Specific Increase in Joint Neutrophil Extracellular Traps and Its Relation to Interleukin 6 in Autoimmune Arthritis.

Neutrophils and their extracellular traps have been shown to play an important role in the pathogenesis of rheumatoid arthritis (RA), but the detailed mechanisms in joints are still unclear, and their regulation remains to be solved. Here, we explored neutrophil extracellular trap (NET)osis in experimental models of arthritis and further investigated the effects of interleukin-6 (IL-6) inhibition in neutrophils and NETosis. In skins of peptide GPI-induced arthritis (pGIA), citrullinated protein was detected as well as citrullinated histone expression in immunized skin but this was not specific to pGIA. Citrullinated histone expression in pGIA joints was specific to pGIA and was merged with neutrophil elastase, suggesting NETosis. Neutrophils in joints tend to upregulate IL-6 receptors when compared with bone marrow neutrophils. Administration of mouse anti-IL-6 receptor antibodies in pGIA suppressed arthritis in association with a decrease in neutrophil infiltration and NETosis in joints. In the plasma of RA patients, citrullinated protein was significantly reduced after tocilizumab treatment. Our results suggest that IL-6 enhances neutrophil chemotaxis and NETosis in inflammatory joints and could be the source of citrullinated proteins.

T follicular helper cell subsets: a potential key player in autoimmunity.

Follicular helper T (Tfh) cells are one of CD4+ helper T subsets which promote B cell maturation, activation and antigen-specific antibody production. Autoantibodies are hallmarks of autoimmune diseases, and crucial contributions of Tfh cells in development of these diseases are now evident. Deregulation of Tfh activities can contribute to a pathogenic autoantibody production and can play an important role in the promotion of autoimmune diseases. These days multiple researchers reported three subpopulations which has distinct effector functions in Tfh cells: Tfh1, Tfh2 and Tfh17 cells. In this review, we summarize the observed alterations in whole Tfh cells and subset distribution during autoimmune diseases.

IgG4-related pleural disease with aortitis and submandibular glands involvement successfully treated with corticosteroid: case-based review.

IgG4-related disease (IgG4-RD) is a fibro-inflammatory condition characterized by increased serum IgG4 level, infiltration of lymphocytes and IgG4-positive (IgG4+) plasma cells and fibrosis. It can occur in almost all organs, commonly affecting the pancreas, biliary tract, salivary and lacrimal glands and kidneys. However, reports of IgG4-RD accompanied by pathologically confirmed, IgG4-related pleural disease are scarce. Here, we present a case of a 64-year-old man with suspected malignant pleural mesothelioma based on imaging findings but finally diagnosed with IgG4-RD (including pleuritis, periaortitis and bilateral submandibular gland enlargement) based on a high serum IgG4 level and pleural histopathological findings such as lymphoplasmacytic infiltration including IgG4+ plasma cells and fibrosis. Systemic corticosteroid therapy was effective at reducing serum IgG4, improving bilateral submandibular gland enlargement, and regressing pleural thickening and periaortic soft tissue. We also discuss clinical characteristics and pleural pathological features of previously reported cases with IgG4-related pleural disease based on a comprehensive literature review. Our case of IgG4-RD with pleura, aorta and submandibular gland involvement, pathologically confirmed by pleural specimen might be unique and very rare.

Revisit of autoimmunity to glucose-6-phosphate isomerase in experimental and rheumatoid arthritis.

Rheumatoid arthritis (RA) is an inflammatory disorder characterized by synovial inflammation in multiple joints. Autoantibodies (Abs) are the hallmark of RA, and as disease-specific and diagnostic markers, rheumatoid factor and anti-citrullinated protein antibody (ACPA) are produced pre-clinically, but their pathogenic roles in RA remain elusive. In this review, we focus on one of the candidate autoantigens in RA; glucose-6-phosphate isomerase (GPI). The arthritogenic role of GPI has been confirmed in two different mouse models: the K/BxN- and GPI-induced arthritis models. Both anti-GPI Abs and citrullinated-GPI peptide Abs have been detected in human RA. Studies conducted in these rodent models have confirmed that the pathogenesis of arthritis involves the localization of autoantigens not only in the joints but also in the circulation. In this review, we revisit and summarize the arthritogenic relevance of GPI in animal RA models and in human RA, and extend the discussion to joint-specific inflammation.

