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ID PMID Title PublicationDate abstract
20188418 Interleukin-15 receptor-directed immunotoxins atteunuate disease severity in rat adjuvant 2010 Apr We previously constructed two Pseudomonas exotoxin (PE)-based immunotoxins, IL15-PEDelta293 (IT1) and IL15M-PEDelta293 (IT2), for eliminating interleukin-15 receptor (IL-15R)-overexpressing cells. These two immunotoxins were generated by fusing either wild-type human IL-15 or an antagonist mutant IL-15 (IL-15M) to a modified form of PE. In this study the anti-arthritic effect of IT1 and IT2 was investigated using the rat model of adjuvant arthritis (AA). We found that both IT1 and IT2 could specifically target IL-15R-positive cells and induce apoptosis. After AA induction, treatment with either IT1 or IT2 resulted in profound improvement of the disease, with reductions in levels of synovial mononuclear leukocytes and certain inflammatory factors. Clinical and histological comparisons, together with the analyses of mRNA expression and the signal transducer and activator of transcription-3 (STAT-3) phosphorylation, revealed that the two immunotoxins decreased joint inflammation in AA rats to a similar extent. These data suggest that eliminating IL-15R-bearing cells via immunotoxins may be a promising approach for RA treatment. In addition, wild-type IL-15-based immunotoxins can be as effective as antagonist mutant IL-15-based immunotoxins in preventing joint inflammation associated with rheumatoid arthritis.
19174762 Tolerance induction using lentiviral gene delivery delays onset and severity of collagen I 2009 Apr The treatment of rheumatoid arthritis remains suboptimal; thus there is considerable interest in the development of strategies that mediate tolerance to autoantigens. Using lentiviral gene transfer in vivo, we expressed the immunodominant epitope of collagen type II (CII) on major histocompatibility complex class II molecules (MHC II) in a mouse model of destructive arthritis. A sequence corresponding to amino acids 259-270 of CII was fused into the class II-associated invariant chain peptide (CLIP) position of the invariant chain to achieve efficient binding to MHC II. Transduction of cloned cells and primary antigen-presenting cells (APCs) in vitro demonstrated successful presentation of the peptide on MHC II, and a physiological glycosylation pattern. Compared with controls, mice intravenously injected with lentiviral vectors encoding this epitope displayed significantly less frequent, less severe, and less destructive arthritis, decreased lymphocyte proliferation in response to restimulation with CII, and lower CII-specific antibody levels. This was associated with an increased production of transforming growth factor-beta (TGF-beta) in vitro. We suggest that overexpression of the immunodominant CII epitope on MHC II induces T cell production of TGF-beta and leads to inhibition of arthritis by means of both antigen-specific and bystander mechanisms. Thus, antigen-specific tolerance induction using lentiviral gene delivery can ameliorate arthritis.
19013431 Hypoxia-inducible factor 1alpha is deregulated by the serum of rats with adjuvant-induced 2009 Jan 2 Rheumatoid arthritis (RA) is known to be associated with increased risks of hypoxia-related diseases, whose progresses are critically determined by HIF-1alpha. The authors hypothesized that the hypoxia-related complications of RA are associated with HIF-1alpha deregulation by some factor(s) in RA serum. Arthritis was induced in female Lewis rats by injecting complete Freund's adjuvant. The effects of arthritic rat serum (ARS) on hypoxic responses were investigated by incubating Hep3B cells in ARS. In the presence of ARS, HIF-1alpha was down-regulated and inactivated under hypoxic conditions. ARS inactivated AKT and mTOR, which led to impaired HIF-1alpha protein synthesis. Furthermore, insulin was found to be deficient in ARS and insulin supplementation fully recovered HIF-1alpha synthesis with AKT and mTOR activation. These results suggest that HIF-1alpha deregulation by components in serum is responsible for the RA-associated aggravation of hypoxic diseases in extra-articular tissues.
