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Introduction: This final analysis of a long-term extension (LTE) study assessed the safety, tolerability, and effectiveness of peficitinib (ASP015K), a pan-Janus kinase inhibitor, in Asian patients with rheumatoid arthritis (RA). Methods: Patients had previously completed the 12-week phase 2b (RAJ1), or 52-week phase 3 (RAJ3 and RAJ4) peficitinib studies in Japan, Korea, and Taiwan, and received oral peficitinib 50 or 100 mg/day. Dose increase to 150 mg/day or reduction to 50 mg/day was permitted. Efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates, 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP), and ACR components. Safety endpoints included treatment-emergent adverse events (TEAEs), and incidence rates (IRs) of adverse events of special interest per 100 patient-years (PY). Results: Overall, 843 patients received peficitinib for a mean 32.0 months (maximum 85.2 months), and most (64.4%) received peficitinib 100 mg/day as a maximum dose. Respective ACR20/50/70 response rates were maintained from baseline (week 0 of LTE; 71.6, 52.1, and 34.7%) to end of treatment (78.7, 63.3, and 44.1%); continuous improvements in ACR components and DAS28-CRP were observed from the baselines of preceding studies and throughout the LTE. Overall, 796/843 (94.4%) patients experienced TEAEs; most were severity grade 1/2. Most common TEAEs were nasopharyngitis (47.0%) and herpes zoster (17.3%). Drug-related TEAEs leading to permanent discontinuation occurred in 140 (16.6%) patients, and IRs (95% confidence interval) per 100 PY of serious infections, herpes zoster-related disease, and malignancies were 2.7 (2.1, 3.4), 7.3 (6.2, 8.6), and 1.2 (0.9, 1.8), respectively. Two deaths occurred during the study; one each from diffuse large B cell lymphoma and pneumonia, which were, respectively considered probably and possibly related to study drug. Conclusions: Improvements in effectiveness variables were maintained during this long-term study of peficitinib in Asian patients with RA; peficitinib was generally well tolerated over a mean 32 months’ duration. Trial Registration: ClinicalTrials.gov. NCT01638013, retrospectively registered on 11 July 2012 https://clinicaltrials.gov/ct2/show/NCT01638013.

ABSTRACTIntroduction: Treatment of rheumatoid arthritis (RA) has been revolutionized by the introduction of biologic disease-modifying antirheumatic drugs, such as tumor necrosis factor (TNF) inhibitors. With patent expiry approaching for many expensive biologic molecules, such as etanercept, more affordable biosimilar drugs are being developed. LBEC0101 is an etanercept biosimilar approved in Japan and South Korea for all etanercept indications including RA.Areas covered: We discuss the pharmacological characteristics, pharmacokinetics, efficacy, and safety of LBEC0101 compared with the etanercept reference product (ETN-RP). Preclinical studies showed that the binding affinity to TNFα and biological activity of LBEC0101 were similar to those of the ETN-RP. The pharmacokinetic profile of LBEC0101 was also similar to that of the ETN-RP. A Phase III, randomized, double-blind, 54-week study showed that the efficacy of LBEC0101 was equivalent to that of the ETN-RP in RA patients. An extension study showed that efficacy was sustained long-term in patients receiving LBEC0101 and in those switching from the ETN-RP to LBEC0101. The safety profile of LBEC0101 was also confirmed to be comparable with the ETN-RP.Expert opinion: LBEC0101 has shown equivalent pharmacokinetics and efficacy and comparable safety to the ETN-RP, and the lower cost of LBEC0101 provides a good cost–benefit ratio.

It appears that several genetic variations of an immune protein in the blood called complement are associated with rheumatoid arthritis among Koreans. Researchers analyzed blood samples from 65 Korean patients with rheumatoid arthritis and 255 healthy Korean volunteers (control group). Patients with rheumatoid arthritis who were either rheumatoid factor positive or negative had higher levels of the complement type C4AQ0 than the control group. C4B5 levels were higher among patients who were rheumatoid factor positive than the control group. Patients who carried the C4B5 type also tended to carry the HLA-DR4 immune complex.

Objective.Patient-reported outcome measures (PROM) that incorporate the patient perspective have not been well established in idiopathic inflammatory myopathies (IIM). As part of our goal to develop IIM-specific PROM, the Outcome Measures in Rheumatology (OMERACT) Myositis special interest group sought to determine which aspects of disease and its effects are important to patients and healthcare providers (HCP).Methods.Based on a prior qualitative content analysis of focus groups, an initial list of 24 candidate domains was constructed. We subsequently conducted an international survey to identify the importance of each of the 24 domains to be assessed in clinical research. Patients with IIM, their caregivers, and HCP treating IIM completed the survey.Results.In this survey, a total of 638 respondents completed the survey, consisting of 510 patients, 101 HCP, and 27 caregivers from 48 countries. Overall, patients were more likely to rank “fatigue,” “cognitive impact,” and “difficulty sleeping” higher compared with HCP, who ranked “joint symptoms,” “lung symptoms,” and “dysphagia” higher. Both patients and providers rated muscle symptoms as their top domain. In general, patients from different countries were in agreement on which domains were most important. One notable exception was that patients from Sweden and the Netherlands ranked lung symptoms significantly higher compared to other countries including the United States and Australia (mean weighted rankings of 2.86 and 2.04 vs 0.76 and 0.80, respectively; p < 0.0001).Conclusion.Substantial differences exist in how IIM is perceived by patients compared to HCP, with different domains prioritized. In contrast, patients’ ratings across the world were largely similar.

