By Norman Latov, MD, PhD
Professor of Neurology and Neuroscience, Weill Cornell Medical College; Director of the Neuropathy Center, Weill Cornell Medicine
SYNOPSIS: Treatment of dermatomyositis with intravenous immunoglobulin (IVIG) resulted in overall better clinical improvement after 16 weeks compared to patients treated with placebo. However, there was a significant number of thromboembolic adverse events in the treatment group. The group of patients treated was a heterogeneous group. However, IVIG now is U.S. Food and Drug Administration-approved for the treatment of dermatomyositis.
SOURCES: Aggarwal R, Charles-Schoeman C, Schessl J, et al. Trial of intravenous immune globulin in dermatomyositis. N Engl J Med 2022;387:1264-1278.
Amato AA. Intravenous immune globulin therapy in dermatomyositis. N Engl J Med 2022;387:1320-1321.
In a randomized, placebo-controlled trial of 95 patients with dermatomyositis, treatment with intravenous immunoglobulin (IVIG; Octagam 10%), 2 g/kg every four weeks for 16 weeks, was associated with a significantly higher rate and magnitude of improvement compared to placebo, as measured by the Total Improvement Score (TIS), which is a composite score of disease activity. In a 24-week open-label extension phase of the study, treatment with IVIG also resulted in improvement in those previously receiving placebo.
In the safety analysis, thromboembolic events considered to be related to the trial regimen occurred in six patients, or 9.1%, of those in the IVIG-treated group compared to none in the placebo group. Other treatment-related adverse events occurred in the IVIG group, including headache (42% of patients), fever (19% of patients), and nausea (16% of patients). Based on the study, the U.S. Food and Drug Administration (FDA) granted approval for the use of IVIG in dermatomyositis.
In the accompanying editorial, Dr. Anthony Amato noted that this is the first therapy approved by the FDA for any of the inflammatory myopathies, which until now typically were treated with corticosteroids or more toxic immunosuppressive agents. He pointed out, however, that dermatomyositis now is recognized to be a heterogeneous syndrome that is defined by distinct clinical and histopathological features and that has different clinical manifestations, disease course, prognosis, and, possibly, responses to specific therapies. The serological abnormalities include anti-TIF-1γ antibodies that are associated with cancer, anti-MDA-5 antibodies that are associated with skin rash in the absence of muscle involvement, and anti-NXP-2 or SAE antibodies, among others.1 As such, future studies would need to use the newer diagnostic criteria, based on clinical, serological, and pathological features. However, these were not available at the start of the trial. The outcome measures would best be tailored to the specific subtypes based on the particular clinical features, such as weakness or rash.
Of note is the high incidence of thromboembolic events, which occurred in 9.1% of cases. This compares to the absence of any thromboembolic events in 116 patients treated with similar doses of the same drug in a clinical trial of immune thrombocytopenia or 201 patients in a clinical trial of chronic inflammatory demyelinating polyradiculoneuropathy who were treated with two other preparations of IVIG, and 3% of 502,492 patients in a UK Biobank database who had no prior history of thromboembolic events and were treated with IVIG.2-5
It may be that patients with dermatomyositis have a predisposition to thrombosis, in which case it may be appropriate to screen patients for pro-thrombotic factors, such as antiphospholipid antibodies, which have been reported to be more frequent in dermatomyositis.6 Prophylaxis with an anticoagulant agent, or treatment with subcutaneous immunoglobulin preparations that avoid the peak serum levels following intravenous administration, might reduce the risk of thrombosis in this patient population.
COMMENTARY
IVIG has been reported to exert its effects via multiple mechanisms. These include inhibition of complement activation, anti-idiotypic activity that interferes with autoantibody binding, blockage of neonatal Fc receptors resulting in increased catabolism of endogenous autoantibodies, and down regulation of macrophage activation or secretion of pro-inflammatory cytokines.7 In dermatomyositis, IVIG was shown to prevent the complement-mediated microangiopathy, which is thought to be responsible for the myopathy.8 The cause for the complement activation, however, is not known.
Further studies with newer agents that target the different immune mechanisms by which IVIG can exert its effects, such as the classical or alternative complement activation pathways, neonatal Fc receptors, or specific cytokines or their receptors, could help reveal the underlying pathogenic mechanisms and lead to the development of more directed or effective therapies.
REFERENCES
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- Robak T, Mainau C, Pyringer B, et al. Efficacy and safety of a new intravenous immunoglobulin 10% formulation (octagam® 10%) in patients with immune thrombocytopenia. Hematology 2010;15:351-359.
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- Kapoor M, Hunt I, Spillane J, et al. IVIg-exposure and thromboembolic event risk: Findings from the UK Biobank. J Neurol Neurosurg Psychiatry 2022;93:876-885.
- Font J, Cervera R, Lopez-Soto A, et al. Anticardiolipin antibodies in patients with autoimmune diseases: Isotype distribution and clinical associations. Clin Rheumatol 1989;8:475-483.
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- Basta M, Dalakas MC. High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J Clin Invest 1994;94:1729-1735.
