Yosuke Kunishita

A novel 8-joint ultrasound score is useful in daily practice for rheumatoid arthritis

Abstract Objectives. To investigate the optimal number and combination of joints to be assessed by power Doppler ultrasonography (PDUS) in daily practice for rheumatoid arthritis (RA). Methods. PDUS were performed in 24 joints, including all proximal interphalangeal, metacarpophalangeal (MCP), and bilateral wrist and knee joints in 234 patients with RA. PD signals were scored semiquantitatively from 0 to 3 in each joint, and total PD score-24 was calculated by summing them up as comprehensive assessment. Results. Positive PD signals were more frequently found in bilateral wrist, knee, and the second and third MCP joints than the other joints. The individual PD scores of these 8 joints also showed higher correlation coefficients with total PD score-24 (rs ≥ 0.4). Among the sum PD scores of various selected joint combinations, the score of the combination of 8 joints (total PD score-8), including bilateral second and third MCP, wrist, and knee joints, showed the highest sensitivity and negative predictive value (98.1% and 96.2%, respectively). Total PD score-8 showed high correlation with the total PD score-24 (rs = 0.97, p < 0.01). Conclusions. Total PD score-8 is simple and efficient enough for monitoring disease activity and judging imaging remission of RA in daily practice.

(18)F-FDG and (18)F-NaF PET/CT demonstrate coupling of inflammation and accelerated bone turnover in rheumatoid arthritis.

Objective. To compare the findings in rheumatoid arthritis (RA)-affected joints between 18F-fluorodeoxyglucose (FDG) and 18F-fluoride (NaF) positron emission tomography (PET)/computed tomography (CT). Methods. We enrolled twelve RA patients who started a new biologic agent (naïve 9 and switch 3). At entry, both hands were examined by 18F-FDG PET/CT, 18F-NaF PET/CT, and X-ray. Intensity of PET signals was determined by standardized uptake value max (SUVmax) in metacarpophalangeal (MCP), proximal interphalangeal (PIP), and ulnar, medial, and radial regions of the wrists. Hand X-rays were evaluated according to the Genant-modified Sharp score at baseline and 6 months. Results. Both 18F-FDG and 18F-NaF accumulated in RA-affected joints. The SUVmax of 18F-FDG correlated with that of 18F-NaF in individual joints (r = 0.65), though detail distribution was different between two tracers. 18F-NaF and 18F-FDG signals were mainly located in the bone and the surrounding soft tissues, respectively. The sum of SUVmax of 18F-NaF correlated with disease activity score in 28 joint (DAS28), modified health assessment questionnaire (MHAQ), and radiographic progression. 18F-FDG and 18F-NaF signals were associated with the presence of erosions, particularly progressive ones. Conclusion. Our data show that both 18F-FDG and 18F-NaF PET signals were associated with RA-affected joints, especially those with ongoing erosive changes.

Predicting joint destruction in rheumatoid arthritis with power Doppler, anti-citrullinated peptide antibody, and joint swelling

Objective. To determine combined evaluation of musculoskeletal ultrasonography (MSUS) and power Doppler (PD) signals, anti-citrullinated peptide antibody (ACPA), and other clinical findings improve the prediction of joint destruction in rheumatoid arthritis (RA). Methods. We performed a retrospective study of 331 RA patients (female n = 280 and male n = 51, mean age: 57.9 ± 13.2 years) who underwent MSUS from 2002 to 2012. Correlations with progression of joint destructions in 1,308 2nd and 3rd metacarpophalangeal (MCP) joints and various factors including PD signals of the same joints, clinical findings, age, disease duration at the study entry, gender, observation period, radiographic bone scores according to modified Sharp–van der Heijde methods, ACPA, and rheumatoid factor (RF) were analyzed in patient- and joint-based fashions, using univariate and multivariate logistic regression analyses and generalized linear mixed model. Results. Patients’ characteristics were as follows: mean disease duration: 5.7 ± 7.5 years, observation period: 4.6 ± 2.6 years, RF positivity: 79.9%, and ACPA positivity: 77.5%. PD-positive 2nd and 3rd joints showed higher rate of joint destruction, especially in ACPA-positive patients. Moreover, PD-positive joints in ACPA-positive patients showed joint destruction even in joints without swelling. Multivariate analysis determined PD, swollen joint (SJ), observation period, basal radiographic bone scores, and ACPA as independent risks for joint destruction. Conclusion. PD, SJ, basal radiographic bone scores, and ACPA are independent predictors for the joint destruction of 2nd and 3rd MCPs in RA; thus, considering these factors would be useful in daily practice.

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.

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.