Mitochondrial dysfunction can drive cellular senescence, which is accompanied by changes in metabolism and increases in senescence-associated secretory phenotypes. Although pyruvate, a key metabolite for numerous aspects of metabolism, has been used as general supplement in synthetic media, the physiological function of pyruvate underlying its protective role against cellular senescence under normal conditions has remained unknown. Here, we show that extracellular pyruvate prevents senescence in normal human dermal fibroblasts through increasing the generation of oxidized nicotinamide adenine dinucleotide (NAD+) during the conversion to lactate. Acetylated peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), vacuolar-type H+-ATPaseV0A1 (v-ATPaseV0A1), NF-κB p65 subunit (RelA), and histone H3 accumulate under pyruvate deprivation conditions, resulting in the onset of senescence in normal human dermal fibroblasts through the accumulation of abnormal mitochondria generated by lysosomal inactivation-induced mitophagy defects, and through an increase in senescence-associated secretory phenotypes. Furthermore, pyruvate showed a protective effect against aging phenotypes in skin equivalents, which consist of a dermis and epidermis that act similarly to in vivo skin tissues. Our findings reveal a connection between pyruvate and mitochondrial dysfunction in the progression of senescence that is, to our knowledge, previously unreported. These results suggest that the pyruvate deprivation-induced senescence model can be used to study the connection between metabolism and senescence under normal conditions.

Objective.To define a set of core patient-reported domains and respective instruments for use in idiopathic inflammatory myopathies (IIM). Previously, we reported a systematic literature review on patient-reported outcomes (PRO) in IIM followed by conducting international focus groups to elicit patient perspectives of myositis symptoms and effects.Methods.Based on qualitative content analysis of focus groups, an initial list of 26 candidate domains was constructed. We subsequently conducted an international modified Delphi survey to identify the importance of each of the 26 domains. Participants were asked to rate each domain on a scale of 0–10 (0 = not important, 10 = very important).Results.In this first round of the Delphi survey, 643 patients participated from the United States (n = 543), Sweden (n = 49), and South Korea (n = 51). Of the 26 domains, 19 (73%) were rated of high importance (≥ 7/10). The top 5 domains were muscle symptoms, fatigue, interactions with healthcare, medication side effects, and pain. During Outcome Measures in Rheumatology (OMERACT) 2016, we discussed the goal for ultimate reduction in the number of domains and the importance of considering representation of healthcare providers from other specialties, caregivers, representatives of pharmaceutical industries, and regulatory authorities in the next rounds of Delphi to represent broader perspectives on IIM.Conclusion.Further prioritization and a reduction in the number of domains will be needed for the next Delphi. At the next biennial OMERACT meeting, we aim to present and seek voting on a Myositis Preliminary PRO Core Set to enable ultimate measure selection and development.

Europe and North America have been leaders in rheumatology for many years. However, for more than a decade now the East Asian region has been catching up dramatically. Some aspects of rheumatology in East Asia are now almost comparable to those in the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). In this article, we describe recent progress in rheumatology in East Asia, focusing specifically on Japan, Korea, and China.

Background: Treatment goals for patients with systemic lupus erythematosus (SLE) include minimising disease activity and reducing the risk of flares. Although belimumab is effective at reducing disease activity and risk of severe flares, it was previously unknown what the clinical effects were upon treatment discontinuation. The objective of this study was to assess the impact of temporary withdrawal of intravenous (IV) belimumab in patients with SLE. Methods: This multicentre, open-label, non-randomised, 52-week study (GSK Study BEL116027; NCT02119156) recruited patients with SLE and stable low disease activity, of whom those on belimumab 10 mg/kg IV plus standard therapy either discontinued belimumab for 24 weeks and then restarted belimumab 10 mg/kg IV every 4 weeks (q4w) for 28 weeks (treatment holiday [TH] group), or continued on belimumab 10 mg/kg IV plus standard therapy q4w for 52 weeks (treatment continuation [TC] group). The primary endpoint was median time to first Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) Flare Index flare. Secondary and other endpoints included rate of any flare, time to severe flare, time to renal flare and rebound (SELENA-SLEDAI score exceeding parent study baseline). Data on rebound phenomenon in patients with any disease level of SLE who had permanently withdrawn from further belimumab treatment (long-term discontinuation group [LTD]) were also assessed. Safety was assessed. Results: The primary endpoint was not evaluable in the TH (n= 12) and TC (n= 29) groups as fewer than half of patients flared. Unadjusted flare rates per patient-year were 1.0 during treatment discontinuation and 0.3 during treatment restart (0.6 overall) in the TH group and 0.6 in the TC group; there were no severe or renal flares. No TH patients rebounded; 2 (6.9%) TC patients rebounded; 2 (5.1%) patients in the LTD group rebounded. There were no new safety signals. Conclusions: Twenty-four-week belimumab discontinuation did not appear to increase the risk of flares or rebound in patients with low SLE disease activity; flare rates were low in both groups. Further studies may help to fully determine the effect of belimumab discontinuation. Trial registration: ClinicalTrials.gov, NCT02119156. Registered on April 21, 2014.

