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ID PMID Title PublicationDate abstract
23221586 Overview of safety of non-biologic and biologic DMARDs. 2012 Dec Safety data come from a number of sources. Randomized clinical trials tend to be relatively short, exclude patients with significant comorbidity, have limited numbers of subjects and are primarily powered for efficacy. The most useful post-marketing data come from large national registries, such as Britain's BSRBR, Sweden's ARTIS, Germany's RABBIT, France's DANBIO, Spain's BIODASER and North America's CORRONA. Among the most commonly used non-biologic DMARDs, MTX is associated with risks of hepatotoxicity and cytopenia, as well as pneumonitis, particularly during the first year of treatment. Regarding TNF inhibitors, there is an increased risk of infection (including serious infections) by bacterial pathogens, atypical fungi and opportunistic pathogens. When possible, pneumococcal and influenza vaccines should be given before initiation of treatment with any biologic DMARD. Screening for latent tuberculosis is recommended for all TNF inhibitors, and has been shown to reduce the risk of reactivation. Evidence from registries suggests that there is no increased risk of solid tumours with TNF inhibitor treatment; however, non-melanoma skin cancers are more common. Specific risks with other biologic DMARDs include gastrointestinal perforation with tocilizumab, progressive multifocal leucoencephalopathy with rituximab and pulmonary infections with abatacept. Overall, the safety of biologic and non-biologic DMARDs appears to be reasonable, particularly compared with the risks associated with the disease itself.
22154309 Recovery of sensory disturbance after arthroscopic decompression of the suprascapular nerv 2012 Jun BACKGROUND: The existence of sensory branches of the suprascapular nerve (SSN) has recently been reported, and sensory disturbance at the lateral and posterior aspect of the shoulder has been focused on as a symptom of SSN palsy. We have performed arthroscopic release of SSN at the suprascapular notch in patients with sensory disturbance since 2006. The purposes of this study were to introduce the arthroscopic surgical technique and investigate postoperative recovery of sensory disturbance. MATERIALS AND METHODS: The study included 11 men and 14 women (25 shoulders), with an average age of 63.9 years (range, 41-77 years). Arthroscopic decompression of the SSN was performed using a suprascapular nerve (SN) portal as a landmark for approaching the suprascapular notch. Sensory disturbance of the shoulder was evaluated preoperatively and postoperatively. The average follow-up was 18.5 months (range, 12-30 months). RESULTS: The arthroscopic procedures were performed safely. The preoperative sensory disturbance fully recovered postoperatively in all shoulders. CONCLUSION: Arthroscopic release of the SSN is a useful procedure for SSN entrapment at the suprascapular notch. The sensory disturbance at the lateral and posterior aspect of the shoulder can be used as one of the criteria of diagnosing SSN palsy, especially in shoulders with massive rotator cuff tear, in which diagnosing and assessing the treatment results of associated SSN palsy is usually difficult.
21326956 Relationship between anti-CCP antibodies and oxidant and anti-oxidant activity in patients 2011 Feb 9 OBJECTIVE/AIM: A new group of autoantibodies in Rheumatoid Arthritis (RA), the anti-cyclic citrullinated peptide (anti-CCP) antibodies directed to citrulline-containing proteins, which are of value for the severity of RA. Up to date, the relationship between anti-CCP antibodies and oxidant, anti-oxidant activity in patients with RA has not been elucidated in the previous studies. In this study we aimed to investigate the effect of anti-CCP antibodies in the circulation on whole blood, serum and synovial fluid oxidant and anti-oxidant activity in patients with RA. MATERIALS AND METHODS: RA patients with anti-CCP (+) (n=25) and anti-CCP (-) (n=24) were recruited into the study. All patients had a positive rheumatoid factor (RF). The patients who were under treatment with only non-steroidal antiinflammatory drugs (NSAID) at the study time included in the study. Catalase (CAT), Glutathione peroxidase (GSHPx), Myeloperoxidase (MPO) activities and the levels of Malondialdehyde (MDA) were measured in whole blood, serum and synovial fluid in both groups. RESULTS: There were no significant differences in terms of the mean whole blood and serum antioxidative activity (CAT, GSHpx) and the mean blood and serum MDA and MPO values (oxidative activity), between the patients with anti-CCP(+) and those with anti-CCP(-). There was increased synovial oxidant activity (MDA and MPO levels) (p<0.05) in anti-CCP(+) RA patients with or without ESR negativity when compared with anti-CCP(-) RA patients. There was positive correlation between anti-CCP antibody levels and synovial MDA and MPO levels (r=0.435, p<0.05, r=0.563, p<0.05 respectively) in anti-CCP (+) group. CONCLUSIONS: In conclusion, anti-CCP antibody positivity seems to be associated with increased synovial fluid oxidant activity (increased MDA and MPO levels) in patients with RA. These conclusions need to be validated in a larger controlled study population.
