Hidehiro Yamada

Clinical Correlations With Dermatomyositis-Specific Autoantibodies in Adult Japanese Patients With Dermatomyositis: A Multicenter Cross-sectional Study

OBJECTIVE To clarify the association of clinical and prognostic features with dermatomyositis (DM)-specific autoantibodies (Abs) in adult Japanese patients with DM. DESIGN Retrospective study. SETTING Kanazawa University Graduate School of Medical Science Department of Dermatology and collaborating medical centers. Patients A total of 376 consecutive adult Japanese patients with DM who visited our hospital or collaborating medical centers between 2003 and 2008. MAIN OUTCOME MEASURES Clinical and laboratory characteristics of adult Japanese patients with DM and DM-specific Abs that include Abs against Mi-2, 155/140, and CADM-140. RESULTS In patients with DM, anti-Mi-2, anti-155/140, and anti-CADM-140 were detected in 9 (2%), 25 (7%), and 43 (11%), respectively. These DM-specific Abs were mutually exclusive and were detected in none of 34 patients with polymyositis, 326 with systemic sclerosis, and 97 with systemic lupus erythematosus. Anti-Mi-2 was associated with classical DM without interstitial lung disease or malignancy, whereas anti-155/140 was associated with malignancy. Patients with anti-CADM-140 frequently had clinically amyopathic DM and rapidly progressive interstitial lung disease. Cumulative survival rates were more favorable in patients with anti-Mi-2 compared with those with anti-155/140 or anti-CADM-140 (P < .01 for both comparisons). Nearly all deaths occurred within 1 year after diagnosis in patients with anti-CADM-140. Conclusion Dermatomyositis-specific Abs define clinically distinct subsets and are useful for predicting clinical outcomes in patients with DM.

Common and Distinct Clinical Features in Adult Patients with Anti-Aminoacyl-tRNA Synthetase Antibodies: Heterogeneity within the Syndrome

Objective To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs). Methods This was a retrospective analysis of 166 adult Japanese patients with anti-ARS Abs detected by immunoprecipitation assays. These patients had visited Kanazawa University Hospital or collaborating medical centers from 2003 to 2009. Results Anti-ARS Ab specificity included anti-Jo-1 (36%), anti-EJ (23%), anti-PL-7 (18%), anti-PL-12 (11%), anti-KS (8%), and anti-OJ (5%). These anti-ARS Abs were mutually exclusive, except for one serum Ab that had both anti-PL-7 and PL-12 reactivity. Myositis was closely associated with anti-Jo-1, anti-EJ, and anti-PL-7, while interstitial lung disease (ILD) was correlated with all 6 anti-ARS Abs. Dermatomyositis (DM)-specific skin manifestations (heliotrope rash and Gottron’s sign) were frequently observed in patients with anti-Jo-1, anti-EJ, anti-PL-7, and anti-PL-12. Therefore, most clinical diagnoses were polymyositis or DM for anti-Jo-1, anti-EJ, and anti-PL-7; clinically amyopathic DM or ILD for anti-PL-12; and ILD for anti-KS and anti-OJ. Patients with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset, and most patients with anti-ARS Abs eventually developed ILD if they did not have ILD at disease onset. Conclusion Patients with anti-ARS Abs are relatively homogeneous. However, the distribution and timing of myositis, ILD, and rashes differ among patients with individual anti-ARS Abs. Thus, identification of individual anti-ARS Abs is beneficial to define this rather homogeneous subset and to predict clinical outcomes within the “anti-synthetase syndrome.”

Role of PGE2 and EP Receptors in the Pathogenesis of Rheumatoid Arthritis and as a Novel Therapeutic Strategy