Rheumatology was first recognized as a distinct clinical specialty in Korea just 35 years ago. Young professors who were trained in rheumatology in the USA and afterwards returned to Korea contributed substantially to advances in rheumatology clinical practice, educational programmes and research activities. They also established the Korean Rheumatism Association, later renamed the Korean College of Rheumatology. These young rheumatologists had a major role not only in raising the level of clinical and scientific activities, but also in promoting academic exchanges around the Asia–Pacific region, the USA and Europe. Subsequently, Korea's rapid economic growth and high education level enabled rheumatology to advance rapidly. Today, continued efforts are required to raise the standard of clinical and basic research, to optimize clinical practice with regard to new biologic agents, to exploit personalized and targeted therapies for the rheumatic diseases, and to meet the medical demands of Korea's ageing society.

Background:Although microbes have been suggested to play a role in the pathogenesis of ankylosing spondylitis (AS), several studies present contradictory results regarding the association between AS and chronic periodontitis (CP). Methods:Clinical, laboratory, and medication data were collected from 84 patients with AS and 84 age‐ and sex‐matched controls. Periodontal measurements, including probing depths (PDs), clinical attachment loss (AL), serum anti‐Porphyromonas gingivalistiters, and the detection of P. gingivalisDNA in gingival crevicular fluid, were recorded. All participants with periodontitis with PD ≥4 to <7 mm received scaling and root planing and were re‐evaluated at 12 weeks; those still exhibiting periodontitis with PD of ≥4 to <7 mm at 12 weeks were followed at 24 weeks. Results:The prevalence of moderate‐to‐severe CP was not different between patients with AS and controls (70.2% versus 66.6%). The P. gingivalisdetection rate was not different between patients with AS and controls or between patients with AS receiving and not receiving anti–tumor necrosis factor (TNF)‐α agents. However, CP was positively associated with impaired spinal mobility of patients with AS in multivariate analyses. After periodontal treatment, PD and AL levels were improved in both groups, but the change was significantly greater in patients with AS than in controls. Patients with AS receiving anti‐TNF‐α agents exhibited a greater improvement in PD and AL than those who did not. Conclusions:Although AS was not associated with the presence of CP, CP was associated positively with the severity of spinal dysmobility in Korean patients with AS. These results suggest that periodontitis can have a negative effect on axial movement in AS.

The newly formed Outcome Measures in Rheumatology (OMERACT) Myositis Special Interest Group (SIG) was established to examine patient-reported outcome measures (PROM) in myositis. At OMERACT 11, a literature review of PROM used in the idiopathic inflammatory myopathies (IIM) and other neuromuscular conditions was presented. The group examined in more detail 2 PROM more extensively evaluated in patients with IIM, the Myositis Activities Profile, and the McMaster-Toronto Arthritis Patient Preference Disability Questionnaire, through the OMERACT filter of truth, discrimination, and feasibility. Preliminary results from a qualitative study of patients with myositis regarding their symptoms were discussed that emphasized the range of symptoms experienced: pain, physical tightness/stiffness, fatigue, disease effect on emotional life and relationships, and treatment-related side effects. Following discussion of these results and following additional discussions since OMERACT 11, a research agenda was developed. The next step in evaluating PROM in IIM will require additional focus groups with a spectrum of patients with different myositis disease phenotypes and manifestations across a range of disease activity, and from multiple international settings. The group will initially focus on dermatomyositis and polymyositis in adults. Qualitative analysis will facilitate the identification of commonalities and divergent patient-relevant aspects of disease, insights that are critical given the heterogeneous manifestations of these diseases. Based on these qualitative studies, existing myositis PROM can be examined to more thoroughly assess content validity, and will be important to identify gaps in domain measurement that will be required to develop a preliminary core set of patient-relevant domains for IIM.

This study focused on the potential therapeutic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on collagen-induced arthritis (CIA) and on the elucidation of the mechanisms involved. DBA/1J mice with established CIA were treated with various amount of recombinant soluble human TRAIL. The effects of TRAIL on the development and severity of CIA in this DBA/1J mouse model were assessed clinically and histologically, and a detailed investigation was conducted on proinflammatory cytokine and anticollagen-specific antibody levels. Cellular immunity was evaluated by investigating the proliferative responses and cytokine release profiles of splenocytes after TRAIL treatment. TRAIL treatment significantly reduced the severity and incidence of CIA, joint swelling, erythema, and edema. Histologic evaluations revealed that inflammatory cell infiltration, cartilage destruction, and bone erosion were significantly reduced in joints of TRAIL-treated mice with dose-dependent manner. TRAIL treatment also strongly decreased and/or normalized the productions of proinflammatory cytokines and of anti-collagen-specific antibodies in the sera of CIA mice. Furthermore, in vitro studies with primary splenocytes showed the cytotoxic effect of TRAIL on activated lymphocytes, with reduction of inflammatory cytokine release. These findings show that TRAIL administration is an effective anti-inflammatory treatment that prevents the development and progression of CIA in DBA/1J mice, and they suggest that TRAIL might be considered a potential treatment for human RA.

