Role of inter-alpha-trypsin inhibitor heavy chain 4 and its citrullinated form in experimental arthritis murine models.

Inter-α-trypsin inhibitor heavy chain 4 (ITIH4) is a major protein in serum and reported to be upregulated at the onset of rheumatoid arthritis (RA). Its citrullinated form, cit-ITIH4, is specifically found in the serum and synovial fluid of patients with RA. However, the detailed function of ITIH4 in arthritis remains unknown. The aim of this study was to clarify the role of ITIH4 and cit-ITIH4 using experimental arthritis models. ITIH4 and cit-ITIH4 expression was examined in steady-state mice and two different arthritis models, and their pathological effects were examined in Itih4-deficient mice. In naïve C57BL/6 (WT) mice, ITIH4 was expressed as mRNA in the liver and the lung and was expressed as protein in serum and hepatocytes. In K/BxN serum transferred arthritis (K/BxN-STA) and collagen-induced arthritis (CIA), ITIH4 and cit-ITIH4 in sera were increased before the onset of arthritis, and cit-ITIH4 was further increased at the peak of arthritis. In Itih4-deficient mice, citrullinated proteins in serum and joints, especially 120 kDa protein, were clearly diminished; however, there was no significant difference in arthritis severity between WT and itih-/- mice either in the K/BxN-STA or CIA model. CIA mice also exhibited pulmonary lesions and itih4-/- mice tended to show enhanced inflammatory cell aggregation compared to WT mice. Neutrophils in the lungs of itih4-/- mice were significantly increased compared to WT mice. In summary, ITIH4 itself did not alter the severity of arthritis but may inhibit autoimmune inflammation via suppression of neutrophil recruitment.

An overlapping case of IgG4-related disease and systemic lupus erythematosus treated with belimumab: a case-based review.

IgG4-related disease (IgG4-RD) is a systemic condition in which IgG4+ plasma cell infiltration and fibrosis cause organ swelling and lead to diverse clinical manifestations. Although IgG4-RD typically responds to glucocorticoids (GCs), relapse during tapering occurs and an early GC-sparing approach might therefore be beneficial. Systemic lupus erythematosus (SLE) is a chronic inflammatory disease with multiple symptoms that is also treated with GCs as a first-line therapy. Recently, belimumab, a recombinant human IgG-1λ monoclonal antibody that inhibits B-cell activating factor, was approved, but reports of use for IgG4-RD are scarce. Here, we present a rare case of IgG4-RD complicated with SLE which was successfully treated with belimumab. A 67-year-old man was diagnosed with IgG4-RD based on a high serum IgG4 level and histopathological findings. Furthermore, he had pericardial effusion on echocardiography, and laboratory tests revealed thrombocytopenia, autoimmune hemolysis, positive anti-nuclear antibodies, positive anti-DNA antibodies, and hypocomplementemia. These data led to an SLE diagnosis. Treatment was started with prednisolone at 40 mg/day, plus hydroxychloroquine, which initially improved both the SLE and IgG4-RD symptoms. During the GC tapering, belimumab was added and clinical symptoms resolved completely. Our case and the literature review summarize reported rare overlapping cases of IgG4-RD and SLE and suggest that belimumab is a promising candidate for the treatment of IgG4-RD.

Clinical importance of anti-Ro52 antibody for polymyositis and dermatomyositis.

