Hidenaga Kawasumi

Cytokine profiles in polymyositis and dermatomyositis complicated by rapidly progressive or chronic interstitial lung disease

OBJECTIVE PM and DM are often complicated by interstitial lung disease (ILD). In this study we aimed to evaluate various serum cytokines in patients with PM/DM with ILD so as to clarify the differences in pathophysiology between anti-melanoma differentiation-associated gene 5 antibody-associated ILD (anti-MDA5-ILD) and anti-aminoacyl tRNA synthetase antibody-associated ILD (anti-ARS-ILD). METHODS We evaluated the serum cytokine profiles of 38 patients with PM/DM and compared the cytokine profiles of the non-ILD and ILD subsets as well as the anti-MDA5-ILD and anti-ARS-ILD subsets. RESULTS The myositis intention-to-treat activity index score, which indicates whole disease activity, significantly correlated with serum IL-6, IL-8, TNF-α and IP-10. These cytokine levels were significantly higher in the ILD subset than the non-ILD subset and were lower in the ILD subset following treatment. By multivariate analysis, TNF-α was the most significant cytokine [P = 0.0006, odds ratio (OR) 1.4, CI 1.1, 2.2] associated with PM/DM with ILD. IL-8 levels were significantly higher in anti-MDA5-ILD than in anti-ARS-ILD, although IL-6, TNF-α and IP-10 levels were high in both subsets. IL-8 was the most significant cytokine (P = 0.0006, OR 1.5, CI 1.1, 3.0) associated with anti-MDA5-ILD by multivariate analysis. Moreover, the ratio of IL-4 to IFN-γ was lower in anti-MDA5-ILD than in anti-ARS-ILD. CONCLUSION IL-6, IL-8, TNF-α and IP-10 are associated with global disease activity in PM/DM. These cytokine levels were high, especially in the ILD subset. Serum IL-8 levels and the balance between IL-4 and IFN-γ may contribute to the differences in pathophysiology between anti-ARS-ILD and anti-MDA5-ILD.

Clinical Manifestations of Adult‐Onset Still's Disease Presenting With Erosive Arthritis: Association With Low Levels of Ferritin and Interleukin‐18

Adult‐onset Stills disease (AOSD) is a clinical entity with a heterogeneous etiology. We have encountered patients with AOSD who had severe polyarthritis and who fulfilled the classification criteria for rheumatoid arthritis (RA); however, most patients with AOSD typically exhibit mild arthritis. In this study, we proposed 2 clinical subsets of AOSD and investigated the clinically significant characteristics of the 2 subtypes.

IL-6, IL-8, and IL-10 Are Associated with Hyperferritinemia in Rapidly Progressive Interstitial Lung Disease with Polymyositis/Dermatomyositis

Objective. Hyperferritinemia is frequently accompanied by rapidly progressive (RP) interstitial lung disease (ILD) with polymyositis (PM)/dermatomyositis (DM). To clarify the mechanism of RP-ILD with hyperferritinemia, we investigated the associations between serum ferritin levels and various cytokines in patients with PM/DM. Methods. This retrospective study included 38 patients admitted to our hospital with PM/DM. Levels of serum ferritin and cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IL-18, TNF-α, IFN-α, IFN-γ, and IP-10) were measured. Disease activity was evaluated using the tool proposed by the International Myositis Assessment and Clinical Studies Group. We analyzed the associations between disease activity and levels of serum ferritin and cytokines. Results. The levels of serum ferritin, IL-8, IL-10, IL-18, and TNF-α, were significantly correlated with disease activity. In a multivariate analysis, IL-6 (t = 3.6, P = 0.0010), IL-8 (t = 4.8, P < 0.0001), and IL-10 (t = 5.7, P < 0.0001) significantly contributed to serum ferritin levels. The levels of serum ferritin, IL-6, IL-8, and IL-10, were higher in the RP-ILD subset than in the non-ILD subset or the chronic ILD subset. Conclusion. IL-6, IL-8, and IL-10 are significant contributors to hyperferritinemia in PM/DM. The regulation of these cytokines might offer a possible treatment strategy for RP-ILD with PM/DM.

