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ID PMID Title PublicationDate abstract
23974054 Altered Th17 cells and Th17/regulatory T-cell ratios indicate the subsequent conversion fr 2013 Dec A shift in the balance between Th17-cells and regulatory T-cells (Treg) is an important feature of systemic autoimmune diseases (SAID), and may also contribute to their development. Hereby, we assessed the distribution of peripheral Th17 and Treg-cells in patients with undifferentiated connective tissue disease (UCTD), the forerunner of SAIDs and followed these parameters during the development towards definitive SAIDs. Fifty-one UCTD patients were investigated and followed-up for 3 years. Flow cytometry was used to identify and follow three cell-populations: Th17-cells (CD4+IL-17+ T-cells), natural regulatory T-cells (CD4(+)CD25(bright)FoxP3(+); nTregs) and IL-10 producing Type-1 regulatory T-cells (CD4+IL-10+ T-cells; Tr1). Altogether 37.3% of these patients progressed into SAIDs. Th17-cells were increased in UCTD vs. controls, which further increased in those, whom developed SAIDs eventually. The Th17/nTreg ratio gradually increased from controls through UCTD patients, reaching the highest values in SAID-progressed patients. Regarding the Th17/Tr1 ratios, a similar tendency was observed moreover Th17/Tr1 could distinguish between UCTD patients with, or without subsequent SAID progression in a very early UCTD stage. Various immunoserological markers showed association with Th17 and Th17/nTreg at baseline, indicating the consecutive development of a distinct SAID. The derailed Th17/Treg balance may contribute to disease progression therefore could function as a prognostic marker.
24782184 Alternative p38 MAPKs are essential for collagen-induced arthritis. 2014 May OBJECTIVE: The role of most p38 MAPK isoforms in inflammatory arthritis is not known. This study was undertaken to evaluate p38γ and p38δ deficiency in the collagen-induced arthritis (CIA) model. METHODS: Wild-type, p38γ(-/-) , p38δ(-/-) , and p38γ/δ(-/-) mice were immunized with chicken type II collagen, and disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum cytokine levels and in vitro T cell cytokine responses were quantified by flow cytometry and multiplex analysis, and serum anticollagen antibody levels by enzyme-linked immunosorbent assay. Cytokine and p38 MAPK isoform expression in joints were determined by quantitative polymerase chain reaction. RESULTS: Compound p38γ and p38δ deficiency markedly reduced arthritis severity compared with that in wild-type mice, whereas lack of either p38γ or p38δ had an intermediate effect. Joint damage was minimal in arthritic p38γ/δ(-/-) mice compared with wild-type mice. The p38γ/δ(-/-) mice had lower levels of pathogenic anticollagen antibodies and interleukin-1β (IL-1β) and tumor necrosis factor α than controls. In vitro T cell assays showed reduced proliferation, interferon-γ (IFNγ) production, and IL-17 production by lymph node cells from p38γ/δ(-/-) mice. IL-17 and IFNγ messenger RNA expression in joints was significantly inhibited in p38γ/δ(-/-) mice. Wild-type chimeric mice with p38γ/δ(-/-) bone marrow did not show decreased CIA. CONCLUSION: Reduced disease severity in p38γ/δ(-/-) mice was associated with lower cytokine production and anticollagen antibody responses than in controls, indicating that p38γ and p38δ are crucial regulators of inflammatory joint destruction in CIA. Our findings indicate that p38γ and p38δ are potential therapeutic targets in complex diseases, such as rheumatoid arthritis, that involve innate and adaptive immune responses.
