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ID PMID Title PublicationDate abstract
26137891 Factors affecting the tuberculosis risk in patients receiving anti-tumor necrosis factor-Π2015 BACKGROUND: Tumor necrosis factor (TNF)-α inhibitors are known to increase the risk of tuberculosis (TB). OBJECTIVES: To examine the factors associated with an increased risk of TB in patients receiving anti-TNF-α treatment (aTNF-α-T). METHOD: Of 3,094 patients who received aTNF-α-T between 2003 and 2013, a total of 1,964 subjects with a follow-up time longer than 6 months were identified and included in this retrospective analysis. Potential risk factors for the development of TB in patients receiving aTNF-α-T were evaluated. RESULTS: Of the 1,964 patients, 1,009 (51%) were male and 955 (49%) were female, with a mean age of 39.7 ± 13.9 years. The primary conditions requiring aTNF-α-T included ankylosing spondylitis (n = 875), rheumatoid arthritis (n = 711), Behçet's disease (n = 83), and others (n = 295). Sixteen patients [8 (50%) males and 8 (50%) females; 5 (31.2%) with pulmonary TB and 11 (68.8%) with extrapulmonary TB] developed TB, with a corresponding TB incidence of 466/100,000. No significant associations were found between age, gender, smoking history, pack-years of smoking, isoniazid (INH) chemoprophylaxis, type of anti-TNF-α agent, use of other immunosuppressive drugs, and the risk of TB (p > 0.05). Multivariate logistic regression analysis showed a significantly higher risk of TB in patients diagnosed with Behçet's disease, and a significantly lower risk of TB in patients with a tuberculin skin test wheal ≥10 mm in diameter (p < 0.05). CONCLUSION: aTNF-α-T is associated with an increased risk of pulmonary or extrapulmonary TB, even when follow-up protocols and INH chemoprophylaxis are implemented, and TB often develops in the later stages of treatment. The risk of TB was higher in patients with Behçet's disease and lower in patients who had a strong tuberculin skin test reaction.
26956410 Interleukin‑12B is upregulated by decoy receptor 3 in rheumatoid synovial fibroblasts. 2016 Apr 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.
25660987 Celastrol, a Chinese herbal compound, controls autoimmune inflammation by altering the bal 2015 Apr Inflammation is an integral component of autoimmune arthritis. The balance of pathogenic T helper 17 (Th17) and protective T regulatory (Treg) cells can influence disease severity, and its resetting offers an attractive approach to control autoimmunity. We determined the frequency of Th17 and Treg in the joints of rats with adjuvant arthritis (AA), a model of rheumatoid arthritis (RA). We also investigated the impact of Celastrol, a bioactive compound from the traditional Chinese medicine Celastrus that can suppress AA, on Th17/Treg balance in the joints. Celastrol treatment reduced Th17 cells but increased Treg in the joints, and it inhibited Th17 differentiation but promoted Treg differentiation in vitro by blocking the activation of pSTAT3. Furthermore, Celastrol limited the production of Th17-differentiating cytokines and chemokines (CCL3, CCL5). Thus, Celastrol suppressed arthritis in part by altering Th17/Treg ratio in inflamed joints, and it should be tested as a potential adjunct/alternative for RA therapy.
26038344 Autoimmune markers and autoimmune disorders in patients with postural tachycardia syndrome 2015 Nov OBJECTIVE: In recent years, there have been a number of studies suggesting that POTS may have an autoimmune etiology. This study examined whether the prevalence of antinuclear antibodies (ANA), other markers of autoimmunity and co-morbid autoimmune disorders is higher in patients with POTS than in the general population. METHODS AND RESULTS: Medical records of 100 consecutive patients with POTS evaluated at our clinic were reviewed. In this cohort (90% females, mean age 32, range 13-54 years), 25% had positive ANA, 7% had at least one positive aPL antibody and 31% had markers of autoimmunity. When compared to the general population, patients with POTS had a higher prevalence of ANA (25% vs. 16%, OR 1.8, CI 1.1-2.8, p < 0.05), aPL antibody (7% vs. 1%, OR 7.5, CI 3.4-16.1, p < 0.001) and co-morbid autoimmune disorders (20% vs. highest estimated 9.4%, OR 2.4, CI 1.5-3.9, p < 0.001). The most prevalent autoimmune disorder was Hashimoto's thyroiditis (11% vs. up to 2%, OR 6.1, CI 3.2-11.3, p < 0.001), followed by RA (4% vs. up to 1%, OR 4.1, CI 1.5-11.2, p < 0.01) and SLE (2% vs. up to 0.12%, OR 17, CI 4.1-69.7, p < 0.001). The prevalence of CVID was very high (2% vs. 0.004%, OR 510.2, CI 92.4-2817.8, p < 0.001), while celiac disease showed a nonsignificant trend toward increased prevalence. CONCLUSION: Patients with POTS have a higher prevalence of autoimmune markers and co-morbid autoimmune disorders than the general population. One in four patients have positive ANA, almost one in three have some type of autoimmune marker, one in five have a co-morbid autoimmune disorder, and one in nine have Hashimoto's thyroiditis.