OBJECTIVES: To clarify clinical features of anti-Ro52 antibody (Ab)-positive polymyositis (PM)/dermatomyositis (DM). PATIENTS AND METHODS: We retrospectively examined clinical features and status of anti-Ro52 Ab in patients with PM/DM admitted at the University of Tsukuba Hospital between January 2019 and February 2023. We compared anti-Ro52 Ab-positive and -negative groups. RESULTS: A total of 40 patients were selected and analyzed. Median age at diagnosis was 61.5 (48.8-69.3) years and 34 cases were female. Twenty-three cases were PM and 17 cases were DM (including 6 clinically amyopathic dermatomyositis: CADM). Twenty-two cases were positive for anti-Ro52 Ab, 14 for anti-ARS Ab, and 6 for anti-MDA5 Ab. Interstitial lung disease (ILD) was detected in 29 cases, 9 of which were rapidly progressive. Glucocorticoid (GC)-resistant cardiomyopathy was detected in 6 cases, malignancy in 3 cases, and Sjögren's syndrome (SS) in 4 cases. Of the 22 anti-Ro52 Ab positive cases, only 3 were single-positive and the remaining 19 cases simultaneously had other autoantibodies. Comparing the anti-Ro52 Ab-positive and -negative groups, the frequencies of anti-ARS Ab positivity (63.6% vs. 0%), ILD (95.5% vs. 44.4%), GC-resistant cardiomyopathy (27.3% vs. 0%), concomitant use of immunosuppressants (95.5% vs. 55.6%), and levels of C-reactive protein (CRP) were significantly higher in the anti-Ro52 Ab-positive group (p<0.05). The frequencies of PM/DM, positivity of anti-MDA5 Ab, malignancies, and SS were comparable between groups. CONCLUSION: Anti-Ro52 Ab were frequently positive in PM/DM and anti-Ro52 Ab-positive patients showed significantly higher rates of anti-ARS Ab positivity and ILD, GC-resistant cardiomyopathy, concomitant use of immunosuppressants, and higher levels of CRP. Anti-Ro52 Ab may be useful as a severity marker in PM/DM.

Comparative analysis of low-field magnetic resonance imaging in patients with rheumatoid arthritis treated with certolizumab pegol or infliximab.

OBJECTIVES: The aim is to clarify the differences in magnetic resonance imaging (MRI) findings between rheumatoid arthritis (RA) patients treated with certolizumab pegol (CZP) and infliximab (IFX). METHODS: The study included RA patients who received CZP or IFX and were examined with low-field MRI (compacTscan; compact magnetic resonance imaging) at the beginning and again within 6 months of treatment initiation. Comparisons were made regarding background, clinical course, and differences in MRI findings following initiation of tumour necrosis factor inhibitors between the CZP and IFX treatment groups. MRI findings were evaluated by scoring erosion, bone marrow oedema (BME), and synovitis. RESULTS: Ten cases in CZP and 18 cases in IFX group were compared. The biologic disease-modifying antirheumatic drug-naïve rate in the IFX group was significantly higher than that in the CZP group. After 6 months, disease activities were significantly decreased from baseline in both groups. Erosion score did not change significantly in both groups after 6 months. BME score was significantly decreased in the CZP group after 6 months, whereas in the IFX group, there was no significant change. Synovitis score was significantly decreased in both groups after 6 months. CONCLUSIONS: The findings of our study suggest that, in patients with RA, CZP might improve BME more effectively than IFX.

Abatacept ameliorates both glandular and extraglandular involvements in patients with Sjögren's syndrome associated with rheumatoid arthritis: Findings from an open-label, multicentre, 1-year, prospective study: The ROSE (Rheumatoid Arthritis with Orencia Trial Toward Sjögren's Syndrome Endocrinopathy) and ROSE II trials.

OBJECTIVE: To clarify the efficacy and safety of intravenous abatacept for glandular and extraglandular involvements in Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA). MATERIALS AND METHODS: We performed an open-label, prospective, 1-year, observational multicenter study (ROSE and ROSE II trials). The primary endpoint was the remission rate as measured by SDAI at 52 weeks. The secondary endpoints included the changes in the Saxon's test, Schirmer's test, ESSDAI and ESSPRI. Adverse events and adherence rates were also analyzed. RESULTS: 68 patients (36 in ROSE and 32 in ROSE II, all women) were enrolled. SDAI decreased significantly from 23.6 ± 13.2 at baseline to 9.9 ± 9.5 at 52 weeks. Patients with SDAI remission increased from 0 (0 weeks) to 19 patients (27.9%) at 52 weeks. Saliva volume increased significantly at 24 weeks. Tear volume increased significantly at 52 weeks. Both ESSDAI and ESSPRI were significantly decreased at 12 weeks, and these responses were maintained up to 52 weeks. The rate of adherence to abatacept over the 52-week period was 83.8%. Twenty-two adverse events occurred in 15 patients. CONCLUSION: Abatacept ameliorated both glandular and extraglandular involvements, as well as the systemic disease activities and patient-reported outcomes based on composite measures, in SS associated with RA.