23349985 Fms-like tyrosine kinase 3 ligand controls formation of regulatory T cells in autoimmune a 2013 Fms-like tyrosine kinase 3 ligand (Flt3L) is known as the primary differentiation and survival factor for dendritic cells (DCs). Furthermore, Flt3L is involved in the homeostatic feedback loop between DCs and regulatory T cell (Treg). We have previously shown that Flt3L accumulates in the synovial fluid in rheumatoid arthritis (RA) and that local exposure to Flt3L aggravates arthritis in mice, suggesting a possible involvement in RA pathogenesis. In the present study we investigated the role of Flt3L on DC populations, Tregs as well as inflammatory responses in experimental antigen-induced arthritis. Arthritis was induced in mBSA-immunized mice by local knee injection of mBSA and Flt3L was provided by daily intraperitoneal injections. Flow cytometry analysis of spleen and lymph nodes revealed an increased formation of DCs and subsequently Tregs in mice treated with Flt3L. Flt3L-treatment was also associated with a reduced production of mBSA specific antibodies and reduced levels of the pro-inflammatory cytokines IL-6 and TNF-α. Morphological evaluation of mBSA injected joints revealed reduced joint destruction in Flt3L treated mice. The role of DCs in mBSA arthritis was further challenged in an adoptive transfer experiment. Transfer of DCs in combination with T-cells from mBSA immunized mice, predisposed naïve recipients for arthritis and production of mBSA specific antibodies. We provide experimental evidence that Flt3L has potent immunoregulatory properties. Flt3L facilitates formation of Treg cells and by this mechanism reduces severity of antigen-induced arthritis in mice. We suggest that high systemic levels of Flt3L have potential to modulate autoreactivity and autoimmunity.
24623727 Antibodies to endothelial cell growth factor and obliterative microvascular lesions in the 2014 Aug OBJECTIVE: Endothelial cell growth factor (ECGF) was recently identified as the first autoantigen known to be a target of T cell and B cell responses in ~20% of patients with antibiotic-refractory Lyme arthritis. The goal of the current study was to look for a pathologic correlate between ECGF autoantibody responses and histologic findings in synovial tissue. METHODS: Synovial tissue was examined from 14 patients with antibiotic-refractory Lyme arthritis and 6 patients with other forms of chronic inflammatory arthritis, primarily rheumatoid arthritis. The tissue sections were subjected to chemical and immunostaining, and IgG antibody responses to ECGF were determined by enzyme-linked immunosorbent assay (ELISA). Each finding was ranked for statistical analysis. RESULTS: In each disease, synovial tissue showed synovial hypertrophy, vascular proliferation, immune cell infiltrates, and fibrosis. However, among the 14 patients with antibiotic-refractory arthritis, 8 (57%) had obliterative microvascular lesions in the tissue, compared with none of the 6 patients with other forms of chronic inflammatory arthritis (P = 0.04). Among the patients with Lyme arthritis, 5 (36%) had autoantibody responses to ECGF, and all 5 had obliterative lesions, as compared with only 3 of 9 patients who lacked ECGF antibody responses (P = 0.009). Moreover, the magnitude of ECGF antibody responses correlated directly with the extent of obliterative lesions (P = 0.02) and with greater vascularity in the tissue (P = 0.05). CONCLUSION: The correlations of ECGF autoantibody reactivity with obliterative microvascular lesions imply that these autoantibodies may be involved in the obliterative process, suggesting that anti-ECGF antibodies have specific pathologic consequences in the synovial tissue of patients with antibiotic-refractory Lyme arthritis.