Clinical Characteristics and Cytokine Profiles of Organizing Pneumonia in Patients with Rheumatoid Arthritis Treated with or without Biologics

Objective. It has been reported that organizing pneumonia (OP) develops when patients with rheumatoid arthritis (RA) are treated with biologic disease-modifying antirheumatic drugs (bDMARD). However, the clinical characteristics and pathophysiology of OP in RA remain unknown in patients treated with bDMARD. We investigated the clinical characteristics and cytokine profiles of patients with RA-OP treated with bDMARD or conventional synthetic DMARD (csDMARD). Methods. Twenty-four patients with RA who had developed OP were enrolled. These patients included 12 treated with bDMARD (bDMARD-OP subset) and 12 treated with csDMARD (csDMARD-OP subset). We compared the clinical characteristics and cytokine profiles between the patients with OP (OP subset, n = 24) and non-OP patients (non-OP subset, n = 29). Results. There was no significant difference in clinical characteristics between the OP subset and the non-OP subset. Four patients developed OP within 2 months of bDMARD administration. In the other 8 patients, OP developed more than 1 year after the initiation of bDMARD. OP improved with corticosteroid treatment in all bDMARD-OP patients. After OP improved, bDMARD were readministered in 6 patients, and no OP recurrence was observed in any of these patients. Our multivariate analysis revealed that serum levels of interferon-α (IFN-α), interleukin (IL)-1β, IL-6, IL-8, and interferon-γ–inducible protein 10 were significantly associated with the development of OP, although these cytokines tended to be lower in the bDMARD-OP subset than in the csDMARD-OP subset. Conclusion. OP is unlikely to be fatal in patients treated with bDMARD or csDMARD. IFN-α and proinflammatory cytokines are associated with the pathophysiology of OP in RA.

Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis

Objectives Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population. Methods We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. Results We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10−8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4isoform (tr-WDFY4), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-κB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells. Conclusions As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.

Sildenafil attenuates the fibrotic phenotype of skin fibroblasts in patients with systemic sclerosis

Systemic sclerosis (SSc) is a multi-organ fibrotic disease that affects the skin and various internal organs. Therapeutic strategies for tissue fibrosis have not been established; however, aberrantly activated fibroblasts in affected lesions are key targets for modulating fibrosis. Recently, increased intracellular cyclic GMP (cGMP) levels were demonstrated to improve fibrosis levels in various diseases. The purpose of this study was to assess the anti-fibrotic properties of cGMP in cultured fibroblasts from patients with SSc. The phosphodiesterase (PDE) 5 inhibitor sildenafil increased the intracellular cGMP levels in skin fibroblasts in a dose-dependent manner. Sildenafil treatment also significantly decreased the expression of several pro-fibrotic factors that were upregulated by TGF-β1 treatment in SSc skin fibroblasts. These inhibitory effects occurred via non-canonical TGF-β signaling. Our findings revealed that sildenafil might be a novel strategy to treat tissue fibrosis and vasculopathy in SSc.

Clinical Manifestations and Myositis-Specific Autoantibodies Associated with Physical Dysfunction after Treatment in Polymyositis and Dermatomyositis: An Observational Study of Physical Dysfunction with Myositis in Japan

Objective. The physical function of PM/DM patients after remission induction therapy remains unknown adequately. The aim of our study was to evaluate the present status of physical dysfunction and to clarify the clinical manifestations and myositis-specific autoantibodies (MSAs) associated with physical dysfunction after treatment in PM/DM. Methods. We obtained clinical data including the age at disease onset, gender, disease duration, laboratory data prior to initial treatment, and the specific treatment administered. We evaluated disease activity and physical dysfunction after treatment using the core set provided by the International Myositis Assessment and Clinical Studies Group. Results. 57% of the 77 enrolled patients with PM/DM had troubles in daily living after treatment. At the enrolment, disease activity evaluated by physicians was only revealed in 20% of patients. In a multivariate analysis, the age at disease onset, female gender, and CK levels before treatment were significantly associated with the severity of physical dysfunction after treatment. Anti-SRP positivity was associated with more severe physical dysfunction after treatment than anti-ARS or anti-MDA5. Conclusions. Half of the PM/DM patients showed physical dysfunction after treatment. Age at disease onset, gender, CK level before treatment, and anti-SRP were significant predictors associated with physical dysfunction after treatment in PM/DM.

