G. Kageyama

The first report of adolescent TAFRO syndrome, a unique clinicopathologic variant of multicentric Castleman’s disease

BackgroundTAFRO syndrome is a unique clinicopathologic variant of multicentric Castleman’s disease that has recently been identified in Japan. It is characterized by a constellation of symptoms: Thrombocytopenia, Anasarca, reticulin Fibrosis of the bone marrow, Renal dysfunction and Organomegaly (TAFRO). Previous reports have shown that affected patients usually respond to immunosuppressive therapy, but the disease sometimes has a fatal course. TAFRO syndrome occurs in the middle-aged and elderly and there are no prior reports of the disease in adolescents. Here we report the first adolescent case, successfully treated with anti-IL-6 receptor antibody (tocilizumab, TCZ) and monitored with serial cytokine profiles.Case presentationA 15-year-old Japanese boy was referred to us with fever of unknown origin. Whole body computed tomography demonstrated systemic lymphadenopathy, organomegaly and anasarca. Laboratory tests showed elevated C-reactive protein and hypoproteinemia. Bone marrow biopsy revealed a hyperplastic marrow with megakaryocytic hyperplasia and mild reticulin fibrosis. Despite methylprednisolone pulse therapy, the disease progressed markedly to respiratory distress, acute renal failure, anemia and thrombocytopenia. Serum and plasma levels of cytokines, including IL-6, vascular endothelial growth factor, neopterin and soluble tumor necrosis factor receptors I and II, were markedly elevated. Repeated weekly TCZ administration dramatically improved the patient’s symptoms and laboratory tests showed decreasing cytokine levels.ConclusionTo our knowledge, this is the first report of TAFRO syndrome in a young patient, suggesting that this disease can occur even in adolescence. The patient was successfully treated with TCZ. During our patient’s clinical course, monitoring cytokine profiles was useful to assess the disease activity of TAFRO syndrome.

Metabolomics analysis of saliva from patients with primary Sjögren's syndrome

The recent development of salivary proteomics has led to the identification of potential biomarkers for diagnosing patients with primary Sjögrens syndrome (pSS). Here we sought to identify differentially produced salivary metabolites from pSS patients and healthy controls (HCs) that might be used to characterize this disease. We obtained salivary samples from 12 female pSS patients (mean age 44.2 ± 13.01) and 21 age‐matched female HCs. The metabolite profiles of saliva were analysed by gas chromatography‐mass spectrometry. The total metabolite levels in each of the samples were calculated and compared across the study participants. A total of 88 metabolites were detected across the study samples, 41 of which were observed at reduced levels in the samples frompSS patients. Principal component analysis (PCA) revealed a loss in salivary metabolite diversity in the pSS patient samples compared to the HC samples. The reduced presence of glycine, tyrosine, uric acid and fucose, which may reflect salivary gland destruction due to chronic sialoadenitis, contributed to the loss of diversity. Comparative PCA of the pSS patients revealed the presence of two subpopulations based on their metabolite profiles, and these two subpopulations showed a significant difference in the prevalence of major salivary glanditis (P = 0·014). In this study, we found that the salivary metabolite profile of pSS patients was less diverse than that of HCs and that the metabolite profiles in pSS patients were affected by the presence of major salivary glanditis.

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.

IgG4-related disease manifesting as pericarditis with elevated adenosine deaminase and IL-10 levels in pericardial fluid.

A 78-year-old female with massive pericardial effusion fulfilled diagnostic criteria for immunoglobulin G4 (IgG4)-related disease. Although her adenosine deaminase (ADA) level in the pericardial effusion was high, all the tests for tuberculosis infection were negative. Immunostaining of the pericardium biopsy specimen revealed remarkably increased IgG4-positive cells. This is the first report describing IgG4-related pericarditis with elevated ADA level. We also demonstrate the elevated interleukin-10 (IL-10) level in pericardial fluid and IL-10-producing T-cells in the pericardium.

Very high frequency of fragility fractures associated with high-dose glucocorticoids in postmenopausal women: A retrospective study ☆

Purpose To evaluate the incidence of fragility fractures associated with high-dose glucocorticoid therapy in patients with systemic rheumatic disease. Methods: A retrospective study of patients who were treated with high-dose prednisolone (> 0.8 mg/kg) for systemic rheumatic disease at Kobe University Hospital from April 1988 to March 2012. The primary outcome was a major osteoporotic fracture (defined as a clinical vertebral, hip, forearm, or proximal humerus fracture) after high-dose glucocorticoid therapy. For postmenopausal women and men over 40 of age, the patients fracture risk at the beginning of high-dose glucocorticoid therapy was assessed by the World Health Organizations Fracture Risk Assessment Tool (FRAX®). Results Of 229 patients (median age: 49 years), 57 suffered a fragility fracture during the observation period (median observation period: 1558 days). Of 84 premenopausal patients, 5 suffered a fracture. In contrast, of 86 postmenopausal female, 36 suffered a fracture. Fragility fractures were far more frequent than predicted by the FRAX® score. Patients with FRAX® scores over 8.3% had a particularly high risk of fracture. Conclusions Fragility fractures associated with high-dose glucocorticoid therapy are common among postmenopausal women. Extreme care should be taken especially for postmenopausal women when high-dose glucocorticoid therapy is required.