Recent progress in understanding the pathogenesis of rheumatoid arthritis (RA) in parallel with elucidation of the functional role of the prostaglandin receptor subfamily has revealed an important regulatory role of PGE2, in addition to its well-known proinflammatory role in the progression of RA. Characteristic features of RA are synovial proliferation and pannus formation, which result in the destruction of cartilage and bone. Pannus tissue is mainly composed of macrophages and fibroblast-like synoviocytes. Both T cell-derived IL-17 and macrophage-derived TNF-alpha seem to play a central role in the progression of proinflammatory cascades in RA. PGE2 is also produced in response to proinflammatory cytokines, which in turn negatively regulates both IL-17 and TNF-alpha expression and TNF/IL-1-induced activation of fibroblast-like synoviocytes through EP2/EP4 receptors, resulting in the modulation of proinflammatory cascades. IL-17- and TNF-activated macrophages differentiate into osteoclasts in the presence of M-CSF and RANKL expressed by fibroblast-like synoviocytes. PGE2 binding to EP4 stimulates osteoclastogenesis through enhancing RANKL expression. At the same time, PGE2 suppresses osteoclastogenesis by inhibiting M-CSF expression of fibroblast-like synoviocytes as well as both IL-17 and IL-17-induced TNF-alpha expression of macrophages. PGE2-EP4 also activates osteoblastogenesis through increasing cbfa1 and osterix, two essential transcription factors required for bone formation. The net effect of PGE2 may direct toward repair of eroding bone through the suppression of inflammation and enhancement of bone remodeling. Here, we discuss a diverse action of PGE2/EP receptors and their important regulatory roles in the pathogenesis of RA, which may lead to a novel therapeutic strategy.

Prostaglandin E2 receptors EP2 and EP4 are up-regulated in peritoneal macrophages and joints of pristane-treated mice and modulate TNF-α and IL-6 production

Prostaglandin E2 (PGE2) can have pro‐ or anti‐inflammatory effects, depending on engagement of different PGE2 receptor (EP) subtypes. The role of EPs in regulating autoimmune inflammation was studied in the murine arthritis/lupus model induced by pristane. Peritoneal macrophages were isolated (biomagnetic beads) from BALB/c, DBA/1, or C57BL/6 mice treated with pristane (intraperitoneally, 3 months earlier) or thioglycolate (3 days earlier) or with untreated controls. EPs, inducible nitric oxide synthase (iNOS), and cyclooxygenase‐2 (COX‐2) mRNA expression was examined by reverse transcriptase‐polymerase chain reaction (RT‐PCR). Cells were cultured unstimulated or stimulated with lipopolysaccharide (LPS) or LPS + interferon‐γ in combination with EP subtype‐specific agonists. Tumor necrosis factor α (TNF‐α) and interleukin (IL)‐6 production was tested by enzyme‐linked immunosorbent assay (culture supernatant) and flow cytometry. TNF‐α mRNA levels also were examined. High levels of EPs (EP4/2>EP1>EP3), iNOS, and COX‐2 mRNA were expressed in peritoneal macrophages from pristane‐treated but not untreated or thioglycolate‐treated mice (RT‐PCR). TNF‐α production was inhibited 50–70% at 2–24 h by EP4/2 agonists, whereas IL‐6 was enhanced up to ∼220%. TNF‐α inhibition is mediated partly via the protein kinase A pathway and partly via IL‐6. Intracellular TNF‐α staining was inhibited 20% by EP4/2 agonists. TNF‐α mRNA levels were inhibited 50–70% at 2–24 h, indicating that TNF‐α inhibition was partly at the level of transcription. EP1/3 agonists had little effect. Synovial cells from mice with pristane‐induced arthritis (DBA/1) also expressed EP2/4, and the EP2/4 agonist inhibited TNF‐α production. PGE2 can modulate inflammatory reactions via the EP2/4 receptor through its regulation of TNF‐α and IL‐6. Modification of EP signaling may be a new therapeutic strategy in inflammatory/autoimmune diseases.

Leflunomide-related lung injury in patients with rheumatoid arthritis: imaging features

Imaging findings of 26 cases of leflunomide (Arava)-related acute lung injury were analyzed. Thirteen cases had pre-existing interstitial pulmonary disease on chest X-ray or computed tomography. The main features of clinically determined leflunomide-induced acute lung injury were similar to those caused by other drugs: diffuse or widespread patchy ground-glass opacities and/or consolidation, frequently accompanied by septal thickening and intralobular reticular opacities. We categorized these findings into four patterns: diffuse alveolar damage (DAD), acute eosinophilic pneumonia, hyperreaction, and cryptogenic organizing pneumonia. The DAD group had a higher mortality rate, but statistically not a significant one. It is impossible to exclude infectious disease such as pneumocystis carinii pneumonia based on imaging findings, and detailed correlation of imaging findings with clinical and laboratory findings is essential in order to make a correct diagnosis.

