Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
21596757 Partnering urban academic medical centers and rural primary care clinicians to provide com 2011 Jun Many of the estimated thirty-two million Americans expected to gain coverage under the Affordable Care Act are likely to have high levels of unmet need because of various chronic illnesses and to live in areas that are already underserved. In New Mexico an innovative new model of health care education and delivery known as Project ECHO (Extension for Community Healthcare Outcomes) provides high-quality primary and specialty care to a comparable population. Using state-of-the-art telehealth technology and case-based learning, Project ECHO enables specialists at the University of New Mexico Health Sciences Center to partner with primary care clinicians in underserved areas to deliver complex specialty care to patients with hepatitis C, asthma, diabetes, HIV/AIDS, pediatric obesity, chronic pain, substance use disorders, rheumatoid arthritis, cardiovascular conditions, and mental illness. As of March 2011, 298 Project ECHO teams across New Mexico have collaborated on more than 10,000 specialty care consultations for hepatitis C and other chronic diseases.
21351607 [Effect of distal femoral flexion angle on sagittal alignment of femoral prosthesis and fu 2011 Jan OBJECTIVE: To analyze the effect of the distal femoral flexion angle (DFFA) on the sagittal alignment of femoral prosthesis and function recovery after total knee arthroplasty (TKA). METHODS: Between January 2007 and January 2009, 35 patients (35 knees) whose distal femoral flexion angle (DFFA) was more than 6 degrees underwent TKA. Reference to the method by Oswald for DFFA measurement, 35 patients were divided into 2 groups: group A (n = 23, 6 degrees < DFFA < 12 degrees, long intramedullary rod system) and group B (n = 12, DFFA > 12 degrees, short intramedullary rod system). Another random 30 osteoarthritis and 10 rheumatoid arthritis patients were selected as control group (group C, DFFA < 6 degrees). The postoperative femoral prosthesis flexion angle (FPFA), knee society score (KSS), the femoral notch, and extension dysfunction were analyzed. RESULTS: All incisions healed by first intention. Seventy-five patients were followed up 1-3 years (mean, 2.1 years). The X-ray films showed that no signs of loosening, fracture, or infection were observed. There were significant differences in FPFA, the femoral notch, and knee extension dysfunction at 1 year after TKA between 3 groups (P < 0.05). The knee extension angle of group B was significantly larger than that of groups A and C (P < 0.05). There was no significant difference in the knee flexion angle and KSS score between 3 groups (P > 0.05). KSS score of postoperation was increased significantly when compared with preoperative values in 3 groups (P < 0.05). CONCLUSION: Long intramedullary rod system in patients with higher DFFA usually leads to anterior femoral notch in TKA, so short intramedullary rods that can effectively avoid the notch should be selected in patients with DFFA > 12 degrees. But when the femoral prosthesis would be in flexion position, extension dysfunction usually occurs.
21339375 Review series: Aspects of interstitial lung disease: connective tissue disease-associated 2011 The lung is frequently involved in connective tissue diseases (CTDs), although the frequency of lung manifestations varies according to the type of CTD. Interstitial lung diseases (ILD) are frequently seen in CTDs, particularly systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM) and rheumatoid arthritis (RA), accounting for a significant proportion of deaths. A large percentage of patients with CTD-associated ILD has limited and stable disease, not requiring treatment. However, a significant minority has severe and/or progressive disease, necessitating prompt initiation of treatment. CTD-ILD histological patterns include non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia (OP), diffuse alveolar damage (DAD) and lymphocytic interstitial pneumonia (LIP). NSIP is the most common pattern in all CTDs, except for RA, characterized by a higher frequency of UIP. ILD can present acutely or chronically, with acute presentations being more common in systemic lupus erythematosus and PM/DM. Idiopathic pulmonary fibrosis (IPF) is a progressively worsening ILD characterized by inflammation and fibrosis. The characteristic histological pattern of IPF is UIP. Interestingly, a UIP pattern is associated with a significantly better survival in CTD-related disease compared to the idiopathic variety. Prognosis in IPF is dismal, with a median survival since diagnosis of 2-3 years. No treatment regimen has been shown to improve survival in IPF. By contrast, although there have been only two randomized placebo-controlled trials investigating the effect of immunosuppressive treatment in SSc-associated ILD, clinical experience suggests that immunosuppressive drugs in CTD-related ILDs are capable of benefiting a significant proportion of patients, particularly those with certain histological patterns of disease. This review will essentially focus on CTD-associated ILD and will compare aspects of clinical presentation and management to those of IPF.