22736176 Modulation of STAT-3 in rheumatoid synovial T cells suppresses Th17 differentiation and in 2012 Nov OBJECTIVE: To investigate the impact of STAT-3-mediated regulation on Th17 differentiation in patients with rheumatoid arthritis (RA). METHODS: CD4+ T cells isolated from peripheral blood (PB) and synovial fluid (SF) were stimulated to differentiate into Th17 cells or Treg cells. The activity of STAT-3 was knocked down by transfecting CD4+ T cells with small interfering RNA (siRNA). After 3 days in culture, the proportions of Th17 cells and Treg cells were measured by flow cytometry, and the production of interleukin-17 (IL-17) was measured by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: The levels of IL-17, IL-6, IL-23, IL-1, and tumor necrosis factor α were significantly higher in RA SF and synovial tissue than in SF and synovial tissue from osteoarthritis patients. In RA synovial tissue, the expression of STAT-3 increased in proportion to the severity of synovitis, as shown by stromal cellularity, intimal hyperplasia, and inflammatory infiltration. The degree of Th17 differentiation was highest in RA SF, followed by RA PB, and lowest in normal subjects. In CD4+ T cells, transfection with STAT-3 siRNA prevented Th17 differentiation of mononuclear cells from RA PB and SF but increased the proportion of Treg cells. In contrast, inhibition of STAT-5, the transcription factor for Treg cells, increased the proportion of Th17 cells and reduced that of Treg cells. CONCLUSION: Our findings indicate that modulation of STAT-3 in CD4+ T cells affects the differentiation of Th17 cells and Treg cells in patients with RA. This role of STAT-3 in RA synovial T cells may provide a new therapeutic target for the management of RA.
22034172 Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular c 2012 Apr OBJECTIVE: To test the hypothesis that autoantigen modifications by peptidylarginine deiminase type 4 (PAD-4) increase immunoreactivity. METHODS: We assembled sera from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Felty's syndrome (FS), and antineutrophil cytoplasmic antibody-associated vasculitides (AAVs), as well as sera from control subjects without autoimmune diseases. The sera were tested for binding to activated neutrophils, deiminated histones, and neutrophil extracellular chromatin traps (NETs). IgG binding to lipopolysaccharide-activated neutrophils was assessed with confocal microscopy, and binding to in vitro-deiminated histones was measured using enzyme-linked immunosorbent assay (ELISA) and Western blotting. In addition, we quantitated histone deimination in freshly isolated neutrophils from the blood of patients and control subjects. RESULTS: Increased IgG reactivity with activated neutrophils, particularly binding to NETs, was paralleled by preferential binding to deiminated histones over nondeiminated histones by ELISA in a majority of sera from FS patients but only in a minority of sera from SLE and RA patients. Immunoblotting revealed autoantibody preference for deiminated histones H3, H4, and H2A in most FS patients and in a subset of SLE and RA patients. In patients with AAVs, serum IgG preferentially bound nondeiminated histones over deiminated histones. Increased levels of deiminated histones were detected in neutrophils from RA patients. CONCLUSION: Circulating autoantibodies in FS are preferentially directed against PAD-4-deiminated histones and bind to activated neutrophils and NETs. Thus, increased reactivity with modified autoantigens in FS implies a direct contribution of neutrophil activation and the production of NET-associated nuclear autoantigens in the initiation or progression of FS.
