Psoriasis, Biologics: Concern Remains About CV Risks

The use of biologic agents for chronic plaque psoriasis was not associated with a significant increase in the risk of major adverse cardiovascular events in a meta-analysis of 22 randomized clinical trials reported in the Aug. 24/31 issue of JAMA.

However, the study had several limitations that prevented the investigators from definitively establishing whether anti-interleukin-12 and anti-interleukin 23 (anti-IL12/23) agents such as usetekinumab and briakinumab or anti-TNFa agents such as adalimumab, etanercept, and infliximab expose psoriasis patients to excess cardiovascular risk.

"Access to patient-level data for these studies was not granted by any of the study sponsors, which precluded the use of a more statistically robust time-to-event analysis. [In addition,] the small number of major adverse CV events in placebo-controlled phases of these studies and the limited duration of the placebo-controlled phases reduce the power of this meta-analysis to detect a change in risk," said Caitriona Ryan, MB, BAO, BCh, of the department of dermatology, Baylor Research Institute, Dallas, and her associates.

"Until more definitive data become available, we believe that dermatologists should exercise heightened vigilance for CV risk factors when initiating anti-Il12/23 agents in psoriasis patients," they noted.

Initially, it was thought that these biologic agents, which help control inflammation in RA and psoriasis patients, might also exert a cardioprotective effect. So there was surprise and concern when preliminary reports showed a numerical excess of major adverse CV events (MACE) in industry-sponsored trials of ustekinumab (Centocor Ortho) and briakinumab (Abbott). "A total of 53 MACEs have occurred to date across all phases of these studies; 26 MACES, including 1 CV death, in studies of ustekinumab and 27 MACEs, including 4 CV deaths, in studies of briakinumab," the investigators said.

To clarify a possible link, they performed a meta-analysis of all randomized clinical trials (RCTs) in which these two agents as well as anti-TNFa agents were compared with placebo in subjects who had chronic plaque psoriasis but no psoriatic arthritis. A total of 10,183 patients comprised the study population. "The primary outcome measure was the number of MACEs during the placebo-controlled phase of treatment," the researchers said.

Although they found no significant rise in risk of MACEs, the investigators said they were limited in their ability to do so by small numbers of subjects, small numbers of MACEs, short duration of drug exposure, and flaws in the RCTs. For example, two myocardial infarctions were not reported in the "adverse event" sections of one prominent industry-sponsored study.

Even though meta-analysis is intended to increase the power to detect rare events by pooling data from several studies, it "cannot correct for limitations in quality of the original clinical trials, most notably the absence of a systematic strategy to screen for, capture, and adjudicate CV events," they noted (JAMA 2011;306:864-71).

"We remain concerned about the MACE rate of 1.33 per 100 patient-years in the placebo-controlled phase of the phase III briakinumab study, with an overall rate of 0.60 events per 100 patient-years across all treatment periods. Indeed, after identification of these cases," patients with two or more CV risk factors were withdrawn from the study. "Subsequently, in July 2011, all clinical trials of briakinumab were discontinued by Abbott, pending further investigations particularly relating to possible mechanistic links to MACEs," the investigators said.

"With numerous therapeutics agents inhibiting IL-17 and IL-23 currently in development, it is essential that the effect of these cytokines on vascular inflammation be fully explored," they stressed.

Their results highlight "the inherent limitations of placebo-controlled clinical trials to reliably interpret the significance of rare events given their current design." RCTs often are underpowered and too brief to detect rare or long-term adverse events, the researchers added.

The investigators reported receiving no external funding for this study. Dr. Ryan reported ties to Janssen-Cilag, Pfizer (a maker of etanercept), Galderma, and Abbott (maker of briakinumab and adalimumab), and his associates reported ties to numerous pharmaceutical companies including the above and Centocor (maker of ustekinumab and infliximab), Amgen (comaker of etanercept), and Schering-Plough (a maker of infliximab).

The use of biologic agents for chronic plaque psoriasis was not associated with a significant increase in the risk of major adverse cardiovascular events in a meta-analysis of 22 randomized clinical trials reported in the Aug. 24/31 issue of JAMA.

However, the study had several limitations that prevented the investigators from definitively establishing whether anti-interleukin-12 and anti-interleukin 23 (anti-IL12/23) agents such as usetekinumab and briakinumab or anti-TNFa agents such as adalimumab, etanercept, and infliximab expose psoriasis patients to excess cardiovascular risk.

"Access to patient-level data for these studies was not granted by any of the study sponsors, which precluded the use of a more statistically robust time-to-event analysis. [In addition,] the small number of major adverse CV events in placebo-controlled phases of these studies and the limited duration of the placebo-controlled phases reduce the power of this meta-analysis to detect a change in risk," said Caitriona Ryan, MB, BAO, BCh, of the department of dermatology, Baylor Research Institute, Dallas, and her associates.

"Until more definitive data become available, we believe that dermatologists should exercise heightened vigilance for CV risk factors when initiating anti-Il12/23 agents in psoriasis patients," they noted.

Initially, it was thought that these biologic agents, which help control inflammation in RA and psoriasis patients, might also exert a cardioprotective effect. So there was surprise and concern when preliminary reports showed a numerical excess of major adverse CV events (MACE) in industry-sponsored trials of ustekinumab (Centocor Ortho) and briakinumab (Abbott). "A total of 53 MACEs have occurred to date across all phases of these studies; 26 MACES, including 1 CV death, in studies of ustekinumab and 27 MACEs, including 4 CV deaths, in studies of briakinumab," the investigators said.

To clarify a possible link, they performed a meta-analysis of all randomized clinical trials (RCTs) in which these two agents as well as anti-TNFa agents were compared with placebo in subjects who had chronic plaque psoriasis but no psoriatic arthritis. A total of 10,183 patients comprised the study population. "The primary outcome measure was the number of MACEs during the placebo-controlled phase of treatment," the researchers said.