21255158 Bone marrow stromal cells inhibit mast cell function via a COX2-dependent mechanism. 2011 Apr BACKGROUND: Mast cells (MCs) have a central role in the induction of allergic inflammation, such as seen in asthma, and contribute to the severity of certain autoimmune diseases, such as rheumatoid arthritis. The MC thus represents an important inflammatory cell, and one which has resisted therapeutic attempts to alter its role in disease. OBJECTIVE: Because bone marrow-derived stromal cells (BMSC, also known as mesenchymal stem cells or MSCs) have been reported to alter allergic inflammation in vivo, we chose to study the interaction between mouse BMSC and mouse bone marrow-derived MCs. METHODS: MC degranulation, cytokine production and chemotaxis were evaluated in vitro following co-culture with BMSCs either in cell contact or a transwell. In addition, MC degranulation was assessed in vivo following administration of BMSCs in a model of passive cutaneous anaphylaxis and a peritoneal degranulation assay. Mechanisms of MC suppression by BMSCs were determined through use of inhibitors or antibodies to COX1, COX2, nitric oxide, indoleamine 2, 3-dioxygenase, EP1-4 receptors, TGF-β and IL-10. Lastly, we utilized either BMSCs or MCs deficient in COX1, COX2 or EP1-4 receptors to confirm the mechanisms of inhibition of MC function by BMSCs. RESULTS: We discovered that BMSCs will effectively suppress specific MC functions in vitro as well as in vivo. When MCs are cocultured with BMSCs to allow cell-to-cell contact, BMSCs suppressed MC degranulation, pro-inflammatory cytokine production, chemokinesis and chemotaxis. Similarly, MC degranulation within mouse skin or the peritoneal cavity was suppressed following in vivo administration of BMSCs. Further, we found that these inhibitory effects were dependent on up-regulation of COX2 in BMSCs; and were facilitated through the activation of EP4 receptors on MCs. CONCLUSION AND CLINICAL RELEVANCE: These observations support the concept that BMSCs have the ability to suppress MC activation and therefore could be the basis for a novel cell based therapeutic approach in the treatment of MC driven inflammatory diseases.
21216608 Phosphonic pseudopeptides as human neutrophil elastase inhibitors--a combinatorial approac 2011 Feb 1 Here we present a simple and rapid method for the construction of phosphonic peptide mimetic inhibitor libraries-products of Ugi and Passerini multicomponent condensations-leading to the selection of new biologically active phosphonic pseudopeptides. As the starting isonitriles, 1-isocyanoalkylphosphonate diaryl ester derivatives were applied. The structure of the synthesized inhibitors was designed to target human neutrophil elastase, a serine protease whose uncontrolled activity may lead to development of several pathophysiological states such as rheumatoid arthritis, cystic fibrosis or tumor growth and invasion. After screening the inhibitory activity of our constructed libraries, the most active compounds were synthesized as single molecules. One of the obtained inhibitors, Cbz-Met-O-Met-Val(P)(OC(6)H(4)-p-Cl)(2), displayed apparent second-order inhibition value at 40,105M(-1)s(-1) as the diastereomers mixture. Inhibition potency and selectivity of action toward other serine proteases as well as the results of initial in vitro experiments regarding inhibitors influence on cancer cell proliferation are presented.
