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Background There have been few head-to-head clinical trials comparing different biologic disease-modifying anti-rheumatic drugs (bDMARDs) in patients (pts) with psoriatic arthritis (PsA). Objectives To report 24-week (wk) results of a study directly comparing efficacy and safety of ixekizumab (IXE), an IL-17A inhibitor, and adalimumab (ADA), a TNF inhibitor, in bDMARD-naive pts with PsA. Methods The study (NCT03151551; SPIRIT-H2H) included pts with active PsA (≥3 TJC + ≥3SJC) and plaque psoriasis (BSA ≥3%) who were bDMARD naive and inadequate responders to csDMARD therapy. Patients were randomised (1:1) to IXE or ADA for 52 wks (on-label dosing based on presence/absence of moderate to severe psoriasis). The primary objective was superiority of IXE vs ADA measured by the proportion of pts achieving both ACR50 and PASI100 responses at wk 24. Key secondary objectives versus ADA at wk 24 were (1) non-inferiority of IXE for ACR50 (noninferiority margin -12%) and (2) superiority of IXE for PASI100. Additional PsA, skin, composite treat-to-target (T2T: MDA, DAPSA 4), PASDAS remission and patient-reported outcomes, and safety were assessed. Nine pts had PASI=0 and BSA≥3% (a medical inconsistency) at baseline; these pts were considered PASI100 responders if PASI=0 and BSA=0 at wk 24. Categorical variables were evaluated using logistic regression analyses with NRI in the ITT population. Continuous variables were analysed using mixed models for repeated measure analysis. Results 566 pts were randomised (283 to IXE and 283 to ADA). Baseline demographics and disease characteristics were generally well balanced between groups (Table 1). All primary and key secondary efficacy endpoints at wk 24 were met (Figure). The proportion of pts achieving both ACR50 and PASI100 was significantly greater for IXE than ADA (36% vs 28%; p Conclusion In bDMARD naive pts with active PsA and skin disease, IXE showed superior efficacy to ADA based on simultaneous achievement of ACR50 and PASI100 responses at wk 24. Greater improvements with IXE vs ADA were also attained in individual PsA domains and composite T2T outcomes. Disclosure of Interests Philip J Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Leo, Eli Lilly, Merck, Novartis, Pfizer, Sun Pharmaceutical Industries, Inc., and UCB., Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Galapagos, Gilead, Janssen, Leo, Eli Lilly, Merck, Novartis, Pfizer, Sun Pharmaceutical Industries, Inc., and UCB., Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Leo, Merck, Novartis, Pfizer and UCB.., Josef S. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, MSD, Pfizer Inc, Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GlaxoSmithKline, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GlaxoSmithKline, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Frank Behrens Grant/research support from: AbbVie, Pfizer, Roche, Chugai, Prophylix, Bioline, Novartis, Consultant for: AbbVie, Pfizer, Roche, Chugai, UCB, Bristol-Myers Squibb, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Eli Lilly, Speakers bureau: Ad board: AbbVie, Pfizer, Roche, Chugai, UCB, Bristol-Myers Squibb, Celgene, Novartis, Biotest, Janssen, Genzyme, Eli Lilly, Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, MSD, Celgene, Gilead, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, MSD, Celgene, Gilead, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, MSD, Celgene, Gilead, Soyi Liu Leage Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Li Lingnan Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Hasan Tahir Grant/research support from: Novartis, Eli-Lilly, Speakers bureau: AbbVie, Janssen, Eli Lilly, and Novartis, Melinda Gooderham Grant/research support from: Abbvie Inc., Actelion Pharmaceuticals, Akros Pharma Inc., AMGEN Inc., Arcutis Pharmaceuticals Inc., Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Celgene Corporation, Dermira Inc., Eli Lilly and Company, Galderma SA, Glenmark, Janssen Inc., LEO Pharma, MedImmune, Merck and Co., Novartis Pharmaceuticals, Pfizer Inc., Regeneron Pharmaceuticals Inc., Roche Laboratories, Sanofi Genzyme, UCB, Valeant Pharmaceuticals Inc., Consultant for: Akros Pharma Inc., AMGEN Inc., Boehringer Ingelheim International GmbH, Celgene Corporation, Eli Lilly and Company, Janssen