators reported having no conflicts of interest.

Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo, in the most comprehensive meta-analysis of the subject so far.

The relative risks with any individual NSAID, compared with placebo, often were double, triple, or quadruple the risk with placebo, the study found. The absolute numbers of MIs and other cardiovascular outcomes were small, but the network meta-analysis design of the study “provides the best available evidence on the safety of this class of drugs,” Dr. Sven Trelle and his associates reported.

Contrary to some previous reports, the current study also found no suggestion that this increased cardiovascular risk is specific to cyclo-oxygenase-2 (COX-2) inhibitors. Therefore the use of all NSAIDs – and the over-the-counter availability of some of them – should be reconsidered, Dr. Trelle stated in a report published online by BMJ (Jan. 11, 2011;342:c7086[doi/10.1136/bmj.c7086]).

Dr. Trelle of the University of Bern, Switzerland, acknowledged that therapeutic options for chronic musculoskeletal pain are limited, but cautioned that “cardiovascular risk needs to be taken into account when prescribing” any NSAID.

The meta-analysis included any large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo. Data were available for naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, and lumiracoxib. The risk for a cardiovascular event had to increase by more than 30% to be considered significant.

Overall, naproxen appeared to be the least harmful NSAID in terms of cardiovascular outcomes. Risks were greatest with ibuprofen, diclofenac, etoricoxib, and lumiracoxib.

Four NSAIDs were associated with significantly increased risk for myocardial infarction (the primary outcome in the current analysis) in 29 of the trials that reported 554 MIs. The relative risk for MI doubled with rofecoxib or lumiracoxib, was 35% higher with celecoxib, and was 61% higher with ibuprofen, compared with placebo. Evidence was lacking for increased MI risk with the other three NSAIDs.

Among secondary outcomes, stroke risk increased with all NSAIDs in 26 trials that reported 377 strokes. The increased risk was significant with four of the drugs, roughly doubling with naproxen and tripling with ibuprofen, diclofenac, etoricoxib, or lumiracoxib, compared with placebo.

Twenty-six trials reported 312 deaths from cardiovascular disease, accounting for 46% of all deaths in the trials. All NSAIDs except naproxen were associated with higher risk for cardiovascular death, which increased by 58% with rofecoxib, roughly doubled with ibuprofen, celecoxib, or lumiracoxib, and increased approximately fourfold with diclofenac or etoricoxib, compared with placebo.

All the NSAIDs were associated with increased risk for death from any cause, compared with placebo, and the increase was significant for all except naproxen. There were 676 deaths from any cause in 28 trials, and the risk of death roughly doubled with any of the other six NSAIDs.

Looking at a composite of nonfatal MI, nonfatal stroke, or cardiovascular death in 30 trials that reported 1,091 composite events, the risk increased with all the NSAIDs and increased significantly with all but naproxen.

View on the News

Time to Reevaluate NSAIDs

The cardiotoxicity of NSAIDs is particularly worrisome because many patients have both cardiovascular disease and musculoskeletal disease, Wayne A. Ray, Ph.D., noted in an editorial accompanying Dr. Trelle's study (BMJ Jan. 11, 2011;342:c6618 [doi:10.1136/bmj. c6618]).

What Dr. Trelle's study adds to the existing literature on NSAIDs is the potentially powerful technique known as network meta-analysis, which can extract more information from the data when certain assumptions are met, compared with traditional analyses, he wrote. The strength of the technique is that it uses all of the data, but it has some inherent weaknesses that should inspire caution when interpreting estimates based on indirect comparisons, explained Dr. Ray.

For example, no large, placebo-controlled trials compared etoricoxib vs. placebo. Risks of etoricoxib vs. placebo were estimated based on a chain of direct comparisons in separate trials – etoricoxib vs. diclofenac; diclofenac vs. rofecoxib or celecoxib, and finally rofecoxib or celecoxib vs. placebo.

Based on all the studies, what are the best strategies for clinicians who are considering NSAIDs for patients at high risk of cardiovascular disease? Avoid COX-2 inhibitors, especially in higher doses, Dr. Ray advised. Avoid diclofenac. Remember that ibuprofen may attenuate the antiplatelet effects of aspirin.

For now, naproxen seems to be the safest NSAID in terms of cardiovascular risk.

With any NSAID, consider also prescribing gastroprotective drugs.

NSAIDs are not the only option for treatment of musculoskeletal symptoms. Clinicians also prescribe paracetamol, low-dose opioid analgesics, and newer drugs, but without large-scale comparison studies, it's impossible to tell which is best for both efficacy and safety, Dr. Ray wrote. “Perhaps it is time for a larger, more systematic evaluation of a broader range of alternatives,” he suggested.

DR. WAYNE A. RAY is a professor and director of pharmacoepidemiology at Vanderbilt University, Nashville, Tenn. Dr. Ray has received financial support from Pfizer, was a paid expert witness in a lawsuit by the state of Texas against Merck, and is a paid expert in an insurance company action against the maker of Prempro.

Major Finding: Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo.

Data Source: Network meta-analysis of 31 large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo in 116,429 patients with 117,218 patient-years of follow-up.

Disclosures: The Swiss National Science Foundation funded the study. The investigators reported having no conflicts of interest.

Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo, in the most comprehensive meta-analysis of the subject so far.

The relative risks with any individual NSAID, compared with placebo, often were double, triple, or quadruple the risk with placebo, the study found. The absolute numbers of MIs and other cardiovascular outcomes were small, but the network meta-analysis design of the study “provides the best available evidence on the safety of this class of drugs,” Dr. Sven Trelle and his associates reported.

Contrary to some previous reports, the current study also found no suggestion that this increased cardiovascular risk is specific to cyclo-oxygenase-2 (COX-2) inhibitors. Therefore the use of all NSAIDs – and the over-the-counter availability of some of them – should be reconsidered, Dr. Trelle stated in a report published online by BMJ (Jan. 11, 2011;342:c7086[doi/10.1136/bmj.c7086]).

Dr. Trelle of the University of Bern, Switzerland, acknowledged that therapeutic options for chronic musculoskeletal pain are limited, but cautioned that “cardiovascular risk needs to be taken into account when prescribing” any NSAID.

The meta-analysis included any large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo. Data were available for naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, and lumiracoxib. The risk for a cardiovascular event had to increase by more than 30% to be considered significant.

Overall, naproxen appeared to be the least harmful NSAID in terms of cardiovascular outcomes. Risks were greatest with ibuprofen, diclofenac, etoricoxib, and lumiracoxib.

Four NSAIDs were associated with significantly increased risk for myocardial infarction (the primary outcome in the current analysis) in 29 of the trials that reported 554 MIs. The relative risk for MI doubled with rofecoxib or lumiracoxib, was 35% higher with celecoxib, and was 61% higher with ibuprofen, compared with placebo. Evidence was lacking for increased MI risk with the other three NSAIDs.

Among secondary outcomes, stroke risk increased with all NSAIDs in 26 trials that reported 377 strokes. The increased risk was significant with four of the drugs, roughly doubling with naproxen and tripling with ibuprofen, diclofenac, etoricoxib, or lumiracoxib, compared with placebo.

Twenty-six trials reported 312 deaths from cardiovascular disease, accounting for 46% of all deaths in the trials. All NSAIDs except naproxen were associated with higher risk for cardiovascular death, which increased by 58% with rofecoxib, roughly doubled with ibuprofen, celecoxib, or lumiracoxib, and increased approximately fourfold with diclofenac or etoricoxib, compared with placebo.

All the NSAIDs were associated with increased risk for death from any cause, compared with placebo, and the increase was significant for all except naproxen. There were 676 deaths from any cause in 28 trials, and the risk of death roughly doubled with any of the other six NSAIDs.

Looking at a composite of nonfatal MI, nonfatal stroke, or cardiovascular death in 30 trials that reported 1,091 composite events, the risk increased with all the NSAIDs and increased significantly with all but naproxen.

View on the News

Time to Reevaluate NSAIDs

The cardiotoxicity of NSAIDs is particularly worrisome because many patients have both cardiovascular disease and musculoskeletal disease, Wayne A. Ray, Ph.D., noted in an editorial accompanying Dr. Trelle's study (BMJ Jan. 11, 2011;342:c6618 [doi:10.1136/bmj. c6618]).

What Dr. Trelle's study adds to the existing literature on NSAIDs is the potentially powerful technique known as network meta-analysis, which can extract more information from the data when certain assumptions are met, compared with traditional analyses, he wrote. The strength of the technique is that it uses all of the data, but it has some inherent weaknesses that should inspire caution when interpreting estimates based on indirect comparisons, explained Dr. Ray.

For example, no large, placebo-controlled trials compared etoricoxib vs. placebo. Risks of etoricoxib vs. placebo were estimated based on a chain of direct comparisons in separate trials – etoricoxib vs. diclofenac; diclofenac vs. rofecoxib or celecoxib, and finally rofecoxib or celecoxib vs. placebo.

Based on all the studies, what are the best strategies for clinicians who are considering NSAIDs for patients at high risk of cardiovascular disease? Avoid COX-2 inhibitors, especially in higher doses, Dr. Ray advised. Avoid diclofenac. Remember that ibuprofen may attenuate the antiplatelet effects of aspirin.

For now, naproxen seems to be the safest NSAID in terms of cardiovascular risk.

With any NSAID, consider also prescribing gastroprotective drugs.

NSAIDs are not the only option for treatment of musculoskeletal symptoms. Clinicians also prescribe paracetamol, low-dose opioid analgesics, and newer drugs, but without large-scale comparison studies, it's impossible to tell which is best for both efficacy and safety, Dr. Ray wrote. “Perhaps it is time for a larger, more systematic evaluation of a broader range of alternatives,” he suggested.

DR. WAYNE A. RAY is a professor and director of pharmacoepidemiology at Vanderbilt University, Nashville, Tenn. Dr. Ray has received financial support from Pfizer, was a paid expert witness in a lawsuit by the state of Texas against Merck, and is a paid expert in an insurance company action against the maker of Prempro.

Major Finding: Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo.

Data Source: Network meta-analysis of 31 large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo in 116,429 patients with 117,218 patient-years of follow-up.

Disclosures: The Swiss National Science Foundation funded the study. The investigators reported having no conflicts of interest.

Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo, in the most comprehensive meta-analysis of the subject so far.

The relative risks with any individual NSAID, compared with placebo, often were double, triple, or quadruple the risk with placebo, the study found. The absolute numbers of MIs and other cardiovascular outcomes were small, but the network meta-analysis design of the study “provides the best available evidence on the safety of this class of drugs,” Dr. Sven Trelle and his associates reported.

Contrary to some previous reports, the current study also found no suggestion that this increased cardiovascular risk is specific to cyclo-oxygenase-2 (COX-2) inhibitors. Therefore the use of all NSAIDs – and the over-the-counter availability of some of them – should be reconsidered, Dr. Trelle stated in a report published online by BMJ (Jan. 11, 2011;342:c7086[doi/10.1136/bmj.c7086]).

Dr. Trelle of the University of Bern, Switzerland, acknowledged that therapeutic options for chronic musculoskeletal pain are limited, but cautioned that “cardiovascular risk needs to be taken into account when prescribing” any NSAID.

The meta-analysis included any large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo. Data were available for naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, and lumiracoxib. The risk for a cardiovascular event had to increase by more than 30% to be considered significant.

Overall, naproxen appeared to be the least harmful NSAID in terms of cardiovascular outcomes. Risks were greatest with ibuprofen, diclofenac, etoricoxib, and lumiracoxib.

Four NSAIDs were associated with significantly increased risk for myocardial infarction (the primary outcome in the current analysis) in 29 of the trials that reported 554 MIs. The relative risk for MI doubled with rofecoxib or lumiracoxib, was 35% higher with celecoxib, and was 61% higher with ibuprofen, compared with placebo. Evidence was lacking for increased MI risk with the other three NSAIDs.

Among secondary outcomes, stroke risk increased with all NSAIDs in 26 trials that reported 377 strokes. The increased risk was significant with four of the drugs, roughly doubling with naproxen and tripling with ibuprofen, diclofenac, etoricoxib, or lumiracoxib, compared with placebo.

Twenty-six trials reported 312 deaths from cardiovascular disease, accounting for 46% of all deaths in the trials. All NSAIDs except naproxen were associated with higher risk for cardiovascular death, which increased by 58% with rofecoxib, roughly doubled with ibuprofen, celecoxib, or lumiracoxib, and increased approximately fourfold with diclofenac or etoricoxib, compared with placebo.

All the NSAIDs were associated with increased risk for death from any cause, compared with placebo, and the increase was significant for all except naproxen. There were 676 deaths from any cause in 28 trials, and the risk of death roughly doubled with any of the other six NSAIDs.

Looking at a composite of nonfatal MI, nonfatal stroke, or cardiovascular death in 30 trials that reported 1,091 composite events, the risk increased with all the NSAIDs and increased significantly with all but naproxen.

View on the News

Time to Reevaluate NSAIDs

The cardiotoxicity of NSAIDs is particularly worrisome because many patients have both cardiovascular disease and musculoskeletal disease, Wayne A. Ray, Ph.D., noted in an editorial accompanying Dr. Trelle's study (BMJ Jan. 11, 2011;342:c6618 [doi:10.1136/bmj. c6618]).

What Dr. Trelle's study adds to the existing literature on NSAIDs is the potentially powerful technique known as network meta-analysis, which can extract more information from the data when certain assumptions are met, compared with traditional analyses, he wrote. The strength of the technique is that it uses all of the data, but it has some inherent weaknesses that should inspire caution when interpreting estimates based on indirect comparisons, explained Dr. Ray.

For example, no large, placebo-controlled trials compared etoricoxib vs. placebo. Risks of etoricoxib vs. placebo were estimated based on a chain of direct comparisons in separate trials – etoricoxib vs. diclofenac; diclofenac vs. rofecoxib or celecoxib, and finally rofecoxib or celecoxib vs. placebo.