Association of Serum Soluble CD163 with Polymyositis and Dermatomyositis, Especially in Anti-MDA5 Antibody–positive Cases

Objective. We elucidated the association of serum soluble CD163 (sCD163) with rapidly progressive interstitial lung disease (RP-ILD), autoantibody profiles, and serum ferritin in patients with polymyositis (PM), classic dermatomyositis (DM), and clinical amyopathic dermatomyositis (CADM). Methods. Serum sCD163 levels were retrospectively measured by ELISA in patients with PM, classic DM, and CADM, as well as in healthy controls (HC). Repeat sera samples were obtained posttreatment from available patients. The associations between serum sCD163 levels and clinical information were analyzed. Results. Serum sCD163 levels in patients with PM/classic DM/CADM were significantly higher than those in HC (n = 72, 56, 34, and 68, respectively; p < 0.001 for all comparisons). No significant difference was observed between serum sCD163 levels in patients with and without ILD (p = 0.16) or between those with RP-ILD and chronic ILD (p = 0.21). Serum sCD163 levels were significantly higher in patients with anti-MDA5 antibodies (n = 27) than in those without (p = 0.001). Serum sCD163 levels were weakly correlated with serum ferritin levels in the patients with PM, classic DM, and CADM (r = 0.21). Serum sCD163 levels decreased significantly following treatment in all patient groups (p = 0.003). Conclusion. The present results suggest an association of serum sCD163 with PM, classic DM, and CADM, especially in anti-MDA5 antibody–positive cases. However, serum sCD163 levels were not specifically associated with ILD or RP-ILD.

FRI0282 Post-Treatment Short-Term Changes in Needle Electromyography among Patients with Polymyositis and Dermatomyositis and Their Clinical Usefulness: A Retrospective Study

Background There is no established single outcome measure of muscle manifestations in polymyositis (PM) and dermatomyositis (DM) although there are partially validated preliminary definitions of improvement by the International Myositis Assessment & Clinical Studies Group (IMACS). They are core set measures including Manual Muscle Testing (MMT), muscle-associated enzymes such as creatine kinase (CK), and so on. Needle electromyography (EMG) is useful in the diagnosis of PM/DM. However, the degree and time course of changes in its findings after treatment and their associations with other measures remain elusive. Objectives We aimed to study post-treatment short-term changes in needle EMG among patients with PM/DM and their clinical usefulness. Methods Patients were included in the present study when they met all these criteria: 1) fulfill the Bohan and Peter classification criteria for PM/DM; 2) were administered to our university hospital for the treatment of muscle manifestations of PM/DM from 2008 through 2015; 3) received needle EMG before and after treatment. Needle EMG was performed by a single experienced electromyographer/neurologist in all the patients. The data of findings of needle EMG, MMT, serum CK levels, and other demographic and clinical information were retrospectively collected. The following findings of needle EMG were transformed into semiquantified relative frequencies on 0–7 point scale: fibrillation potential (Fib), positive sharp wave (Pos), low-amplitude motor unit potential (MUP) (Low), short-duration MUP (Short). MMT was assessed in 10 muscles on 0–5 point scale and their sum scores with maximum of 50 were used. Treatment was determined by physician preference in each individual. Results Ultimately, 24 patients were included in the present study, and 17 and 10 patients received needle EMG at 4 and 8 weeks after treatment, respectively: 3 patients received at both 4 and 8 weeks after treatment. Fib was detected in 23 patients, and Pos, Low, and Short were detected in all the patients before treatment. Fib, Pos, Low, and Short improved in 59%, 65%, 29%, and 24% of the patients at 4 weeks, and in 90%, 90%, 100%, and 90% of the patients at 8 weeks, respectively. When assessed by Wilcoxon signed-rank tests, Fib and Pos significantly improved at 4 weeks, and all of the needle EMG findings improved at 8 weeks (p<0.05 in each comparison). Although MMT scores and CK levels also significantly improved, their improvement did not significantly agree with the improvement of needle EMG findings except for Fib and Pos and CK levels at 8 weeks. Conclusions The present study showed that electrical activity in muscle recorded at rest (Fib and Pos) and during voluntary movement (Low and Short) significantly improved at as early as 4 and 8 weeks after treatment, respectively. It is also suggested that needle EMG findings can serve as different outcome measure from MMT and CK in PM/DM. Disclosure of Interest None declared

