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To investigate the effects of methotrexate (MTX) and the tumour necrosis factor inhibitor infliximab (IFX) on immune cells derived from peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) of inflammatory arthritis patients. Phytohaemagglutinin (PHA)-induced proliferation of healthy donors' PBMCs and synovial intermediate monocytes (CD14+CD16+ cells) in SFMCs derived from psoriatic arthritis (PsA) and rheumatoid arthritis (RA) patients was determined by flow cytometry following co-culture with IFX and MTX. PHA-induced interferon-γ (IFN-γ) production in PBMCs was measured by enzyme-linked immunosorbent assay. The drugs' effect on mRNA expression in SFMCs was determined by quantitative polymerase chain reaction. The combination of IFX 10 μg/mL + MTX 0.1 μg/mL had the strongest inhibitory effect on PBMC proliferation (91%), followed by MTX 0.1 μg/mL (86%) and IFX 10 μg/mL (49%). In PHA-stimulated PBMCs, IFN-γ production was reduced by IFX 10 μg/mL, MTX 0.1 μg/mL, and IFX 10 μg/mL + MTX 0.1 μg/mL by 68%, 90%, and 85%, respectively. In SFMCs, IFX 10 µg/mL significantly reduced CD14+CD16+ cells compared to medium (PsA 54%, p < 0.01; RA 46%, p < 0.05), while MTX had no effect on this population. IFX + MTX led to a similar suppression of CD14+CD16+ cells as achieved by IFX alone. The drugs had different impacts on SFMC gene expression. Both IFX and MTX effectively inhibited PBMC proliferation and IFN-γ production, but only IFX reduced synovial monocytes and pro-inflammatory gene expression in SFMCs, suggesting a differential impact of IFX and MTX on critical inflammatory cell populations ex vivo. [ABSTRACT FROM AUTHOR]

Objective: To investigate the impact of glucocorticoids (GCs) and anti-rheumatic drugs on the lymphocyte activation gene-3 (LAG-3) and on programmed cell death-1 (PD-1) expression on synovial and peripheral cells ex-vivo., Methods: Synovial fluid mononuclear cells (SFMCs) from psoriatic arthritis (PsA, n = 26) and rheumatoid arthritis (RA, n = 13) patients, SFCs from osteoarthritis (OA, n = 5) patients and peripheral blood mononuclear cells (PBMCs) of healthy donors (n = 14) were co-cultured with GCs, glucocorticoid receptor antagonist RU486, methotrexate (MTX) and biologics. LAG-3 and PD-1 expressions on immune subsets were analyzed by flow cytometry., Results: GCs in PsA inhibited SFMCs growth vs medium (2.3 ± 0.4X105  vs 5.3 ± 0.7X105, respectively, p < 0.01) and markedly upregulated CD14+LAG-3+ cells (11.7 ± 2.4% vs 0.8 ± 0.3%, p < 0.0001, respectively), but not CD3+LAG-3+ and CD14+PD-1+ cells. MTX had no effect on CD14+LAG-3+ cells (0.7 ± 0.3%). The TNFi inhibitors, infliximab (IFX) and etanercept, but not IL-12/23i, upregulated CD14+LAG-3+ cells vs medium (2.0 ± 0.6% and 1.6 ± 0.4% vs 0.5 ± 0.1%, p < 0.03, respectively). SFMCs growth inhibition in both PsA and RA correlated with CD14+LAG-3+ cell upregulation (r = 0.53, p = 0.03). RU486 inhibited GC-induced CD14+LAG-3+ cell up-regulation in a dose-dependent manner compared with GC alone (5µM 5.3 ± 1.2% and 50µM 1.3 ± 0.5% vs 7.0 ± 1.4%, p < 0.003), but had no significant effect on CD14+LAG-3+ cells co-cultured with IFX. GCs in healthy donors' PBMCs upregulated the immune subsets CD3+LAG-3+, CD14+LAG-3+ and CD14+PD-1+ cells., Conclusion: This study proposes a novel regulatory mechanism of GCs and of TNFi mediated by LAG-3 upregulation in synovial monocytes and PBMCs. LAG-3 modulation may be a promising target for development of novel therapies for inflammatory arthritis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: TNF inhibitors (TNFi) comprise 5 products whose structure and signalling differ. An individual patient with a rheumatic disease may respond to one TNFi but not to another. In addition, 30-40% of the patients respond inadequately to TNFi. The different TNFi downstream signalling may lead to their clinical efficacy. Several reports showed that TNFi exhibited differential effects on Th17 cells. We analyzed the different TNFi effects on IL-17A expression in the peripheral blood mononuclear cells (PBMCs) of patients with rheumatic diseases in order to evaluate the predictive capability of responses in an ex-vivo setting., Methods: PBMCs were co-cultured with the different TNFi or medium (control), and IL-17A mRNA levels were analyzed by qPCR. IL-17A expression levels in response to 4 TNFi (except certolizumab pegol) were compared with control. IL-17A expression in the assay was correlated to the clinical responses. Assay sensitivity and specificity for distinguishing responders from non-responders was calculated by receiver-operating characteristic (ROC) analysis., Results: The results of a retrospective cohort of patients with rheumatic diseases (n = 82) correlated with their therapeutic responses to the different TNFi with 89.5% accuracy. The assay predicted the responses of a prospective cohort (n = 54) to specific TNFi with 79% accuracy., Conclusion: This functional assay could assist in predicting the odds for response to TNFi therapy, indicating whether a given patient is likely to respond to a specific TNFi., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