Based on all the studies, what are the best strategies for clinicians who are considering NSAIDs for patients at high risk of cardiovascular disease? Avoid COX-2 inhibitors, especially in higher doses, Dr. Ray advised. Avoid diclofenac. Remember that ibuprofen may attenuate the antiplatelet effects of aspirin.

For now, naproxen seems to be the safest NSAID in terms of cardiovascular risk.

With any NSAID, consider also prescribing gastroprotective drugs.

NSAIDs are not the only option for treatment of musculoskeletal symptoms. Clinicians also prescribe paracetamol, low-dose opioid analgesics, and newer drugs, but without large-scale comparison studies, it's impossible to tell which is best for both efficacy and safety, Dr. Ray wrote. “Perhaps it is time for a larger, more systematic evaluation of a broader range of alternatives,” he suggested.

DR. WAYNE A. RAY is a professor and director of pharmacoepidemiology at Vanderbilt University, Nashville, Tenn. Dr. Ray has received financial support from Pfizer, was a paid expert witness in a lawsuit by the state of Texas against Merck, and is a paid expert in an insurance company action against the maker of Prempro.

Major Finding: Opportunistic infections other than tuberculosis were 18 times more likely in patients on infliximab and 10 times more likely in patients on adalimumab, compared with patients on etanercept.

Data Source: A study of a French national registry of all patients with opportunistic infections while they were on TNFi agents, and case-control analysis of 43 patients with 45 non-TB opportunistic infections and 3 matched control patients without infection on anti-TNF agents.

Disclosures: Some of Dr. Salmon-Ceron's coauthors have been consultants or speakers for Abbott, Schering Plough, UCB, or Wyeth. The study was funded by Abbott, Schering Plough, Wyeth, and INSERM (Institut National de la Santé et de la Recherche Médicale.

Patients taking monoclonal anti–tumor necrosis factor antibody therapy were more likely than those on soluble TNF inhibiting therapy to develop opportunistic infections, other than tuberculosis, in a study of a French national registry.

Of the three TNFi agents used in France in 2004-2007, infliximab was associated with an 18-fold increased risk and adalimumab was associated with a 10-fold increased risk for nontuberculosis opportunistic infection, compared with etanercept, Dr. Dominique Salmon-Ceron and her associates reported. A higher incidence of opportunistic infection with infliximab or adalimumab, compared with etanercept, did not reach statistical significance because of the rarity of the infections. But the findings are supported by previous reports from the Food and Drug Administration, a Spanish registry, a study of 21 Japanese patients, and other accounts of a greater risk for opportunistic infection with infliximab, compared with etanercept, the investigators noted (Ann. Rheum. Dis. 2010 Dec. 21 [doi:10.1136/ard.2010. 137422]).

The study also identified a third risk factor: treatment with more than 10 mg/day of oral steroids or IV steroid boluses during the year before a diagnosis of non-TB opportunistic infection. Previous studies also identified this risk factor in patients with rheumatoid arthritis or systemic lupus erythematosus, so the current analysis “strengthens the need to avoid high doses of steroids for patients receiving anti-TNF agents,” reported Dr. Salmon-Ceron, who is professor of infectious diseases at Université René Descartes, Paris, as well as a member of the staff at of Hôpital Cochin in that city.

The data in the study come from the 3-year French RATIO (Research Axed on Tolerance of Biotherapies) registry and involved all cases in France of opportunistic infections in patients receiving TNFi agents for any reason. The case-control analysis matched each of the 43 case patients (with a total of 45 opportunistic infections) with 3 control patients who took TNFi agents without developing opportunistic infections.

Patients had been treated with TNFi agents for RA (26), spondyloarthritides (3), inflammatory colitis (8), psoriasis (1), or other problems (5). Four were on etanercept, 10 received adalimumab, and 39 were on infliximab.

Using pharmaceutical company data, the investigators estimated a total of 57,711 patient-years of use of TNFi therapy during the study period. They calculated an annual incidence of opportunistic infection in patients receiving TNFi agents as 152 per 100,000 patient-years, after adjusting for age and sex.

The incidence of opportunistic infection differed by TNFi agent, but the differences were not statistically significant (7 per 100,000 patient-years with etanercept, 62 per 100,000 patient-years with adalimumab, and 291 per 100,000 patient-years with infliximab). The rarity of opportunistic infections prevented statistical significance in comparisons.

Major Finding: Opportunistic infections other than tuberculosis were 18 times more likely in patients on infliximab and 10 times more likely in patients on adalimumab, compared with patients on etanercept.

Data Source: A study of a French national registry of all patients with opportunistic infections while they were on TNFi agents, and case-control analysis of 43 patients with 45 non-TB opportunistic infections and 3 matched control patients without infection on anti-TNF agents.

Disclosures: Some of Dr. Salmon-Ceron's coauthors have been consultants or speakers for Abbott, Schering Plough, UCB, or Wyeth. The study was funded by Abbott, Schering Plough, Wyeth, and INSERM (Institut National de la Santé et de la Recherche Médicale.

Patients taking monoclonal anti–tumor necrosis factor antibody therapy were more likely than those on soluble TNF inhibiting therapy to develop opportunistic infections, other than tuberculosis, in a study of a French national registry.

Of the three TNFi agents used in France in 2004-2007, infliximab was associated with an 18-fold increased risk and adalimumab was associated with a 10-fold increased risk for nontuberculosis opportunistic infection, compared with etanercept, Dr. Dominique Salmon-Ceron and her associates reported. A higher incidence of opportunistic infection with infliximab or adalimumab, compared with etanercept, did not reach statistical significance because of the rarity of the infections. But the findings are supported by previous reports from the Food and Drug Administration, a Spanish registry, a study of 21 Japanese patients, and other accounts of a greater risk for opportunistic infection with infliximab, compared with etanercept, the investigators noted (Ann. Rheum. Dis. 2010 Dec. 21 [doi:10.1136/ard.2010. 137422]).

The study also identified a third risk factor: treatment with more than 10 mg/day of oral steroids or IV steroid boluses during the year before a diagnosis of non-TB opportunistic infection. Previous studies also identified this risk factor in patients with rheumatoid arthritis or systemic lupus erythematosus, so the current analysis “strengthens the need to avoid high doses of steroids for patients receiving anti-TNF agents,” reported Dr. Salmon-Ceron, who is professor of infectious diseases at Université René Descartes, Paris, as well as a member of the staff at of Hôpital Cochin in that city.

The data in the study come from the 3-year French RATIO (Research Axed on Tolerance of Biotherapies) registry and involved all cases in France of opportunistic infections in patients receiving TNFi agents for any reason. The case-control analysis matched each of the 43 case patients (with a total of 45 opportunistic infections) with 3 control patients who took TNFi agents without developing opportunistic infections.

Patients had been treated with TNFi agents for RA (26), spondyloarthritides (3), inflammatory colitis (8), psoriasis (1), or other problems (5). Four were on etanercept, 10 received adalimumab, and 39 were on infliximab.

Using pharmaceutical company data, the investigators estimated a total of 57,711 patient-years of use of TNFi therapy during the study period. They calculated an annual incidence of opportunistic infection in patients receiving TNFi agents as 152 per 100,000 patient-years, after adjusting for age and sex.

The incidence of opportunistic infection differed by TNFi agent, but the differences were not statistically significant (7 per 100,000 patient-years with etanercept, 62 per 100,000 patient-years with adalimumab, and 291 per 100,000 patient-years with infliximab). The rarity of opportunistic infections prevented statistical significance in comparisons.

Major Finding: Opportunistic infections other than tuberculosis were 18 times more likely in patients on infliximab and 10 times more likely in patients on adalimumab, compared with patients on etanercept.

Data Source: A study of a French national registry of all patients with opportunistic infections while they were on TNFi agents, and case-control analysis of 43 patients with 45 non-TB opportunistic infections and 3 matched control patients without infection on anti-TNF agents.

Disclosures: Some of Dr. Salmon-Ceron's coauthors have been consultants or speakers for Abbott, Schering Plough, UCB, or Wyeth. The study was funded by Abbott, Schering Plough, Wyeth, and INSERM (Institut National de la Santé et de la Recherche Médicale.

Patients taking monoclonal anti–tumor necrosis factor antibody therapy were more likely than those on soluble TNF inhibiting therapy to develop opportunistic infections, other than tuberculosis, in a study of a French national registry.

Of the three TNFi agents used in France in 2004-2007, infliximab was associated with an 18-fold increased risk and adalimumab was associated with a 10-fold increased risk for nontuberculosis opportunistic infection, compared with etanercept, Dr. Dominique Salmon-Ceron and her associates reported. A higher incidence of opportunistic infection with infliximab or adalimumab, compared with etanercept, did not reach statistical significance because of the rarity of the infections. But the findings are supported by previous reports from the Food and Drug Administration, a Spanish registry, a study of 21 Japanese patients, and other accounts of a greater risk for opportunistic infection with infliximab, compared with etanercept, the investigators noted (Ann. Rheum. Dis. 2010 Dec. 21 [doi:10.1136/ard.2010. 137422]).

The study also identified a third risk factor: treatment with more than 10 mg/day of oral steroids or IV steroid boluses during the year before a diagnosis of non-TB opportunistic infection. Previous studies also identified this risk factor in patients with rheumatoid arthritis or systemic lupus erythematosus, so the current analysis “strengthens the need to avoid high doses of steroids for patients receiving anti-TNF agents,” reported Dr. Salmon-Ceron, who is professor of infectious diseases at Université René Descartes, Paris, as well as a member of the staff at of Hôpital Cochin in that city.

The data in the study come from the 3-year French RATIO (Research Axed on Tolerance of Biotherapies) registry and involved all cases in France of opportunistic infections in patients receiving TNFi agents for any reason. The case-control analysis matched each of the 43 case patients (with a total of 45 opportunistic infections) with 3 control patients who took TNFi agents without developing opportunistic infections.

Patients had been treated with TNFi agents for RA (26), spondyloarthritides (3), inflammatory colitis (8), psoriasis (1), or other problems (5). Four were on etanercept, 10 received adalimumab, and 39 were on infliximab.

Using pharmaceutical company data, the investigators estimated a total of 57,711 patient-years of use of TNFi therapy during the study period. They calculated an annual incidence of opportunistic infection in patients receiving TNFi agents as 152 per 100,000 patient-years, after adjusting for age and sex.

The incidence of opportunistic infection differed by TNFi agent, but the differences were not statistically significant (7 per 100,000 patient-years with etanercept, 62 per 100,000 patient-years with adalimumab, and 291 per 100,000 patient-years with infliximab). The rarity of opportunistic infections prevented statistical significance in comparisons.

Major Finding: Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo.

Data Source: Network meta-analysis of 31 large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo in 116,429 patients with 117,218 patient-years of follow-up.

Disclosures: The Swiss National Science Foundation funded the study. The investigators reported having no conflicts of interest.

Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo, in the most comprehensive meta-analysis of the subject so far.

The relative risks with any individual NSAID, compared with placebo, often were double, triple, or quadruple the risk with placebo, the study found. The absolute numbers of MIs and other cardiovascular outcomes were small, but the network meta-analysis design of the study “provides the best available evidence on the safety of this class of drugs,” Dr. Sven Trelle and his associates reported.

Contrary to some previous reports, the current study also found no suggestion that this increased cardiovascular risk is specific to cyclo-oxygenase-2 (COX-2) inhibitors. Therefore the use of all NSAIDs – and the over-the-counter availability of some of them – should be reconsidered, Dr. Trelle stated (BMJ Jan. 11, 2011;342:c7086[doi/10.1136/bmj.c7086]).

The meta-analysis included any large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo. Data were available for naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, and lumiracoxib. The risk for a cardiovascular event had to increase by more than 30% to be considered significant.

Overall, naproxen appeared to be the least harmful NSAID in terms of cardiovascular outcomes. Risks were greatest with ibuprofen, diclofenac, etoricoxib, and lumiracoxib.

Four NSAIDs were associated with significantly increased risk for MI (the primary outcome in the current analysis) in 29 of the trials that reported 554 MIs. The relative risk for MI doubled with rofecoxib or lumiracoxib, was 35% higher with celecoxib, and was 61% higher with ibuprofen, compared with placebo. Evidence was lacking for increased MI risk with the other three NSAIDs.

Twenty-six trials reported 312 deaths from cardiovascular disease, accounting for 46% of all deaths in the trials. All NSAIDs except naproxen were associated with higher risk for cardiovascular death, which increased by 58% with rofecoxib, roughly doubled with ibuprofen, celecoxib, or lumiracoxib, and increased approximately fourfold with diclofenac or etoricoxib, compared with placebo.

All the NSAIDs were linked with increased risk for death from any cause, compared with placebo, and the increase was significant for all except naproxen. There were 676 deaths from any cause in 28 trials, and the risk of death roughly doubled with any of the other six NSAIDs.

Looking at a composite of nonfatal MI, nonfatal stroke, or cardiovascular death in 30 trials that reported 1,091 composite events, the risk increased with all the NSAIDs and increased significantly with all but naproxen. The odds for the composite outcome increased 43% with celecoxib, 44% with rofecoxib, 53% with etoricoxib, 60% with diclofenac, and more than doubled with lumiracoxib or ibuprofen.

An estimated 5% of all visits to U.S. physicians are related to prescribing NSAIDs, which are considered the cornerstone for managing the pain of osteoarthritis and other painful conditions. Rofecoxib, a COX-2 inhibitor, was withdrawn from the market in 2004 after a randomized, placebo-controlled trial found its use was associated with increased cardiovascular risk. The Food and Drug Administration has since denied approval of etoricoxib because of an inadequate risk-benefit profile.

Major Finding: Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo.

Data Source: Network meta-analysis of 31 large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo in 116,429 patients with 117,218 patient-years of follow-up.

Disclosures: The Swiss National Science Foundation funded the study. The investigators reported having no conflicts of interest.

Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo, in the most comprehensive meta-analysis of the subject so far.

