Cardiomyopathy
Usefulness of Immunosuppression for Giant Cell Myocarditis

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Giant cell myocarditis (GCM) is a rare and highly lethal disorder. The only multicenter case series with treatment data lacked cardiac function assessments and had a retrospective design. We conducted a prospective, multicenter study of immunosuppression including cyclosporine and steroids for acute, microscopically-confirmed GCM. From June 1999 to June 2005 in a standard protocol, 11 subjects received high dose steroids and cyclosporine, and 9 subjects received muromonab-CD3. In these, 7 of 11 were women, the mean age was 60 ± 15 years, and the mean time from symptom onset to presentation was 27 ± 33 days. During 1 year of treatment, 1 subject died of respiratory complications on day 178, and 2 subjects received heart transplantations on days 2 and 27, respectively. Serial endomyocardial biopsies revealed that after 4 weeks of treatment the degree of necrosis, cellular inflammation, and giant cells decreased (p = 0.001). One patient who completed the trial subsequently died of a fatal GCM recurrence after withdrawal of immunosuppression. Her case demonstrates for the first time that there is a risk of recurrent, sometimes fatal, GCM after cessation of immunosuppression. In conclusion, this prospective study of immunosuppression for GCM confirms retrospective case reports that such therapy improves long-term survival. Additionally, withdrawal of immunosuppression can be associated with fatal GCM recurrence.

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Methods

The initial design of the study was a multicenter, randomized, open-label, 2-arm trial and parallel prospective treatment registry. The active treatment group received 10 days of muromonab-CD3 and 1 year of cyclosporine and steroids as described later. The control group received “usual care” that could include no immunosuppression or steroids and/or azathioprine at the discretion of the site principal investigator. A prospective treatment registry was an option for subjects who declined to be

Results

The clinical performance sites and principal investigators that participated in study enrollment are listed in the Appendix. Participation is defined as having Institutional Review Board approval for the study and all required contractual and regulatory documentation necessary for screening and enrollment. Enrollment refers to subjects with GCM who signed consent.

A total of 28 subjects signed consent for screening before endomyocardial biopsy. Of these 28 screened subjects, 8 subjects (29%) had

Discussion

Several observations in this study add meaningfully to the very limited knowledge regarding GCM treatment. First, immunosuppressive treatment with the combinations of agents used in this study resulted in relatively low 1-year mortality. Further, abrupt withdrawal of immunosuppression can result in recurrent, fatal GCM. Finally, the rate of adverse events probably has an acceptable safety profile in this high-risk population.

We observed a marked improvement in the inflammatory infiltrate

Acknowledgment

We especially thank Adita Mascaro-Blanco for performing the anti-HCM, anti-β1 and anti-β2 ELISAs in this study.

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This work was supported by US Food and Drug Administration Grant FD-RO-1-001986 and a Leder Family Philanthropic Grant, Washington, DC. Muromonab-CD3 was supplied by Ortho-Biotek, Inc.

Clinical Trial Registration NCT00027443 (http://www.clinicaltrials.gov/ct/show/NCT00027443?order=1).

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