AAD 2019: Anti-Interleukin Agents Show Greatest Efficacy in Meta-Analyses of Treatments for Plaque Psoriasis | PracticeUpdate
AAD 2019: Anti-Interleukin Agents Show Greatest Efficacy in Meta-Analyses of Treatments for Plaque Psoriasis
Risankizumab emerges as the most effective in analyses sponsored by the drug's manufacturer
"The clinical benefits of novel treatments for moderate-to-severe psoriasis have been well-established, but wide variations exist in patient response across different therapies," the study authors wrote in their presentation. "In the absence of head-to-head randomized trials across the entire set of comparators, meta-analyses combining data from multiple studies to assess comparative efficacy are needed."
Results of such meta-analyses were presented by April W. Armstrong, MD, from the Keck School of Medicine at the University of California, Los Angeles.
Dr. Armstrong and colleagues conducted a systematic literature review of 83 phase II or III randomized controlled trials of treatments and dosages licensed by the European Medicines Agency for adult patients with moderate to severe psoriasis. Treatments assessed were: 1) anti-TNF agents (adalimumab, certolizumab pegol, etanercept, and infliximab); 2) anti-IL agents (brodalumab, guselkumab, ixekizumab, risankizumab, secukinumab, tildrakizumab, and ustekinumab); 3) anti-PDE4 agents (apremilast); and 4) fumaric acid esters (dimethyl fumarate).
Outcomes compared were the probabilities of achieving a 90% or 100% reduction in Psoriasis Area and Severity Index from baseline (PASI 90/100) at the end of the primary response period of included trials (10 – 16 weeks from baseline) and at the end of the maintenance period (44 – 60 weeks from baseline).
Overall, 60 trials were included in a network meta-analysis of results at weeks 10 to 16. This analysis revealed that risankizumab, ixekizumab, brodalumab, and guselkumab had the highest PASI 90/100 rates at weeks 10 to 16 among assessed treatments, compared with etanercept, adalimumab, ustekinumab, certolizumab pegol, tildrakizumab, dimethyl fumarate, and apremilast. Risankizumab, ixekizumab, and brodalumab also had significantly higher PASI 90/100 rates than secukinumab and infliximab (P < .05). There were no statistically significant differences among risankizumab, ixekizumab, brodalumab, and guselkumab.
A meta-analysis of results at weeks 44 to 60 included a total of 23 trials on 10 treatments. Long-term data were only reported for the 50 mg biweekly dose for etanercept, and PASI 100 was not reported for apremilast, etanercept, and infliximab.
In this analysis, risankizumab, brodalumab, ixekizumab, guselkumab, and secukinumab had the highest estimated PASI 90/100 response rates, with PASI 90/100 ratings significantly higher than etanercept, infliximab, adalimumab, ustekinumab, and apremilast. Among the five biologics with the greatest activity, risankizumab had a significantly higher PASI 90 rate than ixekizumab and secukinumab. In addition, risankizumab, brodalumab, and ixekizumab had significantly higher PASI 100 rates than secukinumab, while risankizumab and ixekizumab had significantly higher PASI 100 rates than guselkumab (P < .05)
The authors concluded in their presentation that, "over the primary response period, risankizumab, ixekizumab, brodalumab, and guselkumab were associated with the highest estimated PASI response rates. Over the long-term maintenance period, there were some notable differences, with risankizumab having significantly higher PASI 90 rates than secukinumab and ixekizumab and significantly higher PASI 100 rates than guselkumab."
This study received support from AbbVie, manufacturers of risankizumab.
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March 12, 2019
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Biologics and Psoriatic Disease: Have We Finally Detected a Mechanism Linking Treatment to Cardiovascular Risk Improvement?