20120426 Atypical presentation of histoplasmosis in a patient with psoriasis and psoriatic arthriti 2010 Jan Infliximab is a chimeric monoclonal antibody to TNF-alpha which acts on both the soluble and transmembrane forms of TNF-alpha. It has been used successfully for the treatment of psoriasis and psoriatic arthritis, rheumatoid arthritis, Crohn's disease and ankylosing spondylitis either as monotherapy or in combination with drugs such as methotrexate. To date, over 20,440 patients with moderate-to-severe psoriasis have been treated with infliximab worldwide. Opportunistic infections and reactivation of underlying latent infections are an area of concern with the use of infliximab particularly when used in conjunction with other immunosuppresants. The authors report a case of histoplasmosis presenting with signs of severe hypercalcemia and renal failure in a patient on infliximab for approximately three years in combination with low dosages of methotrexate and prednisone. This report stresses the importance of maintaining a high index of suspicion for unusual pathogens while managing patients receiving TNF-alpha inhibitors, particularly when used in combination with other immunosuppressants. In addition, the authors emphasize the role of a multi-disciplinary approach and appropriate coordination among caregivers.
21048388 [Remarkable improvement of the hip joint lesion in a patient with rheumatoid arthritis by 2010 22-year old woman who was previously diagnosed as having juvenile idiopathic arthritis (JIA) was treated with anti-TNF-α agents. Her disease activity was assessed as Stage IV and Class III by Steinbrocker's classification and resistant to steroids and methotrexate. Initially clinical findings responded well to infliximab (IFX), but polyarthritis recurred 15 months after the start of the treatment, and IFX was switched to etanercept (ETN) with good response. On the other hand, effects on the osteoarticular lesions were continuously observed through the period of the treatment with these two biologics. It was thought very rare that weight-bearing joint like the hip joint was restored as was seen in this case, while its mechanism is unknown. Because mechanism for inhibition of inflammation or joint destruction might be independent, we should investigate further the relationship between inflammation and joint destruction in the future.
19208484 Cuff tear arthropathy: current trends in diagnosis and surgical management. 2009 May Massive tears of the rotator cuff resulting in arthritis of the glenohumeral joint remain a difficult challenge. Although cuff tear arthropathy (CTA) has been recognized for more than 150 years, a treatment strategy with uniformly satisfactory outcomes remains elusive, partly due to the difficulty in defining CTA in the literature. Most studies combine true CTA, rheumatoid arthritis, and massive rotator cuff tears under the CTA diagnosis. Determining outcomes from these studies is difficult. Hemiarthroplasty and total shoulder arthroplasty have led to pain relief, but the high rate of glenoid component loosening after total shoulder arthroplasty is a concern, and active range of motion remains limited after hemiarthroplasty. There is increasing interest in the use of a constrained or reverese total shoulder arthroplasty to treat this complex process, with promising early results. This review article studies current trends in the diagnosis and management of arthritis due to massive cuff tears and CTA.
19536543 Permanent renal loss following tumor necrosis factor α antagonists for arthritis. 2010 Jun Tumor necrosis factor alpha (TNF-alpha) antagonists are now widely used in the treatment of aggressive rheumatoid arthritis and are generally well tolerated. Although rare, they could induce systemic lupus erythematosus, glomerulonephritis, and antineutrophil cytoplasmic antibody associated systemic vasculitis. Tumor necrosis factor alpha antagonists associated glomerulonephritis usually subsides after discontinuation of the therapy and subsequent initiation of corticosteroids and immunosuppressive agents. Here we describe crescentic glomerulonephritis progression to end-stage renal disease in a patient following two doses of TNF-alpha antagonists for the treatment of reactive arthritis. To our knowledge, dialysis dependent permanent renal loss after TNF-alpha antagonists has not yet been reported. We suggest the renal function should be closely monitored in patients treated with TNF-alpha antagonists by rheumatologists.
19950249 Pro-inflammatory response resulting from sindbis virus infection of human macrophages: imp 2010 Jan Several viruses cause acute and chronic joint inflammation in humans, and among them, the alphaviruses are of special interest due to the increasing number of outbreaks in which they are the etiological factor. Sindbis virus (SinV), a member of the Alphavirus genus, is the most widely distributed of all known arboviruses. Although SinV causes arthritis in humans, the molecular and cellular factors that contribute to the pathogenesis of this disease are almost completely unknown. Despite the crucial role of macrophages in the development of arthritis, these cells have not been recognized as potential targets for viruses causing arthritis. In this study, replication of SinV in human macrophages was demonstrated. The infection promoted macrophage activation, leading to the release of macrophage migration inhibitor factor (MIF) from intracellular stores and inducing the expression and secretion of TNF-alpha, IL-1beta, and IL-6. Production of these cytokines was followed by the expression of matrix metalloproteinases (MMPs) 1 and 3, which could be involved in the articular damage that has been observed in disease induced by SinV. The use of different strategies to block MIF action, including an anti-MIF antibody, the MIF inhibitor ISO-1 and knockout mice for the MIF gene, showed that cytokine secretion and MMP expression during infection were regulated by MIF, suggesting that this cytokine acts in autocrine and paracrine manner upstream in the macrophage activation cascade. Thus, these are remarkable similarities between macrophage responses induced by SinV infection and those observed in rheumatoid arthritis, despite the different etiologies of infectious and autoimmune arthritides.