Longterm Survival and Associated Risk Factors in Patients with Adult-onset Idiopathic Inflammatory Myopathies and Amyopathic Dermatomyositis: Experience in a Single Institute in Japan

Objective. To analyze clinical characteristics, survival, causes of death, and risk factors associated with mortality in patients with adult-onset idiopathic inflammatory myopathies (IIM) in Japan. Methods. We retrospectively investigated 197 patients diagnosed with adult-onset IIM at our hospital from 1984 to 2009 according to Bohan and Peter criteria for polymyositis (PM)/dermatomyositis (DM) and modified Sontheimer’s criteria for clinically amyopathic DM (ADM). Results. Survival in the whole group at 1, 5, and 10 years was 85%, 75%, and 67%, respectively. Mortality in cancer-associated myositis was the worst (25% at 5 yrs), followed by clinically ADM (61% at 5 yrs) and primary DM (77% at 5 yrs). Primary DM had significantly low survival compared to primary PM (91% at 5 yrs; p = 0.0427). Among the 53 patients who died were 6 patients with ADM (11%) and 20 patients with primary DM (38%). Interstitial lung disease (ILD) was the main cause of death in clinically ADM (71%) and primary DM (60%), most of which occurred within the first few months. Fewer patients died in primary PM (9%) and overlap myositis (13%). Independent risk factors for death were older age (HR 1.031; 95% CI 1.009–1.053) and skin ulcers (HR 3.018; 95% CI 1.340–6.796) in the whole group and ILD with mild serum creatine kinase levels (< 500 IU/l; HR 3.537; 95% CI 1.260–9.928) in primary DM. Conclusion. Survival of clinically ADM and primary DM was low, mainly due to fatal ILD, compared to primary PM. Establishing therapeutic strategy for ILD may improve the survival in our patient population.

Autoantibodies to transcription intermediary factor (TIF)1β associated with dermatomyositis

IntroductionMyositis specific autoantibodies are associated with unique clinical subsets and are useful biomarkers in polymyositis/dermatomyositis (PM/DM). A 120 kD protein recognized by certain patients with DM was identified and clinical features of patients with this specificity were characterized.MethodsThe 120 kD protein recognized by a prototype serum was purified and identified by mass spectrometry and immunological methods. Autoantibody to this 120 kD protein was screened in sera from 2,356 patients with various diagnoses from four countries, including 254 PM/DM, by immunoprecipitation of 35S-methionine labeled K562 cell extracts. Clinical information of patients with this specificity was collected.ResultsThe 120 kD protein, which exactly comigrated with PL-12, was identified as transcription intermediary factor TIF1β (TRIM28) by mass spectrometry and validated by immunoassays. By immunofluorescence, anti-TIF1β positivity showed a fine-speckled nuclear staining pattern. Four cases of anti-TIF1β were identified; all are women, one each in a Japanese, African American, Caucasian, and Mexican individual. Three had a diagnosis of DM and one case was classified as having an undifferentiated connective tissue disease with an elevated CPK but without significant muscle symptoms. This individual also had a history of colon cancer, cervical squamous metaplasia and fibroid tumors of the uterus. Myopathy was mild in all cases and resolved without treatment in one case. The anti-TIF1β specificity was not found in other conditions.ConclusionsAnti-TIF1β is a new DM autoantibody associated with a mild form of myopathy. Whether it has an association with malignancy, as in the case of anti-TIF1γ, or other unique features will need to be evaluated in future studies.

