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ID PMID Title PublicationDate abstract
26135838 Knockdown of ADAM10 inhibits migration and invasion of fibroblast-like synoviocytes in rhe 2015 Oct Rheumatoid arthritis (RA) is a systemic autoimmune disease with high rates of morbidity and mortality. Previous studies proposed that the A disintegrin and metalloprotease (ADAM) family is involved in the regulation of inflammation and arthritis. Thus, the present study investigated whether ADAM10 is involved in the progression of RA. The effects of ADAM10 small interfering (si)RNA on the expression levels of tumor necrosis factor (TNF)‑α, interleukin (IL)‑6, IL‑8 and chemokine (C-X-C motif) ligand 16 (CXCL16) were determined in fibroblast‑like synoviocytes (FLS). In addition, the effects of ADAM10 siRNA on cell proliferation, invasion and migration in human RA‑FLS were assessed in vitro. The therapeutic efficacy and side‑effects of ADAM10 siRNA were examined in a mouse model of collagen‑induced arthritis (CIA). In vitro, ADAM10 silencing suppressed the expression of TNF‑α, IL‑6, IL‑8 and CXCL16 in lipopolysaccharide (LPS)‑stimulated human RA‑FLS. LPS‑induced RA‑FLS proliferation, migration and invasion were significantly attenuated by ADAM10 knockdown. ADAM10 silencing inhibited the secretion of vascular endothelial growth factor A (VEGF‑A) and matrix metalloproteinase (MMP)‑3 and ‑9 from LPS‑stimulated human RA‑FLS, in addition to inhibiting the phosphoinositide 3‑kinase/AKT activation in LPS‑stimulated human RA‑FLS. In vivo, treatment with siRNA against ADAM10 for three weeks reduced the arthritis score. Serum levels of VEGF‑A, MMP‑3 and MMP‑9 were also reduced in CIA mice. These observations indicate that the inhibition of ADAM10 may be a viable therapeutic target in the amelioration of disease progression in RA by attenuating FLS proliferation, migration and invasion.
27535236 Interleukin-21 signaling in B cells, but not in T cells, is indispensable for the developm 2016 Aug 17 BACKGROUND: Interleukin-21 (IL-21) is a T-cell-derived cytokine whose receptor is expressed on a variety of cells and therefore might have pleiotropic roles in the pathogenesis of rheumatoid arthritis (RA). In this study, we investigated the involvement of IL-21 signaling in the development of collagen-induced arthritis (CIA), an animal model of RA, using IL-21 receptor knockout (Il21r KO) mice. METHODS: Il21r KO mice or wild-type (WT) C57BL/6 mice were immunized with chicken type II collagen (CII) emulsified in complete Freund adjuvant on day 0 and were given a boost injection on day 21. The production of anti-CII antibody, development of T-cell and B-cell subsets, and T-cell responses to CII were analyzed. CIA was induced in Rag2 KO mice to which combinations of WT or Il21r KO CD4 T cells and WT or Il21r KO B cells had been transferred, in order to examine the role of IL-21 signaling in each cell subset. RESULTS: Il21r KO mice were resistant to the development of CIA. CII-specific IgG but not IgM production was impaired in Il21r KO mice. This is consistent with a reduction of germinal center B cells in the draining lymph nodes. In contrast, CII-specific Th1 and Th17 responses were unaffected in Il21r KO mice. There was also no difference in the number of CII-specific follicular helper T cells between WT and Il21r KO mice. By analyzing the development of CIA in T-cell and B-cell mixed transfer experiments, we confirmed that IL-21 receptor expression on B cells, but not on T cells, was essential for the development of CIA. CONCLUSION: IL-21 signaling in B cells, but not in T cells, plays essential roles in the production of pathogenic autoantibodies that induce CIA development.
