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ID PMID Title PublicationDate abstract
25424522 Quantifying not only bone loss, but also soft tissue swelling, in a murine inflammatory ar 2015 Feb In rodent models of inflammatory arthritis, bone erosion has been non-invasively assessed by micro-computed tomography (micro-CT). However, non-invasive assessments of paw swelling (oedema) are still based on clinical grading by visual evaluation, or measurements by callipers, not always reliable for the tiny mouse paws. The aim of this work was to demonstrate a novel straightforward 3D micro-CT analysis protocol capable of quantifying not only joint bone erosion, but also soft tissue swelling, from the same scans, in a rodent inflammatory arthritis model. Balb/c mice were divided into two groups: collagen antibody-induced arthritis (CAIA) and CAIA treated with prednisolone, the latter reflecting an established treatment in human rheumatoid arthritis. Clinical paw scores were recorded. On day 10, front paws were assessed by micro-CT and histology. Micro-CT measurements included paw volume (bone and soft tissue together) and bone volume at the radiocarpal joint, and bone volume from the radiocarpal to the metacarpophalangeal joint. Micro-CT analysis revealed significantly lower paw volume (-36%, P < 0.01) and higher bone volume (+17%, P < 0.05) in prednisolone-treated CAIA mice compared with untreated CAIA mice. Paw volume and bone volume assessed by micro-CT correlated significantly with clinical and histological scores (|r| > 0.5, P < 0.01). Untreated CAIA mice showed significantly higher clinical scores, higher inflammation levels histologically, cartilage and bone degradation, and pannus formation, compared with treated mice (P < 0.01). The presented novel micro-CT analysis protocol enables 3D-quantification of paw swelling at the micrometre level, along with the typically assessed bone erosion, using the same images/scans, without altering the scanning procedure or using contrast agents.
26382589 Comparative effectiveness and safety of rituximab versus subsequent anti-tumor necrosis fa 2015 Sep 18 INTRODUCTION: Patients with active rheumatoid arthritis (RA) despite anti-tumor necrosis factor(anti-TNF)agent treatment can switch to either a subsequent anti-TNF agent or a biologic with an alternative mechanism of action, such as rituximab; however, there are limited data available to help physicians decide between these 2 strategies. The objective of this analysis was to examine the effectiveness and safety of rituximab versus a subsequent anti-TNF agent in anti-TNF-experienced patients with RA using clinical practice data from the Corrona registry. METHODS: Rituximab-naive patients from the Corrona registry with prior exposure to ≥1 anti-TNF agent who initiated rituximab or anti-TNF agents (2/28/2006-10/31/2012) were included. Two cohorts were analyzed: the trimmed population (excluding patients who fell outside the propensity score distribution overlap) and the stratified-matched population (stratified by 1 vs.  ≥2 anti-TNF agents, then matched based on propensity score). The primary effectiveness outcome was achievement of low disease activity (LDA)/remission (Clinical Disease Activity Index ≤10) at 1 year. Secondary outcomes included achievement of modified American College of Rheumatology (mACR) 20/50/70 responses and meaningful improvement (≥0.25) in modified Health Assessment Questionnaire (mHAQ) score at 1 year. New cardiovascular, infectious and cancer events were reported. RESULTS: Estimates for LDA/remission, mACR response and mHAQ improvement were consistently better for rituximab than for anti-TNF agent users in adjusted analyses. The odds ratio for likelihood of LDA/remission in rituximab versus anti-TNF patients was 1.35 (95% CI, 0.95-1.91) in the trimmed population and 1.54 (95% CI, 1.01-2.35) in the stratified-matched population. Rituximab patients were significantly more likely than anti-TNF patients to achieve mACR20/50 and mHAQ improvement in the trimmed population and mACR20 and mHAQ in the stratified-matched population. The rate of new adverse events per 100 patient-years was similar between groups. CONCLUSIONS: In anti-TNF-experienced patients with RA, rituximab was associated with an increased likelihood of achieving LDA/remission, mACR response and physical function improvement, with a comparable safety profile, versus subsequent anti-TNF agent users. TRIAL REGISTRATION: ClinicalTrials.gov NCT01402661 . Registered 25 July 2011.
