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ID PMID Title PublicationDate abstract
23792703 Recent insights into the role of the PD-1/PD-L1 pathway in immunological tolerance and aut 2013 Sep Autoimmune diseases represent a heterogeneous group of conditions whose incidence is increasing worldwide. This has stimulated studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors, in order to improve prevention and treatment of these disorders. The relevance of T regulatory cells and of the PD-1/PD-L1 pathway in controlling immune responses has been highlighted. Recent studies have in particular elucidated the putative role of the PD-1/PD-L1 pathway in regulating T cell responses and its effects on immunological tolerance and immune-mediated tissue damage. The role of the PD-1/PD-L1 pathway in autoimmunity has been already investigated in vivo in several experimental animal models including insulin-dependent diabetes mellitus, systemic lupus erythematosus, myocarditis, encephalomyelitis, rheumatoid arthritis and inflammatory bowel diseases. With the advent of candidate gene and genome-wide association studies, single nucleotide polymorphisms (SNPs) in PD-1 gene in humans have demonstrated relevant associations with a higher risk of developing autoimmune diseases in certain ethnic groups. In this review we present recent insights into the role of the PD-1/PD-L1 pathway in regulating lymphocyte activation, promotion of T regulatory cell development and function, breakdown of tolerance and development of autoimmunity. We finally speculate on the possible development of novel therapeutic treatments in human autoimmunity by modulating the PD-1/PD-L1 pathway.
23690573 Systematic functional regulatory assessment of disease-associated variants. 2013 Jun 4 Genome-wide association studies have discovered many genetic loci associated with disease traits, but the functional molecular basis of these associations is often unresolved. Genome-wide regulatory and gene expression profiles measured across individuals and diseases reflect downstream effects of genetic variation and may allow for functional assessment of disease-associated loci. Here, we present a unique approach for systematic integration of genetic disease associations, transcription factor binding among individuals, and gene expression data to assess the functional consequences of variants associated with hundreds of human diseases. In an analysis of genome-wide binding profiles of NFκB, we find that disease-associated SNPs are enriched in NFκB binding regions overall, and specifically for inflammatory-mediated diseases, such as asthma, rheumatoid arthritis, and coronary artery disease. Using genome-wide variation in transcription factor-binding data, we find that NFκB binding is often correlated with disease-associated variants in a genotype-specific and allele-specific manner. Furthermore, we show that this binding variation is often related to expression of nearby genes, which are also found to have altered expression in independent profiling of the variant-associated disease condition. Thus, using this integrative approach, we provide a unique means to assign putative function to many disease-associated SNPs.
23678963 Detection and structural elucidation of esterified oxylipids in human synovial fluid by el 2013 Jun 18 Here, we present the application of a cross-platform approach, combining rapid direct infusion high-resolution/accurate mass electrospray ionization Fourier transform ion-cyclotron mass spectrometry (ESI-FTICRMS) with in-depth data-dependent LC-MS(2) and LC-MS(3) analysis for lipid profiling. The analytical approach as well as the subsequent data handling is described. The method was applied to human synovial fluid samples from osteo- and rheumatoid arthritis patients. Multivariate statistical analysis revealed esterified oxylipids as molecular features in a subset of the patient samples. Employing LC-MS(2) and LC-MS(3) analysis of these species, we were able to clarify the hypothesized lipid structures initially based on the accurate mass measurements performed on the ESI-FTICRMS platform. LC-MS(3) analysis of intact esterified oxy-lipids and LC-MS(2) analysis of the hydrolysis products allowed for the detection of positional isomers. The approach led to the structural elucidation of hydroxylated docosapentaenoic acid-containing diacyl-phosphatidylcholine type phospholipids in human synovial fluid.