24127557 Reduced T cell-dependent humoral immune response in microsomal prostaglandin E synthase-1 2013 Nov 15 Microsomal PGE synthase-1 (mPGES-1) is an inducible enzyme that specifically catalyzes the conversion of PGH2 to PGE2. We showed that mPGES-1 null mice had a significantly reduced incidence and severity of collagen-induced arthritis compared with wild-type (WT) mice associated with a marked reduction in Abs to type II collagen. In this study, we further elucidated the role of mPGES-1 in the humoral immune response. Basal levels of serum IgM and IgG were significantly reduced in mPGES-1 null mice. Compared with WT mice, mPGES-1 null mice exhibited a significant reduction of hapten-specific serum Abs in response to immunization with the T cell-dependent (TD) Ag DNP-keyhole limpet hemocyanin. Immunization with the T cell-independent type 1 Ag trinitrophenyl-LPS or the T cell-independent type 2 Ag DNP-Ficoll revealed minimal differences between strains. Germinal center formation in the spleen of mPGES-1 null and WT mice were similar after immunization with DNP-keyhole limpet hemocyanin. To determine whether the effect of mPGES-1 and PGE2 was localized to hematopoietic or nonhematopoietic cells, we generated bone marrow chimeras. We demonstrated that mPGES-1 deficiency in nonhematopoietic cells was the critical factor for reduced TD Ab production. We conclude that mPGES-1 and PGE2-dependent phenotypic changes of nonhematopoietic/mesenchymal stromal cells play a key role in TD humoral immune responses in vivo. These findings may have relevance to the pathogenesis of rheumatoid arthritis and other autoimmune inflammatory diseases associated with autoantibody formation.
23979709 The multiple chemokine-binding bovine herpesvirus 1 glycoprotein G (BHV1gG) inhibits polym 2013 Chemokines facilitate the recruitment of inflammatory cells into tissues, contributing to target organ injury in a wide range of inflammatory and autoimmune diseases. Targeting either single chemokines or chemokine receptors alters the progression of disease in animal models of rheumatoid arthritis and lupus with varying degrees of efficacy but clinical trials in humans have been less successful. Given the redundancy of chemokine-chemokine receptor interactions, targeting of more than one chemokine may be required to inhibit active inflammatory disease. To test the effects of multiple-chemokine blockade in inflammation, we generated an adenovirus expressing bovine herpesvirus 1 glycoprotein G (BHV1gG), a viral chemokine antagonist that binds to a wide spectrum of murine and human chemokines, fused to the Fc portion of murine IgG2a. Administration of the adenovirus significantly inhibited thioglycollate-induced migration of polymorphonuclear leukocytes into the peritoneal cavity of BALB/c mice and reduced both clinical severity and articular damage in K/BxN serum transfer-induced arthritis. However, treatment with BHV1gG-Ig fusion protein did not prevent monocyte infiltration into the peritoneum in the thioglycollate model and did not prevent renal monocyte infiltration or nephritis in lupus-prone NZB/W mice. These observations suggest that the simultaneous inhibition of multiple chemokines by BHV1gG has the potential to interfere with acute inflammatory responses mediated by polymorphonuclear leukocytes, but is less effective in chronic inflammatory disease mediated by macrophages.
23773635 Leprosy revealed in a rheumatology clinic: a case series. 2013 Apr AIM: Leprosy classically presents with cutaneous and neural involvement. Rheumatological manifestations are frequent, although often under-recognized. At times, these may present to a rheumatology clinic prior to the diagnosis of leprosy. Herein, we present our experience with patients referred with various rheumatological disorders who were subsequently diagnosed as having leprosy. METHODS: This retrospective study (January 2001-September 2010) was carried out at the Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, in northern India. Patients who were confirmed as having leprosy were included. Details regarding demographic and clinical presentations were collected. RESULTS: Forty-four cases (30 male, mean age 40 ± 13.6 years and mean disease duration 18.7 ± 24.3 months) were identified. Musculoskeletal manifestations included arthritis (n = 22), swollen hands and feet syndrome (SHFS) (n = 11), tenosynovitis (n = 9), painful swollen feet (n = 9), arthralgias (n = 7) and vasculitis (n = 1). Distribution of joints mimicked rheumatoid arthritis (n = 14) and spondyloarthropathy (n = 7). Arthritis and/or tenosynovitis were part of spontaneous onset lepra reaction in 28 cases. Other clinical manifestations were: paresthesias (n = 28), erythematous nodules (n = 25) and anesthetic patches (n = 7). Thirty-one patients had thickened nerves (ulnar n = 28, common peroneal n = 21). Eight patients did not have any cutaneous manifestations and had presented with SHFS and arthritis or tenosynovitis. These were labeled as pure neuritic leprosy. Most of the patients responded to multidrug anti-leprosy therapy and glucocorticoids. CONCLUSION: Rheumatological presentations of leprosy may mimic RA, spondyloarthropathy or vasculitis. Pure neuritic variety and spontaneous type 2 lepra reaction pose unique diagnostic challenges. Increased awareness may avoid delay in diagnosis.
