Articles www.thelancet.com Published online May 24, 2017 http://dx.doi.org/10.1016/S0140-6736(17)31429-0 1 Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial Peter Nash, Bruce Kirkham, Masato Okada, Proton Rahman, Benard Combe, Gerd-Ruediger Burmester, David H Adams, Lisa Kerr, Chin Lee, Catherine L Shuler, Mark Genovese, on behalf of the SPIRIT-P2 Study Group * Summary Background Patients who have had inadequate response to tumour necrosis factor inhibitors have fewer treatment options and are generally more treatment refractory to subsequent therapeutic interventions than previously untreated patients. We report the efcacy and safety of ixekizumab, a monoclonal antibody that selectively targets interleukin- 17A, in patients with active psoriatic arthritis and previous inadequate response to tumour necrosis factor inhibitors. Methods In this double-blind, multicentre, randomised, placebo-controlled, phase 3 study (SPIRIT-P2), patients were recruited from 109 centres across ten countries in Asia, Australia, Europe, and North America. Patients were aged 18 years or older, had a confrmed diagnosis of psoriatic arthritis for at least 6 months, and had a previous inadequate response, distinguished by being refractory to therapy or had loss of efcacy, or were intolerant to tumour necrosis factor inhibitors. Patients were randomly assigned (1:1:1) by a computer-generated random sequence to receive a subcutaneous injection of 80 mg ixekizumab every 4 weeks or every 2 weeks after a 160 mg starting dose or placebo. The primary endpoint was the proportion of patients who attained at least 20% improvement in the American College of Rheumatology response criteria (ACR-20) at week 24. This study is registered with ClinicalTrials.gov, number NCT02349295. Findings Between March 3, 2015, to March 22, 2016, 363 patients were randomly assigned to placebo (n=118), ixekizumab every 4 weeks (n=122), or ixekizumab every 2 weeks (n=123). At week 24, a higher proportion of patients attained ACR-20 with ixekizumab every 4 weeks (65 [53%] patients; efect size vs placebo 33·8% [95% CI 22·4–45·2]; p<0·0001) and ixekizumab every 2 weeks (59 [48%] patients; 28 . 5% [17·1–39 . 8]; p<0·0001) than did patients with placebo (23 [20%] patients). Up to week 24, serious adverse events were reported in three (3%) patients with ixekizumab every 4 weeks, eight (7%) with ixekizumab every 2 weeks, and four (3%) with placebo; no deaths were reported. Infections were reported in 47 (39%) patients with ixekizumab every 4 weeks, 47 (38%) with ixekizumab every 2 weeks, and 35 (30%) with placebo. Three (2%) serious infections, all in patients in the ixekizumab every 2 weeks group, were reported. Interpretation Both the 2-week and 4-week ixekizumab dosing regimens improved the signs and symptoms of patients with active psoriatic arthritis and who had previously inadequate response to tumour necrosis factor inhibitors, with a safety profle consistent with previous studies investigating ixekizumab. Funding Eli Lilly and Company. Introduction Psoriatic arthritis is a chronic immune-mediated infam- matory disease with several musculoskeletal (eg, peripheral arthritis, axial involvement, enthesitis, and dactylitis) and extra-articular manifestations (eg, skin and nail psoriasis). 1 Psoriatic arthritis can be progressive and destructive, leading to impaired function, a reduction in quality of life, and increased mortality. 1,2 For patients with psoriatic arthritis for whom conventional treatment is insufcient, biological treatment is recommended, with tumour necrosis factor (TNF) inhibitors being the most frequently used; however, in a substantial proportion of patients, TNF inhibitor treatment might be contraindicated, not tolerated, or associated with transient or insufcient response. 3 Thus, therapies with an alternative mechanism of action in psoriatic arthritis are clinically important. Interleukin-17A is a cytokine that can promote joint infammation and damage by triggering the recruitment of immune cells into sites of infammation and augmenting pro-infammatory cytokine and chemokine production. 4 The concentration of cells (ie, T cells and innate immune cells) that produce interleukin-17A are increased in the peripheral blood and the synovial tissue and fuid of patients with psoriatic arthritis, 5–7 with these Published Online May 24, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)31429-0 See Online/Comment http://dx.doi.org/10.1016/ S0140-6736(17)31427-7 * SPIRIT-P2 Study Group members are listed in the appendix Department of Medicine, University of Queensland, Rheumatology Research Unit, Sunshine Coast, QLD, Australia (Prof P Nash FRACP); Guy’s and St Thomas’ NHS Foundation Trust, London, UK (Prof B Kirkham MD); Immuno-Rheumatology Center, St Luke’s International University, St Luke’s International Hospital, Tokyo, Japan (M Okada MD); Department of Medicine, Memorial University, St Clare’s Mercy Hospital, St John’s, NL, Canada (Prof P Rahman MD); Departement of Rheumatology, Lapeyronie Hospital, Montpellier Université, Montpelier, France (Prof B Combe MD); Department of Rheumatology and Clinical Immunology, Charite University Medicine Berlin, Campus Mitte, Berlin, Germany (Prof G-R Burmester MD); Eli Lilly and Company, Indianapolis, IN, USA (D H Adams PhD, L Kerr MSPH, C Lee MD, C L Shuler MS); and Department of Medicine, Stanford University, Palo Alto, CA, USA (Prof M Genovese MD) Correspondence to: Prof Peter Nash, Department of Medicine, University of Queensland, QLD 4072, Australia drpnash@tpg.com.au