25407647 In ACPA-positive RA patients, antibodies to EBNA35-58Cit, a citrullinated peptide from the 2015 Feb Although several infectious agents and particularly Epstein-Barr virus (EBV) have been suspected to be involved in aetiology of rheumatoid arthritis (RA), their role still remains elusive. Almost 80% of RA sera contain antibodies to citrullinated proteins/peptides. Among them, the autoantibodies to citrullinated human fibrinogen (AhFibA) are composed of two non-cross-reactive subsets directed to immunodominant epitopes borne by the α36-50Cit and β60-74Cit fibrin peptides. RA sera also contain antibodies towards the citrullinated EBNA35-58Cit peptide derived from the EBNA-1 protein of EBV. Here, using a large cohort of RA patients and controls, we showed that for a diagnostic specificity of 98.5%, 47% of the AhFibA-positive patients were anti-EBNA35-58Cit-positive and that almost all (98.5%) the anti-EBNA35-58Cit-positive were AhFibA-positive, whereas 86% were anti-β60-74Cit-positive and only 43% anti-α36-50Cit-positive. AhFibA, anti-EBNA35-58Cit- and anti-β60-74Cit-antibody titres were significantly correlated. Competition assays showed that anti-EBNA35-58Cit antibodies are highly cross-reactive with the β60-74Cit peptide. The demonstration that a citrullinated peptide derived from the EBNA-1 protein of EBV presents a molecular mimicry with human citrullinated fibrin constitutes an additional argument for a possible role of EBV in RA aetiopathogeny.
24733191 Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active r 2015 Jun OBJECTIVES: To compare the efficacy and safety of Tripterygium wilfordii Hook F (TwHF) with methotrexate (MTX) in the treatment of active rheumatoid arthritis (RA). METHODS: Design: a multicentre, open-label, randomised controlled trial. All patients were assessed by trained investigators who were unaware of the therapeutic regimen. INTERVENTION: 207 patients with active RA were randomly allocated (1:1:1) to treatment with MTX 12.5 mg once a week, or TwHF 20 mg three times a day, or the two in combination. At week 12, if reduction of the 28-joint count Disease Activity Score (DAS28) was <30% in the monotherapy groups, the patient was switched to MTX+TwHF. The primary efficacy point was the proportion of patients achieving an American College of Rheumatology (ACR) 50 response at week 24. RESULTS: 174/207 (84.1%) patients completed 24 weeks of the trial. In an intention-to-treat analysis, the proportion of patients reaching the ACR50 response criteria was 46.4% (32/69), 55.1% (38/69) and 76.8% (53/69), respectively, in the MTX, TwHF and MTX+TwHF groups (TwHF vs MTX monotherapy, p=0.014; MTX+TwHF vs MTX monotherapy, p<0.001). Similar statistically significant patterns at week 24 were found for ACR20, ACR70, clinical Disease Activity Index good responses, EULAR good response, remission rate and low disease activity rate. Significant improvement in the Health Assessment Questionnaire and 36-item Short-Form Health Survey questionnaire scores from baseline to week 24 was seen in each treatment arm (p<0.05), though no significant difference was found among the treatment arms (p>0.05). The result of per-protocol analysis agreed with that seen in the intention-to-treat analysis. Seven, three and five women in the TwHF, MTX and combination groups, respectively, developed irregular menstruation (TwHF vs MTX monotherapy, p=0.216). CONCLUSIONS: TwHF monotherapy was not inferior to, and MTX+TwHF was better than, MTX monotherapy in controlling disease activity in patients with active RA. TRIAL REGISTRATION NUMBER: NCT01613079.
25997820 The proto-oncogene survivin splice variant 2B is induced by PDGF and leads to cell prolife 2015 May 22 Survivin is an independent prognostic factor for joint destruction in rheumatoid arthritis (RA). However, the expression and function of survivin in RA synoviocytes remain unclear. We certified the expression of survivin in RA synovial tissues and performed the experiment using RA fibroblast-like synoviocytes (RA-FLS) treated with siRNA. As a result, the expression levels of wild type (WT) survivin and the 2B splice variants in RA synovial tissues were higher than those in osteoarthritis tissue samples, and, these variants were highly expressed in RA-FLS. The expression levels of survivin-WT and -2B in the RA-FLS were upregulated by PDGF. Treatment with siRNA against survivin-2B led to decreased viability of PDGF-treated RA-FLS due to cell cycle suppression and apoptosis promotion, while the siRNA against all survivin isoforms did not affect the viability. Moreover, an overexpression of survivin-2B in RA-FLS led to cell proliferation through cell cycle activation and by conferring resistance to apoptosis. In conclusion, survivin-2B has an important role in RA-FLS proliferation. These data suggest that survivin-2B might contribute to rheumatoid synovial hyperplasia, and have the potential as a novel therapeutic target for RA.
