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Abstract We compared the efficacy of tocilizumab and etanercept in inhibiting radiographic progression of joint destruction in rheumatoid arthritis. Overall, 187 patients treated with etanercept or tocilizumab were selected. To adjust for baseline patient characteristics between the tocilizumab and etanercept treatment groups, a propensity score matching was performed. Radiographic progression of joint destruction was compared between patients treated with tocilizumab or etanercept. Clinical disease activity index (CDAI) and modified health assessment questionnaire (mHAQ) scores at the administration of biologic treatment and after 12 months of tocilizumab and etanercept therapy were measured and compared to radiographical parameters between the groups. Levels of C-reactive protein (CRP), matrix metalloproteinase-3 (MMP-3), CDAI, and mHAQ scores improved after 12 months of treatment in the two groups. Proportion of patients with no Sharp erosion score progression was significantly higher with tocilizumab treatment than with etanercept treatment (p = 0.032). Multivariate analysis demonstrated that Sharp erosion score was significantly associated with baseline CDAI (odds ratio, 1.05; 95% confidence interval, 1.003–1.099, p = 0.037). Tocilizumab treatment suppressed joint erosion progression compared to etanercept, and the progression correlated with baseline CDAI.

Abstract Background To improve implant survival through accelerated early bone remodeling during total hip arthroplasty (THA), hydroxyapatite (HA) is widely used as a bioactive coating, which is believed to enhance initial fixation by osseointegration. We aimed to investigate the relationship between stem insertion alignment and postoperative bone mineral density (BMD) changes in patients with full hydroxyapatite-coated (HA) compaction short stem and short tapered-wedge stem. Methods This retrospective cohort study enrolled 115 consecutive patients (115 joints) undergoing THA using the full HA compaction short (n = 59) and short tapered-wedge (n = 56) stems. Stem alignment, including anteversion, valgus, and anterior tilt were measured by a three-dimensional template using computed tomography data. Post-operative peri-prosthetic BMD was measured by dual-energy X-ray absorptiometry. The relationship between stem alignment and BMD changes in the stems was analyzed. Results Patterns of peri-prosthetic BMD changes were similar in both groups. Stem insertion alignments of anteversion, valgus, and anterior tilt were different between the two stem types. Stem alignment of valgus and anterior tilt did not affect peri-prosthetic BMD in either of the stem type. An absolute anteversion difference between stem anteversion and original canal anteversion caused significant peri-prosthetic BMD loss in Gruen zones one and seven in the tapered-wedge stem. However, stem alignment of absolute anteversion difference did not affect BMD changes in the HA compaction stem. Conclusions Peri-prosthetic bone remodeling remained unaffected by stem alignment after THA with the new short full HA compaction stem.

Abstract We recently reported that cyclin-dependent kinase inhibitor 1 (p21) deficiency induces osteoarthritis susceptibility. Here, we determined the mechanism underlying the effect of p21 in synovial and cartilage tissues in RA. The knee joints of p21-knockout (p21−/−) (n = 16) and wild type C57BL/6 (p21+/+) mice (n = 16) served as in vivo models of collagen antibody-induced arthritis (CAIA). Arthritis severity was evaluated by immunological and histological analyses. The response of p21 small-interfering RNA (siRNA)-treated human RA FLSs (n = 5 per group) to interleukin (IL)-1β stimulation was determined in vitro. Arthritis scores were higher in p21−/− mice than in p21+/+ mice. More severe synovitis, earlier loss of Safranin-O staining, and cartilage destruction were observed in p21−/− mice compared to p21+/+ mice. p21−/− mice expressed higher levels of IL-1β, TNF-α, F4/80, CD86, p-IKKα/β, and matrix metalloproteinases (MMPs) in cartilage and synovial tissues via IL-1β-induced NF-kB signaling. IL-1β stimulation significantly increased IL-6, IL-8, and MMP expression, and enhanced IKKα/β and IκBα phosphorylation in human FLSs. p21-deficient CAIA mice are susceptible to RA phenotype alterations, including joint cartilage destruction and severe synovitis. Therefore, p21 may have a regulatory role in inflammatory cytokine production including IL-1β, IL-6, and TNF-α.

