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ID PMID Title PublicationDate abstract
22285628 Rheumatic autoimmune diseases: proposed elimination of autoreactive B-cells with magnetic 2012 Apr Although the pathogenesis of rheumatoid arthritis and other rheumatic diseases is still not fully understood, it has become clear that in many cases autoimmune responses with production of autoantibodies against physiological targets play a significant and causal role. Current immunosuppressive and immunomodulatory approaches such as bone marrow transplantation or the therapeutic antibody rituximab are effective, but unspecific and have serious side effects. Here, a method for targeted elimination of specific autoreactive B-cells which are essential for autoantibody production and maintenance of the autoimmune response is proposed. By binding to their receptive antigens linked to magnetic nanoparticles, the autoreactive B-cells can be separated from the rest of the blood in an extracorporeal filtration process, reducing the number of autoimmune cells and autoantibodies in the blood. The method can be adapted for use in different autoimmune diseases provided some key aspects of pathogenesis are known, and can be repeated if necessary. Evidence for feasibility and safety of this method is briefly reviewed, and potential limitations and hurdles to overcome are discussed.
22117888 Genetic polymorphism studies in periodontitis and Fcγ receptors. 2012 Jun Periodontitis is a complex chronic subgingival plaque-induced inflammatory disease influenced by multiple factors, including genetics, behavior and the environment. Many genetic association studies have been conducted in periodontology. One of the most extensively investigated gene families is the Fcγ receptor gene family, which plays a key role in regulating host immune responses to bacteria. Unlike other genetic polymorphisms reported in periodontology, most Fcγ receptor polymorphisms reported not only have established biological functions but are reported to associate with other autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. There are, however, few recent reviews summarizing the association of this gene family with periodontitis. This article critically reviews the current understanding of genetic polymorphism studies in periodontitis, then summarizes the research status of Fcγ receptor polymorphisms and periodontitis and also of other genes involved in the regulatory network of Fcγ receptors, with special reference to their anticipated biological roles. Moreover, some possible future research directions in the related area are discussed.
22041580 Genes, epigenetic regulation and environmental factors: which is the most relevant in deve 2012 Jun Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and inflammatory bowel disease, have complex pathogeneses and likely multifactorial etiologies. The current paradigm for understanding their development is that the disease is triggered in genetically-susceptible individuals by exposure to environmental factors. Some of these environmental factors have been specifically identified, while others are hypothesized and not yet proven, and it is likely that most have yet to be identified. One interesting hypothesis is that environmental effects on immune responses could be mediated by changes in epigenetic regulation. Major mechanisms of epigenetic gene regulation include DNA methylation and histone modification. In these cases, gene expression is modified without involving changes in DNA sequence. Epigenetics is a new and interesting research field in autoimmune diseases. We review the roles of genetic factors, epigenetic regulation and the most studied environmental risk factors such as cigarette smoke, crystalline silica, Epstein-Barr virus, and reproductive hormones in the pathogenesis of autoimmune disease.
22012029 [Diabetes and rheumatism: is diabetes mellitus also an inflammatory disease?]. 2011 Nov New studies have demonstrated similarities in the complex pathomechanisms of diabetes mellitus type 1 (T₁D) and rheumatic diseases and in particular rheumatoid arthritis (RA). Common HLA gene complex characteristics and polymorphisms of inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) play a special role in both disorders. The metabolic syndrome, associated with insulin resistance and diabetes mellitus type 2 (T₂D), often shows criteria of a subclinical chronic inflammation. New forms of therapy with monoclonal antibodies against TNF-α, IL-1 and IL-6 have improved the management of patients with RA. Cytokine-induced inflammation also seems to be important in the pathogenesis and progression of T₁D and T₂D. Whether a therapy with the same monoclonal antibodies established in RA could also be successful in diabetes still has to be investigated in further studies. Both RA and T₁D are autoimmune disorders and show a cumulative incidence with further autoimmune diseases.