23334373 Pulmonary hypertension in rheumatic diseases: epidemiology and pathogenesis. 2013 Jul The focus of this review is to increase awareness of pulmonary arterial hypertension (PAH) in patients with rheumatic diseases. Epidemiology and pathogenesis of PAH in rheumatic diseases is reviewed, with recommendations for early screening and diagnosis and suggestion of possible role of immunosuppressive therapy in treatment for PAH in rheumatic diseases. A MEDLINE search for articles published between January 1970 and June 2012 was conducted using the following keywords: pulmonary hypertension, scleroderma, systemic sclerosis, pulmonary arterial hypertension, connective tissues disease, systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis, Sjogren's syndrome, vasculitis, sarcoidosis, inflammatory myopathies, dermatomyositis, ankylosing spondylitis, spondyloarthropathies, diagnosis and treatment. Pathogenesis and disease burden of PAH in rheumatic diseases was highlighted, with emphasis on early consideration and workup of PAH. Screening recommendations and treatment were touched upon. PAH is most commonly seen in systemic sclerosis and may be seen in isolation or in association with interstitial lung disease. Several pathophysiologic processes have been identified including an obliterative vasculopathy, veno-occlusive disease, formation of microthrombi and pulmonary fibrosis. PAH in systemic lupus erythematosus is associated with higher prevalence of antiphospholipid and anticardiolipin antibodies and the presence of Raynaud's phenomenon. Endothelial proliferation with vascular remodeling, abnormal coagulation with thrombus formation and immune-mediated vasculopathy are the postulated mechanisms. Improvement with immunosuppressive medications has been reported. Pulmonary fibrosis, extrinsic compression of pulmonary arteries and granulomatous vasculitis have been reported in patients with sarcoidosis. Intimal and medial hyperplasia with luminal narrowing has been observed in Sjogren's syndrome, mixed connective tissue disease and inflammatory myopathies. Pulmonary arterial hypertension (PAH) associated with rheumatic diseases carries a particularly grim prognosis with faster progression of disease and poor response to therapy. Though largely associated with systemic sclerosis, it is being increasingly recognized in other rheumatic diseases. An underlying inflammatory component may explain the poor response to therapy in patients with rheumatic diseases and is a rationale for consideration of immunosuppressive therapy in conjunction with vasodilator therapy in treatment for PAH. Further studies identifying pathogenetic pathways and possible targets of therapy, especially the role of immunomodulatory medications, are warranted.
23317159 JAK inhibitors: pharmacology and clinical activity in chronic myeloprolipherative neoplasm 2013 The Janus family kinases (JAKs), JAK1, JAK2, JAK3, and TYK2, are involved in cell growth, survival, development, and differentiation of a variety of cells, particularly immune cells and hematopoietic cells. They form a subgroup of the non-receptor protein tyrosine kinases. Activating mutations within each of the JAKs is associated with malignant transformations; the most common are mutations of JAK2 in polycythemia vera (PV) and other myeloproliferative neoplasms (MPN). Identification of the V617F mutation of the JAK2 gene (JAK2 V617F) led to an important breakthrough in the understanding of MPN disease pathogenesis. The JAK2 V617F mutation is present in the majority of PV patients, and about 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) are affected. This mutation leads to hyperactivation of JAK2, cytokine-independent signaling, and subsequent activation of downstream signaling networks. JAK2 ATP-competitive inhibitors that indirectly inhibit the JAK-STAT pathway are new candidates for the treatment of MPN. JAK2 inhibitors in development for the treatment of MPN have demonstrated clinical activity with minimal toxicity. These agents consistently alleviate constitutional symptoms and reduce spleen size in PMF and other MPN. However, some of these inhibitors have additional unique effects. Ruxolitinib causes a significant reduction in the level of pro-inflammatory cytokines. Another inhibitor, CYT387, improves anemia. Many other JAK2 inhibitors such as TG101348 or SAR302503, SB1518, CEP701 and LY2784544 are now under investigation for MPN development. In contrast tasocitinib, a predominantly JAK3 inhibitor, is being evaluated in a number of inflammatory and immunological diseases, including rheumatoid arthritis, psoriasis, ulcerative colitis, dry eye disease and in kidney transplant patients. In conclusion the use of JAK inhibitors in MPN and some of the immune-mediated disorders is a promising new strategy for therapy. However, definitive data from ongoing and future preclinical and clinical trials will aid in better defining the status of these drugs in the treatment of these diseases.
