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ID PMID Title PublicationDate abstract
25352049 Increased serum amyloid A and its association with autoantibodies, acute phase reactants a 2015 Feb Determination of disease activity in patients with rheumatoid arthritis (RA) has become an important component for RA management. The aim of the present study was to investigate the association between circulating levels of serum amyloid A (SAA) and disease activity in RA patients. The types of disease and the respective number of patients enrolled in the present study were as follows: RA, 88; osteoarthritis (OA), 54; systemic lupus erythematosus (SLE), 43; and other autoimmune diseases, 30, as well as 50 healthy controls (HC). SAA levels were measured using an ELISA assay and western blot analysis was used to detect serum SAA levels. The correlations between SAA levels and disease activity score for 28 joints (DAS28), erythrocyte sedimentation rate (ESR) and C‑reactive protein (CRP), respectively, were evaluated; in addition, the presence and absence of rheumatoid factor (RF) and anti‑cyclic citrullinated peptide antibody (anti‑CCP) were detected in respect to SAA levels. The results of the present study demonstrated that serum levels of SAA in RA patients were significantly increased compared to those of the OA, SLE, others and HC patients (P<0.05). SAA levels were found to be positively correlated with DAS28, ESR and CRP levels (R2=0.6174, 0.4422 and 0.3919, respectively). In addition, anti‑CCP was not correlated with DAS28 (R2=0.0154). Furthermore, increased SAA levels were detected in patients with positive anti‑CCP compared with those in anti‑CCP negative subjects (P<0.01). In conclusion, the results of the present study provided further evidence for possible roles of SAA in RA, which indicated that it may be a useful biomarker for assessing disease severity and may provide additional information about disease activity.
25462570 Detection of circulating hcmv-miR-UL112-3p in patients with glioblastoma, rheumatoid arthr 2014 BACKGROUND: microRNAs (miRNA) are 18-22 nucleotides long non-coding RNAs that regulate gene expression at a post-transcriptional level. Human cytomegalovirus (HCMV) encodes at least 26 known mature miRNAs. hcmv-miR-UL112-3p (miR-UL112-3p) is the most well characterized HCMV miRNA, which is suggested to play role in establishment and maintenance of viral latency. Elevated miR-UL112-3p levels have been reported to be present in plasma of patients with hypertension. OBJECTIVES: In this study, we aimed to quantify miR-UL112-3p levels in the plasma/serum of patients with Diabetes Mellitus (DM; from the DIGAMI-2 cohort), Glioblastoma multiforme (GBM), Rheumatoid Arthritis (RA) and Healthy Controls (HC). STUDY DESIGN: Total RNA was isolated from plasma/serum samples of 87 patients and controls, a TaqMan miRNA assay was performed to detect miR-UL112-3p and the copy numbers were normalized to 10 ng of total RNA. HCMV IgG and IgM were analysed using ELISA. RESULTS: HCMV miR-UL112-3p was detected in 14/27 (52%) of DM, 5/20 (25%) of GBM, 1/20 (5%) of RA patients and in 2/20 (10%) of HC, respectively. Anti-HCMV IgG was detected in 85%, 65%, 75% of patients and 70% of HC, respectively. Anti-HCMV IgM was found only in one GBM patient of 87 examined patients and controls. CONCLUSIONS: A higher prevalence of miR-UL112-3p was detected in DM and GBM patients than in RA patients and HC. Elevated levels of miR-UL112-3p and higher prevalence of HCMV IgG were observed in DM patients. Whether the presence of circulating miR-UL112-3p denotes a biomarker of HCMV latency or active replication in patients warrants further investigation.
