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ID PMID Title PublicationDate abstract
20675706 Anti-TNF therapy is associated with an increased risk of serious infections in patients wi 2011 Jan OBJECTIVES: To evaluate the risk of serious infections (SIs) in patients with RA treated with anti-TNF therapy with emphasis on the risk across different ages. METHODS: Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, we compared the risk of SI between 11 798 anti-TNF-treated patients and 3598 non-biologic DMARD (nbDMARD)-treated patients. RESULTS: A total of 1808 patients had at least one SI (anti-TNF: 1512; nbDMARD: 296). Incidence rates were: anti-TNF 42/1000 patient-years of follow-up (95% CI 40, 44) and nbDMARD 32/1000 patient-years of follow-up (95% CI 28, 36). The adjusted hazard ratio (adjHR) for SI in the anti-TNF cohort was 1.2 (95% CI 1.1, 1.5). The risk did not differ significantly between the three agents adalimumab, etanercept and infliximab. The risk was highest during the first 6 months of therapy [adjHR 1.8 (95% CI 1.3, 2.6)]. Although increasing age was an independent risk factor for SI in both cohorts, there was no difference in relative risk of infection in patients on anti-TNF therapy in the older population. There was no difference in hospital stay for SI between cohorts. Mortality within 30 days of SI was 50% lower in the anti-TNF cohort [odds ratio 0.5 (95% CI 0.3, 0.8)]. CONCLUSIONS: These data add to currently available evidence suggesting that anti-TNF therapy is associated with a small but significant overall risk of SI. This must be balanced against the risks associated with poor disease control or alternative treatments.
21834821 Pyoderma gangrenosum requiring inpatient management: a report of 26 cases with follow up. 2011 Aug We present a case series of inpatients with pyoderma gangrenosum (PG), an ulcerative neutrophilic skin condition of unknown aetiology. Twenty-six patients were admitted with PG, nine men and 17 women. At the time of the chart review, seven patients (26.9%) had died. Patients had a mean of 2.0 active ulcerative lesions and 22 patients' ulcers (84.6%) were on the lower limb. Systemic diseases were coexistent in 15 patients (57.7%), the most common being rheumatoid arthritis (19.2%). Thirty-eight wound cultures were taken and were positive for Staphylococcus aureus in 22 cases (57.8%) and Pseudomonas aeruginosa in 20 (52.6%). After prednisolone, cyclosporin was the next most commonly prescribed systemic therapy (34.6%). Surgical debridement was undertaken in seven cases (26.9%) and two patients had skin grafts. Upon discharge from hospital, 21 patients' ulcers (80.8%) had improved. At 6 months 50% showed complete ulcer healing. Our results highlight the potential severity of PG requiring hospital admission, the need for aggressive therapy and the overall high associated morbidity and mortality.
22004846 Towards the next generation of anti-TNF drugs. 2011 Dec Although pivotal to the immune system homeostasis, tumor necrosis factor (TNF) becomes deleterious when de-regulated. The currently marketed TNF blockers are highly efficacious in rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, uveitis and inflammatory bowel disease; reactivation of tuberculosis and exacerbation of pre-existing multiple sclerosis remain their most important safety issues. The endogenous protein progranulin binds TNF receptor-1 (TNFR1) and TNFR2, thus blocking their interactions with TNF. Domains of the extracellular region of TNFR, termed preligand-binding assembly domain (PLAD), mediate receptor-chain trimerization which is essential for signaling. Therapeutic administration of either progranulin or soluble versions of TNFR1 PLAD in mouse models of diseases in which TNF is relevant yielded beneficial results, opening the door to the next generation of non-antibody anti-TNF drugs for a variety of non-infectious inflammatory conditions. Whether these drugs may target TNF in a more refined way than the current blockers, perhaps being more efficacious without compromising the protective role of TNF in host defense and (auto)immunity, remains to be seen.