23149276 Resurfacing humeral prosthesis: do we really reconstruct the anatomy? 2013 May BACKGROUND: The goal of a resurfacing shoulder arthroplasty is to reproduce the individual's anatomy while preserving the bone stock of the humeral head. This study investigated the hypothesis that resurfacing the humeral prosthesis restores normal glenohumeral relationships and correlates with the final clinical results. MATERIALS AND METHODS: A resurfacing shoulder implant was performed in 61 patients (64 shoulders). Indications were primary osteoarthritis in 26, secondary osteoarthritis in 21, avascular necrosis in 4, rheumatoid arthritis in 4, dysplasia in 4, and for others indications in 5. RESULTS: At an average of 36 months (range, 24-65) of follow-up , the Constant score reached 68 points and the Quick-Disabilities of Arm, Shoulder and Hand score reached 28 points. Preoperative and postoperative radiographic analysis showed a decrease of the humeral head diameter (51 ± 5 vs 48 ± 5 mm) and of the height of the humeral head (21 ± 4 vs 19 ± 2 mm), without modification of the radius of curvature or the height of the center of rotation. The medial humeral offset increased from 3.3 ± 3.5 to 6.4 ± 3 mm and the lateral offset from 6.8 ± 9 to 10.4 ± 9 mm. The implant was mainly in varus postoperatively compared with preoperative values (122° ± 11° vs 134° ± 7°). Postoperative radiographic analysis and at the last follow-up did not show any significant difference, except for the increase of the depth of the glenoid from 4.2 ± 1.4 to 4.9 ± 1.8 mm. CONCLUSIONS: The resurfacing shoulder arthroplasty reproduces the normal anatomy and compensates glenohumeral wear. However, there was a tendency to position the prosthesis in varus because of technical imperfections. With follow-up, medialization of the humerus with glenoid wear was observed and was correlated in some patients with reappearance of pain.
23073294 CD226 Gly307Ser association with multiple autoimmune diseases: a meta-analysis. 2013 Feb BACKGROUND: Recently, there has been increasing evidence shown that a non-synonymous exchange (Gly307Ser/rs763361) of the CD226 gene on chromosome 18q22 is linked to several autoimmune diseases (ADs) including type 1 diabetes (T1D), celiac disease (CED), rheumatoid arthritis (RA), multiple sclerosis (MS), Grave's disease, Wegener's granulomatosis (WG), psoriasis, and primary sicca syndrome (pSS). Taking into consideration that different autoimmune diseases may share some common pathogenic pathways and in order to assess the overall relationship between CD226 Gly307Ser (rs763361) polymorphism and multiple autoimmune diseases, we performed this meta-analysis. METHOD: All eligible case-control studies were searched in the US National Library of Medicine's PubMed and Embase database. Crude odds ratios (OR) with 95% confidence intervals (CI) were conducted to assess the association. RESULTS: 7876 cases and 8558 controls from 7 published studies which were selected from 149 articles identified by a search of the US National Library of Medicine's PubMed and Embase databases for the period up to 25th April 2012. The total OR for ADs associated with the T allele was 1.19 (95%CI=1.12-1.27) by random effects model. Significantly increased risks were also observed in the South American (OR=1.72, 95%CI=1.34-2.20), Asian (OR=1.46, 95%CI=1.01-2.10), and European (OR=1.29, 95%CI=1.07-1.58). Similarly, significant associations were observed in two genetic models (OR=1.41, 95%CI=1.23-1.62 in a codominant model; OR=1.33, 95%CI=1.18-1.50 in a recessive model). CONCLUSION: This meta-analysis provided evidence that CD226 Gly307Ser (rs763361) is significantly associated with the risk of multiple autoimmune diseases.