21791128 [Cost effectiveness of biologicals: high costs are the other face of success]. 2011 Where health care is concerned, the introduction of biologicals has greatly improved the treatment of chronic inflammatory disorders. This class of drugs is not only noticeably effective, but is also well tolerated. The cost effectiveness of these drugs means that there are limits to their use. This is the other face of success. The Dutch Ministry of Health, Welfare and Sport recently announced measures intended to limit the growth of costs while at the same time requiring that savings should be made on the current budget. Recently the Canadian Agency for Drugs and Technologies in Health (CADTH) produced a report on the effects and costs of biologicals for adults with rheumatoid arthritis (www.cadth.ca). Here we discuss their findings. Organizations for medical specialists should be societal aware and be able to deal with these drugs in a cost-conscious manner, including the development of dynamic guidelines and quality visitations.
21766018 Smoking and pulmonary fibrosis: novel insights. 2011 The relationship between smoking and pulmonary fibrosis is under debate and intense investigation. The aim of this paper is to review the existing literature and identify further areas of research interest. Recently the negative influence of cigarette smoking on IPF outcome was highlighted, as non-smokers exhibit a better survival than ex-smokers and combined current- and ex-smokers. In patients with non-specific interstitial pneumonia (NSIP), a high prevalence of emphysema was recently demonstrated, providing an indirect support for a smoking pathogenetic hypothesis in NSIP. The coexistence of pulmonary fibrosis and emphysema has been extensively described in a syndrome termed combined pulmonary fibrosis and emphysema (CPFE). Connective tissue disorders (CTDs) are a group of autoimmune diseases which affect the lung, as one of the most common and severe manifestations. However, the relationship between smoking and autoimmune disorders is still conflicting. Rheumatoid arthritis results from the interaction between genetic and environmental factors, while the best established environmental factor is tobacco smoking. Smoking has also a negative impact on the response of the RA patients to treatment. The aforementioned smoking-related implications give rise to further research questions and certainly provide one more important reason for physicians to advocate smoking cessation and smoke-free environment.
20974667 Covariate-adjusted response-adaptive designs for longitudinal treatment responses: PEMF tr 2012 Aug Response-adaptive designs have become popular for allocation of the entering patients among two or more competing treatments in a phase III clinical trial. Although there are a lot of designs for binary treatment responses, the number of designs involving covariates is very small. Sometimes the patients give repeated responses. The only available response-adaptive allocation design for repeated binary responses is the urn design by Biswas and Dewanji [Biswas A and Dewanji AA. Randomized longitudinal play-the-winner design for repeated binary data. ANZJS 2004; 46: 675-684; Biswas A and Dewanji A. Inference for a RPW-type clinical trial with repeated monitoring for the treatment of rheumatoid arthritis. Biometr J 2004; 46: 769-779.], although it does not take care of the covariates of the patients in the allocation design. In this article, a covariate-adjusted response-adaptive randomisation procedure is developed using the log-odds ratio within the Bayesian framework for longitudinal binary responses. The small sample performance of the proposed allocation procedure is assessed through a simulation study. The proposed procedure is illustrated using some real data set.
22465962 Protective effects of a novel trimerized sTNFRII on acute liver injury. 2012 May TNF α plays a central role in the pathogenesis of inflammatory diseases such as rheumatoid arthritis and murine acute liver injury induced by injection of D-galactosamine and subsequent LPS. Recombinant Fc-fused soluble TNF receptor II (sTNFRII-Fc) has been used in the treatment of rheumatoid arthritis for a decade. We have recently constructed a novel fusion protein sTNFRII-gAD, which is composed of a soluble TNF receptor II and a globular domain of adiponectin. Utilizing the inclination of gAD to form homologous trimer naturally, we sought to explore TNFα antagonism of the novel trimerized sTNFRII-gAD and meantime compare TNFα-neutralizing effects in vitro and in vivo between sTNFRII-Fc and sTNFRII-gAD. Here, we evaluated the TNFα-antagonizing activity of sTNFRII-gAD with TNFα-induced L929 cytotoxicity assay. Furthermore, sTNFRII-Fc or sTNFRII-gAD was administered simultaneously with d-galactosamine 1h prior to LPS injection in the murine model of acute liver injury. Serum TNFα and TNFα-sTNFRII-gAD complex were measured by ELISA and the liver injury was assessed through alanine transaminase measurement and liver histological analysis. sTNFRII-gAD was shown to have higher TNFα-neutralizing activity than sTNFRII-Fc (p<0.05) in the L929 cytotoxicity assay. With a significant attenuation of murine lethality (p<0.05), sTNFRII-gAD showed more protective effects than sTNFRII-Fc in the murine model of acute liver injury. These results demonstrated that sTNFRII-gAD was more efficacious than sTNFRII-Fc as a TNFα antagonist, highlighting the potential of sTNFRII-gAD for the treatment of diseases associated with excessive TNFα.