Introduction: Retroperitoneal fibrosis (RPF) is characterized by a highly fibrotic retroperitoneal mass and encompasses the idiopathic form and secondary to malignancies. Because we have limited knowledge whether RPF is associated with malignancy, we aimed to investigate the relationship between RPF and malignancy and to compare the characteristics and prognosis of cancers among patients with RPF. Methods: Medical records of 111 patients diagnosed as having RPF were reviewed and 38 cases of cancer, confirmed by biopsy, were identified. Standardized incidence ratios (SIRs) were calculated for cancers and stratified according to cancer type and RPF-cancer diagnosis interval. Cancer characteristics and outcomes were compared between RPF-cancer diagnosis intervals. Results: The average age at RPF diagnosis was 59.2 ± 15.0 years, and 69.4% of the patients were male. The cancer SIRs in patients with RPF relative to age- and sex-matched individuals in the general population was 2.2 (1.6–3.1). SIRs of renal pelvis cancer and multiple myeloma were significantly higher than in the general population. When stratified by RPF-cancer intervals, the SIRfor cancer was 9.9 within 1 year of RPF diagnosis, while no significant increase in the SIRwas found after 1 year from RPF diagnosis. Cancer stage was more advanced at the time of diagnosis in patients within a 1-year interval for RPF than those with cancer within a >5-year interval, with a correspondingly increased mortality in the former patients. Conclusions: RPF was significantly associated with malignancy, particularly those diagnosed within 1 year of RPF diagnosis. Cancer stages at diagnosis were more advanced and the mortality rate was higher in patients within a 1-year interval between RPF and cancer diagnosis than in those with a >5-year interval between diagnoses.

Background: To investigate the effects of inhibiting histone deacetylase (HDAC) 6 on inflammatory responses and tissue-destructive functions of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). Methods: FLS from RA patients were activated with interleukin (IL)-1β in the presence of increasing concentrations of M808, a novel specific HDAC6 inhibitor. Production of ILs, chemokines, and metalloproteinases (MMPs) was measured in ELISAs. Acetylation of tubulin and expression of ICAM-1 and VCAM-1 were assessed by Western blotting. Wound healing and adhesion assays were performed. Cytoskeletal organization was visualized by immunofluorescence. Finally, the impact of HDAC6 inhibition on the severity of arthritis and joint histology was examined in a murine model of adjuvant-induced arthritis (AIA). Results: HDAC6 was selectively inhibited by M808. The HDAC6 inhibitor suppressed the production of MMP-1, MMP-3, IL-6, CCL2, CXCL8, and CXCL10 by RA-FLS in response to IL-1β. Increased acetylation of tubulin was associated with decreased migration of RA-FLS. Inhibiting HDAC6 induced cytoskeletal reorganization in RA-FLS by suppressing the formation of invadopodia following activation with IL-1β. In addition, M808 tended to decrease the expression of ICAM-1 and VCAM-1. In the AIA arthritis model, M808 improved the clinical arthritis score in a dose-dependent manner. Also, HDAC6 inhibition was associated with less severe synovial inflammation and joint destruction. Conclusion: Inhibiting HDAC6 dampens the inflammatory and destructive activity of RA-FLS and reduces the severity of arthritis. Thus, targeting HDAC6 has therapeutic potential.

This study was undertaken to assess the prevalence of psoriatic arthritis (PsA) in Korean psoriasis patients and to evaluate its clinical features. The authors evaluated 504 patients with psoriasis who visited the dermatology clinic at Seoul National University Hospital. Fifty-three of these patients (10.5%) were diagnosed as having PsA. Plaque-type psoriasis was the most common in both the PsA and psoriasis only groups, and pustular psoriasis was more frequent in the PsA group (19.0%) than in the psoriasis only group (4.3%, p=0.001). Nail change was more common in the PsA group (54.3% vs 35.3%, respectively; p=0.015). Dactylitis and enthesopathy were observed in 8.5% and 9.1% of PsA patients, respectively. Psoriasis was followed by arthritis in 73.6% of PsA patients, with a mean interval of 12.2 ± 10.1 (mean ± SD) years, and spondylitis (43.4%) was the most predominant disease type. HLA-B27 was detected in 21.1% of patients in the PsA group. In conclusion, plaque-type psoriasis was most common in PsA patients, and nail change was more common in PsA patients than in patients with psoriasis only. Spondylitis was the most predominant form of arthritis.

Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1; previously known as p43) is a multifunctional protein that was initially found in multitRNA synthetase complex. In the present study, screening of the AIMP1-binding proteins revealed that AIMP1 can form a molecular complex with heat shock protein gp96. AIMP1 enhances gp96 dimerization and the interaction between gp96 and KDEL receptor-1 (KDELR-1), which mediates the retrieval of KDEL-containing proteins from Golgi to the endoplasmic reticulum (ER). The interaction between gp96 and KDELR-1 was reduced in AIMP1-deficient cells, and this disturbed ER retention of gp96 and increased its cell surface localization. Moreover, this localization of gp96 at the cell surface was suppressed by its interaction with AIMP1 and enhanced by the depletion of endogenous AIMP1. In addition, AIMP1-deficient mice showed dendritic cell activation attributable to increased gp96 surface presentation and lupus-like autoimmune phenotypes. These results suggest that AIMP1 acts as a regulator of the ER retention of gp96 and provide a new perspective of the regulatory mechanism underlying immune stimulation by gp96.

Radiation synovectomy is a useful local treatment for patients with refractory synovitis. We previously demonstrated the efficacy and safety of 188Re–tin colloid for treating rheumatoid arthritis patients with refractory knee synovitis. This open-label, prospective controlled study investigates magnetic resonance imaging (MRI) changes as well as clinical response in knees after receiving different radioactivities of intra-articular 188Re–tin colloid.