21904784 Celecoxib, a cyclooxygenase-2 inhibitor, improved upper gastrointestinal lesions in rheuma 2012 Jun We prospectively evaluated the effects of celecoxib (CEL) on the gastrointestinal (GI) tract of rheumatoid arthritis (RA) patients with endoscopically identified GI mucosal injury after therapeutic switching from the long-term use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Upper GI endoscopy was performed on RA patients who had been treated with NSAIDs for ≥3 months. GI mucosal injury was evaluated according to the modified LANZA score. Patients with mucosal injury without ulcers were switched from NSAIDs to CEL, while those with ulcers were switched to CEL with famotidine after ulcer healing. At week 16 of treatment, GI mucosal injury was endoscopically revaluated. An efficacy analysis was performed before therapeutic switching and at 8 and 16 weeks post-switching. Endoscopic analysis revealed GI mucosal injury, including six ulcers, in 45 of the 82 patients (54.9%). Sixteen weeks after switching to CEL, LANZA scores were significantly improved [2.1 ± 0.8 (pre-switching) vs. 1.6 ± 1.3, P = 0.0073] in patients with LANZA scores of 1, 2, or 3 (n = 35). The Disease Activity Score using 28 joint counts (DAS28) [erythrocyte sedimentation rate item score (ESR4) (P = 0.0257) and C-reactive protein item score (CRP4) (P = 0.0031)] was also significantly improved by week 16. Based on these results, we conclude that preexisting NSAID-induced upper GI injury is improved following therapeutic switching to CEL without any reduction in analgesic efficacy.
22982203 Recombinant mycobacterial HSP65 in combination with incomplete Freund's adjuvant induced r 2012 Dec 14 Complete Freund's adjuvant (CFA) containing the inactivated mycobacterium has been conventionally used to induce typical arthritis in rats. In comparison, incomplete Freund's adjuvant (IFA), lacking the mycobacterium, can only induce less severe arthritis. However, the key components responsible for the arthritogenic effect of the whole mycobacterium are rarely known. Although mycobacterial heat-shock protein 65 (MHSP65) specific humoral and cellular immune responses were detected in rats with arthritis induced by CFA, MHSP65 alone cannot induce arthritis. In this study, we replaced the whole mycobacterium in CFA with recombinant MHSP65 (rMHSP65), prepared rMHSP65-IFA emulsion by mixing rMHSP65 and IFA, and investigated whether rMHSP65-IFA could induce arthritis in rats as CFA did. We found that intradermal injection of the rMHSP65-IFA emulsion induced arthritic lesions in testing animals to the same degree as those induced by CFA, manifested by severe swelling in hind paws, and synovial thickening, cartilage erosion and lymphocytes infiltration in ankle joints. Notably, the rMHSP65-IFA recipe also induced the production of anti-dsDNA and -rMHSP65 antibodies in rats. These results thus demonstrate that rMHSP65 can be used to substitute the inactivated mycobacteria in CFA to induce typical arthritis in rats.
21933041 Clinicopathological analyses in patients with other iatrogenic immunodeficiency-associated 2012 Apr Despite numerous attempts to uncover the mechanism of other iatrogenic immunodeficiency-associated lymphoproliferative diseases (OIIA-LPDs), this mechanism remains poorly understood, especially in rheumatoid arthritis (RA) patients. We analyzed the data on 23 patients with LPDs and RA. Patients were categorized into three groups according to whether they had methotrexate (MTX); MTX-regressive LPDs, MTX-persistent LPDs or other drugs-mediated LPDs. The LPDs seen in OIIA-LPDs-RA might have a unique behavior to think about several rare phenotypes. The overall survival of all patients was 74% at 5 years, and those of the three groups were 100%, 64% and 60%, respectively. Among the 6 patients who died, 4 had LPDs that were detected late, and thus adequate treatment was not given. In addition, several patients with diffuse large B cell lymphoma with a complex karyotype achieved complete remission (CR). Only one among the 17 patients who achieved CR relapsed. OIIA-LPDs-RA appeared to have a better prognosis than other more common types of lymphomas. Regarding RA treatment, various anti-RA drugs were given to the patients after developing LPDs, including MTX, but no recurrent patients were documented.