23291555 A retrospective review of the primus first MTP joint double-stemmed silicone implant. 2013 Apr Implant arthroplasty has been a surgical alternative for correction of hallux rigidus for many decades. A study is presented reviewing the authors' experience using the (Tornier/Futura) Primus double-stemmed silicone implant. A total of 144 patients representing 201 implants were identified and invited to participate in the study. The postoperative period ranged from 32 to 108 months, with an average of 66.4 months. Chart review was performed on all cases. This review revealed that there were 2 implants that had been removed, each for reasons other than implant breakdown. Several indications in addition to hallux rigidus were found, including hallux valgus with arthritis, geriatric bunion, rheumatoid arthritis, and iatrogenic and traumatic arthritis. The outcomes are presented for all patients, with additional breakdown by their indication for surgery. In all, 54 patients involving 70 implants responded and were clinically evaluated. This study included a Visual Analogue Scale, Foot and Ankle (VAS FA) patient outcome and satisfaction questionnaire, clinical examination, and X-ray evaluation. Patients with hallux rigidus had an average postoperative American Orthopaedic Foot and Ankle Society (AOFAS) score of 88.2, and those with hallux valgus with arthritis had an average score of 88.6. The average AOFAS score for all patients was 87.4. The average VAS patient satisfaction for all patients was 8.5 (with 10 being highest satisfaction). Implant arthroplasty continues to be a viable alternative for surgical correction of hallux rigidus as well as other degenerative conditions of the first MTP joint. This procedure is particularly effective in older, less-active patients with lower functional demand. LEVELS OF EVIDENCE: Therapeutic, Level IV, Retrospective case series.
23675440 A soft coral-derived compound, 11-epi-sinulariolide acetate suppresses inflammatory respon 2013 In recent years, a significant number of metabolites with potent anti-inflammatory properties have been discovered from marine organisms, and several of these compounds are now under clinical trials. In the present study, we isolated 11-epi-sinulariolide acetate (Ya-s11), a cembrane-type compound with anti-inflammatory effects, from the Formosa soft coral Sinularia querciformis. Preliminary screening revealed that Ya-s11 significantly inhibited the expression of the proinflammatory proteins induced nitric oxide synthase and cyclooxygenase-2 in lipopolysaccharide-stimulated murine macrophages. We also examined the therapeutic effects of Ya-s11 on adjuvant-induced arthritis (AIA) in female Lewis rats, which demonstrate features similar to human rheumatoid arthritis (RA). Animal experiments revealed that Ya-s11 (subcutaneously 9 mg/kg once every 2 days from day 7 to day 28 postimmunization) significantly inhibited AIA characteristics. Moreover, Ya-s11 also attenuated protein expression of cathepsin K, matrix metalloproteinases-9 (MMP-9), tartrate-resistant acid phosphatase (TRAP), and tumor necrosis factor-α (TNF-α) in ankle tissues of AIA-rats. Based on its attenuation of the expression of proinflammatory proteins and disease progression in AIA rats, the marine-derived compound Ya-s11 may serve as a useful therapeutic agent for the treatment of RA.
