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...

IntroductionThe role of adiponectin in the pathogenesis of arthritis is still controversial. This study was performed to examine whether adiponectin is involved in joint inflammation and destruction in rheumatoid arthritis (RA) in relation to the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs).MethodsSynovial cells from RA patients were treated with adiponectin or interleukin (IL)-1β for 24 hours. The culture supernatant was collected and analyzed for the levels of IL-6, IL-8, prostaglandin E2 (PGE2), VEGF, and MMPs by enzyme-linked immunosorbent assay. The levels of adiponectin, VEGF, MMP-1, and MMP-13 in the joint fluids from 30 RA or osteoarthritis (OA) patients were also measured.ResultsAdiponectin at the concentration of 10 μg/mL stimulated the production of IL-6, IL-8, and PGE2 in RA fibroblast-like synoviocytes (FLSs), although the level of these was much lower than with 1 ng/mL IL-1β. However, adiponectin stimulated the production of VEGF, MMP-1, and MMP-13 at the same level as IL-1β. In addition, the level of adiponectin and MMP-1 in the joint fluid of RA patients was significantly higher than in OA patients. Adiponectin was positively correlated with VEGF in RA patients but not in OA patients, while the level of MMPs in joint fluid was not correlated with adiponectin in either RA or OA patients.ConclusionsAdiponectin may play a significant role in the pathogenesis of RA by stimulating the production of VEGF and MMPs in FLSs, leading to joint inflammation and destruction, respectively.

This study was performed to provide evidence, albeit indirectly, as to which matrix metalloproteinases (MMPs), among the gelatinases MMP-2 and MMP-9 and the collagenases MMP-1 and MMP-13, play a more proactive role in the angiogenic process in arthritic joint. Joint fluid was collected from 33 patients with rhuematoid arthritis (RA) and osteoarthritis (OA), and protein (MMPs and vascular endothelial growth factor (VEGF)) levels were measured by ELISA, and the association of MMPs with VEGF was evaluated in joint fluid of patients with RA or OA. The levels of collagenases (total MMP-1 and total MMP-13) and gelatinases (total MMP-2 and total MMP-9) in RA joint fluid were significantly higher than those in OA fluid. Total MMP-9 levels were significantly associated with VEGF levels in RA fluids, but not in OA fluid, while total MMP-13 levels were strongly associated with VEGF levels in both RA and OA fluid. However, total MMP-2 and total MMP-1 levels were not associated with VEGF levels in either RA or OA joint fluid. Our results indirectly suggest that in RA and OA, MMP-9 and MMP-13 may play a more important role in angiogenesis than MMP-2 and MMP-1.

ObjectiveHealth-related quality of life (HRQOL) in patients with fibromyalgia (FM) is lower than in patients with other chronic diseases and the general population. Although various factors affect HRQOL, no study has examined a structural equation model of HRQOL as an outcome variable in FM patients. The present study assessed relationships among physical function, social factors, psychological factors, and HRQOL, and the effects of these variables on HRQOL in a hypothesized model using structural equation modeling (SEM).MethodsHRQOL was measured using SF-36, and the Fibromyalgia Impact Questionnaire (FIQ) was used to assess physical dysfunction. Social and psychological statuses were assessed using the Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory (STAI), the Arthritis Self-Efficacy Scale (ASES), and the Social Support Scale. SEM analysis was used to test the structural relationships of the model using the AMOS software.ResultsOf the 336 patients, 301 (89.6%) were women with an average age of 47.9±10.9 years. The SEM results supported the hypothesized structural model (χ2 = 2.336, df = 3, p = 0.506). The final model showed that Physical Component Summary (PCS) was directly related to self-efficacy and inversely related to FIQ, and that Mental Component Summary (MCS) was inversely related to FIQ, BDI, and STAI.ConclusionsIn our model of FM patients, HRQOL was affected by physical, social, and psychological variables. In these patients, higher levels of physical function and self-efficacy can improve the PCS of HRQOL, while physical function, depression, and anxiety negatively affect the MCS of HRQOL.

Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily involving the spine and sacroiliac joint and rarely the kidneys. This study aimed to define the clinical and histological features and biology of renal disease in AS. We reviewed the medical records of 681 patients diagnosed with AS from November 2008 to November 2009. Baseline characteristics and laboratory and urinalysis results were reviewed. We identified patients with proteinuria or hematuria and analyzed their risk factors. After providing informed consent, 6 patients underwent a renal biopsy to determine the cause of proteinuria or hematuria. Of the 681 enrolled patients, 547 were men and 134 were women; 81 % were HLA B27 positive, and 8 % had abnormal urinalysis findings (proteinuria, 5.9 %; hematuria, 2.8 %; both, 0.7 %). Incidences of peripheral arthritis and uveitis were 29 % and 18.6 %, respectively. Immunoglobulin (Ig)A and uric acid levels were significantly different between patients with and without proteinuria. Erythrocyte sedimentation rate (ESR), total cholesterol, creatinine, and C-reactive protein (CRP) levels were not statistically significantly different between the 2 groups nor were there any significant differences in IgA, uric acid, ESR, total cholesterol, creatinine, and CRP levels between patients with and without hematuria. Six patients who had >1 g/day proteinuria underwent a renal biopsy; 2 were diagnosed with IgA nephropathy, 1 with amyloidosis, and 3 with non-specific glomerulonephropathy. In the amyloidosis patient, severe proteinuria was the dominant feature. For patients with renal amyloidosis and other forms of glomerulonephritis who initially had normal creatinine levels, tumor necrosis factor (TNF)-alpha blocker therapy resolved proteinuria, but this was not the case for patients with initial renal insufficiency. Renal involvement is not a rare complication of AS, and prognoses differ depending on kidney pathology. Serum levels of uric acid and IgA may predict renal involvement in AS. In cases where abnormal urine sediment is identified, renal biopsy is required to determine prognosis and decide the treatment protocol. Baseline serum creatinine level is important for predicting treatment response.

It has been suggested that taurine chloramine (TauCl) plays an important role in the downregulation of proinflammatory mediators. However, little is known about its effect on the expression of matrix metalloproteinases (MMPs). In this study, we investigated the effects of TauCl on synovial expression of MMPs. The effects of TauCl on MMP expression in IL-1β stimulated fibroblast-like synoviocytes (FLSs) were studied using the following techniques. Real-time PCR and semi-quantitative PCR were employed to analyze the mRNA expression of MMPs. ELISA was used to determine protein levels of MMPs. Western blot analyses were performed to analyze the mitogen-activated protein kinase and inhibitor of nuclear factor-κB (IκB) kinase signalling pathways. Finally, electrophoretic mobility shift assay and immunohistochemistry were used to assess localization of transcription factors. IL-1β increased the transcriptional and translational levels of MMP-1 and MMP-13 in rheumatoid arthritis FLSs, whereas the levels of MMP-2 and MMP-9 were unaffected. TauCl at a concentration of 400 to 600 μmol/l greatly inhibited the transcriptional and translational expression of MMP-13, but the expression of MMP-1 was significantly inhibited at 800 μmol/l. At a concentration of 600 μmol/l, TauCl did not significantly inhibit phosphorylation of mitogen-activated protein kinase or IκB degradation in IL-1β stimulated rheumatoid arthritis FLSs. The degradation of IκB was significantly inhibited at a TauCl concentration of 800 μmol/l. The inhibitory effect of TauCl on IκB degradation was confirmed by electrophoretic mobility shift assay and immunochemical staining for localization of nuclear factor-κB. TauCl differentially inhibits the expression of MMP-1 and MMP-13, and inhibits expression of MMP-1 primarily through the inhibition of IκB degradation, whereas it inhibits expression of MMP-13 through signalling pathways other than the IκB pathway.

Our objective was to examine whether adjunct teriparatide administration and local application of recombinant human bone morphogenetic protein-2 (rhBMP-2) is beneficial for the regeneration of jaw bone in patients with medication-related osteonecrosis of the jaw (MRONJ). This study enrolled 17 patients diagnosed with MRONJ. All patients received sequestrectomy under general or local anesthesia with suspension of bisphosphonate. The bone regeneration ratio was compared on cone beam computed tomography (CBCT) scans, acquired immediately post-operation and after 6 months. The patients were divided into groups, based on their treatment regimens: teriparatide combined with rhBMP-2 (parathyroid hormone [PTH]+BMP), rhBMP-2 (BMP), and the control. Biochemical markers were also evaluated at the baseline (T0), 1 month (T1), and 3 months (T2) after surgery. Significant increase was observed in the values of the biochemical markers, serum osteocalcin, and serum C-terminal telopeptide cross-link of type I collagen, within 3 months of surgery in the PTH+BMP group, whereas the mean value in the BMP group did not show a significant change. In all groups, the MRONJ lesions were healed and new bone formation was detected in the CBCT images. The regeneration ratio was significantly greater in the group PTH+BMP than in the BMP and control groups. Significantly greater amount of bone formation was observed in the group PTH+BMP than in the BMP and control groups. Local application of rhBMP-2 alone also had a beneficial effect on bone regeneration but was not more significant than control. Based on these findings, administration of short-term teriparatide with rhBMP-2 in MRONJ patients may maximize the regeneration of bone after surgery. © 2017 American Society for Bone and Mineral Research.

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