PsoP27 is an antigen expressed in psoriatic lesions. It plays an inflammatory role in psoriasis. This study objective was to characterize antibodies (Abs) against PsoP27 in patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA). Levels of Abs against native and citrullinated PsoP27 in PsA and RA patients' synovial fluid (SF) and sera were determined by ELISA. SF of osteoarthritis (OA) patients and sera of healthy donors were used as controls. Levels of Abs against PsoP27 were correlated with disease activity scores. Abs against native and citrullinated PsoP27 levels in SF of PsA ( n  = 48; 0.38 ± 0.03 and 0.44 ± 0.04, respectively) and RA ( n  = 22; 0.57 ± 0.1 and 0.62 ± 0.09, respectively) were significantly higher than in OA patients ( n  = 23; 0.14 ± 0.01 and 0.15 ± 0.01, respectively) ( p  < .0001). For both Abs, there were no significant differences between their level in PsA and RA patients. There was no difference in the level of Abs against citrullinated PsoP27 in SF of seronegative versus seropositive RA patients. Levels of Abs against both native and citrullinated PsoP27 in the SF and level of systemic C-reactive protein in PsA correlated positively, while in RA there were no significant correlations with disease activity scores. No differences in level of Abs against PsoP27 were found in the sera of all three study groups. Abs against native and citrullinated PsoP27 are present in PsA and RA SF but not in those of OA patients, suggesting a potential role of those Abs in inflammatory joint diseases.

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4, anti-programmed cell death 1, and anti-programmed cell death ligand 1 (PD-L1) antibodies, are currently widely used in oncology clinical practice, achieving considerable success in improving disease outcomes. New checkpoint targets are being discovered and investigated through basic science research and clinical trials. ICI remove negative regulatory immune signals on T cells, leading to immune activation and induction of antitumor immunity. Patients who receive ICI, however, are at risk for developing immune-related adverse events (irAEs), which are attributed to increased T cell activity against antigens in both tumors and in healthy tissues, to increased inflammatory cytokine levels, to increased levels of preexisting autoantibodies, and to enhanced complement-mediated inflammation. Arthritis is one of the most common irAEs. ICI-induced rheumatic irAEs are categorized by levels of severity which guide the choice of treatment options. Management of ICI-induced rheumatic irAEs includes the use of glucocorticoids, disease-modifying antirheumatic drugs (mainly methotrexate), and biological agents (e.g., tumor necrosis factor, interleukin-6 receptor, and CD20 inhibitors). This review aims to summarize the current ICI subtypes, their role in rheumatic irAEs development, and therapies currently used in clinical practice to manage irAEs. In addition, we propose to use an ex vivo personalized diagnostic assay for the selection of the most effective ICI with antirheumatic drugs combinations that will inhibit the advancement of ICI-induced adverse events.

Monocytes are innate immune cells that play a dual role in protection of host against pathogens and initiation and perpetuation of inflammatory disorders including joint diseases. During inflammation, monocytes migrate from peripheral blood to tissues via chemokine receptors where they produce inflammatory factors. Monocytes are classified into three subsets, namely: classical, intermediate and non-classical, each subset has particular function. Synovium of patients with inflammatory joint diseases, such as rheumatoid arthritis and psoriatic arthritis as well as osteoarthritis, is enriched by monocytes that differ from circulatory ones by distinct subsets distribution. Several therapeutic agents used systemically or locally through intra-articular injections in arthritis management modulate monocyte subsets. This scoping review summarized the existing literature delineating the effect of common therapeutic agents used in arthritis management on circulating and synovial monocytes/macrophages. As certain agents have an inhibitory effect on monocytes, we propose to test their potential to inhibit synovial monocytes via an ex-vivo platform based on cultured synovial fluid mononuclear cells derived from patients with rheumatic diseases. Information obtained from the ex-vivo platform can be applied to explore the therapeutic potential of medications in clinical practice.