25211510 Eye-mediated immune tolerance to Type II collagen in arthritis-prone strains of mice. 2014 Dec Type II collagen (CII) is a cartilage structural protein that plays important roles in joint function, arthritis and ageing. In studying the ability of CII to induce eye-mediated specific immune tolerance, we have recently proven that CII is capable of inducing anterior chamber-associated immune deviation (ACAID) in Balb/c mice. Here, we study the ability of CII to induce eye-mediated immune tolerance in strains of mice that are prone to the induction of rheumatoid arthritis. Thus, we hypothesized that CII induces ACAID in DBA/1 mice and in C57BL/6 mice through the AC route (direct injection) or the intravenous route (adoptive transfer of in vitro-generated CII-specific ACAID macrophages or of CII-specific in vitro-generated T regulatory cells). Specific immune tolerance induction was assessed using both delayed-type hypersensitivity (DTH) and local adoptive transfer (LAT) assays. Results indicated the ability of CII to generate CII-specific ACAID-mediated immune tolerance in vivo and in vitro in both DBA/1 mice and C57BL/6 mice. These findings could be beneficial in studies of immune tolerance induction using CII.
24712657 Chlamydia trachomatis elementary bodies in synovial fluid of patients with reactive arthri 2016 May OBJECTIVES: Reportedly, there is little information on the magnitude of genitourinary-induced reactive arthritis (gReA) from India. Genital infection with Chlamydia trachomatis is a major health problem in India because of its high prevalence; therefore, this study was conducted with the aim to screen ReA/undifferentiated spondyloarthropathy (uSpA) patients (n = 20) attending a major city hospital in New Delhi, for investigating the presence of intra-articular chlamydial antigen in knee joints. Patients with rheumatoid arthritis (RA) and osteoarthritis (OA) served as controls (n = 20). METHODS: Synovial fluid samples were screened for chlamydial elementary bodies (EBs) using a commercial kit (MicroTrak C. trachomatis Direct Specimen Test; Trinity Biotech, USA) for performing direct fluorescence assay (DFA). RESULTS: Chlamydia trachomatis EBs were detected in the synovial fluid cell deposits of six patients in Group I, namely, 33.3% (4/12) ReA and 25% (2/8) uSpA. All C. trachomatis positive patients exhibited an oligoarticular clinical picture with knee joint involvement. In the synovial fluid cell deposits of control patients, namely, RA/OA, no chlamydial EBs could be detected. CONCLUSIONS: This is the first study reporting the presence of C. trachomatis EBs in the synovial fluid of spondyloarthropathy patients, namely, ReA/uSpA from our country and it can be concluded that the prevalence of C. trachomatis-induced ReA is underestimated. Although our study had limitations in terms of sample size and lower sensitivity of DFA, yet this test can be used as an initial diagnostic tool for screening and patients with positive results may undergo specific tests for validation.
24623960 Potent anti-inflammatory and antiproliferative effects of gambogic acid in a rat model of 2014 BACKGROUND: We have previously reported a continuous activation of caspase-1 and increased interleukin (IL)-1β levels in early rheumatoid arthritis (RA). These observations raised the hypothesis that drugs targeting the IL-1β pathway, in addition to tumour necrosis factor (TNF), may be particularly effective for early RA treatment. We have recently identified gambogic acid as a promising therapeutic candidate to simultaneously block IL-1β and TNF secretion. Our main goal here was to investigate whether gambogic acid administration was able to attenuate inflammation in antigen-induced arthritis (AIA) rats. METHODS: Gambogic acid was administered to AIA rats in the early and late phases of arthritis. The inflammatory score, ankle perimeter, and body weight were evaluated during the period of treatment. Rats were sacrificed after 19 days of disease progression and paw samples were collected for histological and immunohistochemical evaluation. RESULTS: We found that inflammation in joints was significantly suppressed following gambogic acid administration. Histological and immunohistochemical evaluation of treated rats revealed normal joint structures with complete abrogation of the inflammatory infiltrate and cellular proliferation. CONCLUSIONS: Our results suggest that gambogic acid has significant anti-inflammatory properties and can possibly constitute a prototype anti-inflammatory drug with therapeutic efficacy in the treatment of inflammatory diseases such as RA.