21537832 DcR3-TL1A signalling inhibits cytokine-induced proliferation of rheumatoid synovial fibrob 2011 Sep Decoy receptor 3 (DcR3), a member of the tumour necrosis factor receptor (TNFR) superfamily, lacks the transmembrane domain of conventional TNFRs in order to be a secreted protein. DcR3 competitively binds and inhibits members of the TNF family, including Fas ligand (FasL), LIGHT and TL1A. We previously reported that TNFα-induced DcR3 overexpression in rheumatoid synovial fibroblasts (RA-FLS) protects the cells from Fas-induced apoptosis and that DcR3 induces VLA-4 expression in THP-1 macrophages to inhibit cycloheximide-induced apoptosis. Meanwhile, recent studies have suggested that DcR3 acting as a ligand directly induces the differentiation of macrophages to osteoclasts. Therefore, in the present study, we analyzed the direct effects of DcR3 as a ligand in RA-FLS. The experiments showed that DcR3 binds to TL1A expressed in RA-FLS resulting in the negative regulation of cell proliferation induced by inflammatory cytokines. DcR3-TL1A signalling may be involved in the pathogenesis of rheumatoid arthritis (RA).
21957688 Influenza and pneumococcal vaccination and varicella status in inflammatory arthritis pati 2011 Jul Patients with inflammatory arthritis are at increased risk of vaccine preventable infections. This risk is increased by immunomodulatory therapies. Vaccination for influenza and pneumococcal disease reduces the risk. Severe cases of varicella infection have occurred in patients on biologic therapies. We sought to identify vaccination rates for commonly acquired infections and to ascertain varicella immune status in patients with inflammatory arthritis. 100 patients with inflammatory arthritis were administered a standardised questionnaire. Data collected included age, diagnosis, vaccination history, history of varicella, treatment and the presence of other indications for vaccination. 58 patients (58%) had not received the influenza vaccine in the past year. Only 19 patients (19%) had ever received pneumococcal vaccine. Anti TNF use did not predict vaccination (p = .46). An increasing number of co morbid conditions predicted both pneumococcal (p < 0.003) and influenza vaccine (p < 0.03) administration. Nineteen patients (19%) gave no history of varicella infection, none having had varicella titres checked pre treatment. Immunisation rates in patients with inflammatory arthritis on immunosuppressive therapies are low. Immunisation schedules should be available for each patient during rheumatology and general practice consultations.
22858099 Discovery of potent and selective rhodanine type IKKβ inhibitors by hit-to-lead strategy. 2012 Sep 1 Regulation of NF-κB activation through the inhibition of IKKβ has been identified as a promising target for the treatment of inflammatory and autoimmune disease such as rheumatoid arthritis. In order to develop novel IKKβ inhibitors, we performed high throughput screening toward around 8000 library compounds, and identified a hit compound containing rhodanine moiety. We modified the structure of hit compound to obtain potent and selective IKKβ inhibitors. Throughout hit-to-lead studies, we have discovered optimized compounds which possess blocking effect toward NF-κB activation and TNFα production in cell as well as inhibition activity against IKKβ. Among them, compound 3q showed the potent inhibitory activity against IKKβ, and excellent selectivity over other kinases such as p38α, p38β, JNK1, JNK2, and JNK3 as well as IKKα.