27736699 Blockade of IL-7Rα alleviates collagen-induced arthritis via inhibiting Th1 cell differen 2016 Nov T cell response is crucial to the pathogenesis and progression of rheumatoid arthritis (RA). IL-7/IL-7R axis has significant effect on CD4(+) T cell response, including proliferation, differentiation, survival and migration. However, whether blockade of IL-7/IL-7R axis signaling can relieve RA and what is the potential treatment mechanisms are still remaining unclear. In this paper, we established collagen-induced arthritis (CIA) model and observed the effect of IL-7Rα antibody in the treatment of CIA mice. It is demonstrated that IL-7Rα antibody significantly alleviated clinical symptoms of CIA mice, accompanied with reduced CD4(+) T cell number in both spleen and joints. Decreased CII-specific CD4(+) T cell proliferation and reduced mRNA expression of inflammatory cytokines in IL-7Rα antibody-treated mice were observed. Subsequently, IL-7Rα antibody treatment in vivo downregulated the percentages of Th1 and Th17 cells and the mRNA expression of T-bet and RORγt gene. Moreover, it was found that IL-7 promoted Th1 cell differentiation in vitro, while having no effect on Th17 cell differentiation. In addition, administration of IL-7Rα antibody reduced the mRNA expression of chemokine receptors (CCR7, CXCR3, CXCR6 and XCR1) on CD4(+) T cells and chemokine CXCL2 in joints. The results suggested that IL-7Rα antibody treated CIA mice via the inhibition of CII-specific CD4(+) T cell proliferation, the reduction of Th1 cell differentiation and the restrain of CD4(+) T cell migration to joint lesion site. This investigation indicates that IL-7Rα is a potential therapeutic target for RA.
25735643 EULAR recommendations for patient education for people with inflammatory arthritis. 2015 Jun OBJECTIVES: The task force aimed to: (1) develop evidence-based recommendations for patient education (PE) for people with inflammatory arthritis, (2) identify the need for further research on PE and (3) determine health professionals' educational needs in order to provide evidence-based PE. METHODS: A multidisciplinary task force, representing 10 European countries, formulated a definition for PE and 10 research questions that guided a systematic literature review (SLR). The results from the SLR were discussed and used as a basis for developing the recommendations, a research agenda and an educational agenda. The recommendations were categorised according to level and strength of evidence graded from A (highest) to D (lowest). Task force members rated their agreement with each recommendation from 0 (total disagreement) to 10 (total agreement). RESULTS: Based on the SLR and expert opinions, eight recommendations were developed, four with strength A evidence. The recommendations addressed when and by whom PE should be offered, modes and methods of delivery, theoretical framework, outcomes and evaluation. A high level of agreement was achieved for all recommendations (mean range 9.4-9.8). The task force proposed a research agenda and an educational agenda. CONCLUSIONS: The eight evidence-based and expert opinion-based recommendations for PE for people with inflammatory arthritis are intended to provide a core framework for the delivery of PE and training for health professionals in delivering PE across Europe.
26645159 Short-term efficacy to conventional blind injection versus ultrasound-guided injection of 2016 Mar OBJECTIVE: To compare the short-term efficacy of conventional blind injection (CBI) versus ultrasound-guided injection (USGI) of corticosteroids (CS) injection in tenosynovitis in patients with chronic arthritis and to investigate if the USGI is a less painful procedure and if there are differences in the changes of US findings during the post injection follow-up. METHODS: Patients presenting tenosynovitis requiring CS injection were involved. After clinical and US evaluation, patients were randomized to receive CBI or USGI. Efficacy of procedure was assessed by the improvement in both Health Assessment Questionnaire (HAQ) and pain visual analogue scale (VAS), including procedure-VAS global-VAS and local-VAS, after 1 and 4 weeks post-procedure. Power Doppler (PD) and greyscale (GS) US findings were also object of the follow-up. CBI or USGI under an aseptic technique were performed according the local guidelines using 20mg of methylprednisolone acetate. RESULTS: A total of 114 patients were randomized to receive CBI (54 patients) or USGI (60 patients) procedure. No significant difference was observed in terms of gender, age and pain duration among CBI and USGI groups at baseline. USGI proved to be significantly less painful than CBI (P=0.0001). AUC analysis showed that during the follow up visits, the USGI procedure had significantly better response in HAQ, local-VAS and global-VAS (P=0.0001, P=0.012 and P=0.0001 respectively) compared to CBI. During the follow up period, a significant greater reduction in the PD scores was found in the USGI group compared to the CBI group (P=0.0002), whereas no statistical differences were found in the GS findings between the groups (P=0.5627). CONCLUSION: Our study demonstrates superiority of USGI over CBI for CS injections in painful tenosynovitis, having better short-term outcomes measured by functional, clinical and US scores. These data support the use of USGI for tenosynovits in typical inpatient and/or outpatient in rheumatological practices.