23279976 Anti-carbamylated protein antibodies are present in arthralgia patients and predict the de 2013 Apr OBJECTIVE: Recently, we discovered a new autoantibody system in rheumatoid arthritis (RA): anti-carbamylated protein (anti-CarP) antibodies. These antibodies have value in predicting joint destruction; however, it is not clear whether they are present before the diagnosis of RA and whether they have value as predictors of RA development. Therefore, we studied whether anti-CarP antibodies are present in patients with arthralgia and whether their presence is associated with the development of RA. METHODS: Sera from 340 arthralgia patients who did not have clinical signs of arthritis but who were positive for IgM rheumatoid factor (IgM-RF) and/or anti-cyclic citrullinated peptide 2 (anti-CCP-2) and 32 healthy controls were tested for anti-CarP IgG antibodies. Of the patients with arthralgia, 111 were IgM-RF positive/anti-CCP-2 antibody negative and 229 were anti-CCP-2 antibody positive. Patients were observed for the development of RA (based on the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria) during a median followup period of 36 months. Cox proportional hazards regression analysis was performed to compare the risk of developing RA between arthralgia patients who were positive for anti-CarP antibodies and those who were negative for anti-CarP antibodies during followup. RESULTS: Anti-CarP antibodies were present in the sera of 39% of the patients. One hundred twenty patients developed RA, after a median of 12 months (interquartile range [IQR] 6-24). The presence of anti-CarP antibodies was associated with the development of RA in the entire arthralgia cohort after correction for RF and anti-CCP-2 antibody status (hazard ratio 1.56 [95% confidence interval 1.06-2.29], P=0.023), as well as in the anti-CCP-2 antibody-positive subgroup (odds ratio 2.231 [95% confidence interval 1.31-3.79], P=0.003). CONCLUSION: Anti-CarP antibodies are present in patients with arthralgia, and their presence predicts the development of RA independent of anti-CCP-2 antibodies.
23901242 Unusual upper gastrointestinal bleeding: Ruptured superior mesenteric artery aneurysm in r 2013 Jul 28 This case report describes an unusual case of upper gastrointestinal (UGI) bleeding caused by a ruptured superior mesenteric artery (SMA) aneurysm in the duodenum in a patient with rheumatoid arthritis. The patient presented with UGI bleeding and hemorrhagic shock. Emergency UGI endoscopy could not identify the source of the bleeding because of excessive blood clots under the second portion of the duodenum. An SMA aneurysm with active contrast extravasation was diagnosed by computed tomography. The aneurysm, together with the fourth portion of the duodenum and the proximal portion of the jejunum, was surgically resected, and the SMA was skeletonized. On postoperative day 15, the patient was discharged from hospital under satisfactory conditions. Rheumatoid arthritis has been known to cause a wide spectrum of manifestations, and an SMA aneurysm is an unusual extra-articular manifestation. An SMA aneurysm rupture presenting as upper gastrointestinal bleeding is a rare complication with a high mortality rate. The clinician must be alert to this potential issue to achieve rapid diagnostic confirmation, and immediate surgical or radiological intervention.
23638884 A complicated liaison: IL-33 and IL-33R in arthritis pathogenesis. 2013 Interruption of cytokine signaling, by targeting either the cytokine itself or its cellular receptor, is a mainstay in the therapy for patients with rheumatic diseases. Interleukin (IL)-33, a member of the IL-1 cytokine family, has emerged as an important mediator of inflammatory responses. In a side-by-side examination of IL-33-deficient and IL-33 receptor (IL-33R)-deficient mice in the K/BxN serum transfer model, arthritis was ameliorated in the IL-33R knockout (KO) mice but not in the IL-33 KO mice. These findings complement previous knowledge on IL-33R signaling, demonstrating that the IL-33R cross-activates other signaling pathways in addition to IL-33-mediated signals. The results reported by Martin and colleagues in a previous issue of Arthritis Research & Therapy underline the clinical relevance of IL-33R cross-signaling and further illustrate that targeting a cytokine receptor (IL-33R) can have completely different clinical outcomes than targeting the respective cytokine.
23274520 The effect of autoimmune arthritis treatment strategies on regulatory T-cell dynamics. 2013 Mar PURPOSE OF REVIEW: Since their discovery over 15 years ago, intensive research has focused on the presence, phenotype and function of FOXP3(+) regulatory T cells (Treg) in autoimmune diseases such as rheumatoid arthritis (RA). The questions of whether Treg deficiencies underlie autoimmune pathology and whether or how Treg-related therapeutic approaches might be successful are still a subject of a vivid debate. In this review we give an overview of how current therapies influence Treg numbers and function in RA and juvenile idiopathic arthritis (JIA) and discuss these findings in the light of new Treg-based intervention strategies for autoimmune arthritis. RECENT FINDINGS: The attempt to relate rheumatic diseases like rheumatoid arthritis and juvenile idiopathic arthritis to Treg has led to somewhat heterogeneous observations. So far, no clear defects in Treg numbers or function have been identified in autoimmune arthritis. The current standard therapies, that is methotrexate and biologicals, are generally effective, but the exact mechanism of action and their effect on Treg is not fully known. Nevertheless, the majority of in-vitro and ex-vivo data point towards a positive influence of these treatments on Treg number and function. These observations are not all consistent, however, and it is not known whether the observed effects on Treg are primary or secondary effects. To safely conduct targeted regulatory T-cell therapy in rheumatic diseases more knowledge about regulatory T-cell function in an inflammatory environment is needed that coincides with the initiative to elucidate the exact mechanism of current therapies.