25125593 Tumour necrosis factor inhibitor therapy and infection risk in axial spondyloarthritis: re 2015 Jan OBJECTIVES: Long-term data on infection risk in axial SpA (axSpA) are sparse. TNF inhibitors (TNFis) are increasingly being used in axSpA, with infection being the most important adverse event. We aimed to investigate the frequency of infections in axSpA and to identify factors predisposing to infection. METHODS: Data were extracted from a longitudinal observational cohort of patients with axSpA. Infection rates were calculated and multivariate analysis was performed to investigate the association of independent variables with infection. RESULTS: Data were analysed for 440 patients followed for a total of 1712 patient-years (pys). A total of 259 infections, of which 23 were serious, were recorded in 185 patients. The overall rate of any infection was 15 (95% CI 13, 17)/100 pys and the serious infection rate was 1.3 (95% CI 0.9, 2.0)/100 pys. There was no significant difference in the rate of any infection or serious infection in patients on TNFis compared with patients never on biologic agents. In the multivariate analysis, DMARD treatment, but not TNFi treatment, was associated with risk of infection. Age, disease duration, smoking status, BASFI, BASDAI, co-morbidity score and hospitalization were not associated with an increased risk of infection. CONCLUSION: The serious infection rate in axSpA in this observational cohort is low when compared with rates reported in other rheumatic diseases. Biologic use was not a significant risk factor for serious infection.
26879143 The importin protein karyopherin-β1 regulates the mice fibroblast-like synoviocytes infla 2016 Mar 18 Karyopherin-β1 (KPNB1) which is an adaptor protein which transports several proteins to the nucleus. We study the functions and possible mechanisms of KPNB1 in collagen-induced arthritis (CIA). Western blotting and immunohistochemistry shows the protein expression of KPNB1 is increased in synovial tissue of CIA mice compared with the controls. Double immunofluorescent staining suggests that KPNB1 is expressed in CIA mice fibroblast-like synoviocytes (FLS). Moreover, the expression of KPNB1 in FLS is upregulated in time-dependent manner by IL-1β stimulation. Both immunoprecipitation and immunofluorescent staining assay reveals the interaction between KPNB1 and STAT3 and their translocation from cytoplasm to nucleus in IL-1β-treated FLS. Furthermore, suppression of KPNB1 inhibits IL-1β-induced the nucleus expression of STAT3 in FLS and decreases the expression of IL-6 and MMP-1, leading to attenuation of FLS invasion. Finally, the transport function of KPNB1 is depended on KPNA2. Therefore, we infer that KPNB1 may play a key role in the inflammation process of RA via STAT3 signal transduction pathway.
27092776 A Combination of CD28 (rs1980422) and IRF5 (rs10488631) Polymorphisms Is Associated with S 2016 INTRODUCTION: The aim of the study was to analyse genetic architecture of RA by utilizing multiparametric statistical methods such as linear discriminant analysis (LDA) and redundancy analysis (RDA). METHODS: A total of 1393 volunteers, 499 patients with RA and 894 healthy controls were included in the study. The presence of shared epitope (SE) in HLA-DRB1 and 11 SNPs (PTPN22 C/T (rs2476601), STAT4 G/T (rs7574865), CTLA4 A/G (rs3087243), TRAF1/C5 A/G (rs3761847), IRF5 T/C (rs10488631), TNFAIP3 C/T (rs5029937), AFF3 A/T (rs11676922), PADI4 C/T (rs2240340), CD28 T/C (rs1980422), CSK G/A (rs34933034) and FCGR3A A/C (rs396991), rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA) and clinical status was analysed using the LDA and RDA. RESULTS: HLA-DRB1, PTPN22, STAT4, IRF5 and PADI4 significantly discriminated between RA patients and healthy controls in LDA. The correlation between RA diagnosis and the explanatory variables in the model was 0.328 (Trace = 0.107; F = 13.715; P = 0.0002). The risk variants of IRF5 and CD28 genes were found to be common determinants for seropositivity in RDA, while positivity of RF alone was associated with the CTLA4 risk variant in heterozygous form. The correlation between serologic status and genetic determinants on the 1st ordinal axis was 0.468, and 0.145 on the 2nd one (Trace = 0.179; F = 6.135; P = 0.001). The risk alleles in AFF3 gene together with the presence of ACPA were associated with higher clinical severity of RA. CONCLUSIONS: The association among multiple risk variants related to T cell receptor signalling with seropositivity may play an important role in distinct clinical phenotypes of RA. Our study demonstrates that multiparametric analyses represent a powerful tool for investigation of mutual relationships of potential risk factors in complex diseases such as RA.
