Maasa Tamura

Initial predictors of poor survival in myositis-associated interstitial lung disease: a multicentre cohort of 497 patients

Objective To identify initial predictors of poor survival in patients with PM/DM-associated interstitial lung disease (ILD). Methods We established a multicentre retrospective cohort of incident cases of PM/DM-associated ILD from 44 institutions across Japan (Multicentre Retrospective Cohort of Japanese Patients with Myositis-associated ILD, JAMI). Inclusion criteria were an onset age ⩾16 years; PM/DM or clinically amyopathic DM according to the published criteria; imaging evidence of ILD; and availability of serum samples for assays of autoantibodies such as anti-melanoma differentiation-associated gene 5 and anti-aminoacyl tRNA synthetase. We collected demographic data and clinical characteristics recorded at the time of diagnosis, as well as follow-up survival data. Predictors of ILD-related mortality were identified by univariate and multivariate analyses. Results JAMI enrolled a cohort of 497 patients with PM (15%), classic DM (32%) and clinically amyopathic DM (53%). During the observation period (median 20 months), 76 died of respiratory insufficiency directly related to ILD. Univariate analysis revealed several initial parameters associated with ILD mortality, including demographic, clinical, laboratory, imaging and autoantibody variables. We used multivariate analysis with a stepwise selection of parameters to generate an appropriate predictive model, and identified the following independent risk factors for ILD mortality: age at onset ⩾60 years [hazard ratio (HR) = 4.3, 95% CI: 2.4, 7.5], CRP ⩾1 mg/dl (HR = 2.6, 95% CI: 1.5, 4.8), peripheral capillary oxygen saturation <95% (HR = 2.0, 95% CI: 1.2, 3.4) and anti-melanoma differentiation-associated gene 5 antibody (HR = 7.5, 95% CI: 2.8, 20.2). Conclusion We established a large cohort of incident cases of PM/DM-associated ILD, and successfully identified independent predictors of short-term ILD mortality.

Comparison of clinical and laboratory features of patients with and without allergic conditions in IgG4-related disease: A single-center experience in Japan

Abstract Objective: The objective of this study is to compare the clinical and laboratory features of Japanese patients with IgG4-related disease, with and without allergic conditions. Methods: We retrospectively examined the clinical and laboratory features and clinical courses of 51 patients with definitively diagnosed IgG4-RD, collected from Nagaoka Red Cross Hospital between January 2004 and August 2017, with reference to the presence of allergic conditions. Results: Among these patients, 43% had allergic conditions. In the allergy group, the proportion of females was significantly higher, the age at diagnosis was significantly lower, and upper body organ involvement was predominant in comparison with the non-allergy group. There was no significant inter-group difference in the absolute number of peripheral blood eosinophils, the levels of serum IgG4 and IgE, the response to steroid, or the proportion of patients who relapsed. Conclusion: The present findings suggest that there may be some differences in the clinical features of IgG4-RD patients according to the allergic conditions that are present, although eosinophilia and high serum levels of IgE and IgG4 are common features regardless of allergy.

Successful treatment of a patient with refractory haemophagocytic syndrome in systemic lupus erythematosus with mycophenolate mofetil

Abstract Haemophagocytic syndrome (HPS) is one of the most severe complications of systemic lupus erythematosus (SLE). Although corticosteroids are usually selected as an initial treatment, some patients are corticosteroid-resistant and require additional immunosuppressants. Here, we report a case of SLE-associated HPS patient who was resistant to prednisolone, calcineurin inhibitors, cyclophosphamide, plasma exchange and infliximab but was successfully treated with mycophenolate mofetil (MMF). MMF could be an alternative treatment for intractable HPS complicated with SLE.

Musculoskeletal ultrasonography delineates ankle symptoms in rheumatoid arthritis