21229234 High incidence of vertebral and non-vertebral fractures in the OSTRA cohort study: a 5-yea 2011 Sep A 5-year follow-up study was performed in female RA patients with established disease looking at vertebral fractures, scored on spinal X-rays, and non-vertebral fractures. We found a high incidence rate of vertebral and non-vertebral fractures in these patients compared to population-based studies. INTRODUCTION: The aim of this study is to investigate the incidence of vertebral and non-vertebral fractures over a 5-year period in a cohort of postmenopausal patients with established rheumatoid arthritis (RA). METHODS: One hundred and fifty female patients with established RA were included into the OSTRA cohort. The cohort was assessed at baseline and at 5 years for incident vertebral and non-vertebral fractures. Spinal X-rays were taken at baseline and at follow-up and scored using the semi-quantitative method according to Genant. RESULTS: At 5 years, 102 patients (68%) were examined and included in the present analysis. At baseline, the mean age was 61 years, disease duration 17 years, body mass index 25.5 kg/m(2) and 65% of the patients were rheumatoid factor positive. Fifteen percent were treated with bisphosphonates, 25% received calcium supplementation and 20% vitamin-D supplementation at baseline. During the 5-year follow-up, a total of 16 patients out of 102 patients (16%) had a new non-vertebral fracture [annual incidence of 3.2 (95% CI 1.8-5.5) per 100 patients/year]. In 18 patients out of 97 patients (19%), new vertebral fractures were identified on spinal X-ray [annual incidence of 3.7 (95% C.I. 2.2-5.8) per 100 patients/year]. CONCLUSIONS: We found a high incidence of vertebral and non-vertebral fractures in a cohort of women with established RA compared to population-based studies.
22492217 Suppression of dendritic cell maturation and T cell proliferation by synovial fluid myeloi 2012 Oct OBJECTIVE: To determine whether myeloid cells (such as granulocytes) present in the synovial fluid (SF) of arthritic joints have an impact on adaptive immunity. Specifically, we investigated the effects of SF cells harvested from the joints of mice with proteoglycan-induced arthritis (PGIA), on dendritic cell (DC) maturation and antigen-specific T cell proliferation. METHODS: We monitored DC maturation (MHCII and CD86 expression) by flow cytometry upon coculture of DCs with SF cells or spleen myeloid cells from mice with PGIA. The effects of these myeloid cells on T cell proliferation were studied using T cells purified from PG-specific T cell receptor (TCR)-transgenic (Tg) mice. Phenotype analysis of myeloid cells was performed by immunostaining, reverse transcription-polymerase chain reaction, Western blotting, and biochemical assays. RESULTS: Inflammatory SF cells significantly suppressed the maturation of DCs upon coculture. PG-TCR-Tg mouse T cells cultured with antigen-loaded DCs showed dramatic decreases in proliferation in the presence of SF cells. Spleen myeloid cells from arthritic mice did not have suppressive effects. SF cells were unable to suppress CD3/CD28-stimulated proliferation of the same T cells, suggesting a DC-dependent mechanism. SF cells exhibited all of the characteristics of myeloid-derived suppressor cells (MDSCs) and exerted suppression primarily through the production of nitric oxide and reactive oxygen species by granulocyte-like cells. CONCLUSION: SF in the joints of mice with PGIA contains a population of granulocytic MDSCs that potently suppress DC maturation and T cell proliferation. These MDSCs have the potential to limit the expansion of autoreactive T cells, thus breaking the vicious cycle of autoimmunity and inflammation.