25228497 Impaired degradation and aberrant phagocytosis of necrotic cell debris in the peripheral b 2015 Jan Aberrant removal of necrotic debris is considered a feature with inflammatory consequences in SLE. Herein, primary Sjögren's syndrome (SS) patients were investigated for the first time for the capacity of their sera to degrade secondary necrotic cell remnants (SNEC) and DNA (endonuclease DNase1 activity), as well as for uptake of SNEC by blood-borne phagocytes. For comparison, specimens from unselected SLE and RA patients and from healthy blood donors (HBD) were also studied. Compared to HBD, the sera from SS and SLE patients studied (but not RA) were found to exhibit significantly impaired capacity for degradation of SNEC (both for p = 0.007) and deficient DNase1 activity (both for p < 0.0001). The deficient DNase1 activity in SS and SLE sera did not owe to decreased DNase1 protein levels. It correlated inversely with increased serum levels of circulating nucleosomes and cell-free DNA (p < 0.0001), as well as with the disease activity indices of SS (r = -0.445, p = 0.0001) and SLE (r = -0.500, p = 0.013). In ex-vivo whole blood analyses, SS and SLE patients (but not RA) also manifested significantly increased SNEC-phagocytosis by monocytes and granulocytes (all for p < 0.0001) that also correlated with disease severity indices of SS (p = 0.001) and SLE (p = 0.01). In various cross-admixture experiments, such aberration was found to reside in the hyperfunctional activity of phagocytes, the impaired degrading activity of serum DNase1 and the SNEC-binding capacity of serum IgG of SS and SLE patients. The sera of SS and SLE patients (but not of RA) induced significant SNEC-phagocytosis by healthy monocytes that correlated inversely with the DNase1 activity (r = -0.634, p < 0.0001) of these sera. In line with this, the inhibition of DNase1 in HBD sera by G-actin was found to lead to significantly diminished SNEC degradation and increased SNEC uptake by healthy phagocytes (p = 0.0009), supporting the important physiologic role of serum DNase1 in the prevention of SNEC-phagocytosis. Purified serum IgG preparations from SS and SLE patients manifested increased binding to SNEC and were able to enhance significantly the engulfment of SNEC by healthy phagocytes both directly (under serum-free conditions, p ≤ 0.009) and via the prevention of physiologic degradation of SNEC by serum, most likely due to their "shielding" against endonuclease digestion (p = 0.0005). These data indicate that upon cell necrosis, the immune system of SS and SLE patients may be overly exposed to the necrotic debris, a fact that probably holds a key role in the pathogenesis of inflammatory and autoimmune reactions observed in these disorders.
26983232 [Effect of Different Processed Products and Extracts of Morinda officinalis Root on Adjuva 2015 Aug OBJECTIVE: To study the therapeutic effects of different processed products and extracts of Morinda officinalis root in rat adjuvant-induced arthritis (AA) model, and to explore the possible mechanism. METHODS: AA model in SD rats was established, then the arthritic rats were randomly divided into seven groups such as model, Tripterygium Glycosides Tablet (TGT), morinda with xylem, morinda, salt-steamed morinda, licorice-processed morinda, morinda EtOAc extract, morinda n-BuOH extract, H₂O residue, total polysaccharides and control groups. The paw edema and arthritis indexes were observed, and the contents of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-2 and INF-γ in AA rats serum were detected by ELISA. RESULTS: Morinda processed by salt and n-BuOH extract could reduce paw swelling and levels of TNF-α, IL-1β, IL-6 and INF-γ in AA rats serum, which followed by morinda EtOAc extract. The differences were significant compared with the model group (P < 0.05 or P < 0.01). CONCLUSION: Salt-steamed morinda and morinda n-BuOH extract have the best curative effect, followed by morinda EtOAc extract. Reducing TNF-α, IL-1β, IL-6 and INF-γ contents in serum may be the mechanism of drug treatment of rheumatoid arthritis.
26882474 Cigarette smoke inhibits ROCK2 activation in T cells and modulates IL-22 production. 2016 Mar Gene-environment interactions are known to play a key role in the development of rheumatoid arthritis (RA). Exposure to cigarette smoke (CS) is one of the strongest environmental risk factors associated with RA and has been shown to mediate a range of complex immunomodulatory effects from decreased T and B cell activation to depressed phagocytic function. The effects of CS on the function of TH17 cells, one of the key TH effector subsets implicated in RA pathogenesis, are not fully understood. IRF4 is one of the crucial transcription factors involved in TH-17 differentiation and is absolutely required for the production of IL-17 and IL-21 but, interestingly, inhibits the synthesis of IL-22. The production of IL-17 and IL-21 by IRF4 can be augmented by its phosphorylation by the serine-threonine kinase ROCK2. Given that CS has been reported to increase ROCK activity in endothelial cells, here we investigated the effects of CS on the ROCK2-IRF4 axis in T cells. Surprisingly, we found that CS leads to decreased ROCK2 activation and IRF4 phosphorylation in T cells. This effect was associated with increased IL-22 production. Using a GEF pull-down assay we furthermore identify ARHGEF1 as a key upstream regulator of ROCK2 whose activity in T cells is inhibited by CS. Thus CS can inhibit the ROCK2-IRF4 axis and modulate T cell production of IL-22.