Although they found no significant rise in risk of MACEs, the investigators said they were limited in their ability to do so by small numbers of subjects, small numbers of MACEs, short duration of drug exposure, and flaws in the RCTs. For example, two myocardial infarctions were not reported in the "adverse event" sections of one prominent industry-sponsored study.

Even though meta-analysis is intended to increase the power to detect rare events by pooling data from several studies, it "cannot correct for limitations in quality of the original clinical trials, most notably the absence of a systematic strategy to screen for, capture, and adjudicate CV events," they noted (JAMA 2011;306:864-71).

"We remain concerned about the MACE rate of 1.33 per 100 patient-years in the placebo-controlled phase of the phase III briakinumab study, with an overall rate of 0.60 events per 100 patient-years across all treatment periods. Indeed, after identification of these cases," patients with two or more CV risk factors were withdrawn from the study. "Subsequently, in July 2011, all clinical trials of briakinumab were discontinued by Abbott, pending further investigations particularly relating to possible mechanistic links to MACEs," the investigators said.

"With numerous therapeutics agents inhibiting IL-17 and IL-23 currently in development, it is essential that the effect of these cytokines on vascular inflammation be fully explored," they stressed.

Their results highlight "the inherent limitations of placebo-controlled clinical trials to reliably interpret the significance of rare events given their current design." RCTs often are underpowered and too brief to detect rare or long-term adverse events, the researchers added.

The investigators reported receiving no external funding for this study. Dr. Ryan reported ties to Janssen-Cilag, Pfizer (a maker of etanercept), Galderma, and Abbott (maker of briakinumab and adalimumab), and his associates reported ties to numerous pharmaceutical companies including the above and Centocor (maker of ustekinumab and infliximab), Amgen (comaker of etanercept), and Schering-Plough (a maker of infliximab).

The use of biologic agents for chronic plaque psoriasis was not associated with a significant increase in the risk of major adverse cardiovascular events in a meta-analysis of 22 randomized clinical trials reported in the Aug. 24/31 issue of JAMA.

However, the study had several limitations that prevented the investigators from definitively establishing whether anti-interleukin-12 and anti-interleukin 23 (anti-IL12/23) agents such as usetekinumab and briakinumab or anti-TNFa agents such as adalimumab, etanercept, and infliximab expose psoriasis patients to excess cardiovascular risk.

"Access to patient-level data for these studies was not granted by any of the study sponsors, which precluded the use of a more statistically robust time-to-event analysis. [In addition,] the small number of major adverse CV events in placebo-controlled phases of these studies and the limited duration of the placebo-controlled phases reduce the power of this meta-analysis to detect a change in risk," said Caitriona Ryan, MB, BAO, BCh, of the department of dermatology, Baylor Research Institute, Dallas, and her associates.

"Until more definitive data become available, we believe that dermatologists should exercise heightened vigilance for CV risk factors when initiating anti-Il12/23 agents in psoriasis patients," they noted.

Initially, it was thought that these biologic agents, which help control inflammation in RA and psoriasis patients, might also exert a cardioprotective effect. So there was surprise and concern when preliminary reports showed a numerical excess of major adverse CV events (MACE) in industry-sponsored trials of ustekinumab (Centocor Ortho) and briakinumab (Abbott). "A total of 53 MACEs have occurred to date across all phases of these studies; 26 MACES, including 1 CV death, in studies of ustekinumab and 27 MACEs, including 4 CV deaths, in studies of briakinumab," the investigators said.

To clarify a possible link, they performed a meta-analysis of all randomized clinical trials (RCTs) in which these two agents as well as anti-TNFa agents were compared with placebo in subjects who had chronic plaque psoriasis but no psoriatic arthritis. A total of 10,183 patients comprised the study population. "The primary outcome measure was the number of MACEs during the placebo-controlled phase of treatment," the researchers said.

Although they found no significant rise in risk of MACEs, the investigators said they were limited in their ability to do so by small numbers of subjects, small numbers of MACEs, short duration of drug exposure, and flaws in the RCTs. For example, two myocardial infarctions were not reported in the "adverse event" sections of one prominent industry-sponsored study.

Even though meta-analysis is intended to increase the power to detect rare events by pooling data from several studies, it "cannot correct for limitations in quality of the original clinical trials, most notably the absence of a systematic strategy to screen for, capture, and adjudicate CV events," they noted (JAMA 2011;306:864-71).

"We remain concerned about the MACE rate of 1.33 per 100 patient-years in the placebo-controlled phase of the phase III briakinumab study, with an overall rate of 0.60 events per 100 patient-years across all treatment periods. Indeed, after identification of these cases," patients with two or more CV risk factors were withdrawn from the study. "Subsequently, in July 2011, all clinical trials of briakinumab were discontinued by Abbott, pending further investigations particularly relating to possible mechanistic links to MACEs," the investigators said.

"With numerous therapeutics agents inhibiting IL-17 and IL-23 currently in development, it is essential that the effect of these cytokines on vascular inflammation be fully explored," they stressed.

Their results highlight "the inherent limitations of placebo-controlled clinical trials to reliably interpret the significance of rare events given their current design." RCTs often are underpowered and too brief to detect rare or long-term adverse events, the researchers added.

The investigators reported receiving no external funding for this study. Dr. Ryan reported ties to Janssen-Cilag, Pfizer (a maker of etanercept), Galderma, and Abbott (maker of briakinumab and adalimumab), and his associates reported ties to numerous pharmaceutical companies including the above and Centocor (maker of ustekinumab and infliximab), Amgen (comaker of etanercept), and Schering-Plough (a maker of infliximab).