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.

Incidence and predictive factors for malignancies in 136 Japanese patients with dermatomyositis, polymyositis and clinically amyopathic dermatomyositis.

The aim of this study was to define the standardized incidence ratio (SIR) of malignancy and the potential risk factors of concomitant malignancies in patients with inflammatory myopathies, including clinically amyopathic dermatomyositis (CADM). A total of 145 patients diagnosed with either dermatomyositis/polymyositis (DM/PM) or CADM at our institute between 1984 and 2002 were enrolled in the study. The demographic, clinical and laboratory features of the patients at the time of DM/PM or CADM diagnosis were compared between patients with and without malignancies, respectively. Multivariate analysis by logistic regression was used to determine the independent risk factors for the development of malignancies in DM/PM patients. Malignancy was found in 17 of 70 patients with DM (24%), three of 15 patients with CADM (20%), and three of 51 patients with PM (6%). Gastric cancer (8/23) was the most common malignancy. Compared with general population, the SIR of malignancies was 13.8 (range 9.0-21.1). The patients who developed malignancies were older (61.5 vs. 51.1 years; P < 0.005), presented more often with dysphagia (61 vs. 15%; P < 0.0001) and were less likely to have the complication of interstitial lung disease (30 vs. 60%; P < 0.05). These features were independent predictive factors for developing malignancies in multiple logistic regression analysis. The results of our study confirm that CADM in addition to DM was associated with high rates of malignancy among our patient cohort.

Immunosuppressive effect of angiotensin receptor blocker on stimulation of mice CTLs by angiotensin II.

While angiotensin II, which is produced by the renin-angiotensin-aldosterone system, is considered to be the major regulator molecule that controls both the blood pressure and fluid system, there is an increasing body of evidence that this bioactive peptide and its receptor might also contribute to the immune system. However, there are few details known about the direct effect that angiotensin type I receptors (AT1R) have on the cytotoxic T cell (CTL). To clarify the relationship between angiotensin II and its CTL receptor, we used murine splenic and antigen-specific CTLs. Murine CTLs constantly expressed AT1R, with the activation of the AT1R expression strengthened by both anti-CD3 Ab and the use of an antigen-specific methodology. Moreover, the production of IFN-gamma and TNF-alpha through CTL stimulation can be inhibited by the selective AT1R inhibitor, Losartan. In particular, the TNF-alpha production from activated CTL that had been magnified by angiotensin II, was nullified by the AT1R inhibitor. However, a cytotoxic assay indicated it did not have any effect on the cognate interaction of the CTLs. In addition, the antigen-specific CTL induction by immunization with the CTL antigenic peptide was reduced by angiotensin II type 1 receptor blocker (ARB) in vivo. These findings suggest that ARBs might have the ability to suppress excessive antigen-specific activation and induction of CTLs promoted by angiotensin II.

Fli1 and Ets1 have distinct roles in connective tissue growth factor/CCN2 gene regulation and induction of the profibrotic gene program.

CCN2 (connective tissue growth factor), an important regulator of angiogenesis, chondrogenesis, and wound healing, is overexpressed in a majority of fibrotic diseases and in various tumors. This study investigated regulation of CCN2 gene expression by Ets family of transcription factors, focusing on two members, Fli1 and Ets1, with deregulated expression during fibrosis and tumorigenesis. We show that Ets1 and Fli1 have opposite effects on CCN2 gene expression. Ets1 functions as an activator of CCN2 transcription, whereas Fli1 acts as a repressor. A functional Ets binding site was mapped at -114 within the CCN2 promoter. This site not only mediates stimulation by Ets factors, including Ets1, Ets2, and GABPalpha/beta, but is also required for the transforming growth factor (TGF)-beta response. The contrasting functions of Ets1 and Fli1 in regulation of the CCN2 gene were confirmed by suppressing their endogenous levels using adenoviral vectors expressing specific small interfering RNAs. Additional experiments using chromatin immunoprecipitation assays have revealed that in fibroblasts both Ets1 and Fli1 occupy the CCN2 promoter. TGF-beta stimulation resulted in displacement of Fli1 from the CCN2 promoter and a transient inhibition of Fli1 synthesis. Moreover, reduction of Fli1 expression resulted in up-regulation of COL1A1 and COL1A2 genes and down-regulation of the MMP1 gene. Thus, inhibition of Fli1 recapitulated some of the key effects of TGF-beta, suggesting that Fli1 suppression is involved in activation of the profibrotic gene program in fibroblasts. On the other hand, activation of the CCN2 gene downstream of Ets1 is consistent with its role in angiogenesis and extracellular matrix remodeling. This study strongly supports a critical role of Fli1 and Ets1 in the pathological extracellular matrix regulation during fibrosis and cancer.

Methotrexate-induced pulmonary injury: serial CT findings.

UNLABELLED: We describe serial computed tomographic (CT) findings of methotrexate (MTX)-induced pulmonary injury. MATERIALS AND METHODS: The cases of 8 patients (3 men and 5 women; mean age 58.6 years, range 16 to 75 years) of clinically diagnosed MTX-induced pulmonary injury were reviewed. Six patients had rheumatoid arthritis, 1 had lupus erythematosus profundus, and 1 had juvenile rheumatoid arthritis. CT findings on admission and at follow-up were evaluated. RESULTS: The most common CT features were diffuse and patchy bilateral ground-glass opacity with (n = 3) or without reticulation (n = 4) and consolidation (n = 1). These opacities showed no predilection for any particular lung zone in 6 patients but did show dependent predilection in 1 patient and upper lobe predilection in 1. Diffuse centrilobular ill-defined nodules were noted in 1 patient, which disappeared on follow-up. During the average post-treatment follow-up period of 31.0 days (range 3 to 76 days), the opacities quickly improved after treatment in 6 patients; however, in 2 patients with pre-existing interstitial pneumonitis the opacities were refractory. CONCLUSION: CT features of MTX-induced pulmonary injury were variable and included diffuse parenchymal opacification, reticular opacities, and centrilobular nodules. These opacities usually responded quickly to treatment; however, those patients with lung fibrosis at presentation may have worse prognosis.