Background: Biologic disease modifying anti-rheumatic drugs (bDMARDs) are recommended for radiographic axial spondyloarthritis (r-axSpA), otherwise known as ankylosing spondylitis, when conventional therapies fail. We report efficacy and safety results of a Phase 3 study of ixekizumab, a high-affinity monoclonal antibody that selectively targets IL-17A, in bDMARDnaïve patients with r-axSpA. Methods: In this randomized, double-blind, Phase 3 study, adult patients with inadequate response/intolerance to NSAIDs, an established diagnosis of r-axSpA, and with radiographic sacroiliitis centrally defined by modified New York criteria and ≥1 spondyloarthritis feature according to Assessment of Spondyloarthritis International Society (ASAS) criteria were recruited from 84 sites (12 countries) in Europe, Asia, and North America. Patients were randomized 1:1:1:1 using a computer-generated random sequence to 80 mg subcutaneous ixekizumab every two (Q2W) or four (Q4W) weeks, 40 mg adalimumab Q2W (active reference arm), or placebo. The primary endpoint was the proportion of patients achieving an ASAS40 response at Week 16. Findings: Between June 20, 2016 and August 22, 2017, 341 patients were randomized to placebo (N=87), adalimumab (N=90), ixekizumab Q2W (N=83), or ixekizumab Q4W (N=81). At Week 16, significantly more patients achieved ASAS40 with ixekizumab Q2W (n=43, 51•8%, p<0•0001), ixekizumab Q4W (n=39, 48•1%, p<0•0001), and adalimumab (n=32, 35•6%; p=0•0053) versus placebo (n=16, 18•4%). One serious infection occurred in each of the ixekizumab Q2W (1•2%), ixekizumab Q4W (1•2%), and adalimumab (1•1%) arms; none were reported with placebo. One (1•1%) Candida infection occurred in the adalimumab arm and one (1•2%) patient receiving ixekizumab Q2W was adjudicated as having probable Crohn's disease. No opportunistic infections, malignancies, or deaths occurred. Interpretation: Each dosing regimen of ixekizumab was superior to placebo for improving r-axSpA signs and symptoms in bDMARD-naïve patients; the safety profile was consistent with previous studies of ixekizumab. The adalimumab control arm performed as expected. Funding: Eli Lilly and Company Research in context Evidence before this study Pubmed was searched using the terms "ankylosing spondylitis", "axial spondyloarthritis", and "disease-modifying anti-rheumatic drugs", including articles through May 30, 2018. Axial spondyloarthritis (axSpA) is a chronic immune-mediated disease characterized by inflammation of the spine and sacroiliac joint (SIJ), peripheral joint involvement, extra articular manifestations, and a strong genetic association with human leukocyte antigen (HLA)-B27. Radiographic axSpA (r-axSpA) was previously classified as ankylosing spondylitis (AS) in 1984 and updated to r-axSpA as part of the ASAS criteria. Both criteria sets require the same radiographically confirmed structural damage to the sacroiliac joint as well as at least one accompanying clinical element. Recommendations for the management of r-axSpA generally include exercise and physiothera...

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SUMMARYVascular endothelial growth factor (VEGF) is abundant in synovium and synovial fluids, where it probably contributes to vascular permeability and angiogenesis in arthritic joints. To investigate the probable sources of VEGF in synovium, we compared the ability of several cytokines (TGF-b, plateletderived growth factor (PDGF), IL-1, tumour necrosis factor (TNF), basic fibroblast growth factor (bFGF) that are associated with arthritis and angiogenesis, to stimulate secretion of VEGF protein by human synovial fibroblasts. TGF-b was the strongest inducer of VEGF secretion; six times more VEGF was secreted when cells were stimulated by TGF-b than when stimulated by PDGF or IL-1 for 24 h. TNF-a and bFGF did not stimulate any secretion of VEGF. The stimulatory effects of TGF-b and IL-1 on VEGF secretion were additive. Hypoxic culture alone also stimulated VEGF secretion, but more importantly, hypoxic culture conditions doubled the rate of VEGF secretion stimulated by the cytokines TGF-b and IL-1. When dermal and synovial fibroblasts were stimulated identically by hypoxia and cytokines (TGF-b and IL-1), synovial fibroblasts secreted four times more VEGF than did dermal fibroblasts. Thus in rheumatoid arthritis, the capacity of synovial fibroblasts in the hypoxic environment to secrete large amounts of VEGF in response to cytokines such as TGF-b probably contributes significantly to angiogenesis in the synovium.