25707478 The Rheumatoid Arthritis Risk Gene LBH Regulates Growth in Fibroblast-like Synoviocytes. 2015 May OBJECTIVE: Fibroblast-like synoviocytes (FLS) are key players in the synovial pathology of rheumatoid arthritis (RA). Currently, there is no treatment that specifically targets these aggressive cells. By combining 3 different "omics" data sets, i.e., 1) risk genes in RA, 2) differentially expressed genes, and 3) differential DNA methylation in RA versus osteoarthritis (OA) FLS, we identified LBH (limb bud and heart development) as a candidate gene in RA. The present study was undertaken to define the role of this gene in FLS. METHODS: Synovial tissue specimens from RA and OA patients were collected at the time of joint replacement surgery. LBH expression was silenced using small interfering RNA or overexpressed using an LBH expression vector in primary FLS. Gene expression profiles were determined by microarray and assessed using Ingenuity Pathway Analysis. Effects of modified LBH expression were investigated in functional assays. RESULTS: LBH was expressed in the synovial lining layer in patients with RA. Transforming growth factor β1 significantly increased LBH expression in primary FLS, and platelet-derived growth factor BB decreased it. Pathway analysis of the transcriptome of LBH-deficient FLS compared to control FLS identified "cellular growth and proliferation" as the most significantly enriched pathway. In growth assays, LBH deficiency increased FLS proliferation. Conversely, LBH overexpression significantly inhibited cell growth. Cell cycle analysis demonstrated a marked increase in cells entering the cell cycle in LBH-deficient FLS compared to controls. LBH did not alter apoptosis. CONCLUSION: LBH is a candidate gene for synovial pathology in RA. It is regulated by growth factors and modulates cell growth in primary FLS. Our data suggest a novel mechanism for synovial intimal hyperplasia and joint damage in RA.
25200918 The return of subscapularis strength after shoulder arthroplasty. 2015 Feb BACKGROUND: During shoulder arthroplasty, the subscapularis tendon is released and repaired. Whether subscapularis strength subsequently returns to normal is poorly understood. This study's purpose was to determine whether subscapularis strength returns to normal after shoulder replacement and whether any preoperative factors predict the return of strength postoperatively. METHODS: Sixty-four patients underwent unilateral shoulder arthroplasty. Subscapularis strength was compared between the surgical and contralateral (normal) limbs at baseline (preoperatively) and follow-up. In addition, operative arm subscapularis strength recovery was compared with ipsilateral supraspinatus strength recovery. Independent variables were assessed for their effect on subscapularis strength, including sex, age, dominant-side surgery, preoperative strength, preoperative external rotation, subscapularis management technique, and fatty infiltration. RESULTS: The mean subscapularis strength ratio at 24 months from baseline was 1.19 ± 2.23 (P = .0007). The normal side was significantly stronger than the operative side at all time points (P < .0001). The operative-side subscapularis mean strength ratio was 0.54 ± 0.28 of normal at baseline and 0.70 ± 0.24 at 24 months. Defining normal strength as ±15%, 15% of patients were normal at baseline up to 22% at 24 months. At 24 months, the mean supraspinatus strength ratio from baseline (3.13 ± 6.11) was significantly greater than the subscapularis mean strength ratio (P = .0007). Multivariable regression analysis did not demonstrate any correlation (P > .05) between the independent variables studied and final subscapularis strength. DISCUSSION: Although significant strength improvement from baseline was observed at 2 years after shoulder arthroplasty, subscapularis strength returned to normal in only a minority of patients. Potential prognostic variables associated with final subscapularis strength remain elusive.