Objectives: Synovial monocytes (expressing CD14+CD16+) affect pro-inflammatory responses in the synovium microenvironment of psoriatic arthritis (PsA) and rheumatoid arthritis (RA). The effect of various drugs on those cells was evaluated., Methods: Synovial fluid mononuclear cells (SFMCs) from PsA (n=29) and RA (n=11) patients were cultured with biologics or glucocorticoids (GCs). CD14+CD16+ cells were analysed by flow cytometry. TNF secretion was assessed by ELISA and changes in cytokine and matrix metalloproteinase-9 (MMP-9) mRNA by qPCR., Results: TNF inhibitors (i) [adalimumab (ADA) and infliximab (IFX)] significantly reduced the %CD14+CD16+ cells (p<0.04 and p<0.02, respectively) compared to IL-17Ai, IL-12/23i, and GCs in PsA patients' SFMCs. Similarly, those TNFi reduced the %CD14+CD16+ cells (p<0.05 and p<0.02, respectively) compared to IL-6Ri, CD20i and GCs in RA patients' SFMCs. TNFi (ADA p<0.01, IFX p=0.0003), and GCs (p<0.05) reduced TNF levels in PsA patients SFMCs supernatants. IFX down-regulated IL-1β mRNA (p<0.005) while GCs betamethasone (BET) (p<0.01) and methylprednisolone acetate (MPA) (p<0.005) led to IL-1β up-regulation. IFX down-regulated IL-8 and MMP-9 (p<0.01) and up-regulated IL-10 (p<0.005), and GCs did so to a greater extent (for IL-8, BET p<0.0001 and MPA p<0.005, for MMP-9, BET and MPA p<0.0001 and for IL-10, BET and MPA p<0.0001)., Conclusions: TNFi but not GCs reduced the inflammatory monocytes. Both TNFi and GCs inhibited TNF secretion but differently modulated IL-1β, IL-8, MMP-9 and IL-10 gene expression. Our data point to TNFi as a modulator of synovial monocytes.

Background: The parasympathetic system and its main neurotransmitter, acetylcholine, contributes to homeostasis of inflammation. Cholinergic dysregulation is thought to contribute to the pathogenesis of inflammatory rheumatic diseases. Cholinesterase activity in patients with psoriatic arthritis (PsA) has not been investigated., Objectives: To compare the cholinesterase activity in patients with PsA and immunocompetent controls and to explore the correlation between cholinergic status (CS) and PsA disease activity., Methods: Serum acetylcholinesterase (AChE) and total cholinesterase activity were measured in patients with PsA (n=88) and matched controls (n=84). Cholinergic activity before and 3-6 months after the initiation of a biologic treatment was evaluated in seven patients with PsA., Results: The levels of AChE and CS were similar in both PsA patients and controls. PsA patients treated with biologics had significantly lower levels of AChE and CS compared to patients treated with non-biologics: 447.4 vs. 526 substrate hydrolyzed/min/ml, P = 0.005, and 1360.9 vs. 1536, P = 0.029, respectively. We found an association between C-reactive protein levels, AChE activity (r = 0.291, P = 0.008), and cholinergic status (r = 0.247, P = 0.026) in patients with PsA but not in controls. No correlation between AChE activity, cholinergic status, and the indices of PsA disease activity was found. After initiating or switching biologic treatment in 7 patients, AChE levels remained stable., Conclusions: We demonstrated similar cholinesterase activity in patients with psoriatic arthritis and controls, highlighting a potential effect of biologic treatment on cholinergic activity in patients with PsA.