The relative risks with any individual NSAID, compared with placebo, often were double, triple, or quadruple the risk with placebo, the study found. The absolute numbers of MIs and other cardiovascular outcomes were small, but the network meta-analysis design of the study “provides the best available evidence on the safety of this class of drugs,” Dr. Sven Trelle and his associates reported.

Contrary to some previous reports, the current study also found no suggestion that this increased cardiovascular risk is specific to cyclo-oxygenase-2 (COX-2) inhibitors. Therefore the use of all NSAIDs – and the over-the-counter availability of some of them – should be reconsidered, Dr. Trelle stated (BMJ Jan. 11, 2011;342:c7086[doi/10.1136/bmj.c7086]).

The meta-analysis included any large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo. Data were available for naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, and lumiracoxib. The risk for a cardiovascular event had to increase by more than 30% to be considered significant.

Overall, naproxen appeared to be the least harmful NSAID in terms of cardiovascular outcomes. Risks were greatest with ibuprofen, diclofenac, etoricoxib, and lumiracoxib.

Four NSAIDs were associated with significantly increased risk for MI (the primary outcome in the current analysis) in 29 of the trials that reported 554 MIs. The relative risk for MI doubled with rofecoxib or lumiracoxib, was 35% higher with celecoxib, and was 61% higher with ibuprofen, compared with placebo. Evidence was lacking for increased MI risk with the other three NSAIDs.

Twenty-six trials reported 312 deaths from cardiovascular disease, accounting for 46% of all deaths in the trials. All NSAIDs except naproxen were associated with higher risk for cardiovascular death, which increased by 58% with rofecoxib, roughly doubled with ibuprofen, celecoxib, or lumiracoxib, and increased approximately fourfold with diclofenac or etoricoxib, compared with placebo.

All the NSAIDs were linked with increased risk for death from any cause, compared with placebo, and the increase was significant for all except naproxen. There were 676 deaths from any cause in 28 trials, and the risk of death roughly doubled with any of the other six NSAIDs.

Looking at a composite of nonfatal MI, nonfatal stroke, or cardiovascular death in 30 trials that reported 1,091 composite events, the risk increased with all the NSAIDs and increased significantly with all but naproxen. The odds for the composite outcome increased 43% with celecoxib, 44% with rofecoxib, 53% with etoricoxib, 60% with diclofenac, and more than doubled with lumiracoxib or ibuprofen.

An estimated 5% of all visits to U.S. physicians are related to prescribing NSAIDs, which are considered the cornerstone for managing the pain of osteoarthritis and other painful conditions. Rofecoxib, a COX-2 inhibitor, was withdrawn from the market in 2004 after a randomized, placebo-controlled trial found its use was associated with increased cardiovascular risk. The Food and Drug Administration has since denied approval of etoricoxib because of an inadequate risk-benefit profile.

Major Finding: Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo.

Data Source: Network meta-analysis of 31 large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo in 116,429 patients with 117,218 patient-years of follow-up.

Disclosures: The Swiss National Science Foundation funded the study. The investigators reported having no conflicts of interest.

Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo, in the most comprehensive meta-analysis of the subject so far.

The relative risks with any individual NSAID, compared with placebo, often were double, triple, or quadruple the risk with placebo, the study found. The absolute numbers of MIs and other cardiovascular outcomes were small, but the network meta-analysis design of the study “provides the best available evidence on the safety of this class of drugs,” Dr. Sven Trelle and his associates reported.

Contrary to some previous reports, the current study also found no suggestion that this increased cardiovascular risk is specific to cyclo-oxygenase-2 (COX-2) inhibitors. Therefore the use of all NSAIDs – and the over-the-counter availability of some of them – should be reconsidered, Dr. Trelle stated (BMJ Jan. 11, 2011;342:c7086[doi/10.1136/bmj.c7086]).

The meta-analysis included any large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo. Data were available for naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, and lumiracoxib. The risk for a cardiovascular event had to increase by more than 30% to be considered significant.

Overall, naproxen appeared to be the least harmful NSAID in terms of cardiovascular outcomes. Risks were greatest with ibuprofen, diclofenac, etoricoxib, and lumiracoxib.

Four NSAIDs were associated with significantly increased risk for MI (the primary outcome in the current analysis) in 29 of the trials that reported 554 MIs. The relative risk for MI doubled with rofecoxib or lumiracoxib, was 35% higher with celecoxib, and was 61% higher with ibuprofen, compared with placebo. Evidence was lacking for increased MI risk with the other three NSAIDs.

Twenty-six trials reported 312 deaths from cardiovascular disease, accounting for 46% of all deaths in the trials. All NSAIDs except naproxen were associated with higher risk for cardiovascular death, which increased by 58% with rofecoxib, roughly doubled with ibuprofen, celecoxib, or lumiracoxib, and increased approximately fourfold with diclofenac or etoricoxib, compared with placebo.

All the NSAIDs were linked with increased risk for death from any cause, compared with placebo, and the increase was significant for all except naproxen. There were 676 deaths from any cause in 28 trials, and the risk of death roughly doubled with any of the other six NSAIDs.

Looking at a composite of nonfatal MI, nonfatal stroke, or cardiovascular death in 30 trials that reported 1,091 composite events, the risk increased with all the NSAIDs and increased significantly with all but naproxen. The odds for the composite outcome increased 43% with celecoxib, 44% with rofecoxib, 53% with etoricoxib, 60% with diclofenac, and more than doubled with lumiracoxib or ibuprofen.

An estimated 5% of all visits to U.S. physicians are related to prescribing NSAIDs, which are considered the cornerstone for managing the pain of osteoarthritis and other painful conditions. Rofecoxib, a COX-2 inhibitor, was withdrawn from the market in 2004 after a randomized, placebo-controlled trial found its use was associated with increased cardiovascular risk. The Food and Drug Administration has since denied approval of etoricoxib because of an inadequate risk-benefit profile.

LAS VEGAS – Topical tar therapy for psoriasis may be making a comeback thanks to more user-friendly formulations.

That trend is happening in Europe and may be replicated in the United States, said Dr. Linda Stein Gold, director of dermatology research at Henry Ford Hospital, Detroit.

“Topical therapy is the bread and butter of psoriasis treatment,” and coal tar has been used for centuries to control the symptoms of plaque psoriasis, she said. The Goeckerman regimen, a combination of topical tar and ultraviolet light therapy in use since the 1920s, proved “exceptionally” effective and durable, with an average time of 18 days to 90% clearing of psoriatic lesions and 90% of patients remaining clear for up to 8 months.

But tar therapy was time consuming, a logistical hassle, and aesthetically unpleasing, and its use declined in recent decades with the advent of systemic biologic medications. “People weren't using tar before because it's messy and it smelled. Now we have some better options,” Dr. Stein Gold said.

One of the newer topical solutions is a transparent gel of 15% liquor carbonis distillate (LCD), the equivalent of 2.3% coal tar (Psorent, NeoStrata Co.). “It doesn't discolor bleached hair” when used for scalp psoriasis, it is quick-drying, and it comes in bottles with “dab-on” applicators so that patients don't have to come in contact with it, she said.

In a controlled comparison with calcipotriol cream in 12 weeks of treatment of 60 adults with moderate plaque psoriasis, the LCD solution was more effective and led to fewer relapses 6 weeks after treatment. Among 55 patients with complete data, mean Psoriasis Area Severity Index (PASI) scores improved by 58% in the LCD solution group and 37% in the calcipotriol group, a significant difference (J. Am. Acad. Dermatol. 2009;60 [issue 3, suppl. 1]:Ab174 [doi: 10.1016/j.jaad.2008.11.757]).

A 75% improvement in PASI scores was seen in 11 of 27 (41%) of the LCD solution group and none of the 28 patients on calcipotriol. A 50% improvement in PASI scores was seen in 18 of 27 (67%) in the LCD group and 10 of 28 (36%) in the calcipotriol group. These differences between groups were statistically significant.

Among 42 patients with Physician Global Assessment (PGA) scores 6 weeks after treatment, the PGA scores worsened to baseline in 5 of 22 patients (23%) in the LCD solution group and in 14 of 20 patients (70%) in the calcipotriol group, again a significant difference.

A separate study compared the LCD solution in combination with UVB therapy on one side of the body with UVB light therapy alone on the other side of the body in 12 patients in 4 weeks of therapy. “Very quickly, the combo therapy gets more rapid and complete efficacy compared with UVB alone,” said Dr. Stein Gold (J. Drugs Dermatol. 2009;8:351-7).

Another relatively user-friendly product is an over-the-counter 2% coal tar formulation in a foam base (Scytera, Promius Pharma). The foam is “a much more cosmetically elegant” treatment compared with older tar therapies, she said. It spreads easily, dries quickly, and has an acceptable fragrance, Dr. Stein Gold added.

In a randomized, observer-blind study of 38 patients with chronic plaque-type psoriasis, two lesions on each patient were treated for 8 weeks with a 1% coal tar foam or calcipotriol cream. The treatments appeared to be comparably effective. More patients reported itching, unpleasant odor or staining with the tar foam than with calcipotriol cream, but the foam is considerably less expensive, the investigators noted (Br. J. Dermatol. 2003;149:350-3).

“Tar is something we probably should look at again,” Dr. Stein Gold said.

Other useful topical therapies include corticosteroids, she said. While studies with objective measures of atrophy have proved that potent topical corticosteroids do lead to thinning of the skin over time, often this effect is not clinically noticeable, and it reverses over time once treatment is stopped.

Topical vitamin D is complementary to topical steroids for psoriasis therapy and helps counteract some of the side effects of topical steroids on skin.

Dr. Stein Gold said she has had financial associations with Leo Pharma, Medicis Pharmaceutical Corp., Stiefel Laboratories, Galderma, and Novartis. SDEF and this news organization are owned by Elsevier.

LAS VEGAS – Topical tar therapy for psoriasis may be making a comeback thanks to more user-friendly formulations.

That trend is happening in Europe and may be replicated in the United States, said Dr. Linda Stein Gold, director of dermatology research at Henry Ford Hospital, Detroit.

“Topical therapy is the bread and butter of psoriasis treatment,” and coal tar has been used for centuries to control the symptoms of plaque psoriasis, she said. The Goeckerman regimen, a combination of topical tar and ultraviolet light therapy in use since the 1920s, proved “exceptionally” effective and durable, with an average time of 18 days to 90% clearing of psoriatic lesions and 90% of patients remaining clear for up to 8 months.

But tar therapy was time consuming, a logistical hassle, and aesthetically unpleasing, and its use declined in recent decades with the advent of systemic biologic medications. “People weren't using tar before because it's messy and it smelled. Now we have some better options,” Dr. Stein Gold said.

One of the newer topical solutions is a transparent gel of 15% liquor carbonis distillate (LCD), the equivalent of 2.3% coal tar (Psorent, NeoStrata Co.). “It doesn't discolor bleached hair” when used for scalp psoriasis, it is quick-drying, and it comes in bottles with “dab-on” applicators so that patients don't have to come in contact with it, she said.

In a controlled comparison with calcipotriol cream in 12 weeks of treatment of 60 adults with moderate plaque psoriasis, the LCD solution was more effective and led to fewer relapses 6 weeks after treatment. Among 55 patients with complete data, mean Psoriasis Area Severity Index (PASI) scores improved by 58% in the LCD solution group and 37% in the calcipotriol group, a significant difference (J. Am. Acad. Dermatol. 2009;60 [issue 3, suppl. 1]:Ab174 [doi: 10.1016/j.jaad.2008.11.757]).

A 75% improvement in PASI scores was seen in 11 of 27 (41%) of the LCD solution group and none of the 28 patients on calcipotriol. A 50% improvement in PASI scores was seen in 18 of 27 (67%) in the LCD group and 10 of 28 (36%) in the calcipotriol group. These differences between groups were statistically significant.

Among 42 patients with Physician Global Assessment (PGA) scores 6 weeks after treatment, the PGA scores worsened to baseline in 5 of 22 patients (23%) in the LCD solution group and in 14 of 20 patients (70%) in the calcipotriol group, again a significant difference.

A separate study compared the LCD solution in combination with UVB therapy on one side of the body with UVB light therapy alone on the other side of the body in 12 patients in 4 weeks of therapy. “Very quickly, the combo therapy gets more rapid and complete efficacy compared with UVB alone,” said Dr. Stein Gold (J. Drugs Dermatol. 2009;8:351-7).

Another relatively user-friendly product is an over-the-counter 2% coal tar formulation in a foam base (Scytera, Promius Pharma). The foam is “a much more cosmetically elegant” treatment compared with older tar therapies, she said. It spreads easily, dries quickly, and has an acceptable fragrance, Dr. Stein Gold added.

In a randomized, observer-blind study of 38 patients with chronic plaque-type psoriasis, two lesions on each patient were treated for 8 weeks with a 1% coal tar foam or calcipotriol cream. The treatments appeared to be comparably effective. More patients reported itching, unpleasant odor or staining with the tar foam than with calcipotriol cream, but the foam is considerably less expensive, the investigators noted (Br. J. Dermatol. 2003;149:350-3).

“Tar is something we probably should look at again,” Dr. Stein Gold said.

Other useful topical therapies include corticosteroids, she said. While studies with objective measures of atrophy have proved that potent topical corticosteroids do lead to thinning of the skin over time, often this effect is not clinically noticeable, and it reverses over time once treatment is stopped.

Topical vitamin D is complementary to topical steroids for psoriasis therapy and helps counteract some of the side effects of topical steroids on skin.

Dr. Stein Gold said she has had financial associations with Leo Pharma, Medicis Pharmaceutical Corp., Stiefel Laboratories, Galderma, and Novartis. SDEF and this news organization are owned by Elsevier.

LAS VEGAS – Topical tar therapy for psoriasis may be making a comeback thanks to more user-friendly formulations.

That trend is happening in Europe and may be replicated in the United States, said Dr. Linda Stein Gold, director of dermatology research at Henry Ford Hospital, Detroit.