Objective. The zinc-finger protein tristetraprolin (TTP) has been demonstrated to regulate tumor necrosis factor ␣ (TNF␣) messenger RNA (mRNA) instability in murine macrophages. We sought to develop a model system to characterize the effects of human TTP (hTTP) on TNF␣ 3-untranslated region (3-UTR)-mediated expression. We also generated a specific polyclonal antibody against hTTP that enabled the examination of the subcellular distribution of hTTP and its RNA binding in vivo.Methods. Transfection of reporter gene constructs were used to functionally characterize the role of hTTP in regulating TNF␣ expression in a 3-UTRdependent manner. An immunoprecipitation reverse transcription-polymerase chain reaction technique, immunoblotting, immunocytochemistry, and sucrose density fractionation were used to identify and localize hTTP.Results. We found that hTTP interacted with human TNF␣ mRNA in the cytoplasm. The presence of the TNF␣ 3-UTR was sufficient to confer binding by TTP in vivo. This interaction resulted in reduced luciferase reporter gene activity in a TNF␣ 3-UTR adenineuridine-rich element (ARE)-dependent manner. Immunoblotting and immunocytochemistry indicated that endogenous and transfected hTTP localized to the cytoplasm. Results of sucrose density fractionation studies were consistent with a polysomal location of hTTP. In rheumatoid synovium, hTTP expression was restricted to cells in the synovial lining layers.Conclusion. Through the development of an antiserum specific for hTTP, we have been able to demonstrate that hTTP binds specifically to the TNF␣ 3-UTR and reduces reporter gene expression in an AREspecific manner. These studies establish that hTTP is likely to function in a similar, if not identical manner, in the posttranscriptional regulation of TNF␣. Understanding the posttranscriptional regulation of TNF␣ biosynthesis is important for the development of novel treatment strategies in rheumatoid arthritis.

An increased risk for Systemic Autoimmune Diseases (SAID) has been reported in Libby, Montana, where extensive exposures to fibrous amphiboles occurred due to mining and use of asbestos-laden vermiculite. In addition, positive antinuclear autoantibody tests are associated with exposure to Libby Asbestiform Amphiboles (LAA) in both humans and mice. Among 6603 subjects who underwent health screening at the Center for Asbestos Related Diseases (CARD, Libby MT), 13.8% were diagnosed with an autoimmune disease, with prevalence values for the most common SAID being significantly higher than expected in the United States. Among the CARD screening population, serological and clinical profiles are diverse, representing symptoms and autoantibodies reflective of systemic lupus erythematosus (SLE), scleroderma, rheumatoid arthritis and other rheumatic syndromes including Undifferentiated Connective Tissue Disease (UCTD). Based upon screening of medical records by physicians with rheumatology expertise, the evolving nature of rheumatological disease in these patients is often atypical, with mixed diagnostic criteria and with a 1:1 male-to-female ratio. Through the Libby Epidemiology Research Program, cases were identified that illustrate clinical autoimmune outcomes with LAA exposure. Our goal was to better characterize SAID in Libby, MT in order to improve recognition of autoimmune outcomes associated with this exposure. In view of recent discoveries of widespread exposure to fibrous minerals in several areas of the U.S. and globally, it is critical to evaluate rheumatologic manifestations in other cohorts so that screening, surveillance and diagnostic procedures are able to detect and recognize potential autoimmune outcomes of asbestos exposure.