21208219 Anti-tumor necrosis factor-alpha treatment reduces allergic responses in an allergic rhini 2011 Feb BACKGROUND:   Tumor necrosis factor (TNF)-α is a principal mediator of the acute inflammatory response, including allergic rhinitis. TNF-α inhibitors are widely used for the treatment of inflammatory conditions such as rheumatoid arthritis and inflammatory bowel diseases; however, the effects of TNF-α inhibitors on allergic rhinitis are not well established. We aimed to investigate the effects of infliximab, a TNF-α inhibitor, on allergic rhinitis in a mouse model. METHODS:   BALB/c mice were sensitized with ovalbumin (OVA) and alum, and challenged intranasally with OVA. The TNF-α inhibitor, infliximab was administered intraperitoneally, and multiple parameters of allergic responses were evaluated to determine the effects of infliximab. RESULTS:   Infliximab reduced allergic symptoms and eosinophilic infiltration into the nasal mucosa. It also suppressed total and OVA-specific IgE levels, and inhibited local Th2 cytokine transcription in the nasal mucosa and systemic Th2 cytokine production by splenocytes. Furthermore, the expression of E-selectin, neither intercellular adhesion molecule 1 (ICAM-1) nor vascular cell adhesion molecule 1 (VCAM-1), in the nasal mucosa was suppressed in the infliximab-treated group when compared to the nontreated group. CONCLUSION:   This study shows that the TNF-α inhibitor infliximab induces anti-allergic effects by decreasing local and systemic Th2 cytokine (IL-4) production, total and OVA-specific IgE levels, adhesion molecule (E-selectin) expression, and eosinophil infiltration into the nasal mucosa in an allergic rhinitis model. Therefore, infliximab should be considered as a potential agent in treating allergic rhinitis.
21083541 Clinical experience of QuantiFERON(®) -TB Gold testing in patients with psoriasis treated 2011 Mar BACKGROUND: In Taiwan, an intermediate tuberculosis burden country, around 9·3% of patients with rheumatoid arthritis treated with adalimumab develop tuberculosis despite prescreening with the tuberculin skin test. Within the Asia-Pacific region, the tuberculosis risk in patients with psoriasis who use tumour necrosis factor (TNF) blockers is unknown. OBJECTIVES: This study reports the use of QuantiFERON(®) -TB Gold (QFT-G) (Cellestis, Melbourne, Vic., Australia) as a screening method for latent tuberculosis infection (LTBI) in patients with psoriasis. METHODS: This retrospective review evaluated 216 patients with psoriasis in whom TNF blockers were considered between 2004 and 2009 in a tertiary referral hospital in Taiwan. Beginning in 2007, QFT-G was performed on all patients who were candidates for TNF blockers. RESULTS: Seventeen patients who used TNF blockers for less than 4 weeks were excluded. Of the 147 assessed patients receiving TNF blockers, 110 (75%) underwent QFT-G tests. A total of 126 (86%) patients used etanercept and 40 (27%) patients used adalimumab. Nineteen patients switched between both. Overall, patients had a median of 24 weeks (range 4-307) exposure to TNF blockers. Twelve patients (11%) who were treated with TNF blockers and eight (15%) without TNF blockers had positive QFT-G results. Of all TNF blocker users, only one patient (0·68%) developed tuberculosis. CONCLUSIONS: QFT-G can be used to screen for LTBI in a tuberculosis endemic area where bacille Calmette-Guérin vaccination coverage is high. Isoniazid prophylaxis is recommended for those who have positive QFT-G test results.
20957678 Prevalence of connective tissue disease in silicosis (1985-2006)-a report from the state o 2011 Apr BACKGROUND: The risk of developing clinical connective tissue disease (CTD) has been reported to be increased among individuals with silica exposure. METHODS: We reviewed the medical records of individuals reported to the Michigan Silicosis Surveillance system from 1985 to 2006 to confirm the diagnosis of silicosis and determine the presence of CTDs. RESULTS: From 1985 to 2006, 1,022 cases were confirmed to have silicosis. Medical records of 790 cases were available. Thirty-three individuals had rheumatoid arthritis (RA) [prevalence 4.2% (prevalence ratio (RR) ranged from 2.26, 95% CI: 1.57-3.25 to 6.96, 95% CI: 2.93-16.53) depending on the reference rate used], two had scleroderma [prevalence 0.3% (RR 28.3, 95% CI: 6.09-129.98)], one had systemic lupus erythematosus [prevalence 0.1% (RR 2.53, 95% CI: 0.30-21.64)], two had Sjogrens syndrome [prevalence 0.3% (RR 0.42, 95% CI: 0.09-2.08)], and six had anti-neutrophil cytoplasm antibody (ANCA) vasculitis [prevalence 0.8% (RR 25.3, 95% CI: 6.34-101.04)]. There was no difference between those with and without CTD with respect to age, race, industry type, history of tuberculosis, application for workers' compensation, or severity of fibrotic changes on chest X-ray. CONCLUSIONS: A two- to eightfold risk for RA and systemic lupus erythematosus, with a greater than 24-fold risk for scleroderma and ANCA vasculitis was found in individuals with silicosis. The most common CTD among silicotics in the Michigan disease registry was RA. Though not classically included in the category of CTD, ANCA-associated vasculitis was found to have a much greater prevalence amongst silicosis patients than the general population.