27650650 Infliximab Biosimilar (CT-P13; Infliximab-dyyb): A Review in Autoimmune Inflammatory Disea 2016 Oct Infliximab biosimilar (CT-P13/infliximab-dyyb; Remsima(®), Inflectra(®)) is approved in several countries for use in all indications for which reference infliximab (Remicade(®)) is approved, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis, psoriasis, Crohn's disease, and ulcerative colitis. Clinical data contributing to the EU approval of infliximab biosimilar were obtained from two pivotal double-blind clinical trials in patients with AS (PLANETAS) or RA (PLANETRA). Infliximab biosimilar demonstrated equivalence to reference infliximab in terms of its pharmacokinetic profile in patients with AS, patients with RA, and in healthy volunteers, and in terms of its efficacy in patients with RA. Clinical response rates in patients with RA or AS were maintained over the longer term (up to 102 weeks). In addition, the efficacy of infliximab biosimilar in patients with RA or Crohn's disease and ulcerative colitis [i.e. inflammatory bowel disease (IBD)] has been demonstrated in the real-world setting. Infliximab biosimilar was generally well tolerated, with a tolerability profile similar to that of reference infliximab. Switching from reference infliximab to infliximab biosimilar had no detrimental effect on efficacy, safety, or immunogenicity compared with continuous infliximab biosimilar therapy, according to the extensions of PLANETAS and PLANETRA, and real-world data in IBD. Current evidence therefore suggests that infliximab biosimilar is a useful alternative to reference infliximab in patients with autoimmune inflammatory diseases.
27348861 Hematological Indices May Be Useful in the Diagnosis of Systemic Lupus Erythematosus and i 2016 OBJECTIVES: The aim of this study was to investigate the relationships between clinical features of rheumatic diseases and hematologic indices, including mean platelet volume (MPV), MPV/platelet ratio (MPR), platelet/lymphocyte ratio, and neutrophil/lymphocyte ratio (NLR). Subjects andMethods: Rheumatoid arthritis (RA; n = 91), systemic lupus erythematosus (SLE; n = 51), systemic sclerosis (SSc; n = 39), and Behçet's disease (BD; n = 53) patients, and 55 healthy controls (HC) were enrolled. Hematological indices were calculated and one-way analysis of variance, Mann-Whitney U and χ2 tests, and receiver operating characteristic (ROC) analyses were performed. RESULTS: The MPV and MPR were higher in the SLE group than the RA group (p < 0.05 and p < 0.01, respectively). ROC analysis indicated that MPV (area under the curve, AUC, 0.68, 95% CI 0.58-0.77) and MPR (AUC 0.69, 95% CI 0.59-0.78) were sensitive and specific markers for SLE against RA. The NLR was higher in the RA, SLE, and SSc groups compared to the HC group (p < 0.05, p < 0.001, and p < 0.01, respectively). The NLR was higher in the active BD patients than those that were inactive (p = 0.008). Besides, NLR was higher in patients with neuro-BD and patients with active genital ulcers compared to patients without neurological involvement (p < 0.01) and active genital ulcers (p < 0.05). CONCLUSION: The MPV and MPR were significantly higher in the SLE group than in the RA group. They were also higher in the active than in the inactive BD patients. The MPV and MPR are useful diagnostic tools for SLE, and NLR reflects disease activity in BD. However, further research should be performed to standardize these tools.
27355582 Evaluation of X Chromosome Inactivation with Respect to HLA Genetic Susceptibility in Rheu 2016 BACKGROUND: Autoimmune diseases, including rheumatoid arthritis (RA) and systemic sclerosis (SSc) are characterized by a strong genetic susceptibility from the Human Leucocyte Antigen (HLA) locus. Additionally, disorders of epigenetic processes, in particular non-random X chromosome inactivation (XCI), have been reported in many female-predominant autoimmune diseases. Here we test the hypothesis that women with RA or SSc who are strongly genetically predisposed are less susceptible to XCI bias. METHODS: Using methylation sensitive genotyping of the androgen receptor (AR) gene, XCI profiles were performed in peripheral blood mononuclear cells from 161 women with RA, 96 women with SSc and 100 healthy women. HLA-DRB1 and DQB1 were genotyped. Presence of specific autoantibodies was documented for patients. XCI skewing was defined as having a ratio ≥ 80:20 of cells inactivating the same X chromosome. RESULTS: 110 women with RA, 68 women with SSc, and 69 controls were informative for the AR polymorphism. Among them 40.9% of RA patients and 36.8% of SSc patients had skewed XCI compared to 17.4% of healthy women (P = 0.002 and 0.018, respectively). Presence of RA-susceptibility alleles coding for the "shared epitope" correlated with higher skewing among RA patients (P = 0.002) and such correlation was not observed in other women, healthy or with SSc. Presence of SSc-susceptibility alleles did not correlate with XCI patterns among SSc patients. CONCLUSION: Data demonstrate XCI skewing in both RA and SSc compared to healthy women. Unexpectedly, skewed XCI occurs more often in women with RA carrying the shared epitope, which usually reflects severe disease. This reinforces the view that loss of mosaicism in peripheral blood may be a consequence of chronic autoimmunity.