Dual role of interleukin-17 in pannus growth and osteoclastogenesis in rheumatoid arthritis

IntroductionIn a murine model, interleukin (IL)-17 plays a critical role in the pathogenesis of arthritis. There are controversies, however, regarding whether IL-17 is a proinflammatory mediator in rheumatoid arthritis (RA). We previously established an ex vivo cellular model using synovial tissue (ST)-derived inflammatory cells, which reproduced pannus-like tissue growth and osteoclastic activity in vitro. Using this model, we investigated the effects of IL-17 on pannus growth and osteoclastogenesis in RA.MethodsInflammatory cells that infiltrated synovial tissue from patients with RA were collected without enzyme digestion and designated as ST-derived inflammatory cells. ST-derived inflammatory cells were cultured in the presence or absence of IL-17 or indomethacin, and the morphologic changes were observed for 4 weeks. Cytokines produced in the culture supernatants were measured by using enzyme-linked immunosorbent assay kits. Osteoclastic activity was assessed by the development of resorption pits in calcium phosphate-coated slides.ResultsExogenous addition of IL-17 dramatically enhanced the spontaneous production of IL-6 and prostaglandin E2 (PGE2) by the ST-derived inflammatory cells, while it had no effect on the production of tumor necrosis factor (TNF)-α and macrophage colony-stimulating factor (M-CSF). Furthermore, IL-17 did not affect the spontaneous development of pannus-like tissue growth and osteoclastic activity by the ST-derived inflammatory cells. On the other hand, IL-17 enhanced pannus-like tissue growth, the production of TNF-α and M-CSF and the development of osteoclastic activity in the presence of indomethacin, an inhibitor of endogenous prostanoid production, while exogenous addition of PGE1 suppressed their activities.ConclusionsThe present study suggests that IL-17 induces negative feedback regulation through the induction of PGE2, while it stimulates proinflammatory pathways such as inflammatory cytokine production, pannus growth and osteoclastogenesis in RA.

ANCA: associated lung fibrosis.

The possible link between pulmonary fibrosis, anti-neutrophil cytoplasmic autoantibody (ANCA) positivity, and vasculitis is poorly understood. During the past 6 years, five retrospective case-control studies have been published. These studies suggest that pulmonary fibrosis (PF) is an underestimated manifestation of ANCA-associated vasculitis. Common clinical characteristics include older age (around 70 years), constant positivity of myeloperoxidase (MPO)-ANCA and the poor prognosis of the pulmonary disease. The diagnosis of PF often predates the development of vasculitis. There are no significant differences of pulmonary function parameters, bronchoalveolar lavage analysis, or high-resolution computed tomographic (HRCT) findings between ANCA-associated PF and idiopathic pulmonary fibrosis (IPF). The high mortality rate of ANCA-associated PF indicates that a search for ANCAs should be performed at diagnosis in every patient with PF because the presence of ANCAs increases the risk of development of vasculitis and should promote specific monitoring of patients with positive MPO-ANCA.

Simple exercise echocardiography using a Master's two-step test for early detection of pulmonary arterial hypertension

BACKGROUND Early detection of pulmonary arterial hypertension (PAH) is indispensable, although, echocardiography at rest alone does not provide sufficient evidence for it. Here, this study aimed to investigate the usefulness of simple exercise echocardiography using a Masters two-step test for detecting early PAH. METHODS This study included 52 connective tissue disease patients who had mild symptoms in World Health Organization functional classification 2, suspected as having early PAH, and underwent exercise echocardiography and right heart catheterization. Echocardiography was performed before and after the Masters two-step exercise test; the study patients were classified into the non-PAH (mean pulmonary arterial pressure <25 mmHg, n=37) or PAH (mean pulmonary arterial pressure ≥25 mmHg, n=15) groups. RESULTS Rest systolic pulmonary artery pressure estimated using echocardiography did not significantly differ between the two groups; however, a significant difference in post-exercise systolic pulmonary artery pressure was found (non-PAH, 58.8±10.8 mmHg; PAH, 80.2±14.3 mmHg, p<0.0001). The multiple logistic regression analysis indicated post-exercise systolic pulmonary artery pressure as an independent predictor of PAH (p=0.013). The area under the curve by post-exercise systolic pulmonary artery pressure was 0.91 for PAH. Post-exercise systolic pulmonary artery pressure ≥69.6 mmHg predicted PAH with the sensitivity of 93% and the specificity of 90%. CONCLUSIONS Simple exercise echocardiography using the Masters two-step test could detect PAH in mildly symptomatic connective tissue disease patients. The usefulness of this method should be verified for the early detection of PAH.