Inc., Novartis Pharmaceuticals, Sanofi Genzyme, Valeant Pharmaceuticals Inc., Speakers bureau: Abbvie Inc., Actelion Pharmaceuticals, AMGEN Inc., Boehringer Ingelheim International GmbH, Celgene Corporation, Eli Lilly and Company, Galderma SA, Glenmark, Janssen Inc., LEO Pharma, Novartis Pharmaceuticals, Pfizer Inc., Regeneron Pharmaceuticals Inc., Sanofi Genzyme, Valeant Pharmaceuticals Inc., Eswar Krishnan Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Paul Emery Grant/research support from: Pfizer, MSD, AbbVie, Bristol-Myers Squibb, Roche, Consultant for: Pfizer, MSD, AbbVie, Bristol-Myers Squibb, UCB, Roche, Novartis, Gilead,Samsung, Sandoz and Lilly, Sreekumar Pillai Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Philip Helliwell Grant/research support from: Paid to charity: from AbbVie, Janssen and Novartis, Consultant for: Paid to charity: from AbbVie, Amgen, Pfizer, and UCB and Celgene. Paid to self: from Celgene and Galapagos

A combined chromatographic method using high-speed counter-current chromatography (HSCCC) and Sephadex LH-20 chromatography was established for bioassay-guided separation and purification of water-soluble antioxidants from Carthamus tinctorius L florets. The crude sample II obtained by an initial cleanup step on the AB-8 macroporous resin exhibited a potential ABTS radical cation scavenging activity with the SC50 value of 49.28 mu g/mL. The HSCCC separation was performed with a two-phase solvent system composed of n-butanol-0.1 mol/L HCl (1:1, v/v) at a flow rate of 1.2 mL/min. After a single run, 3 mg hydroxysafflor yellow A (HSYA) with 98% purity was separated as a major component from 20 mg of crude sample II. In order to increase the yield and investigate the minor components, the sample size of HSCCC separation was enlarged to 1 g. Then, HSCCC fractions were subjected to Sephadex LH-20 chromatography and eluted with distilled water at a flow rate of 1.5 mL/min to remove the acid and further separate the components. This separation yielded 184.0 mg of HSYA (1), 10.0 mg of 5,4'-dihydroxyflavone-3,6-di-O-beta-D-glucoside-7-O-beta-D-glucuronide (2), 3.0 mg of 3-O-caffeoylquinic acid (3), and 3.2 mg of 4-O-beta-D-glucosyl-trans-p-coumaric acid (4) from 1 g crude sample II of C tinctorius L. florets. The purity of the separated compounds were over 95% by HPLC analysis, and their chemical structures were confirmed by MS, H-1 NMR and C-13 NMR. Compounds 3 and 4 were found from this plant for the first time. Antioxidant activities assayed in vitro by ABTS radical cation scavenging showed that the SC50 values of the above four compounds were 44.39 +/- 1.62 mu g/mL, 78.13 +/- 1.00 mu g/mL, 21.85 +/- 1.96 mu g/mL, and 31.44 +/- 2.06 mu g/mL, respectively.

In the first part of this thesis, we study maximum empirical likelihood estimates (MELE's) in U-statistics based general estimating equations (UGEE's). Our technical maneuver is the jackknife empirical likelihood (JEL) approach. We give the local uniform asymptotic normality condition for the log-JEL for UGEE's. We derive the estimating equations for finding MELE's and provide their asymptotic normality. We obtain easy MELE's which have less computational burden than the usual MELE's and can be easily implemented using existing software. We investigate the use of side information of the data to improve efficiency. We exhibit that the MELE's are fully efficient, and the asymptotic variance of a MELE will not increase as the number of UGEE's increases. We give several important examples and demonstrate that efficient estimates of moment based distribution characteristics in the presence of side information can be obtained using JEL for U-statistics. In the second part, we propose several JEL goodness-of-fit tests for spherical symmetry, rotational symmetry, antipodal symmetry, coordinatewise symmetry and exchangeability. We employ the jackknife empirical likelihood for vector U-statistics to incorporate side information. We use estimated constraint functions and allow the number of constraints and the dimension to grow with the sample size so that these tests can be used to test hypotheses for high dimensional symmetries. We demonstrate that these tests are distribution free and asymptotically chisquare distributed. We conduct extensive simulations to evaluate the performance of these tests.