26978416 [Matrix metalloproteinase 2, 3, and 9 gene polymorphisms in women with rheumatoid arthriti 2015 AIM: To study the promoter regions of the matrix metalloproteinase (MMP)2, MMP3, and MMP9 genes to assess their associations with the risk of rheumatoid arthritis (RA) and with the types of its clinical course in women. SUBJECTS AND METHODS: 162 female patients with RA and 329 women without this condition were examined. Polymorphisms in the gene promoter region for MMP2 (-1306 С→Т), MMP3 (-1171 5A→6А), and MMP9 (-1562 С→Т) were studied. Genotyping was carried out using the restriction fragment length polymorphism method. RESULTS: In the RA group, the -1306TT genotype of MMP2 was significantly more frequently encountered and the 6A6A genotype was less frequently seen. In the seropositive RA group, the frequency of the -1306ТТ genotype of MMP2 was significantly higher than that in the healthy individuals. The significant differences shown for the entire group of patients with RA were preserved when they were divided into groups according to the presence or absence of rheumatoid nodules. Furthermore, the frequency of the homozygous -1306 genotypes of MMP2 was higher in both groups than in the healthy individuals. CONCLUSION: The presence of the allelic variants of the MMP genes may be one of the genetic factors that predispose to RA in women.
26062995 Polyfunctional, Pathogenic CD161+ Th17 Lineage Cells Are Resistant to Regulatory T Cell-Me 2015 Jul 15 In autoimmune diseases such as rheumatoid arthritis (RA), regulatory T cells (Tregs) fail to constrain autoimmune inflammation; however, the reasons for this are unclear. We investigated T cell regulation in the RA joint. Tregs from RA synovial fluid suppressed autologous responder T cells; however, when compared with Tregs from healthy control peripheral blood, they were significantly less suppressive. Despite their reduced suppressive activity, Tregs in the RA joint were highly proliferative and expressed FOXP3, CD39, and CTLA-4, which are markers of functional Tregs. This suggested that the reduced suppression is due to resistance of RA synovial fluid responder T cells to Treg inhibition. CD161(+) Th17 lineage cells were significantly enriched in the RA joint; we therefore investigated their relative susceptibility to Treg-mediated suppression. Peripheral blood CD161(+) Th cells from healthy controls were significantly more resistant to Treg-mediated suppression, when compared with CD161(-) Th cells, and this was mediated through a STAT3-dependant mechanism. Furthermore, depletion of CD161(+) Th cells from the responder T cell population in RA synovial fluid restored Treg-mediated suppression. In addition, CD161(+) Th cells exhibited pathogenic features, including polyfunctional proinflammatory cytokine production, an ability to activate synovial fibroblasts, and to survive and persist in the inflamed and hypoxic joint. Because CD161(+) Th cells are known to be enriched at sites of autoinflammation, our finding that they are highly proinflammatory and resistant to Treg-mediated suppression suggests an important pathogenic role in RA and other autoimmune diseases.
27618024 Increased Serum Levels of Anti-Carbamylated 78-kDa Glucose-Regulated Protein Antibody in P 2016 Sep 8 The objective of this study was to investigate the presence and titer of anti-carbamylated 78-kDa glucose-regulated protein (anti-CarGRP78) antibody in serum from controls, and patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and primary Sjögren syndrome (pSS). Thirty-three RA patients, 20 SLE patients, 20 pSS patients, and 20 controls were enrolled from our outpatient clinic. GRP78 was cloned and carbamylated. Serum titers of anti- cyclic citrullinated peptides (anti-CCP), anti-GRP78, and anti-CarGRP78 were measured with an enzyme-linked immunosorbent assay. No differences in serum titers of anti-GRP78 antibody in patients with RA, SLE, or pSS compared with the controls were observed. Serum levels of anti-carGRP78 antibody in patients with RA, but not SLE or pSS, were significantly higher compared with the controls (OD405 0.15 ± 0.08 versus 0.11 ± 0.03, p = 0.033). There was a positive correlation between the serum levels of anti-GRP78 antibody, but not anti-CarGRP78 antibody, with the levels of anti-CCP antibody in patients with RA. Both anti-GRP78 and anti-carGRP78 antibodies failed to correlate with C-reactive protein levels in patients with RA. In conclusion, we demonstrated the presence of anti-CarGRP78 antibody in patients with RA. In addition, the serum titer of anti-CarGRP78 antibody was significantly elevated in patients with RA compared with the controls. Anti-CarGRP78 antibody could also be detected in patients with SLE or pSS.