“Topical therapy is the bread and butter of psoriasis treatment,” and coal tar has been used for centuries to control the symptoms of plaque psoriasis, she said. The Goeckerman regimen, a combination of topical tar and ultraviolet light therapy in use since the 1920s, proved “exceptionally” effective and durable, with an average time of 18 days to 90% clearing of psoriatic lesions and 90% of patients remaining clear for up to 8 months.

But tar therapy was time consuming, a logistical hassle, and aesthetically unpleasing, and its use declined in recent decades with the advent of systemic biologic medications. “People weren't using tar before because it's messy and it smelled. Now we have some better options,” Dr. Stein Gold said.

One of the newer topical solutions is a transparent gel of 15% liquor carbonis distillate (LCD), the equivalent of 2.3% coal tar (Psorent, NeoStrata Co.). “It doesn't discolor bleached hair” when used for scalp psoriasis, it is quick-drying, and it comes in bottles with “dab-on” applicators so that patients don't have to come in contact with it, she said.

In a controlled comparison with calcipotriol cream in 12 weeks of treatment of 60 adults with moderate plaque psoriasis, the LCD solution was more effective and led to fewer relapses 6 weeks after treatment. Among 55 patients with complete data, mean Psoriasis Area Severity Index (PASI) scores improved by 58% in the LCD solution group and 37% in the calcipotriol group, a significant difference (J. Am. Acad. Dermatol. 2009;60 [issue 3, suppl. 1]:Ab174 [doi: 10.1016/j.jaad.2008.11.757]).

A 75% improvement in PASI scores was seen in 11 of 27 (41%) of the LCD solution group and none of the 28 patients on calcipotriol. A 50% improvement in PASI scores was seen in 18 of 27 (67%) in the LCD group and 10 of 28 (36%) in the calcipotriol group. These differences between groups were statistically significant.

Among 42 patients with Physician Global Assessment (PGA) scores 6 weeks after treatment, the PGA scores worsened to baseline in 5 of 22 patients (23%) in the LCD solution group and in 14 of 20 patients (70%) in the calcipotriol group, again a significant difference.

A separate study compared the LCD solution in combination with UVB therapy on one side of the body with UVB light therapy alone on the other side of the body in 12 patients in 4 weeks of therapy. “Very quickly, the combo therapy gets more rapid and complete efficacy compared with UVB alone,” said Dr. Stein Gold (J. Drugs Dermatol. 2009;8:351-7).

Another relatively user-friendly product is an over-the-counter 2% coal tar formulation in a foam base (Scytera, Promius Pharma). The foam is “a much more cosmetically elegant” treatment compared with older tar therapies, she said. It spreads easily, dries quickly, and has an acceptable fragrance, Dr. Stein Gold added.

In a randomized, observer-blind study of 38 patients with chronic plaque-type psoriasis, two lesions on each patient were treated for 8 weeks with a 1% coal tar foam or calcipotriol cream. The treatments appeared to be comparably effective. More patients reported itching, unpleasant odor or staining with the tar foam than with calcipotriol cream, but the foam is considerably less expensive, the investigators noted (Br. J. Dermatol. 2003;149:350-3).

“Tar is something we probably should look at again,” Dr. Stein Gold said.

Other useful topical therapies include corticosteroids, she said. While studies with objective measures of atrophy have proved that potent topical corticosteroids do lead to thinning of the skin over time, often this effect is not clinically noticeable, and it reverses over time once treatment is stopped.

Topical vitamin D is complementary to topical steroids for psoriasis therapy and helps counteract some of the side effects of topical steroids on skin.

Dr. Stein Gold said she has had financial associations with Leo Pharma, Medicis Pharmaceutical Corp., Stiefel Laboratories, Galderma, and Novartis. SDEF and this news organization are owned by Elsevier.

LAS VEGAS – Improved understanding of itching and best practices in management of the condition may lead to U.S. medical centers specializing in treating pruritus.

A recent gathering of experts convened by the National Institutes of Health (NIH) may be the first step in this direction, Dr. Timothy G. Berger said at the meeting.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) pulled together 50 physicians to discuss the topic of pruritus. One of a series of roundtable discussions held by NIAMS, this was the first to focus on itching. A summary of the meeting and a list of attendees has been posted on the NIAMS Web site, NIAMS media liaison Trish Reynolds said in an interview.

“These things are usually followed by calls for proposals,” said Dr. Berger of the University of California, San Francisco (UCSF), who did not attend the roundtable discussion. “The NIH is moving to a model of having major itch referral centers at several sites.”

Patients with itch would be referred to a center where their tissue samples and data could be stored and analyzed while they get expert treatment. “There will be direct translational benefits” from this approach, he predicted.

These centers would be patterned after two models – referral centers for pain, and European itch centers. The U.S. itch centers might first appear at UCSF; Washington University, St. Louis; and Harvard University, Boston, he said.

“In Europe, every patient with itch goes to a medical center for itch, is seen in a standard way, and has a defined database established about that patient. They now have tens of thousands of itch patients of various types logged into this database,” and data it provides are helping to build greater understanding of the problem of itching, Dr. Berger said.

One of the key insights into itching in recent years has been the understanding that chronic itch is like chronic pain. Chronic itch is thought to begin peripherally but then trigger anatomic changes in the CNS that make treatment much more difficult. “This suggests that we will have agents that will act both peripherally and centrally” to ease itching, he said. “We're now at the verge of being able to do something about itching.”

Chronic itching should be treated aggressively because once central sensitization occurs, it is very, very hard to manage, he advised. Chronic itching has a huge impact on quality of life, earning the same scores by patients as the reduced quality of life reported by patients with chronic renal failure on dialysis.

Once itch is chronic, the threshold for sensation of itch is reduced. “Even if you make their rash better, they still itch,” he said. Itch intensity increases with chronicity, producing more itch from the same rash. Even when the skin is clear, patients may have short bursts of spontaneous itch. In atopic dermatitis and perhaps some other forms of itchy lesions, patients may scratch themselves raw because inflammatory mediators of pain are perceived as itch.

“This whole system is miswired” in chronic itch, Dr. Berger said.

Perceived itch is a delicate interaction between the skin, nerves, and immune system, and treatments may target one or more of these pathways. The most common medication for chronic itch is second-generation antihistamines, in higher doses than used for the approved indication of allergic rhinitis. “These substances also block other inflammatory mediators that may be important for itch, so they may have benefit beyond what we know,” Dr. Berger said.

Neuroleptic medications for itch include amitriptyline or other tricyclic antidepressants, gabapentin, pregabalin, duloxetine, or thalidomide for prurigo nodularis. “These act primarily on the neural axis,” he said.

Central-acting agents include paroxetine, amitriptyline, doxepin, or mirtazapine. In a large European cohort, 6-9 months of treatment with paroxetine reduced chronic itch by 75% in 70% of patients. “It's now become one of our drugs to treat itch, and is the treatment of choice for itch in polycythemia vera,” he said.

Research has shown that patients who have liver disease can develop itch caused by abnormalities in opiate metabolism, leading some clinicians to treat chronic itch with naltrexone, butorphanol, or other agents that act on the opiate pathway.

Phototherapy also has been used to treat chronic itch, including narrow-band UVB, psoralen plus UVA, or broadband UVB for itch associated with renal disease. “Phototherapy probably has an immunomodulatory effect that can benefit itch,” Dr. Berger said.

Several European itch centers incorporate a biopsychosocial approach to managing itch. As with chronic pain, focusing on the itch through education and support from nurses helps reduce the itch and decrease feelings of helplessness or inability to cope. Patients miss less work and report more low-itch days and improved quality of life. “So, there's a biopsychosocial aspect that probably will need to be addressed,” he said. Some U.S. centers have employed this approach in managing atopic dermatitis.

Dr. Berger has been a consultant for Prescription Solutions and received research funding from GlaxoSmithKline, Clinsys Clinical Research, Merz Pharmaceuticals, and Pharmanet, none of which is relevant to this topic, he said. All the medications for itching that he discussed are used off-label.

Skin Disease Education Foundation and this news organization are owned by Elsevier.

'In Europe, every patient with itch goes to a medical center for itch [and] is seen in a standard way.'

Source DR. BERGER

LAS VEGAS – Improved understanding of itching and best practices in management of the condition may lead to U.S. medical centers specializing in treating pruritus.

A recent gathering of experts convened by the National Institutes of Health (NIH) may be the first step in this direction, Dr. Timothy G. Berger said at the meeting.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) pulled together 50 physicians to discuss the topic of pruritus. One of a series of roundtable discussions held by NIAMS, this was the first to focus on itching. A summary of the meeting and a list of attendees has been posted on the NIAMS Web site, NIAMS media liaison Trish Reynolds said in an interview.

“These things are usually followed by calls for proposals,” said Dr. Berger of the University of California, San Francisco (UCSF), who did not attend the roundtable discussion. “The NIH is moving to a model of having major itch referral centers at several sites.”

Patients with itch would be referred to a center where their tissue samples and data could be stored and analyzed while they get expert treatment. “There will be direct translational benefits” from this approach, he predicted.

These centers would be patterned after two models – referral centers for pain, and European itch centers. The U.S. itch centers might first appear at UCSF; Washington University, St. Louis; and Harvard University, Boston, he said.

“In Europe, every patient with itch goes to a medical center for itch, is seen in a standard way, and has a defined database established about that patient. They now have tens of thousands of itch patients of various types logged into this database,” and data it provides are helping to build greater understanding of the problem of itching, Dr. Berger said.

One of the key insights into itching in recent years has been the understanding that chronic itch is like chronic pain. Chronic itch is thought to begin peripherally but then trigger anatomic changes in the CNS that make treatment much more difficult. “This suggests that we will have agents that will act both peripherally and centrally” to ease itching, he said. “We're now at the verge of being able to do something about itching.”

Chronic itching should be treated aggressively because once central sensitization occurs, it is very, very hard to manage, he advised. Chronic itching has a huge impact on quality of life, earning the same scores by patients as the reduced quality of life reported by patients with chronic renal failure on dialysis.

Once itch is chronic, the threshold for sensation of itch is reduced. “Even if you make their rash better, they still itch,” he said. Itch intensity increases with chronicity, producing more itch from the same rash. Even when the skin is clear, patients may have short bursts of spontaneous itch. In atopic dermatitis and perhaps some other forms of itchy lesions, patients may scratch themselves raw because inflammatory mediators of pain are perceived as itch.

“This whole system is miswired” in chronic itch, Dr. Berger said.

Perceived itch is a delicate interaction between the skin, nerves, and immune system, and treatments may target one or more of these pathways. The most common medication for chronic itch is second-generation antihistamines, in higher doses than used for the approved indication of allergic rhinitis. “These substances also block other inflammatory mediators that may be important for itch, so they may have benefit beyond what we know,” Dr. Berger said.

Neuroleptic medications for itch include amitriptyline or other tricyclic antidepressants, gabapentin, pregabalin, duloxetine, or thalidomide for prurigo nodularis. “These act primarily on the neural axis,” he said.

Central-acting agents include paroxetine, amitriptyline, doxepin, or mirtazapine. In a large European cohort, 6-9 months of treatment with paroxetine reduced chronic itch by 75% in 70% of patients. “It's now become one of our drugs to treat itch, and is the treatment of choice for itch in polycythemia vera,” he said.

Research has shown that patients who have liver disease can develop itch caused by abnormalities in opiate metabolism, leading some clinicians to treat chronic itch with naltrexone, butorphanol, or other agents that act on the opiate pathway.

Phototherapy also has been used to treat chronic itch, including narrow-band UVB, psoralen plus UVA, or broadband UVB for itch associated with renal disease. “Phototherapy probably has an immunomodulatory effect that can benefit itch,” Dr. Berger said.

Several European itch centers incorporate a biopsychosocial approach to managing itch. As with chronic pain, focusing on the itch through education and support from nurses helps reduce the itch and decrease feelings of helplessness or inability to cope. Patients miss less work and report more low-itch days and improved quality of life. “So, there's a biopsychosocial aspect that probably will need to be addressed,” he said. Some U.S. centers have employed this approach in managing atopic dermatitis.

Dr. Berger has been a consultant for Prescription Solutions and received research funding from GlaxoSmithKline, Clinsys Clinical Research, Merz Pharmaceuticals, and Pharmanet, none of which is relevant to this topic, he said. All the medications for itching that he discussed are used off-label.

Skin Disease Education Foundation and this news organization are owned by Elsevier.

'In Europe, every patient with itch goes to a medical center for itch [and] is seen in a standard way.'

Source DR. BERGER

LAS VEGAS – Improved understanding of itching and best practices in management of the condition may lead to U.S. medical centers specializing in treating pruritus.

A recent gathering of experts convened by the National Institutes of Health (NIH) may be the first step in this direction, Dr. Timothy G. Berger said at the meeting.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) pulled together 50 physicians to discuss the topic of pruritus. One of a series of roundtable discussions held by NIAMS, this was the first to focus on itching. A summary of the meeting and a list of attendees has been posted on the NIAMS Web site, NIAMS media liaison Trish Reynolds said in an interview.

“These things are usually followed by calls for proposals,” said Dr. Berger of the University of California, San Francisco (UCSF), who did not attend the roundtable discussion. “The NIH is moving to a model of having major itch referral centers at several sites.”

Patients with itch would be referred to a center where their tissue samples and data could be stored and analyzed while they get expert treatment. “There will be direct translational benefits” from this approach, he predicted.

These centers would be patterned after two models – referral centers for pain, and European itch centers. The U.S. itch centers might first appear at UCSF; Washington University, St. Louis; and Harvard University, Boston, he said.

“In Europe, every patient with itch goes to a medical center for itch, is seen in a standard way, and has a defined database established about that patient. They now have tens of thousands of itch patients of various types logged into this database,” and data it provides are helping to build greater understanding of the problem of itching, Dr. Berger said.