On-demand ultrasonography assessment in the most symptomatic joint supports the 8-joint score system for management of rheumatoid arthritis patients

Abstract Objectives: To investigate whether on-demand ultrasonography (US) assessment alongside a routine examination is useful in the management of rheumatoid arthritis (RA). Methods: US was performed in eight (bilateral MCP 2, 3, wrist and knee) joints as the routine in a cumulative total of 406 RA patients. The most symptomatic joint other than the routine joints was additionally scanned. Power Doppler (PD) and gray-scale images were scored semiquantitatively. Eight-joint scores were calculated as the sum of individual scores for the routine joints. Results: The most symptomatic joint was found among the routine joints in 209 patients (Group A) and in other joints in 148 (Group B). The PD scores of the most symptomatic joint correlated well with the 8-joint scores in Group A (rs = 0.66), but not in Group B (rs = 0.33). The sensitivity and specificity of assessment of the most symptomatic joint for routine assessment positivity were high (84.0% and 100%, respectively) in Group A, but low (50.0% and 61.8%, respectively) in Group B. Additional examination detected synovitis in 38% of Group B with negative results in the routine. Conclusions: On-demand US assessment in the most symptomatic joint, combined with the routine assessment, is useful for detecting RA synovitis.

FRI0305 Relative fdg accumulation of the aortic wall lesions to aortic blood pool in 18F-FDG-PET and PET/CT could be a useful parameter for the prediction of disease relapse after successful treatmen in takayasu arteritis

Background The assessment of disease activity of Takayasu arteritis (TA) is difficult if symptoms and serum inflammatory marker were not detected. Even in those conditions, relapses were frequently observed during the dose reduction of corticosteroid and immunosuppressant. There is accumulating evidence that 18F-fluolodeoxyglucose-positron emission tomography (FDG-PET) and PET/ computed tomography (PET/CT) is useful for monitoring patients with TA when TA was clinically active. However, it is not clear the significance of FDG accumulations when TA was inactive. Objectives To investigate a quantitative predictor in FDG-PET or PET/CT scans for the relapse of TA. Methods We retrospectively investigated 76 FDG-PET or PET/CT scans and extracted 37 scans which were performed in inactive status. These scans were divided in two groups according to relapse of TA for 5years. The relapse was defined the increase of CRP and steroid dose or addition of immunosuppressant. FDG accumulations in aortic wall lesions of TA was evaluated by semi-quantitative index; the standardized uptake value (SUV). In addition to SUVmax in the aortic wall, we also calculated SUV ratio of maximum aortic wall uptake to mean lung uptake (ratio Lu), SUV ratio of maximum aortic wall uptake to mean liver uptake (ratio Li), and SUV ratio of maximum aortic wall uptake to mean aortic blood pool uptake (ratio BP). We compared groups using these parameters. We also determined the cutoff levels, sensitivity, and specificity of 4 sets of SUVs (SUVmax, ratio Lu, ratio Li, and ratio BP) for the prediction of relapse using Receiver Operating Characteristic (ROC) analysis. Moreover, Kaplan-Mayer analysis for the long-term relapse-free survival was performed to assess the reliability of these cutoff levels. ResultsTable 1. Characteristics of two groups Relapse (−) (+) # 17 20 Age (yr) 47 [30–72] 28.5 [14–68] CRP (mg/dl) 0.13±0.03 0.13±0.03 Steroid dose (mg/d equivalent to prednisolone) 15.6±2.4 17.7±3.6 Immunosuppressant 2/17 7/35 Duration until relapse (Days) 702.5 [4–1769] In 37 total PET and PET/CT scan examinations, non-relapse and relapse groups included 17 and 20 scans, respectively. Relapse group had more immunosuppressant users than non-relapse group. Although CRP level and SUVmax were equivalent, ratio of SUV, especially ratio BP of relapse group was higher than that of non-relapse group (p=0.09) (Figure top panel). The cut-off level of these parameters was calculated as follows; SUVmax 1.4, ratio Lu 5.31, ratio Li 1.01, and ratio BP 1.41, respectively. Using these cut-off level, relapse rates of below and over cut-off level were as follows; SUVmax 50% vs 54%, ratio Lu 43% vs 62%, ratio Li 43% vs 69%, and ratio BP 31% vs 67%, respectively (Figure middle panel). Using Kaplan-Mayer analysis, relapse rate of these two groups divided by ratio BP was not significantly different (p=0.268) though these two curves looked different (Figure bottom panel).Figure 1 Conclusions Our data suggest that ratio BP at stable condition, which represents relative FDG accumulation of the aortic wall lesions to aortic blood pool, could be a promising predictor to assess the relapse after successful treatment. Disclosure of Interest None declared

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