RORγt+Foxp3+ regulatory T cells in the regulation of autoimmune arthritis.

RORγt+Foxp3+regulatory T (Treg) cells, known as T regulatory 17 cells (Tr17 cells), are a novel subset of Treg cells, which have the potential to regulate the development of experimental autoimmune encephalomyelitis (EAE) thorough a specific repression of T helper 17 (Th17) cell-mediated inflammation. However, the function of Tr17 cells the development of other autoimmune diseases such as autoimmune arthritis remains unclear. Collagen-induced arthritis (CIA) was found to be prolonged in Foxp3creRORγtfl/fl mice, in which Tr17 cells were deleted, compared with Foxp3wtRORγtfl/fl mice. Tr17 cells were significantly increased in ankle joints (AJ) compared with draining lymph nodes after the onset of arthritis. CC chemokine receptor 6 (CCR6) was up-regulated on Tr17 cells compared to RORγt negative Treg cells. CD25, cytotoxic T-lymphocyte antigen 4 (CTLA-4), glucocorticoid-induced TNF-receptor (GITR), and inducible T-cell co-stimulator (ICOS) expression was also up-regulated on Tr17 cells compared to RORγt negative Treg cells. IL-10-producing cells and Blimp-1+ and T-bet+ cells were increased in Tr17 cells compared to RORγt-negative Treg cells. Tr17-enriched Treg cells significantly suppressed proliferation of conventional T cells through IL-10 compared with CCR6-Treg cells. Tr17 cells increased during the clinical course of CIA and accumulated in inflamed joints. Taken together, it appears that Tr17 cells play a crucial role in the regulation of autoimmune arthritis.

Impaired function of PD-1+ follicular regulatory T cells in systemic lupus erythematosus.

Aberrant autoantibody production is characteristic of systemic lupus erythematosus (SLE), but follicular regulatory T (TFR) cells can potentially suppress this abnormality. We investigate functional changes in TFR cells from SLE patients. Circulating TFR cells were collected from 19 SLE patients and 14 healthy controls (HC) to compare molecular expression and in-vitro suppressive capacity of follicular helper T (TFH) cell proliferation. To reveal the stability of forkhead box protein 3 (FoxP3) in TFR, pyrosequencing of conserved non-coding sequence (CNS) 2 at the FoxP3 gene locus was performed. We then tested interleukin (IL)-2 in SLE-TFR cells to check restoration of suppressor function. Programmed cell death 1 (PD-1) expression in SLE-TFR cells was positively correlated with anti-DNA antibody levels and disease activity. These cells had impaired suppressive function for TFH cells with decreased expression of suppression mediators FoxP3, cytotoxic T lymphocyte antigen 4 (CTLA-4) and IL-2 receptor alpha (IL-2Rα). Pyrosequencing identified hyper-methylation in CNS2 region of SLE-TFR cells comparing to HC. With in-vitro IL-2 stimulation, PD-1 expression of TFR cells significantly decreased, together with increased expression of FoxP3 and CTLA-4, especially at a low dose. Thus, SLE-TFR cells have functionally defective to TFH suppression, but low-dose IL-2 therapy might be useful to restore this ability.

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.

Clinical features of large vessel vasculitis (LVV): Elderly-onset versus young-onset.

