Spontaneous resolution of focal eosinophilic myositis of the adductor pollicis complicated by lung lesions.

Eosinophilic myositis is characterised by peripheral blood eosinophilia and eosinophilic infiltration in muscles, and is comprised three subtypes: focal eosinophilic myositis (FEM), eosinophilic polymyositis, and eosinophilic perimyositis. Muscle involvement of FEM is usually limited to the lower legs, and pulmonary complications have not been reported. We report a rare case of FEM in the left adductor pollicis complicated by lung lesions. A 37-year-old woman developed swelling of the first web space in the left hand. Magnetic resonance imaging (MRI) of the left hand demonstrated increased signal on fat-suppressed T2-weighted imaging in the left adductor pollicis. A muscle biopsy specimen demonstrated perimysial and endomysial infiltration of mononuclear cells and eosinophils, and necrosis and regeneration of muscle fibres. Chest computed tomography (CT) revealed upper-lobe-dominant ground-glass opacities (GGO). Both focal myositis and pulmonary lesions improved without treatment. This case suggests that FEM could involve adductor pollicis and have pulmonary lesions. In this case, myositis and GGO resolved spontaneously. Some FEM cases treated with glucocorticoids were reported in the past. Further studies are required to determine whether patients with FEM require therapeutic intervention.

Serum levels of soluble programmed cell death protein 1 and soluble programmed cell death protein ligand 2 are increased in systemic lupus erythematosus and associated with the disease activity.

OBJECTIVE: Programmed cell death protein 1 (PD-1) pathway plays important roles in systemic lupus erythematosus (SLE). We aimed to elucidate the association of serum soluble PD-1 (sPD-1) and related molecules with SLE and to explore their usefulness as biomarkers. METHODS: We retrospectively measured the serum levels of sPD-1, soluble PD-ligand 1 (sPD-L1), soluble PD-ligand 2 (sPD-L2) and interleukin (IL)-21 by ELISA in SLE patients, systemic sclerosis patients and healthy controls. Repeat sera samples were also obtained post treatment. RESULTS: The serum levels of sPD-1 and sPD-L2 in SLE patients with high disease activity were significantly higher than those in SLE patients with low disease activity, systemic sclerosis patients and healthy controls (n = 58, 15, 20 and 21, respectively; p < 0.001). However, the serum levels of sPD-L1 and IL-21 were not elevated in SLE patients. The serum levels of sPD-1 and sPD-L2 were higher among active SLE patients who tested positive for anti-dsDNA antibodies than in those who tested negative (p = 0.002 and <0.001, respectively). There were moderate correlations between the serum levels of sPD-1 and sPD-L2 and the SLE Disease Activity Index 2000 scores, the titres of anti-dsDNA antibodies and the serum levels of complements. Furthermore, the serum levels of sPD-1 and sPD-L2 decreased significantly in accordance with disease amelioration following treatment (p < 0.001). CONCLUSION: The present study demonstrated the association of serum sPD-1 and sPD-L2 with SLE and suggests their usefulness as disease activity biomarkers for SLE.

KL-6 is a long-term disease-activity biomarker for interstitial lung disease associated with polymyositis/dermatomyositis, but is not a short-term disease-activity biomarker.

Objectives: We aimed to evaluate the usefulness of serum KL-6 for interstitial lung disease (ILD) with polymyositis/dermatomyositis (PM/DM). Methods: All consecutive and previously untreated adult patients with PM/DM who were admitted to our hospital from 2010 to 2015 were included. The associations between serum KL-6 levels and clinical information were retrospectively analyzed. Results: Baseline serum KL-6 levels were significantly higher in patients with ILD than in those without (n = 41 and 15, respectively; p < .001). In the 14 patients whose ILD improved within 4 weeks post-treatment, their serum KL-6 levels did not significantly decrease at 2 weeks, 4 weeks, or 3 months post-treatment (p = 1.00, 1.00, and .83, respectively). Conversely, their serum KL-6 levels significantly decreased at 6, 9, and 12 months post-treatment (p = .01 in all comparisons). In the 12 patients whose ILD remained unchanged or deteriorated in 4 weeks post-treatment, only the difference between their serum KL-6 levels at 3 and 12 months was significant (p = .003). Conclusions: The present study validated the serum KL-6 as a diagnostic marker for ILD in PM/DM. However, serum KL-6 is not a short-term disease-activity biomarker for ILD with PM/DM, but it is a long-term disease-activity biomarker.

