Kengo Akashi

Tofacitinib Facilitates the Expansion of Myeloid-Derived Suppressor Cells and Ameliorates Arthritis in SKG Mice

Myeloid‐derived suppressor cells (MDSCs) are a heterogeneous population of cells that have the ability to suppress T cell responses. The aim of this study was to evaluate the effects of the JAK inhibitor tofacitinib on MDSCs in a mouse model of rheumatoid arthritis.

Drug retention and discontinuation reasons between seven biologics in patients with rheumatoid arthritis -The ANSWER cohort study-

The purpose of this study was to evaluate the retention and discontinuation reasons of seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with rheumatoid arthritis (RA). 1,037 treatment courses with bDMARDs from 2009 to 2016 [female, 81.8%; baseline age, 59.6 y; disease duration 7.8 y; rheumatoid factor positivity 81.5%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR), 4.4; concomitant prednisolone 43.5% and methotrexate 68.6%; Bio-naïve, 57.1%; abatacept (ABT), 21.3%; tocilizumab (TCZ), 20.7%; golimumab (GLM), 16.9%; etanercept (ETN), 13.6%; adalimumab (ADA), 11.1%; infliximab (IFX), 8.5%; certolizumab pegol (CZP), 7.9%] were included in this multi-center, retrospective study. Drug retention and discontinuation reasons at 36 months were estimated using the Kaplan-Meier method and adjusted by potent confounders using Cox proportional hazards modeling. As a result, 455 treatment courses (43.9%) were stopped, with 217 (20.9%) stopping due to inefficacy, 113 (10.9%) due to non-toxic reasons, 86 (8.3%) due to toxic adverse events, and 39 (3.8%) due to remission. Drug retention rates in the adjusted model were as follows: total retention (ABT, 60.7%; ADA, 32.7%; CZP, 43.3%; ETN, 51.9%; GLM, 45.4%; IFX, 31.1%; and TCZ, 59.2%; P < 0.001); inefficacy (ABT, 81.4%; ADA, 65.7%; CZP, 60.7%; ETN, 71.3%; GLM, 68.5%; IFX, 65.0%; and TCZ, 81.4%; P = 0.015), toxic adverse events (ABT, 89.8%; ADA, 80.5%; CZP, 83.9%; ETN, 89.2%; GLM, 85.5%; IFX, 75.6%; and TCZ, 77.2%; P = 0.50), and remission (ABT, 95.5%; ADA, 88.1%; CZP, 91.1%; ETN, 97.5%; GLM, 94.7%; IFX, 86.4%; and TCZ, 98.4%; P < 0.001). In the treatment of RA, ABT and TCZ showed higher overall retention, and TCZ showed lower inefficacy compared to IFX, while IFX showed higher discontinuation due to remission compared to ABT, ETN, GLM, and TCZ in adjusted modeling.

Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis

BackgroundThe recent findings of cancer-specific metabolic changes, including increased glucose and glutamine consumption, have provided new therapeutic targets for consideration. Fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients exhibit several tumor cell-like characteristics; however, the role of glucose and glutamine metabolism in the aberrant proliferation of these cells is unclear. Here, we evaluated the role of these metabolic pathways in RA-FLS proliferation and in autoimmune arthritis in SKG mice.MethodsThe expression of glycolysis- or glutaminolysis-related enzymes was evaluated by real-time polymerase chain reaction (PCR) and Western blotting, and the intracellular metabolites were evaluated by metabolomic analyses. The effects of glucose or glutamine on RA-FLS cell growth were investigated using glucose- or glutamine-free medium. Glutaminase (GLS)1 small interfering RNA (siRNA) and the GLS1 inhibitor compound 968 were used to inhibit GLS1 in RA-FLS, and compound 968 was used to study the effect of GLS1 inhibition in zymosan A-injected SKG mice.ResultsGLS1 expression was increased in RA-FLS, and metabolomic analyses revealed that glutamine metabolism was increased in RA-FLS. RA-FLS proliferation was reduced under glutamine-deprived, but not glucose-deprived, conditions. Cell growth of RA-FLS was inhibited by GLS1 siRNA transfection or GLS1 inhibitor treatment. Treating RA-FLS with either interleukin-17 or platelet-derived growth factor resulted in increased GLS1 levels. Compound 968 ameliorated the autoimmune arthritis and decreased the number of Ki-67-positive synovial cells in SKG mice.ConclusionsOur results suggested that glutamine metabolism is involved in the pathogenesis of RA and that GLS1 plays an important role in regulating RA-FLS proliferation, and may be a novel therapeutic target for RA.

CD11b+Gr-1dim Tolerogenic Dendritic Cell–Like Cells Are Expanded in Interstitial Lung Disease in SKG Mice

SKG mice develop interstitial lung disease (ILD) resembling rheumatoid arthritis–associated ILD in humans. The aim of this study was to clarify the mechanism underlying the lung pathology by analyzing lung‐infiltrating cells in SKG mice with ILD.