22674737 Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and the risk 2012 Aug PURPOSE: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are effective in the treatment of cardiovascular disease. Next to effects on hypertension and cardiac function, these drugs have anti-inflammatory and immunomodulating properties which may either facilitate or protect against the development of autoimmunity, potentially resulting in autoimmune diseases. Therefore, we determined in the current study the association between ACE inhibitor and ARB use and incident rheumatoid arthritis (RA). METHODS: A matched case-control study was conducted among patients treated with antihypertensive drugs using the Netherlands Information Network of General Practice (LINH) database in 2001-2006. Cases were patients with a first-time diagnosis of RA. Each case was matched to five controls for age, sex, and index date, which was selected 1 year before the first diagnosis of RA. ACE inhibitor and ARB exposure was considered to be any prescription issued in the period before index date. Logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CI). RESULTS: Our study included 211 cases and 667 matched controls. After controlling for potential confounders, ever use of ACE inhibitors or ARBs was not associated with incident RA (adjusted ORs [95%CI], 0.99 [0.55-1.79] and 1.02 [0.67-1.56], respectively). The adjusted ORs (95%CI) for current and past use of ACE inhibitors were 1.18 (0.75-1.85) and 0.61 (0.28-1.35). For current and past use of ARBs, these adjusted ORs (95%CI) were 1.40 (0.80-2.45) and 0.29 (0.05-1.67), respectively. No duration and dose-effect relationship was observed. CONCLUSIONS: ACE inhibitor or ARB use is not associated with incident RA.
22589260 Safety of infliximab treatment in patients with rheumatoid arthritis in a real-world clini 2012 Aug OBJECTIVE: To describe acute and delayed infusion reactions in a large cohort of patients with inflammatory arthritis, treated with infliximab (IFX). METHODS: We conducted a retrospective chart review of patients treated with IFX at the Mary Pack Arthritis Centre between 2000 and 2008. The primary outcome was the occurrence of acute infusion reactions during infusions or 1-2 hours after each infusion, and secondary outcome was the occurrence of delayed infusion reactions 1-14 days after an infusion. Descriptive analyses were conducted to summarize study outcomes and identify trends over followup. RESULTS: Since 2000, 376 patients were referred to the Mary Pack IFX clinic and 200 received 4399 IFX infusions over a mean 140 ± 132 weeks of followup. Of these, 135 were patients with RA who received 2977 IFX infusions over mean followup of 138 ± 132 weeks. In total 258 episodes of acute reactions were observed for an overall acute reaction rate of 5.8%. Acute infusion reactions were mostly mild (42.6%) and moderate (43.8%) and commonly affected sites were head and neck (31.5%) and cutaneous (21.1%). A total of 37 delayed infusion reaction episodes were observed (0.9% rate); reactions were also mostly mild (16.2%) and moderate (64.9%). CONCLUSION: These clinical data from 200 patients treated with IFX demonstrate that acute and delayed infusion reactions occur infrequently and are mostly mild to moderate in presentation.
22840496 IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR signaling cascade. 2012 Oct OBJECTIVE: Interleukin 22 (IL-22), a relatively new cytokine has been found to induce significant proliferation of human keratinocytes and fibroblast like synoviocytes (FLS) and thus plays an important role in the pathogenesis of autoimmune diseases like psoriasis and rheumatoid arthritis (RA) which are characterized by hyperproliferation of keratinocytes and FLS respectively. PI3K/Akt/mTOR signaling cascade plays crucial role in cell growth and survival. Therefore our objective was to see the regulatory role of PI3K/Akt/mTOR signaling cascade in IL-22 induced proliferation of keratinocytes and FLS. METHODS: Normal human epidermal keratinocytes (NHEK) and FLS were isolated from skin of healthy volunteer's undergone plastic surgery and synovial tissue of psoriatic arthritis (PsA) and RA patients respectively. IL-22 induced proliferation of NHEK and FLS was measured by MTT assay. Phosphorylation of Akt/mTOR was determined by western blot assay and further confirmed by real time polymerase chain reaction (RT-PCR). RESULTS: We observed that IL-22 induced significant proliferation of NHEK and FLS which was effectively inhibited by dual kinase (PI3K/mTOR) inhibitor, NVP-BEZ235 and specific mTOR inhibitor, Rapamycin. In NHEK and FLS, IL-22 significantly induced phosphorylation of Akt and mTOR which was effectively blocked by Rapamycin and NVP-BEZ235. Further we did RT-PCR in NHEK and found that IL-22 significantly upregulated AKT1 and MTOR gene. CONCLUSION: These results show that IL-22 induced proliferation of NHEK and FLS is dependent on PI3K/Akt/mTOR signaling pathway. This novel observation provides the scope to develop new therapeutics targeting PI3K/Akt/mTOR signaling pathway in autoimmune diseases like psoriasis and rheumatoid arthritis.