OBJECTIVES: We compared large vessel vasculitis (LVV) clinical features between age groups. METHODS: We retrospectively examined clinical features and therapies in 41 LVV patients at our hospital from January 2010 to March 2020. We compared two patient groups, elderly (≥50 years) and young (<50 years). RESULTS: Of all patients, 29 were elderly and 12 were young. In the younger group, upper extremity symptoms (p <.05), bruits (p <.01), and cardiovascular complications (p <.01) were more common. Of the elderly group, 7 (24%) met classification criteria for giant cell arteritis while none of the younger group met these criteria; however, 10 (83%) of the younger group and 3 (10%) of the elderly group met the ACR classification criteria for Takayasu arteritis (p <.01). In the elderly group, 16 patients (66%) met no criteria (p <.01). There were no significant differences in laboratory findings but imaging showed a significantly higher incidence of head and neck artery lesions in the younger group (p <.05). The younger group was more likely to receive additional tocilizumab (p <.01) and cardiovascular complications were more likely to occur in younger patients (p < .01). CONCLUSION: LVV clinical features differed between elderly- and young-age-onset groups.

QTc interval prolongation in patients with systemic lupus erythematosus treated with hydroxychloroquine.

OBJECTIVES: The primary objective is to reveal the effect of hydroxychloroquine (HCQ) treatment on corrected QT (QTc) interval in patients with systemic lupus erythematosus (SLE). The secondary objective is to investigate factors that affect QTc prolongation. METHODS: SLE patients who had electrocardiograms between 2015 and 2020 were recruited and assigned to two groups based on whether they were treated with HCQ (HCQ group) or not (control group). Change of QTc before and after HCQ administration in the HCQ group was measured and compared with the control group. Patients treated with HCQ were further divided into two groups based on presence or absence of QTc prolongation and the characteristics were compared. RESULTS: In total, 126 patients were recruited, of whom 42 were treated with HCQ. In the HCQ group, the mean QTc significantly increased (p < .001), while there was no significant difference of mean QTc in the control group. Moreover, those in the HCQ group with QTc prolongation showed a significantly higher proportion of hypertension and longer SLE duration compared to those without QTc prolongation. However, the multiple logistic regression analysis showed that there were no significant differences among them. CONCLUSION: HCQ could induce QTc prolongation in SLE patients. It might be better that the possibility of QTc prolongation was taken into consideration when HCQ was administered in the patients with longer disease duration of SLE and coincidence of hypertension.

Clinical features and prognosis of nocardiosis in patients with connective tissue diseases.

OBJECTIVES: To investigate the clinical features and prognosis of nocardiosis complicated by connective tissue diseases (CTDs). METHODS: We examined patients with CTDs who were diagnosed with nocardiosis from October 2004 to 2019. We retrospectively investigated patient characteristics and therapeutic outcomes. We then performed a comparison between survivors and non-survivors. RESULTS: Fourteen patients were examined. Underlying CTDs were systemic lupus erythematosus (28.6%), vasculitis syndrome (28.6%), rheumatoid arthritis (21.4%), adult Still disease (14.3%) and dermatomyositis (7.1%). Infected organs were lung (85.7%), brain (42.9%), skin/cutaneous lesions (28.6%) and muscle (7.1%). Disseminated infections were seen in nine patients (64.3%). At the onset of nocardiosis, all patients were given prednisolone (23.2 ± 11.9 mg/day). Only two patients (14.3%) were given TMP-SMX for prophylaxis of pneumocystis pneumonia. Relapse occurred in one patient (7.1%) and four patients (28.6%) died from nocardiosis for a cumulative survival rate at 52 weeks of 76.9%. In a comparison of survivors (71.4%) and non-survivors (28.6%), cutaneous lesions were significantly more frequent in the latter (10 vs 75%, p = .04) with an odds ratio of 27.0 (95% CI: 1.7-453.4). CONCLUSION: Cutaneous lesions as a result of dissemination might be a risk factor for nocardiosis mortality in patients with CTDs.

Placenta Specific 8 Suppresses IL-18 Production through Regulation of Autophagy and Is Associated with Adult Still Disease.