22038403 The response of T cells to interleukin-6 is differentially regulated by the microenvironme 2011 Nov OBJECTIVE: Interleukin-6 (IL-6) is a proinflammatory cytokine with regulatory effects on the survival and differentiation of T cells. It exerts its biologic function in 2 ways: by directly binding to the IL-6 receptor (IL-6R; CD126) or via trans-signaling, in which soluble IL-6R/IL-6 complexes bind to the signaling component CD130. This study was undertaken to assess the expression and regulation of CD126 and CD130 and determine how these affect the response of CD4+ T cells to IL-6 in the joints of patients with rheumatoid arthritis (RA). METHODS: Flow cytometry and immunofluorescence microscopy were used to determine the expression, function, and regulation of CD126 and CD130 in CD4+ T cells from the peripheral blood (PB), synovial fluid (SF), and synovial tissue of RA patients. RESULTS: Compared to the findings in RA PB, CD4+ T cells in the SF and synovial tissue expressed low levels of CD126. In contrast, whereas CD4+ T cell expression of CD130 was minimal in the SF, its level in the synovial tissue was high. Consistent with this phenotype, synovial tissue T cells responded to trans-signaling by soluble IL-6R/IL-6 complexes, whereas no response was evident in CD4+ T cells from the SF. Down-regulation of both receptor components in SF T cells could be explained by exposure to high levels of IL-6. Increased levels of CD130 messenger RNA and protein in synovial tissue CD4+ T cells suggested that CD130 is up-regulated locally. Among a range of cytokines tested, only IL-10 induced CD130 expression in T cells. CONCLUSION: The inflamed microenvironment in the synovial tissue maintains responsiveness to IL-6 trans-signaling through the up-regulation of CD130 expression in CD4+ T cells, and this process may be driven by IL-10.
21284685 NFKBIL1 confers resistance to experimental autoimmune arthritis through the regulation of 2011 May We and others have reported that human NF-κB inhibitor-like-1 (NFKBIL1) was a putative susceptible gene for autoimmune diseases such as rheumatoid arthritis (RA). However, its precise role in the pathogenesis of RA is still largely unknown. In this study, we generated transgenic mice expressing human NFKBIL1 (NFKBIL1-Tg) and examined whether NFKBIL1 plays some role(s) in the development of autoimmune arthritis. In both a collagen-induced arthritis model and a collagen antibody-induced arthritis model, NFKBIL1-Tg mice showed resistance to arthritis compared to control mice, indicating that the gene product of NFKBIL1 was involved in the control of thusly induced arthritis. Total spleen cells of NFKBIL1-Tg mouse showed decreased proliferation to mitogenic stimuli, consistent with its resistance to arthritis. Unexpectedly, purified T cells of NFKBIL1-Tg mouse showed increased proliferation and cytokine production. This apparent discrepancy was accounted for by the impaired functions of antigen-presenting cells of NFKBIL1-Tg mouse; both T/B cell-depleted spleen cells and bone marrow-derived dendritic cells of the Tg mouse induced less prominent proliferation and IL-2 production of T cells. Furthermore, dendritic cells (DCs) derived from NFKBIL1-Tg mouse showed lower expression of co-stimulatory molecules and decreased production of inflammatory cytokines when they were activated by lipopolysaccharide. Taken together, these results indicated that NFKBIL1 affected the pathogenesis of RA at least in part through the regulation of DC functions.
21680138 Comparison of surgical outcomes and implant wear between ceramic-ceramic and ceramic-polye 2011 Sep The results of a prospective multicenter trial comparing 357 hips randomized to total hip arthroplasty with either ceramic-ceramic or ceramic-polyethylene couplings are presented. No statistically significant difference in clinical outcomes scores between the ceramic-ceramic and ceramic-polyethylene groups was observed at any time interval. The mean linear rate was statistically lower (P < .001) in the ceramic-ceramic group (30.5 μm/year) when compared with the ceramic-polyethylene group (218.2 μm/year). The rates of ceramic implant fracture (2.6%) and audible component-related noise (3.1%) were statistically higher in the ceramic-ceramic group when compared with the ceramic-polyethylene group (P < .05). Lastly, there was no statistically significant difference in the dislocation or revision rate between the groups at the time of last clinical follow-up.