The bone marrow (BM) serves as a reservoir for different classes of stem cells. In addition to haematopoietic stem cells, bone marrow contains a population of mesenchymal stem cells (MSCs). These cells have a multilineage differentiation capacity and are able to generate progenitors with restricted developmental potential, which include fibroblasts, osteoblasts, adipocytes, and chondrocytes. Characteristic markers have been reported for expanded MSCs, but none of these markers are specific for MSCs. Thus, the objective of this study was to produce monoclonal antibodies against MSCs. MSCs derived from human bone marrow were cultured, expanded, and immunized into mice, and spleen cells subsequently harvested were used to generate hybridoma cell lines secreting antibodies against MSCs. Hybridoma culture supernatants were screened for antibodies against MSCs by enzyme-linked immunosorbent assay (ELISA), and 33 positive clones were then screened against cell suspensions of MSCs by immunofluorescence staining and flow cytometry. Ten clones were positive in immunofluorescence staining. Amomg these, three hybridoma cell lines, namely, YS08, YS14, and YS18 were found to be reactive with MSC by flow cytometry, but non-reactive with human tumor cell lines and hematopoietic stem cells. YS08 and YS14 showed specific bands in Western blotting. In conclusion, we developed three monoclonal antibodies, YS08, YS14, and YS18, that recognize human MSC cell surface antigen.

OBJECTIVE: To assess the frequency of juvenile onset ankylosing spondylitis (JAS) in Korean patients with AS and to differentiate the clinical characteristics of JAS from adult onset ankylosing spondylitis (AAS). METHODS: We studied 98 consecutive patients with AS who visited the rheumatology clinic of a tertiary referral center and compared clinical and radiographic features of JAS (n = 41) with those of AAS (n = 57). RESULTS: Median age at onset in JAS was 14 years (range 7-16) and in AAS 22 years (range 17-38) (p < 0.01). Patients with JAS at presentation showed fewer spinal symptoms and more frequent peripheral joint symptoms than those with AAS (41.5% vs 80.7% and 73.2% vs 36.8%, respectively; p < 0.01). Current cervical spine disease was more frequent in AAS (66.7% vs 43.9%; p = 0.02) and current knee disease in JAS (26.8% vs 8.8%; p = 0.02). Patients with JAS showed a shorter tragus-wall distance (mean +/- SD 10.6 +/- 1.7 vs 13.1 +/- 6.9 cm; p < 0.01), more mobility on the modified Schober test (5.7 +/- 2.0 vs 4.0 +/- 2.6 cm; p < 0.01) and chest expansion (4.4 +/- 1.7 vs 3.2 +/- 1.8 cm; p < 0.01), and a better forced vital capacity (75.1 +/- 14.1% vs 82.1 +/- 16.1% of predicted value; p = 0.03) than those with AAS. Totally ankylosed sacroiliitis and spinal syndesmophyte on radiographs were less frequent in JAS patients than in AAS (19.5% vs 47.4% and 17.1% vs 54.4%, respectively; p < 0.01). CONCLUSION: The frequency of JAS (41.3%) among Koreans was higher than that reported for Caucasians. General joint involvement pattern at disease onset in JAS was similar to previous reports. Our data suggest that clinically and radiographically JAS has a less severe spinal disease course than AAS.

Reactive arthritis (ReA) is postulated to be caused by a defective host defense against gram‐negative bacteria. HLA–B27 could play a role in this process, but does not account for the many HLA–B27 negative patients. The objective of this study was to test the expression of 3 macrophage scavenger receptors (SRs) that are responsible for innate immunity against gram‐negative bacteria: SR class A type I (SR‐AI), SR‐AII, and the macrophage receptor with collagenous structure (MARCO). We postulate that defects in such receptors might also contribute to the host risk factors that increase the predisposition to ReA and perhaps other subtypes of spondylarthropathy (SpA).Peripheral blood, synovial fluid, and synovial tissue samples were obtained from patients with recent Salmonella infection, ReA, other SpA, and rheumatoid arthritis (RA). The expression of SRs receptors was assessed by semiquantitative reverse transcriptase–polymerase chain reaction.Evaluation of the peripheral blood mononuclear cells (PBMC) from 4 patients who were recently infected with Salmonella, showed that PBMC from 2 patients who developed ReA expressed positive levels of MARCO, while PBMC from 2 patients who recovered from infection without sequelae did not. The synovial fluid mononuclear cells (SFMC) from some ReA patients expressed MARCO, but the levels were only moderate. The level of MARCO in the SFMC from the SpA patient group was low. In marked contrast, MARCO expression was high in almost all samples of RA SFMC. These findings also extended to synovial tissues.Expression of the host defense gene MARCO was susceptible to modulation, not only during infections, but also in the inflammatory arthritis conditions RA and SpA. MARCO is a variable to be considered as a candidate factor that might contribute to ReA.