24880937 Mid-term result of ceramic bearings in total hip arthroplasty. 2014 Oct PURPOSE: The purpose of this study was to evaluate our clinical experience with ceramic-on-ceramic cementless total hip arthroplasty (THA) and complications after an average follow-up of more than eight years. METHODS: From January 2001 to December 2008, 540 THA with ceramic-on-ceramic bearings were performed in 448 patients (92 bilateral, 54 of which were operated simultaneously) with a mean age 49.9 years (range 18-84) by a senior surgeon. Pre-operative aetiological reasons were developmental dysplasia of the hip (DDH) in 205 hips, degenerative arthritis in 157 hips, avascular necrosis in 51 hips, rheumatoid diseases in 40 hips, posttraumatic arthritis in 40 hips, other reasons in 25 hips and revision surgery in 22 hips. Patients were evaluated with Harris hip score (HSS), and radiological findings of acetabular and femoral component loosening or osteolysis with ceramic bearing related complications like squeaking, liner and head fractures were recorded. RESULT: The average duration of follow-up time was 8.2 years (range, five to 13.2). The main Harris hip score increased from 42.4 points preoperatively to 94.9 points at the time of last follow-up. We had one fracture of the ceramic head, 11 clicking and four squeaking; one of them was revised because of terrible squeaking due to acetabular liner fracture, the other three were seldom audible from the outside and followed conservatively. We did not observed loosening or osteolysis due to ceramic bearings at the time of the final follow-up. CONCLUSION: Our study has demonstrated that ceramic-on-ceramic bearings can be used safely in different etiological problems. Incidences of noisy hips are becoming less frequent.
23663103 Streptococcal-vimentin cross-reactive antibodies induce microvascular cardiac endothelial 2013 Sep Rheumatic heart disease (RHD) is characterized by the presence of anti-streptococcal group A antibodies and anti-endothelial cell antibodies (AECA). Molecular mimicry between streptococcal antigens and self proteins is a hallmark of the pathogenesis of rheumatic fever. We aimed to identify, in RHD patients, autoantibodies specific to endothelial autoantigens cross-reactive with streptococcal proteins and to evaluate their role in inducing endothelial damage. We used an immunoproteomic approach with endothelial cell-surface membrane proteins in order to identify autoantigens recognized by AECA of 140 RHD patients. Cross-reactivity of purified antibodies with streptococcal proteins was analysed. Homologous peptides recognized by serum cross-reactive antibodies were found through comparing the amino acid sequence of streptococcal antigens with human antigens. To investigate interleukin (IL)-1R-associated kinase (IRAK1) and nuclear factor-κB (NF-κB) activation, we performed a Western blot analysis of whole extracts proteins from unstimulated or stimulated human microvascular cardiac endothelial cells (HMVEC-C). Adhesion molecule expression and release of proinflammatory cytokines and growth factors were studied by multiplex bead based immunoassay kits. We observed anti-vimentin antibodies in sera from 49% RHD AECA-positive patients. Cross-reactivity of purified anti-vimentin antibodies with heat shock protein (HSP)70 and streptopain streptococcal proteins was shown. Comparing the amino acid sequence of streptococcal HSP70 and streptopain with human vimentin, we found two homologous peptides recognized by serum cross-reactive antibodies. These antibodies were able to stimulate HMVEC-C inducing IRAK and NF-κB activation, adhesion molecule expression and release of proinflammatory cytokines and growth factors. In conclusion, streptococcal-vimentin cross-reactive antibodies were able to activate microvascular cardiac endothelium by amplifying the inflammatory response in RHD.
23574319 Ro52- and Ro60-specific B cell pattern in the salivary glands of patients with primary Sjà 2013 May Primary Sjögren's syndrome (pSS) is characterized by the presence of autoantibodies against the ribonucleoprotein (RNP) particles Ro/SSA and La/SSB, and mononuclear cell infiltration of exocrine tissues, especially salivary and lachrymal glands. Low numbers of autoantigen-specific memory B cells and elevated levels of plasma cells have been detected previously in the peripheral blood (PB) of pSS patients compared to controls. As both Ro52 and Ro60-specific cells have been detected in the salivary glands (SG) of pSS patients, we aimed to characterize the SSA-specific B cell pattern in SG biopsies. A series of double immunohistochemical stainings were performed on paraffin-embedded tissue from 10 well-characterized pSS patients for each Ro52 and Ro60 along with CD19, CD5, CD20 or CD27, respectively. Ro52 and Ro60-specific cells detected in SG tissue were found to be CD19(+) B cells located outside the CD19(+)/CD20(+) B cell zones (BCZ) and also interstitially. These SSA-specific cells were also quantified. No SSA-specific cells were CD5(+), indicating that they do not belong to the B-1 B cell subset. Furthermore, no SSA-specific cells were observed within the CD20(+) BCZ. Hence, no SSA-specific memory B cells were detected in these individuals. Contrary to this, SSA-specific cells were found to be CD19(+)/CD27(++), demonstrating that they are differentiating short or long-lived plasma cells. Taken together, our findings suggest that these lower levels of SSA-specific memory B cells in PB and absence of SSA-specific memory B cells in SG of pSS patients could result from activation of these cells into plasma cells at the site of inflammation.