21392075 Pharmacokinetics, pharmacodynamics and safety of a human anti-IL-6 monoclonal antibody (si 2011 Aug WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Interleukin (IL)-6 is a cytokine known for pleiotropic and pro-inflammatory functions. IL-6 is involved in various disease processes including lupus erythematosus, rheumatoid arthritis, insulin resistance and malignancy. Anti-IL-6 receptor therapy has recently been demonstrated to be effective in the treatment of patients with rheumatoid arthritis. WHAT THIS STUDY ADDS: Sirukumab, a human monoclonal antibody against soluble IL-6, has been found to bind to human IL-6 with high affinity and specificity and thus suppress the biological activity of IL-6. Preclinical studies have demonstrated the safety of sirukumab in cynomolgus monkeys, a toxicologically relevant animal species, following repeated intravenous and subcutaneous administrations. This study shows that sirukumab has desirable pharmacokinetic characteristics (linear pharmacokinetics with long half-life), a low incidence of immunogenicity and a well-tolerated safety profile in healthy subjects, supporting further development of sirukumab as a potentially valuable therapeutic agent. AIMS: To assess the safety, tolerability, pharmacokinetics (PK) and immunogenicity of sirukumab (CNTO 136) following intravenous (i.v.) infusion in healthy subjects. METHODS: Forty-five healthy adult subjects (38 men and seven women) were randomly assigned to receive a single i.v. dose of placebo or sirukumab (0.3, 1, 3, 6 or 10 mg kg(-1) in a dose-escalating manner). All treated subjects were observed for 96 h post infusion and underwent 20-week follow-up evaluations. Serum samples were collected to measure sirukumab concentrations, pharmacodynamic biomarkers and antibodies to sirukumab. Non-compartmental analysis and population PK modelling were conducted to characterize the PK of sirukumab. RESULTS: Adverse events were generally brief in duration, mild or moderate in intensity and non-dose-dependent. No serious adverse events were observed in the sirukumab-treated subjects. Both C(max) and AUC(0,∞) increased in an approximately dose-proportional manner. Median terminal half-life ranged from 18.5 to 29.6 days. A two-compartment model adequately described the PK of sirukumab following i.v. administration. Population estimates for the clearance (CL), the central volume of distribution (V(1)), the inter-compartmental clearance (Q) and the peripheral volume of distribution (V(2)) were 0.364 l day(-1), 3.28 l, 0.588 l day(-1) and 4.97 l, respectively. Compared with placebo subjects, a sustained decrease from baseline in C-reactive protein was observed in all sirukumab-treated dose groups, although no clear dose-response relationship was observed. No subjects were positive for antibodies to sirukumab. CONCLUSIONS: Sirukumab had a well-tolerated safety profile, desirable PK characteristics and a low incidence of immunogenicity following an i.v. infusion of 0.3 to 10 mg kg(-1) in healthy subjects.