19296404 Prevalence of antibodies against Chlamydia trachomatis and incidence of C. trachomatis-ind 2009 OBJECTIVE: To study the prevalence of different serotypes of Chlamydia trachomatis antibodies and the incidence of C. trachomatis-induced reactive arthritis (ReA) among patients with early arthritis in a defined population. METHODS: Serum samples were collected from a cohort of 122 adult patients in the age group 18-65 years included in the Kuopio 2000 Arthritis Survey. Antibodies against C. trachomatis serotypes C, E, and G were studied using enzyme immunoassay (EIA) tests among patients and in a control cohort of 78 adults without any joint symptoms. The incidence assessment for Chlamydia-induced ReA was based on a ligase chain reaction (LCR) test in urine and clinical symptoms and signs appropriate for ReA. RESULTS: Of 122 patients, with the baseline diagnosis of rheumatoid arthritis (RA) in 11, spondyloarthropathy (SpA) in 28, and undifferentiated arthritis (UA) in 83 cases, 42 (34%) showed immunoglobulin (Ig)G or IgA antibodies against at least one serotype C, E, or G. Among the patients with UA the prevalence was significantly increased compared with the controls (p = 0.010). C. trachomatis-induced ReA arthritis was diagnosed in only three patients with the LCR test. On this basis the incidence of C. trachomatis-induced arthritis was 5.4/100 000 [95% confidence interval (CI) 1.1-15.7] in the age group 18-65 years. CONCLUSION: Antibodies against C. trachomatis were most common in patients with UA reflecting the fact that cases with chlamydia-induced ReA are included in this subgroup.
20201625 Coexistence of adult-onset Still's disease and autoimmune hyperthyroidism in a patient who 2010 Dec The pathogenesis of adult-onset Still's disease (AOSD), which is currently thought to be an autoimmune disorder, may share similarities with autoimmune hyperthyroidism. This report describes a middle-aged woman in whom hyperthyroidism and Still's disease developed concurrently. During the course of her illness, the hyperthyroidism was observed to be aggravated whenever her AOSD was in the active stage. After her AOSD activity was controlled, her hyperthyroidism improved clinically. The extent of activation of her hyperthyroidism was observed in parallel to the extent of activation of her AOSD. Furthermore, the patient developed neutropenia after receiving either propylthiouracil (PTU) or methimazole, both of which are standard accepted medications for treatment of hyperthyroidism. Immune mechanisms contributed to PTU induced neutropenia have been proposed, and hyperthyroid patients treated with standard antithyroid agents should be monitored for blood cell counts especially for AOSD patients. Corticosteroid may effect Graves' disease activity, and steroids may play a role in the treatment of hyperthyroidism if a patient had drug allergies to antithyroid agents.
20171708 Clinical progression of chikungunya fever during acute and chronic arthritic stages and th 2010 Jun This longitudinal follow-up study of 203 patients with serologically confirmed chikungunya (CHIK) virus infection describes the clinical features of CHIK fever during the first and tenth months of illness. During the acute stage CHIK fever presents with a wide array of symptoms. The foremost chronic symptoms at the end of a month were rheumatism (75%) and fatigue (30%). During the tenth month of follow-up the symptoms/signs observed were joint pain/swelling (46%), fatigue (13%) and neuritis (6%). The cure rate at the end of 9 months was 51%. Among the patients who had joint pain, 36% (34/94) met the American College of Rheumatology criteria to classify them as having rheumatoid arthritis. A subpopulation of the patients with joint pain (20/94) was tested for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody, and the joints were imaged by X-ray and magnetic resonance imaging (MRI). All tested negative for RF and one tested positive for anti-CCP. A radiolucent lesion in the X-ray was seen in the bones of five patients. The MRI findings were joint effusion, bony erosion, marrow oedema, synovial thickening, tendinitis and tenosynovitis. The study proves with relative certainty that CHIK arthritis is chronic inflammatory erosive arthritis, which has implications for management of the infection.