Adult Still disease (ASD) is a systemic disorder of unknown etiology characterized by high spiking fever, rash, and arthritis. The purpose of this study was to identify genes specifically associated with the active phase of the disease. In this study, we have reported that placenta specific 8 (PLAC8) was a newly specific gene involved in ASD. DNA microarray and validation analysis using human monocytes revealed that the expression of PLAC8 was significantly higher in active-ASD patients than in inactive-ASD patients and healthy controls. In ASD, PLAC8 expression level correlated with serum levels of CRP, ferritin, IL-1ß, and IL-18. Stimulation of monocytes with LPS results in PLAC8 upregulation. LPS or nigericin stimulation of PLAC8-overexpressing human monocytic cell line (THP-1), but not mock THP-1 cells, was associated with a significant decrease in IL-1ß and IL-18 production. PLAC8 overexpression in THP-1 cells was associated with enhanced autophagy and suppression of IL-1ß and IL-18 production. Therefore, we found that PLAC8 was upregulated in activated monocytes, as was IL-1ß and IL-18. The upregulated PLAC8 acts on the synthesis of inactive precursors of IL-1ß and IL-18 and seemed to suppress the production of IL-1ß and IL-18 by negative feedback through enhanced autophagy, resulting in the suppression of ASD. The results highlight the role of PLAC8 in the pathogenesis of ASD and suggest its potential suitability as an activity marker and therapeutic target in ASD.

RORγt antagonist improves Sjögren's syndrome-like sialadenitis through downregulation of CD25.

OBJECTIVE: We reported previously that T-cell-specific RORγt-transgenic mice under human CD2 promoter (RORγt-Tg mice) developed severe spontaneous Sjögren's syndrome (SS)-like sialadenitis, induced by RORγt-overexpressing CD4+ T cells and reduced regulatory T cells. The purpose of this study was to clarify the effectiveness and mechanisms of action of A213, a RORγt antagonist, in RORγt-Tg mice with SS-like sialadenitis. METHODS: Six-week-old RORγt-Tg mice were administered orally of A213 or phosphate-buffered saline every 3 days for 2 weeks. We analyzed saliva volume, histopathology of salivary glands, populations of T cells in splenocytes and cervical lymph nodes (cLNs), and the protein expression levels of CD69 on CD4+ CD25+ Foxp3- and CD4+ CD25+ Foxp3+ cells in cLNs. We also investigated in vitro the potential immunomechanisms of action of A213. RESULTS: A213 significantly increased saliva volume, reduced mononuclear cell infiltration in salivary glands, and reduced the focus score of sialadenitis. Analysis of the immunomechanisms using cLNs showed A213 significantly reduced the proportion of CD4+ CD25+ /CD4+ T cells and the protein expression levels of CD69 on CD4+ CD25+ Foxp3- cells. In vitro experiments showed that A213 suppressed CD25 expression on CD4+ T cells and reduced IL-2 production from CD4+ T cells derived from RORγt-Tg mice. CONCLUSION: A213 improves SS-like sialadenitis through the inhibition of CD4+ CD25+ cells in cLNs.

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.

Ganglionic Acetylcholine Receptor Antibodies and Autonomic Dysfunction in Autoimmune Rheumatic Diseases.

Autonomic neuropathy has been reported in autoimmune rheumatic diseases (ARD) including Sjögren's syndrome, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. However, the pathophysiological mechanism underlying autonomic dysfunction remains unknown to researchers. On the other hand, autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder, which causes dysautonomia that is mediated by autoantibodies against ganglionic acetylcholine receptors (gAChRs). The purpose of this review was to describe the characteristics of autonomic disturbance through previous case reports and the functional tests used in these studies and address the importance of anti-gAChR antibodies. We have established luciferase immunoprecipitation systems to detect antibodies against gAChR in the past and determined the prevalence of gAChR antibodies in various autoimmune diseases including AAG and rheumatic diseases. Autonomic dysfunction, which affects lower parasympathetic and higher sympathetic activity, is usually observed in ARD. The anti-gAChR antibodies may play a crucial role in autonomic dysfunction observed in ARD. Further studies are necessary to determine whether anti-gAChR antibody levels are correlated with the severity of autonomic dysfunction in ARD.