Objectives: To evaluate long-term kinetics of the BNT162b2 mRNA vaccine-induced immune response in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) and immunocompetent controls., Methods: A prospective multicentre study investigated serum anti-SARS-CoV-2 S1/S2 IgG titre at 2-6 weeks (AIIRD n=720, controls n=122) and 6 months (AIIRD n=628, controls n=116) after the second vaccine, and 2-6 weeks after the third vaccine dose (AIIRD n=169, controls n=45). T-cell immune response to the third vaccine was evaluated in a small sample., Results: The two-dose vaccine regimen induced a higher humoral response in controls compared with patients, postvaccination seropositivity rates of 100% versus 84.72%, p<0.0001, and 96.55% versus 74.26%, p<0.0001 at 2-6 weeks and at 6 months, respectively. The third vaccine dose restored the seropositive response in all controls and 80.47% of patients with AIIRD, p=0.0028. All patients treated with methotrexate monotherapy, anticytokine biologics, abatacept and janus kinase (JAK) inhibitors regained the humoral response after the third vaccine, compared with only a third of patients treated with rituximab, entailing a 16.1-fold risk for a negative humoral response, p≤0.0001. Cellular immune response in rituximab-treated patients was preserved before and after the third vaccine and was similar to controls. Breakthrough COVID-19 rate during the Delta surge was similar in patients and controls, 1.83% versus 1.43%, p=1., Conclusions: The two-dose BNTb262 regimen was associated with similar clinical efficacy and similar waning of the humoral response over 6 months among patients with AIIRD and controls. The third vaccine dose restored the humoral response in all of the controls and the majority of patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Regulatory T cells (Tregs) comprise a CD4 + CD25 + Foxp3 + T cell subset for maintaining immune tolerance, and their deficits and/or dysfunction are observed in autoimmune diseases. The lymphocyte activation gene 3 (LAG-3, also known as CD223), which is an immunoglobulin superfamily member expressed on peripheral immune cells, is recognized as an inhibitory regulator of Tregs. LAG-3 + T cells represent a novel protective Tregs subset that produces interleukin-10. Alterations in LAG-3 + Tregs have been reported in several autoimmune diseases, suggesting their potential pathogenic role. Recent studies have indicated that LAG-3 + Tregs may be associated not only with immunopathology but also with response to therapy in several autoimmune and autoinflammatory diseases, such as rheumatoid arthritis, psoriasis, psoriatic arthritis and others. We present a review of Tregs phenotypes and functions, with a focus on LAG-3 + Tregs, and discuss their potential role as biomarkers for treatment response in autoimmune diseases., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: The impact of biologics used in PsA management on T cells is unknown. This study evaluated the effect of tumour necrosis factor-alpha (TNFα), interleukin-17A (IL-17A), and IL-6 receptor (IL-6R) blockers on T cell function in PsA patients and healthy controls peripheral blood mononuclear cells (PBMCs)., Methods: A total of 111 PsA patients and 32 healthy controls were recruited. PBMCs were co-cultured in presence of the biologics. T cell activation and proliferation were analysed by flow cytometry and cytokines in supernatants were measured by ELISA. The effect of biologics on lymphocyte proliferation was determined in response to phytohemagglutinin (PHA)., Results: Activated CD4+CD25+ T cells were significantly reduced by adalimumab (ADA) in PsA patients as compared to medium, ixekizumab (IXE), and tocilizumab (TCZ), while in healthy controls, ADA reduced the activated CD4+CD25+ T cells non-significantly. Elevated TNFα and IL-1β levels were produced in supernatants of PsA patients as compared to healthy controls. TNFα, IL-17A, IL-1β, and MMP-3 levels were reduced by ADA compared to medium (p<0.0001, p<0.0004, p<0.04, p<0.04, respectively). IXE reduced IL-17A (p<0.0001) but not the other cytokines. ADA had higher susceptibility to inhibit PHA-induced proliferation in both PsA patients and healthy controls (p<0.03) as compared to IXE and TCZ., Conclusions: Both TNF and IL-17A blockers are suitable for PsA treatment, but exhibit different activity on T cells. Moreover, the study reveals part of the mechanism exerted by ADA and provides a possible explanation for TCZ inefficacy in PsA.

Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with T cell dysregulation. The lymphocyte-activation gene (LAG)-3 is one of the regulatory receptors expressed on T cells in a soluble form. LAG-3 expression on T cells was analyzed in vitro in PsA patients with minimal disease activity (MDA), active disease (non-MDA) and healthy controls. In cultured in-vitro peripheral blood mononuclear cells (PBMCs), LAG-3 expression on CD4 + T cells was similar in both MDA PsA patients (7.5 ± 0.9) (n = 14) and healthy controls (7.8 ± 0.6) (n = 15), but significantly lower in non-MDA PsA patients (3.1 ± 0.3) (n = 13) (p < 0.0001). An inverse correlation between PsA clinical disease activity and %CD4 + LAG-3 + T cells in vitro was observed (composite psoriatic disease activity index r = -0.47, p < 0.02 and psoriatic arthritis disease activity score, r = -0.51, p < 0.008). In-vitro co-culture of CD4 + T cells with anti-tumor necrosis factor (TNF) or anti-interleukin (IL)-17A had no effect on LAG-3 + expression in MDA PsA patients and healthy controls. In non-MDA patients, anti-TNF, but not anti-IL-17A, restored the %CD4 + LAG-3 + T cells (7.9 ± 0.9 and 3.2 ± 0.4, respectively) (p < 0.0004). Lower soluble LAG-3 levels were found in sera of naive to biological PsA patients (n = 39) compared to healthy controls (n = 35) (p < 0.03). Impaired LAG-3 on CD4 + T cells may reflect active PsA disease state. Anti-TNFs have potency to up-regulate the CD4 + LAG-3 + T cells in vitro., (© 2021 British Society for Immunology.)