22811011 Relationship of ultrasonographic findings with synovial angiogenesis modulators in differe 2013 Apr Angiogenesis is controlled by a variety of angiogenesis stimulators and inhibitors. The increased power Doppler (PD) signals determined by ultrasonography is an indirect marker of synovial vascularity in arthritis. We aimed to investigate relationship between ultrasonographic findings and synovial angiogenesis modulators. Thirteen Behcet's disease (BD), 15 spondyloarthropathy, 21 rheumatoid arthritis (RA), and 15 osteoarthritis (OA) patients with knee arthritis were included. Cumulative effusion, synovial hypertrophy, and PD signal scores were calculated in arthritic joints. In synovial fluid samples, angiogenesis inhibitors (angiostatin, thrombospondin-1, and endostatin) and stimulators [bFGF (basic fibroblast growth factor), angiopoietin-1] were studied. The comparisons between groups were made by Kruskal-Wallis test, and correlation analysis was calculated with Pearson and Spearman tests. Effusion scores were significantly higher in inflammatory arthritis than in OA. Synovial hypertrophy scores were higher in RA and spondylarthritis than in OA and BD. PD scores were not different between the groups. Synovial angiostatin and bFGF levels were significantly higher in patients with inflammatory arthritis than in OA. Cumulative effusion scores were positively correlated with angiopoietin-1, angiostatin, and bFGF and negatively correlated with thrombospondin-1 levels. Synovial hypertrophy scores were positively correlated with angiostatin and bFGF levels and negatively correlated with thrombospondin-1. No correlation was found between PD scores and modulators of angiogenesis. In large joints like knee, detecting PD signals alone was not sufficient to assess the angiogenesis. However, cumulative activity scores were positively correlated with angiogenesis stimulators. Therefore, when investigating the angiogenesis, PD technique should be added to gray-scale examinations.
21673997 Myelin basic protein as a novel genetic risk factor in rheumatoid arthritis--a genome-wide 2011 Rheumatoid arthritis (RA) is a major cause of adult chronic inflammatory arthritis and a typical complex trait. Although several genetic determinants have been identified, they account for only a part of the genetic susceptibility. We conducted a genome-wide association study of RA in Japanese using 225,079 SNPs genotyped in 990 cases and 1,236 controls from two independent collections (658 cases and 934 controls in collection1; 332 cases and 302 controls in collection2), followed by replication studies in two additional collections (874 cases and 855 controls in collection3; 1,264 cases and 948 controls in collection4). SNPs showing p<0.005 in the first two collections and p<10(-4) by meta-analysis were further genotyped in the latter two collections. A novel risk variant, rs2000811, in intron2 of the myelin basic protein (MBP) at chromosome 18q23 showed strong association with RA (p = 2.7×10(-8), OR 1.23, 95% CI: 1.14-1.32). The transcription of MBP was significantly elevated with the risk allele compared to the alternative allele (p<0.001). We also established by immunohistochemistry that MBP was expressed in the synovial lining layer of RA patients, the main target of inflammation in the disease. Circulating autoantibody against MBP derived from human brain was quantified by ELISA between patients with RA, other connective tissue diseases and healthy controls. As a result, the titer of anti-MBP antibody was markedly higher in plasma of RA patients compared to healthy controls (p<0.001) and patients with other connective tissue disorders (p<0.001). ELISA experiment using citrullinated recombinant MBP revealed that a large fraction of anti-MBP antibody in RA patients recognized citrullinated MBP. This is the first report of a genetic study in RA implicating MBP as a potential autoantigen and its involvement in pathogenesis of the disease.