20704611 A can of red herrings. 2010 Aug Lymphomatoid granulomatosis is a rare disease. Anti-cyclic citrullinated peptide (anti-CCP) antibody is more commonly found in patients with rheumatoid arthritis and less frequently in some of the other rheumatic and non-rheumatic conditions. It is not recognized to be present in lymphoproliferative disease on its own. We report the first case of anti-CCP antibody positivity in lymphomatoid granulomatosis presenting with polyarthritis. This case illustrates the evolving nature of this disease and its characteristics at different stages leading to the challenge of an accurate diagnosis in the setting of a paraneoplastic polyarthritis.
20953422 Electroacupuncture inhibits inflammation reaction by upregulating vasoactive intestinal Pe 2011 Acupuncture is emerging as an alternative therapy for rheumatoid arthritis (RA). However, the molecular mechanism underlying this beneficial effect of acupuncture has not been fully understood. Here, we demonstrated that electroacupuncture at acupoints Zusanli (ST36), Xuanzhong (GB39); and Shenshu (BL23) markedly decreased the paw swelling and the histologic scores of inflammation in the synovial tissue, and reduced the body weight loss in an adjuvant-induced arthritis rat model. However, the electrical stimulation at nonacupoint did not produce any beneficial effects against the experimental arthritis. Most interestingly, the electroacupuncture treatment resulted in an enhanced immunostaining for vasoactive intestinal peptide (VIP), a potent anti-inflammatory neuropeptide, in the synovial tissue. Moreover, the VIP-immunostaining intensity was significantly negatively correlated with the scores of inflammation in the synovial tissue (r = -0.483, P = .0026). In conclusion, these findings suggest that electroacupuncture may offer therapeutic benefits for the treatment of RA, at least partially through the induction of VIP expression.
21686697 Hydroxychloroquine: a diabetic drug in disguise? 2009 Hydroxychloroquine (HCQ) is an antimalarial agent that is commonly used to treat rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The present report documents a case of hypoglycaemia due to HCQ in a patient with SLE and diabetes mellitus type 2, in which the HCQ completely replaced the need for daily subcutaneous insulin.
18568424 Kinase inhibitors for the treatment of inflammatory and autoimmune disorders. 2009 Mar Drugs targeting inhibition of kinases for the treatment of inflammation and autoimmune disorders have become a major focus in the pharmaceutical and biotech industry. Multiple kinases from different pathways have been the targets of interest in this endeavor. This review describes some of the recent developments in the search for inhibitors of IKK2, Syk, Lck, and JAK3 kinases. It is anticipated that some of these compounds or newer inhibitors of these kinases will be approved for the treatment of rheumatoid arthritis, psoriasis, organ transplantation, and other autoimmune diseases.
20635922 Conference scene: the 4th Asian Congress on Autoimmunity: meeting highlights. 11-13 Septem 2010 Mar The 4th Asian Congress on Autoimmunity was held in Suntec City, Singapore from September 11-13, 2009. The congress was addressed by senior investigators in the field of autoimmunity, rheumatology, immunology and diabetology. Yehuda Shoenfeld and his colleagues put together a vibrant scientific program with focus on the pathogenesis, genetics, mechanisms and clinical aspects of the autoimmune diseases and their treatment modalities. Rheumatoid arthritis, systemic lupus erythmetosus, Type I diabetes and autoimmune hepatitis were the main diseases that were discussed by the various scientists, not only from Asia but also from other parts of the world.
19204106 Structure and pathogenicity of antibodies specific for citrullinated collagen type II in e 2009 Feb 16 Antibodies to citrulline-modified proteins have a high diagnostic value in rheumatoid arthritis (RA). However, their biological role in disease development is still unclear. To obtain insight into this question, a panel of mouse monoclonal antibodies was generated against a major triple helical collagen type II (CII) epitope (position 359-369; ARGLTGRPGDA) with or without arginines modified by citrullination. These antibodies bind cartilage and synovial tissue, and mediate arthritis in mice. Detection of citrullinated CII from RA patients' synovial fluid demonstrates that cartilage-derived CII is indeed citrullinated in vivo. The structure determination of a Fab fragment of one of these antibodies in complex with a citrullinated peptide showed a surprising beta-turn conformation of the peptide and provided information on citrulline recognition. Based on these findings, we propose that autoimmunity to CII, leading to the production of antibodies specific for both native and citrullinated CII, is an important pathogenic factor in the development of RA.
