Infections in Patients Receiving Subcutaneous Biological Treatments for Moderate to Severe Psoriasis

Abstract

In a previous study, we evaluated the safety of biological drugs in the treatment of moderate to severe psoriasis [1] and we found a quite favourable profile for these agents (adalimumab, ustekinumab and etanercept). More recently, a systematic review [2] has found an increase in the incidence of serious infections in patients with rheumatoid arthritis treated with biological agents. To re-evaluate this issue, we carried out an updated analysis (Analysis 1) in which we included the data of the most recently approved agent for this indication (i.e. secukinumab). Furthermore, we performed a Bayesian meta-regression analysis (Analysis 2; temporal trend analysis) to investigate whether the incidence of infections has undergone any changes from 2000 to 2015. Our updated literature search, based on PubMed, covered the previous 15 years and included only randomized controlled trials (see also Fig. S1 in the Supplementary Material and the PRISMA schematic of our search). In comparison with the search carried out for our previous study, the main difference was that secukinumab was also included among the agents evaluated for safety. In Analysis 1, we employed the same Bayesian network meta-analysis [3–5] as in our previous report, but the outcome measure was the odds ratio (rather than the risk difference) because in this way our results were comparable to those published by Singh et al. [2]. In Analysis 2, we employed a meta-regression model based on the same Bayesian approach [6], in which the covariate (calendar year) was handled as a continuous variable. All the Bayesian models adopted for our analyses [3–6] have been developed by the National Institute for Health and Care Excellence Support Unit (UK) and are available as a fixed-effects model and a random-effects model. In both analyses, we employed the random-effects model (which is more conservative) because we anticipated the presence of heterogeneity. All statistical calculations were performed using the software package WinBUGS 1.4.3 (Cambridge, UK). Our literature search extracted a total of 121 eligible citations. We excluded 95 citations on the basis of the abstract or the title. We then examined the full text of the remaining 26 articles and we finally selected a total of 13 randomized controlled trials that met our inclusion criteria. Of these 13 studies, two evaluated adalimumab, five ustekinumab (45 and 90 mg), four low- and high-dose etanercept and two secukinumab (150 and 300 mg). All of these trials adopted a double-blind design and analysed the safety of these treatments in terms of any infectious adverse event. Table 1 illustrates the raw data of infection incidence, extracted from these 13 trials. Table 1 Incidence of any infectious adverse event in 13 randomized trialsa Study no. First author or trial acronym (year of publication) Any infectious adverse event Total no. of patients Treatment Follow-up 1 Menter et al. (2008) 89 398 Placebo At week 16 1 Menter et al. (2008) 235 814 Adalimumab 2 Asahina et al. (2010) 23 46 Placebo At week 24 2 Asashina et al. (2010) 18 43 Adalimumab 3 Papp et al. (2008) 82 410 Placebo At week 12 3 Papp et al. (2008) 88 409 Ustekinumab 45 mg 3 Papp et al. (2008) 92 411 Ustekinumab 90 mg 4 Igarashi et al. (2012) 6 32 Placebo At week 12 4 Igarashi et al. (2012) 13 64 Ustekinumab 45 mg 4 Igarashi et al. (2012) 15 62 Ustekinumab 90 mg 5 Leonardi et al. (2008) 68 255 Placebo At week 12 5 Leonardi et al. (2008) 80 255 Ustekinumab 45 mg 5 Leonardi et al. (2008) 66 255 Ustekinumab 90 mg 6 Tsai et al. (2011) 14 60 Placebo At week 12 6 Tsai et al. (2011) 20 61 Ustekinumab 45 mg 7 Zhu et al. (2013) 31 161 Placebo At week 12 7 Zhu et al. (2013) 41 160 Ustekinumab 45 mg 8 Tyring et al. (2006) 71 306 Placebo At week 12 8 Tyring et al. (2006) 87 312 HDE 9 Papp et al. (2005) 25 193 Placebo At week 12 9 Papp et al. (2005) 26 196 LDE 9 Papp et al. (2005) 75 194 HDE 10 Leonardi et al. (2003) 19 166 Placebo At week 12 10 Leonardi et al. (2003) 16 160 LDE 10 Leonardi et al. (2003) 9 164 HDE 11 Van de Kerkhof et al. (2008) 12 46 Placebo At week 24 11 Van de Kerkhof et al. (2003) 17 96 HDE 12 FIXTURE (2014) 163 327 Placebo At week 12 12 FIXTURE (2014) 101 327 Secukinumab 150 mg 12 FIXTURE (2014) 87 326 Secukinumab 300 mg 13 ERASURE (2014) 40 248 Placebo At week 12 13 ERASURE (2014) 66 245 Secukinumab 150 mg 13 ERASURE (2014) 72 245 Secukinumab 300 mg HDE high-dose etanercept, LDE low-dose etanercept aTable S1 in the Supplementary Material provides the full bibliographic details of the 13 trials included in our analysis Figure 1 shows the results of Analysis 1 focused on the incidence of any infectious adverse event. The analysis generated seven direct comparisons between an active agent (adalimumab, ustekinumab 45 mg, ustekinumab 90 mg, high-dose etanercept, low-dose etanercept, secukinumab 150 mg or secukinumab 300 mg) and placebo and 17 indirect comparisons between the active agents in all possible combinations. Because all the indirect comparisons were little informative, Fig. 1 has been restricted to the direct comparisons, which however were very far from demonstrating any difference. Analysis 2 (temporal trend analysis) found a regression coefficient close to 0 (value: +0.0336; 95 % credible interval −0.219 to 0.283); this result identifies a flat (i.e. approximately horizontal) meta-regression line that fails to suggest any effect of time on the risk of infection related to biologic drugs. Because the risk of infection is not likely to depend on the patients’ disease condition (rheumatoid arthritis or psoriasis), further studies are needed to shed light on this controversial issue. Fig. 1 Endpoint of any infectious adverse event. Forest plot of the values of odds ratios (with 95 % credible intervals) calculated for seven direct comparisons of active agents vs. controls according to the Bayesian random-effects model. ADA adalimumab, U45 ustekinumab 45 mg, U90 ustekinumab 90 mg, HDE high-dose etanercept, LDE low-dose etanercept, SEC150 secukinumab 150 mg, SEC300 secukinumab 300 mg In conclusion, our results provided a synthesis of the information currently available from randomized trials concerning the risk of infections attributable to biological agents in patients with moderate to severe psoriasis. All biological agents currently approved in Europe were tested. Interestingly enough, while in their study on rheumatoid arthritis Singh et al. [2] found a significantly increased risk of infections in the direct comparisons between biological agents and controls, our results from patients with psoriasis did not suggest any such conclusion. Electronic supplementary material Below is the link to the electronic supplementary material. Supplementary material 1 (DOC 61 kb)