27631111 Exploring the Inflammatory Metabolomic Profile to Predict Response to TNF-α Inhibitors in 2016 In clinical practice, approximately one-third of patients with rheumatoid arthritis (RA) respond insufficiently to TNF-α inhibitors (TNFis). The aim of the study was to explore the use of a metabolomics to identify predictors for the outcome of TNFi therapy, and study the metabolomic fingerprint in active RA irrespective of patients' response. In the metabolomic profiling, lipids, oxylipins, and amines were measured in serum samples of RA patients from the observational BiOCURA cohort, before start of biological treatment. Multivariable logistic regression models were established to identify predictors for good- and non-response in patients receiving TNFi (n = 124). The added value of metabolites over prediction using clinical parameters only was determined by comparing the area under receiver operating characteristic curve (AUC-ROC), sensitivity, specificity, positive- and negative predictive value and by the net reclassification index (NRI). The models were further validated by 10-fold cross validation and tested on the complete TNFi treatment cohort including moderate responders. Additionally, metabolites were identified that cross-sectionally associated with the RA disease activity score based on a 28-joint count (DAS28), erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Out of 139 metabolites, the best-performing predictors were sn1-LPC(18:3-ω3/ω6), sn1-LPC(15:0), ethanolamine, and lysine. The model that combined the selected metabolites with clinical parameters showed a significant larger AUC-ROC than that of the model containing only clinical parameters (p = 0.01). The combined model was able to discriminate good- and non-responders with good accuracy and to reclassify non-responders with an improvement of 30% (total NRI = 0.23) and showed a prediction error of 0.27. For the complete TNFi cohort, the NRI was 0.22. In addition, 88 metabolites were associated with DAS28, ESR or CRP (p<0.05). Our study established an accurate prediction model for response to TNFi therapy, containing metabolites and clinical parameters. Associations between metabolites and disease activity may help elucidate additional pathologic mechanisms behind RA.
27619991 A Broad Blockade of Signaling from the IL-20 Family of Cytokines Potently Attenuates Colla 2016 Oct 15 Two heterodimeric receptors consisting of either IL-20R1 or IL-22R1 in complex with a common β receptor subunit IL-20R2 are shared by three of the IL-20 family of cytokines: IL-19, IL-20, and IL-24. These proinflammatory cytokines have been implicated in the pathogenesis of some autoimmune diseases, including rheumatoid arthritis (RA), psoriasis, and atopic dermatitis. Although mAbs against IL-19 and IL-20 have each been shown to modulate disease severity of collagen-induced arthritis in animal models, and anti-IL-20 therapeutic Ab has exhibited some efficacy in the treatment of RA in clinical trials, benefits for a complete blockade of these functionally redundant cytokines remain to be explored. In this report, we show that recombinant human soluble IL-20R2-Fc fusion protein binds to IL-19, IL-20, and IL-24 with similar high affinity and blocks their signaling in vitro. In DBA/1 mouse collagen-induced arthritis model, recombinant human IL-20R2-Fc exhibits comparable efficacy as TNF blocker etanercept in the treatment of established arthritis, whereas the combined use of both biologics manifests little synergistic therapeutic effects. In situ ligand-receptor functional binding analysis shows that a large amount of immune infiltrates expressing high levels of TNFR and IL-20 subfamily cytokines congregate within the inflamed disease tissues. Colocalization experiments reveal that signals from IL-20R2 and TNF transduction pathways seem to converge in macrophages and function in tandem in orchestrating the pathogenesis of RA. Elucidation of this interaction provides a better understanding of cytokine cross-talk in RA and a rationale for more effective biologic therapies that target IL-20R2 instead of individual cytokines from IL-20 family.