26852644 TREM-1, a negative regulator of human osteoclastogenesis. 2016 Mar Triggering receptor expressed on myeloid cells (TREMs) are a family of cell surface receptors that play important roles in innate and adaptive immunity. Among them, TREM-2 has been extensively studied for its role in osteoclast differentiation and its essential role in human osteoclastogenesis has been well established. However, much less has been discovered about the role of TREM-1 in human osteoclast differentiation. In this study, we investigate the role of TREM-1 in human osteoclast differentiation. Consistent with previous reports, TREM-2 expression was strongly increased during the generation of human osteoclast precursors. In contrast, TREM-1 expression was decreased during the generation of human osteoclast precursors. Stimulation of TREM-1 using agonistic anti-TREM-1 antibody resulted in suppression of RANKL-induced osteoclastogenesis, as evidenced by diminished formation of TRAP+ multinucleated cells. In addition, TREM-1 stimulation strongly suppressed RANKL-induced expression of osteoclast-related genes such as cathepsin K and NFATc1. TREM-1 stimulation also down-regulated gene expression and cell surface expression of M-CSF receptor that is essential for osteoclast differentiation and survival. In synovial fluid macrophages of rheumatoid arthritis (RA) patients, TREM-1 stimulation suppressed osteoclastogenesis. In conclusion, we demonstrate that TREM-1 acts as a negative regulator of human osteoclast differentiation and identify a novel mechanism of negative regulation of osteoclastogenesis that plays a role in inflammation.
27930739 Heterogeneity in Comparisons of Discontinuation of Tumor Necrosis Factor Antagonists in Rh 2016 OBJECTIVE: We did a systematic review of studies comparing discontinuation of tumor necrosis factor alpha (TNF) antagonists in rheumatoid arthritis (RA) patients, pooled hazard ratios and assessed clinical and methodological heterogeneity. METHODS: We searched MEDLINE and EMBASE until June 2015 for pairwise hazard ratios for discontinuing infliximab, etanercept, and adalimumab from cohorts of RA patients. Hazard ratios were pooled using inverse variance weighting and random effects estimates of the combined hazard ratio were obtained. Clinical and methodological heterogeneity was assessed using the between-subgroup I-square statistics and meta-regression. RESULTS: Twenty-four unique studies were eligible and large heterogeneity (I-square statistics > 50%) was observed in all comparisons. Type of data, location, and order of treatment (first or second line) modified the magnitude and direction of discontinuation comparing infliximab with either adalimumab or etanercept; however, some heterogeneity remained. No effect modifier was identified when adalimumab and etanercept were compared. CONCLUSION: Heterogeneity in studies comparing discontinuation of TNF antagonists in RA is partially explained by type of data, location, and order of treatment. Pooling hazard ratios for discontinuing TNF antagonists is inappropriate because largely unexplained heterogeneity was demonstrated when random effect estimates were calculated.
