| BackgroundPsoriasis is a common, chronic inflammatory skin disease with high rate of recurrence. Its morbility is approximately0.123%in China,1%to2%in European and0.2%to1%in Japan. This disease occurs the most common in young adults, in1992someone in China had reported the average age of onset was26.5years old from1246psoriasis patients. Psoriatic disease is stubborn and difficult to cure, with a great impact on patients’ physical and mental health.In recent years, with the constantly deepening research of the pathogenesis of psoriasis, psoriasis is thinked as a disease of autoimmune disorders with polygenic inheritance background. Its incidence is mainly related to T cells-mediated immunity process, including initialT cells activation to memory-effector T cells, memory effector T cells entering into the circulation and migrating to the skin, and then cells secrete cytokines to play a variety of biological functions. So far psoriasis can’t be cured completely. The treatments for psoriasis include phototherapy, taking the medicine such as methotrexate, retinoid, cyclosporin A, using steroid hormone partly or systematicly, and so on. While the curative effect is not optimistic because of the lack of the specificly organized drugs, and taking the drugs for a long time will lead to serious side-effect or inconvenience. So the drugs are limited to take during the treament. Therefore, it is quiet necessary to develop and apply the target-specific biological agents to cure psoriasis. People have achieved great improvement in the treating of psoriasis biologically, which is based on new awareness on the pathogenesis of psoriasis.There are various kinds of biological agents for psoriasis, including monoclonal antibodies, fusion proteins, recombinant human cytokines or growth factors. According to the mechanism of action, the biological agents for psoriasis can be clarrified into inhibition of T cell activation, such as alefacept, efalizumab, daclizumab, siplizumab;inhibition of TNF-alpha, such as infliximab, adalimumab, etanercept;adjustment of the balance of cytokines, such as IL-4, IL-10, IL-11; anti-IL-12/IL-23, such as ustekinumab. The U.S. Food and Drug Administration (FDA) is one of the most strict and authoritative in supervising the medicine in the world. FDA approved sorts of biological agents to treat moderate-severe plaque psoriasis, such as alefacept, etanercept, and efalizumab; for psoriatic arthritis include infliximab, adalimumab, etanercept. Ustekinumab is a humanized monoclonal antibody and anti IL-12/IL-23. IL-12binding with IL-12receptor on T cells can induce the classic Thl-mediated immune response, such as the production of IFN-γ. And IL-23can induce and maintain Th17-mediated immune response. Ustekinumab can bind with IL-12and IL-23p40subunit, and then inhibit the biological activity of IL-12/IL-23. Ustekinumab was assented for the treatment of moderate-severe plaque psoriasis by the FDA latest. Though the drug was assented to use in clinical therapy, the efficacy and safety of long-term use need to be constantly observed and summarized. For example, because of the serious adverse events, in2009the FDA stopped the production and application of efalizumab. Therefore the efficacy and safety of ustekinumab need more research to analyze.Systematic reviews are different from traditional description reviews, according to the epidemiological principles and methods which can reduce bias and random errors, they collect the published and unpublished clinical trials on a concrete clinical problem all over the world from which they select the literatures meeting the criterion, make qualitative and quantitative analysises, then make a reliable conclusion eventually. And qualitative analysis, also called Meta-analysis can reflect the results more precisely by mathematics, which combine reviews and statistics together. So Meta-analysis was used more widly.With more relevant trails were carried out and completed, our study collected the latest data, including European and American and Asian. If the heterogeneity was caused by different usage of ustekinumab, sensitivity analysis was made. The results of the meta-analysis were applicable for more crowd, and were more reliable.ObjectiveTo assess the efficacy and safety of ustekinumab for plaque psoriasis with meta-analysis, to inform clinicians and other healthcare professionals of this new biologic therapy for psoriasis.Methods1.Set out inclusion and exclusion critera for analysis according to the requests of systematic review, including the characteristics of the subjects, interventions and measure indexes.2.We searched the electronic database::the Cochrane Library, Pubmed, CNKI, Wan Fang Database, CBM and VIP according to the standard comprehensive search strategy. We also searched the references of all primary studies in some academic journals. 