Abstract Objectives: To clarify the use of musculoskeletal ultrasonography (US) of ankle joints in rheumatoid arthritis (RA). Methods: Consecutive RA patients with or without ankle symptoms participated in the study. The US, clinical examination (CE), and patients’ visual analog scale for pain (pVAS) for ankles were assessed. Prevalence of tibiotalar joint synovitis and tenosynovitis were assessed by grayscale (GS) and power Doppler (PD) US using a semi-quantitative grading (0–3). The positive US and CE findings were defined as GS score ≥2 and/or PD score ≥1, and joint swelling and/or tenderness, respectively. Multivariate analysis with the generalized linear mixed model was performed by assigning ankle pVAS as a dependent variable. Results: Among a total of 120 ankles from 60 RA patients, positive ankle US findings were found in 21 (35.0%) patients. The concordance rate of CE and US was moderate (kappa 0.57). Of the 88 CE negative ankles, US detected positive findings in 9 (10.2%) joints. Multivariate analysis revealed that ankle US, clinical disease activity index, and foot Health Assessment Questionnaire, but not CE, was independently associated with ankle pVAS. Conclusion: US examination is useful to illustrate RA ankle involvement, especially for patients who complain ankle pain but lack CE findings.

Regional cerebral glucose metabolism in systemic lupus erythematosus patients with major depressive disorder

OBJECTIVES Depression is frequently observed in patients with systemic lupus erythematosus (SLE). Neuropsychiatric SLE (NPSLE) patients often exhibit cerebral hypometabolism, but the association between cerebral metabolism and depression remains unclear. To elucidate the features of cerebral metabolism in SLE patients with depression, we performed brain 18F-fluoro-d-glucose positron emission tomography (FDG-PET) on SLE patients with and without major depressive disorder. METHODS We performed brain FDG-PET on 20 SLE subjects (5 male, 15 female). The subjects were divided into two groups: subjects with major depressive disorder (DSLE) and subjects without major depressive disorder (non-DSLE). Cerebral glucose metabolism was analyzed using the three-dimensional stereotactic surface projection (3D-SSP) program. Regional metabolism was evaluated by stereotactic extraction estimation (SEE), in which the whole brain was divided into segments. RESULTS Every SLE subject exhibited cerebral hypometabolism, in contrast to the normal healthy subjects. Regional analysis revealed a significantly lower ER in the left medial frontal gyrus (p=0.0055) and the right medial frontal gyrus (p=0.0022) in the DSLE group than in the non-DSLE group. CONCLUSION Hypometabolism in the medial frontal gyrus may be related to major depressive disorder in SLE. Larger studies are needed to clarify this relationship.

Dysfunction of TRIM21 in interferon signature of systemic lupus erythematosus

Abstract Objectives: TRIM21 is an E3 ubiquitin ligase for interferon regulatory factors (IRFs) that are involved in innate and acquired immunity. Here, we evaluated the role of TRIM21 in the interferon (IFN) signature of systemic lupus erythematosus (SLE). Methods: Twenty SLE patients and 24 healthy controls were enrolled in this study. We analyzed mRNA expression of TRIM21, type I IFN, and IFN-inducible genes in peripheral blood mononuclear cell (PBMC). The protein levels of IRFs were assessed by Western blotting in PBMCs cultured with or without MG-132. Results: The expression of TRIM21 mRNA and protein was significantly higher in SLE PBMCs as compared to healthy controls. There was a correlation between TRIM21 mRNA expression and SLE activities. In contrast to a negative correlation between mRNA expression level of TRIM21 and those of type I IFNs in healthy controls, we found a positive correlation between them in anti-TRIM21 antibody-positive SLE patients. Neither positive nor negative correlation was observed in the autoantibody-negative SLE patients. Western-blotting analysis revealed impaired ubiquitin-dependent proteasomal degradation of IRFs in SLE PBMCs. Conclusion: Our study showed ubiquitin-dependent proteasomal degradation of IRFs was impaired in anti-TRIM21 antibody-dependent and -independent fashions, leading to amplification of IFN signature in SLE.

Dysregulated heme oxygenase-1 low M2-like macrophages augment lupus nephritis via Bach1 induced by type I interferons