21232092 Blood lipid profiles and peripheral blood mononuclear cell cholesterol metabolism gene exp 2011 Jan 13 BACKGROUND: Methotrexate (MTX) is the most commonly prescribed disease-modifying antirheumatic drug (DMARD) in rheumatoid arthritis. ATP-binding cassette transporter-A1 (ABCA1) and 27-Hydroxylase (HY27) are known antiatherogenic proteins that promote cellular cholesterol efflux. In THP-1 macrophages, MTX can promote the reversal of cholesterol transport, limit foam cell formation and also reverse COX-2 inhibitor-mediated downregulation of ABCA1. Despite its antiatherogenic potential in vitro, the impact of clinical use of low-dose MTX on cholesterol metabolism in humans is unknown. Objective of the study was to examine whether clinical MTX use is associated with altered blood lipids and/or ABCA1/HY27 expressions. METHODS: In all, 100 rheumatoid arthritis subjects were recruited from a medical center in central Taiwan. Plasma lipid profiles and peripheral blood mononuclear cell HY27 and ABCA1 expressions were compared between subjects taking MTX (MTX+) and other disease-modifying antirheumatic drugs (DMARDs) (MTX-). Dietary intake was assessed by a registered dietician. RESULTS: Though no difference observed in the blood lipids between MTX+ and MTX- subjects, the expressions of ABCA1 and HY27 were significantly elevated in MTX+ subjects (n = 67) compared to MTX- subjects (n = 32, p < 0.05). ABCA expression correlated with MTX doses (r = 0.205, p = 0.042), and MTX+ subjects are more likely to have increased HY27 compared to MTX- subjects (OR = 2.5, p = 0.038). Prevalence of dyslipidemia and overweight, and dietary fat/cholesterol intake were lower than that of the age-matched population. Although no differences were observed in the blood lipids, the potential impacts of MTX on cholesterol metabolism should not be overlooked and the atheroprotective effects from MTX induced HY27 and ABCA1 expressions may still be present in those persons with pre-existing dyslipidemia. CONCLUSIONS: We demonstrated novel findings on the increased gene expressions of atheroprotective protein HY27 and ABCA1 in human peripheral blood mononuclear cells (PBMCs) with clinical use of low-dose MTX. Whether MTX induced HY27 and ABCA1 expressions can protect against cardiovascular disease in patients with chronic inflammation through the facilitation of cholesterol export remains to be established. Further studies on the impacts of low-dose MTX on hypercholesterolemic patients are underway.
22708578 Risk of subsequent ischemic and hemorrhagic stroke in patients hospitalized for immune-med 2012 Jun 18 BACKGROUND: Certain immune-mediated diseases (IMDs) have been associated with increased risk for cardiovascular disorders. The aim of the present study was to examine whether there is an association between 32 different IMDs and first hospitalization for ischemic or hemorrhagic stroke. METHODS: All individuals in Sweden hospitalized with a main diagnosis of IMD (without previous or coexisting stroke), between January 1, 1987 and December 31, 2008 (n = 216,291), were followed for first hospitalization for ischemic or hemorrhagic stroke. The reference population was the total population of Sweden. Adjusted standardized incidence ratios (SIRs) for ischemic and hemorrhagic stroke were calculated. RESULTS: Totally 20 and 15 of the 32 IMDs studied, respectively, were associated with an increased risk of ischemic and hemorrhagic stroke during the follow-up. The overall risks of ischemic and hemorrhagic stroke during the first year after hospitalization for IMD were 2.02 (95% CI 1.90-2.14) and 2.65 (95% CI 2.27-3.08), respectively. The overall risk of ischemic or hemorrhagic stroke decreased over time, to 1.50 (95% CI 1.46-1.55) and 1.83 (95% CI 1.69-1.98), respectively, after 1-5 years, and 1.29 (95% CI 1.23-1.35) and 1.47 (95% CI 1.31-1.65), respectively, after 10+ years. The risk of hemorrhagic stroke was ≥2 during the first year after hospitalization for seven IMDs: ankylosing spondylitis (SIR = 8.11), immune thrombocytopenic purpura (SIR = 8.60), polymyalgia rheumatica (SIR = 2.06), psoriasis (SIR = 2.88), rheumatoid arthritis (SIR = 3.27), systemic lupus erythematosus (SIR = 8.65), and Wegener's granulomatosis (SIR = 5.83). The risk of ischemic stroke was ≥2 during the first year after hospitalization for twelve IMDs: Addison's disease (SIR = 2.71), Crohn's disease (SIR = 2.15), Grave's disease (SIR = 2.15), Hashimoto's thyroiditis (SIR = 2.99), immune thrombocytopenic purpura (SIR = 2.35), multiple sclerosis (SIR = 3.05), polymyositis/dermatomyositis (SIR = 3.46), rheumatic fever (SIR = 3.91), rheumatoid arthritis (SIR = 2.08), Sjögren's syndrome (SIR = 2.57), systemic lupus erythematosus (SIR = 2.21), and ulcerative colitis (SIR = 2.15). CONCLUSIONS: Hospitalization for many IMDs is associated with increased risk of ischemic or hemorrhagic stroke. The findings suggest that several IMDs are linked to cerebrovascular disease.