Objective: Subclinical myocardial dysfunction has been reported to occur early in systemic lupus erythematous (SLE). The study aim was to search for biomarkers of subclinical myocardial dysfunction which may correlate with disease activity in SLE patients., Methods: This is a prospective, controlled, cross-sectional study of 57 consecutive patients with SLE and 18 controls. Serum samples were obtained to determine serum soluble ST2 (sST2), CXCL-10 and high-sensitivity troponin (hs-troponin) levels. All participants underwent an echocardiographic tissue Doppler study., Results: sST2, CXCL-10 and hs-troponin levels were higher in patients with higher SLE disease activity (SLEDAI). sST2 and CXCL-10 levels were higher in patients with more disease damage as measured by the SLE damage index. Measures of diastolic dysfunction, as assessed by echocardiographic tissue Doppler negatively correlated with log CXCL-10: including E/A; E/e' lateral and E/e' septal , while E/e' positively correlated with CXCL-10. Diastolic dysfunction parameters also correlated with log sST2 levels, a negative correlation was seen with E/e' lateral and a positive correlation was seen with E/e'. Systolic dysfunction parameters positively correlated with hs-troponin: LVED, LVES, IVS, LVMASS and LVMASS index. In a multivariate analysis, sST2 and CXCL-10 were found to be significantly different in SLE vs. healthy controls, independent of each other and independent of cardiovascular risk factors., Conclusions: Soluble ST2 and CXCL-10 are markers of disease activity and accrued damage in SLE and may serve as sensitive biomarkers for detection of subclinical diastolic dysfunction, independent of traditional cardiovascular risk factors.