21285425 Receipt of disease-modifying antirheumatic drugs among patients with rheumatoid arthritis 2011 Feb 2 CONTEXT: In 2005, the Healthcare Effectiveness Data and Information Set (HEDIS) introduced a quality measure to assess the receipt of disease-modifying antirheumatic drugs (DMARDs) among patients with rheumatoid arthritis (RA). OBJECTIVE: To identify sociodemographic, community, and health plan factors associated with DMARD receipt among Medicare managed care enrollees. DESIGN, SETTING, AND PARTICIPANTS: We analyzed individual-level HEDIS data for 93,143 patients who were at least 65 years old with at least 2 diagnoses of RA within a measurement year (during 2005-2008). Logistic regression models with generalized estimating equations were used to determine factors associated with DMARD receipt and logistic regression was used to adjust health plan performance for case mix. MAIN OUTCOME MEASURES: Receipt or nonreceipt of DMARD. RESULTS: The mean age of patients was 74 years; 75% were women and 82% were white. Overall performance on the HEDIS measure for RA was 59% in 2005, increasing to 67% in 2008 (P for trend <.001). The largest difference in performance was based on age: patients aged 85 years and older had a 30 percentage point lower rate of DMARD receipt (95% confidence interval [CI], -29 to -32 points; P < .001), compared with patients 65 to 69 years of age, even after adjusting for other factors. Lower percentage point rates were also found for patients who were men (-3 points; 95% CI, -5 to -2 points; P < .001), of black race (-4 points; 95% CI, -6 to -2 points; P < .001), with low personal income (-6 points; 95% CI, -8 to -5 points; P < .001), with the lowest zip code-based socioeconomic status (-4 points; 95% CI, -6 to 2 points; P < .001), or enrolled in for-profit health plans (-4 points; 95% CI, -7 to 0 points; P < .001); and in the Middle Atlantic region (-7 points; 95% CI, -13 to -2 points; P < .001) and South Atlantic regions (-11 points; 95% CI, -20 to -3 points; P < .001) as compared with the Pacific region. Performance varied widely by health plan, ranging from 16% to 87%. CONCLUSIONS: Among Medicare managed care enrollees carrying a diagnosis of RA between 2005 and 2008, 63% received a DMARD. Receipt of DMARDs varied based on demographic factors, socioeconomic status, geographic location, and health plan.
23273377 Complex fractures of the distal humerus in the elderly: is primary total elbow arthroplast 2013 Feb INTRODUCTION: Distal humerus fractures are fairly rare. But as our population ages, these fractures become more complex and the choice of treatment more delicate. Poor bone quality results in many technical problems and the fixation hardware stability remains at risk. The goal of this study was to evaluate the functional recovery and morbidity of complex distal humerus fractures in elderly patients when treated with elbow prosthesis. HYPOTHESIS: Good functional recovery can be achieved with a total joint replacement. PATIENTS AND METHODS: This series consisted of 20 patients (18 women and two men) having an average age of 80years (range 65-93, median 80). Based on the AO classification, there were two Type A2 fractures, two Type B fractures, 15 Type C fractures and one fracture that could not be classified because of previous rheumatoid disease history at this elbow. Two fractures were open. In two cases, the olecranon was also fractured. Treatment consisted of the implantation of a Coonrad-Morrey, hinge-type total elbow prosthesis (Zimmer(®), Warsaw, IN, USA). The Mayo Clinic surgical approach was used 17 times and the transolecranon approach was used three times. Primary arthroplasty was performed in 19 cases and the surgery was performed after six weeks of conservative treatment (diagnostic delay) in one case. Unrestricted motion was allowed after surgery, but a maximum of 0.5kg could be carried during the first 3months; this was subsequently increased to 2.5kg. RESULTS: Fifteen of the 20 patients were available for reevaluation with an average follow-up of 3.6years (range 1.7-5.5, median 3.4). Four patients had died and one was lost to follow-up. The average range of motion was 97° (range 60-130°), comprising an average flexion of 130° (range 110-140°) and average loss of extension of 33° (range 0-80°). Pronation and supination were normal. The average Mayo Elbow Performance Score (MEPS) was 83 (range 60-100, median 80). X-rays revealed seven cases of radiolucent lines, with two being progressive. There was no visible wear of the polyethylene bushings at the hinge. Six patients had moderate periarticular heterotopic ossification. The two cases of olecranon osteotomy and one case of olecranon fracture had healed. There were no surgical site infections but two cases of ulnar compression, one of which required neurolysis. There was one case of humeral component loosening after 6years, but the implant was not changed. DISCUSSION: The clinical range of motion results were comparable to published data. The functional scores were slightly lower, mainly because of the pain factor. The initial results were encouraging and consistent with published data as long as the indications were well-chosen. Based on this retrospective study, total elbow arthroplasty can be a valid alternative in the surgeon's treatment armamentarium for complex distal humerus fractures in elderly patients who have moderate functional demands. Our results support our hypothesis, since we found good functional recovery without associated morbidity. LEVEL OF EVIDENCE: Level IV retrospective study without comparator.
