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      Quantitative Evaluation of Biologic Therapy Options for Psoriasis: A Systematic Review and Network Meta-Analysis

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          Abstract

          Multiple biologic treatments are licensed for psoriasis. The lack of head-to-head randomized controlled trials makes choosing between them difficult for patients, clinicians, and guideline developers. To establish their relative efficacy and tolerability, we searched MEDLINE, PubMed, Embase, and Cochrane for randomized controlled trials of licensed biologic treatments for skin psoriasis. We performed a network meta-analysis to identify direct and indirect evidence comparing biologics with one another, methotrexate, or placebo. We combined this with hierarchical cluster analysis to consider multiple outcomes related to efficacy and tolerability in combination for each treatment. Study quality, heterogeneity, and inconsistency were evaluated. Direct comparisons from 41 randomized controlled trials (20,561 participants) were included. All included biologics were efficacious compared with placebo or methotrexate at 3–4 months. Overall, cluster analysis showed adalimumab, secukinumab, and ustekinumab were comparable in terms of high efficacy and tolerability. Ixekizumab and infliximab were differentiated by very high efficacy but poorer tolerability. The lack of longer term controlled data limited our analysis to short-term outcomes. Trial performance may not equate to real-world performance, and so results need to be considered alongside real-world, long-term safety and effectiveness data. These data suggest that it is possible to discriminate between biologics to inform clinical practice and decision making (PROSPERO 2015:CRD42015017538).

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          The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials.

          When little or no data directly comparing two treatments are available, investigators often rely on indirect comparisons from studies testing the treatments against a control or placebo. One approach to indirect comparison is to pool findings from the active treatment arms of the original controlled trials. This approach offers no advantage over a comparison of observational study data and is prone to bias. We present an alternative model that evaluates the differences between treatment and placebo in two sets of clinical trials, and preserves the randomization of the originally assigned patient groups. We apply the method to data on sulphamethoxazole-trimethoprim or dapsone/pyrimethamine as prophylaxis against Pneumocystis carinii in HIV infected patients. The indirect comparison showed substantial increased benefit from the former (odds ratio 0.37, 95% CI 0.21 to 0.65), while direct comparisons from randomized trials suggests a much smaller difference (risk ratio 0.64, 95% CI 0.45 to 0.90; p-value for difference of effect = 0.11). Direct comparisons of treatments should be sought. When direct comparisons are unavailable, indirect comparison meta-analysis should evaluate the magnitude of treatment effects across studies, recognizing the limited strength of inference.
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            Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.

            17,187 patients entering 417 hospitals up to 24 hours (median 5 hours) after the onset of suspected acute myocardial infarction were randomised, with placebo control, between: (i) a 1-hour intravenous infusion of 1.5 MU of streptokinase; (ii) one month of 160 mg/day enteric-coated aspirin; (iii) both active treatments; or (iv) neither. Streptokinase alone and aspirin alone each produced a highly significant reduction in 5-week vascular mortality: 791/8592 (9.2%) among patients allocated streptokinase infusion vs 1029/8595 (12.0%) among those allocated placebo infusion (odds reduction: 25% SD 4; 2p less than 0.00001); 804/8587 (9.4%) vascular deaths among patients allocated aspirin tablets vs 1016/8600 (11.8%) among those allocated placebo tablets (odds reduction: 23% SD 4; 2p less than 0.00001). The combination of streptokinase and aspirin was significantly (2p less than 0.0001) better than either agent alone. Their separate effects on vascular deaths appeared to be additive: 343/4292 (8.0%) among patients allocated both active agents vs 568/4300 (13.2%) among those allocated neither (odds reduction: 42% SD 5; 95% confidence limits 34-50%). There was evidence of benefit from each agent even for patients treated late after pain onset (odds reductions at 0-4, 5-12, and 13-24 hours: 35% SD 6, 16% SD 7, and 21% SD 12 for streptokinase alone; 25% SD 7, 21% SD 7, and 21% SD 12 for aspirin alone; and 53% SD 8, 32% SD 9, and 38% SD 15 for the combination of streptokinase and aspirin). Streptokinase was associated with an excess of bleeds requiring transfusion (0.5% vs 0.2%) and of confirmed cerebral haemorrhage (0.1% vs 0.0%), but with fewer other strokes (0.6% vs 0.8%). These "other" strokes may have included a few undiagnosed cerebral haemorrhages, but still there was no increase in total strokes (0.7% streptokinase vs 0.8% placebo infusion). Aspirin significantly reduced non-fatal reinfarction (1.0% vs 2.0%) and non-fatal stroke (0.3% vs 0.6%), and was not associated with any significant increase in cerebral haemorrhage or in bleeds requiring transfusion. An excess of non-fatal reinfarction was reported when streptokinase was used alone, but this appeared to be entirely avoided by the addition of aspirin. Those allocated the combination of streptokinase and aspirin had significantly fewer reinfarctions (1.8% vs 2.9%), strokes (0.6% vs 1.1%), and deaths (8.0% vs 13.2%) than those allocated neither. The differences in vascular and in all-cause mortality produced by streptokinase and by aspirin remain highly significant (2p less than 0.001 for each) after the median of 15 months of follow-up thus far available.
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              Determining the Minimal Clinically Important Difference and Responsiveness of the Dermatology Life Quality Index (DLQI): Further Data