23817979 Sputum autoantibodies in patients with established rheumatoid arthritis and subjects at ri 2013 Oct OBJECTIVE: To evaluate the generation of rheumatoid arthritis (RA)-related autoantibodies in the lung. METHODS: Simultaneous collection of serum and induced sputum was performed in 21 healthy controls, 49 at-risk subjects without inflammatory arthritis but at risk of RA due to family history or seropositivity for anti-citrullinated protein antibodies, and 14 subjects with early RA. Samples were tested for anti-cyclic citrullinated peptide 2 (anti-CCP2), anti-CCP3, anti-CCP3.1, rheumatoid factor isotypes IgM, IgG, and IgA, and total IgM, IgG, and IgA. RESULTS: One or more autoantibodies were present in sputum of 39% of at-risk seronegative subjects, 65% of at-risk seropositive subjects, and 86% of subjects with early RA. In at-risk seronegative subjects, the rate of anti-CCP3.1 positivity and the median number of autoantibodies were elevated in sputum versus serum. In subjects with early RA, the rate of positivity for several individual autoantibodies and the median number of autoantibodies were higher in serum than in sputum. Results in at-risk seropositive subjects were intermediate between these groups. In at-risk subjects with autoantibody positivity in sputum, the ratios of autoantibody to total Ig were higher in sputum than in serum, suggesting that these autoantibodies are generated or sequestered in the lung. CONCLUSION: RA-related autoantibodies are detectable in sputum in subjects at risk of RA and in subjects with early RA. In a subset of at-risk subjects, the presence of sputum autoantibodies in the absence of seropositivity, and the increased autoantibody-to-total Ig ratios in sputum, suggest that the lung may be a site of autoantibody generation in the early development of RA. These findings suggest an important role of the lung in the pathogenesis of RA.
24022229 Identification of BACH2 and RAD51B as rheumatoid arthritis susceptibility loci in a meta-a 2013 Dec OBJECTIVE: A recent high-density fine-mapping (ImmunoChip) study of genetic associations in rheumatoid arthritis (RA) identified 14 risk loci with validated genome-wide significance, as well as a number of loci showing associations suggestive of significance (P = 5 × 10(-5) < 5 × 10(-8)), but these have yet to be replicated. The aim of this study was to determine whether these potentially significant loci are involved in the pathogenesis of RA, and to explore whether any of the loci are associated with a specific RA serotype. METHODS: A total of 16 single-nucleotide polymorphisms (SNPs) were selected for genotyping and association analyses in 2 independent validation cohorts, comprising 6,106 RA cases and 4,290 controls. A meta-analysis of the data from the original ImmunoChip discovery cohort and from both validation cohorts was carried out, for a combined total of 17,581 RA cases and 20,160 controls. In addition, stratified analysis of patient subsets, defined according to their anti-cyclic citrullinated peptide (anti-CCP) antibody status, was performed. RESULTS: A significant association with RA risk (P < 0.05) was replicated for 6 of the SNPs assessed in the validation cohorts. All SNPs in the validation study had odds ratios (ORs) for RA susceptibility in the same direction as those in the ImmunoChip discovery study. One SNP, rs72928038, mapping to an intron of BACH2, achieved genome-wide significance in the meta-analysis (P = 1.2 × 10(-8), OR 1.12), and a second SNP, rs911263, mapping to an intron of RAD51B, was significantly associated in the anti-CCP-positive RA subgroup (P = 4 × 10(-8), OR 0.89), confirming that both are RA susceptibility loci. CONCLUSION: This study provides robust evidence for an association of RA susceptibility with genes involved in B cell differentiation (BACH2) and DNA repair (RAD51B). The finding that the RAD51B gene exhibited different associations based on serologic subtype adds to the expanding knowledge base in defining subgroups of RA.