20398026 Psoriatic arthritis: clinical improvement and correlation with hormone axes in etanercept- 2010 Apr In a chronic inflammatory disease, such as rheumatoid arthritis (RA), the hypothalamic-pituitary-adrenal axis is altered in three ways: (1) the inflammation-related spontaneous and stimulated secretion of cortisol is inadequate; (2) the inflammation-related secretion of adrenocorticotropic hormone (ACTH) is low; and (3) the levels of adrenal androgens decrease. In patients with RA, long-term therapy with anti-TNF therapy sensitizes the pituitary gland and improves adrenal androgen secretion. We have recently found that the mean serum levels of ACTH, cortisol, 17-hydroxyprogesterone (17OHP), and androstenedione (ASD) in 11 prednisolone-naïve patients with psoriatic arthritis did not markedly change during 12 weeks of etanercept treatment, nor did the serum cortisol/ACTH ratio. However, the greater increase in serum cortisol in comparison with serum 17OHP or ASD was related to clinical improvement, which indicates that the improvement was more related to the higher cortisol levels.
21062294 Mechanical loading, cartilage degradation, and arthritis. 2010 Nov Joint tissues are exquisitely sensitive to their mechanical environment, and mechanical loading may be the most important external factor regulating the development and long-term maintenance of joint tissues. Moderate mechanical loading maintains the integrity of articular cartilage; however, both disuse and overuse can result in cartilage degradation. The irreversible destruction of cartilage is the hallmark of osteoarthritis and rheumatoid arthritis. In these instances of cartilage breakdown, inflammatory cytokines such as interleukin-1 beta and tumor necrosis factor-alpha stimulate the production of matrix metalloproteinases (MMPs) and aggrecanases (ADAMTSs), enzymes that can degrade components of the cartilage extracellular matrix. In order to prevent cartilage destruction, tremendous effort has been expended to design inhibitors of MMP/ADAMTS activity and/or synthesis. To date, however, no effective clinical inhibitors exist. Accumulating evidence suggests that physiologic joint loading helps maintain cartilage integrity; however, the mechanisms by which these mechanical stimuli regulate joint homeostasis are still being elucidated. Identifying mechanosensitive chondroprotective pathways may reveal novel targets or therapeutic strategies in preventing cartilage destruction in joint disease.
20131275 Deletion of either CD55 or CD97 ameliorates arthritis in mouse models. 2010 Apr OBJECTIVE: CD55 (decay-accelerating factor) is best known for its role in the negative regulation of the complement system. Indeed, lack of this molecule leads to disease aggravation in many autoimmune disease models. However, CD55 is abundantly present on fibroblast-like synoviocytes and is also a ligand of the adhesion-class heptahelical receptor CD97, which is expressed by infiltrating macrophages. Treatment with antibodies to CD97 ameliorates the collagen-induced model of rheumatoid arthritis (RA) in DBA/1 mice, but the net contribution of CD55 is unknown. This study was undertaken to investigate the role of CD55 in experimental RA. METHODS: Arthritis was induced in wild-type, CD55(-/-), and CD97(-/-) mice using collagen-induced and K/BxN serum-transfer models. Incidence of arthritis was monitored over time, and disease activity was assessed by clinical and immunohistochemical evaluation. RESULTS: In contrast to observations in many inflammatory disease models, lack of CD55 resulted in decreased arthritis in experimental models of RA. Consistent with the previously reported effects of anti-CD97 antibody treatment, CD97(-/-) mice had reduced arthritis activity compared with wild-type controls. CONCLUSION: Our findings indicate that the lack of CD55 or CD97 in 2 different models of arthritis increases resistance to the disease. These findings provide insight into a role for CD55 interaction with CD97 in the pathogenesis of RA and suggest that therapeutic strategies that disrupt CD55/CD97 may be clinically beneficial.