Abstract Background Novel therapeutic strategies for the healing of nonunion, which has serious effects on the quality of life of patients, are needed. We evaluated the therapeutic effect of local transplantation of human stromal vascular fraction (SVF) cells on fracture healing in a rat non-healing fracture model and compared the effects between freshly isolated (F) and cryopreserved (C)-SVFs. Methods Non-healing fracture model was induced in the femur of female immunodeficient rats (F344/N Jcl rnu/rnu) with cauterizing periosteum. Immediately after the creation of non-healing fracture, rats received local transplantation of F and C-SVFs suspended in phosphate-buffered saline (PBS) or the same volume of PBS without cells using the same scaffold as a control group. During 8 weeks post-surgery, radiologic, histological, immunohistochemical, and biomechanical analyses were performed to evaluate fracture healing. The comparison of radiological results was performed with a chi-square test, and the multiple comparisons of immunohistochemical, histological, and biomechanical results among groups were made using a one-way analysis of variance. A probability value of 0.05 was considered to denote statistical significance. Results At week 8, in 60% of animals receiving F-SVF cells and in 50% of animals receiving C-SVF cells, the fracture radiologically healed with bone union whereas nonunion was observed in the control group. The healing potential was also confirmed by histological and biomechanical assessments. One of the mechanisms underlying healing involving intrinsic angiogenesis/osteogenesis was enhanced in F- and C-SVF groups compared with that in the control group. Human cell-derived vasculogenesis/osteogenesis, which was also confirmed in an in vitro differentiation assay, was also enhanced in the F- and C-SVF groups compared with that in the control groups and could be another mechanism for healing. Conclusions SVF cells can enhance bone healing and cryopreserved cells have almost equal potential as fresh cells. SVF cells can be used for improving nonunion bone fracture healing as an alternative to other mesenchymal stem cells and the effect of SVF cells can be maintained under cryopreservation.

Introduction: The concept of anatomic restoration has garnered considerable interest in the form of kinematically aligned total knee arthroplasty (KA-TKA). KA-TKAs have been reported to reproduce natural alignment and kinematics. However, few randomized controlled trials (RCTs) have compared the biomechanical outcomes and the long-term clinical outcomes of KA-TKA with those of mechanically aligned TKA (MA-TKA). We aim to investigate the long-term clinical and biomechanical effects of KA-TKA and to determine whether KA-TKA or MA-TKA is more appropriate for primary TKA. Methods: This trial will compare clinical and biomechanical outcomes of KA-TKA to those of MA-TKA. Two hundred patients will be enrolled in the RCT and randomized into KA-TKA or MA-TKA groups. Both the groups will be evaluated 1 week before the operation, on the day of the operation, 6 months after the operation, and 1, 5, and 10 years after the operation. The primary outcome is the difference between preoperative and 1-year postoperative functional activity scores of the 2011 Knee Society Score (2011 KSS) in both groups as well as the differences between the scores of both groups. The secondary outcomes will include differences in symptom, satisfaction, and expectation scores of the 2011 KSS, intraoperative kinematics evaluation, postoperative clinical outcomes and complications, pre- and postoperative gait analyses and radiograph evaluations between both KA-TKA and MA-TKA.

ABSTRACT Improving patient health‐related quality of life (HRQOL) and prevention of bone fracture are important components of the treatment of osteoporosis. Our aim in this study was to evaluate the effect of denosumab treatment in improving HRQOL among patients with osteoporosis. Our analysis was based on 332 patients with osteoporosis, followed for 24 months. All patients received denosumab (60 mg) subcutaneously every 6 months. Bone mineral density (BMD) was assessed at the distal radius, with serum concentration of calcium, phosphate, P1NP, and TRACP5b also measured. HRQOL assessment included pain (visual analogue scale [VAS]) and the EQ‐5D questionnaire. A multivariate analysis was performed to identify the possible confounders associated with deterioration in the EQ‐5D utility score in response to denosumab treatment. Denosumab treatment yielded a 3.4% increase in BMD at 24 months. Serum levels of TRACP5b and P1NP decreased significantly, from baseline, at 6 months, with no effect on calcium and phosphate levels. Pain VAS and EQ‐5D utility score improved significantly, from baseline, at 6 months, with the EQ‐5D utility score correlating with the BMD at all time points of measurement over the 24‐month period of observation. Knee osteoarthritis and multiple comorbidities were significantly associated with a worse HRQOL in response to denosumab treatment. Denosumab treatment increased BMD, with improvements in BMD correlating with improved HRQOL, supporting a possible benefit of using denosumab for the treatment of osteoporosis. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Objectives: Methotrexate (MTX) is recommended as a first-line conventional synthetic disease-modifying antirheumatic drug (csDMARD) for treating rheumatoid arthritis (RA). This retrospective study sought to identify an add-on csDMARD treatment strategy for RA patients with MTX-inadequate response (IR). Methods: We collected the cases of RA patients treated with salazosulfapyridine (SASP) or iguratimod (IGU) as the additional csDMARD for MTX-IR during a 24-month follow-up. We performed propensity score matching to evaluate the retention rate, clinical efficacy, and safety profile (푛 = 54, each group). Results: The retention rates at 24 months were 38.5% (MTX+SASP group) and 67.8% (MTX+IGU group). At 3 and 6 months, the MTX+IGU group’s 28 joint-disease activity score (DAS28) was significantly decreased versus the MTX+SASP group, and at 3 months the MTX+IGU group’s good-responder percentage (22.9%) was significantly higher versus the MTX+SASP group’s good-responder percentage (10.7%). Conversely, compared to the MTX+SASP group, the MTX+IGU group showed a greater reduction in the estimated glomerular filtration rate from baseline during follow-up. Conclusions: IGU is a useful add-on csDMARD for RA patients with MTX-IR; its high retention rate and good clinical response make it a useful combination therapy for controlling RA disease activity. However, the renal function should be monitored during follow-up. [ABSTRACT FROM AUTHOR]