24129963 Osteopontin has a crucial role in osteoclast-like multinucleated giant cell formation. 2014 Mar The osteoclast (OC) is a major player in the pathogenic bone destruction of inflammatory bone diseases such as rheumatoid arthritis and Langerhans cell histiocytosis. Recently, it was shown that immature dendritic cells (iDC) fuse faster and more efficiently than monocytes in forming OC-like multinucleated giant cells (MGCs), and that osteopontin (OPN) is involved in the pathogenesis of inflammatory bone diseases. In this study, we hypothesized that OPN is a key factor for generation of OC-like MGCs from iDCs. We used an in vitro culture system to differentiate iDCs, derived from monocytes obtained from the blood of healthy donors, into OC-like MGCs. We evaluated OPN levels and expression of OPN receptors during the course of differentiation. OPN has an arginine-glycine-aspartic acid (RGD) motif, and protease cleavage reveals a SVVYGLR motif. The concentrations of both full-length and cleaved forms of OPN increased during the course of OC-like MGC formation. Expression of OPN RGD- and SVVYGLR-recognizing receptors also increased at later stages. We analyzed whether blocking OPN binding to its receptors affected OC-like MGC formation. Monocytes treated with OPN siRNA were able to differentiate into iDCs effectively; however, differentiation of these iDCs into OC-like MGCs was significantly reduced. The formation of OC-like MGCs was not significantly reduced by RGD synthetic peptide. By contrast, SVVYGLR synthetic peptide caused a significant reduction. These data suggest that the cleaved form of OPN plays a critical role in driving iDC differentiation into OC-like MGCs in the early phase of differentiation, in an autocrine and/or paracrine fashion.
23031059 Differential effects of decoy receptor- and antibody-mediated tumour necrosis factor block 2013 Apr Our aim was to clarify if anti-tumour necrosis factor (TNF) drugs have effect on expression of three splice forms of FoxP3 mRNA in blood CD4+ T cells from rheumatoid arthritis (RA) patients compared with healthy controls. Forty-five rheumatoid arthritis patients treated with anti-TNF therapy were investigated in a 12-week prospective cohort study. FoxP3 isoforms, CD25 and CTLA-4 mRNA in blood CD4+ T cells were measured with quantitative real-time PCR. Patients benefitting from the treatment, based on changes in DAS28 scores, revealed a significant decrease in expression of full-length FoxP3 following 12 weeks treatment with TNF receptor 2 fusion protein (Etanercept), but not following treatment with anti-TNF antibodies (Adalimumab or Infliximab). A partial normalization of the CTLA-4/FoxP3fl ratio and a correlation between clinical improvement and change in FoxP3 mRNA expression were also seen in Etanercept responders. These changes were not observed in responsive patients treated with the antibody therapies. Our data suggest that TNF decoy receptor and anti-TNF antibodies differ in their effect on FoxP3 expression in responsive patients. As Etanercept binds both TNF-α and Lymphotoxin-α (LT-α), whereas the antibodies only target TNF-α, LT-α may regulate FoxP3 expression in a subset of RA patients. Our findings support the view that anti-TNF treatment is mainly symptomatic.
23908081 [Chuju total flavonoids control the SFRP4 expression in Wnt pathway in rheumatoid arthriti 2013 Jul OBJECTIVE: To determine the effect of Chuju total flavonoids (CJTF) on the secreted frizzledrelated protein 4 (SFRP4) expression in Wnt pathway in rheumatoid arthritis (RA) model rats. METHODS: The role of CJTF in the treatment of RA model rats was evaluated by rat arthritis score and paw edema score. The expression regulation of the SFRP4, β-catenin and C-myc in Wnt pathway in RA model rats was detected by RT-PCR and Western blot after CJTF gavage treatment. RESULTS: After CJTF treatment, the rat arthritis score and paw edema score in RA model rats were significantly decreased when the RA model rats were treated with CJTF, the SFRP4 expression was significantly up-regulated, while the β-catenin and C-myc gene expression were significantly downregulated in RA model rat synovial tissues. CONCLUSION: CJTF has significant therapeutic effect and inhibitory effect on Wnt pathway activation by targeting SFRP4 in RA model rat synovium.