24377394 Anti-tissue transglutaminase antibody inhibits apoptotic cell clearance by macrophages in 2014 Jun Autoimmunity is a feature of celiac disease (CD) with tissue transglutaminase (tTG) as a major autoantigen. A correlation between gynecological-obstetric disorders in CD patients and the presence of circulating antibodies anti-tTG that inhibited tTG activity was reported. Serum anti-tTG antibodies were detected in a non-obese diabetic (NOD) mouse model of type I insulin-dependent diabetes mellitus and Sjögren's syndrome, two comorbid states with CD. Since pregnancy complications have been described in NOD mice, we evaluated the ability of anti-tTG antibodies to affect the functions of tTG relevant to the normal course of an early pregnancy like extracellular matrix assembling and apoptotic cell phagocytosis by macrophages. Circulating IgG antibodies against tTG were detected in NOD mice with titers that decreased at early pregnancy; interestingly, the in vitro transamidating activity of tTG was reduced by NOD serum samples. Particularly, anti-tTG antibody inhibited apoptotic cell phagocytosis by peritoneal macrophages from pregnant NOD mice that express the enzyme on surface. Evidence provided support for a role for anti-tTG antibodies through reduced transamidating activity and reduced apoptotic cell clearance by the macrophages of pregnant NOD mice.
25268749 Clinical and biological differences between cryoglobulinaemic and hypergammaglobulinaemic 2015 OBJECTIVES: To determine the clinical and laboratory differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren's syndrome (pSS), in a large Italian multicentre cohort. METHOD: Patients were selected according to the following criteria: fulfilling the American-European classification criteria for pSS, serum cryoglobulin and gammaglobulin levels evaluated, and lack of hepatitis C virus (HCV) infection. Multinomial analyses were performed by distinguishing three groups of pSS: (i) purpura associated with cryoglobulinaemic vasculitis (CV), (ii) purpura associated with hypergammaglobulinaemic vasculitis (HGV), and (iii) pSS patients without purpura (pSS controls). Patients with purpura but without cryoglobulins or hypergammaglobulinaemia were excluded. RESULTS: A total of 652 patients were enrolled in this study. Group 1/CV comprised 23/652 patients (3.53%), group 2/HGV 40/652 patients (6.13%), and group 3/pSS controls 589/652 (90.34%). The three groups were found to be significantly different from each other (post-estimation test: group 1/CV vs. group 3/pSS controls: p < 0.0001; group 1/CV vs. group 2/HGV: p = 0.0001; group 2/HGV vs. group 3/pSS controls: p = 0.0003), thus confirming the different phenotypes of purpura in pSS.Multivariate analyses revealed that peripheral neuropathy (p < 0.001), low C4 (p < 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.02), and the presence of anti-SSB/La antibodies (p = 0.02) characterized CV whereas rheumatoid factor (p = 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.01), and anti-SSA/Ro antibodies (p = 0.049) were significantly associated with HGV. Lymphoma was associated only with CV. CONCLUSIONS: HGV is a cutaneous vasculitis, related to a benign B-cell proliferation, whereas CV is a systemic immune complex-mediated vasculitis with complement activation and a higher risk of lymphoma, thus confirming CV but not HGV as a prelymphomatous condition in pSS.