Demyelination, axonal loss and failure of tissue repair characterize MS lesions. Bone morphogenetic proteins (BMPs) signaling is associated with remyelination failure. Coco is one of the BMP antagonists. We found reduced Coco serum levels in relapsing-remitting MS (RR-MS) and primary progressive MS (PP-MS) patients compared to matched healthy controls (HC) and patients with rheumatoid arthritis. Exposure of P19 cells, in the presence of retinoic acid, BMP-2, or BMP-4 to Coco, at average sera level of MS patients failed to induce neuronal phenotype, in contrast to the average sera level of HC. Coco may be a player in the BMP dysregulation and the tissue repair failure in MS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Anti-citrullinated peptide antibodies (ACPA) play an important role in rheumatoid arthritis (RA) diagnosis. In our study, we sought to assess the potential diagnostic value of synthetically manufactured peptides that contain epitopes believed to have a pathogenic role in RA., Methods: Serum samples from RA patients and healthy controls were obtained. Two synthetic peptides were manufactured containing the common epitopes considered to play a pivotal role in the RA pathogenesis including the antigenic epitopes of filaggrin, beta-fibrinogen, collagen, vimentin and enolase. Three different ELISA kits for citrullinated peptides (namely: CCP3, Cit-ME-Vim and Cit-ME-Eno) were tested and compared. To assess the diagnostic value of the three ELISA tests, for each test the optical densities (OD) were recorded. The statistical power of each test was calculated measuring the area under the curve (AUC) corresponding with each peptide., Results: Serum levels of ACPA recognized by the commercial CCP3 in RA and healthy controls were 1.31 ± 0.88 optic density units (ODU) and 0.21 ± 0.11 ODU, respectively. Cit-ME-Vim levels were 0.55 ± 0.46 ODU in RA subjects and 0.17 ± 0.182 ODU in healthy controls whereas Cit-ME-Eno was 0.61 ± 0.65 ODU in RA subjects and 0.22 ± 0.20 ODU in healthy controls. AUC results were as follows: CCP3, 0.89 [95%CI 0.75-0.87]; Cit-ME-Vim, 0.76 [95%CI 0.69-0.82]; Cit-ME-Eno, 0.73 [95%CI 0.65-0.79]. Statistical significance for all results was achieved (p < .0001). Sensitivity values for each kit are as follow: CCP3 70.42%; Cit-ME-Vim 63.38%; Cit-ME-Eno 40.85%, and specificity 91% for all tests., Conclusion: Our study supports the presence of an added value for the Cit-ME-Vim peptides in the diagnosis of RA. Further studies are needed to replicate such findings., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Anticitrullinated protein antibodies (ACPA) have major diagnostic significance in rheumatoid arthritis (RA). ACPA are directed against different citrullinated antigens, including filaggrin, fibrinogen, vimentin, and collagen. The presence of ACPA is associated with joint damage and extraarticular manifestations, suggesting that ACPA may have a significant role in the pathogenesis of RA., Methods: To verify the effect of ACPA on RA-immune cells, peripheral blood mononuclear cells (PBMC) from cyclic citrullinated peptide (CCP)-positive patients with RA and healthy controls were cocultured in vitro with ACPA. ACPA-positive stained cells were analyzed by flow cytometry and the effect of ACPA on mRNA expression levels was evaluated by real-time PCR. We tested whether the stimulatory effects induced by ACPA could be inhibited by the addition of a new multiepitope citrullinated peptide (Cit-ME)., Results: We found that ACPA bind specifically to PBMC from CCP-positive patients with RA through the Fab portion. ACPA induce upregulation of pathogenic cytokine expression (4- to 13-fold increase) in PBMC derived from CCP-positive patients with RA. Moreover, ACPA upregulated IL-1β and IL-6 mRNA expression levels by 10- and 6-fold, respectively, compared to control IgG. Cit-ME, a genuine ligand of ACPA, inhibited the ACPA-induced upregulation of IL-1β and IL-6 by 30%., Conclusion: ACPA bind to a limited percentage of PBMC and upregulate inflammatory cytokine expression, suggesting that ACPA is involved in RA pathogenesis. Targeting ACPA to decrease their pathogenic effects might provide a novel direction in developing therapeutic strategies for RA.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by pronounced inflammation and leukocyte infiltration in affected joints. Tofacitinib is new agent, a selective inhibitor of Janus kinase (JAK) signaling pathways mediated by JAK1 and JAK3 and inhibits the key transcription factors STAT1 and STAT3. We investigated the action mechanisms of tofacitinib in rats with adjuvant-induced-arthritis (AIA). AIA-rats were treated orally with tofacitinib or with methotrexate. Arthritis severity and serum C-reactive protein (CRP) levels were evaluated, splenic cells were examined by flow cytometry and cytokines were analyzed by real-time PCR. Tofacitinib markedly reduced the clinical status of treated rats in comparison to control group. Reduced joints inflammation and down-regulated serum CRP levels reflected the clinical manifestations of the treated rats. Tofacitinib down-regulated significantly the frequency of CD4 + IFN-γ + T cells and reduced IL-1β mRNA expression levels in the spleen of the treated rats. These results show that tofacitinib attenuated arthritis severity, modified splenic populations and cytokine imbalance., (Copyright © 2017. Published by Elsevier Inc.)

Citrullinated peptides are used for measuring anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA). Accumulation of citrullinated proteins in the inflamed synovium suggests that they may be good targets for inducing peripheral tolerance. In view of the multiplicity of citrullinated autoantigens described as ACPA targets, we generated a multiepitope citrullinated peptide (Cit-ME) from the sequences of major citrullinated autoantigens: filaggrin, β -fibrinogen, vimentin, and collagen type II. We assessed the ability of Cit-ME or the citrullinated β 60-74 fibrinogen peptide ( β 60-74-Fib-Cit) which bears immunodominant citrullinated epitopes (i) to modify cytokine gene expression and (ii) to modulate Treg and Th17 subsets in PBMC derived from newly diagnosed untreated RA patients. RA patient's PBMC incubated with Cit-ME or β 60-74-Fib-Cit, showed upregulation of TGF- β expression (16% and 8%, resp.), and increased CD4 + Foxp3 + Treg (22% and 19%, resp.). Both peptides were shown to downregulate the TNF- α and IL-1 β expression; in addition, Cit-ME reduced CD3 + IL17 + T cells. We showed that citrullinated peptides can modulate the expression of anti- and proinflammatory cytokines in PBMC from RA patients as well as the proportions of Treg and Th17 cells. These results indicate that citrullinated peptides could be active in vivo and therefore might be used as immunoregulatory agents in RA patients.