Abstract: We assessed the prevalence and clinical features of psoriatic arthritis (PsA) in Korean patients with psoriasis. The prevalence of PsA in patients with psoriasis was 9%. Patients with PsA were older and had a longer duration of skin disease than those with psoriasis alone (median age, 40 vs 35 years, P = 0.03, and 15.3 vs 11.7 years, P = 0.04, respectively). Spondylitis was the most common pattern of PsA (50%). Nail change, dactylitis, and enthesopathy were observed in 36%, 15.4%, and 15.6% of patients with PsA, respectively. Increased erythrocyte sedimentation rate (ESR), antinuclear antibody, and radiological sacroiliitis were more frequent in patients with PsA than in those with uncomplicated psoriasis (25.8% vs 10.3%, P = 0.04; 37.9% vs 16.7%, P = 0.02; and 37.8% vs 1.1%, P < 0.01, respectively). The onset ages of psoriasis and arthritis in the spondylitis group were significantly lower than those in the non-spondylitis group (median age, 21.5 vs 31 years, P = 0.03, and 28.5 vs 43.5 years, P = 0.01, respectively). HLA-B27 was prevalent in 8% of patients with PsA.

Recently, chondrocytes were shown to undergo apoptosis by the addition of nitric oxide and by coupling of Fas/Fas ligand in vitro, suggesting the possibility that chondrocytes have an inherent programmed cell death pathway that operates in adult cartilage. Chondrocyte apoptosis was verified in situ in articular cartilage samples from humans with osteoarthritis (OA) and from an animal model of OA. The present study investigates apoptotic chondrocyte death and the expression of Bcl-2 and Fas in rheumatoid arthritis (RA) cartilage. Cartilage samples were obtained from 13 RA patients at the time of joint replacement surgery and from 8 normal subjects at autopsy. Apoptotic chondrocytes were observed and counted in hematoxylin and eosin–stained cartilage specimens. Apoptosis was verified by TUNEL, electron microscopy, and DNA ladder assay. Bcl-2 and Fas expression were evaluated by immunohistochemistry. Apoptotic cells were frequently observed in RA cartilage, whereas normal cartilage rarely showed apoptotic cells (3.01% versus 0.15%, respectively), a finding that was further confirmed by TUNEL staining. On electron microscopy, numerous apoptotic cells with typical chromatin condensation were observed in RA cartilage. DNA from RA cartilage also revealed 180-basepair nucleosome ladders on electrophoresis. Bcl-2 expression was significantly lower in RA cartilage than in normal cartilage (23.3% versus 43.1%, respectively), whereas Fas expression was not statistically different. Apoptotic chondrocyte death and decreased Bcl-2 expression were verified in RA cartilage. They might provide a novel model system for the research of cartilage breakdown and joint destruction in RA.

To better understand genetic contributions to autoimmunity, immunogenetic markers were studied in two racially discrete and geographically isolated populations of patients with idiopathic inflammatory myopathy (IIM). Clinical characteristics, as well as clinical and autoantibody subsets, were defined in 151 American white patients and 50 Korean patients with IIM. HLA–DRB1 and DQA1 genotyping was performed on patients and racially matched controls by standard molecular techniques. Gm allotypes and phenotypes were determined by the hemagglutination-inhibition method. HLA–DRB1*0301, the linked allele DQA1*0501, and DRB1 alleles sharing the first hypervariable region motif ⁹EYSTS¹³ were major genetic risk factors for the development of myositis in whites (corrected P [Pcorr] &lt; 0.0004, odds ratio [OR] 11.2, 4.5, and 3.1, respectively, for each factor versus controls). Although both the white and Korean patients had a similar distribution of clinical characteristics, autoantibody profiles, and clinical groups, no HLA–DRB1 nor DQA1 allele or motif was found to be a risk factor for IIM in the Korean patients. However, DRB1*14 was a protective factor in Korean patients without myositis-specific autoantibodies (Pcorr = 0.004, OR 0.046). In addition, although no Gm phenotype or allotype was identified as a risk factor in whites, Gm 21 was a protective factor for the development of IIM in Koreans (Pcorr = 0.024, OR 0.3). Although myositis patients in the US and Korea share similar clinical and serologic features, the immune response genes predisposing to and protecting from myositis in each of these ethnic groups differ at two chromosomal loci. These data suggest that multiple genetic loci should be studied to identify risk and protective factors for some autoimmune diseases in various ethnic populations.

Objectives: Histone deacetylase (HDAC) 6 promotes inflammation. We investigated the anti-arthritic effects of CKD-506, a novel HDAC6 inhibitor, in vitro and in a murine model of arthritis as a novel treatment option for rheumatoid arthritis (RA). Methods: HDAC6 was overexpressed in mouse peritoneal macrophages and RAW 264.7 cells, and the effects of a HDAC6 inhibitor CKD-506 on cytokine production and activity of NF-κB and AP-1 signaling were examined. Peripheral blood mononuclear cells (PBMCs) from RA patients and fibroblast-like synoviocytes (FLS) were activated in the presence of CKD-506. Next, regulatory T cells (Tregs) were induced from RA patients and co-cultured with healthy effector T cells (Teffs) and cell proliferation was analyzed by flow cytometry. Finally, the effects of the inhibitor on the severity of arthritis were assessed in a murine model of adjuvant-induced arthritis (AIA). Results: Overexpression of HDAC6 induced macrophages to produce TNF-α and IL-6. The inhibitory effect of CKD-506 was mediated via blockade of NF-κB and AP-1 activation. HDAC6 inhibition reduced TNF-α and IL-6 production by activated RA PBMCs. CKD-506 inhibited production of MMP-1, MMP-3, IL-6, and IL-8 by activated FLS. In addition, CKD-506 inhibited proliferation of Teffs directly and indirectly by improving iTreg function. In AIA rats, oral CKD-506 improved clinical arthritis in a dose-dependent manner. A combination of sub-therapeutic CKD-506 and methotrexate exerted a synergistic effect. Conclusion: The novel HDAC6 inhibitor CKD-506 suppresses inflammatory responses by monocytes/macrophages, improves Treg function, and ameliorates arthritis severity in a murine model of RA. Thus, CKD-506 might be a novel and effective treatment option for RA.