Pathogenesis of IgG4-related disease. Comparison with Sjögren's syndrome.

IgG4-related disease (IgG4-RD) is characterized by lympho-plasmacytic infiltration and fibrosis in multiple organs, accompanied by high serum IgG4 levels. Although both IgG4-RD and Sjögren's syndrome (SS) frequently affect salivary and lacrimal glands, the clinical and pathological features of these two conditions are different. In an attempt to delineate the pathomechanisms of IgG4-RD, we compared the gene expression patterns of various molecules in labial salivary glands (LSGs) between IgG4-RD and SS. First, using quantitative PCR, we demonstrated significantly higher mRNA expression levels of activation-induced cytidine deaminase (AID), IL-10, and TGFß in LSGs of IgG4-RD than SS and healthy controls (HCs). We propose that the combination of AID and IL-10 contributes to IgG4-specific immunoglobulin class switch recombination, and that TGFß induces LSGs fibrosis in IgG4-RD. Second, DNA microarray identified 2641 differentially expressed genes (DEGs) in LSGs; with 1321 up-regulated and 1320 down-regulated genes in IgG4-RD, relative to SS. Among the up-regulated DEGs in IgG4-RD, quantitative PCR confirmed significantly higher expression levels of chemokine (C-C motif) ligand 18 (CCL18) and lactotransferrin in LSGs of IgG4-RD than SS and HCs. The former has chemotactic activity on various types of lymphocytes and enhances collagen production from fibroblasts, while lactotransferrin is an iron-binding protein abundantly present in milk and has a wide range of functions, including fibroblast proliferation and maturation of dendritic cells (DCs). Third, immunofluorescence staining confirmed specific upregulation of CCL18 in macrophages, CD11c + and B cells, and plasmacytes of LSGs-IgG4-RD. These pathological findings could help in the identification of disease-specific biomarkers as well as development of novel therapeutic strategies.

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.

Association of anti-cyclic citrullinated peptide antibody with clinical features in patients with psoriatic arthritis.

Background: Although anti-cyclic citrullinated peptide antibody (anti-CCP Ab) is reported to be found in 5-20% of patients with psoriatic arthritis (PsA), its clinical significance has not been elucidated.Objective: To clarify the association of anti-CCP Ab with clinical features in PsA.Methods: Patients were enrolled who fulfilled the classification criteria for psoriatic arthritis (CASPAR) criteria and visited our hospital. We retrospectively compared clinical characteristics between those who were positive and negative for anti-CCP Ab and further compared changes in disease activity in the patients treated with biological disease-modifying anti-rheumatic drugs (DMARDs).Results: We examined 41 patients (11 females), seven were anti-CCP Ab-positive and 34 were negative. Age (55.0 ± 15.1 years old) and frequency of lung involvements (71.4%) in the anti-CCP Ab-positive group were significantly higher than those (40.0 ± 16.0 and 0%, respectively) in the negative group (p < .05). Rheumatoid factor (RF) titer (749.4 ± 860.7 U/mL) and MMP-3 (604.8 ± 1060.6) in the anti-CCP Ab-positive group was significantly higher than that (3.6 ± 4.4 U/mL and 111.2 ± 77.4, respectively) in the negative group (p < .05). Five patients were treated with tumor necrosis factor (TNF) inhibitors (infliximab (IFX): 3 and adalimumab (ADA): 2) in the anti-CCP Ab-positive group, while in the negative group there were 11 (IFX: 6, ADA: 4, and etanercept (ETN): 1). Within 6 months of treatment, arthritis did not improve with TNF inhibitors in the anti-CCP Ab-positive group, whereas it improved significantly in the negative group.Conclusion: In patients with PsA, anti-CCP Ab might be related to lung involvements, elderly onset, RF and MMP-3 titers, and resistance to TNF inhibitor.

Transgenic rice seeds expressing altered peptide ligands against the M3 muscarinic acetylcholine receptor suppress experimental sialadenitis-like Sjögren's syndrome.