Potential involvement of OX40 in the regulation of autoantibody sialylation in arthritis.

OBJECTIVE: An increased proportion of circulating follicular helper T (Tfh) cells was reported in rheumatoid arthritis (RA), but it remains uncertain how Tfh cells affect antibody hyposialylation. We investigated the regulation of autoantibody hyposialylation by Tfh cells in RA using murine model. METHODS: Behaviours of Tfh cells and their function on B cell promotion were analysed. Change of arthritogenicity and sialylation of autoantibodies during the course of arthritis was examined by mass spectrometry. Tfh-mediated regulation of hyposialylation was investigated, and the responsible cell surface molecule was specified both in vitro and in vivo. The relation between circulating Tfh cells and hyposialylation was analysed in patients with RA. RESULTS: An increase in Tfh, particularly interleukin-17 producing Tfh (Tfh17) cells, at the onset of arthritis and their enhancement of autoantibody production were found. Autoantibodies at the onset phase demonstrated stronger inflammatory properties than those at the resolution phase, and mass spectrometric analysis revealed their difference in sialylation. In vitro coculture showed enhanced hyposialylation by the Tfh cells via OX40, which was highly expressed in the Tfh and Tfh17 cells. Blockade of OX40 prevented the development of arthritis with reduction in Tfh17 cells and recovery of autoantibody sialylation. Analysis of patients with RA showed abundance of OX40-overexpressing Tfh17 cells, and their proportion correlated negatively with the expression of α2,6-sialyltransferase 1, an enzyme responsible for sialylation. CONCLUSIONS: OX40 expressed on Tfh cells can regulate autoantibody sialylation and play a crucial role in the development of autoimmune arthritis.

Effect of Biological Disease-modifying Anti-rheumatic Drugs on Airway and Interstitial Lung Disease in Patients with Rheumatoid Arthritis.

Objective Biological disease-modifying anti-rheumatic drugs (bDMARDs) represent an important advance in alleviating rheumatoid arthritis (RA), but their effect on rheumatic airway disease (AD) and interstitial lung disease (ILD) is still unclear. This study was performed to evaluate the association of the use of different bDMARDs with new-onset or worsening of RA-AD/ILD. Methods We performed a retrospective cohort study of RA patients who received bDMARDs and assessed their AD/ILD before and after drug initiation in our hospital over the past 10 years. We evaluated the serial changes in computed tomography (CT), classified patients according to AD/ILD progression, and analyzed associations between clinical characteristics and outcomes. Results We enrolled 49 patients. Thirty patients received tumor necrosis factor inhibitors (TNFis), 12 received abatacept (ABT), and the remaining 7 received tocilizumab (TCZ). Seventeen patients had ILD, 10 had AD, and 6 had both AD and ILD before the initiation of bDMARDs. New emergence or exacerbation of AD/ILD was observed in 18 patients after drug initiation, while the remaining 31 remained stable or improved. Multiple logistic regression analyses revealed that pre-existing AD was an independent risk factor against the emergence or exacerbation of RA-AD/ILD, and ABT use was a protective factor against it. Conclusion Our study showed that pre-existing RA-AD is associated with future worsening of RA-AD/ILD, and ABT over other bDMARDs was associated with a better prognosis. Future studies to confirm our results are needed.

Peptidyl arginine deiminase inhibition suppresses arthritis via decreased protein citrullination in joints and serum with the downregulation of interleukin-6.

Objective: To explore the relevance of citrullinated proteins and anti-citrullinated protein antibodies (ACPA) via protein arginine deiminase (PAD) inhibition in peptide glucose-6-phosphate isomerase-induced arthritis (pGIA).Methods: Cl-amidine, a PAD inhibitor, was injected into pGIA. Clinical scores and histopathological findings of ankle joints were assessed. Serum ACPA titers were analyzed using ELISA. Citrullinated protein expression in joints and sera were examined with immunohistochemistry and Western blot analysis, respectively. Serum levels of IL-6, TNFα, and IL-1ß were measured with cytometric bead array (CBA). Gene expression levels of IL-6 and TNFα in joints, lymph nodes, and spleens were analyzed with quantitative PCR. GPI-specific productions of IFNγ and IL-17 from T cells in lymph nodes were evaluated.Results: Cl-amidine treatment significantly reduced arthritis severity while ACPA titers tended to be lower, but not significantly different compared to the control. Citrullinated proteins in joints and sera from treated mice were clearly decreased. With Cl-amidine treatment, serum IL-6 levels were significantly decreased, and IL-6 and TNFα gene expression were significantly reduced in joints. IL-17 production from GPI-specific T cells tended to be lower in Cl-amidine-treated mice, but not significantly different.Conclusion: Our results suggested that PAD-mediated citrullinated protein was involved in the pathogenesis of arthritis via IL-6.