Objectives: Decoy receptor 3 (DcR3) competitively binds to Fas ligand, lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpes virus entry mediator on T cells (LIGHT) and TNF-like ligand 1A (TL1A), thereby preventing their effects. Using a microarray assay, we previously newly identified centrosomal protein 70 kDa (CEP70) as one of the genes whose expression in fibroblast-like synoviocytes from patients with rheumatoid arthritis (RA-FLS) is reduced by DcR3. Here, we investigated the significance of DcR3 regulation of CEP70 for RA-FLS. Methods: Synovial samples were obtained from RA patients who had never been treated with biologics and from osteoarthritis (OA) patients. CEP70 mRNA expression was quantified using RT-qPCR analysis. CEP70 protein expression was assessed using immunohistochemical and western blot analyses. Results: CEP70 was expressed predominantly in the superficial lining layer in RA synovial tissue. CEP70 expression was dose-dependently downregulated by DcR3-Fc in RA-FLS but was not downregulated in OA-FLS. TL1A antibody prevented the DcR3-Fc inhibitory effects on CEP70 expression in RA-FLS. Conclusions: These results indicated that DcR3 reduces CEP70 expression in RA-FLS by binding to membrane-bound TL1A and may suppress RA-FLS proliferation. The reduction in CEP70 expression by DcR3/TL1A signaling may control the hyperplasia of RA synovium. [ABSTRACT FROM AUTHOR]

Decoy receptor 3 (DcR3) competitively binds to three ligands, Fas ligand, lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells and tumor necrosis factor-like ligand 1A (TL1A), to prevent their effects. Recent studies have suggested that DcR3 directly affects cells as a ligand. Using a microarray assay, our group newly identified interleukin (IL)-12B, which encodes the p40 subunit common to IL-12 and IL-23, as one of the genes for which expression in fibroblast-like synoviocytes from patients with rheumatoid arthritis (RA-FLS) is induced by DcR3. The present study demonstrated that IL-12B mRNA expression was upregulated by DcR3-Fc in RA-FLS in a dose-dependent manner, but not in OA-FLS. IL-12B p40 protein in RA-FLS was increased when stimulated with DcR3-Fc. Pre-treatment with anti-TL1A antibody suppressed the upregulation of IL-12B mRNA in RA-FLS stimulated with DcR3-Fc. DcR3 mRNA expression in RA-FLS was induced by IL-23, but not by IL-12. These results indicated that DcR3 may increase IL-12 or IL-23 by inducing IL-12B p40 expression via membrane-bound TL1A on RA-FLS and that IL-23 reciprocally induces DcR3 expression in RA-FLS. DcR3 and IL-23 may interact in a feedback loop that aggravates local inflammation in patients with RA. [ABSTRACT FROM AUTHOR]

Decoy receptor 3 (DcR3) is expressed in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and downregulates the expression of tryptophan hydroxylase 1 (TPH1), which is the rate-limiting enzyme in serotonin synthesis. The aim of the present study was to determine the specificity of the effects of DcR3 on TPH1 in RA-FLS, and therefore determine whether DcR3 had the potential to modulate the pathogenesis of RA. The present study also aimed to compare the effects of DcR3 and inflammatory cytokines on the expression of TPH1 in RA-FLS and osteoarthritis (OA)-FLS. Primary cultured RAor OA-FLS were incubated with 1.0 µg/ml DcR3-Fc protein or 1.0 µg/ml control immunoglobulin G (IgG)1 for 12 h, or with 1.0 ng/ml tumor necrosis factor (TNF)α, 1.0 ng/ml interleukin (IL)-1β or serum-free Opti-MEM only, for 24 h. The relative mRNA expression levels of TPH1 were subsequently quantified using reverse transcription-polymerase chain reaction. The expression of serotonin in RA or OA synovial tissue was detected using immunohistochemistry. The mRNA expression of TPH1 was observed in both RA- and OA-FLS and was significantly decreased following treatment with DcR3 in the RA-FLS, however, not in the OA-FLS. The mRNA expression of TPH1 was significantly decreased following treatment with TNFα or IL-1β in both the RA- and OA-FLS. The expression of serotonin in the multi-layered lining synovial cells of RA and the outer layer lining synovial cells of OA was detected using immunohistochemistry. The present study is the first, to the best of our knowledge, to demonstrate that the expression of TPH1 in FLS is downregulated by inflammatory cytokines, and that DcR3 suppressed the expression of TPH1 in RA-FLS in a disease-specific manner. These results suggested that synovial serotonin may be involved in the pathogenesis of RA, and that TPH1 and DcR3 may be potential therapeutic targets for the treatment of RA. [ABSTRACT FROM AUTHOR]