27334114 Efficacy and safety of an anti-CD20 monoclonal antibody (Reditux™) for the treatment of 2016 Aug Rituximab (anti-CD20 monoclonal antibody) has shown to improve symptoms in rheumatoid arthritis (RA) patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). An anti-CD20 monoclonal antibody (Reditux™) developed by Dr. Reddy's Laboratories, India, is currently approved for use both in rheumatology and oncology patients. This retrospective report evaluates the efficacy and safety data from the real-world use of Reditux™ over a 6-month period in Indian patients with RA. All consecutive moderate to severe RA patients who failed therapy with at least two DMARDs including methotrexate (MTX) for 6 months, TNFα inhibitor naive, and willing to take Reditux™ were included. They were prescribed two doses of 1 g Reditux™, at least 15 days apart, with continued stable doses of methotrexate. Efficacy and safety after 24 weeks relative to baseline was assessed using various health assessment variables. A total of 39 patients (mean age of 46 years; 67.5 % females) treated with Reditux™ were evaluated. Statistically significant differences were observed in mean changes of DAS28-CRP, DAS28-ESR, SDAI, HAQ and Patient Global Assessment scores from baseline to 24 weeks (p < 0.0001 for all). Average steroid use per week also significantly reduced at 24 weeks (p = 0.0002). There was no significant gender difference. Mean changes in SDAI, HAQ and Patient Global Assessment scores for patients on steroids were significantly different from those not on steroids (p < 0.05 for all). At 24 weeks, 97 % of patients achieved ACR20 response demonstrating the efficacy of Reditux™ treatment. The treatment was well tolerated by patients without any clinically relevant serious adverse events over 24 weeks. Though limited by number of patients and retrospective in nature, this analysis serves as a real-world evidence of efficacy and safety of Dr. Reddy's rituximab (Reditux™) in the treatment of csDMARD-failed patients with RA over a 6-month period.
26672064 Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy i 2016 Jun OBJECTIVE: To evaluate the efficacy, safety and dose response of a novel oral Janus kinase inhibitor, peficitinib (ASP015K), as monotherapy in Japanese patients with moderate to severe rheumatoid arthritis (RA). METHODS: In a 12-week, double-blind study, 281 adult patients with RA with active disease not on concomitant disease-modifying antirheumatic drug therapy were randomised equally to once-daily placebo or peficitinib 25, 50, 100 and 150 mg. The primary endpoint was American College of Rheumatology (ACR) 20 response in the peficitinib treatment groups versus placebo at week 12. RESULTS: Mean age was 53.0 years, 81.1% were female and 25.3% had previously used antitumour necrosis factor therapy. Peficitinib 50, 100 and 150 mg each showed statistically significantly higher ACR20 response rates compared with placebo, and response rates increased up to 150 mg with a statistically significant dose response. The total incidence of treatment-emergent adverse events (TEAEs) was similar between the placebo (64.3%) and peficitinib 25, 50, 100 and 150 mg groups (70.9%, 64.9%, 52.7% and 67.2%, respectively). TEAEs occurring more frequently in the peficitinib group compared with the placebo group included nasopharyngitis, increased blood creatine phosphokinase and diarrhoea. No cases of serious infections were reported. Herpes zoster occurred in four patients (two each in peficitinib 25 and 100 mg). CONCLUSIONS: Treatment with peficitinib as monotherapy for 12 weeks in Japanese patients with moderate to severe RA is efficacious and showed acceptable safety profile. These findings support further developments of peficitinib for RA treatment. TRIAL REGISTRATION NUMBER: NCT01649999; Results.