Objective: We previously reported that Rag1-/- mice inoculated with splenocytes from M3 muscarinic acetylcholine receptor (M3R) knockout mice immunized with an M3R peptide mixture developed sialadenitis-like Sjögren's syndrome (M3R-induced sialadenitis [MIS]). We also found that intravenous administration of altered peptide ligand (APL) of N-terminal 1 (N1), which is one of the T-cell epitopes of M3R, suppressed MIS. In this study, we aimed to evaluate the suppressive ability and its mechanisms of rice seeds expressing N1-APL7 against MIS.Methods: Rice seeds expressing N1 and N1-APL7 were orally administered to MIS mice for 2 weeks. The changes in saliva flow and sialadenitis (salivary gland inflammation) were analyzed. The M3R-specific T-cell response in the spleen and the expression of regulatory molecules in the cervical lymph nodes and mesenteric lymph nodes were also analyzed.Results: Oral administration of N1-APL7-expressing rice seeds significantly recovered reduction in saliva flow and suppressed sialadenitis when compared with treatment with nontransgenic rice seeds and N1 rice seeds. IFNγ production from M3R-reactive T cells tended to decline in the N1-APL7 rice-treated group as compared with those in the other groups. In the N1-APL7 rice-treated group, the mRNA expression levels of Foxp3 in the cervical-lymph-node CD4+ T cells were higher than those in the other groups.Conclusion: Oral administration of N1-APL7-expressing rice suppressed MIS via suppression of M3R-specific IFNγ and IL-17 production and via enhancement of regulatory molecule expression.Key messagesWe generated N1-peptide- or N1-APL7-expressing rice seeds. Oral administration of N1-APL7-expressing rice seeds significantly recovered the reduction of saliva flow and suppressed sialadenitis via the suppression of M3R specific IFNγ and IL-17 production and via enhancement of regulatory T (Treg) cells.

Upregulation and pathogenic roles of CCL18-CCR8 axis in IgG4-related disease.

Objectives: To determine the protein expression level, expressing cell types, and pathogenic roles of chemokine (C-C motif) ligand 18 (CCL18) and its receptor chemokine (C-C motif) receptor 8 (CCR8) in affected tissues of patients with IgG4-related disease (IgG4-RD).Methods: The protein expression levels of CCL18 in labial salivary glands (LSGs) assessed by immunofluorescence (IF) staining were compared among patients with IgG4-RD (n = 3), primary Sjögren's syndrome (pSS; n = 4), and control subjects (n = 5). CCL18 expression levels in macrophages, CD11c+ cells, B cells, and plasmacytes in LSGs were examined by double IF staining. The protein expression levels of CCR8 and expressing cells (T, B cells, and plasmacytes) in LSGs were also compared among patients with IgG4-RD, pSS, and control subjects by double IF staining. The effects of the CCL18-CCR8 axis on total IgG, IgG2, and IgG4 production by peripheral blood mononuclear cells (PBMCs) stimulated with CD40L, IL-4, IL-10, and IL-21 were examined by in vitro assays.Results: CCL18 was specifically upregulated in LSGs of patients with IgG4-RD, compared with only a few cells in pSS patients and none of the controls. The numbers of CCL18-producing macrophages, CD11c+ cells, and plasmacytes in LSGs were significantly higher in IgG4-RD patients than in pSS patients and control (p < .05, each). Many T and B cells and some plasmacytes expressed CCR8 in LSGs of IgG4-RD and pSS patients. CCL18 specifically enhanced IgG4 production by stimulated PBMCs.Conclusion: CCL18-CCR8 axis was upregulated in LSGs of patients with IgG4-RD, suggesting possible roles of this axis in the pathogenesis of IgG4-RD.Key messagesThe CCL18-CCR8 axis in labial salivary glands (LSGs) and lacrimal glands of IgG4-RD patients was specifically upregulated compared with primary Sjögren's syndrome and control subjects.This axis might be a potentially novel therapeutic target in IgG4-RD, based on its important etiopathogenic roles, such as chemotaxis of various cells, induction of fibrosis, and enhancement of IgG4 production.