22529989 A dynamic real time in vivo and static ex vivo analysis of granulomonocytic cell migration 2012 Neutrophilic granulocytes and monocytes (granulomonocytic cells; GMC) drive the inflammatory process at the earliest stages of rheumatoid arthritis (RA). The migratory behavior and functional properties of GMC within the synovial tissue are, however, only incompletely characterized. Here we have analyzed GMC in the murine collagen-induced arthritis (CIA) model of RA using multi-photon real time in vivo microscopy together with ex vivo analysis of GMC in tissue sections.GMC were abundant as soon as clinical arthritis was apparent. GMC were motile and migrated randomly through the synovial tissue. In addition, we observed the frequent formation of cell clusters consisting of both neutrophilic granulocytes and monocytes that actively contributed to the inflammatory process of arthritis. Treatment of animals with a single dose of prednisolone reduced the mean velocity of cell migration and diminished the overall immigration of GMC.In summary, our study shows that the combined application of real time in vivo microscopy together with elaborate static post-mortem analysis of GMC enables the description of dynamic migratory characteristics of GMC together with their precise location in a complex anatomical environment. Moreover, this approach is sensitive enough to detect subtle therapeutic effects within a very short period of time.
23126644 Increased circulating myeloid-derived suppressor cells correlated negatively with Th17 cel 2013 OBJECTIVES: Myeloid-derived suppressor cells (MDSCs) have recently been identified as an important mediator in inflammatory and autoimmune diseases through the production of arginase (Arg)-1 and inducible nitric oxide synthase (iNOS). The aim of this study was to investigate the prevalence of MDSCs in the peripheral blood of patients with rheumatoid arthritis (RA) and evaluate their correlation with T-helper (Th)17 cells. METHOD: The frequency of MDSCs and Th17 cells and the mRNA expression of transcriptional factor RORγ-t and iNOS in the peripheral blood of RA patients and healthy controls (HC) were determined by flow cytometry and real-time reverse transcription polymerase chain reaction (RT-PCR), respectively. Plasma levels of interleukin (IL)-17, IL-6, tumour necrosis factor (TNF)-α, and Arg-1 were analysed by enzyme-linked immunosorbent assays (ELISA). RESULTS: Compared with HC, both the prevalence of circulating MDSCs and plasma Arg-1 increased significantly in RA patients. However, no significant difference was observed in the mRNA level of iNOS between RA patients and HC. The frequency of Th17 cells in RA patients was significantly higher than in HC but correlated negatively with the frequency of MDSCs and plasma Arg-1. A negative correlation between MDSCs and plasma TNF-α was also observed. However, the frequency of MDSCs was not correlated with plasma IL-6 and IL-17, nor with the mRNA level of RORγ-t. CONCLUSIONS: We found a negative correlation between increased circulating MDSCs and Th17 cells in RA patients, which may provide new insights into the mechanisms involved in RA.