23934220 Yoga for rheumatic diseases: a systematic review. 2013 Nov OBJECTIVE: To evaluate the quality of evidence and the strength of recommendation for yoga as an ancillary intervention in rheumatic diseases. METHODS: Medline/PubMed, Scopus, the Cochrane Library and IndMED were searched through February 2013. Randomized controlled trials (RCTs) comparing yoga with control interventions in patients with rheumatic diseases were included. Two authors independently assessed the risk of bias using the Cochrane Back Review Group risk of bias tool. The quality of evidence and the strength of the recommendation for or against yoga were graded according to the GRADE recommendations. RESULTS: Eight RCTs with a total of 559 subjects were included; two RCTs had a low risk of bias. In two RCTs on FM syndrome, there was very low evidence for effects on pain and low evidence for effects on disability. In three RCTs on OA, there was very low evidence for effects on pain and disability. Based on two RCTs, very low evidence was found for effects on pain in RA. No evidence for effects on pain was found in one RCT on CTS. No RCT explicitly reported safety data. CONCLUSION: Based on the results of this review, only weak recommendations can be made for the ancillary use of yoga in the management of FM syndrome, OA and RA at this point.
23573111 Higher levels of autoantibodies targeting mutated citrullinated vimentin in patients with 2013 Antibodies against citrullinated proteins/peptides (ACPAs), and especially antibodies targeting mutated citrullinated vimentin (anti-MCVs), are novel biomarkers of rheumatoid arthritis (RA). Whereas ACPAs are specific and sensitive markers for RA, there have hardly been any reports relating to ACPAs in psoriatic arthritis (PsA) or in psoriasis without joint symptoms (PsO). The aim of the present study was to investigate the prevalence of anti-MCVs in PsA and PsO. Serum anti-MCV titers were measured in 46 PsA and 42 PsO patients and in 40 healthy controls by means of a commercial enzyme-linked immunosorbent assay. The potential correlations of the serum autoantibody levels with several clinical and laboratory parameters were examined. The anti-MCV levels in the PsA patients were significantly higher than those in the PsO group. Among the clinical variables, the presence of tender knee joints and nail psoriasis was significantly associated with anti-MCV positivity in the PsA patients. Higher anti-MCV titers in the PsO patients were associated with a more severe disease course and with the early onset of psoriatic skin symptoms. Our results suggest that anti-MCVs can be used as novel markers in the diagnosis of PsA and in a subset of PsO patients.
25028072 The role of total and cartilage-specific estrogen receptor alpha expression for the amelio 2014 Jul 15 INTRODUCTION: Estrogen (E2) delays onset and decreases severity of experimental arthritis. The aim of this study was to investigate the importance of total estrogen receptor alpha (ERα) expression and cartilage-specific ERα expression in genetically modified mice for the ameliorating effect of estrogen treatment in experimental arthritis. METHODS: Mice with total (total ERα-/-) or cartilage-specific (Col2α1-ERα-/-) inactivation of ERα and wild-type (WT) littermates were ovariectomized, treated with E2 or placebo, and induced with antigen-induced arthritis (AIA). At termination, knees were collected for histology, synovial and splenic cells were investigated by using flow cytometry, and splenic cells were subjected to a T-cell proliferation assay. RESULTS: E2 decreased synovitis and joint destruction in WT mice. Amelioration of arthritis was associated with decreased frequencies of inflammatory cells in synovial tissue and decreased splenic T-cell proliferation. E2 did not affect synovitis or joint destruction in total ERα-/- mice. In Col2α1-ERα-/- mice, E2 protected against joint destruction to a similar extent as in WT mice. In contrast, E2 did not significantly ameliorate synovitis in Col2α1-ERα-/- mice. CONCLUSIONS: Treatment with E2 ameliorates both synovitis and joint destruction in ovariectomized mice with AIA via ERα. This decreased severity in arthritis is associated with decreased synovial inflammatory cell frequencies and reduced splenic T-cell proliferation. ERα expression in cartilage is not required for estrogenic amelioration of joint destruction. However, our data indicate that ERα expression in cartilage is involved in estrogenic effects on synovitis, suggesting different mechanisms for the amelioration of joint destruction and synovitis by E2.