One of the key insights into itching in recent years has been the understanding that chronic itch is like chronic pain. Chronic itch is thought to begin peripherally but then trigger anatomic changes in the CNS that make treatment much more difficult. “This suggests that we will have agents that will act both peripherally and centrally” to ease itching, he said. “We're now at the verge of being able to do something about itching.”

Chronic itching should be treated aggressively because once central sensitization occurs, it is very, very hard to manage, he advised. Chronic itching has a huge impact on quality of life, earning the same scores by patients as the reduced quality of life reported by patients with chronic renal failure on dialysis.

Once itch is chronic, the threshold for sensation of itch is reduced. “Even if you make their rash better, they still itch,” he said. Itch intensity increases with chronicity, producing more itch from the same rash. Even when the skin is clear, patients may have short bursts of spontaneous itch. In atopic dermatitis and perhaps some other forms of itchy lesions, patients may scratch themselves raw because inflammatory mediators of pain are perceived as itch.

“This whole system is miswired” in chronic itch, Dr. Berger said.

Perceived itch is a delicate interaction between the skin, nerves, and immune system, and treatments may target one or more of these pathways. The most common medication for chronic itch is second-generation antihistamines, in higher doses than used for the approved indication of allergic rhinitis. “These substances also block other inflammatory mediators that may be important for itch, so they may have benefit beyond what we know,” Dr. Berger said.

Neuroleptic medications for itch include amitriptyline or other tricyclic antidepressants, gabapentin, pregabalin, duloxetine, or thalidomide for prurigo nodularis. “These act primarily on the neural axis,” he said.

Central-acting agents include paroxetine, amitriptyline, doxepin, or mirtazapine. In a large European cohort, 6-9 months of treatment with paroxetine reduced chronic itch by 75% in 70% of patients. “It's now become one of our drugs to treat itch, and is the treatment of choice for itch in polycythemia vera,” he said.

Research has shown that patients who have liver disease can develop itch caused by abnormalities in opiate metabolism, leading some clinicians to treat chronic itch with naltrexone, butorphanol, or other agents that act on the opiate pathway.

Phototherapy also has been used to treat chronic itch, including narrow-band UVB, psoralen plus UVA, or broadband UVB for itch associated with renal disease. “Phototherapy probably has an immunomodulatory effect that can benefit itch,” Dr. Berger said.

Several European itch centers incorporate a biopsychosocial approach to managing itch. As with chronic pain, focusing on the itch through education and support from nurses helps reduce the itch and decrease feelings of helplessness or inability to cope. Patients miss less work and report more low-itch days and improved quality of life. “So, there's a biopsychosocial aspect that probably will need to be addressed,” he said. Some U.S. centers have employed this approach in managing atopic dermatitis.

Dr. Berger has been a consultant for Prescription Solutions and received research funding from GlaxoSmithKline, Clinsys Clinical Research, Merz Pharmaceuticals, and Pharmanet, none of which is relevant to this topic, he said. All the medications for itching that he discussed are used off-label.

Skin Disease Education Foundation and this news organization are owned by Elsevier.

'In Europe, every patient with itch goes to a medical center for itch [and] is seen in a standard way.'

Source DR. BERGER

Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo, in the most comprehensive meta-analysis of the subject so far.

The relative risks with any individual NSAID, compared with placebo, often were double, triple, or quadruple the risk with placebo, the study found.

The absolute numbers of MIs and other cardiovascular outcomes were small, but the network meta-analysis design of the study “provides the best available evidence on the safety of this class of drugs,” Dr. Sven Trelle and his associates reported.

Contrary to some previous reports, the current study also found no suggestion that this increased cardiovascular risk is specific to cyclo-oxygenase-2 (COX-2) inhibitors.

Therefore the use of all NSAIDs – and the over-the-counter availability of some of them – should be reconsidered, Dr. Trelle stated in a report published online by BMJ (Jan. 11, 2011;342:c7086 [doi/10.1136/bmj.c7086]).

Dr. Trelle of the University of Bern, Switzerland, acknowledged that therapeutic options for chronic musculoskeletal pain are limited, but cautioned that “cardiovascular risk needs to be taken into account when prescribing” any NSAID.

The meta-analysis included any large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo. Data were available for naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, and lumiracoxib. The risk for a cardiovascular event had to increase by more than 30% to be considered significant.

Overall, naproxen appeared to be the least harmful NSAID in terms of cardiovascular outcomes. Risks were greatest with ibuprofen, diclofenac, etoricoxib, and lumiracoxib.

Four NSAIDs were associated with significantly increased risk for myocardial infarction (the primary outcome in the current analysis) in 29 of the trials that reported 554 MIs.

The relative risk for MI doubled with rofecoxib or lumiracoxib, was 35% higher with celecoxib, and was 61% higher with ibuprofen, compared with placebo. Evidence was lacking for increased MI risk with the other three NSAIDs.

Among secondary outcomes, stroke risk increased with all NSAIDs in 26 trials that reported 377 strokes. The increased risk was significant with four of the drugs, roughly doubling with naproxen and tripling with ibuprofen, diclofenac, etoricoxib, or lumiracoxib, compared with placebo.

Twenty-six trials reported 312 deaths from cardiovascular disease, accounting for 46% of all deaths in the trials. All NSAIDs except naproxen were associated with higher risk for cardiovascular death, which increased by 58% with rofecoxib, roughly doubled with ibuprofen, celecoxib, or lumiracoxib, and increased approximately fourfold with diclofenac or etoricoxib, compared with placebo.

All the NSAIDs were associated with increased risk for death from any cause, compared with placebo, and the increase was significant for all except naproxen. There were 676 deaths from any cause in 28 trials, and the risk of death roughly doubled with any of the other six NSAIDs.

Looking at a composite of nonfatal MI, nonfatal stroke, or cardiovascular death in 30 trials that reported 1,091 composite events, the risk increased with all the NSAIDs and increased significantly with all but naproxen.

The odds for the composite outcome increased 43% with celecoxib, 44% with rofecoxib, 53% with etoricoxib, 60% with diclofenac, and more than doubled with lumiracoxib or ibuprofen.

An estimated 5% of all visits to U.S. physicians are related to prescribing NSAIDs, which are considered the cornerstone for managing the pain of osteoarthritis and other painful conditions.

Rofecoxib, a COX-2 inhibitor, was withdrawn from the market in 2004 after a randomized, placebo-controlled trial found its use was associated with increased cardiovascular risk.

The Food and Drug Administration has since denied approval of etoricoxib because of an inadequate risk-benefit profile.

Debate about the safety of NSAIDs has continued despite several conventional meta-analyses that could not integrate all available randomized evidence. That's the strength of the network meta-analysis, which allowed a unified analysis of all the large trials while respecting randomization, according to Dr. Trelle.

Because of the low absolute numbers of events, more than 100,000 patients would need to be followed in a trial for at least a year to evaluate the cardiovascular safety of an NSAID, which is unlikely to happen, he added.

The Swiss National Science Foundation funded the study. The investigators reported having no conflicts of interest.

Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo, in the most comprehensive meta-analysis of the subject so far.

The relative risks with any individual NSAID, compared with placebo, often were double, triple, or quadruple the risk with placebo, the study found.

The absolute numbers of MIs and other cardiovascular outcomes were small, but the network meta-analysis design of the study “provides the best available evidence on the safety of this class of drugs,” Dr. Sven Trelle and his associates reported.

Contrary to some previous reports, the current study also found no suggestion that this increased cardiovascular risk is specific to cyclo-oxygenase-2 (COX-2) inhibitors.

Therefore the use of all NSAIDs – and the over-the-counter availability of some of them – should be reconsidered, Dr. Trelle stated in a report published online by BMJ (Jan. 11, 2011;342:c7086 [doi/10.1136/bmj.c7086]).

Dr. Trelle of the University of Bern, Switzerland, acknowledged that therapeutic options for chronic musculoskeletal pain are limited, but cautioned that “cardiovascular risk needs to be taken into account when prescribing” any NSAID.

The meta-analysis included any large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo. Data were available for naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, and lumiracoxib. The risk for a cardiovascular event had to increase by more than 30% to be considered significant.

Overall, naproxen appeared to be the least harmful NSAID in terms of cardiovascular outcomes. Risks were greatest with ibuprofen, diclofenac, etoricoxib, and lumiracoxib.

Four NSAIDs were associated with significantly increased risk for myocardial infarction (the primary outcome in the current analysis) in 29 of the trials that reported 554 MIs.

The relative risk for MI doubled with rofecoxib or lumiracoxib, was 35% higher with celecoxib, and was 61% higher with ibuprofen, compared with placebo. Evidence was lacking for increased MI risk with the other three NSAIDs.

Among secondary outcomes, stroke risk increased with all NSAIDs in 26 trials that reported 377 strokes. The increased risk was significant with four of the drugs, roughly doubling with naproxen and tripling with ibuprofen, diclofenac, etoricoxib, or lumiracoxib, compared with placebo.

Twenty-six trials reported 312 deaths from cardiovascular disease, accounting for 46% of all deaths in the trials. All NSAIDs except naproxen were associated with higher risk for cardiovascular death, which increased by 58% with rofecoxib, roughly doubled with ibuprofen, celecoxib, or lumiracoxib, and increased approximately fourfold with diclofenac or etoricoxib, compared with placebo.

All the NSAIDs were associated with increased risk for death from any cause, compared with placebo, and the increase was significant for all except naproxen. There were 676 deaths from any cause in 28 trials, and the risk of death roughly doubled with any of the other six NSAIDs.

Looking at a composite of nonfatal MI, nonfatal stroke, or cardiovascular death in 30 trials that reported 1,091 composite events, the risk increased with all the NSAIDs and increased significantly with all but naproxen.

The odds for the composite outcome increased 43% with celecoxib, 44% with rofecoxib, 53% with etoricoxib, 60% with diclofenac, and more than doubled with lumiracoxib or ibuprofen.

An estimated 5% of all visits to U.S. physicians are related to prescribing NSAIDs, which are considered the cornerstone for managing the pain of osteoarthritis and other painful conditions.

Rofecoxib, a COX-2 inhibitor, was withdrawn from the market in 2004 after a randomized, placebo-controlled trial found its use was associated with increased cardiovascular risk.

The Food and Drug Administration has since denied approval of etoricoxib because of an inadequate risk-benefit profile.

Debate about the safety of NSAIDs has continued despite several conventional meta-analyses that could not integrate all available randomized evidence. That's the strength of the network meta-analysis, which allowed a unified analysis of all the large trials while respecting randomization, according to Dr. Trelle.

Because of the low absolute numbers of events, more than 100,000 patients would need to be followed in a trial for at least a year to evaluate the cardiovascular safety of an NSAID, which is unlikely to happen, he added.

The Swiss National Science Foundation funded the study. The investigators reported having no conflicts of interest.

Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo, in the most comprehensive meta-analysis of the subject so far.

The relative risks with any individual NSAID, compared with placebo, often were double, triple, or quadruple the risk with placebo, the study found.

The absolute numbers of MIs and other cardiovascular outcomes were small, but the network meta-analysis design of the study “provides the best available evidence on the safety of this class of drugs,” Dr. Sven Trelle and his associates reported.

Contrary to some previous reports, the current study also found no suggestion that this increased cardiovascular risk is specific to cyclo-oxygenase-2 (COX-2) inhibitors.

Therefore the use of all NSAIDs – and the over-the-counter availability of some of them – should be reconsidered, Dr. Trelle stated in a report published online by BMJ (Jan. 11, 2011;342:c7086 [doi/10.1136/bmj.c7086]).

Dr. Trelle of the University of Bern, Switzerland, acknowledged that therapeutic options for chronic musculoskeletal pain are limited, but cautioned that “cardiovascular risk needs to be taken into account when prescribing” any NSAID.

The meta-analysis included any large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo. Data were available for naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, and lumiracoxib. The risk for a cardiovascular event had to increase by more than 30% to be considered significant.

Overall, naproxen appeared to be the least harmful NSAID in terms of cardiovascular outcomes. Risks were greatest with ibuprofen, diclofenac, etoricoxib, and lumiracoxib.

Four NSAIDs were associated with significantly increased risk for myocardial infarction (the primary outcome in the current analysis) in 29 of the trials that reported 554 MIs.

The relative risk for MI doubled with rofecoxib or lumiracoxib, was 35% higher with celecoxib, and was 61% higher with ibuprofen, compared with placebo. Evidence was lacking for increased MI risk with the other three NSAIDs.

Among secondary outcomes, stroke risk increased with all NSAIDs in 26 trials that reported 377 strokes. The increased risk was significant with four of the drugs, roughly doubling with naproxen and tripling with ibuprofen, diclofenac, etoricoxib, or lumiracoxib, compared with placebo.

Twenty-six trials reported 312 deaths from cardiovascular disease, accounting for 46% of all deaths in the trials. All NSAIDs except naproxen were associated with higher risk for cardiovascular death, which increased by 58% with rofecoxib, roughly doubled with ibuprofen, celecoxib, or lumiracoxib, and increased approximately fourfold with diclofenac or etoricoxib, compared with placebo.

All the NSAIDs were associated with increased risk for death from any cause, compared with placebo, and the increase was significant for all except naproxen. There were 676 deaths from any cause in 28 trials, and the risk of death roughly doubled with any of the other six NSAIDs.

Looking at a composite of nonfatal MI, nonfatal stroke, or cardiovascular death in 30 trials that reported 1,091 composite events, the risk increased with all the NSAIDs and increased significantly with all but naproxen.

The odds for the composite outcome increased 43% with celecoxib, 44% with rofecoxib, 53% with etoricoxib, 60% with diclofenac, and more than doubled with lumiracoxib or ibuprofen.

An estimated 5% of all visits to U.S. physicians are related to prescribing NSAIDs, which are considered the cornerstone for managing the pain of osteoarthritis and other painful conditions.

Rofecoxib, a COX-2 inhibitor, was withdrawn from the market in 2004 after a randomized, placebo-controlled trial found its use was associated with increased cardiovascular risk.