Background: Peficitinib (ASP015K), a novel oral Janus kinase inhibitor, has demonstrated efficacy and safety for the treatment of rheumatoid arthritis (RA) in randomized, controlled trials of up to 52 weeks’ duration. However, safety and effectiveness after long-term treatment have not been assessed. Methods: This was an interim analysis of an ongoing open-label, multicenter extension study in RA patients who completed phase 2b (RAJ1; 12 weeks) and phase 3 (RAJ3 and RAJ4; 52 weeks) peficitinib studies in Asia (mainly Japan). Eligible patients (n= 843) received oral peficitinib once daily (100 mg, or 50 mg for patients transferring from RAJ1). The peficitinib dose could be increased (up to 150 mg) or reduced (to 50 mg) at the discretion of the investigator. Efficacy variables assessed included American College of Rheumatology (ACR) response rates, ACR components, and disease activity score in 28 joints based on C-reactive protein (DAS28-CRP). Results: Results up to May 2018 are summarized. Mean peficitinib duration of exposure was 22.7 months and the maximum dose was 100 mg in most (66.5%) patients. ACR responses were maintained during the extension study, with ACR20/50/70 response rates of 71.6%, 52.1%, and 34.7% at week 0 and 78.9%, 61.4%, and 42.7% at end of treatment, respectively. ACR components and DAS28-CRP showed improvements from baselines of the preceding studies and continued to show improvements during the extension study. Treatment-emergent adverse events (TEAEs) were reported in 757/843 (89.8%) patients, the most common being nasopharyngitis (39.7%) and herpes zoster (11.7%). The majority of TEAEs were severity grade 1/2. Drug-related TEAEs leading to permanent study drug discontinuation occurred in 55/843 (6.5%) patients. Regarding AEs of special interest, the incidence per 100 patient-years of serious infections was 2.3 (95% CI 1.6 – 3.1), herpes zoster-related disease 6.8 (95% CI, 5.6 – 8.3), and malignancies 1.1 (95% CI, 0.7 – 1.8). One death from diffuse large B cell lymphoma during the study and one death from uterine sarcoma after the study were considered probably and possibly related to study drug, respectively. Conclusions: The effectiveness of peficitinib was maintained or improved during long-term administration and treatment up to 6 years was well tolerated in Asian patients with RA. Trial registration: ClinicalTrials.gov, NCT01638013, registered retrospectively 11 July 2012.

An amendment to this paper has been published and can be accessed via the original article.

An amendment to this paper has been published and can be accessed via the original article.

Background: The tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear. Methods: We measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA. Results: Soluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions. Conclusions: TL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA.

Thrombocytopenia is one of the common manifestations of systemic lupus erythematosus (SLE). Its treatment consists of corticosteroids and/or other immunosuppressive drug such as azathioprine, vincristine, cyclosporine, and mycophenolate mofetil. Common adverse reactions of immunosuppressive treatment are infections, hematologic and liver function abnormalities, but neurologic complications may also be seen. Reversible posterior leukoencephalopathy syndrome (RPLS) is a syndrome manifested by headache, nausea, vomiting, seizures, cortical blindness, and visual disturbances. Neuroimaging shows bilateral subcortical and cortical edema with prominent posterior distribution. Moreover, treatment with immunosuppressive drugs such as cyclosporine, cisplatin, tacrolimus, and interferon-alpha can induce a condition resembling RPLS. We report a case of a young woman with SLE and thrombocytopenia, who developed severe perspiration, headache, and seizure after receiving cyclosporine. A brain magnetic resonance image showed multiple high signal intensities on T2-weighted images predominantly located at the parietooccipital lobe. The patient recovered completely clinically and radiologically after discontinuing cyclosporine.

Osteoclasts are responsible for the bone erosion associated with rheumatoid arthritis (RA). The upregulation of the chemokines CCL19 and CCL21 and their receptor CCR7 has been linked to RA pathogenesis. The purpose of this study was to evaluate the effects of CCL19 and CCL21 on osteoclasts and to reveal their underlying mechanisms. The expression of CCL19, CCL21 and CCR7 was higher in RA patients than in osteoarthritis patients. In differentiating osteoclasts, tumor necrosis factor-α, interleukin-1β and lipopolysaccharide stimulated CCR7 expression. CCL19 and CCL21 promoted osteoclast migration and resorption activity. These effects were dependent on the presence of CCR7 and abolished by the inhibition of the Rho signaling pathway. CCL19 and CCL21 promoted bone resorption by osteoclasts in an in vivo mice calvarial model. These findings demonstrate for the first time that CCL19, CCL21 and CCR7 play important roles in bone destruction by increasing osteoclast migration and resorption activity. This study also suggests that the interaction of CCL19 and CCL21 with CCR7 is an effective strategic focus in developing therapeutics for alleviating inflammatory bone destruction.