26041850 Intermediate to Long-Term Outcomes of Total Ankle Replacement with the Scandinavian Total 2015 Jun 3 BACKGROUND: The Scandinavian Total Ankle Replacement (STAR) prosthesis has been in clinical use since 1981, with investigational use in the U.S. since 1998. Few studies of the North American version of the STAR are available. This prospective cohort study analyzed intermediate to long-term outcomes of total ankle arthroplasty with use of the STAR prosthesis at two Canadian centers. METHODS: Consecutive patients who received the STAR prosthesis between 2001 and 2005 were enrolled at two large, urban teaching hospitals. Patients were annually evaluated clinically, and the Ankle Osteoarthritis Scale (AOS) and the Short Form (SF)-36 were administered. RESULTS: One hundred and eleven ankles underwent arthroplasty with the STAR prosthesis. One-half of the patients were male; the mean age was 61.9 ± 11.7 years. Sixty-eight of the ankles underwent a total of 121 additional procedures during ankle arthroplasty, including gastrocnemius release, subtalar arthrodesis, triple arthrodesis, tendoachilles lengthening, and removal of hardware. The mean duration of follow-up for all living patients without revision (seventy-three ankles) was 9.0 ± 1.0 years. Thirteen (12%) of the ankles required metal component revision at a mean of 4.3 ± 3.0 years (range, 0.6 to 10.2 years). Twenty (18%) of the prostheses underwent polyethylene bearing exchange, mostly due to fracture, at a mean of 5.2 ± 2.1 years (range, 1.5 to 9.3 years). Most (97%) of the revisions and exchanges occurred in patients with a diagnosis of primary, secondary, or posttraumatic osteoarthritis (p = 0.0003). The mean change from baseline to final follow-up was -36.5 ± 23.3 points for AOS pain, -38.6 ± 26.8 points for AOS disability, and 9.6 ± 10.3 points for the SF-36 physical component summary score. The SF-36 mental component summary score was unchanged. CONCLUSIONS: Intermediate patient-reported outcomes were good after ankle arthroplasty with the STAR prosthesis performed by experienced surgeons, and long-term outcomes demonstrated a 12% rate of metal component revision and 18% rate of polyethylene bearing failure. The revision rate was substantially higher among the first twenty ankles than among subsequent ankles, but the early ankles had nearly two years' longer follow-up than subsequent ankles. Additional study to elucidate possible reasons for polyethylene bearing failure is warranted. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
26621504 CXCL16 upregulates RANKL expression in rheumatoid arthritis synovial fibroblasts through t 2016 Mar OBJECTIVE: To explore the influence of chemokine, CXCL16, on the expression of the receptor activator nuclear factor κB ligand (RANKL) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLS). METHODS: The expression of CXCL16/CXCR6 and RANKL in RA or osteoarthritis (OA) patient synovia was examined by Western blot and immunohistochemistry. The serum concentration of CXCL16 and RANKL was measured by enzyme-linked immunosorbent assay (ELISA). RA-FLS were treated with recombinant CXCL16, and RANKL mRNA and protein were measured using PCR, Western blot and ELISA. RESULTS: The synovial expression of CXCL16, CXCR6, and RANKL was higher in RA patients than in patients with OA. The serum CXCL16 and RANKL levels were higher in RA patients compared with OA patients and healthy controls. CXCL16 correlated with erythrocyte sedimentation rate, C reactive protein, disease activity, serum rheumatoid factor, and RANKL. RA-FLS treated with CXCL16 showed markedly increased expression of RANKL. When STAT3 or p38 activation was blocked by an inhibitor, CXCL16 failed to upregulate RANKL expression. In contrast, inhibiting the Akt or Erk pathway did not achieve the same effect. CONCLUSIONS: CXCL16 upregulates RANKL expression in RA-FLS and these effects are mainly mediated by the JAK2/STAT3 and p38/MAPK signaling pathways.
27617528 Micosis fungoide e inhibidores del TNFα: ¿riesgo o beneficio? 2016 May 15 The growing use of anti-TNF drugs during the last years has reopened the discussion about the possible increased risk of developing non-Hodgkin lymphoma in patients with such type of treatments. We present our clinical experience and critical opinion about the current situation of such issue regarding cutaneous T-cell lymphomas.El creciente uso de fármacos anti-TNF durante los últimos años ha reabierto el debate sobre el posible aumento de riesgo de linfomas no Hodgkin en los pacientes con este tipo de tratamientos. Presentamos nuestra experiencia clínica y opinión critica sobre la situación actual de este tema en relación a los linfomas cutáneos de células T.