Following a hallmark study revealing that psoriasis is an individual risk factor for future myocardial infarction (MI), an explosion of research has solidified an association between moderate to severe psoriasis and increased risk of cardiovascular disease.1,2 More recently, imaging studies using FDG-PET/CT have shown that patients with psoriasis have inflammation in numerous organs, including the aorta and other vascular beds, compared with healthy individuals without psoriasis.3 Thus, a fundamental hypothesis has been that adequately treating moderate to severe psoriasis should decrease vascular inflammation, and thus, future risk of cardiovascular events.
Unfortunately, results of studies exploring the relationship between adequately treating psoriasis and decreasing future cardiovascular events have been conflicting. Epidemiologic studies using claims databases suggest that treating psoriasis with biologics decreases cardiovascular events compared with treating psoriasis with phototherapy and methotrexate.4,5 However, several relatively well-designed, prospective studies have recently failed to show that biologic therapy decreases aortic vascular inflammation in moderate to severe psoriasis patients.6,7,8 These studies do, however, show a trend in decreased biomarkers of vascular inflammation, such as hsCRP, with biologic treatment. Although lack of positive impact on vascular inflammation may be surprising, trends in decreased biomarkers suggest that study designs with more patients followed for longer time periods may allow detection of positive results. Nevertheless, this remains to be seen.
Results of this study by Elnabawi et al suggest that researchers may have found a mechanism alternative to direct effect on vascular inflammation that links biologic therapy to decreased risk of cardiovascular events. In a prospective, observational study, 215 patients were followed for 1 year, with 121 biologic- and systemic therapy–naïve patients initiated on biologic therapy. The other patients were treated with topical medications and phototherapy. After following patients with serial coronary computed tomography angiography (CCTA) over 1 year, the patients treated with biologics (anti-TNF, anti-IL12/23, or anti-23 therapies) demonstrated significant decreases in noncalcified coronary plaque burden and reduction in necrotic core, with no effect on fibrous burden, compared with the nonbiologic-treated cohort. The decrease in noncalcified plaque burden was significant even after adjustment for traditional cardiovascular risk factors. Additionally, reduction in coronary plaque burden was significantly greater with anti-IL17 therapy compared with anti-IL12/23 therapy and no biologic therapy. On the other hand, there was progression of coronary artery disease with conversion of fibrous burden to fibro-fatty burden of plaques in the nonbiologic-treated cohort.
Although this is a relatively small study following patients for a short period of time, it may be significant. Could decreasing noncalcified coronary plaque burden and coronary plaque characteristics be the key to preventing future myocardial infarctions and strokes in psoriasis patients who are known to be at risk for developing them? Recently, it has been shown that CCTA plaque features are important for defining accurate cardiovascular risk.9 Although the progression rate of subclinical atherosclerosis on CCTA in psoriasis patients is unknown, lipid-rich plaque and necrotic core, both of which decreased with biologic therapy in the study by Elnabawi et al, are known to be inflammation-driven. This inflammatory component would support the positive results that may truly be related to biologic therapy. The results of this study are exciting, but there are important limitations preventing definitive statements concerning the impact of biologic therapy on coronary plaque burden and characteristics in psoriasis patients.
Importantly, patients in the study by Elnabawi et al had low cardiovascular risk per Framingham score. Also, patients had a relatively low median PASI score of 8.6. These characteristics make it attractive to hypothesize that psoriasis patients with higher Framingham scores and/or PASI scores may have more significant improvement in coronary plaque burden and plaque characteristics when treated with biologics than seen in the current study. This is underscored by the fact that patients in the Elnabawi study had a noncalcified coronary plaque burden that correlated with increasing PASI scores. Hopefully larger, better-designed studies in the future will include psoriasis patients with a wider variety of disease severity and cardiovascular risk to further explore such hypotheses.
In short, more work needs to be done, and we are only beginning to understand the true relationship between psoriasis and cardiovascular disease. For the moment, however, the study by Elnabawi et al appears to have potentially uncovered an exciting piece of the puzzle concerning how biologic therapy may positively impact cardiovascular disease risk in psoriasis patients.
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