23132777 Curcumin serves as a human kv1.3 blocker to inhibit effector memory T lymphocyte activitie 2013 Sep Curcumin, the principal active component of turmeric, has long been used to treat various diseases in India and China. Recent studies show that curcumin can serve as a therapeutic agent for autoimmune diseases via a variety of mechanisms. Effector memory T cells (T(EM), CCR7⁻ CD45RO⁺ T lymphocyte) have been demonstrated to play a crucial role in the pathogenesis of T cell-mediated autoimmune diseases, such as multiple sclerosis (MS) or rheumatoid arthritis (RA). Kv1.3 channels are predominantly expressed in T(EM) cells and control T(EM) activities. In the present study, we examined the effect of curcumin on human Kv1.3 (hKv1.3) channels stably expressed in HEK-293 cells and its ability to inhibit proliferation and cytokine secretion of T(EM) cells isolated from patients with MS or RA. Curcumin exhibited a direct blockage of hKv1.3 channels in a time-dependent and concentration-dependent manner. Moreover, the activation curve was shifted to a more positive potential, which was consistent with an open-channel blockade. Paralleling hKv1.3 inhibition, curcumin significantly inhibited proliferation and interferon-γ secretion of T(EM) cells. Our findings demonstrate that curcumin is able to inhibit proliferation and proinflammatory cytokine secretion of T(EM) cells probably through inhibition of hKv1.3 channels, which contributes to the potency of curcumin for the treatment of autoimmune diseases. This is probably one of pharmacological mechanisms of curcumin used to treat autoimmune diseases.
22673798 Kirenol exerts a potent anti-arthritic effect in collagen-induced arthritis by modifying t 2012 Jul 15 Rheumatoid arthritis is characterized by the imbalance of T cells, which leads to increased pro-inflammatory and reduced anti-inflammatory cytokines. Modulating the balance among T cells is crucial for the treatment of RA. Kirenol is a major diterpenoid components of Herba Siegesbeckiae, which has been applied for arthritic therapy for centuries. Since prior research showed Kirenol exhibited anti-inflammatory effect in rats, in this study we have evaluated the effect and mechanism of bioactive Kirenol in a rat model of collagen-induced arthritis (CIA) on modulation of T cells. After immunization with bovine type II collagen (CII), Wistar rats were orally administered saline (CIA group), 2 mg/kg Kirenol or 2 mg/kg prednisolone daily for 30 days. The severity of arthritis was clinically and histologically assessed. The numbers of CD4⁺CD25⁺Foxp3⁺ T regulatory cells (Tregs) and IFNγ⁺CD4⁺ and IL4⁺CD4⁺ T cells were determined by flow cytometry, the mRNA expression level of Foxp3 was quantified by RT-PCR, cytokine levels were measured by ELISA and CII-induced cell proliferation was quantified in vitro. Kirenol significantly delayed the occurrence and reduced the disease severity of CIA. Histological analysis confirmed Kirenol suppressed joint inflammation and inhibited cartilage and bone destruction, compared to the CIA group. Kirenol also upregulated the mRNA expression of Foxp3, increased the numbers of CD4⁺CD25⁺Foxp3⁺ and IL4⁺CD4⁺ T cells, and reduced the number of IFNγ⁺CD4⁺ T cells. Kirenol reduced the levels of TNF-α, IL-17A and IL-6 in synovial fluid and TNF-α, IL-17A and IFN-γ in serum, and increased the serum levels of IL-4, IL-10 and TGF-β1. In addition, Kirenol inhibited the ability of CII to induce splenocyte, PBMC and lymph node cell proliferation in vitro, compared to cells from CIA rats. In conclusion, these results suggest that Kirenol may be a potential immunosuppressant for the treatment for rheumatoid arthritis.