FRI0259 A Retrospective Study: Predictive Factors for Insufficient Improvement of Muscle Weakness after Treatment among Patients with Polymyositis and Dermatomyositis

Background The severity of muscle involvement and the response to immunosuppressive drugs are highly variable among patients with polymyositis (PM) and dermatomyositis (DM). Although previous studies reported that some clinical and laboratory features were associated with a poorer prognosis, the results were not consistent through those studies. A decade ago, we reported that the height of the baseline serum creatine kinase (CK) elevation predict the course of disease among patients treated with glucocorticoids (GCs) alone. However, other groups reported conflicting results. In addition, we later changed our basic treatment strategy to combination therapy with another immunosuppressive agent to improve response and reduce the need for GCs. Objectives We aimed to identify predictive factors for insufficient improvement of muscle weakness after treatment among patients with PM/DM, focusing more recent patients than those included in our previous report. Methods Patients were included in this retrospective study when they met all these criteria: 1) fulfill the Bohan and Peter classification criteria for PM/DM; 2) were administered to our university hospital for the treatment of muscle manifestations of PM/DM from 2008 through 2015. In addition, these patients were excluded from the study: those with clinically amyopathic DM and those complicated with other overlapping systemic autoimmune diseases or cancer. Manual muscle testing (MMT) was assessed using traditional 5 point MMT scales (i.e. the Medical Research Council Scale.) The Total MMT score included 2 axial and 8 proximal muscle groups, with a maximum potential value of 50. The Total MMT score less than 48 at 6 to 8 weeks after initiation of GC treatment was defined as insufficient improvement of muscle weakness. Clinical and laboratory parameters were statistically compared between patients with sufficient and insufficient improvement of muscle weakness. Odds ratios (ORs) for insufficient improvement of muscle weakness were assessed by multiple logistic regression analysis. Results Ultimately, 45 patients, comprising 30 PM and 15 DM patients were included in the present study. Among these, 22 were positive for anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies, the mean age was 55 years, and the mean CK level before treatment was 2,544 U/l. GCs (≥0.5 mg/kg/day) were administered in all the patients and another immunosuppressant were concomitantly used in 39 patients. By univariate analyses, age and CK levels before treatment were significantly higher in patients with insufficient improvement of muscle weakness than those with sufficient improvement (p<0.05). The cut off values were determined by receiver operating characteristic curve analyses as ≥65 years for age and ≥1,900 U/l for CK level. The patients with ≥65 years old, CK ≥1,900 U/l, or negative anti-ARS antibodies were more frequent in patients with insufficient improvement. By multivariate analyses, ORs (95% confidence interval) for ≥65 years old, CK ≥1,900 U/l, and negative anti-ARS antibodies were 16 (2 to 342), 22 (3 to 526), and 9 (1.3 to 104), respectively. Conclusions The present study suggested that ≥65 years old, CK ≥1,900 U/l before treatment, and negative anti-ARS antibodies were predictive factors for insufficient improvement of muscle weakness in patients with PM/DM. Disclosure of Interest None declared