Hepatitis B Virus Reactivation Following Salazosulfapyridine Monotherapy in a Patient with Rheumatoid Arthritis

A 72-year-old man was diagnosed with rheumatoid arthritis (RA) and prior hepatitis B virus (HBV) infection. He began treatment with salazosulfapyridine (SASP). Several months later, his blood tests reflected a slightly elevated liver function. Serum tests were positive for hepatitis B surface antigen and HBV-DNA, and the diagnosis of de novo HBV hepatitis was made. A genetic analysis showed that he had polymorphisms of ABCG2 and NAT2, which could lead to high plasma concentrations of SASP and sulfapyridine. To the best of our knowledge, this is the first report of de novo hepatitis developing during SASP monotherapy for RA.

Knockout of endothelin type B receptor signaling attenuates bleomycin-induced skin sclerosis in mice

BackgroundEndothelin-1 (ET-1) is important in the pathogenesis of systemic sclerosis (SSc). ET-1 binds two receptors, endothelin type A (ETA) and endothelin type B (ETB). Dual ETA/ETB receptor antagonists and a selective ETA receptor antagonist are used clinically to treat SSc, and the effect of these antagonists on fibroblast activation has been described. However, the role of ETB receptor signaling in fibrogenesis is less clear. This study was conducted to evaluate the profibrotic function of ETB receptor signaling in a murine model of bleomycin (BLM)-induced scleroderma.MethodsWe used ETB receptor–knockout (ETBKO) mice, which are genetically rescued from lethal intestinal aganglionosis by an ETB receptor transgene driven by the human dopamine β-hydroxylase (DβH)-gene promoter, and wild-type mice with DβH-ETB (WT). BLM or phosphate-buffered saline (PBS) was administered subcutaneously by osmotic minipump, and skin fibrosis was assessed by dermal thickness, subcutaneous fat atrophy, and myofibroblast count in the dermis. Dermal fibroblasts isolated from ETBKO and WT mice were cultured in vitro, stimulated with BLM or ET-1, and the expression of profibrotic genes was compared by quantitative PCR.ResultsDermal thickness, subcutaneous fat atrophy, and myofibroblast counts in the dermis were significantly reduced in ETBKO mice compared to WT mice, after BLM treatment. Compared with wild-type, dermal fibroblasts isolated from ETBKO mice showed lower gene expressions of α-smooth muscle actin and collagen 1α1 in response to BLM or ET-1 stimulation in vitro.ConclusionsET-1–ETB receptor signaling is involved in skin sclerosis and in collagen synthesis by dermal fibroblasts.

FRI0553 The efficacy of 2-years denosumab treatment for glucocorticoid-induced osteoporosis (GIOP)

Background Osteoporosis is one of the important adverse effects in the glucocorticoids treatment for the patients with rheumatoid arthritis (RA) and connective tissue diseases (CTDs). Although the usefulness of denosmab for primary osteoporosis has been well-established, the efficacy for GIOP remains unclear. Objectives This study aimed to clarify the therapeutic effects of denosumab for GIOP. Methods We evaluated bone mineral density (BMD) and serum markers of bone metabolism (BAP, NTx, TRACP-5b and P1NP) of patients who had been treated with over 5mg of predonisolone for RA and CTDs, and denosumab for GIOP, for two years in Kobe University Hospital. BMD and serum markers were evaluated every six months for 2 years from the baseline. The changes of those data from baseline were analyzed by Students t test using GraphPad Prism 5 software and p<0.05 was considered statistically significant. Results Number of the patients were 53 (male: 4 cases, female: 49 cases), and their characteristics at the beginning of denosumab treatment were as below; age: 64.19±12.0 years old, dose of prednisolon: 10.59±9.97mg/day, BMD of lumber spine: 0.768±0.112g/cm3, T-score of lumber spine: -2.28±1.01, BMD of femoral neck: 0.540±0.085g/cm3, T-score of femoral neck: -2.28±0.76. After 2-years denosumab treatment, T-scores of lumber spine (0.54±0.39 gain) and femoral neck (0.13±0.26 gain) were significantly increased from baseline (Figure; mean ± SEM. *:p<0.05). In addition, the serum markers of bone metabolism, both absorption and formation, were significantly suppressed with denosumab. Conclusions Denosumab can suppress bone metabolic turnover, and increase lumber spine and femoral neck T-scores of GIOP patients. Disclosure of Interest None declared

THU0611 Subjective Well-Being of Japanese RA Patients Who Reach Treatment Target Is Higher than The Japanese Average