21798287 IL-17 increases cadherin-11 expression in a model of autoimmune experimental arthritis and 2011 Oct 30 IL-17 plays important roles in synovial inflammation and bone destruction in the mouse model of autoimmune arthritis and in rheumatoid arthritis (RA). Cadherin-11 determines the behavior of synovial cells in their proinflammatory and destructive tissue response in inflammatory arthritis, and promotes the invasive behavior of fibroblast-like synoviocytes (FLS). The purpose of this study was to examine the effect of IL-17 on the expression of cadherin-11 in autoimmune experimental arthritis and in RA synovium. The severity of synovial inflammation and bone destruction were examined in IL-17-injected knee joints of mice with collagen-induced arthritis (CIA). Cadherin-11 expression was examined in the synovium of mice with CIA, of IL-1 receptor antagonist (IL-1Ra)-deficient mice and of patients with RA and osteoarthritis (OA). Cadherin-11 expression was also examined in the synovium of IL-17 injected knee joints from CIA mice and in IL-17-stimulated FLS of CIA mice and RA patients. IL-17 aggravated synovial inflammation and bone destruction in CIA. By immunohistochemistry, cadherin-11 expression was increased in the synovium of mice with CIA and IL-1Ra-deficient mice and in patients with RA. Synovial cadherin-11 expression in IL-17-injected knee joints, measured by real-time RT-PCR, Western blot and immunohistochemistry, was increased in CIA. Cadherin-11 expression was significantly increased by IL-17 in cultured FLS of CIA mice and RA patients, and these increases were blocked by NF-κB inhibitors. IL-17 increased the expression of cadherin-11 in vivo and in vitro, which implies that an IL-17-induced increase of cadherin-11 is involved in IL-17-induced aggravation of joint destruction and inflammation.
20937671 Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate 2011 Jan OBJECTIVES: Rituximab is an effective treatment in patients with established rheumatoid arthritis (RA). The objective of the IMAGE study was to determine the efficacy of rituximab in the prevention of joint damage and its safety in combination with methotrexate (MTX) in patients initiating treatment with MTX. METHODS: In this double-blind randomised controlled phase III study, 755 MTX-naïve patients with active RA were randomly assigned to MTX alone, rituximab 2×500 mg + MTX or rituximab 2×1000 mg + MTX. The primary end point at week 52 was the change in joint damage measured using a Genant-modified Sharp score. RESULTS: 249, 249 and 250 patients were randomly assigned to MTX alone, rituximab 2×500 mg + MTX or rituximab 2×1000 mg + MTX, respectively. At week 52, treatment with rituximab 2×1000 mg + MTX compared with MTX alone was associated with a reduction in progression of joint damage (mean change in total modified Sharp score 0.359 vs 1.079; p=0.0004) and an improvement in clinical outcomes (ACR50 65% vs 42%; p<0.0001); rituximab 2×500 mg + MTX improved clinical outcomes (ACR50 59% vs 42%; p<0.0001) compared with MTX alone but did not significantly reduce the progression of joint damage. Safety outcomes were similar between treatment groups. CONCLUSIONS: Treatment with rituximab 2×1000 mg in combination with MTX is an effective therapy for the treatment of patients with MTX-naïve RA. ClinicalTrials.gov identifier NCT00299104.