Background: The prevalence of hypothyroidism in SLE patients varies considerably and early reports were mainly based on small cohorts., Objectives: To investigate the association between SLE and hypothyroidism., Methods: Patients with SLE were compared with age and sex-matched controls regarding the proportion of hypothyroidism in a case-control study. Chi-square and t-tests were used for univariate analysis and a logistic regression model was used for multivariate analysis. The study was performed utilizing the medical database of Clalit Health Services., Results: The study included 5018 patients with SLE and 25,090 age and sex-matched controls. The proportion of hypothyroidism in patients with SLE was increased compared with the prevalence in controls (15.58% and 5.75%, respectively, P<0.001). In a multivariate analysis, SLE was associated with hypothyroidism (odds ratio 2.644, 95% confidence interval 2.405-2.908)., Conclusions: Patients with SLE have a greater proportion of hypothyroidism than matched controls. Therefore, physicians treating patients with SLE should be aware of the possibility of thyroid dysfunction., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The association between smoke habit and autoimmunity has been hypothesized a long time ago. Smoke has been found to play a pathogenic role in certain autoimmune disease as it may trigger the development of autoantibodies and act on pathogenic mechanism possibly related with an imbalance of the immune system. Indeed, both epidemiological studies and animal models have showed the potential deleterious effect caused by smoke. For instance, smoke, by provoking oxidative stress, may contribute to lupus disease by dysregulating DNA demethylation, upregulating immune genes, thereby leading to autoreactivity. Moreover, it can alter the lung microenvironment, facilitating infections, which, in turn, may trigger the development of an autoimmune condition. This, in turn, may result in a dysregulation of immune system leading to autoimmune phenomena. Not only cigarette smoke but also air pollution has been reported as being responsible for the development of autoimmunity. Large epidemiological studies are needed to further explore the accountability of smoking effect in the pathogenesis of autoimmune diseases., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Citrullinated peptides are major targets of disease-specific autoantibodies in rheumatoid arthritis. Currently, citrullinated peptides are used as biomarkers for diagnosing rheumatoid arthritis by measuring anti-citrullinated protein Ab (ACPA) titers in patients' sera. The accumulation of citrullinated proteins at synovial inflammation sites suggests that they are possible targets for tolerance induction. The objective of the present study was to determine whether citrullinated peptides could induce tolerance in an experimental arthritis model in rats. In view of the multiplicity of target citrullinated autoantigens described for ACPA, we generated a multiepitope citrullinated peptide (Cit-ME), derived from major prevalent citrullinated autoantigens (citrullinated filaggrin, fibrinogen, vimentin, and collagen type II), and studied its effects on arthritic rats. Adjuvant-induced arthritis was induced in Lewis rats. Beginning at day 7 after disease induction, the rats received eight s.c. injections of Cit-ME on alternate days. Differences in clinical status and modulation of T cell populations were analyzed. In adjuvant-induced arthritis rats treated with Cit-ME, disease severity was significantly reduced compared with that of untreated rats. Moreover, amelioration of disease manifestations was related to an increased regulatory T cell subset and an elevated apoptosis rate of T cells associated with reduced Th17 cells. Thus, the use of citrullinated peptides-based immunotherapy may be a promising approach for tolerance induction in experimental arthritis and perhaps even in susceptible individuals that are ACPA-seropositive in human arthritis., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Tolerogenic dendritic cells (tDCs) have the potential to control the outcome of autoimmunity by modulating the immune response. The aim of this study was to uncover the tolerance efficacy attributed to beta-2-glycoprotein-I (β2GPI) tDCs or β2GPI domain-I (D-I) and domain-V (D-V)-tDCs in mice with antiphospholipid syndrome (APS). tDCs were pulsed with β2GPI or D-I or D-V derivatives. Our results revealed that β2GPI related tDCs phenotype includes CD80(high), CD86(high) CD40(high) MHC class II(high). The miRNA profiling encompass miRNA 23b(high), miRNA 142-3p(low) and miRNA 221(low). In addition the β2GPI related tDCs showed reduced secretion of IL-1β, IL-12 and IL-23. D-I tDCs treatment was more efficient than β2GPI tDCs in inducing of tolerance in APS mice, manifested by lowered titers of anti- β2GPI antibodies (Abs) and reduced percentage of fetal loss. Tolerance induction was accompanied by poor T cell response to β2GPI, high numbers of CD4 + CD25 + FOXP3 + T-regulatory cells (Treg), reduced levels of IFNγ, IL-17 and increased expression of IL-10 and TGFβ. Tolerance was successfully transferred by Treg cells from the tolerized mice to β2GPI immunized mice. We conclude that predominantly D-I-tDCs and β2GPI tDCs have the potential to attenuate experimental APS by induction of Treg cells, reduction of anti- β2GPI Abs titers and increased expression of anti-inflammatory cytokines. We suggest that β2-GPI-D-I-tDCs may offer a novel approach for developing therapy for APS patients., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The major autoantigens in the inflamed synovium in rheumatoid arthritis (RA) are citrullinated peptides. Citrullinated peptides are employed in diagnostic kits for detection of anti-citrullinated protein antibodies (ACPA), a serological marker with high specificity and sensitivity in the diagnosis of RA, and have been included in the new ACR/EULAR classification criteria for RA. ACPA-positive R patients suffer from an erosive and more aggressive disease compared to ACPA-negative patients. In view of the mounting indications that ACPA plays a seminal role in the pathogenesis of RA, it might be valuable to. pursue a specific treatment aiming ACPA as a target. We found that citrullinated peptides, which contain a unique amino acid, citrulli`ne, alter the protein structure within the connective tissue, leading to tolerance breakdown and triggering the autoimmune response in RA. However, with different doses and routes of administration, citrullinated peptides can promote immune tolerance rather than induction of disease.