24952418 Neuromyelitis optica spectrum disorders associated with other autoimmune diseases. 2015 Feb Neuromyelitis optica (NMO) is an inflammatory demyelinating autoimmune disease with severe, tremendously incapacitating, consequences in the patient's health and wellbeing. Until 2004, NMO was considered a restricted type of multiple sclerosis but in the same year an auto-antibody reacting against aquaporin-4 (NMO-IgG) was found to be related with NMO and it was considered the main etiologic agent of this disease. Its detection is very sensitive and specific allowing an early diagnosis and a better treatment and prognosis. With this tool, a spectrum of diseases including other autoimmune diseases was found to have NMO-IgG antibodies and a new classification named NMO spectrum disorders was created. In this review, we sum up the developments in this field associated with other autoimmune diseases. We approach the latest discoveries in the diagnosis like the new biomarkers that will possibly be used in the close future or the developments in the neuroimaging techniques. We reviewed the literature and synthesized case reports of NMO patients with concurrent autoimmune diseases and the information from useful larger studies. Finally, we summarize the commonly used treatments in NMO and we try to specify the best treatment for NMO with simultaneous autoimmune disease. This review updates the information about this issue and raises the awareness of rheumatologists for these severe diseases.
24891301 Interleukin-6 deficiency corrects nephritis, lymphocyte abnormalities, and secondary Sjög 2014 Sep OBJECTIVE: To assess disease features in Sle1.Yaa mice with genetic interleukin-6 (IL-6) deficiency. METHODS: Sera and tissues were collected from C57BL/6 (B6), Sle1.Yaa, and Sle1.Yaa.IL-6(-/-) mice and analyzed for various features of disease. Using serum samples, autoantibody specificities were determined by enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence, cytokine production was analyzed by Luminex and ELISA, and levels of blood urea nitrogen were determined by ELISA. Renal, lung, and salivary gland tissue sections were evaluated for pathologic changes. Lymphocyte phenotypes, including CD4+ T cell cytokine production, and those of follicular and extrafollicular T helper subsets, germinal center B cells, and plasma cells, were determined using flow cytometry. RESULTS: IL-6 deficiency not only ameliorated autoantibody production and renal disease in this model, but also effectively reduced inflammation of lungs and salivary glands. Furthermore, IL-6 deficiency abrogated differentiation of Th1 and extrafollicular T helper cells, germinal center B cells, and plasma cells in the spleen and eliminated renal T cells with IL-17, interferon-γ, and IL-21 production potential. CONCLUSION: Our findings highlight IL-6-mediated T cell aberrations in Yaa-driven autoimmunity and support the concept of therapeutic IL-6/IL-6 receptor blockade in systemic lupus erythematosus and Sjögren's syndrome by impairing the production of autoantibodies and lymphocytic infiltration of the kidneys, lungs, and salivary glands.
24767802 The serological profiles of subgroup of primary Sjögren's syndrome correlation with the c 2014 Oct OBJECTIVE: To investigate the difference of serological profile in pSS and their correlation with the clinical characteristics of parotid glands. METHODS: This retrospective study includes 289 patients who fulfilled the 2002 American-European Consensus Group Criteria for pSS. The patients were categorized by the clinical features of parotid glands: Group 1 (massive group), Group 2 (infection group), Group 3 (swelling group) and Group 4 (others). The demographic data and serological profiles among these groups were compared. Statistical analyses of the results between groups were performed using the Student t test, Fisher's exact test, chi-square and analysis of variance. RESULTS: There was a difference of serological profile in the different clinical characteristics of parotid glands of pSS. Serum Ig G value of Group 1 was the greatest, and complement C4 was lowest in the four groups. Serum Ig E value of Group 2 was the greatest and ESR of Group 3 was the greatest in the four groups. CONCLUSION: This study has determined the differences of serological profile in the different clinical features of parotid glands of pSS patients, which may help advance our understanding of the disease and improve patient management.