20955778 Immune suppression and immune activation in depression. 2011 Feb Depression has been characterized as a disorder of both immune suppression and immune activation. Markers of impaired cellular immunity (decreased natural killer cell cytotoxicity) and inflammation (elevated IL-6, TNFα, and CRP) have been associated with depression. These immunological markers have been associated with other medical illnesses, suggesting that immune dysregulation may be a central feature common to both depression and to its frequent medical comorbidities. Yet the significant associations of findings of both immune suppression and immune activation with depression raise questions concerning the relationship between these two classes of immunological observations. Depressed populations are heterogeneous groups, and there may be differences in the immune profiles of populations that are more narrowly defined in terms of symptom profile and/or demographic features. There have been few reports concurrently investigating markers of immune suppression and immune activation in the same depressed individuals. An emerging pre-clinical literature suggests that chronic inflammation may directly contribute to the pathophysiology of immune suppression in the context of illnesses such as cancer and rheumatoid arthritis. This literature provides us with specific immunoregulatory mechanisms mediating these relationships that could also explain differences in immune disturbances between subsets of depressed individuals We propose a research agenda emphasizing the assessment of these immunoregulatory mechanisms in large samples of depressed subjects as a means to define the relationships among immune findings (suppression and/or activation) within the same depressed individuals and to characterize subsets of depressed subjects based on shared immune profiles. Such a program of research, building on and integrating our knowledge of the psychoneuroimmunology of depression, could lead to innovation in the assessment and treatment of depression and its medical comorbidities.
23171454 Genetic support for the role of the NLRP3 inflammasome in psoriasis susceptibility. 2012 Dec NACHT leucine-rich repeat- and PYD-containing (NLRP)3 protein controls the inflammasome by regulating caspase-1 activity and interleukin (IL)-1β processing. The contribution of IL-1β in the pathogenesis of psoriasis is well recognized. Polymorphisms in NLRP3 and caspase recruitment domain-containing protein (CARD)8, a negative regulator of caspase-1 activity, have been associated with susceptibility to common inflammatory diseases, such as Crohn's disease and rheumatoid arthritis. To investigate the role for genetic variants in the NLRP3 inflammasome in psoriasis susceptibility. In a patient sample comprising 1988 individuals from 491 families and 1002 healthy controls, genotypes for four selected single-nucleotide polymorphisms (SNPs) in NLRP3 (three SNPs) and CARD8 (one SNP) were determined by TaqMan(®) Allelic Discrimination. Using the transmission disequilibrium test (TDT), a significant increase in the transmission of the NLRP3 rs10733113G genotype to a subgroup of patients with more widespread psoriasis was demonstrated (P = 0.015). Using logistic regression analysis in 741 patients with psoriasis and 1002 controls, the CARD8 rs2043211 genotype was significantly different in cases and controls in overall terms [OR 1.3 (1.1-1.5), P = 0.004] and for both genders. Our data support the hypothesis that the inflammasome plays a role in psoriasis susceptibility.