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.

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.

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.

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)-1ß, 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.

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-ß1 treatment in SSc skin fibroblasts. These inhibitory effects occurred via non-canonical TGF-ß signaling. Our findings revealed that sildenafil might be a novel strategy to treat tissue fibrosis and vasculopathy in SSc.

Recent Treatment of Interstitial Lung Disease with Idiopathic Inflammatory Myopathies.

Interstitial lung disease (ILD) is a prognostic factor for poor outcome in polymyositis (PM)/dermatomyositis (DM). The appropriate management of ILD is very important to improve the prognosis of patients with PM/DM. ILD activity and severity depend on the disease subtype. Therefore, clinicians should determine therapeutic strategies according to the disease subtype in each patient with PM/DM. Anti-melanoma differentiation-associated gene 5 antibody and hyperferritinemia predict the development and severity of rapidly progressive (RP) ILD, particularly in East Asian patients. Combination therapy with corticosteroids, intravenous cyclophosphamide pulse, and calcineurin inhibitors should be administered in RP-ILD. In contrast, patients with anti-aminoacyl-tRNA synthetase (ARS) show better responses to corticosteroids alone. However, ILDs with anti-ARS often display disease recurrence or become refractory to corticosteroid monotherapy. Recent studies have demonstrated that the administration of tacrolimus or rituximab in addition to corticosteroids may be considered in ILD patients with anti-ARS. Large-scale, multicenter randomized clinical trials should be conducted in the future to confirm that the aforementioned agents exhibit efficacy in ILD patients with PM/DM. The pathophysiology of ILD with PM/DM should also be elucidated in greater detail to develop effective therapeutic strategies for patients with ILD in PM/DM.

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.

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-1ß, 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 manifestations of Adult-onset Still's disease presenting with erosive arthritis: Association with low levels of ferritin and Interleukin-18.

Objective: Adult-onset Still's disease (AOSD) is a clinical entity with 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 two clinical subsets of AOSD and investigated the clinically significant characteristics of the two subtypes. Methods: We retrospectively analyzed 71 consecutive patients with AOSD. We reviewed the medical records of all patients who were followed up for more than 2 years. We classified all the patients with AOSD into the following 2 subsets: an RA subtype for patients who met the criteria for RA according to the American College of Rheumatology and a non-RA subtype for patients who did not meet the criteria for RA. Results: Our results indicated that the non-RA subtype was accompanied by severe inflammatory complications, including pleuritis and hemophagocytic syndrome. In addition, the serum ferritin and serum IL-18 levels were significantly higher in patients with the non-RA subtype than in those with the RA subtype. Interestingly, only 1 patient with the RA subtype had anti-CCP antibodies, and 1 non-RA subtype patient had rheumatoid factor. These findings distinguish these patients from patients with true RA. Conclusions: There were two subsets of patients with AOSD in the examined population. Patients with high levels of IL-18 or ferritin presented with severe systemic inflammatory disorders (the non-RA subtype), and patients with low levels of IL-18 or ferritin developed severe arthritis (RA subtype).

Methemoglobinemia induced by trimethoprim-sulfamethoxazole in a patient with systemic lupus erythematosus.

We herein report a case of methemoglobinemia induced by trimethoprim-sulfamethoxazole (TMP/SMX). A 41-year-old woman with systemic lupus erythematosus (SLE) received TMP/SMX for prophylaxis of pneumocystis pneumonia (PCP) on the 7th day of hospitalization. She suddenly developed dyspnea and cyanosis on the 9th day of hospitalization. The level of oxygen saturation (SaO2) decreased, and the concentration of methemoglobin (MetHb) in the blood was elevated. We diagnosed the patient with methemoglobinemia induced by TMP/SMX. Methemoglobinemia should be considered in cases of sudden dyspnea following TMP/SMX administration.