24834925 Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopath 2015 Jun OBJECTIVE: To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). METHODS: This three-part, randomised, placebo-controlled, double-blind withdrawal study (NCT00988221) included patients who had active pcJIA for ≥6 months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4 weeks (8 or 10 mg/kg for body weight (BW) <30 kg; 8 mg/kg for BW ≥30 kg). At week 16, patients with ≥JIA-American College of Rheumatology (ACR) 30 improvement entered the 24-week, double-blind part 2 after randomisation 1:1 to placebo or tocilizumab (stratified by methotrexate and steroid background therapy) for evaluation of the primary end point: JIA flare, compared with week 16. Patients flaring or completing part 2 received open-label tocilizumab. RESULTS: In part 1, 188 patients received tocilizumab (<30 kg: 10 mg/kg (n=35) or 8 mg/kg (n=34); ≥30 kg: n=119). In part 2, 163 patients received tocilizumab (n=82) or placebo (n=81). JIA flare occurred in 48.1% of patients on placebo versus 25.6% continuing tocilizumab (difference in means adjusted for stratification: -0.21; 95% CI -0.35 to -0.08; p=0.0024). At the end of part 2, 64.6% and 45.1% of patients receiving tocilizumab had JIA-ACR70 and JIA-ACR90 responses, respectively. Rates/100 patient-years (PY) of adverse events (AEs) and serious AEs (SAEs) were 480 and 12.5, respectively; infections were the most common SAE (4.9/100 PY). CONCLUSIONS: Tocilizumab treatment results in significant improvement, maintained over time, of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis. TRIAL REGISTRATION NUMBER: NCT00988221.
24190965 Targeted deletion of the gene encoding the La autoantigen (Sjögren's syndrome antigen B) 2014 Jan La antigen (Sjögren's syndrome antigen B) is a phosphoprotein associated with nascent precursor tRNAs and other RNAs, and it is targeted by autoantibodies in patients with Sjögren's syndrome, systemic lupus erythematosus, and neonatal lupus. Increased levels of La are associated with leukemias and other cancers, and various viruses usurp La to promote their replication. Yeast cells (Saccharomyces cerevisiae and Schizosaccharomyces pombe) genetically depleted of La grow and proliferate, whereas deletion from mice causes early embryonic lethality, raising the question of whether La is required by mammalian cells generally or only to surpass a developmental stage. We developed a conditional La allele and used it in mice that express Cre recombinase in either B cell progenitors or the forebrain. B cell Mb1(Cre) La-deleted mice produce no B cells. Consistent with αCamKII Cre, which induces deletion in hippocampal CA1 cells in the third postnatal week and later throughout the neocortex, brains develop normally in La-deleted mice until ∼5 weeks and then lose a large amount of forebrain cells and mass, with evidence of altered pre-tRNA processing. The data indicate that La is required not only in proliferating cells but also in nondividing postmitotic cells. Thus, La is essential in different cell types and required for normal development of various tissue types.
24022789 CD8⁺ cells regulate the T helper-17 response in an experimental murine model of Sjögren 2014 Mar This study investigated the regulatory function of CD8⁺ cells in T helper-17 (Th17) cell-mediated corneal epithelial barrier disruption that develops in a murine desiccating stress (DS) model that resembles Sjögren syndrome. CD8⁺ cell depletion promoted generation of interleukin-17A (IL-17A)-producing CD4⁺ T cells via activation of dendritic cells in both the ocular surface and draining cervical lymph nodes in C57BL/6 mice subjected to DS. T-cell-deficient nude recipient mice receiving adoptively transferred CD4⁺ T cells from CD8⁺ cell-depleted donors exposed to DS displayed increased CD4⁺ T-cell infiltration and elevated IL-17A and CC-chemokine attractant ligand 20 levels in the ocular surface, which was associated with greater corneal barrier disruption. Enhanced DS-specific corneal barrier disruption in CD8-depleted donor mice correlated with a Th17-mediated expression of matrix metalloproteinases (MMP-3 and MMP-9) in the recipient corneal epithelium. Co-transfer of CD8⁺CD103⁺ regulatory T cells did not affect the ability of DS-specific pathogenic CD4⁺ T cells to infiltrate and cause ocular surface disease in the nude recipients, showing that CD8⁺ cells regulate the efferent arm of DS-induced immune response. In summary, CD8⁺ regulatory cells suppress generation of a pathogenic Th17 response that has a pivotal role in DS-induced disruption of corneal barrier function.