              Aims: To determine the minimal clinically important difference (MCID) of the Dermatology Life Quality Index (DLQI) and its responsiveness to change in inflammatory skin diseases. Methods: A longitudinal study: at stage 1, patients completed the DLQI and a disease severity global question; at stage 2, a global rating of change in quality of life (QoL; Global Rating of Change Questionnaire, GRCQ) was added and used as an anchor to measure the MCID of the DLQI. Results: 192 patients completed stage 1 and 107 completed stage 2. The mean DLQI score at stage 1 was 9.8 and 7.4 at stage 2 with a mean change of 2.4 (p < 0.0001). 31 patients experienced a ‘small change' in their QoL (±3 and ±2) on the GRCQ. The mean corresponding change in DLQI scores was 3.3, which is regarded as the approximate MCID. Conclusions: Previous estimates of the MCID of the DLQI have varied from 3 to 5. Although this study demonstrated a MCID of 3.3, we recommend that the MCID in inflammatory skin diseases should be 4.
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                Author and article information

                Contributors
                Journal
                J Invest Dermatol
                J. Invest. Dermatol
                The Journal of Investigative Dermatology
                Elsevier
                0022-202X
                1523-1747
                1 August 2017
                August 2017
                : 137
                : 8
                : 1646-1654
                Affiliations
                [1 ]Unit for Population-Based Dermatology Research, St John's Institute of Dermatology, King's College London and Guy's and St Thomas' NHS Foundation Trust, London, UK
                [2 ]Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
                [3 ]University College London Hospital, London, UK
                [4 ]British Association of Dermatologists, London, UK
                [5 ]National Guideline Centre, Royal College of Physicians, London, UK
                [6 ]Department of Dermatology, Royal Infirmary of Edinburgh, Edinburgh, UK
                [7 ]Sheffield University Teaching Hospitals and Sheffield Children’s Hospitals, Sheffield, UK
                [8 ]Department of Dermatology, East Lancashire Hospitals NHS Trust, Royal Blackburn Hospital, Blackburn, UK
                [9 ]Department of Dermatology, Royal Liverpool and Broadgreen University Hospitals Trust, Liverpool, UK
                [10 ]Department of Dermatology, Oxford University Hospitals Foundation Trust, Oxford, UK
                [11 ]St John’s Institute of Dermatology, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK
                Author notes
                []Correspondence: Catherine H. Smith, St John’s Institute of Dermatology, 9th Floor, Tower Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK.St John’s Institute of Dermatology9th Floor, Tower Wing, Guy’s Hospital, Great Maze PondLondon SE1 9RTUK catherine.smith@ 123456kcl.ac.uk
                Article
                S0022-202X(17)31427-6
                10.1016/j.jid.2017.04.009
                5519491
                28457908
                f30c2c75-7ed5-4367-a790-a2ddcf4d4250
                © 2017 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 3 January 2017
                : 15 March 2017
                : 4 April 2017
                Categories
                Original Article
                Clinical Research

                Dermatology
                ci, confidence interval,dlqi, dermatology life quality index,nma, network meta-analysis,pasi, psoriasis area and severity index,rct, randomized controlled trial,sucra, surface under the cumulative ranking curve

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