Anti-citrullinated peptide antibodies (ACPA) are detected in the sera of rheumatoid arthritis (RA) patients and have a profound role in diagnosis of the disease. In this review we discuss the different cohorts of RA patients in whom the presence, sensitivity and specificity of ACPA were evaluated. The significance of ACPA in the pathogenesis and prognosis RA is also interpreted. Recent advances in the understanding of molecular pathways involved in the pathogenesis of RA have led to the identification of novel biologic agents that are now widely used in patients with RA.

To assess the association between RA and chronic obstructive pulmonary disease (COPD) in a population-based case-control study. A cross-sectional analysis performed utilizing the database of Clalit Health Services, the largest healthcare provider organization in Israel. Patients over the age of 20 years who were diagnosed with RA ('cases') and who were treated with any anti-rheumatic drug were compared with a sample of age- and gender-matched enrollees ('controls') without regard for the prevalence of COPD. Data on health-related lifestyles and other comorbidities were collected. χ(2), t tests, and logistic regression models were used to compare the study groups. The study included 9,039 RA cases and 15,070 controls. The proportion of COPD was significantly higher in patients with RA as compared to the control group (8.6 vs. 4.4%, p < 0.0001, odds ratio (OR) 2.06, 95% confidence interval (CI) 1.85-2.29). A multivariate logistic regression model demonstrated that RA was significantly associated with COPD, after controlling for confounders, including age, sex, socioeconomic status, smoking, and obesity (adjusted OR 1.98, 95% CI 1.77-2.21, p < 0.0001). In this large data-based study, RA was found to be associated with COPD.

Objective: To assess whether hospital work constitutes a risk factor for hepatitis C virus (HCV) infection among employees of a large hospital in Israel., Design: Seroprevalence survey., Setting: A 1,006-bed, tertiary-care university hospital in Jerusalem., Participants: All 5,444 employees (18-65 years old) were eligible; 4,287 (79%) participated in the survey., Methods: Sera were tested for antibodies to HCV (anti-HCV) using a third-generation enzyme immunoassay. A third-generation strip immunoblot assay was used for confirmation. Participants were interviewed regarding their occupational history, and they completed a self-administered questionnaire covering history of non-occupational exposure to blood and country of birth. Other demographic information was obtained from the personnel department. Rates and odds ratios (ORs) were calculated, and multivariate logistic-regression analyses were performed to adjust for potential confounding variables., Results: Anti-HCV was found in 0.9% of employees (37/4,287; 95% confidence interval, 0.6-1.1), ranging from 0.1% among those born in Israel to 5.7% among those born in Central Asia. After age, gender, social status, country of birth, and history of blood transfusion were controlled for in a logistic regression, occupational exposure to blood > or = 10 years was significantly associated with the presence of antibodies (OR, 2.6; P=.01). Presence of anti-HCV also was associated with country of birth (range: Israel OR, 1; West OR, 3.8 [P=.1]; Central Asia OR, 48.6 [P<.0001]) and history of blood transfusion (OR, 2.7; P=.01). No significant associations were found between anti-HCV and age, gender, social status, history of tattoo, acupuncture, current occupation, department, exposure to blood in current occupation, adherence to safety precautions, or history of percutaneous injury. The association with length of exposure was stronger (OR, 3.6; P=.01) when the same logistic regression was run excluding the outlier ethnic group of Central Asia., Conclusions: Hospital work does not seem to constitute a major risk factor for HCV infection in Israel today. A higher prevalence of anti-HCV among employees with longer versus shorter lengths of occupational exposure may be due to a cumulative effect of exposure over the years. Infection control efforts in recent years may have contributed to this association.