27766916 A real-world risk analysis of biological treatment (adalimumab and etanercept) in a countr 2017 May OBJECTIVES: Few studies on tumour necrosis factor (TNF) inhibitor-associated tuberculosis (TB) and hepatic events have been performed in regions where these risks are elevated. This study aimed to provide a direct comparison between adalimumab and etanercept in a high-risk population and to address the implications for physicians working with patients in such an environment. METHOD: Data collected from the National Health Insurance Research Database (NHIRD) in Taiwan between 2007 and 2011 were analysed retrospectively for incidences of eight adverse events associated with TNF-α inhibitors. Hazard ratios (HRs) of adalimumab vs. etanercept were calculated using a Cox proportional hazards model. RESULTS: During this 5-year period, 86 events of TB were reported after 5317 person-years of exposure to adalimumab (1.62 events per 100 person-years), compared to 44 events after 7690 person-years of exposure to etanercept (0.57 events per 100 person-years). For serious hepatic events that led to hospitalization, 0.75 events were reported per 100 person-years of exposure to adalimumab compared to 0.39 events per 100 person-years of exposure to etanercept. Adjusted HRs for TB [aHR 3.06, 95% confidence interval (CI) 2.09-4.49, p < 0.0001], hospitalization due to a hepatic event (aHR 2.05, 95% CI 1.27-3.30, p = 0.0035), and serious infection (aHR 1.48, 95% CI 1.19-1.84, p = 0.0005) attained significance. CONCLUSIONS: TNF-α-targeting therapies with the monoclonal antibody adalimumab confers significant added risk of TB and serious hepatic events compared to therapies with the soluble fusion protein etanercept. Tailored strategies to attenuate these risks are warranted in high-risk regions such as Taiwan.
27175934 Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate 2016 May 13 BACKGROUND: This is an update of the 2009 Cochrane overview and network meta-analysis (NMA) of biologics for rheumatoid arthritis (RA). OBJECTIVES: To assess the benefits and harms of nine biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib, versus comparator (MTX, DMARD, placebo (PL), or a combination) in adults with rheumatoid arthritis who have failed to respond to methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs), i.e., MTX/DMARD incomplete responders (MTX/DMARD-IR). METHODS: We searched for randomized controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (via The Cochrane Library Issue 6, June 2015), MEDLINE (via OVID 1946 to June 2015), and EMBASE (via OVID 1947 to June 2015). Data extraction, risk of bias and GRADE assessments were done in duplicate. We calculated both direct estimates using standard meta-analysis and used Bayesian mixed treatment comparisons approach for NMA estimates to calculate odds ratios (OR) and 95% credible intervals (CrI). We converted OR to risk ratios (RR) which are reported in the abstract for the ease of interpretation. MAIN RESULTS: This update included 73 new RCTs for a total of 90 RCTs; 79 RCTs with 32,874 participants provided usable data. Few trials were at high risk of bias for blinding of assessors/participants (13% to 21%), selective reporting (4%) or major baseline imbalance (8%); a large number had unclear risk of bias for random sequence generation (68%) or allocation concealment (74%).Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a statistically significant and clinically meaningful improvement in ACR50 versus comparator (RR 2.71 (95% confidence interval (CI) 2.36 to 3.10); absolute benefit 24% more patients (95% CI 19% to 29%), number needed to treat for an additional beneficial outcome (NNTB) = 5 (4 to 6). NMA estimates for ACR50 in tumor necrosis factor (TNF) biologic+MTX/DMARD (RR 3.23 (95% credible interval (Crl) 2.75 to 3.79), non-TNF biologic+MTX/DMARD (RR 2.99; 95% Crl 2.36 to 3.74), and anakinra + MTX/DMARD (RR 2.37 (95% Crl 1.00 to 4.70) were similar to the direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a clinically and statistically important improvement in function measured by the Health Assessment Questionnaire (0 to 3 scale, higher = worse function) with a mean difference (MD) based on direct evidence of -0.25 (95% CI -0.28 to -0.22); absolute benefit of -8.3% (95% CI -9.3% to -7.3%), NNTB = 3 (95% CI 2 to 4). NMA estimates for TNF biologic+MTX/DMARD (absolute benefit, -10.3% (95% Crl -14% to -6.7%) and non-TNF biologic+MTX/DMARD (absolute benefit, -7.3% (95% Crl -13.6% to -0.67%) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with clinically and statistically significantly greater proportion of participants achieving remission in RA (defined by disease activity score DAS < 1.6 or DAS28 < 2.6) versus comparator (RR 2.81 (95% CI, 2.23 to 3.53); absolute benefit 18% more patients (95% CI 12% to 25%), NNTB = 6 (4 to 9)). NMA estimates for TNF biologic+MTX/DMARD (absolute improvement 17% (95% Crl 11% to 23%)) and non-TNF biologic+MTX/DMARD (absolute improvement 19% (95% Crl 12% to 28%) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), radiographic progression (scale 0 to 448) was statistically significantly reduced in those on biologics + MTX/DMARDs versus comparator, MD -2.61 (95% CI -4.08 to -1.14). The absolute reduction was small, -0.58% (95% CI -0.91% to -0.25%) and we are unsure of the clinical relevance of this reduction. NMA estimates of TNF biologic+MTX/DMARD (absolute reduction -0.67% (95% Crl -1.4% to -0.12%) and non-TNF biologic+MTX/DMARD (absolute reduction, -0.68% (95% Crl -2.36% to 0.92%)) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for imprecision), results for withdrawals due to adverse events were inconclusive, with wide confidence intervals encompassing the null effect and evidence of an important increase in withdrawals, RR 1.11 (95% CI 0.96 to 1.30). The NMA estimates of TNF biologic+MTX/DMARD (RR 1.24 (95% Crl 0.99 to 1.57)) and non-TNF biologic+MTX/DMARD (RR 1.20 (95% Crl 0.87 to 1.67)) were similarly inconclusive and downgraded to low for both imprecision and indirectness.Based on direct evidence of high quality, biologic+MTX/DMARD was associated with clinically significantly increased risk (statistically borderline significant) of serious adverse events on biologic+MTX/DMARD (Peto OR [can be interpreted as RR due to low event rate] 1.12 (95% CI 0.99 to 1.27); absolute risk 1% (0% to 2%), As well, the NMA estimate for TNF biologic+MTX/DMARD (Peto OR 1.20 (95% Crl 1.01 to 1.43)) showed moderate quality evidence of an increase in the risk of serious adverse events. The other two NMA estimates were downgraded to low quality due to imprecision and indirectness and had wide confidence intervals resulting in uncertainty around the estimates: non-TNF biologics + MTX/DMARD: 1.07 (95% Crl 0.89 to 1.29) and anakinra: RR 1.06 (95% Crl 0.65 to 1.75).Based on direct evidence of low quality (downgraded for serious imprecision), results were inconclusive for cancer (Peto OR 1.07 (95% CI 0.68 to 1.68) for all biologic+MTX/DMARD combinations. The NMA estimates of TNF biologic+MTX/DMARD (Peto OR 1.21 (95% Crl 0.63 to 2.38) and non-TNF biologic+MTX/DMARD (Peto OR 0.99 (95% Crl 0.58 to 1.78)) were similarly inconclusive and downgraded to low quality for both imprecision and indirectness.Main results text shows the results for tofacitinib and differences between medications. AUTHORS' CONCLUSIONS: Based primarily on RCTs of 6 months' to 12 months' duration, there is moderate quality evidence that the use of biologic+MTX/DMARD in people with rheumatoid arthritis who have failed to respond to MTX or other DMARDs results in clinically important improvement in function and higher ACR50 and remission rates, and increased risk of serious adverse events than the comparator (MTX/DMARD/PL; high quality evidence). Radiographic progression is slowed but its clinical relevance is uncertain. Results were inconclusive for whether biologics + MTX/DMARDs are associated with an increased risk of cancer or withdrawals due to adverse events.
26063682 Adiponectin exacerbates collagen-induced arthritis via enhancing Th17 response and prompti 2015 Jun 11 We previously reported adiponectin (AD) is highly expressed in the inflamed synovial joint tissue and correlates closely with progressive bone erosion in Rheumatoid arthritis (RA) patients. Here, we investigate the role of adiponectin in regulating Th17 response and the expression of receptor activator of nuclear factor-κB ligand (RANKL) in mice with CIA mice by intraarticularly injection of adiponectin into knee joints on day 17, day 20 and day 23 post first collagen immunization. The increased adiponectin expression was found in inflamed joint tissue of collagen-induced arthritis (CIA) mice. Adiponectin injection resulted in an earlier onset of arthritis, an aggravated arthritic progression, more severe synovial hyperplasia, bone erosion and osteoporosis in CIA mice. CD4(+)IL-17(+) Th17 cells, IL-17 mRNA and RANKL mRNA expression were markedly increased in the joint tissue of adiponectin treated CIA mice. Moreover, adiponectin treatment markedly enhanced Th17 cell generation from naive CD4(+) T cells in vitro, which accompanied by the high expression of Th17 transcription factor ROR-γt, and Th17 cytokine genes included IL-22 and IL-23. This study reveals a novel effect of adiponectin in exacerbating CIA progression by enhancing Th17 cell response and RANKL expression.