21824083 Analogs of the sea anemone potassium channel blocker ShK for the treatment of autoimmune d 2011 Oct CCR7- effector memory T (TEM) lymphocytes are involved in autoimmune diseases such as multiple sclerosis, type 1 diabetes mellitus and rheumatoid arthritis. These cells express Kv1.3 potassium channels that play a major role in their activation. Blocking these channels preferentially inhibits the activation of CCR7- TEM cells, with little or no effects on CCR7+ naïve and central memory T cells. Blockers of lymphocyte Kv1.3 channels therefore show considerable potential as therapeutics for autoimmune diseases. ShK, a 35-residue polypeptide isolated from the Caribbean sea anemone Stichodactyla helianthus, blocks Kv1.3 channels at picomolar concentrations. Although ShK was effective in treating rats with delayed type hypersensitivity and a model of multiple sclerosis, it lacks selectivity for Kv1.3 channels over closely-related Kv1 channels. Extensive mutagenesis studies combined with elucidation of the structure of ShK led to models of ShK docked with the channel. This knowledge was valuable in the development of new ShK analogs with improved selectivity and increasing stability, which have proven efficacious in preventing and/or treating animal models of delayed type hypersensitivity, type 1 diabetes, rheumatoid arthritis, and multiple sclerosis without inducing generalized immunosuppression. They are currently undergoing further evaluation as potential immunomodulators for the treatment of autoimmune diseases.
21074471 Does rituximab increase the incidence of infectious complications? A narrative review. 2011 Jan BACKGROUND: Rituximab has increasingly been used for the treatment of hematological malignancies and autoimmune diseases, and its efficacy and safety are well established. Although clinical trials have shown conflicting results regarding the association of rituximab with infections, an increased incidence of infections has recently been reported in patients with lymphomas being treated with rituximab. However, clinical experience regarding the association of rituximab with different types of infection is lacking and this association has not been established in patients with rheumatoid arthritis. METHODS: All previous studies included in our literature review were found using a PubMed, EMBASE, and Cochrane database search of the English-language medical literature applying the terms 'rituximab', 'monoclonal antibodies', 'infections', 'infectious complications', and combinations of these terms. In addition, the references cited in these articles were examined to identify additional reports. RESULTS: We performed separate analyses of data regarding the association of rituximab with infection in (1) patients with hematological malignancies, (2) patients with autoimmune disorders, and (3) transplant patients. Recent data show that rituximab maintenance therapy significantly increases the risk of both infection and neutropenia in patients with lymphoma or other hematological malignancies. On the other hand, data available to date do not indicate an increased risk of infections when using rituximab compared with concurrent control treatments in patients with rheumatoid arthritis. However, there is a lack of sufficient long-term data to allow such a statement to be definitively made, and caution regarding infections should continue to be exercised, especially in patients who have received repeated courses of rituximab, are receiving other immunosuppressants concurrently, and in those whose immunoglobulin levels have fallen below the normal range. Few data are available concerning the risk of organ transplant recipients developing infections following rituximab therapy. Data from case reports, case series, and retrospective studies correlate rituximab use with the development of a variety of infections in transplant patients. CONCLUSIONS: Further studies are needed to clarify the association of rituximab with infection. Physicians and patients should be educated about the association of rituximab with infectious complications. Monitoring of absolute neutrophil count and immunoglobulin levels and the identification of high-risk groups for the development of infectious complications, with timely vaccination of these groups, are clearly needed.
22038404 Molecular signature of a public clonotypic autoantibody in primary Sjögren's syndrome: a 2011 Nov OBJECTIVE: This study was undertaken to determine the molecular characteristics of clonotypic autoantibodies in the sera of patients with primary Sjögren's syndrome (SS). This characterization is hampered by the presence of mixed anti-Ro/La specificities that may conceal clonotypic species. In order to narrow clonotypic diversity, a positive selection step was performed on a peg-like determinant of Ro 60 (termed Ro 60-peg) prior to analysis of the autoantibody proteome. METHODS: Monospecific anti-Ro 60-peg IgG were isolated by affinity purification from the sera of 7 patients with primary SS and anti-Ro/La and subjected to 2-dimensional gel electrophoresis and high-resolution orbitrap mass spectrometric sequencing. V regions of heavy and light chains were analyzed by combined database and de novo amino acid sequencing. RESULTS: Proteomic analysis revealed a Ro 60-peg-specific IgG1κ-restricted monoclonal autoantibody that was present in the sera of all patients and specified by a V(H) 3-23 heavy chain paired with a V(κ) 3-20 light chain. The public anti-Ro 60-peg clonotype was specified further by common mutations in the heavy-chain and light-chain complementarity-determining regions. Titers and relative affinities of clonotypic IgG did not vary over the course of the disease. CONCLUSION: The expression of a Ro 60-reactive public B cell clonotype in a subset of patients with primary SS as a long-lived, class-switched circulating autoantibody implies a common breach of B cell tolerance checkpoints in these patients. The unique heavy chain/light chain signature opens the possibility of tracking the development of a "forbidden" clone against a bona fide systemic autoantigen in human disease.
