Acute hemorrhagic myositis in inflammatory myopathy and review of the literature.

We describe two patients with dermatomyositis that presented with interstitial lung disease, positive V and Shawl sign who developed acute spontaneous abdominal/retroperitoneal bleed. Both patients expired despite aggressive treatment and resuscitation. Hemorrhagic myositis in these two patients with inflammatory myopathy is a very rare complication. The association of anti-Ro52 with this potentially very serious complication remains unclear. This potential relationship should be further evaluated in future studies.

The heart in inflammatory myopathies.

Systemic autoimmune diseases are becoming increasingly linked to accelerated risks of cardiovascular disease and events. What is apparent from the above review is that the IIM are not an exception to this growing pattern. Although not always clinically apparent, there seems to be a large percentage of patients who have subclinical CV involvement. Many of the traditional risk factors for CAD, such as hypertension and hyperlipidemia, are associated with developing cardiac involvement in patients with IIM. At this time, it is unclear how much of the atherosclerotic CV morbidity and mortality in IIM patients is driven by traditional CV risk factors versus the effects of chronic systemic inflammation from the underlying IIM. The effects of immunosuppression on cardiac disease and events in IIM patients requires further investigation in carefully controlled studies. IIM patients with cardiac involvement are at increased risk for overall mortality when compared with IIM patients without CV disease. The risk of severe cardiac and vascular disease complications seems to be higher than that of the general population. Treatments can be focused on preventing traditional cardiovascular risk factors including avoidance of corticosteroids when possible, although this task remains challenging in IIM as is true of other rheumatic diseases. Once complications do develop, they should be managed similarly to patients without IIM. The use of statins for hyperlipidemia and atherosclerosis in IIM is an area that is in need of further investigation, although initial work suggests that their use is not uncommon by IIM specialists. Further work is needed to determine whether aggressive immunosuppressive treatment of patients with subclinical cardiac disease will lead to better outcomes. Work is also needed in the area of better laboratory, imaging, and serologic testing to identify patients at risk for the worst cardiovascular complications. At this point, based on the body of evidence reviewed here and elsewhere, it is imperative that physicians treating IIM patients performa routine cardiovascular risk assessment at the onset of diagnosis. Appropriate diagnostic and monitoring studies should be performed on those patients who screening history or examination is suggestive of cardiac involvement.

Activin receptor-like kinase-7 induces apoptosis through activation of MAPKs in a Smad3-dependent mechanism in hepatoma cells.

Activin receptor-like kinase (ALK)7 is a type I serine/threonine kinase receptor of the transforming growth factor (TGF)-beta family of proteins that has similar properties to other type I receptors when activated. To see whether ALK7 can induce apoptosis as can some of the other ALK proteins, we infected the FaO rat hepatoma cell line with adenovirus expressing a constitutively active form of the ALK7. Cells infected with active ALK7 adenovirus showed an apoptotic-positive phenotype, as opposed to those that were infected with a control protein. DNA fragmentation assays and fluorescence-activated cell sorter analysis also indicated that ALK7 infection induced apoptosis in FaO cells. We also confirmed this finding in Hep3B human hepatoma cells by transiently transfecting the constitutively active form of ALK7, ALK7(T194D). Investigation into the downstream targets and mechanisms involved in ALK7-induced apoptosis revealed that the TGF-beta signaling intermediates, Smad2 and -3, were activated, as well as the MAPKs JNK and p38. In addition, caspase-3 and -9 were also activated, and cytochrome c release from the mitochondria was observed. Short interfering RNA-mediated inhibition of Smad3 markedly suppressed ALK7-induced caspase-3 activation. Treatment with protein synthesis inhibitors or the expression of the dominant-negative form of the stress-activated protein/extracellular signal-regulated kinase 1 abolished not only JNK activation but apoptosis as well. Taken together, these results suggest that ALK7 induces apoptosis through activation of the traditional TGF-beta pathway components, thus resulting in new gene transcription and JNK and p38 activation that initiates cross-talk with the cellular stress death pathway and ultimately leads to apoptosis.