26608909 Impaired SNX9 Expression in Immune Cells during Chronic Inflammation: Prognostic and Diagn 2016 Jan 1 Chronic inflammation is associated with immunosuppression and downregulated expression of the TCR CD247. In searching for new biomarkers that could validate the impaired host immune status under chronic inflammatory conditions, we discovered that sorting nexin 9 (SNX9), a protein that participates in early stages of clathrin-mediated endocytosis, is downregulated as well under such conditions. SNX9 expression was affected earlier than CD247 by the generated harmful environment, suggesting that it is a potential marker sensing the generated immunosuppressive condition. We found that myeloid-derived suppressor cells, which are elevated in the course of chronic inflammation, are responsible for the observed SNX9 reduced expression. Moreover, SNX9 downregulation is reversible, as its expression levels return to normal and immune functions are restored when the inflammatory response and/or myeloid-derived suppressor cells are neutralized. SNX9 downregulation was detected in numerous mouse models for pathologies characterized by chronic inflammation such as chronic infection (Leishmania donovani), cancer (melanoma and colorectal carcinoma), and an autoimmune disease (rheumatoid arthritis). Interestingly, reduced levels of SNX9 were also observed in blood samples from colorectal cancer patients, emphasizing the feasibility of its use as a diagnostic and prognostic biomarker sensing the host's immune status and inflammatory stage. Our new discovery of SNX9 as being regulated by chronic inflammation and its association with immunosuppression, in addition to the CD247 regulation under such conditions, show the global impact of chronic inflammation and the generated immune environment on different cellular pathways in a diverse spectrum of diseases.
26473505 Regulation of Transforming Growth Factor β-Activated Kinase Activation by Epigallocatechi 2016 Feb OBJECTIVE: Transforming growth factor β-activated kinase 1 (TAK1) is a key MAPKKK family protein in interleukin-1β (IL-1β), tumor necrosis factor (TNF), and Toll-like receptor signaling. This study was undertaken to examine the posttranslational modification of TAK1 and its therapeutic regulation in rheumatoid arthritis (RA). METHODS: The effect of TAK1, IL-1 receptor-associated kinase 1 (IRAK-1), and TNF receptor-associated factor 6 (TRAF6) inhibition was evaluated in IL-1β-stimulated human RA synovial fibroblasts (RASFs). Western blotting, immunoprecipitation, and 20S proteasome assay were used to study the ubiquitination process in RASFs. The efficacy of epigallocatechin-3-gallate (EGCG), a potent antiinflammatory molecule, in regulating these processes in RASFs was evaluated. Molecular docking was performed to examine the interaction of EGCG with human TAK1, IRAK-1, and TRAF6. These findings were confirmed using a rat model of adjuvant-induced arthritis (AIA). RESULTS: Inhibition of TAK1, but not IRAK-1 or TRAF6, completely abrogated IL-1β-induced IL-6 and IL-8 synthesis in RASFs. EGCG inhibited TAK1 phosphorylation at Thr(184/187) and occupied the C(174) position, an ATP-binding site, to inhibit its kinase activity. EGCG pretreatment also inhibited K(63) -linked autoubiquitination of TRAF6, a posttranslational modification essential for TAK1 autophosphorylation, by forming a stable H bond at the K(124) position on TRAF6. Furthermore, EGCG enhanced proteasome-associated deubiquitinase expression to rescue proteins from proteasomal degradation. Western blot analyses of joint homogenates from rats with AIA showed a significant increase in K(48) -linked polyubiquitination, TAK1 phosphorylation, and TRAF6 expression when compared to naive rats. Administration of EGCG (50 mg/kg/day) for 10 days ameliorated AIA in rats by reducing TAK1 phosphorylation and K(48) -linked polyubiquitination. CONCLUSION: Our findings provide a rationale for targeting TAK1 for the treatment of RA with EGCG.