21926185 Efficacy of rituximab in primary Sjogren's syndrome with peripheral nervous system involve 2012 Jan OBJECTIVE: To evaluate rituximab (RTX) in primary Sjögren's syndrome (pSS) with peripheral nervous system (PNS) involvement. METHODS: Patients with pSS and PNS involvement who were included in the French AIR registry were analysed. RESULTS: 17 patients (age 60 years (44-78 years); 14 were female) were analysed. Neurological improvement was noted in 11 patients (65%) at 3 months. Rankin scale decreased from 3 (1-5) to 2 (1-5), 2 (1-5) and 2 (1-6) after 3, 6 and 9 months (p=0.02). European Sjögren's Syndrome Disease Activity Index decreased from 18 (10-44) to 11 (5-20), 11 (5-29) and 12 (5-30) after 3, 6 and 9 months (p<0.05). RTX was effective in neurological involvement in 9/10 patients with vasculitis or cryoglobulinaemia (90%) (group 1) at 3 months and in 2/7 cases (29%) without cryoglobulinaemia and vasculitis (p=0.03). Rankin and European Sjögren's Syndrome Disease Activity Index scales decreased significantly in group 1. CONCLUSION: RTX seems effective in cryoglobulinaemia or vasculitis-related PNS involvement in pSS.
20931272 Successful tocilizumab treatment in a patient with adult-onset Still's disease complicated 2011 Apr We report successful tocilizumab (TCZ) use in a patient with adult-onset Still's disease (AOSD) complicated by chronic hepatitis B (CHB) and AA amyloidosis (AAA). Treatments with corticosteroid and various types of immunosuppressants were unsuccessful. Aggravation of CHB ensued, and entecavir was started. Normalisation of liver function and hepatitis B virus (HBV) DNA were confirmed. TCZ was then started. His arthritis and AAA improved dramatically. TCZ is an excellent treatment for refractory AOSD and is feasible in an HBV-infected patient.
21651907 Anti-oxidative and TNF-α suppressive activities of puerarin derivative (4AC) in RAW264.7 2011 Sep Puerarin is a major active ingredient extracted from the root of P. lobata, a traditional Chinese herb, and possesses anti-oxidative and anti-inflammatory activities. However, the low oral bioavailability of puerarin limits its further application. Therefore, we synthesized tetraacetyl puerarin (4AC) through acetylation to improve its liposolubility and bioavailability. In the present investigations, we tested the anti-oxidative and TNF-α suppressive activity of 4AC in lipopolysaccharide (LPS)-induced RAW264.7 macrophages and bovine type II collagen-induced arthritic (CIA) rats. The results showed that 4AC retained the bioactivity of puerarin. And 4AC significantly increased the activity of SOD and reduced the level of MDA both in vitro and in vivo. It also improved the level of GSH-PX and the total antioxidant capacity in vivo. Furthermore, it dramatically decreased TNF-α level in the cultured supernatant of RAW264.7 cells treated with LPS and in the serum of CIA rats. These initial results indicated that 4AC had a potential therapeutic effect on CIA rats through an anti-oxidative and TNF-α suppressive activity. In addition, the molecular mechanism of anti-oxidation of 4AC was explored by testing the MAPKs/NF-κB signaling pathway. The results showed that 4AC significantly inhibited NF-κB expression and down-regulated the levels of p-ERK and p-JNK in LPS-activated RAW264.7 cells. These results indicated that 4AC had bioactive anti-oxidative effects and suggest the potential value of 4AC for the treatment of rheumatoid arthritis.