23085014 Vitamin D: health panacea or false prophet? 2013 Jan Vitamin D deficiency, diagnosed when the serum 25-hydroxyvitamin D (25-OHD(3)) concentration is less than 20 ng/mL, has joined vitamin A deficiency as two of the most common nutrition-responsive medical conditions worldwide. There have been more scientific articles published about vitamin D in the 21st century than about any other vitamin, reflecting the massive expansion of the field of vitamin D research. Adequate vitamin D status has been linked to decreased risks of developing specific cancers, including cancers of the esophagus, stomach, colon, rectum, gallbladder, pancreas, lung, breast, uterus, ovary, prostate, urinary bladder, kidney, skin, thyroid, and hematopoietic system (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma); bacterial infections; rheumatoid arthritis; Crohn's disease; periodontal disease; multiple sclerosis; asthma; type 2 diabetes; cardiovascular disease; stroke; peripheral artery disease; hypertension; chronic kidney disease; muscle weakness; cognitive impairment; Alzheimer's disease; clinical depression; and premature death. On the other hand, inadequate vitamin D status during human pregnancy may be associated with increased risk for the development of type 1 diabetes in the offspring. However, this point of view may be excessively optimistic. There also is evidence that despite the current heavy reliance on serum 25-OHD(3) concentration for the diagnosis of an individual's vitamin D status, local tissue vitamin D intoxication may be present in individuals with much lower serum 25-OHD(3) concentrations than are currently appreciated. Only rarely are the symptoms of local tissue vitamin D intoxication associated with vitamin D status or intake. An individual's serum 25-OHD(3) concentration may appear to be "low" for reasons totally independent of sunlight exposure or vitamin D intake. Serum 25-OHD(3) concentration is only poorly responsive to increases in vitamin D intake, and the prolonged routine consumption of thousands of international units of vitamin D may interfere with the regulation of phosphate homeostasis by fibroblast growth factor-23 (FGF23) and the Klotho gene product, with consequences that are detrimental to human health. In light of these counterbalancing observations, curbing excessive enthusiasm for universally increasing vitamin D intake recommendations may be in order.
22723834 Metabolic disturbances associated with systemic lupus erythematosus. 2012 The metabolic disturbances that underlie systemic lupus erythematosus are currently unknown. A metabolomic study was executed, comparing the sera of 20 SLE patients against that of healthy controls, using LC/MS and GC/MS platforms. Validation of key differences was performed using an independent cohort of 38 SLE patients and orthogonal assays. SLE sera showed evidence of profoundly dampened glycolysis, Krebs cycle, fatty acid β oxidation and amino acid metabolism, alluding to reduced energy biogenesis from all sources. Whereas long-chain fatty acids, including the n3 and n6 essential fatty acids, were significantly reduced, medium chain fatty acids and serum free fatty acids were elevated. The SLE metabolome exhibited profound lipid peroxidation, reflective of oxidative damage. Deficiencies were noted in the cellular anti-oxidant, glutathione, and all methyl group donors, including cysteine, methionine, and choline, as well as phosphocholines. The best discriminators of SLE included elevated lipid peroxidation products, MDA, gamma-glutamyl peptides, GGT, leukotriene B4 and 5-HETE. Importantly, similar elevations were not observed in another chronic inflammatory autoimmune disease, rheumatoid arthritis. To sum, comprehensive profiling of the SLE metabolome reveals evidence of heightened oxidative stress, inflammation, reduced energy generation, altered lipid profiles and a pro-thrombotic state. Resetting the SLE metabolome, either by targeting selected molecules or by supplementing the diet with essential fatty acids, vitamins and methyl group donors offers novel opportunities for disease modulation in this disabling systemic autoimmune ailment.