24600033 Siglec-G deficiency leads to more severe collagen-induced arthritis and earlier onset of l 2014 Apr 1 Siglec-G is a member of the sialic acid-binding Ig-like lectin (Siglec) family expressed on all B cells. Siglec-G-deficient mice show a large expansion of the B1 cell compartment, demonstrating the crucial role of Siglec-G as an inhibitory receptor on this cellular subset. Although Siglec-G-deficient mice did not develop spontaneous autoimmunity, mice double-deficient for Siglec-G and the related Siglec protein CD22 did show autoimmunity at an older age. In this study, we addressed the question of whether loss of Siglec G on its own affects disease severity in animal models of rheumatoid arthritis and systemic lupus erythematosus. Siglec-G-deficient mice showed moderately increased clinical severity and higher inflammation of the knee joints following collagen-induced arthritis, when compared with control mice. The Siglec-G-deficient mouse was also backcrossed to the autoimmune prone MLR/lpr background. Although both Siglec-G-deficient and control MRL/lpr mice developed a lupus-like disease, Siglec-G-deficient MRL/lpr mice showed an earlier occurrence of autoantibodies; a higher lymphoproliferation of B and T cells; and an earlier onset of disease, as shown by proteinuria and glomerular damage in the kidney. Moreover, Siglec-G-deficient female mice showed a significantly reduced survival compared with female control MRL/lpr mice. Thus, the loss of the inhibitory receptor Siglec-G led to a moderate exacerbation of disease severity and early onset in both collagen-induced arthritis and spontaneous lupus nephritis in MRL/lpr mice.
23376792 Amelioration of arthritis through mobilization of peptide-specific CD8+ regulatory T cells 2013 Mar Current therapies to treat autoimmune disease focus mainly on downstream targets of autoimmune responses, including effector cells and cytokines. A potentially more effective approach would entail targeting autoreactive T cells that initiate the disease cascade and break self tolerance. The murine MHC class Ib molecule Qa-1b (HLA-E in humans) exhibits limited polymorphisms and binds to 2 dominant self peptides: Hsp60(p216) and Qdm. We found that peptide-induced expansion of tetramer-binding CD8(+) Tregs that recognize Qa-1-Hsp60(p216) but not Qa-1-Qdm strongly inhibited collagen-induced arthritis, an animal model of human rheumatoid arthritis. Perforin-dependent elimination of autoreactive follicular Th (T(FH)) and Th17 cells by CD8(+) Tregs inhibited disease development. Infusion of in vitro-expanded CD8(+) Tregs increased the efficacy of methotrexate treatment and halted disease progression after clinical onset, suggesting an alternative approach to this first-line treatment. Moreover, infusion of small numbers of Qa-1-Hsp60(p216)-specific CD8(+) Tregs resulted in robust inhibition of autoimmune arthritis, confirming the inhibitory effects of Hsp60(p216) peptide immunization. These results suggest that strategies designed to expand Qa-1-restricted (HLA-E-restricted), peptide-specific CD8(+) Tregs represent a promising therapeutic approach to autoimmune disorders.