23194101 A case of urinary incontinence by hydroxychloroquine in a geriatric patient. 2013 Apr WHAT IS KNOWN AND OBJECTIVE: Rheumatoid arthritis is an autoimmune disorder characterized by persistent synovitis and systemic inflammation. Genetic factors account for approximately 50% of cases of rheumatoid arthritis and environmental factors include smoking. Urinary incontinence may occur as a medication adverse effect. We present the first report of a case of hydroxychloroquine-induced urinary incontinence in rheumatoid arthritis. DETAILS OF THE CASE: A 71-year-old female with a history of rheumatoid arthritis developed urinary incontinence as an adverse drug reaction to hydroxychloroquine administered at therapeutic doses. Urinary incontinence remitted with drug withdrawal and reappeared on rechallenge. The Naranjo's algorithm indicated that hydroxychloroquine was a probable cause of this adverse drug reaction. The likely mechanism of this adverse drug is a direct action of the quinolone on the urinary system. WHAT IS NEW AND CONCLUSION: This is the first report of hydroxychloroquine-induced urinary incontinence. The absence of previous reports suggest that the drug rarely causes this adverse effect. Methotrexate is most often used as first-line treatment, and several other drugs are now available to act as Disease-Modifying Antirheumatic Drugs (DMARDs). These drugs may be used alone or combined with methotrexate, most often to increase efficacy and reduce toxicity. The introduction of new biological agents, such as abatacept, rituximab, tocilizumab and inhibitors of tumour necrosis factor, has opened new therapeutic perspectives but are restricted by high costs and risk of infections. Thus, antimalarial drugs, especially the quinolones chloroquine (CQ) and hydroxychloroquine (HCQ), are still in use, and the latter is very efficacious. An advantage of HCQ is its low toxicity compared with other antimalarial drugs. Common side-effects of HCQ and the other antimalarial drugs include gastrointestinal effects such as nausea and vomiting, as well as skin rashes and headache, whereas their most common and severe side-effect is retinopathy. No case of urinopathy has been reported previously with HCQ.
25274900 Patients with rheumatoid arthritis in clinical remission manifest persistent joint inflamm 2014 Nov OBJECTIVE: The purpose of our study was to test the hypothesis that synovitis on magnetic resonance imaging (MRI) and ultrasound (US) observed in patients with rheumatoid arthritis (RA) who meet remission criteria reflects active inflammation on histopathology. METHODS: We analyzed 15 synovial specimens obtained during surgical procedures from 14 patients with RA in clinical remission as defined by the American College of Rheumatology criteria. Histological specimens were scored for hyperplasia of synovial lining and synovial stroma, inflammation, lymphoid follicles, and vascularity. The histology scores were classified as minimal, mild, moderate, or severe disease activity. US and MRI performed within a 4-month period of surgery were scored for disease activity. The correlation between histology and imaging scores was examined. RESULTS: Four of 14 patients were receiving anti-tumor necrosis factor (TNF) therapy, 4 were receiving methotrexate (MTX) alone, 4 were taking MTX and hydroxychloroquine (HCQ), and 1 was taking HCQ and sulfasalazine. Four specimens had severe, 6 moderate, 3 mild, and 2 minimal disease activity on histology. Three of 4 specimens with minimal and mild histology were observed in subjects receiving anti-TNF therapy. Synovitis was noted on greyscale in 80% of joints and Doppler signal in 60%. MRI demonstrated synovitis and bone marrow edema in 86% of images. Positive but not significant correlations were noted between histology and synovitis scores on US. CONCLUSION: Despite clinical remission, histology and imaging studies documented a persistently active disease state that may explain the mechanism for radiographic progression.
25179850 Disease activity improvement in rheumatoid arthritis treated with tumor necrosis factor-α 2014 Oct OBJECTIVE: Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation and hyperplasia. Tumor necrosis factor-α (TNF-α) plays a pivotal role in RA by interfering with the Fas-Fas ligand (FasL) proapoptotic pathway. We investigated the circulating levels of soluble Fas (sFas) and soluble FasL (sFasL), and their possible correlation with disease activity and improvement after anti-TNF-α treatment in RA. METHODS: Serum levels of sFas and sFasL were measured by quantitative ELISA in 52 patients with RA before and after 3 months of anti-TNF-α treatment (adalimumab, n = 32; infliximab, n = 20). Disease activity measures [Disease Activity Score at 28 joints-erythrocyte sedimentation rate (DAS28-ESR), C-reactive protein (CRP)] were recorded before and after treatment. Forty age-matched and sex-matched healthy subjects served as controls. RESULTS: No significant differences in serum sFas levels were detected between anti-TNF-α-naive patients with RA and controls. After anti-TNF-α treatment, serum sFas levels significantly increased in patients with RA compared to both anti-TNF-α-naive patients and controls. Increased sFas levels inversely correlated with disease activity variables (DAS28-ESR: r = -0.739, CRP: r = -0.636, both p < 0.001). No significant differences in sFasL levels were detected in patients with RA before and after anti-TNF-α treatment. CONCLUSION: In RA, an increase in sFas levels closely correlates with improvement in disease activity induced by TNF-α inhibitors, suggesting their ability to modulate Fas-mediated synoviocyte apoptosis.