3.Assess the quality of eligible trials independently using a predefined quality assessment tool including random analysis, allocation concealment, blinding and completeness of primary outcome reporting with the method recommended in Cochrane Reviewer’s Handbook4.2.6, divided to A、B、C grade.Meanwhile, assess the quality using Jadad schedule, score of1or2is considered as low quality trial,3-5as high quality trial. And grasp if use intention to treat when patients discontinued from the trial.4.We pooled data using Review Manager4.2.2and showed dichotomous outcomes as relative risk (RR), with95%confidence intervals (CI), with the chi-square test to assess the extent of inconsistency, the size of test a=0.1. Data analysis was performed using the fixed-effect mode with no significant heterogeneity or using a random-effect with significant heterogeneity.. Subgroup analyses were intended to explore important clinical differences. If heterogeneity derived from low-quality studies, the sensitivity analysis was performed. Excluded the studies of lager heterogeneity (such as different interventions), re-Meta-analysis, if there was no significant difference between the two results, the results were more reliable. With the μ test (Z test) to assess if the combined statistical outcomes were significantly different, the size of test P=0.05. With the funnel plot to assess the publication bias.Results1.Description of studiesA total of4studies were included into the review, all were randomized controlled trials. They reported that patients with moderate-to-severe plaque psoriasis were randomly allocated into receive subcutaneous injections of ustekinumab (45mg or90mg at week0and4and then every12weeks or only at week0) or placebo. All the trials included a total of2437patients.Of these,1648were in treatment group, while789were in controlled group. There is no statistical significant differences on the base line comparability between the groups in all trials (P>0.05).2.Results of meta-analysis2.1The efficacy of ustekinumab treatment at week12:(1) ustekinumab groups versus placebo group:PASI75:As no heterogeneity was detected between the included trials, a fixed-effect model was used to perform meta-analysis. It was shown that on PASI75ustekinumab45mg group had more benefit (RR=19.18,95%CI[13.20,27.88]) compared with the placebo group (P<0.00001). As no heterogeneity was detected between the included trials, a fixed-effect model was used to perform meta-analysis. It was shown that on PASI75ustekinumab90mg group had more benefit (RR=21.56,95%CI[14.51,32.04]) compared with the placebo group (P<0.00001). Sensitivity analysis:As no heterogeneity was detected between the included trials, a fixed-effect model was used to perform meta-analysis. It was shown that on PASI75ustekinumab45mg group had more benefit (RR=18.65,95%CI[12.74,27.29]) compared with the placebo group (P<0.00001). As no heterogeneity was detected between the included trials, a fixed-effect model was used to perform meta-analysis. It was shown that on PASI75ustekinumab90mg group had more benefit (RR=20.85,95%CI[13.92,31.24]) compared with the placebo group (P<0.00001). There was no significant difference between the two results, the results were more reliable.PGA (clear):As no heterogeneity was detected between the included trials, a fixed-effect model was used to perform meta-analysis. It was shown that on PGA (clear) ustekinumab45mg group had more benefit (RR=164.90,95%CI[18.69,225.33]) compared with the placebo group (P<0.00001). As no heterogeneity was detected between the included trials, a fixed-effect model was used to perform meta-analysis. It was shown that on PGA (clear) ustekinumab90mg group had more benefit (RR=85.78,95%CI[21.35,344.63]) compared with the placebo group (P <0.00001).DLQI of0or1:As no heterogeneity was detected between the included trials, a fixed-effect model was used to perform meta-analysis. It was shown that on DLQI of0or1ustekinumab45mg group had more benefit (RR=12.81,95%CI[8.91,18.42]) compared with the placebo group (P<0.00001). As no heterogeneity was detected between the included trials, a fixed-effect model was used to perform meta-analysis. It was shown that on DLQI of0or1ustekinumab90mg group had more benefit (RR=13.00,95%CI[9.04,18.69]) compared with the placebo group (P<0.00001).