Background Subjective Well-Being (SWB) refers to a construct which includes ones emotional responses, domain satisfactions, and global judgments of life satisfaction. Many variables such as age, sex, income, employment and marital status are related to SWB. Being healthy is also an important factor of SWB. RA is a chronic illness which is considered to influence SWB. However, little is known about the impact of RA on SWB. Objectives To evaluate the SWB of Japanese RA patients and identify factors that associate with SWB. Methods This study was done in cooperation with the Cabinet Office Government of Japan Economic and Social Research Institute. This institute had previously conducted the “Well-being studies 2014” surveying the SWB of randomly selected Japanese citizens. In this survey, SWB was determined by having the participants rate their happiness between 10 (Very happy) and 0 (very unhappy). The Well-being studies 2014 also included a questionnaire consisting of 56 questions covering topics closely associated with well-being such as socioeconomic and health status. The same survey was done for RA patients at Kobe University Hospital and clinical data including disease duration, stage, class, disease activity, HAQ, complications and the therapeutic drug was also collected at the same time. Results Multivariate analysis on data including RA patients (n=339) and Japanese controls (n=7690) revealed that RA patients with high or moderate disease activity had similar SWB scores as Japanese controls. However, the SWB of RA patients with remission or low disease activity were higher than Japanese controls. Age, sex, marital status, presence of child, household income, financial leeway, working status, psychological distress (Kessler 6 scale), self-assessment of health, and social connection were all associated with SWB. Conclusions Japanese RA patients may be able to get higher SWB than Japanese controls by achieving treatment target. Disclosure of Interest None declared

AB0192 Some of The Painful RA Patients Underrate Global Health VAS at Hospitals

Background Evaluating patient global VAS is one of the most essential process in RA practice. Despite reliability of patient global VAS being highly important in clinical practice, there has been no study comparing global VAS scores obtained at hospitals and those obtained at home where patients answer anonymously. Objectives To compare the patient global VAS obtained before clinical examination in hospital with those answered anonymously at home. Methods We asked RA patients to answer and mail the EQ5D data set anonymously. EQ5D consisted of 5 component questions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and patient assessment global health VAS. EQ5D global VAS is anonymized patient global VAS evaluated at home. We compared the patient global VAS which is routinely surveyed at hospital before clinical examination with those surveyed anonymously at home. Results The anonymized VAS score was higher than those routinely evaluated at hospital (p<0.0001). Global VAS scores obtained at hospital poorly correlated with those obtained anonymously at home (r=0.426). We compared patients who had higher patient global VAS at hospital than anonymized VAS at home with patients who had lower patient global VAS at hospital than anonymized VAS at home. Pain VAS scores remained to be risk factor to be higher anonymized VAS at home than those routinely evaluated at hospital after multivariate analysis. Conclusions Discrepancy exists between patient global VAS evaluated in the hospital before clinical examination and those evaluated anonymously at home. There is a possibility that patients rating high pain VAS are underrating their global VAS scores at hospital. Disclosure of Interest None declared

OP0297 Knockout of Endothelin Type B Receptor Signaling Attenuates Bleomycin-Induced Skin Sclerosis in Mice

Background Endothelin-1 (ET-1) is important in the pathogenesis of systemic sclerosis (SSc). It has been reported that plasma concentration of ET-1 are higher in SSc patients, and that endothelin receptor expression are also increased in lungs and skins in the patients. ET-1 binds two receptors, endothelin type A (ETA) and endothelin type B (ETB). Dual ETA/ETB receptor antagonists and a selective ETA receptor antagonist are used clinically to treat SSc, and the effect of these antagonists on fibroblast activation has been described. However, the role of ETB receptor signaling in fibrogenesis is less clear. Objectives This study was conducted to evaluate the profibrotic function of ETB receptor signaling in a murine model of bleomycin (BLM)-induced scleroderma. Methods We used ETB receptor–knockout (ETBKO) mice, which are genetically rescued from lethal intestinal aganglionosis by an ETB receptor transgene driven by the human dopamine β-hydroxylase (DβH)-gene promoter, and wild-type mice with DβH-ETB (WT). BLM or phosphate-buffered saline (PBS) was administered subcutaneously by osmotic minipump, and skin fibrosis was assessed by dermal thickness, subcutaneous fat atrophy, and alpha-smooth muscle actin (αSMA)-expressing myofibroblast count in the dermis. Dermal fibroblasts isolated from ETBKO and WT mice were cultured in vitro, stimulated with BLM or ET-1, and the expression of profibrotic genes was compared by quantitative PCR. Results Dermal thickness, subcutaneous fat atrophy, and myofibroblast counts in the dermis were significantly reduced in ETBKO mice compared to WT mice, after BLM treatment. Compared with wild-type, dermal fibroblasts isolated from ETBKO mice showed lower gene expressions of αSMA and collagen 1α1 in response to BLM or ET-1 stimulation in vitro. Conclusions ET-1–ETB receptor signaling is involved in skin sclerosis and in collagen synthesis by dermal fibroblasts. Disclosure of Interest None declared