22157270 Inflammatory and noninflammatory arthropathy in patients with 18q deletion syndrome. 2012 Jan A 7-year-old girl with 18q deletion syndrome developed chronic progressive polyarticular inflammatory arthropathy. Atypical features of her arthritis included lack of morning stiffness, absence of pain and discomfort, normal acute-phase reactants, and the presence of clinodactyly, low-set thumbs, metatarsus adductus of her feet, and overriding nontender swollen toes. She had a positive antinuclear antibody test, negative rheumatoid factor and anti-cyclic citrullinated peptide, and undetectable immunoglobulin A level. Magnetic resonance imaging of the right knee and the result of the synovial biopsy were consistent with synovitis. She was treated with naproxen, short course of prednisone, and methotrexate with good clinical response that plateaued over time. We analyzed the scarce reports of inflammatory arthropathy in 18q deletion syndrome and proposed an outline for investigating arthropathies in patients with chromosomal aberrations.
21877998 Failure of oral DHEA treatment to increase local salivary androgen outputs of female patie 2011 OBJECTIVES: Sjögren's syndrome (SS) is a female-dominant autoimmune disease characterized by androgen depletion and defective dehydroepiandrosterone (DHEA) processing enzymatic machinery in the salivary glands. We hypothesized that, because of these local failures, DHEA replacement therapy would be unable to improve the local androgen deficiency in SS salivary glands. METHODS: DHEA-deficient female SS patients (n = 12) were treated with placebo for 4 months followed by DHEA 50 mg q.d. for 4 months. Serum and saliva, collected in the morning before the trial and after both periods, were analysed for pro-hormones, androgens, and androgen metabolite using an enzyme-linked immunosorbent assay (ELISA). RESULTS: DHEA treatment increased serum DHEA-sulfate from 1.3 ± 0.1 to 6.4 ± 1.3 µM (p = 0.005), DHEA from 16.5 ± 2.8 to 34.8 ± 8.2 nM (p = 0.012), androstenedione from 3.1 ± 0.3 to 17.2 ± 1.9 nM (p = 0.002), free testosterone from 2.2 ± 0.1 to 7.7 ± 1.1 pM (p = 0.002), DHT from 275.5 ± 24.4 to 834.6 ± 122.8 pM (p = 0.002) and 3-α-diol-G from 3.8 ± 0.6 to 13.6 ± 2.0 nM (p = 0.001). However, only salivary DHEA and DHT outputs increased significantly and 25% of the patients showed no increases, except for DHEA itself. Outputs of active androgens (T, DHT) and 3-α-diol-G metabolite correlated with salivation. CONCLUSIONS: The local androgen deficiency in SS salivary glands is not only caused by low serum DHEA(-S) because restoration of systemic androgen levels by DHEA treatment did not correct local androgen depletion. This could be explained by low or no capacity of DHEA-substituted patients to convert the pro-steroid to active androgen metabolites. Such intracrine failures affect women in particular, who must produce their salivary T and DHT locally from DHEA.
23153390 Sjøgren's syndrome-associated oxidative stress and mitochondrial dysfunction: prospects f 2013 Feb An involvement of oxidative stress (OS) was found in recent studies of Sjøgren's syndrome (SS) that reported significant changes in protein oxidation, myeloperoxidase activity, TNF-α, nitrotyrosine, and GSH levels in plasma from SS patients. Excess levels of OS markers, as oxidative DNA damage and propanoyl-lysine, were reported in saliva from SS patients. Previous reports concurred with a role of OS in SS pathogenesis, by showing a decreased expression of antioxidant activities in conjunctival epithelial cells of SS patients and in parotid gland tissue samples from SS patients. A link between OS and mitochondrial dysfunction (MDF) is recognized both on the grounds of the established role of mitochondria in reactive oxygen species (ROS) formation and by the occurrence of MDF in a set of OS-related disorders. Earlier studies detected mitochondrial alterations in cells from SS patients, related to the action of antimitochondrial autoantibodies, and affecting specific mitochondrial activities. Thus, a link between MDF and OS may be postulated in SS, prompting studies aimed at elucidating SS pathogenesis and in the prospect of chemoprevention trials in SS clinical management.