The Food and Drug Administration has since denied approval of etoricoxib because of an inadequate risk-benefit profile.

Debate about the safety of NSAIDs has continued despite several conventional meta-analyses that could not integrate all available randomized evidence. That's the strength of the network meta-analysis, which allowed a unified analysis of all the large trials while respecting randomization, according to Dr. Trelle.

Because of the low absolute numbers of events, more than 100,000 patients would need to be followed in a trial for at least a year to evaluate the cardiovascular safety of an NSAID, which is unlikely to happen, he added.

The Swiss National Science Foundation funded the study. The investigators reported having no conflicts of interest.

New federal recommendations on screening for osteoporosis provide more detail on when to screen women younger than age 65 years and – for the first time – point to a lack of data for screening decisions in men.

The U.S. Preventive Services Task Force updated its 2002 recommendations on osteoporosis screening to call for routine screening in all women aged 65 years or older and in any younger women whose fracture risk is equal to or greater than that of a 65-year-old white woman who has no additional risk factors (equivalent to a 9.3% or greater risk of fracture within 10 years). Previously, women younger than 65 years would be screened if they were at least 60 years old with risk factors for fracture.

The new recommendations were posted on the USPSTF Web site and published online by the Annals of Internal Medicine.

For the first time, the USPSTF evaluated the evidence for osteoporosis screening in men and found insufficient evidence to form any recommendation, Dr. Ned Colange, chair of the USPSTF, said in an interview. There's not enough evidence to recommend osteoporosis screening or treatment in men with no prior osteoporotic fractures, and “there's certainly not enough evidence to say, 'Don't' do it,” he said.

“While there's not a call to action, that's an important call for research,” added Dr. Colange, who is president and CEO of the Colorado Trust Foundation, Denver.

In women, the recommendations do not say to stop osteoporosis screening at any specific age, because the risk of fractures continues to increase with advancing age, and the minimal potential harms of treatment remain small.

Clinicians who are considering treating older patients with significant morbidity should take into account data showing that the benefits of osteoporosis treatment emerge 18-24 months after starting treatment.

To predict an individual's risk for osteoporotic fracture, the USPSTF used the online FRAX tool, developed by the World Health Organization and the National Osteoporosis Foundation.

“The nice thing about the FRAX calculator is, the patient herself can determine that risk. It's available online. It uses measures that the woman should know,” Dr. Colange said. “The clinician can do it, but the patient herself could do it as well.”

The FRAX tool estimates 10-year fracture risk based on easily obtained information such as age, body mass index (BMI), parental fracture history, and tobacco or alcohol use. It asks about results of dual-energy x-ray absorptiometry scans but does not require this information to calculate fracture risk.

Younger women can reach the new threshold for screening because of various risk factors. For example, a white woman would qualify for screening if she is 50 years old, smokes, drinks alcohol daily, has a BMI less than 21, and has a parental history of fracture. A 55-year-old white woman would need only a parental fracture history to warrant osteoporosis screening. A 60-year-old white woman who smokes and drinks alcohol daily would fit the 10-year risk profile for screening (Ann. Intern. Med. 2011 Jan. 18. [Epub ahead of print]).

White women are more likely than women of other races or ethnic backgrounds to develop osteoporosis and fractures. Although there are fewer data on nonwhite women, the USPSTF recommended screening all women at age 65 years because the consequences of failing to identify and treat low bone-mineral density are considerable, the potential risks of treatment are small, and it's unclear if there's a better strategy for screening nonwhite women.

There are not enough data to recommend when to rescreen women without osteoporosis on their initial screen, the USPSTF stated, but at least a 2-year interval would be needed to assess a change in bone density and perhaps longer for better prediction of fracture risk.

The new recommendations are based on a 2010 review of studies published since 2002 by a team at the University of Oregon Health and Science University's Evidence-Based Practice Center in Portland.

An estimated 12 million Americans aged 50 years or older will have osteoporosis in 2012. Among postmenopausal women, 15% will develop a hip fracture during their lifetime, 25% will develop a vertebral deformity, and osteoporotic fractures of any kind will affect 50%.

In a new effort at transparency, the USPSTF first published a draft of the new recommendations online in the summer of 2010 and invited public comment.

They received more than 50 comments from individuals, professional organizations, advocates, and pharmaceutical companies, Dr. Colange said, which led the USPSTF to clarify its approach to fracture risk assessment in the final version.

The USPSTF “has been criticized in the past for not being more transparent,” Dr. Colange explained. “We're an independent panel, and everyone is a volunteer. It was never our intent to do stuff in secret. It was our intent to make sure that we deliberated and evaluated evidence free from the impact of advocacy, politics, and special interests. I think that was translated to a sense of 'outside the public eye.'”

The USPSTF plans to use the new public-comment process for future statements. “Transparency is always good,” he said.

Dr. Colange said he has no pertinent conflicts of interest.

New federal recommendations on screening for osteoporosis provide more detail on when to screen women younger than age 65 years and – for the first time – point to a lack of data for screening decisions in men.

The U.S. Preventive Services Task Force updated its 2002 recommendations on osteoporosis screening to call for routine screening in all women aged 65 years or older and in any younger women whose fracture risk is equal to or greater than that of a 65-year-old white woman who has no additional risk factors (equivalent to a 9.3% or greater risk of fracture within 10 years). Previously, women younger than 65 years would be screened if they were at least 60 years old with risk factors for fracture.

The new recommendations were posted on the USPSTF Web site and published online by the Annals of Internal Medicine.

For the first time, the USPSTF evaluated the evidence for osteoporosis screening in men and found insufficient evidence to form any recommendation, Dr. Ned Colange, chair of the USPSTF, said in an interview. There's not enough evidence to recommend osteoporosis screening or treatment in men with no prior osteoporotic fractures, and “there's certainly not enough evidence to say, 'Don't' do it,” he said.

“While there's not a call to action, that's an important call for research,” added Dr. Colange, who is president and CEO of the Colorado Trust Foundation, Denver.

In women, the recommendations do not say to stop osteoporosis screening at any specific age, because the risk of fractures continues to increase with advancing age, and the minimal potential harms of treatment remain small.

Clinicians who are considering treating older patients with significant morbidity should take into account data showing that the benefits of osteoporosis treatment emerge 18-24 months after starting treatment.

To predict an individual's risk for osteoporotic fracture, the USPSTF used the online FRAX tool, developed by the World Health Organization and the National Osteoporosis Foundation.

“The nice thing about the FRAX calculator is, the patient herself can determine that risk. It's available online. It uses measures that the woman should know,” Dr. Colange said. “The clinician can do it, but the patient herself could do it as well.”

The FRAX tool estimates 10-year fracture risk based on easily obtained information such as age, body mass index (BMI), parental fracture history, and tobacco or alcohol use. It asks about results of dual-energy x-ray absorptiometry scans but does not require this information to calculate fracture risk.

Younger women can reach the new threshold for screening because of various risk factors. For example, a white woman would qualify for screening if she is 50 years old, smokes, drinks alcohol daily, has a BMI less than 21, and has a parental history of fracture. A 55-year-old white woman would need only a parental fracture history to warrant osteoporosis screening. A 60-year-old white woman who smokes and drinks alcohol daily would fit the 10-year risk profile for screening (Ann. Intern. Med. 2011 Jan. 18. [Epub ahead of print]).

White women are more likely than women of other races or ethnic backgrounds to develop osteoporosis and fractures. Although there are fewer data on nonwhite women, the USPSTF recommended screening all women at age 65 years because the consequences of failing to identify and treat low bone-mineral density are considerable, the potential risks of treatment are small, and it's unclear if there's a better strategy for screening nonwhite women.

There are not enough data to recommend when to rescreen women without osteoporosis on their initial screen, the USPSTF stated, but at least a 2-year interval would be needed to assess a change in bone density and perhaps longer for better prediction of fracture risk.

The new recommendations are based on a 2010 review of studies published since 2002 by a team at the University of Oregon Health and Science University's Evidence-Based Practice Center in Portland.

An estimated 12 million Americans aged 50 years or older will have osteoporosis in 2012. Among postmenopausal women, 15% will develop a hip fracture during their lifetime, 25% will develop a vertebral deformity, and osteoporotic fractures of any kind will affect 50%.

In a new effort at transparency, the USPSTF first published a draft of the new recommendations online in the summer of 2010 and invited public comment.

They received more than 50 comments from individuals, professional organizations, advocates, and pharmaceutical companies, Dr. Colange said, which led the USPSTF to clarify its approach to fracture risk assessment in the final version.

The USPSTF “has been criticized in the past for not being more transparent,” Dr. Colange explained. “We're an independent panel, and everyone is a volunteer. It was never our intent to do stuff in secret. It was our intent to make sure that we deliberated and evaluated evidence free from the impact of advocacy, politics, and special interests. I think that was translated to a sense of 'outside the public eye.'”

The USPSTF plans to use the new public-comment process for future statements. “Transparency is always good,” he said.

Dr. Colange said he has no pertinent conflicts of interest.

New federal recommendations on screening for osteoporosis provide more detail on when to screen women younger than age 65 years and – for the first time – point to a lack of data for screening decisions in men.

The U.S. Preventive Services Task Force updated its 2002 recommendations on osteoporosis screening to call for routine screening in all women aged 65 years or older and in any younger women whose fracture risk is equal to or greater than that of a 65-year-old white woman who has no additional risk factors (equivalent to a 9.3% or greater risk of fracture within 10 years). Previously, women younger than 65 years would be screened if they were at least 60 years old with risk factors for fracture.

The new recommendations were posted on the USPSTF Web site and published online by the Annals of Internal Medicine.

For the first time, the USPSTF evaluated the evidence for osteoporosis screening in men and found insufficient evidence to form any recommendation, Dr. Ned Colange, chair of the USPSTF, said in an interview. There's not enough evidence to recommend osteoporosis screening or treatment in men with no prior osteoporotic fractures, and “there's certainly not enough evidence to say, 'Don't' do it,” he said.

“While there's not a call to action, that's an important call for research,” added Dr. Colange, who is president and CEO of the Colorado Trust Foundation, Denver.

In women, the recommendations do not say to stop osteoporosis screening at any specific age, because the risk of fractures continues to increase with advancing age, and the minimal potential harms of treatment remain small.

Clinicians who are considering treating older patients with significant morbidity should take into account data showing that the benefits of osteoporosis treatment emerge 18-24 months after starting treatment.

To predict an individual's risk for osteoporotic fracture, the USPSTF used the online FRAX tool, developed by the World Health Organization and the National Osteoporosis Foundation.

“The nice thing about the FRAX calculator is, the patient herself can determine that risk. It's available online. It uses measures that the woman should know,” Dr. Colange said. “The clinician can do it, but the patient herself could do it as well.”

The FRAX tool estimates 10-year fracture risk based on easily obtained information such as age, body mass index (BMI), parental fracture history, and tobacco or alcohol use. It asks about results of dual-energy x-ray absorptiometry scans but does not require this information to calculate fracture risk.

Younger women can reach the new threshold for screening because of various risk factors. For example, a white woman would qualify for screening if she is 50 years old, smokes, drinks alcohol daily, has a BMI less than 21, and has a parental history of fracture. A 55-year-old white woman would need only a parental fracture history to warrant osteoporosis screening. A 60-year-old white woman who smokes and drinks alcohol daily would fit the 10-year risk profile for screening (Ann. Intern. Med. 2011 Jan. 18. [Epub ahead of print]).

White women are more likely than women of other races or ethnic backgrounds to develop osteoporosis and fractures. Although there are fewer data on nonwhite women, the USPSTF recommended screening all women at age 65 years because the consequences of failing to identify and treat low bone-mineral density are considerable, the potential risks of treatment are small, and it's unclear if there's a better strategy for screening nonwhite women.

There are not enough data to recommend when to rescreen women without osteoporosis on their initial screen, the USPSTF stated, but at least a 2-year interval would be needed to assess a change in bone density and perhaps longer for better prediction of fracture risk.

The new recommendations are based on a 2010 review of studies published since 2002 by a team at the University of Oregon Health and Science University's Evidence-Based Practice Center in Portland.

An estimated 12 million Americans aged 50 years or older will have osteoporosis in 2012. Among postmenopausal women, 15% will develop a hip fracture during their lifetime, 25% will develop a vertebral deformity, and osteoporotic fractures of any kind will affect 50%.

In a new effort at transparency, the USPSTF first published a draft of the new recommendations online in the summer of 2010 and invited public comment.

They received more than 50 comments from individuals, professional organizations, advocates, and pharmaceutical companies, Dr. Colange said, which led the USPSTF to clarify its approach to fracture risk assessment in the final version.

The USPSTF “has been criticized in the past for not being more transparent,” Dr. Colange explained. “We're an independent panel, and everyone is a volunteer. It was never our intent to do stuff in secret. It was our intent to make sure that we deliberated and evaluated evidence free from the impact of advocacy, politics, and special interests. I think that was translated to a sense of 'outside the public eye.'”

The USPSTF plans to use the new public-comment process for future statements. “Transparency is always good,” he said.

Dr. Colange said he has no pertinent conflicts of interest.

LAS VEGAS – Increased risk for major cardiovascular events may be a "class effect" associated with two monoclonal antibody therapies for psoriasis, Dr. Craig Leonardi said.

"I used to give them a pass on this, but no more. I'm going to point out a few things that bother me," he said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Ustekinumab, which is approved to treat adults with moderate to severe plaque psoriasis, and the investigational psoriasis drug briakinumab inhibit interleukin 12 (IL-12) and IL-23 proteins linked to inflammation. Conventional thought holds that reducing systemic inflammation should decrease cardiovascular risk, but ustekinumab and briakinumab have been associated with an increase in major cardiovascular events in clinical trials, said Dr. Leonardi, a dermatologist and psoriasis specialist at St. Louis University.

(Abbott Laboratories pulled briakinumab from the drug approval process in the United States and Europe in a financial filing on Jan. 14.)