23617702 Role of N- or C-terminal biotinylation in autoantibody recognition of citrullin containing 2013 May 15 Here, we report on the synthesis, conformational analysis, and autoantibody binding properties of new sets of rheumatoid arthritis (RA) specific biotin-peptide conjugates derived from filaggrin epitope peptides. The biotin with or without a linker was attached to the Cit or Arg containing epitope core ((311)TXGRS(315)) or epitope region ((306)SHQESTXGXSXGRSGRSGS(324)) peptide (where X = Cit), through an amide bond at the N- or C-terminal of the epitopes. Antibody binding was detected by indirect enzyme-linked immunosorbent assay (ELISA) using sera from RA, Systemic lupus erythematosus (SLE) patients, as well as healthy individuals, and the secondary structure of conjugates was investigated by electronic circular dichroism (ECD). We found that autoantibodies from RA patients recognize specifically both filaggrin epitope region ((306)SHQESTXGXSXGRSGRSGS(324)) and short epitope core ((311)TXGRS(315)) peptides. Our data also indicate that the positioning of the biotin label within a peptide sequence can markedly influence the antibody binding, but the length of the linker incorporated has essentially no effect on the recognition. ECD experiments demonstrate that the Arg/Cit change does not influence the solution conformation of the peptide conjugates. However, the presence and position of the biotin moiety has a pronounced effect on the conformation of the 5-mer epitope core peptides, while it does not alter the secondary structure of the 19-mer epitope region peptides.
24706282 Bayesian systems-based genetic association analysis with effect strength estimation and om 2014 Rich dependency structures are often formed in genetic association studies between the phenotypic, clinical, and environmental descriptors. These descriptors may not be standardized, and may encompass various disease definitions and clinical endpoints which are only weakly influenced by various (e.g., genetic) factors. Such loosely defined complex intermediate clinical phenotypes are typically used in follow-up candidate gene association studies, e.g., after genome-wide analysis, to deepen the understanding of the associations and to estimate effect strength. This chapter discusses a solid methodology, which is useful in such a scenario, by using probabilistic graphical models, namely, Bayesian networks in the Bayesian statistical framework. This method offers systematically scalable, comprehensive hierarchical hypotheses about multivariate relevance. We discuss its workflow: from data engineering to semantic publication of the results. We overview the construction, visualization, and interpretation of complex hypotheses related to the structural analysis of relevance. Furthermore, we illustrate the use of a dependency model-based relevance measure, which takes into account the structural properties of the model, for quantifying the effect strength. Finally, we discuss the "interpretational" or translational challenge of a genetic association study, with a focus on the fusion of heterogeneous omic knowledge to reintegrate the results into a genome-wide context.
24374661 Human regulatory T cells are selectively activated by low-dose application of the CD28 sup 2014 Apr CD28 superagonists (CD28SAs) are potent T-cell-activating monoclonal antibodies (mAbs). In contrast to their benign behavior and marked therapeutic efficacy as activators of regulatory T (Treg) cells in preclinical rodent models, a phase I trial of the human CD28SA TGN1412 (now called TAB08) in 2006 resulted in a life-threatening cytokine release syndrome (CRS). We studied TAB08-mediated Treg-cell activation in a recently developed in vitro system of human PBMCs, which also reproduces the CRS experienced by the healthy volunteers. We show that just as in rodents, CD28SAs are potent activators and expanders of Treg cells from healthy donors and rheumatoid arthritis patients, even under effective blockade of pro-inflammatory cytokine release by a corticosteroid. Moreover, CD28SA titration identifies a dose range where pro-inflammatory cytokine secretion from conventional T cells is absent while appreciable Treg-cell activation is maintained. Finally, we report that low-dose application of TAB08 to healthy volunteers results in dose-dependent systemic release of the Treg-cell signature cytokine IL-10 in the absence of the pro-inflammatory factors associated with the CRS of the 2006 TGN1412 study. These results demonstrate the potential of appropriately dosed CD28SA and corticosteroid comedication to mobilize human Treg cells for the treatment of autoimmune and inflammatory conditions.