(2) ustekinumab45mg group versus ustekinumab90mg group:PASI75:As no heterogeneity was detected between the included trials, a fixed-effect model was used to perform meta-analysis. It was shown that on PASI75ustekinumab90mg group had more benefit (RR=0.92,95%CI[0.86,0.99]) compared with the ustekinumab45mg group(P=0.02). Sensitivity analysis:As significant heterogeneity was detected between the included trials, a random-effect model was used to perform meta-analysis. It was shown that on PASI75, there was no significant difference between the two groups (RR=0.94,95%CI[0.82,1.07])(P=0.34).PGA (clear):As no heterogeneity was detected between the included trials, a fixed-effect model was used to perform meta-analysis. It was shown that on PGA (clear), there was no significant difference between the two groups (RR=0.85,95%CI[0.70,1.03])(P=0.09).DLQI of0or1:As no heterogeneity was detected between the included trials, a fixed-effect model was used to perform meta-analysis. It was shown that on DLQI of0or1(clear), there was no significant difference between the two groups (RR=0.99,95%CI[0.89,1.09])(P=0.78). 2.2The efficacy of ustekinumab treatment at week28ustekinumab45mg group versus ustekinumab90mg group:PASI75:As no heterogeneity was detected between the included trials, a fixed-effect model was used to perform meta-analysis. It was shown that on PASI75ustekinumab90mg group had more benefit (RR=0.89,95%CI[0.84,0.95]) compared with ustekinumab45mg group (P=0.0006).PGA (clear):As no heterogeneity was detected between the included trials, a fixed-effect model was used to perform meta-analysis. It was shown that on PGA (clear) ustekinumab90mg group had more benefit (RR=0.69,95%CI[0.58,0.82]) compared with ustekinumab45mg group(P<0.0001).DLQI of0or1:As no heterogeneity was detected between the included trials,a fixed-effect model was used to perform meta-analysis.It was shown that on DLQI of0or1(clear), there was no significant difference between the two groups (RR=0.93,95%CI[0.85,1.01])(P=0.08).2.3Adverse effectsAll four trails observed adverse events during treatment period, the most common adverse events were upper respiratory tract infection, nasopharyngitis, headache both of the treatment group and the control group, and there were no significant difference between the groups. Serious adverse events were serious infections, malignancies and cardiovascular events. In ustekinumab45mg group, the incidence of adverse events was53.1%-90%, the incidence of infection was21.5%-56%, the incidence of serious adverse events was0.0%-5%, and there were10cases withdrew from the study because of adverse events (the data from four trials); In ustekinumab90mg groups, the incidence of adverse events was47.9%-81%, the incidence of infection was22.4%-44%, the incidence of serious adverse events was1.2%-2%, and there were7cases withdrew from the study because of adverse events (the data from three trials). Krueger’s study reported2cases of tumors in ustekinumab treatment group and1in the placebo group. Papp’s study reported1case of tumors in ustekinumab treatment group and2in the placebo group. Leonardi’s study reported no incidence of tumors in the randomized controlled period. In Tsai’s study, they didn’t observed the incidence of tumors.ConclusionsThis study included four randomized controlled trials. Meta-analysis results suggested that the efficacy of ustekinumab for moderate to severe plaque psoriasis in the12-week course was superior to placebo, both in the skin lesions subsidence and the improvement of the life quality. Between the two doses of ustekinumab, in the12-week course, there was no significant difference of the efficacy;in the28-week course, the ustekinumab90mg group was superior to the ustekinumab45mg group in the skin lesions subsidence, but there was no significant difference in the improvement of the life quality. The most common adverse events were upper respiratory tract infection, nasopharyngitis, headache, the differences between the groups had no statistically significant. The number of included trials was limited, and the usage of ustekinumab was not consistent, and the negative results of the test were not collected. Because of all above, maybe there was a certain bias, and the conclusions should be confirmed with more trails. The treatment course and follow-up time of the enrolled trails were not long enough, so some rare adverse events or adverse events taking a long time to occur could not be found, the sustained efficacy was also not clear. The efficacy and safety of ustekinumab treatment for plaque psoriasis need more long-term observations of relative trails to verify. |
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