23281243 Predictors of pain for patients with early inflammatory polyarthritis. 2013 Jun OBJECTIVE: To identify predictors of pain at 1 year in patients with early inflammatory polyarthritis (EIP). METHODS: Using a prospective design, patients were examined by a rheumatologist and completed questionnaires at baseline and at 1 year after symptom onset. Separate regression analyses were run for pain intensity, sensory pain, and affective pain. Age and sex were adjusted in cross-sectional and longitudinal analyses; baseline potential predictors consisted of measures for corresponding pain values and disease activity, depression, coping scores, medication use, rheumatoid arthritis criteria being met, and duration of symptoms. RESULTS: A total of 211 patients were enrolled in the study (mean ± SD age 58.8 ± 14.2 years, 63% women). There were significant improvements at 1 year for disease activity, instrumental coping, emotional coping, depression, and all 3 pain measures. At baseline, disease activity and depression were positively associated with all types of pain; in addition, instrumental coping was positively associated with sensory pain and palliative coping was positively associated with affective pain. At 1 year, pain intensity was predicted by baseline pain intensity, duration of symptoms, use of disease-modifying antirheumatic drugs (DMARDs), and emotional coping. Sensory pain was predicted by baseline sensory pain and DMARD use. Affective pain was predicted by baseline affective pain, DMARD use, and emotional coping. CONCLUSION: The majority of treated EIP patients can expect improvements in clinical and psychosocial variables over the first year of their illness. Emotional coping at baseline may contribute to pain in the future, and therefore it may be useful for patients to learn other means of dealing with this chronic disease.
24286442 Amyloid arthropathy associated with multiple myeloma: polyarthritis without synovial infil 2014 Mar OBJECTIVES: To describe histological, immunohistochemical and ultrastructural features of synovial biopsies of amyloid arthropathy associated with multiple myeloma (MM). METHODS: Synovial biopsies from affected joints of two patients with MM and amyloid arthropathy were examined with light and electron microscopy, and immunohistochemically for expression of CD3, CD8, CD20, CD38, CD68, Ki-67 and vWF. Results were compared to values from osteoarthritis (OA, n = 26), rheumatoid arthritis (RA, n = 24) and normal (n = 15) synovial membranes. RESULTS: There was no or only mild lining hyperplasia. Vascular density was not elevated, and there were few Ki-67+ proliferating cells in the stroma. The Krenn synovitis score classified one specimen as "low-grade" and one as "high-grade" synovitis. CD68+ and CD3+ cells were the predominant mononuclear inflammatory cells, whereas CD20+ and CD38+ cells were absent from both synovial membrane and synovial fluid sediment. Electron microscopy demonstrated amyloid phagocytosis by synovial macrophages. In hierarchical clustering the two amyloid arthropathy specimens were more closely related to OA than to RA or normal synovium. CONCLUSIONS: This first detailed immunohistological analysis of MM-associated amyloid arthropathy suggests that it is a chronic synovitis that evolves despite the loss of humoral immunity seen in advanced MM. Instead, amyloid phagocytosis by synovial macrophages likely triggers and perpetuates local disease.
23909844 Associations between periodontitis and systemic inflammatory diseases: response to treatme 2013 Sep There is a significant prevalence of subjects with periodontitis presenting with other inflammatory conditions such as coronary heart disease, insulin resistance and arthritis. This pattern of disease presentation underscores the importance of inflammatory loading from chronic diseases, in driving their pathogeneses in a multidirectional manner. Pro-inflammatory cytokines and other agents play an important role in this process; for example, a single nucleotide polymorphism of the TNF-α gene is associated with significant periodontal attachment loss in patients with coronary heart disease. Changes in gene expression associated with inflammation and lipid metabolism in response to oral infection with the periodontal pathogen Porphyromonas gingivalis (Pg) have been demonstrated in mouse models, independent of the demonstration of atherosclerotic lesions. Insulin resistance is considered to be a chronic low-grade inflammatory condition, associated with altered glucose tolerance, hypertriglyceridemia, central obesity and coronary heart disease. It is accompanied by elevated levels of IL-1, IL-6 and TNF-α also relevant to the progression of periodontitis. There is evidence that uncontrolled periodontal disease contributes to maintenance of systemic diseases, including rheumatoid arthritis (RA), with increased risk of periodontitis in subjects with RA. The periodontal pathogen Pg is significant in contributing to citrullination of proteins resulting in immune dysregulation and autoimmune responses, seen in RA. However, they are both multifactorial chronic diseases with complex etiopathogeneses that affect their presentation. Consistent but weak associations are seen for surrogate markers of periodontitis such as tooth loss, with multiple systemic conditions. Effective treatment of periodontitis would be important in reducing systemic inflammatory loading from chronic local inflammation and in achieving systemic health. Lack of a consistent cause and effect relationship in all subjects would be influenced by genetic, epigenetic and other subject variables, although there are clear mechanisms that link the associations. This article includes an appraisal of patents and their applications.