22646970 Epstein-Barr virus early antigen diffuse (EBV-EA/D)-directed immunoglobulin A antibodies i 2012 Aug OBJECTIVE: We sought to determine whether the serological response towards lytic cycle antigens of Epstein-Barr virus (EBV) is altered in systemic lupus erythematosus (SLE) patients. METHOD: We used enzyme-linked immunosorbent assay (ELISA) to investigate the prevalence of EBV early antigen diffuse (EBV-EA/D) antibodies in sera from 60 patients with SLE, 40 with scleroderma (SSc), 20 with primary Sjögren's syndrome (pSS), 20 with rheumatoid arthritis (RA), 20 healthy controls, and also subjects with various circulating autoantibodies. Samples from patients were obtained from clinics specialized within the diseases in Denmark and Sweden and samples from healthy controls were obtained from volunteers. RESULTS: A significant elevated titre of immunoglobulin (Ig)A, IgG, and IgM EBV-EA/D antibodies was found in SLE patients compared to healthy controls, a finding not explained by immunosuppressive treatment or disease activity. The largest difference was observed for IgA EBV-EA/D antibodies (p = 0.0013) with a seropositive rate of 58% in SLE patients and 0% in healthy controls. RA and SSc patients and individuals seropositive for anti-Scl-70 were additionally found to have elevated titres of IgA EBV-EA/D antibodies (40%, p = 0.014; 60%, p = 0.015; and 38.5%, p = 0.045, respectively). However, the titres were generally lower than in SLE patients. CONCLUSION: Our findings support an association between EBV and SLE. The elevated titre of EBV-EA/D-directed IgA antibodies found in SLE patients could suggest reactivation of EBV in epithelial cells or reinfection of epithelial cells after reactivation in B cells, indicating lack of control of the latent infection.
22608366 Roles of promoter and 3' untranslated motifs in expression of the human C5a receptor. 2012 Sep The C5a receptor (C5aR) is a 7 transmembrane G-protein coupled receptor (GPCR) that mediates the powerful pro-inflammatory effect of the complement activation product C5a. Excess C5a generated under pathological conditions has been implicated in a variety of conditions including sepsis, asthma and rheumatoid arthritis, but very little is known about the regulation of expression of the C5aR. The 5' promoter region and 3' untranslated region (UTR) of the C5aR mRNA were cloned, generating enhanced green fluorescent protein (EGFP)-reporter plasmids, which were transfected into the monocytic cell line U937. Most of the cloned 2kb 5' region was dispensable for the expression of the reporter constructs and the majority of regulatory sequences are in the first 200 bp. Three motifs, a NFκB, a CCAAT and a NFAT site, were identified to be of importance by site directed mutagenesis for basal expression. Analysis of the 3'UTR of the C5aR mRNA showed that it contained two AU-rich elements (AREs), however site directed mutagenesis showed that these had no effect on basal expression. While the phorbol ester PMA and dibutyryl cAMP increased C5aR protein expression, these agents had no effect on the regulation of expression via the promoter or the 3'UTR. This is the first study to investigate the role of both the promoter and 3'UTR in regulating C5aR expression and our results show that regulation of the human C5aR is similar but not identical to that of the mouse C5aR.
22395482 Etiological factors in primary hepatic B-cell lymphoma. 2012 Apr Sixty-four cases of malignant lymphoma involving the liver were examined. Of these, 20 cases were histologically confirmed to be primary hepatic B-cell lymphoma. Twelve of these 20 cases were diffuse large B-cell lymphoma (DLBCL) and eight cases were mucosa-associated lymphoid tissue (MALT) lymphoma. Of the 12 cases of DLBCL, six were immunohistologically positive for CD10 and/or Bcl6 (indicating a germinal center phenotype), six were positive for Bcl2, and five were positive for CD25. Eight of the 12 DLBCL cases (66.7%) and two of the eight MALT lymphoma cases (25%) had serum anti-hepatitis C virus (HCV) antibodies and HCV RNA. The incidence of HCV infection was significantly higher in the hepatic DLBCL cases than in systemic intravascular large B-cell cases with liver involvement (one of 11 cases, 9.1%) and T/NK-cell lymphoma cases (one of 19 cases, 5.3%) (p < 0.01 for both). Two hepatic DLBCL cases (16.7%) had rheumatoid arthritis treated with methotrexate, and four MALT lymphoma cases (50%) had Sjögren's syndrome, primary biliary cirrhosis, or autoimmune hepatitis; one case in each of these two groups was complicated by chronic HCV-seropositive hepatitis. Although primary hepatic lymphoma is rare, persistent inflammatory processes associated with HCV infection or autoimmune disease may play independent roles in the lymphomagenesis of hepatic B cells.
