Serious infections were reported in 0

Serious infections were reported in 0.9%, 0.7% and 0.9% of patients, respectively, through week 18, and were numerically greater in the sirukumab 100?mg every?2?weeks combined (3.3%) and 50?mg every?4?weeks combined (4.1%) groups (including EE patients) compared with the placebo group (1.8%) through week 52. patients achieved American College of Rheumatology 20% (ACR20) response at week 16 (coprimary endpoint) with sirukumab 100?mg every 2 weeks (53.5%) or 50?mg every 4 weeks (54.8%) versus placebo (26.4%; both p 0.001). Mean (SD) change from baseline in modified Sharp/van der Heijde score at week 52 (coprimary endpoint) was significantly lower with sirukumab (100?mg every 2 weeks: 0.46 (3.26); 50?mg every 4 weeks: 0.50 (2.96)) versus placebo (3.69 (9.25); both p 0.001). All major secondary endpoints Mouse monoclonal to EphB3 (week 24 Health Assessment QuestionnaireCDisability Index change from baseline, ACR50 response, 28-joint Disease Activity Score based on C reactive protein and major clinical response (ACR70 for six continuous months by week 52)) were met. The most common adverse events with sirukumab were elevated liver enzymes, upper respiratory tract infection, injection site erythema and nasopharyngitis. Conclusions Sirukumab 100?mg every 2 weeks and 50?mg every 4 weeks led to significant reductions in RA symptoms, inhibition of structural damage progression and physical function and quality of life improvements, with an expected safety profile. Trial registration number “type”:”clinical-trial”,”attrs”:”text”:”NCT01604343″,”term_id”:”NCT01604343″NCT01604343; Results. strong class=”kwd-title” Keywords: rheumatoid arthritis, cytokines, DMARDs (biologic), DMARDs (synthetic), treatment Introduction Patients with rheumatoid arthritis (RA) often have increased levels of interleukin?(IL)-6 in serum and the synovial compartment where its levels are correlated to local disease activity.1C3 In the RA synovium, both tumour necrosis factor (TNF) and IL-1 can stimulate IL-6 production by multiple cell types.4 Local concentrations of IL-6 may stimulate leucocyte recruitment to the joint, promote osteoclast maturation GSK 4027 and activation, suppress chondrocytes and stimulate synovial proliferation, summarily contributing to joint damage.5 Systemically, elevated IL-6 levels in patients with RA may induce haepatic production of acute-phase proteins6 and likely increase hepcidin and the development of anaemia of chronic inflammation.7 Elevated IL-6 may also be responsible for autoimmune features in RA, such as autoreactive T?cell activation and hypergammaglobulinaemia.8 Therefore, GSK 4027 IL-6 is an attractive target for the treatment of RA. In patients with active RA and inadequate response to disease-modifying antirheumatic drug (DMARD) therapy, inhibition of the IL-6 receptor with the monoclonal antibody (mAb) tocilizumab reduced joint swelling and tenderness, improved physical function and reduced the rate of radiographic progression.9C12 Another antiCIL-6 receptor mAb, sarilumab, demonstrated similar efficacy in patients with RA and inadequate GSK 4027 response to methotrexate (MTX).13 Although the clinical relevance of a different mechanism of targeting the IL-6 pathway is not fully understood, sirukumab is a human mAb that selectively binds to the IL-6 cytokine with high affinity. Sirukumab was shown to significantly improve signs and symptoms (eg, American College of Rheumatology 20% (ACR20) response at week 16), functionality and quality of life versus placebo in a difficult-to-treat population of RA patients refractory to anti-TNF and other biologicals.14 Two other antibodies to IL-6, clazakizumab and olokizumab, have demonstrated activity in phase II studies of RA patients with an inadequate response to MTX or failure to anti-TNF therapy, respectively.15 16 The SIRROUND-D study ( identifier “type”:”clinical-trial”,”attrs”:”text”:”NCT01604343″,”term_id”:”NCT01604343″NCT01604343) was designed to assess efficacy and safety of subcutaneous (SC) GSK 4027 sirukumab in patients with active RA despite DMARD therapy over 52?weeks. Methods Patients Patients from 18 countries (USA, Canada, Mexico, Colombia, Chile, South Africa, Lithuania, Poland, Russia, Ukraine, Serbia, Croatia, Bulgaria, Romania, Japan, South Korea, Taiwan?and Malaysia) were enrolled and monitored between July 2012 and September 2015. Eligible patients were aged?18?years, had moderately to severely active RA and were refractory to single-agent or combination DMARD therapy including MTX or sulfasalazine, based on lack of benefit after?12?weeks. Patients needed?6/68 tender joints and?6/66 swollen joints at screening and baseline; C?reactive protein (CRP)?8.0?mg/L; and?1?of the following three criteria to be met prior to treatment: (A) anticitrullinated peptide antibody-positive (measured by anticyclic citrullinated peptide antibody test) at screening; (B) rheumatoid factor positive at screening; or (C) documented history of radiographic evidence of erosive RA in the?hands and/or feet. Patients using non-biological DMARDs must have been on a stable dose for?4?weeks prior to receiving study drug. Patients not currently using DMARDs must not have received DMARDs for?4?weeks prior to receiving study drug. Patients who previously were treated with biologicals were permitted, as long as they had not failed anti-TNF or tocilizumab for safety or efficacy reasons and had not received biologicals within the past 3?months (6?weeks for etanercept or yisaipu and 4?weeks for anakinra). Patients with a history of or current serious infection (including tuberculosis) were excluded. Study design This global, phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group study randomised patients 1:1:1 at week 0 to sirukumab 100?mg SC every 2?weeks, sirukumab 50?mg SC every 4?weeks or placebo SC every?2?weeks (see online supplementary figure S1). These doses were previously studied in a.