THU0668 Reliability of patient global assessment in rheumatoid arthritis patients

Background Patients global assessment (PtGA) is one of the most widely used patient reported outcomes in rheumatoid arthritis (RA) that reflects both disease activity and other factors. PtGA is onymous and obtained at hospital, which may cause a conscious or unconscious bias, whereas PtGA obtained anonymously may be free from any bias. The credibility of PtGA to report RA patient outcomes has been usually investigated by assessing test-retest reliability. There has been no study comparing routine PtGA and PtGA where patients answered anonymously. Objectives The aim of this study was to compare routinely obtained in-hospital PtGA before clinical examination with those answered anonymously at home. Additionally, physicians global assessment (PhyGA) was compared with routine PtGA and anonymized PtGA Methods We asked RA patients (n=389) to answer and mail the PtGA test anonymously, Clinical data regarding disease duration, stage, class, swollen joint counts, tender joint counts, pain visual analog scale (VAS), PhyGA, Health Assessment Questionnaire (HAQ), EuroQOL five dimensions questionnaire (EQ5D), Kessler 6 scale (anxiety/ depression), treatment data, laboratory data, and socioeconomic factors were collected simultaneously. We compared the PtGA that is routinely surveyed at hospital before clinical examination with those surveyed anonymously at home. We calculated a discrepancy score by subtracting anonymized PtGA from routine in-hospital PtGA. We defined (1) positive discrepancy when routine PtGA was over-rated relative to the anonymized PtGA; (2) negative discrepancy when routine in-hospital PtGA was under-rated relative to the anonymized PtGA. Results The anonymized PtGA score was higher than routinely evaluated in-hospital PtGA (p<0.0001). The anonymized PtGA poorly correlated with routine in-hospital PtGA (r=0.426, p<0.0001). We compared patients who had discordance between in-hospital PtGA and anonymized PtGA. We used 3 models in which the discordance between both PtGAs was set at 10 mm, 20 mm, or 30 mm. If we adopted 30 mm as discordance, the pain scale remained to be a risk factor of positive discrepancy (higher in-hospital PtGA than anonymized PtGA). If we adopted 20 mm or 10 mm as discordance, the pain scale remained to be a risk factor of positive discrepancy and remaining low quality of life (QOL) negative discrepancy (lower in-hospital PtGA than anonymized PtGA) after multivariate analysis. The discordance between PhyGA and routine PtGA are associated with high pain VAS. The discordance between PhyGA and anonymized PtGA is associated with tender joint counts, swollen joint counts, and low QOL. Conclusions Discrepancy exists between routine in-hospital PtGA and anonymized PtGA. The high pain VAS scale and low QOL are risk factors that could make the difference between routine PtGA from anonymized PtGA. There is a possibility that high pain VAS score and low QOL influence the reliability of PtGA. Disclosure of Interest None declared

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

Expression and Functions of Immediate Early Response Gene X-1 (IEX-1) in Rheumatoid Arthritis Synovial Fibroblasts

In rheumatoid arthritis (RA), synovial fibroblasts (RA-SFs) accumulate in affected joints, where they play roles in inflammation and joint destruction. RA-SFs exhibit tumor-like proliferation and are resistant to apoptosis. Although RA-SF activation is well described, negative regulators of RA-SF activation are unknown. We previously reported that histone deacetylase (HDAC) inhibitors facilitate apoptosis in RA-SFs. Here we found that RA-SFs treated with the HDAC inhibitor Trichostatin A (TSA) exhibited an upregulation of the immediate early response gene X-1 (IEX-1). IEX-1 has roles in apoptosis sensitivity, cell-cycle progression, and proliferation, and is reported to be involved in immune responses, inflammation, and tumorigenesis, and to have anti-arthritic properties. To investigate IEX-1’s role in RA-SFs, we used in vitro-cultured synovial fibroblasts from RA and osteoarthritis (OA) patients. We confirmed that TSA upregulated the IEX-1 protein and mRNA expressions in RA-SFs by western blotting and quantitative RT-PCR. Inhibiting HDAC1, 2, and 3 (but not 6 or 8) also upregulated IEX-1. The IEX-1 mRNA levels were higher in RA-SFs than in OA-SFs, and were further upregulated in RA-SFs by the pro-inflammatory cytokines TNFα and IL-1β. The staining of surgical specimens showed that IEX-1 was present in the pannus from affected RA joints. Si-RNA-mediated IEX-1 knockdown upregulated the lipopolysaccharide (LPS)-induced expression of TNFα and various chemokine mRNAs, indicating that IEX-1 downregulates TNFα and chemokines. Furthermore, apoptosis analysis showed that IEX-1 knockdown protected RA-SFs from apoptosis induced by TSA or by an anti-Fas mAb, indicating that IEX-1 is pro-apoptotic in RA-SFs. Collectively, our results showed that IEX-1 is induced by TNFα and IL-1β in RA-SFs, in which it suppresses TNFα and chemokine production and induces apoptosis; thus, IEX-1 negatively regulates RA-SF activation. Further investigation of IEX1’s functions in RA-SFs may lead to new therapeutic approaches for RA.

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