23781264 The Predicted Proteomic Network Associated with the Antiarthritic Action of Qingfu Guanjie 2013 Qingfu Guanjieshu (QFGJS) is an herbal preparation for treating rheumatoid arthritis (RA). Previous studies revealed that QFGJS significantly inhibited experimental arthritis and acute inflammation, accompanied by reduction of proinflammatory cytokines and elevation of anti-inflammatory cytokines. This study aims to identify the targeted proteins and predict the proteomic network associated with the drug action of QFGJS by using 2D gel and MALDI-TOF-MS/MS techniques. Thirty female Wistar rats were evenly grouped as normal and vehicle- and QFGJS-treated CIA rats. The antiarthritic effect of QFGJS was examined with a 19-day treatment course, and the knee synovial tissues of animals from each group were obtained for 2D gel and MALDI-TOF-MS/MS analysis. Results showed that QFGJS significantly ameliorated collagen II-induced arthritis when administrated at 2.8 g/kg body weight for 19 days. 2D gel image analysis revealed 89 differentially expressed proteins in the synovial tissues among the normal and vehicle- and QFGJS-treated CIA rats from over 1000 proteins of which 63 proteins were identified by MALDI-TOF-MS/MS analysis, and 32 proteins were included for classification of functions using Gene Ontology (GO) method. Finally, 14 proteins were analyzed using bioinformatics, and a predicted proteomic network related to the anti-arthritic effect of QFGJS was established, and Pgk1 plays a central role.
25000588 Discovery of selective and orally bioavailable protein kinase Cθ (PKCθ) inhibitors from 2015 Jan 8 Protein kinase Cθ (PKCθ) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKCθ inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design. Compound 41 demonstrates excellent in vitro activity, good oral pharmacokinetics, and efficacy in both an acute in vivo mechanistic model and a chronic in vivo disease model but suffers from tolerability issues upon chronic dosing.
24718489 Vitamin D status of patients with early inflammatory arthritis. 2015 Feb The present study aimed to investigate the vitamin D status in patients with early inflammatory arthritis (EIA). We conducted a retrospective study among patients who presented with EIA at the outpatient rheumatology clinic of a tertiary referral center between March 2012 and February 2013. In total, 101 subjects with EIA (≥1 swollen joint and symptom duration of ≤6 months, not explained by another disease) and 101 healthy controls matched for age, sex, and the month of serum vitamin D measurements were enrolled. Serum 25-hydroxy vitamin D (25-OHD) concentrations were assessed by radioimmunoassay. Vitamin D "deficiency" and "severe deficiency" were defined as serum 25-OHD levels <20 and <10 ng/mL, respectively. Among EIA patients, rheumatoid arthritis (RA) was classified according to the 2010 American College of Rheumatology/European League against Rheumatism criteria. Vitamin D deficiency was highly prevalent among EIA patients, but no significant differences in the frequency of vitamin D deficiency of EIA patients and controls were observed (75.2 vs 65.3%, p = 0.106). Additionally, in spring and summer, EIA patients had significantly lower serum 25-OHD concentrations than controls, but the opposite trend was observed in autumn. Among 101 EIA patients, 38 (37.1%) were classified as having RA. Severe vitamin D deficiency in EIA patients was significantly associated with the higher likelihood of being classified as having RA. In conclusion, the frequency of vitamin D deficiency in EIA patients was comparable to that in controls, but severe vitamin D deficiency was associated with the presence of RA among EIA patients.