BackgroundInnate immunity including macrophages (Mϕ) in lupus nephritis (LN) has been gaining attention, but roles of Mϕ in LN remain uncertain.MethodsImmunohistochemical staining was performed to determine CD68, CD163, heme oxygenase (HO)-1 (a stress-inducible heme-degrading enzyme with anti-inflammatory property), pSTAT1, and CMAF-expressing Mϕ in the glomeruli of patients with LN. Effects of type I interferons on the expression levels of CD163, HO-1, BTB and CNC homology 1 (Bach1; a transcriptional HO-1 repressor), interleukin (IL)-6, and IL-10 by human M2-like Mϕ, which were differentiated in vitro from peripheral monocytes with macrophage colony-stimulating factor, were assessed by RT-PCR and immunocytostaining. Clinical manifestations, anti-double-stranded DNA (anti-dsDNA), and local HO-1 expression were compared in Bach1-deficient and wild-type MRL/lpr mice.ResultsThe number of glomerular M2-like Mϕ correlated with the amounts of proteinuria in patients with LN. Unlike monocyte-derived M2-like Mϕ, HO-1 expression was defective in the majority of glomerular M2-like Mϕ of patients with LN. Stimulation of human M2-like Mϕ with type I interferons led to reduced HO-1 expression and increased Bach1 and IL-6 expression. Bach1-deficient MRL/lpr mice exhibited increased HO-1 expression in kidneys, prolonged survival, reduced urine proteins, and serum blood urea nitrogen levels, but serum anti-dsDNA antibody levels were comparable. Increased expression of CD163 and HO-1 was found in peritoneal Mϕ from Bach1-deficient MRL/lpr mice.ConclusionsOur data suggest that dysregulated M2-like Mϕ play a proinflammatory role in LN. Bach1 is a potential therapeutic target that could restore the anti-inflammatory property of M2 Mϕ.

FRI0419 The predictive prognostic factors for clinical course of polymyositis/dermatomyositis-associated interstitial lung disease

Background Interstitial lung disease (ILD) and concomitant infectious diseases are the predominant causes of death in polymyositis/dermatomyositis (PM/DM). We have already reported that hypocapnea and ILD lesion in upper lung fields are independent prognostic factors. Micro RNA is a non-coding RNA, which has a certain function such as transcriptional regulation. miR-1 has been reported to be associated with myocyte differentiation and to decrease in muscle tissue from patients with inflammatory myopathies. Objectives Here we investigated the association of serum miR-1 level with clinical course of PM/DM-associated ILD (PM/DM-ILD). Methods We retrospectively analyzed clinical baseline, serum miR-1 level, initial therapeutic regimens, total amounts of PSL, clinical outcomes, and episode of infection of patient with PM/DM-ILD who had received initial treatment at six hospitals associated with Yokohama City University from 2003 to 2016. The serum miR-1 level was measured by quantitative real-time PCR. Results One hundred sixteen (PM 22, DM 51, and clinically amyopathic DM 43) patients were included. The mean age was 56±15 years and 83 were female. As initial therapies, oral PSL, methylprednisolone (mPSL) pulse, intravenous cyclophosphamide (IVCY), and oral calcineurin inhibitor therapies were performed in 113 (97%), 80 (69%), 48 (41%) and 80 (69%), respectively. Forty-one patients had a serious infection at 51±38 days from initiation of immunosuppressants and 10 died of infections. Old age, low PaCO2 and albumin, high LDH and KL-6, high score of ILD, high initial dose of PSL, mPSL pulse, IVCY, calcineurin inhibitor and combination therapy were extracted as risk factors for infection by univariate analyses. A multivariate logistic regression analyses revealed that combination therapy (p=0.012, OR 2.83), old age (p=0.024, OR 2.12), high initial dose of PSL (p=0.024, OR 2.69), low albumin (p=0.031, OR 3.56), and low PaCO2 (p=0.038, OR 2.67) were independent risk factors for infection. Serum samples were obtained from total of 14 patients and 13 healthy controls. Serum miR-1 levels in PM/DM-ILD patients before treatment were significantly higher than those in healthy controls (p=0.047). Also serum miR-1 levels were significantly higher in PM/DM-ILD patients with concomitant infectious diseases as compared to patients without infectious diseases (p=0.043). We further divided the PM/DM-ILD cases into two groups by the serum miR-1 level. The higher miR-1 group showed poorer effectiveness of ILD treatment (p=0.040), and lower lymphocyte count (p=0.013) as compared to the lower miR-1 group. Conclusions Appropriate monitoring is important for PM/DM-ILD, especially in older patients with malnutrition or decreased respiratory function. miR-1 can be a new biomarker for predicting treatment response and concomitant infectious diseases during treatment for PM/DM-ILD. References Robert W. Georgantas et al, Inhibition of myogenic microRNAs 1, 133, and 206 by inflammatory cytokines links inflammation and muscle degeneration in adult inflammatory myopathies, Arthritis Rheum, 2014;66:1022–33. Disclosure of Interest None declared