With use of intravenous immune globulin (IVIg) for the treatment of adults with dermatomyositis, a significantly higher percentage of patients experienced at least minimal improvement in disease activity in comparison with placebo in the first-ever phase 3 trial of the blood-product therapy for the condition.
Until this trial, published October 5 in The New England Journal of Medicine, there had not been an extensive evaluation of IVIg for the treatment of dermatomyositis, the study’s authors note.
Glucocorticoids are typically offered as first-line therapy, followed by various immunosuppressants. IVIg is composed of purified liquid IgG concentrates from human plasma. It has been prescribed off label as second- or third-line therapy for dermatomyositis, usually along with immunosuppressive drugs. In European guidelines, it has been recommended as a glucocorticoid-sparing agent for patients with this condition.
“The study provides support that IVIg is effective in treating the signs and symptoms of patients with dermatomyositis, at least in the short term,” said David Fiorentino, MD, PhD, professor of dermatology and associate residency program director at Stanford Health Care, Stanford, California, who was not involved in the study.
“IVIg appears to be effective for patients with any severity level and works relatively quickly [within 1 month of therapy],” he added. “IVIg is effective in treating both the muscle symptoms as well as the rash of dermatomyositis, which is important, as both organ systems can cause significant patient morbidity in this disease.”
Time to improvement was shorter with IVIg than with placebo (a median of 35 days vs 115 days), said Kathryn H. Dao, MD, associate professor in the Division of Rheumatic Diseases at the University of Texas Southwestern Medical Center in Dallas, who was not involved in the study.
The study’s greatest strengths are its international, multicenter, randomized, placebo-controlled design, Dao said. In addition, “these patients were permitted to be on background medicines that we typically use in real-world situations,” she said.
Researchers led by Rohit Aggarwal, MD, of the Division of Rheumatology and Clinical Immunology at the University of Pittsburgh, Pennsylvania, recruited patients aged 18–80 with active dermatomyositis. Individuals were randomly assigned in a 1:1 ratio to receive either IVIg at a dose of 2.0 g/kg of body weight or placebo (0.9% sodium chloride) every 4 weeks for 16 weeks.
Those who were administered placebo and those who did not experience confirmed clinical deterioration while receiving IVIg could participate in an open-label extension phase for another 24 weeks.
The primary endpoint was a response, defined as a Total Improvement Score (TIS) of at least 20 (indicating at least minimal improvement) at week 16 and no confirmed deterioration up to week 16. The TIS is a weighted composite score that reflects the change in a core set of six measures of myositis activity over time. Scores span from 0 to 100, with higher scores indicating more significant improvement.
Key secondary endpoints included moderate improvement (TIS ≥40) and major improvement (TIS ≥60) and change in score on the Cutaneous Dermatomyositis Disease Area and Severity Index.
A total of 95 patients underwent randomization; 47 patients received IVIg, and and 48 received placebo. At 16 weeks, a TIS of ≥20 occurred in 37 of 47 (79%) patients who received IVIg and in 21 of 48 (44%) patients with placebo (difference, 35%; 95% CI, 17% – 53%; P < .001).
The results with respect to the secondary endpoints, including at least
moderate improvement and major improvement, were generally in the same direction as the results of the primary endpoint analysis, except for change in creatine kinase (CK) level (an individual core measure of the TIS), which did not differ meaningfully between the two groups.
Over the course of 40 weeks, 282 treatment-related adverse events were documented among patients who received IVIg. Headache was experienced by 42%; pyrexia, 19%; and nausea, 16%. Nine serious adverse events occurred and were believed to be associated with IVIg, including six thromboembolic events.
Despite the favorable outcome observed with IVIg, in an editorial that accompanied the study, Anthony A. Amato, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, noted that “most of the core components of the TIS are subjective. Because of the high percentage of patients who had a response with placebo, large numbers of patients will be needed in future trials to show a significant difference between trial groups, or the primary endpoint would need to be set higher (eg, a TIS of ≥40).”
Dao thought it was significant that the study proactively assessed patients for venous thrombotic events (VTEs) after each infusion. There were eight events in six patients who received IVIg. “Of interest and possibly practice changing is the finding that slowing the IVIg infusion rate from 0.12 to 0.04 mL/kg/min reduced the incidence of VTEs from 1.54/100 patient-months to 0.54/100 patient-months,” she said. “This is important, as it informs clinicians that IVIg infusion rates should be slower for patients with active dermatomyositis to reduce the risk for blood clots.”
A considerable proportion of patients with dermatomyositis do not have clinical muscle involvement but do have rash and do not substantially differ in any other ways from those with classic dermatomyositis, Fiorentino said.
“These patients were not eligible to enter the trial, and so we have no data on the efficacy of IVIg in this population,” he said. “Unfortunately, these patients might now be denied insurance reimbursement for IVIg therapy, given that they are not part of the indicated patient population in the label.”
In addition, there is limited information about Black, Asian, or Hispanic patients because few of those patients participated in the study. That is also the case for patients younger than 18, which for this disease is relevant because incidence peaks in younger patients (juvenile dermatomyositis), Fiorentino noted.
Among the study’s weaknesses, Dao noted that more than 70% of participants were women. The study was short in duration, fewer than half of patients underwent muscle biopsy to confirm myositis, and only two thirds of patients underwent electromyography/nerve conduction studies to show evidence of myositis. There was a high placebo response (44%), the CK values were not high at the start of the trial, and they did not change with treatment.
No analysis was performed to evaluate the efficacy of IVIg across dermatomyositis subgroups – defined by autoantibodies – but the study likely was not powered to do so. These subgroups might respond differently to IVIg, yielding important information, Fiorentino said.
The study provided efficacy data for only one formulation of IVIg, Octagam 10%, which was approved for dermatomyositis by the US Food and Drug Administration (FDA) in 2021 on the basis of this trial. However, in the United States, patients with dermatomyositis are treated with multiple brands of IVIg. “The decision around IVIg brand is largely determined by third-party payers, and for the most part, the different brands are used interchangeably from the standpoint of the treating provider,” Fiorentino said. “This will likely continue to be the case, as the results of this study are generally being extrapolated to all brands of IVIg.”
Multiple IVIg brands that have been used for immune-mediated diseases differ in concentration, content of IgA, sugar concentration, additives, and preparations (eg, the need for reconstitution vs being ready to use), Dao said. Octagam 10% is the only brand approved by the FDA for adult dermatomyositis; hence, cost can be an issue for patients if other brands are used off label. The typical cost of IVIg ranges from $100 to $400 per gram; a typical course of treatment is estimated to be $30,000 to $40,000 per month. “However, if Octagam is not available or a patient has a reaction to it, clinicians may use other IVIg brands as deemed medically necessary to treat their patients,” she said.
Aggarwal has financial relationships with more than 15 pharmaceutical companies, including Octapharma, which provided financial support for this trial. Some of the co-authors were employees of Octapharma or had financial relationships with the company. Dao has disclosed no relevant financial relationships. Fiorentino has conducted sponsored research for Pfizer and Argenyx, has received research funding from Serono, and is a paid adviser to Bristol-Myers Squibb, Janssen, Acelyrin, and Corbus
N Engl J Med. Published online October 5, 2022. Abstract