27233606 SP600125 enhances the anti-apoptotic capacity and migration of bone marrow mesenchymal ste 2016 Jul 8 Osteoarthritis (OA) and rheumatoid arthritis (RA) are chronic disorders associated with inflammation of joints characterized by damage to the underlying cartilage and bone. Bone marrow mesenchymal stem cells (BMSCs) are candidates for regeneration of bone and cartilage, which is inhibited by inflammatory cytokines in OA and RA, in particular tumor necrosis factor-α (TNF-α). This study aimed to investigate if the c-Jun N-terminal kinases (JNK)-specific inhibitor SP600125 could enhance the anti-apoptosis and migration of BMSCs treated with TNF-α. The level of apoptosis was evaluated via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)/4',6-diamidino-2-phenylindole (DAPI) staining, annexin V/propidium iodide (PI) staining and western blotting. Migration of BMSCs was assessed using transwell migration chambers. We showed that the survival capacity and migration of BMSCs was significantly inhibited by TNF-α, which was blocked by pretreatment with SP600125. In the presence of SP600125, expression of cleaved caspase-9/-3 and p53 as well as the ratio of Bax to Bcl-2 was significantly decreased compared to treatment with TNF-α alone. Our results therefore indicate that SP600125 improves the migration capacity of TNF-α-treated BMSCs and exerts a significant effect on the viability of TNF-α-treated BMSCs through reducing the up-regulation of p53, caspase-9/-3 and the Bcl-2 family induced by TNF-α. These findings suggest that SP600125 is of potential use in promoting the regeneration of bone and cartilage in OA and RA.
27111000 Associations of Circulating Cytokines and Chemokines With Cancer Mortality in Men With Rhe 2016 Oct OBJECTIVE: To examine the potential of circulating cytokines and chemokines as biomarkers of cancer mortality risk in patients with rheumatoid arthritis (RA). METHODS: Male participants in the Veterans Affairs RA registry were followed up from the time of enrollment until death or December 2013. Cytokines and chemokines were measured in banked serum obtained at the time of enrollment, using a bead-based multiplex assay, and a previously developed cytokine score was calculated. Vital status and cause of death were determined through the National Death Index. Associations of cytokines with cancer mortality were examined using multivariable competing-risks regression. RESULTS: Among 1,190 men with RA, 60 cancer deaths (30 of which were attributable to lung cancer) occurred over 5,307 patient-years of follow-up. The patients had a mean age of 64.5 years, had established disease (median duration 8.7 years), were seropositive for rheumatoid factor (81%) or anti-cyclic citrullinated peptide antibody (77%), and frequently had a history of smoking (82% current or former). Seven of 17 analytes examined were individually associated with cancer mortality. The cytokine score was associated with overall cancer (subhazard ratio [SHR] 1.42, 95% confidence interval [95% CI] 1.08-1.85) and lung cancer (SHR 1.86, 95% CI 1.57-2.19) mortality in multivariable analyses. Those in the highest quartile of cytokine scores had a >2-fold increased risk of overall cancer mortality (P = 0.039) and a 6-fold increased risk of lung cancer mortality (P = 0.028) relative to the lowest quartile. A synergistic interaction between current smoking and high cytokine score was observed. CONCLUSION: Serum cytokines and chemokines are associated with cancer and lung cancer mortality in men with RA, independent of multiple factors including age, smoking status, and prevalent cancer.
27421624 Maturation and cytokine production potential of dendritic cells isolated from rheumatoid a 2016 Oct BACKGROUND: Since dendritic cells (DC) are involved in the development of autoimmune inflammation, researchers consider DC both as target cells for specific therapy of rheumatoid arthritis (RA) and as candidate cells for the development of cell-based methods to treat autoimmune diseases. The development of treatment strategies requires comprehensive research into the quantitative and qualitative characteristics of DC subtypes both ex vivo from RA patients and in vitro, to determine the possibility of inducing functionally mature DC in RA. OBJECTIVE: To study the phenotypic and functional properties of myeloid (mDC) and plasmacytoid (pDC) DC isolated from the peripheral blood of patients with RA and induced in vitro. MATERIALS AND METHODS: Blood samples were obtained from RA patients and healthy donors. Immature DC in the whole blood and in vitro induced DC were characterized by the positive expression of CD80, CD83, CCR7, IL-10, IL-4, IL-12 and IFN-α. R848 and lipopolysaccharide were used to determine DC maturation ability. From PBMCs of RA patients and health donors DCs with myeloid (imDC) and plasmacytoid (ipDC) phenotype were induced. RESULTS: The relative count of mDC in the peripheral blood between studied groups did not differ. pDC count was significantly lower for RA patients. DC from RA patients were characterized by low expression levels of CD80 and CD83 on both populations cells and high expression of CCR7 only on pDC. An increase in pDC producing IL-12 and IFN-α and a decrease in mDC and pDC producing IL-4 and IL-10 were shown in RA. imDC and ipDC obtained from RA patients according to their phenotype and cytokine profile did not differ from those obtained from healthy donors. CONCLUSIONS: There is an imbalance between subpopulations of DC in the peripheral blood of RA patients. DC of RA patients are less mature. The data suggest the involvement of DC in RA pathogenesis and confirm DC participation in balance shift towards Th1-type immune responses. At the same time, in vitro induced RA DC are phenotypically and functionally competent.