He recently conducted a meta-analysis summarizing major cardiovascular events during the placebo-controlled portions of 19 trials encompassing all the biologic therapies for psoriasis. Only one patient on placebo developed a major cardiovascular event in a study of etanercept. Five patients on ustekinumab, five on briakinumab, and one on adalimumab developed major cardiovascular events.

In a separate look at Phase III trials data on ustekinumab, adverse events included chest pain in one patient on placebo, a case of angina, and a case of stroke in patients on low-dose therapy (45 mg). On high-dose therapy (90 mg) one patient developed congestive cardiomyopathy and died and another required a coronary artery bypass graft, he noted.

"I think there's a bit of an imbalance when I look at these data" in major cardiovascular events, he said.

In data on 3,117 patients followed for 3 years or less, the risk for major cardiovascular events (MI, stroke, or death from cardiovascular causes) seemed to be higher on ustekinumab during the initial 12-week placebo-controlled portions of the study but the risk leveled out between groups over time, Dr. Leonardi said.

During the controlled period, the incidence of major cardiovascular events was 0 per 100 patient-years in the placebo group, 0.98/100 patient-years on low-dose ustekinumab, and 1.47/100 patient-years on high-dose ustekinumab. Over the 3-year period, the incidence was 0.55, 0.41, and 0.35 per 100 patient-years, respectively.

Even in Phase II trial data on ustekinumab there was a potential "signal" of increased risk for major cardiovascular events, Dr. Leonardi added. Looking at data from all trials of ustekinumab for any indication (not just psoriasis), there's a "flurry" of major cardiovascular events early in treatment that then settles down and becomes comparable to the placebo group over time.

"The statisticians will say that there's no statistically significant difference between the treated versus the placebo" in major cardiovascular events, "but I don't think we have to be a rocket scientist to see that there’s something very different going on" between groups, Dr. Leonardi said.

Safety data from the placebo-controlled periods in phase III data on briakinumab suggest even greater problems. "The news here, quite frankly, is not good," he said.

There were three MIs, one cardiac arrest, and a stroke in 981 patients on briakinumab, compared with none in 484 patients on placebo. In addition, five patients on briakinumab and one on placebo developed serious infections requiring hospitalization and IV antibiotics. Six patients on briakinumab and none on placebo developed malignancies, all of them squamous cell carcinomas of the skin, lung, or nasopharynx.

"Cancers usually take months or years to show up, and yet these showed up in the first 12 weeks" on treatment," he noted.

The combination of increased risks for major cardiovascular events, malignancies, and infections with briakinumab is "unprecedented," he said. "We should pay close attention to this data."

Both drugs can boast "impressive" efficacy in treating plaque psoriasis, but the potential risks need to be carefully considered, Dr. Leonardi said.

He recommends considering all options when selecting a biologic treatment for psoriasis, even if patients request the treatment they only have to get every 3 months. Remember that patients with psoriasis typically have multiple cardiac risk factors. If ustekinumab is used, start with a low dose regardless of the patient’s weight, Dr. Leonardi advised.

"Consider adding low-dose aspirin, 81 mg per day," he added. "That's what I’m doing."

Analyses underway by the Food and Drug Administration and the drug companies should provide further insights into the potential risks and benefits of these drugs.

"Remember that all new drugs are new," Dr. Leonardi cautioned. "We don't know everything we need to know about new drugs, especially when there's a new mechanism of action."

He speculated that the monoclonal antibody therapies increase major cardiovascular events by increasing delivery of IL-12 and IL-23 to atherosclerotic plaques, or perhaps the p40 subunits of IL-12 and IL-23 form dimers that become bioactive. Or, some unknown biologic activity could be at play.

SDEF and this news organization are owned by Elsevier. Dr. Leonardi declared having potential conflicts of interest with Abbott and Centocor, which manufacture briakinumab and ustekinumab, and with Abgenix, Allergan, Alza, Amgen, Biogen-IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, Medimmune, Miravant, Pfizer, Schering Plough, Serono, Synta, Wyeth, and Xoma.

LAS VEGAS – Increased risk for major cardiovascular events may be a "class effect" associated with two monoclonal antibody therapies for psoriasis, Dr. Craig Leonardi said.

"I used to give them a pass on this, but no more. I'm going to point out a few things that bother me," he said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Ustekinumab, which is approved to treat adults with moderate to severe plaque psoriasis, and the investigational psoriasis drug briakinumab inhibit interleukin 12 (IL-12) and IL-23 proteins linked to inflammation. Conventional thought holds that reducing systemic inflammation should decrease cardiovascular risk, but ustekinumab and briakinumab have been associated with an increase in major cardiovascular events in clinical trials, said Dr. Leonardi, a dermatologist and psoriasis specialist at St. Louis University.

(Abbott Laboratories pulled briakinumab from the drug approval process in the United States and Europe in a financial filing on Jan. 14.)

He recently conducted a meta-analysis summarizing major cardiovascular events during the placebo-controlled portions of 19 trials encompassing all the biologic therapies for psoriasis. Only one patient on placebo developed a major cardiovascular event in a study of etanercept. Five patients on ustekinumab, five on briakinumab, and one on adalimumab developed major cardiovascular events.

In a separate look at Phase III trials data on ustekinumab, adverse events included chest pain in one patient on placebo, a case of angina, and a case of stroke in patients on low-dose therapy (45 mg). On high-dose therapy (90 mg) one patient developed congestive cardiomyopathy and died and another required a coronary artery bypass graft, he noted.

"I think there's a bit of an imbalance when I look at these data" in major cardiovascular events, he said.

In data on 3,117 patients followed for 3 years or less, the risk for major cardiovascular events (MI, stroke, or death from cardiovascular causes) seemed to be higher on ustekinumab during the initial 12-week placebo-controlled portions of the study but the risk leveled out between groups over time, Dr. Leonardi said.

During the controlled period, the incidence of major cardiovascular events was 0 per 100 patient-years in the placebo group, 0.98/100 patient-years on low-dose ustekinumab, and 1.47/100 patient-years on high-dose ustekinumab. Over the 3-year period, the incidence was 0.55, 0.41, and 0.35 per 100 patient-years, respectively.

Even in Phase II trial data on ustekinumab there was a potential "signal" of increased risk for major cardiovascular events, Dr. Leonardi added. Looking at data from all trials of ustekinumab for any indication (not just psoriasis), there's a "flurry" of major cardiovascular events early in treatment that then settles down and becomes comparable to the placebo group over time.

"The statisticians will say that there's no statistically significant difference between the treated versus the placebo" in major cardiovascular events, "but I don't think we have to be a rocket scientist to see that there’s something very different going on" between groups, Dr. Leonardi said.

Safety data from the placebo-controlled periods in phase III data on briakinumab suggest even greater problems. "The news here, quite frankly, is not good," he said.

There were three MIs, one cardiac arrest, and a stroke in 981 patients on briakinumab, compared with none in 484 patients on placebo. In addition, five patients on briakinumab and one on placebo developed serious infections requiring hospitalization and IV antibiotics. Six patients on briakinumab and none on placebo developed malignancies, all of them squamous cell carcinomas of the skin, lung, or nasopharynx.

"Cancers usually take months or years to show up, and yet these showed up in the first 12 weeks" on treatment," he noted.

The combination of increased risks for major cardiovascular events, malignancies, and infections with briakinumab is "unprecedented," he said. "We should pay close attention to this data."

Both drugs can boast "impressive" efficacy in treating plaque psoriasis, but the potential risks need to be carefully considered, Dr. Leonardi said.

He recommends considering all options when selecting a biologic treatment for psoriasis, even if patients request the treatment they only have to get every 3 months. Remember that patients with psoriasis typically have multiple cardiac risk factors. If ustekinumab is used, start with a low dose regardless of the patient’s weight, Dr. Leonardi advised.

"Consider adding low-dose aspirin, 81 mg per day," he added. "That's what I’m doing."

Analyses underway by the Food and Drug Administration and the drug companies should provide further insights into the potential risks and benefits of these drugs.

"Remember that all new drugs are new," Dr. Leonardi cautioned. "We don't know everything we need to know about new drugs, especially when there's a new mechanism of action."

He speculated that the monoclonal antibody therapies increase major cardiovascular events by increasing delivery of IL-12 and IL-23 to atherosclerotic plaques, or perhaps the p40 subunits of IL-12 and IL-23 form dimers that become bioactive. Or, some unknown biologic activity could be at play.

SDEF and this news organization are owned by Elsevier. Dr. Leonardi declared having potential conflicts of interest with Abbott and Centocor, which manufacture briakinumab and ustekinumab, and with Abgenix, Allergan, Alza, Amgen, Biogen-IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, Medimmune, Miravant, Pfizer, Schering Plough, Serono, Synta, Wyeth, and Xoma.

LAS VEGAS – Increased risk for major cardiovascular events may be a "class effect" associated with two monoclonal antibody therapies for psoriasis, Dr. Craig Leonardi said.

"I used to give them a pass on this, but no more. I'm going to point out a few things that bother me," he said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Ustekinumab, which is approved to treat adults with moderate to severe plaque psoriasis, and the investigational psoriasis drug briakinumab inhibit interleukin 12 (IL-12) and IL-23 proteins linked to inflammation. Conventional thought holds that reducing systemic inflammation should decrease cardiovascular risk, but ustekinumab and briakinumab have been associated with an increase in major cardiovascular events in clinical trials, said Dr. Leonardi, a dermatologist and psoriasis specialist at St. Louis University.

(Abbott Laboratories pulled briakinumab from the drug approval process in the United States and Europe in a financial filing on Jan. 14.)

He recently conducted a meta-analysis summarizing major cardiovascular events during the placebo-controlled portions of 19 trials encompassing all the biologic therapies for psoriasis. Only one patient on placebo developed a major cardiovascular event in a study of etanercept. Five patients on ustekinumab, five on briakinumab, and one on adalimumab developed major cardiovascular events.

In a separate look at Phase III trials data on ustekinumab, adverse events included chest pain in one patient on placebo, a case of angina, and a case of stroke in patients on low-dose therapy (45 mg). On high-dose therapy (90 mg) one patient developed congestive cardiomyopathy and died and another required a coronary artery bypass graft, he noted.

"I think there's a bit of an imbalance when I look at these data" in major cardiovascular events, he said.

In data on 3,117 patients followed for 3 years or less, the risk for major cardiovascular events (MI, stroke, or death from cardiovascular causes) seemed to be higher on ustekinumab during the initial 12-week placebo-controlled portions of the study but the risk leveled out between groups over time, Dr. Leonardi said.

During the controlled period, the incidence of major cardiovascular events was 0 per 100 patient-years in the placebo group, 0.98/100 patient-years on low-dose ustekinumab, and 1.47/100 patient-years on high-dose ustekinumab. Over the 3-year period, the incidence was 0.55, 0.41, and 0.35 per 100 patient-years, respectively.

Even in Phase II trial data on ustekinumab there was a potential "signal" of increased risk for major cardiovascular events, Dr. Leonardi added. Looking at data from all trials of ustekinumab for any indication (not just psoriasis), there's a "flurry" of major cardiovascular events early in treatment that then settles down and becomes comparable to the placebo group over time.

"The statisticians will say that there's no statistically significant difference between the treated versus the placebo" in major cardiovascular events, "but I don't think we have to be a rocket scientist to see that there’s something very different going on" between groups, Dr. Leonardi said.

Safety data from the placebo-controlled periods in phase III data on briakinumab suggest even greater problems. "The news here, quite frankly, is not good," he said.

There were three MIs, one cardiac arrest, and a stroke in 981 patients on briakinumab, compared with none in 484 patients on placebo. In addition, five patients on briakinumab and one on placebo developed serious infections requiring hospitalization and IV antibiotics. Six patients on briakinumab and none on placebo developed malignancies, all of them squamous cell carcinomas of the skin, lung, or nasopharynx.

"Cancers usually take months or years to show up, and yet these showed up in the first 12 weeks" on treatment," he noted.

The combination of increased risks for major cardiovascular events, malignancies, and infections with briakinumab is "unprecedented," he said. "We should pay close attention to this data."

Both drugs can boast "impressive" efficacy in treating plaque psoriasis, but the potential risks need to be carefully considered, Dr. Leonardi said.

He recommends considering all options when selecting a biologic treatment for psoriasis, even if patients request the treatment they only have to get every 3 months. Remember that patients with psoriasis typically have multiple cardiac risk factors. If ustekinumab is used, start with a low dose regardless of the patient’s weight, Dr. Leonardi advised.

"Consider adding low-dose aspirin, 81 mg per day," he added. "That's what I’m doing."

Analyses underway by the Food and Drug Administration and the drug companies should provide further insights into the potential risks and benefits of these drugs.

"Remember that all new drugs are new," Dr. Leonardi cautioned. "We don't know everything we need to know about new drugs, especially when there's a new mechanism of action."

He speculated that the monoclonal antibody therapies increase major cardiovascular events by increasing delivery of IL-12 and IL-23 to atherosclerotic plaques, or perhaps the p40 subunits of IL-12 and IL-23 form dimers that become bioactive. Or, some unknown biologic activity could be at play.

SDEF and this news organization are owned by Elsevier. Dr. Leonardi declared having potential conflicts of interest with Abbott and Centocor, which manufacture briakinumab and ustekinumab, and with Abgenix, Allergan, Alza, Amgen, Biogen-IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, Medimmune, Miravant, Pfizer, Schering Plough, Serono, Synta, Wyeth, and Xoma.

LAS VEGAS – Increased risk for major cardiovascular events may be a "class effect" associated with two monoclonal antibody therapies for psoriasis, Dr. Craig Leonardi said.