22351790 Effect of a single-cycle alternative dosing regimen for rituximab for recalcitrant pemphig 2012 Jun BACKGROUND: There is increasing evidence that a single cycle of rituximab (375 mg per square meter [corrected] of body surface area once weekly for 4 weeks) is efficacious in patients with severe pemphigus. The approved protocol in rheumatoid arthritis is 1 g on days 1 and 15. We report herein on the efficacy and safety of this latter protocol for rituximab in 9 patients with pemphigus. OBSERVATIONS: Nine patients with recalcitrant pemphigus were treated with prednisone, immunosuppressive agents, and/or intravenous immunoglobulin. Rituximab, 1 g, was infused on days 1 and 15. Each patient was observed for a minimum of 6 months. Reepithelialization of at least 50% of the affected areas occurred in all patients within 16 weeks. Three of 6 patients (50%) discontinued intravenous immunoglobulin therapy. A significant decrease in the pemphigus severity score and the mean dosage of prednisone was observed at 3 and 6 months. Relapses were observed in 4 patients between 5 and 13 months after rituximab treatment; these patients completed a second cycle of rituximab. There were no serious adverse effects observed during the follow-up period. CONCLUSIONS: A single cycle of rituximab, 1 g on days 1 and 15, is an effective treatment for pemphigus. Further studies are needed to determine the efficacy and safety of repeated treatment courses in patients who experience recurrences.
22323540 Midkine inhibits inducible regulatory T cell differentiation by suppressing the developmen 2012 Mar 15 Midkine (MK), a heparin-binding growth factor, reportedly contributes to inflammatory diseases, including Crohn's disease and rheumatoid arthritis. We previously showed that MK aggravates experimental autoimmune encephalomyelitis (EAE) by decreasing regulatory CD4(+)CD25(+)Foxp3(+) T cells (Tregs), a population that regulates the development of autoimmune responses, although the precise mechanism remains uncertain. In this article, we show that MK produced in inflammatory conditions suppresses the development of tolerogenic dendritic cells (DCregs), which drive the development of inducible Treg. MK suppressed DCreg-mediated expansion of the CD4(+)CD25(+)Foxp3(+) Treg population. DCregs expressed significantly higher levels of CD45RB and produced significantly less IL-12 compared with conventional dendritic cells. However, MK downregulated CD45RB expression and induced IL-12 production by reducing phosphorylated STAT3 levels via src homology region 2 domain-containing phosphatase-2 in DCreg. Inhibiting MK activity with anti-MK RNA aptamers, which bind to the targeted protein to suppress the function of the protein, increased the numbers of CD11c(low)CD45RB(+) dendritic cells and Tregs in the draining lymph nodes and suppressed the severity of EAE, an animal model of multiple sclerosis. Our results also demonstrated that MK was produced by inflammatory cells, in particular, CD4(+) T cells under inflammatory conditions. Taken together, these results suggest that MK aggravates EAE by suppressing DCreg development, thereby impairing the Treg population. Thus, MK is a promising therapeutic target for various autoimmune diseases.
22298125 Soft tissue composition and the risk of low bone mineral density: the Fourth Korea Nationa 2012 Mar The effects of total fat mass (FM) and total lean mass (LM) on total bone mineral density (BMD) were examined using the Fourth Korea National Health and Nutrition Examination Survey, 2009. FM, LM, and BMD were measured by DXA in a population-based sample of 6,762 Koreans, aged 19-93 (1,613 men < 50 years, 1,400 men ≥ 50 years, 2,120 premenopausal women, and 1,629 postmenopausal women). After adjusting for confounders (age, height, education, economic status, physical activity, smoking, alcohol use, serum vitamin D, medical history [diabetes, dyslipidemia, rheumatoid arthritis, and osteoporosis], family history of osteoporosis, multivitamin use, dietary intake [energy, calcium, and sodium], age at menarche, age at menopause, and hormone replacement therapy) and FM, higher LM was associated with a lower odds ratio for being in the group-specific lowest quintile of BMD (low BMD) in all groups. The odds for low BMD increased with higher FM in multivariate-adjusted analyses in men < 50 years, but this was not significant in other groups. Total BMD decreased with a decrease in the LM quintile across all FM subgroups in men of all ages, in the lower two subgroups of FM quintile in premenopausal women, and in the middle subgroup of FM quintile in postmenopausal women. In conclusion, higher LM was associated with a lower risk of low BMD in both genders, while higher FM was associated with a higher risk of low BMD for men < 50 years but not for women and men ≥ 50 years. The combined effects of LM and FM on BMD were gender- and menopause status-specific.