27855242 Biologic or tofacitinib monotherapy for rheumatoid arthritis in people with traditional di 2016 Nov 17 BACKGROUND: We performed a systematic review, a standard meta-analysis and network meta-analysis (NMA), which updates the 2009 Cochrane Overview, 'Biologics for rheumatoid arthritis (RA)'. This review is focused on biologic monotherapy in people with RA in whom treatment with traditional disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) had failed (MTX/other DMARD-experienced). OBJECTIVES: To assess the benefits and harms of biologic monotherapy (includes anti-tumor necrosis factor (TNF) (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) or non-TNF (abatacept, anakinra, rituximab, tocilizumab)) or tofacitinib monotherapy (oral small molecule) versus comparator (placebo or MTX/other DMARDs) in adults with RA who were MTX/other DMARD-experienced. METHODS: We searched for randomized controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2015, Issue 6, June), MEDLINE (via OVID 1946 to June 2015), and Embase (via OVID 1947 to June 2015). Article selection, data extraction and risk of bias and GRADE assessments were done in duplicate. We calculated direct estimates with 95% confidence intervals (CI) using standard meta-analysis. We used a Bayesian mixed treatment comparisons (MTC) approach for NMA estimates with 95% credible intervals (CrI). We converted odds ratios (OR) to risk ratios (RR) for ease of understanding. We calculated absolute measures as risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB). MAIN RESULTS: This update includes 40 new RCTs for a total of 46 RCTs, of which 41 studies with 14,049 participants provided data. The comparator was placebo in 16 RCTs (4,532 patients), MTX or other DMARD in 13 RCTs (5,602 patients), and another biologic in 12 RCTs (3,915 patients). Monotherapy versus placeboBased on moderate-quality direct evidence, biologic monotherapy (without concurrent MTX/other DMARDs) was associated with a clinically meaningful and statistically significant improvement in American College of Rheumatology score (ACR50) and physical function, as measured by the Health Assessment Questionnaire (HAQ) versus placebo. RR was 4.68 for ACR50 (95% CI, 2.93 to 7.48); absolute benefit RD 23% (95% CI, 18% to 29%); and NNTB = 5 (95% CI, 3 to 8). The mean difference (MD) was -0.32 for HAQ (95% CI, -0.42 to -0.23; a negative sign represents greater HAQ improvement); absolute benefit of -10.7% (95% CI, -14% to -7.7%); and NNTB = 4 (95% CI, 3 to 5). Direct and NMA estimates for TNF biologic, non-TNF biologic or tofacitinib monotherapy showed similar results for ACR50 , downgraded to moderate-quality evidence. Direct and NMA estimates for TNF biologic, anakinra or tofacitinib monotherapy showed a similar results for HAQ versus placebo with mostly moderate quality evidence.Based on moderate-quality direct evidence, biologic monotherapy was associated with a clinically meaningful and statistically significant greater proportion of disease remission versus placebo with RR 1.12 (95% CI 1.03 to 1.22); absolute benefit 10% (95% CI, 3% to 17%; NNTB = 10 (95% CI, 8 to 21)).Based on low-quality direct evidence, results for biologic monotherapy for withdrawals due to adverse events and serious adverse events were inconclusive, with wide confidence intervals encompassing the null effect and evidence of an important increase. The direct estimate for TNF monotherapy for withdrawals due to adverse events showed a clinically meaningful and statistically significant result with RR 2.02 (95% CI, 1.08 to 3.78), absolute benefit RD 3% (95% CI,1% to 4%), based on moderate-quality evidence. The NMA estimates for TNF biologic, non-TNF biologic, anakinra, or tofacitinib monotherapy for withdrawals due to adverse events and for serious adverse events were all inconclusive and downgraded to low-quality evidence. Monotherapy versus active comparator (MTX/other DMARDs)Based on direct evidence of moderate quality, biologic monotherapy (without concurrent MTX/other DMARDs) was associated with a clinically meaningful and statistically significant improvement in ACR50 and HAQ scores versus MTX/other DMARDs with a RR of 1.54 (95% CI, 1.14 to 2.08); absolute benefit 13% (95% CI, 2% to 23%), NNTB = 7 (95% CI, 4 to 26) and a mean difference in HAQ of -0.27 (95% CI, -0.40 to -0.14); absolute benefit of -9% (95% CI, -13.3% to -4.7%), NNTB = 2 (95% CI, 2 to 4). Direct and NMA estimates for TNF monotherapy and NMA estimate for non-TNF biologic monotherapy for ACR50 showed similar results, based on moderate-quality evidence. Direct and NMA estimates for non-TNF biologic monotherapy, but not TNF monotherapy, showed similar HAQ improvements , based on mostly moderate-quality evidence.There were no statistically significant or clinically meaningful differences for direct estimates of biologic monotherapy versus active comparator for RA disease remission. NMA estimates showed a statistically significant and clinically meaningful difference versus active comparator for TNF monotherapy (absolute improvement 7% (95% CI, 2% to 14%)) and non-TNF monotherapy (absolute improvement 19% (95% CrI, 7% to 36%)), both downgraded to moderate quality.Based on moderate-quality direct evidence from a single study, radiographic progression (scale 0 to 448) was statistically significantly reduced in those on biologic monotherapy versus active comparator, MD -4.34 (95% CI, -7.56 to -1.12), though the absolute reduction was small, -0.97% (95% CI, -1.69% to -0.25%). We are not sure of the clinical relevance of this reduction.Direct and NMA evidence (downgraded to low quality), showed inconclusive results for withdrawals due to adverse events, serious adverse events and cancer, with wide confidence intervals encompassing the null effect and evidence of an important increase. AUTHORS' CONCLUSIONS: Based mostly on RCTs of six to 12-month duration in people with RA who had previously experienced and failed treatment with MTX/other DMARDs, biologic monotherapy improved ACR50, function and RA remission rates compared to placebo or MTX/other DMARDs.Radiographic progression was reduced versus active comparator, although the clinical significance was unclear.Results were inconclusive for whether biologic monotherapy was associated with an increased risk of withdrawals due to adverse events, serious adverse events or cancer, versus placebo (no data on cancer) or MTX/other DMARDs.