23027388 [Fear of progression in partners of chronically ill patients]. 2012 Sep Fear of progression (FoP) is one of the most prevalent symptoms in patients with chronic diseases. Little is known about FoP in partners of chronically ill patients. Therefore, this study assessed FoP in 332 partners of lung, colon cancer, migraine and rheumatism patients. Objectives were to ascertain the influence of individual, dyadic and disease related factors on FoP. 49% of partners were experiencing high levels of FoP varied according to the nature of the disease (highest FoP in spouses of lung cancer patients, lowest in partners of migraine patients). As significant predictors emerged more medical consultations of the patient, high avoidance symptoms, and own dyadic coping nor dyadic coping of the patient. FoP seems to impact the psychological functioning of the partner as well. Therefore, investigating FoP in partners of chronically ill patients is a promising approach to extending a program of care for patients to their partners.
22480748 Effects of polymorphisms in TRAILR1 and TNFR1A on the response to anti-TNF therapies in pa 2012 Dec OBJECTIVES: As the role of polymorphisms in death receptors (DRs) such as Tumor Necrosis Factor-related Apoptosis-inducing Ligand Receptor 1 (TRAIL-R1) and Tumor Necrosis Factor Receptor 1A (TNF-R1A) on the response to anti-TNF therapy remains unknown, we evaluated the association between TRAILR1 and TNFR1A gene polymorphisms (rs20575/C626G and rs767455/G36A) and the pharmacogenetics of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with TNFα blockers. METHODS: One hundred and forty-five patients (90 RA and 55 PsA) treated with anti-TNFα therapy (RA: 75 infliximab, 8 etanercept, 7 adalimumab. PsA: 27 infliximab, 19 etanercept, 9 adalimumab) were genotyped for TRAILR1 and TNFR1A polymorphisms by allelic discrimination. The response to anti-TNFα was assessed by EULAR criteria. RESULTS: In RA, the TRAILR1 CC genotype was associated with a better response after 3 and 6 months of anti-TNFα treatment (CC: 91.7% vs. CG/GG: 62.2%; P=0.019, and CC: 82.6% vs. CG/GG: 56.1%; P=0.019, respectively). Similar results were observed in only infliximab-treated RA patients. With respect to the TNFR1A polymorphism, there was an association between the AA genotype and a poorer response at 3 months in RA patients (AA: 39.3% vs. AG/GG: 19.0%; P=0.04). In PsA, TRAILR1 CC genotype was only associated with EULAR response to infliximab at 6 months (CC: 71.4% vs CG/GG: 50%P=0.048). In contrast to RA, the TNFR1 polymorphism in PsA was associated with a better response at 3 months (AA 88% vs AG/GG 58.9%; P=0.04). CONCLUSIONS: This study provides the first evidence that a polymorphism in TRAILR1 influences the response to anti-TNFα therapy in RA and also suggests that TNFR1A polymorphism may have opposing effects on the response to anti-TNFα in RA and PsA.
20663637 Dermatitis associated with chromium following total knee arthroplasty. 2011 Jun All metal implants release metal ions because of corrosion. Although 20% to 25% of patients develop metal sensitivity after total joint arthroplasty, which is 10% higher than that in the general population, only very few highly susceptible patients exhibit symptoms. Even patients with known metal allergy often do not react to their metal prosthesis. Systemic allergic contact dermatitis is particularly uncommon with total knee arthroplasty because there is no metal-on-metal contact between the femoral and tibial components. We present a case report of 62-year-old man with dermatitis most likely caused by chromium after total knee arthroplasty and review the relevant literature. Although this complication is very rare, it sometimes can be painful enough for the patient to undergo revision surgery.