Background: Exosomes are involved in intercellular communication. The aim of this study was to investigate whether circulating exosomes effectively contribute to the inflammatory response in systemic lupus erythematosus (SLE). Methods: Exosomes were purified from SLE patients and healthy controls (HCs). Healthy peripheral blood mononuclear cells (PBMCs) were stimulated with exosomes isolated from SLE patients and HCs in the presence or absence of Toll-like receptor (TLR) inhibitors. Production of interferon (IFN)-α, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were measured. Correlation between exosome levels and SLE disease activity was examined. Results: The serum exosomes levels were significantly higher in SLE patients than in HCs. SLE exosomes induced a higher production of IFN-α, TNF-α, IL-1β, and IL-6 compared to healthy exosomes. SLE serum that was depleted of exosomes and SLE exosomes that were mechanically disrupted failed to induce any significant cytokine production. Exosome-mediated production of TNF-α, IL-1β, and IL-6 was decreased by the TLR4 antagonist, whereas that of IFN-α was suppressed by the TLR1/2, TLR7, and TLR9 antagonists. Exosome levels correlated with disease activity in SLE patients (rho = 0.846, p= 0.008). Conclusions: The circulating exosomes are immunologically active and their levels correlate with disease activity in SLE patients. The circulating exosomes might serve as novel biomarkers of SLE disease activity.

CAAT/enhancer-binding protein-beta (C/EBPβ) is a transcription factor that regulates interleukin-1β (IL-1β)-induced catabolic pathways, including the expression of matrix metalloproteinases (MMPs), in chondrocytes. We previously reported that suppressor of cytokine signaling 1 (SOCS1) inhibits IL-1β signaling in chondrocytes. However, the effect of SOCS1 on C/EBPβ has not been explored. To investigate the interaction between SOCS1 and C/EBPβ, we established human SW1353 cells with overexpression or knockdown of SOCS1 or C/EBPβ. Both SOCS1 and C/EBPβ were involved in transcription of MMP-3 and MMP-13. When stimulated with IL-1β, C/EBPβ levels were significantly increased by SOCS1 knockdown and decreased by SOCS1 overexpression. A similar change in IL-1β-induced C/EBPβ expression was observed in SOCS1-transfected human articular chondrocytes. However, C/EBPβ overexpression or knockdown did not change the levels of IL-1β-induced SOCS1. SOCS1 regulated the levels of C/EBPβ mRNA by ubiquitination of C/EBPβ as well as transcriptional regulation. Furthermore, it suppressed the phosphorylation of cAMP response element-binding protein (CREB), an active transcription factor of C/EBPβ. In addition, p38 mitogen-activated protein kinases, a target of SOCS1, was involved in CREB phosphorylation. The chromatin immunoprecipitation assay confirmed that SOCS1 overexpression led to reduced binding of C/EBPβ to the MMP-13 promoter. Taken together, our results demonstrate that SOCS1 downregulates the p38-CREB-C/EBPβ pathway resulting in increased expression of MMPs in chondrocytes.

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Introduction: The objective was to investigate associations between the HLA-Agene and Behcet's disease (BD) and its clinical manifestations. Methods: Genotyping for the HLA-Alocus was performed using the polymerase chain reaction-Luminex typing method in 223 BD patients and 1,398 healthy controls. Results: The phenotypic frequencies of HLA-A*02:07(odds ratio (OR) = 2.03, P= 0.002), A*26:01(OR = 1.85, P= 0.008), and A*30:04(OR = 2.51, P= 0.006) tended to be higher in BD patients than in normal controls, but the frequency of A*33:03(OR = 0.59, P= 0.003) tended to be lower in BD patients. A meta-analysis adopting our and the Japanese data confirmed the associations of HLA-A*02:07, A*26:01, and A*33:03with BD. Furthermore, the frequencies of the HLA-A*02:07, A*26:01, and A*30:04were significantly higher in patients with skin lesions (OR = 2.37, P&lt; 0.0005, Pc&lt; 0.012) and arthritis (OR = 2.32, P= 0.002, Pc= 0.048), with uveitis (OR = 3.01, P&lt; 0.0005, Pc&lt; 0.012), and with vascular lesions (OR = 9.80, P&lt; 0.0005, Pc &lt;0.012) and a positive pathergy test (OR = 4.10, P= 0.002, Pc= 0.048), respectively, than in controls. In HLA-B*51non-carriers, these associations were also significant, being much stronger between HLA-A*26:01and uveitis (OR = 4.19, P&lt; 0.0005, Pc&lt; 0.012) and between HLA-A*30:04and vascular lesions (OR = 13.97, P&lt; 0.00005, Pc&lt; 0.0012). In addition, HLA-A*30:04was associated with genital ulcers in HLA-B*51non-carriers (OR = 3.89, P= 0.002, Pc= 0.048). Conclusions: HLA-A*02:07, A*26:01, and A*30:04were associated with increased risk for BD, while HLA-A*33:03with decreased risk. HLA-A*02:07, A*26:01, and A*30:04were associated with skin lesions and arthritis, with uveitis, and with vascular lesions, genital ulcers, and a positive pathergy test, respectively.

Heat shock protein 70 (Hsp70) is a well-known anti-apoptotic protein that blocks multiple steps in the stress-induced apoptotic pathway. Enhanced Hsp70 expression has previously been demonstrated in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs). The authors investigated the role of Hsp70 in the survival of RA FLSs in a sodium nitroprusside (SNP)-treated environment.