26653668 Effect of abatacept on the immunogenicity of 23-valent pneumococcal polysaccharide vaccina 2015 Dec 10 INTRODUCTION: Patients with rheumatoid arthritis (RA) treated with abatacept (ABT) are at increased risk for vaccine-preventable infections. The aim of the present study is to evaluate the humoral response to 23-valent pneumococcal polysaccharide (PPSV23) vaccination in RA patients receiving ABT. METHODS: The immunogenicity study was nested within a randomized, double-blind placebo-controlled study, designed to evaluate the efficacy of the PPSV23. PPSV23 was given to 111 RA patients, who were classified into three groups: RA control (n = 35), methotrexate (MTX) alone (n = 55), and ABT (n = 21). Before and 4-6 weeks after vaccination, we measured the patients' concentrations of antibodies against pneumococcal serotypes 6B and 23F using an enzyme-linked immunosorbent assay and determined their antibody functionality using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI). RESULTS: The pneumococcal serotype-specific IgG concentrations and OIs were both significantly increased in all treatment groups in response to PPSV23 vaccination. In the ABT group, the IgG responses for the 6B serotype were lower compared with those in the MTX alone or control groups, whereas the OI responses were similar to those in the other two groups. In a subgroup analysis, the pneumococcal serotype-specific IgG responses were significantly lower in both serotypes (6B and 23F) in the ABT/MTX group; however, the OI responses in the ABT group were not different from the control group. There was no association between the pneumococcal serotype-specific IgG and OI responses for the 6B serotype in patients receiving ABT in contrast to the control or MTX alone patients. No severe adverse effects were observed in any of the treatment groups. CONCLUSIONS: OI responses indicate antibody functionality rather than simply their amount, so the similarity of these measurements between all three groups suggests that RA patients receiving ABT still benefit from receiving the PPSV23 vaccination, even though they produce less IgG in response to it. The results suggest an influence of ABT on the humoral response to PPSV23 vaccination under MTX treatment; however, preserved opsonin responses are expected in RA patients treated with ABT plus MTX. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry: UMIN000009566. Registered 12 December 2012.
25894827 Homeostatic regulation of T cell trafficking by a B cell-derived peptide is impaired in au 2015 May During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3 zeta delta (14.3.3.ζδ) protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin-induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type 1 diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to that of healthy age-matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Control of patient T cell trafficking is re-established by treatment with exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis and Sjögren's syndrome, PEPITEM reduced T cell recruitment into inflamed tissues.
25645456 B cells expressing IFN-γ suppress Treg-cell differentiation and promote autoimmune experi 2015 Apr Clinical efficacy in the treatment of rheumatoid arthritis with anti-CD20 (Rituximab)-mediated B-cell depletion has garnered interest in the mechanisms by which B cells contribute to autoimmunity. We have reported that B-cell depletion in a murine model of proteoglycan-induced arthritis (PGIA) leads to an increase in Treg cells that correlate with decreased autoreactivity. Here, we demonstrate that the increase in Treg cells after B-cell depletion is due to an increase in the differentiation of naïve CD4(+) T cells into Treg cells. Since the development of PGIA is dependent on IFN-γ and B cells are reported to produce IFN-γ, we hypothesized that B-cell-specific IFN-γ plays a role in the development of PGIA. Accordingly, mice with B-cell-specific IFN-γ deficiency were as resistant to the induction of PGIA as mice that were completely IFN-γ deficient. Importantly, despite a normal frequency of IFN-γ-producing CD4(+) T cells, B-cell-specific IFN-γ-deficient mice exhibited a higher percentage of Treg cells compared with that in WT mice. These data indicate that B-cell IFN-γ production inhibits Treg-cell differentiation and exacerbates arthritis. Thus, we have established that IFN-γ, specifically derived from B cells, uniquely contributes to the pathogenesis of autoimmunity through prevention of immunoregulatory mechanisms.
25358907 A unification of models for meta-analysis of diagnostic accuracy studies without a gold st 2015 Jun Several statistical methods for meta-analysis of diagnostic accuracy studies have been discussed in the presence of a gold standard. However, in practice, the selected reference test may be imperfect due to measurement error, non-existence, invasive nature, or expensive cost of a gold standard. It has been suggested that treating an imperfect reference test as a gold standard can lead to substantial bias in the estimation of diagnostic test accuracy. Recently, two models have been proposed to account for imperfect reference test, namely, a multivariate generalized linear mixed model (MGLMM) and a hierarchical summary receiver operating characteristic (HSROC) model. Both models are very flexible in accounting for heterogeneity in accuracies of tests across studies as well as the dependence between tests. In this article, we show that these two models, although with different formulations, are closely related and are equivalent in the absence of study-level covariates. Furthermore, we provide the exact relations between the parameters of these two models and assumptions under which two models can be reduced to equivalent submodels. On the other hand, we show that some submodels of the MGLMM do not have corresponding equivalent submodels of the HSROC model, and vice versa. With three real examples, we illustrate the cases when fitting the MGLMM and HSROC models leads to equivalent submodels and hence identical inference, and the cases when the inferences from two models are slightly different. Our results generalize the important relations between the bivariate generalized linear mixed model and HSROC model when the reference test is a gold standard.