26315675 Comparative Risk of Hospitalized Infection Associated With Biologic Agents in Rheumatoid A 2016 Jan OBJECTIVE: The risks of hospitalized infection associated with biologic agents used to treat rheumatoid arthritis (RA) are unclear. The aim of this study was to determine whether the associated risk of hospitalized infections differed between specific biologic agents used to treat RA. METHODS: In a retrospective cohort study using Medicare data from 2006-2011 for all enrolled patients with RA, new episodes of treatment with etanercept, adalimumab, certolizumab, golimumab, infliximab, abatacept, rituximab, and tocilizumab were identified. Patients were required to have received another biologic agent previously and to have been continuously enrolled in Medicare medical and pharmacy plans during the baseline period and throughout followup. Followup started on the date of initiation of treatment with the new biologic agent (after previous treatment with a different biologic agent) and ended on the date of the earliest hospitalized infection, at 12 months, after an exposure gap of >30 days, or at the time of death or loss of Medicare coverage. Cox regression analysis was used to calculate the adjusted hazard ratio (HR) for hospitalized infection, adjusting for an infection risk score and other confounders. RESULTS: Of 31,801 new biologic treatment episodes in patients who had previously received another biologic agent, 12.0% were with etanercept, 15.2% with adalimumab, 5.9% with certolizumab, 4.4% with golimumab, 12.4% with infliximab, 28.9% with abatacept, 14.8% with rituximab, and 6.3% with tocilizumab. During followup, we identified 2,530 hospitalized infections; incidence rates ranged from 13.1 per 100 person-years (abatacept) to 18.7 per 100 person-years (rituximab). After adjustment, etanercept (HR 1.24, 95% confidence interval [95% CI] 1.07-1.45), infliximab (HR 1.39, 95% CI 1.21-1.60), and rituximab (HR 1.36, 95% CI 1.21-1.53) had significantly higher HRs for hospitalized infection compared with abatacept. CONCLUSION: In RA patients with prior exposure to a biologic agent, exposure to etanercept, infliximab, or rituximab was associated with a greater 1-year risk of hospitalized infection compared with the risk associated with exposure to abatacept.
26351388 Association Between Infliximab Trough Levels and the Occurrence of Paradoxical Manifestati 2015 Nov BACKGROUND AND AIM: Anti-tumour necrosis factor [TNF] agents have dramatically improved the prognosis of inflammatory bowel disease [IBD]. However, despite their good safety profile, use of these agents may lead to paradoxical manifestations involving skin or joints. Pathogenesis of such side effects is poorly understood and may involve anti-TNF pharmacokinetics. The aim of the present study was to look for an association between infliximab trough levels [ITL] and cutaneous [CPM] or rheumatological [RPM] paradoxical manifestations. METHODS: IBD patients receiving infliximab as maintenance therapy were included in a cross-sectional prospective monocentre study. At inclusion, patients had an ITL measurement [LISA-TRACKER®, Biomedical Diagnostics BMD] and were assessed for paradoxical manifestations: a CPM was defined by new onset or exacerbation of pre-existing psoriasis lesions during IFX therapy, and an RPM by new onset of severe poly-arthralgia during IFX therapy. RESULTS: Among the 121 patients included [69 female; median age: 38.9 years; 92 with Crohn's disease], 7% had CPM and 8% RPM. Median ITL values were 5.87 [range: 0.52-19.53] µg/ml in patients with CPM and 1.90 [0.00-13.5] µg/ml in those with RPM, as compared respectively with 5.12 [0.00-49.12] µg/ml in patients without CPM [p = 0.56] and 5.57 [0.00-49.12] µg/ml in those without RPM [p = 0.058]. No prognostic factor was associated with CPM. The single factor associated with RPM was elevated antinuclear antibodies. CONCLUSION: ITL were not elevated in IBD patients developing cutaneous or rheumatological paradoxical manifestations when receiving IFX as maintenance therapy. As suggested by the high level of antinuclear antibodies, RPM could be related to an induced autoimmune disorder.
26427573 Does Treatment of Periodontal Disease Influence Systemic Disease? 2015 Oct Periodontal diseases are the most common human diseases globally, with gingivitis affecting up to 90% and periodontitis affecting 50% of adults. Tooth enamel is the only nonshedding tissue in the human body. In the absence of proper oral hygiene measures, microbial biofilm (dental plaque) develops on the teeth to include more than 700 different bacterial species, along with viruses, fungi, archea, and parasites. With time, ecological imbalances promote the growth of selected commensal species that induce host inflammatory pathways resulting in tissue destruction, including ulceration of the periodontal epithelium.