"I used to give them a pass on this, but no more. I’m going to point out a few things that bother me," he said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Ustekinumab, which is approved to treat adults with moderate to severe plaque psoriasis, and the investigational psoriasis drug briakinumab inhibit interleukin 12 (IL-12) and IL-23 proteins linked to inflammation. Conventional thought holds that reducing systemic inflammation should decrease cardiovascular risk, but ustekinumab and briakinumab have been associated with an increase in major cardiovascular events in clinical trials, said Dr. Leonardi, a dermatologist and psoriasis specialist at St. Louis University.

(Abbott Laboratories pulled briakinumab from the drug approval process in the United States and Europe in a financial filing on Jan. 14.)

He recently conducted a meta-analysis summarizing major cardiovascular events during the placebo-controlled portions of 19 trials encompassing all the biologic therapies for psoriasis. Only one patient on placebo developed a major cardiovascular event in a study of etanercept. Five patients on ustekinumab, five on briakinumab, and one on adalimumab developed major cardiovascular events.

In a separate look at Phase III trials data on ustekinumab, adverse events included chest pain in one patient on placebo, a case of angina, and a case of stroke in patients on low-dose therapy (45 mg). On high-dose therapy (90 mg) one patient developed congestive cardiomyopathy and died and another required a coronary artery bypass graft, he noted.

"I think there’s a bit of an imbalance when I look at these data" in major cardiovascular events, he said.

In data on 3,117 patients followed for 3 years or less, the risk for major cardiovascular events (MI, stroke, or death from cardiovascular causes) seemed to be higher on ustekinumab during the initial 12-week placebo-controlled portions of the study but the risk leveled out between groups over time, Dr. Leonardi said.

During the controlled period, the incidence of major cardiovascular events was 0 per 100 patient-years in the placebo group, 0.98/100 patient-years on low-dose ustekinumab, and 1.47/100 patient-years on high-dose ustekinumab. Over the 3-year period, the incidence was 0.55, 0.41, and 0.35 per 100 patient-years, respectively.

Even in Phase II trial data on ustekinumab there was a potential "signal" of increased risk for major cardiovascular events, Dr. Leonardi added. Looking at data from all trials of ustekinumab for any indication (not just psoriasis), there’s a "flurry" of major cardiovascular events early in treatment that then settles down and becomes comparable to the placebo group over time.

"The statisticians will say that there’s no statistically significant difference between the treated versus the placebo" in major cardiovascular events, "but I don’t think we have to be a rocket scientist to see that there’s something very different going on" between groups, Dr. Leonardi said.

Safety data from the placebo-controlled periods in phase III data on briakinumab suggest even greater problems. "The news here, quite frankly, is not good," he said.

There were three MIs, one cardiac arrest, and a stroke in 981 patients on briakinumab, compared with none in 484 patients on placebo. In addition, five patients on briakinumab and one on placebo developed serious infections requiring hospitalization and IV antibiotics. Six patients on briakinumab and none on placebo developed malignancies, all of them squamous cell carcinomas of the skin, lung, or nasopharynx.

"Cancers usually take months or years to show up, and yet these showed up in the first 12 weeks" on treatment," he noted.

The combination of increased risks for major cardiovascular events, malignancies, and infections with briakinumab is "unprecedented," he said. "We should pay close attention to this data."

Both drugs can boast "impressive" efficacy in treating plaque psoriasis, but the potential risks need to be carefully considered, Dr. Leonardi said.

He recommends considering all options when selecting a biologic treatment for psoriasis, even if patients request the treatment they only have to get every 3 months. Remember that patients with psoriasis typically have multiple cardiac risk factors. If ustekinumab is used, start with a low dose regardless of the patient’s weight, Dr. Leonardi advised.

"Consider adding low-dose aspirin, 81 mg per day," he added. "That’s what I’m doing."

Analyses underway by the Food and Drug Administration and the drug companies should provide further insights into the potential risks and benefits of these drugs.

"Remember that all new drugs are new," Dr. Leonardi cautioned. "We don’t know everything we need to know about new drugs, especially when there’s a new mechanism of action."

He speculated that the monoclonal antibody therapies increase major cardiovascular events by increasing delivery of IL-12 and IL-23 to atherosclerotic plaques, or perhaps the p40 subunits of IL-12 and IL-23 form dimers that become bioactive. Or, some unknown biologic activity could be at play.

SDEF and this news organization are owned by Elsevier. Dr. Leonardi declared having potential conflicts of interest with Abbott and Centocor, which manufacture briakinumab and ustekinumab, and with Abgenix, Allergan, Alza, Amgen, Biogen-IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, Medimmune, Miravant, Pfizer, Schering Plough, Serono, Synta, Wyeth, and Xoma.

LAS VEGAS – Increased risk for major cardiovascular events may be a "class effect" associated with two monoclonal antibody therapies for psoriasis, Dr. Craig Leonardi said.

"I used to give them a pass on this, but no more. I’m going to point out a few things that bother me," he said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Ustekinumab, which is approved to treat adults with moderate to severe plaque psoriasis, and the investigational psoriasis drug briakinumab inhibit interleukin 12 (IL-12) and IL-23 proteins linked to inflammation. Conventional thought holds that reducing systemic inflammation should decrease cardiovascular risk, but ustekinumab and briakinumab have been associated with an increase in major cardiovascular events in clinical trials, said Dr. Leonardi, a dermatologist and psoriasis specialist at St. Louis University.

(Abbott Laboratories pulled briakinumab from the drug approval process in the United States and Europe in a financial filing on Jan. 14.)

He recently conducted a meta-analysis summarizing major cardiovascular events during the placebo-controlled portions of 19 trials encompassing all the biologic therapies for psoriasis. Only one patient on placebo developed a major cardiovascular event in a study of etanercept. Five patients on ustekinumab, five on briakinumab, and one on adalimumab developed major cardiovascular events.

In a separate look at Phase III trials data on ustekinumab, adverse events included chest pain in one patient on placebo, a case of angina, and a case of stroke in patients on low-dose therapy (45 mg). On high-dose therapy (90 mg) one patient developed congestive cardiomyopathy and died and another required a coronary artery bypass graft, he noted.

"I think there’s a bit of an imbalance when I look at these data" in major cardiovascular events, he said.

In data on 3,117 patients followed for 3 years or less, the risk for major cardiovascular events (MI, stroke, or death from cardiovascular causes) seemed to be higher on ustekinumab during the initial 12-week placebo-controlled portions of the study but the risk leveled out between groups over time, Dr. Leonardi said.

During the controlled period, the incidence of major cardiovascular events was 0 per 100 patient-years in the placebo group, 0.98/100 patient-years on low-dose ustekinumab, and 1.47/100 patient-years on high-dose ustekinumab. Over the 3-year period, the incidence was 0.55, 0.41, and 0.35 per 100 patient-years, respectively.

Even in Phase II trial data on ustekinumab there was a potential "signal" of increased risk for major cardiovascular events, Dr. Leonardi added. Looking at data from all trials of ustekinumab for any indication (not just psoriasis), there’s a "flurry" of major cardiovascular events early in treatment that then settles down and becomes comparable to the placebo group over time.

"The statisticians will say that there’s no statistically significant difference between the treated versus the placebo" in major cardiovascular events, "but I don’t think we have to be a rocket scientist to see that there’s something very different going on" between groups, Dr. Leonardi said.

Safety data from the placebo-controlled periods in phase III data on briakinumab suggest even greater problems. "The news here, quite frankly, is not good," he said.

There were three MIs, one cardiac arrest, and a stroke in 981 patients on briakinumab, compared with none in 484 patients on placebo. In addition, five patients on briakinumab and one on placebo developed serious infections requiring hospitalization and IV antibiotics. Six patients on briakinumab and none on placebo developed malignancies, all of them squamous cell carcinomas of the skin, lung, or nasopharynx.

"Cancers usually take months or years to show up, and yet these showed up in the first 12 weeks" on treatment," he noted.

The combination of increased risks for major cardiovascular events, malignancies, and infections with briakinumab is "unprecedented," he said. "We should pay close attention to this data."

Both drugs can boast "impressive" efficacy in treating plaque psoriasis, but the potential risks need to be carefully considered, Dr. Leonardi said.

He recommends considering all options when selecting a biologic treatment for psoriasis, even if patients request the treatment they only have to get every 3 months. Remember that patients with psoriasis typically have multiple cardiac risk factors. If ustekinumab is used, start with a low dose regardless of the patient’s weight, Dr. Leonardi advised.

"Consider adding low-dose aspirin, 81 mg per day," he added. "That’s what I’m doing."

Analyses underway by the Food and Drug Administration and the drug companies should provide further insights into the potential risks and benefits of these drugs.

"Remember that all new drugs are new," Dr. Leonardi cautioned. "We don’t know everything we need to know about new drugs, especially when there’s a new mechanism of action."

He speculated that the monoclonal antibody therapies increase major cardiovascular events by increasing delivery of IL-12 and IL-23 to atherosclerotic plaques, or perhaps the p40 subunits of IL-12 and IL-23 form dimers that become bioactive. Or, some unknown biologic activity could be at play.

SDEF and this news organization are owned by Elsevier. Dr. Leonardi declared having potential conflicts of interest with Abbott and Centocor, which manufacture briakinumab and ustekinumab, and with Abgenix, Allergan, Alza, Amgen, Biogen-IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, Medimmune, Miravant, Pfizer, Schering Plough, Serono, Synta, Wyeth, and Xoma.

LAS VEGAS – Increased risk for major cardiovascular events may be a "class effect" associated with two monoclonal antibody therapies for psoriasis, Dr. Craig Leonardi said.

"I used to give them a pass on this, but no more. I’m going to point out a few things that bother me," he said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Ustekinumab, which is approved to treat adults with moderate to severe plaque psoriasis, and the investigational psoriasis drug briakinumab inhibit interleukin 12 (IL-12) and IL-23 proteins linked to inflammation. Conventional thought holds that reducing systemic inflammation should decrease cardiovascular risk, but ustekinumab and briakinumab have been associated with an increase in major cardiovascular events in clinical trials, said Dr. Leonardi, a dermatologist and psoriasis specialist at St. Louis University.

(Abbott Laboratories pulled briakinumab from the drug approval process in the United States and Europe in a financial filing on Jan. 14.)

He recently conducted a meta-analysis summarizing major cardiovascular events during the placebo-controlled portions of 19 trials encompassing all the biologic therapies for psoriasis. Only one patient on placebo developed a major cardiovascular event in a study of etanercept. Five patients on ustekinumab, five on briakinumab, and one on adalimumab developed major cardiovascular events.

In a separate look at Phase III trials data on ustekinumab, adverse events included chest pain in one patient on placebo, a case of angina, and a case of stroke in patients on low-dose therapy (45 mg). On high-dose therapy (90 mg) one patient developed congestive cardiomyopathy and died and another required a coronary artery bypass graft, he noted.

"I think there’s a bit of an imbalance when I look at these data" in major cardiovascular events, he said.

In data on 3,117 patients followed for 3 years or less, the risk for major cardiovascular events (MI, stroke, or death from cardiovascular causes) seemed to be higher on ustekinumab during the initial 12-week placebo-controlled portions of the study but the risk leveled out between groups over time, Dr. Leonardi said.

During the controlled period, the incidence of major cardiovascular events was 0 per 100 patient-years in the placebo group, 0.98/100 patient-years on low-dose ustekinumab, and 1.47/100 patient-years on high-dose ustekinumab. Over the 3-year period, the incidence was 0.55, 0.41, and 0.35 per 100 patient-years, respectively.

Even in Phase II trial data on ustekinumab there was a potential "signal" of increased risk for major cardiovascular events, Dr. Leonardi added. Looking at data from all trials of ustekinumab for any indication (not just psoriasis), there’s a "flurry" of major cardiovascular events early in treatment that then settles down and becomes comparable to the placebo group over time.

"The statisticians will say that there’s no statistically significant difference between the treated versus the placebo" in major cardiovascular events, "but I don’t think we have to be a rocket scientist to see that there’s something very different going on" between groups, Dr. Leonardi said.

Safety data from the placebo-controlled periods in phase III data on briakinumab suggest even greater problems. "The news here, quite frankly, is not good," he said.

There were three MIs, one cardiac arrest, and a stroke in 981 patients on briakinumab, compared with none in 484 patients on placebo. In addition, five patients on briakinumab and one on placebo developed serious infections requiring hospitalization and IV antibiotics. Six patients on briakinumab and none on placebo developed malignancies, all of them squamous cell carcinomas of the skin, lung, or nasopharynx.

"Cancers usually take months or years to show up, and yet these showed up in the first 12 weeks" on treatment," he noted.

The combination of increased risks for major cardiovascular events, malignancies, and infections with briakinumab is "unprecedented," he said. "We should pay close attention to this data."

Both drugs can boast "impressive" efficacy in treating plaque psoriasis, but the potential risks need to be carefully considered, Dr. Leonardi said.

He recommends considering all options when selecting a biologic treatment for psoriasis, even if patients request the treatment they only have to get every 3 months. Remember that patients with psoriasis typically have multiple cardiac risk factors. If ustekinumab is used, start with a low dose regardless of the patient’s weight, Dr. Leonardi advised.

"Consider adding low-dose aspirin, 81 mg per day," he added. "That’s what I’m doing."

Analyses underway by the Food and Drug Administration and the drug companies should provide further insights into the potential risks and benefits of these drugs.

"Remember that all new drugs are new," Dr. Leonardi cautioned. "We don’t know everything we need to know about new drugs, especially when there’s a new mechanism of action."

He speculated that the monoclonal antibody therapies increase major cardiovascular events by increasing delivery of IL-12 and IL-23 to atherosclerotic plaques, or perhaps the p40 subunits of IL-12 and IL-23 form dimers that become bioactive. Or, some unknown biologic activity could be at play.

SDEF and this news organization are owned by Elsevier. Dr. Leonardi declared having potential conflicts of interest with Abbott and Centocor, which manufacture briakinumab and ustekinumab, and with Abgenix, Allergan, Alza, Amgen, Biogen-IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, Medimmune, Miravant, Pfizer, Schering Plough, Serono, Synta, Wyeth, and Xoma.