25994180 The preclinical pharmacology of the high affinity anti-IL-6R Nanobody® ALX-0061 supports 2015 May 20 INTRODUCTION: The pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of different diseases, including rheumatoid arthritis (RA). ALX-0061 is a bispecific Nanobody® with a high affinity and potency for IL-6 receptor (IL-6R), combined with an extended half-life by targeting human serum albumin. We describe here the relevant aspects of its in vitro and in vivo pharmacology. METHODS: ALX-0061 is composed of an affinity-matured IL-6R-targeting domain fused to an albumin-binding domain representing a minimized two-domain structure. A panel of different in vitro assays was used to characterize the biological activities of ALX-0061. The pharmacological properties of ALX-0061 were examined in cynomolgus monkeys, using plasma levels of total soluble (s)IL-6R as pharmacodynamic marker. Therapeutic effect was evaluated in a human IL-6-induced acute phase response model in the same species, and in a collagen-induced arthritis (CIA) model in rhesus monkeys, using tocilizumab as positive control. RESULTS: ALX-0061 was designed to confer the desired pharmacological properties. A 200-fold increase of target affinity was obtained through affinity maturation of the parental domain. The high affinity for sIL-6R (0.19 pM) translated to a concentration-dependent and complete neutralization of sIL-6R in vitro. In cynomolgus monkeys, ALX-0061 showed a dose-dependent and complete inhibition of hIL-6-induced inflammatory parameters, including plasma levels of C-reactive protein (CRP), fibrinogen and platelets. An apparent plasma half-life of 6.6 days was observed after a single intravenous administration of 10 mg/kg ALX-0061 in cynomolgus monkeys, similar to the estimated expected half-life of serum albumin. ALX-0061 and tocilizumab demonstrated a marked decrease in serum CRP levels in a non-human primate CIA model. Clinical effect was confirmed in animals with active drug exposure throughout the study duration. CONCLUSIONS: ALX-0061 represents a minimized bispecific biotherapeutic of 26 kDa, nearly six times smaller than monoclonal antibodies. High in vitro affinity and potency was demonstrated. Albumin binding as a half-life extension technology resulted in describable and expected pharmacokinetics. Strong IL-6R engagement was shown to translate to in vivo effect in non-human primates, demonstrated via biomarker deregulation as well as clinical effect. Presented results on preclinical pharmacological properties of ALX-0061 are supportive of clinical development in RA.
27181233 [Assessment of disease activity in rheumatoid arthritis by multi-biomarker disease activit 2016 For assessing clinical disease activity in rheumatoid arthritis (RA), several composite measures of physical findings, patents'/evaluators' visual analog scales, and acute phase reactants has been used, contributing to advance in therapies through many clinical trials. However, more objective indices have been desired due to subjectivity in conventional indices. The Multi-Biomarker Disease Activity (MBDA) score is a novel blood-test based disease activity score of single integer ranging 1-100, derived from pre-specified algorithms in combination with 12 serum biomarkers (VCAM-1, EGF, VEGF-A, IL-6, TNF-RI, YKL-40, MMP-1, MMP-3, leptin, resistin, SAA, CRP). The MBDA score not only reflects disease activity in RA, but also is predictive for radiographic progression and risk of flare after drug reduction. Herein we review clinical usefulness of the MBDA score in RA.