27401097 Visual detection of cortical breaks in hand joints: reliability and validity of high-resol 2016 Jul 11 BACKGROUND: To study the reliability and validity of high-resolution peripheral quantitative CT (HR-pQCT) with microCT (μCT) as gold standard in the visual detection of cortical breaks in metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints. METHODS: Ten cadaveric fingers (10 MCP and 9 PIP joints) were imaged by HR-pQCT and μCT and visually analyzed by two independent readers. Intra- and interreader reliability were evaluated for the presence (yes/no, kappa statistics) and the total number (intraclass correlation coefficient, ICC) of cortical breaks. Sensitivity, specificity, positive and negative predictive value (PPV respectively NPV) of HR-pQCT in detecting cortical breaks were calculated. RESULTS: With HR-pQCT, mean 149 cortical breaks were identified and with μCT mean 129 (p < 0.05). Intrareader reliability for the presence of a cortical break per quadrant was 0.52 (95 % CI 0.48-0.56) and 0.71 (95 % CI 0.67-0.75) for HR-pQCT and μCT, respectively, and for the total number of cortical breaks 0.61 (95 % CI 0.49-0.70) and 0.75 (95 % CI 0.68-0.82). Interreader reliability for the presence of a cortical break per quadrant was 0.37 (95 % CI 0.33-0.41) and 0.45 (95 % CI 0.41-0.49) for HR-pQCT and μCT, respectively, and for the number of cortical breaks 0.55 (95 % CI 0.43-0.65) and 0.54 (95 % CI 0.35-0.67). Sensitivity, specificity, PPV and NPV of HR-pQCT were 81.6, 64.0, 81.6, and 64 % respectively. CONCLUSION: Cortical breaks were commonly visualized in MCP and PIP joints with HR-pQCT and μCT. Reliability of both HR-pQCT and μCT was fair to moderate. HR-pQCT was highly sensitive to detect cortical breaks with μCT as gold standard.
27089204 Sclerostin inhibition promotes TNF-dependent inflammatory joint destruction. 2016 Mar 16 Sclerostin, an inhibitor of the Wnt/β-catenin pathway, has anti-anabolic effects on bone formation by negatively regulating osteoblast differentiation. Mutations in the human sclerostin gene (SOST) lead to sclerosteosis with progressive skeletal overgrowth, whereas sclerostin-deficient (Sost(-/-)) mice exhibit increased bone mass and strength. Therefore, antibody-mediated inhibition of sclerostin is currently being clinically evaluated for the treatment of postmenopausal osteoporosis in humans. We report that in chronic TNFα (tumor necrosis factor α)-dependent arthritis, fibroblast-like synoviocytes constitute a major source of sclerostin and that either the lack of sclerostin or its antibody-mediated inhibition leads to an acceleration of rheumatoid arthritis (RA)-like disease in human TNFα transgenic (hTNFtg) mice with enhanced pannus formation and joint destruction. Inhibition of sclerostin also failed to improve clinical signs and joint destruction in the partially TNFα-dependent glucose-6-phosphate isomerase-induced arthritis mouse model, but ameliorated disease severity in K/BxN serum transfer-induced arthritis mouse model, which is independent of TNF receptor signaling, thus suggesting a specific role for sclerostin in TNFα signaling. Sclerostin effectively blocked TNFα- but not interleukin-1-induced activation of p38, a key step in arthritis development, pointing to a previously unrealized protective role of sclerostin in TNF-mediated chronic inflammation. The possibility of anti-sclerostin antibody treatment worsening clinical RA outcome under chronic TNFα-dependent inflammatory conditions in mice means that caution should be taken both when considering such treatment for inflammatory bone loss in RA and when using anti-sclerostin antibodies in patients with TNFα-dependent comorbidities.
26388304 Inflammatory focal bone destruction in femoral heads with end-stage haemophilic arthropath 2015 Nov INTRODUCTION: Focal bone destruction has a high prevalence in haemophilic arthropathy (HA) affected joints, but the mechanism remains unclear. AIM: We undertook this study on clinic samples to explore the focal bone destruction in femoral heads suffered with end-stage HA. METHODS: Twenty-one femoral heads from HA patients and 19 femoral heads from rheumatoid arthritis (RA) patients were scanned by micro-CT. Histological analysis, including TRAP staining of subchondral bone were performed to evaluate the bone destruction and osteoclasts activity. RANKL, OPG as well as pro-inflammatory cytokines, such as TNF-α and IL-1β in subchondral bone were detected by immunohistochemistry (IHC) method. RESULTS: Severe focal lesion was observed in all the HA and RA femoral heads by micro-CT imaging and histological analysis. The mean percentage of lesion volume to total volume of the femoral heads from HA patients was significantly higher than those from RA patients. There was no significant difference in osteoclasts numbers in subchondral bone between HA and RA groups. By IHC analysis, high expression of RANKL, TNF-α, IL-1β and low expression of OPG and RANK were observed in subchondral bone, and there were no significant differences in the expression of RANKL, OPG, RANK, TNF-α and IL-1β in femoral heads derived from HA and RA patients. CONCLUSION: Our findings demonstrated the focal bone destruction coupled with inflammatory osteoclastogenesis at subchondral bone in femoral heads from patients with end-stage HA, and that was similar to the changes in the femoral heads of RA patients.
