Cardiovascular Events and Biologic Therapies for Chronic Plaque Psoriasis

In the past 10 years, researchers have found links between autoimmune diseases including rheumatoid arthritis (RA), psoriasis, and Crohn’s disease with chronic systemic inflammation. Links have also emerged between autoimmune diseases and increases in occlusive vascular disease and cardiovascular risk. The findings have led to the possibility that control of inflammation may help reduce cardiovascular morbidity; there have been suggestions of a cardioprotective effect with systemic agents such as methotrexate and anti–tumor necrosis factor (TNF)-alpha agents in patients with RA or psoriasis. Previous studies of treatment for psoriasis with ustekinumab and briakinumab, monoclonal antibodies to the shared p40 subunit of interleukin (IL)-12 and IL-23, have shown efficacy for the agents; however, reports of major adverse cardiovascular events (MACEs) have prompted concern. There were 10 MACEs in IL-12/23–treated patients in the placebo-controlled phases of phase 2 and 3 studies of ustekinumab (n=5) and briakinumab (n=5) compared with patients receiving placebo. There were few events reported in studies of psoriasis patients treated with an anti–TNF-alpha agent (n=23 across all phases of these studies). Given this context, researchers recently conducted a meta-analysis to evaluate a possible association between biologic therapies for chronic plaque psoriasis (CPP) and MACEs. They reported results in the Journal of the American Medical Association [2011;306(8):864-871].

The researchers reviewed all randomized controlled trials (RCTs) of ustekinumab and briakinumab (anti–IL-12/23 agents) and adalimumab, etanercept, and infliximab (anti–TNF-alpha agents) for treatment of patients with CPP. They conducted a meta-analysis using the Preferred Reporting Items for Systematic Reviews and Meta-analyses 2009 guidelines. Data from the Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, and Ovid MEDLINE from the beginning of the database through May 2011 were used, as were results of registered, non-published completed studies reported in abstract publications or poster presentations. After applying predefined inclusion criteria, a total of 22 RCTs representing 10,183 patients were included in the analysis. The primary outcome measure was a composite end point of myocardial infarction, cerebrovascular accident, or cardiovascular death (MACE) during the placebo-controlled phase of treatment in patients receiving at least 1 dose of the study agent or placebo. Effect measure was illustrated using differences in absolute risk. Eligibility criteria were similar for all studies, as were baseline patient characteristics, including patient age, duration of psoriasis, severity of baseline psoriasis defined by the Psoriasis Area and Severity Index, and percentage of body area affected.

Because there was no evidence of statistical heterogeneity across the studies using the I2 test (I2=0), results of the trials included in the meta-analysis were combined using the Mantel-Haenszel fixed-effects method. In the placebo-controlled phases of the anti–IL-12/23 trials, 10 of the 3129 patients treated with an anti–IL-12/23 agent had a MACE, compared with no events in the 1471 patients receiving placebo, representing a Mantel-Haenszel risk difference of 0.012 events per person-year (95% confidence interval [CI], –0.001 to 0.026; P=.12). In trials involving anti–TNF-alpha agents, 1 of the 3858 patients receiving the treatment had a MACE compared with 1 of the 1812 study participants receiving placebo (Mantel-Haenszel risk difference, –0.0005 events/person-year; 95% CI, –0.010 to 0.009; P=.04). Limitations to the study cited by the authors included lack of access to patient-level data, precluding the use of a more statistically robust time-to-event analysis and the inability to obtain accurate P values for rare and no-event data. There may also have been publication bias in some of the studies included in the analysis, the authors said. Acknowledging that the study may have been underpowered to identify a significant difference, the authors summarized their findings, noting that “compared with placebo, there was no significant difference in the rate of MACEs observed in patients receiving anti–IL-12/23 antibodies or anti–TNF-alpha treatments.”