22297145 Prevalence of anti-Toxoplasma antibodies in patients with autoimmune diseases. 2012 Aug The identification of etiological factors in the induction of autoimmunity has remained elusive despite an enormous effort at dissection of the molecular structure of the target antigens and effector mechanisms. One characteristic feature of autoantigens is their repetitive structure as well as their conservation and evolution. Toxoplasma (T.) gondii is a primitive protozoan. We hypothesized that patients with autoimmune disease would have broad reactions against Toxoplasma antigens based on autoantigen conservation. To address this issue, we assessed serologic evidence of reactivity to Toxoplasma gondii along with a large profile of autoantibodies in patients with various autoimmune diseases (AID). We included sera of 1514 patients with 11 different AID collected from referral centers in Europe and Latin America as well as from 437 geographically matched controls, for the prevalence of anti Toxoplasma antibodies (ATxA) IgG and IgM and serum autoantibodies utilizing the BioPlex 2200 system (Bio- Rad Laboratories, USA). Serum ATxA IgG were positive in 42% of patients with AID versus 29% of controls (p < 0.0001). Among Europeans, ATxA IgG were associated with anti-phospholipid syndrome (APS; p < 0.0001), cryoglobulinemia (p < 0.0001), ANCA-associated vasculitides (p < 0.01), autoimmune thyroid diseases (p < 0.0001), systemic sclerosis (SSc; p < 0.0001) and rheumatoid arthritis (RA; p < 0.0001). Of note, Latin American RA sera exhibited similar frequency of ATxA IgG as controls. ATxA IgM were more prevalent in European patients with APS (p < 0.01), SSc (p < 0.05) and inflammatory bowel disease (IBD, p < 0.05) than in controls. Further, in AID patients the presence of ATxA correlated with autoantibodies characteristic of APS (anti- cardiolipin, B2GPI, complex of cardiolipin- B2GPI, prothrombin, phosphatydilethanolamine), and of SSc (anti-centromere, Scl-70). Our findings suggest that T. gondii may contribute to the pathogenesis of AID. This interaction may depend on or explain observed geoepidemiological variance in AID.
22172512 Depth and volume of resorption induced by osteoclasts generated in the presence of RANKL, 2012 Feb Rheumatoid arthritis (RA) is associated with pathological bone destruction mediated by osteoclasts. Although RANKL has been reported as a crucial factor for osteoclastogenesis, several other factors increased in RA support osteoclast formation and resorption in the absence of RANKL such as TNF-alpha and LIGHT. To date, in vitro bone resorption experiments are reported as the mean area of bone resorption per cortical or dentine slices and do not provide any information about depth and volume of resorption. The aims of this study were to assess these parameters by light microscopy and vertical scanning profilometry (VSP). Peripheral blood mononuclear cells were used as a source of osteoclast precursors and were cultured for up to 21 days in the presence of RANKL, TNF-alpha/IL-1 or LIGHT. Mean area, depth and volume of resorption were assessed by light microscopy and vertical scanning profilometry. As expected, RANKL induced large resorption pits (10,876 ± 2190μm(2)) whereas TNF-alpha/IL-1 and LIGHT generated smaller pits (respectively 1328 ± 210 and 1267 ± 173μm(2)) with no noticeable differences between these two cytokines. Depth and volume of resorption measured by VSP showed that RANKL promoted deep resorption pits resulting in large volume of resorption. Interestingly, although mean area of resorption was similar between TNF-alpha/IL-1 and LIGHT, the depth and volume of resorption of these lacunae were significantly increased by 2-fold with TNF-alpha/IL-1. These results provide evidence that although LIGHT appeared elevated in the synovial fluid of RA patients, its role in bone resorption is less than TNF-alpha/IL-1 or RANKL.