23504210 Serum β2-microglobulin level is a useful indicator of disease activity and hemophagocytic 2013 Jul This study demonstrates whether serum β2-microglobulin (β2-MG) level can be an indicator of the status of systemic lupus erythematosus (SLE) and adult-onset Still's disease (AOSD), and development of hemophagocytic syndrome (HPS) complication. Serum β2-MG level was compared between the active and inactive statuses of SLE and AOSD in hospitalized patients. Active status was defined as a state for which a therapy was introduced. Serum β2-MG level was also compared between patients with and without HPS complication. HPS was diagnosed on the basis of clinical and pathological findings. Laboratory markers of HPS including peripheral blood cell counts and levels of serum lactate dehydrogenase (LDH), serum ferritin, plasma fibrin/fibrinogen degradation product (FDP), and plasma D-dimer were examined to determine their correlations with serum β2-MG level. Sixteen SLE and seven AOSD patients (all females, aged 39.0 ± 16.4) were included. The serum β2-MG level was high in the active status of underlying diseases and decreased significantly after the therapy (3.5 ± 1.4 vs. 2.1 ± 0.8 mg/L, p < 0.001). Among patients with active status, the β2-MG level was higher in patients with HPS (two with SLE and three with AOSD) than in patients without HPS (4.9 ± 1.8 vs. 3.3 ± 1.4 mg/L, p < 0.05). Serum β2-MG level significantly correlated with the levels of serum LDH (r(s) = 0.42, p < 0.05), plasma FDP (r(s) = 0.58, p < 0.05), and plasma D-dimer (r(s) = 0.77, p < 0.01). Serum β2-MG level would be a useful indicator of disease activity and development of HPS complication in patients with SLE and AOSD.
23143555 Effect of cyclophosphamide on cytokines in patients with primary Sjögren's syndrome-assoc 2013 Jun The objective of the study is to investigate the mechanisms of cyclophosphamide sequential therapy for patient with primary Sjögren's syndrome-associated interstitial lung disease (PSS-ILD). This was a retrospective review of 15 patients (2005-2008) with PSS-ILD who underwent cyclophosphamide sequential therapy. Peripheral blood and bronchoalveolar lavage (BALF) were obtained before and 3, 6, 12 and 24 months after the treatment. The TNF-α and TGF-β1 mRNA levels in peripheral blood were measured using reverse transcription polymerase chain reaction. Serum and BALF TNF-α, TGF-β1 and MMP-9 levels were measured using sandwich enzyme-linked immunosorbent assay. The average levels of serum TNF-α (0.39 ± 0.22) and TGF-β1 (0.31 ± 0.18) mRNA in patients with PSS-ILD were higher compared with that in patients with PSS without ILD. TNF-α level (0.23 ± 0.19) was significantly decreased 3 months after cyclophosphamide treatment (t = 2.533, p < 0.05), and TGF-β1 (0.31 ± 0.18) level markedly decreased after 6 months of treatment (t = 2.617, p < 0.05). The levels of serum TNF-α (11.2 ± 2.6) μg/L, TGF-β1 (72 ± 19) μg/L and MMP-9 (38 ± 9) μg/L in patients with PSS-ILD were higher than that in patients with PSS without ILD. TGF-β1 (36 ± 12) μg/L level decreased significantly after 3 months of treatment (t = 2.526, p < 0.05), and TNF-α level (7.1 ± 1.3) μg/L markedly decreased after 6 months of therapy (t = 2.578, p < 0.05). MMP-9 level (18 ± 4) μg/L decreased significantly after 12-month treatment (t = 2.329, p < 0.05). The levels of BALF TNF-α (17.1 ± 3.5) μg/L, TGF-β1 (36 ± 17) μg/L and MMP-9 (27 ± 10) μg/L in patients with PSS-ILD were higher than that in patients with PSS without ILD. TGF-β1 (21 ± 14) μg/L level decreased significantly after 3-month treatment, and TNF-α level (9.4 ± 1.7) μg/L was decreased after 6 months of cyclophosphamide treatment that may be associated with its inhabitation on production of TNF-α, TGF-β1 and MMP-9.