25940005 Familial Risk of Sjögren's Syndrome and Co-aggregation of Autoimmune Diseases in Affected 2015 Jul OBJECTIVE: To investigate familial aggregation of Sjögren's syndrome (SS) and the relative risks (RRs) of other autoimmune disease in relatives of patients with SS. METHODS: We identified 23,658,577 beneficiaries enrolled in the Taiwan National Health Insurance system in 2010, of whom 12,754 had SS. We identified 21,009,551 parent-child relationships and 17,168,340 pairs of full siblings. The familial risks of SS and other autoimmune diseases, tetrachoric correlation, and familial transmission were estimated. RESULTS: We identified 105 patients with SS who had an affected first-degree relative. The RR of SS was 18.99 (95% confidence interval [95% CI] 9.76-36.93) in siblings of patients with SS, 11.31 (95% CI 8.34-15.33) in offspring, and 12.46 (95% CI 9.34-16.62) in parents. Tetrachoric correlation coefficients were 0.53 (95% CI 0.41-0.65) for cotwins of affected individuals and 0.21 (95% CI 0.16-0.26) for full siblings. The familial transmission (heritability plus shared environmental contribution) was 0.54 (95% CI 0.44-0.77). In first-degree relatives of patients with SS, the RRs were 2.95 (95% CI 2.33-3.73) for rheumatoid arthritis, 6.25 (95% CI 5.15-7.58) for systemic lupus erythematosus, 2.39 (95% CI 0.77-7.41) for systemic sclerosis, 0.71 (95% CI 0.10-5.07) for idiopathic inflammatory myopathy, 1.97 (95% CI 1.29-3.02) for type 1 diabetes mellitus, 3.38 (95% CI 1.26-9.05) for multiple sclerosis, 1.67 (95% CI 0.83-3.33) for myasthenia gravis, 1.25 (95% CI 1.04-1.50) for psoriasis, 1.21 (95% CI 0.39-3.76) for inflammatory bowel disease, and 2.29 (95% CI 1.19-4.40) for vasculitis. CONCLUSION: The risk of SS and other autoimmune diseases is increased in relatives of patients with SS, and more than one-half of phenotypic variance in SS can be explained by familial factors.
26013051 The effects of high intensity interval training in women with rheumatic disease: a pilot s 2015 Oct PURPOSE: Rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) are inflammatory diseases which involve increased risk of cardiovascular disease (CVD). High intensity interval training (HIIT) is known to be effective in improving cardiovascular health. The aim of this study was to investigate whether 10 weeks of HIIT at 85-95% of HRmax would improve important risk factors of CVD in rheumatic patients, and if these patients would tolerate exercise intensities above today's recommendations. METHODS: Seven women with RA and eleven with adult-JIA, 20-50 years, were recruited to this cross-over study. Participants performed HIIT, consisting of 4 × 4 min intervals at 85-95% of HRmax twice a week for 10 weeks on spinning bikes. Maximal oxygen uptake (VO2max), heart rate recovery, blood pressure, body composition, and blood variables were measured before and after the exercise and control period. Disease activity was determined and questionnaire data were collected. RESULTS: HIIT resulted in 12.2% increase in VO2max and 2.9% improvement in heart rate recovery (p < 0.05). BMI, body fat, and waist circumference decreased 1.2, 1.0, and 1.6%, respectively, whereas muscle mass increased 0.6% (p < 0.05). A trend toward decreased CRP was detected after HIIT (p = 0.08). No changes were detected in disease activity or pain. CONCLUSION: Despite rigorous high intensity exercise, no increase was detected in disease activity or pain, indicating that HIIT was well tolerated by these patients. Furthermore, HIIT had positive effects on several CVD risk factors. In light of this pilot study, HIIT seems like a promising non-pharmacological treatment strategy for patients with RA and adult-JIA.