22033883 Cyst-like lesions in finger joints detected by conventional radiography: comparison with 3 2012 Apr OBJECTIVE: Many rheumatologists and radiologists routinely assess conventional radiographs of the hands, and it is often unclear how to proceed if radiography reveals only cyst-like lesions (CLLs), with otherwise normal findings. The present study was undertaken to evaluate the use of 320-row multidetector computed tomography (MDCT) of the hands in the further assessment of CLLs of metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints identified on conventional radiography. METHODS: MCP and PIP joints (n = 1,120 joints) of 56 consecutive patients (44 women [mean age 55 years, range 31-72 years] and 12 men [mean age 57 years, range 37-77 years]) were prospectively scored for the presence of cysts, CLLs, and erosions of the PIP and MCP joints, first on conventional radiographs, then on MDCT. Scoring was performed by 2 independent readers under blinded conditions. Intraclass correlation coefficients were calculated. RESULTS: By conventional hand radiography, 13 patients (total of 260 joints assessed) were identified as having CLLs in 1 or more joints (total of 36 joints [11 PIP and 25 MCP]). By MDCT, the findings in 19 of 36 joints (53%) were diagnosed as erosions, while 7 of 36 (19%) were confirmed as true cysts, and 10 joints (28%) were normal (false positive). Among the patients with CLLs, 10 of 224 joints with no abnormality seen radiographically had erosions as seen on MDCT. Interreader agreement for erosions was 0.854 (95% confidence interval [95% CI] 0.831-0.874) by conventional hand radiography and 0.952 (95% CI 0.943-0.959) by MDCT. CONCLUSION: Our results indicate that radiographic appearance of cyst-like lesions may actually represent erosions and should lead to initiation of further imaging tests.
22777994 Glycoprotein 96 perpetuates the persistent inflammation of rheumatoid arthritis. 2012 Nov OBJECTIVE: The mechanisms that contribute to the persistent activation of macrophages in rheumatoid arthritis (RA) are incompletely understood. The aim of this study was to determine the contribution of endogenous gp96 in Toll-like receptor (TLR)-mediated macrophage activation in RA. METHODS: RA synovial fluid was used to activate macrophages and HEK-TLR-2 and HEK-TLR-4 cells. Neutralizing antibodies to TLR-2, TLR-4, and gp96 were used to inhibit activation. RA synovial fluid macrophages were isolated by CD14 negative selection. Cell activation was measured by the expression of tumor necrosis factor α (TNFα) or interleukin-8 messenger RNA. Arthritis was induced in mice by K/BxN serum transfer. The expression of gp96 was determined by immunoblot analysis, enzyme-linked immunosorbent assay, and immunohistochemistry. Arthritis was treated with neutralizing anti-gp96 antiserum or control serum. RESULTS: RA synovial fluid induced the activation of macrophages and HEK-TLR-2 and HEK-TLR-4 cells. RA synovial fluid-induced macrophage and HEK-TLR-2 activation was suppressed by neutralizing anti-gp96 antibodies only in the presence of high (>800 ng/ml) rather than low (<400 ng/ml) concentrations of gp96. Neutralization of RA synovial fluid macrophage cell surface gp96 inhibited the constitutive expression of TNFα. Supporting the role of gp96 in RA, joint tissue gp96 expression was induced in mice with the K/BxN serum-induced arthritis, and neutralizing antibodies to gp96 ameliorated joint inflammation, as determined by clinical and histologic examination. CONCLUSION: These observations support the notion that gp96 plays a role as an endogenous TLR-2 ligand in RA and identify the TLR-2 pathway as a therapeutic target.
22160261 GABA is an effective immunomodulatory molecule. 2013 Jul In recent years, it has become clear that there is an extensive cross-talk between the nervous and the immune system. Somewhat surprisingly, the immune cells themselves do express components of the neuronal neurotransmitters systems. What role the neurotransmitters, their ion channels, receptors and transporters have in immune function and regulation is an emerging field of study. Several recent studies have shown that the immune system is capable of synthesizing and releasing the classical neurotransmitter GABA (γ-aminobutyric acid). GABA has a number of effects on the immune cells such as activation or suppression of cytokine secretion, modification of cell proliferation and GABA can even affect migration of the cells. The immune cells encounter GABA when released by the immune cells themselves or when the immune cells enter the brain. In addition, GABA can also be found in tissues like the lymph nodes, the islets of Langerhans and GABA is in high enough concentration in blood to activate, e.g., GABA-A channels. GABA appears to have a role in autoimmune diseases like multiple sclerosis, type 1 diabetes, and rheumatoid arthritis and may modulate the immune response to infections. In the near future, it will be important to work out what specific effects GABA has on the function of the different types of immune cells and determine the underlying mechanisms. In this review, we discuss some of the recent findings revealing the role of GABA as an immunomodulator.