Effectiveness of abatacept for patients with Sjögren's syndrome associated with rheumatoid arthritis. An open label, multicenter, one-year, prospective study: ROSE (Rheumatoid Arthritis with Orencia Trial toward Sjögren's syndrome Endocrinopathy) trial.

OBJECTIVE: To clarify the efficacy and safety of abatacept for secondary Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA). METHODS: The primary endpoint of this open-labeled, prospective, observational multicenter study for secondary SS with RA was the remission rate of Simplified Disease Activity Index (SDAI) at 52 weeks after initiation of abatacept. The secondary endpoints included Saxon's test and Schirmer's test. Adverse events and adherence rate during the study period were also analyzed. RESULTS: Thirty-six patients (all females) were enrolled in this study. The mean SDAI decreased significantly from 20.6 ± 11.2 (±SD) at baseline to 10.0 ± 10.5 at 52 weeks (p < 0.05). Patients with SDAI remission increased from 0 (0 week) to 12 patients (33.3%) at 52 weeks. Saliva volume assessed by Saxon's test increased significantly from 2136 ± 1809 (0 week) to 2397 ± 1878 (24 weeks) mg/2 min (n = 34, p < 0.05). Saliva volume increased significantly from 2945 ± 2090 (0 week) to 3419 ± 2121 (24 weeks) mg/2 min in 11 patients with Greenspan grade 1 or 2 of labial salivary gland biopsy (p < 0.05), but no change was noted in 18 patients with Greenspan grade 3 or 4. Tear volume by Schirmer's test increased significantly from 4.2 ± 4.8 (0 week) to 6.4 ± 7.8 (24 weeks) mm/5 min (n = 30, p < 0.05). The adherence rate to abatacept was 80.6% (29/36) over the 52-week period. Twelve adverse events occurred in 10 of the 36 patients, and 7 of these events were infections. CONCLUSION: Abatacept seems to be effective for both RA and SS related manifestations.

Association of anti-Ro/SSA antibody with response to biologics in patients with rheumatoid arthritis.

OBJECTIVE: To compare the effectiveness of three different biologics in anti-Ro/SSA antibody-positive and antibody-negative patients with rheumatoid arthritis (RA). METHODS: The study subjects were 110 biologics naïve patients with RA who started treatment with biologics and examined for anti-Ro/SSA antibody between December 2003 and March 2014. For patients treated with intravenous infliximab (IFX), tocilizumab (TCZ), or abatacept (ABT), we compared the clinical characteristics and changes in composite disease activity index, such as DAS28, SDAI, and CDAI, for 12 months in anti-Ro/SSA antibody-positive and antibody-negative patients. RESULTS: We examined 59 patients (nine were positive and 50 were negative for anti-Ro/SSA antibody) treated with IFX, 27 patients (5 positive and 22 negative) treated with TCZ, and 24 patients (13 positive and 11 negative) treated with ABT. For patients treated with IFX, parameters of disease activity did not change significantly from baseline in anti-Ro/SSA antibody-positive patients, whereas they improved in antibody-negative patients. On the other hand, treatment with TCZ and ABT significantly decreased disease activity, relative to baseline, in both anti-Ro/SSA antibody-positive and antibody-negative patients. Anti-Ro/SSA antibody-positive patients treated with IFX showed higher frequency of HACA and seroconversion of ANA, and lower serum TGF-ß levels. CONCLUSIONS: Positivity to anti-Ro/SSA in RA seems to confer resistance to IFX via production of HACA and ANA, and low serum TGF-ß levels, but not to TCZ and ABT.