21452294 Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate 2011 Jul OBJECTIVE: To assess the efficacy, safety, and biologic activity of atacicept in tumor necrosis factor antagonist-naive patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate. METHODS: In this phase II study, patients with active RA (n = 311) were randomized 1:1:1:1 to receive placebo, atacicept 150 mg weekly with or without a 4-week loading period (twice-weekly dosing), or open-label adalimumab 40 mg every other week, for 25 weeks. The primary end point was 20% improvement in disease severity according to the American College of Rheumatology criteria, assessed using the C-reactive protein level (ACR20-CRP), at week 26. Secondary end points included additional assessments of efficacy, biologic activity, and safety. RESULTS: The proportion of patients meeting the primary end point (ACR20-CRP response) did not differ significantly in the atacicept groups and the placebo group (46% in the placebo group, 45% in the atacicept loading group, and 58% in the atacicept nonloading group). In contrast, an ACR20-CRP response was observed in 71% of patients in the adalimumab group (P < 0.001 versus placebo). ACR50-CRP response rates were significantly higher in all active-treatment groups compared with placebo, but ACR70-CRP response rates were superior only in the adalimumab group. Atacicept treatment reduced the levels of serum IgG, IgA, and IgM rheumatoid factor and the levels of circulating mature B cells and plasma cells. The effects of treatment were similar with and without loading. Immunoglobulin levels returned toward baseline values during the treatment-free followup period (week 38). The most frequent adverse events associated with atacicept represented common illnesses. No serious infections occurred among patients treated with atacicept. CONCLUSION: The primary end point (ACR20-CRP response) was not met despite significant biologic effects of atacicept that were consistent with its proposed mechanism of action. Modest effects of atacicept were seen for some secondary efficacy end points. Treatment with atacicept raised no new safety concerns.
22122521 Interleukin-6 gene promoter methylation in rheumatoid arthritis and chronic periodontitis. 2012 Jul BACKGROUND: Methylation status of the cytokine genes may play a role in the pathogenesis of inflammatory diseases, such as rheumatoid arthritis (RA) and chronic periodontitis (CP). This study was undertaken to evaluate whether the DNA methylation profile of the interleukin-6 (IL-6) gene promoter was unique to individuals with RA and CP. METHODS: The study participants consisted of 30 patients with RA, 30 patients with CP, and 30 age-, sex-, and smoking status-balanced healthy controls. Genomic DNA isolated from peripheral blood was modified by sodium bisulfite and analyzed for DNA methylation levels of IL-6 gene with direct sequencing. Levels of IL-6 were determined by an enzyme-linked immunosorbent assay. RESULTS: The region of IL-6 gene promoter from -1200 to +27 bp was shown to contain 19 CpG motifs. The methylation levels of the CpG motif at -74 bp were significantly lower in patients with RA and CP than those in controls (P = 0.0001). Both levels of serum IL-6 and IL-6 production by mononuclear cells were significantly different between individuals with and without the methylation at -74 bp (P = 0.03). The +19 bp motif exhibited differential levels of the methylation among the groups, which was not associated with serum levels of IL-6. The other 17 CpG motifs exhibited comparable levels of the methylation between the groups. CONCLUSION: These results suggest that hypomethylated status of a single CpG in the IL-6 promoter region may lead to increased levels of serum IL-6, implicating a role in the pathogenesis of RA and CP.