Trial Confirms IVIG as Useful Therapy for Inflammatory Myopathy

Patients with newly diagnosed idiopathic inflammatory myopathies (IIMs) such as dermatomyositis improved more when they received intravenous immunoglobulin (IVIG) alongside prednisone than with the steroid alone in a placebo-controlled, randomized trial.

Total Improvement Score (TIS), based on six measures of IIM disease activity, increased by an average of 60 points among 23 patients treated with IVIG plus prednisone for 12 weeks, compared with a 42.5-point increase in 19 patients only given prednisone, the current standard of care, according to Joost Raaphorst, MD, PhD, of Amsterdam University Medical Center in the Netherlands, and colleagues.

Secondary efficacy endpoints also favored IVIG, the researchers reported in JAMA Neurology, but a deep vein thrombosis (DVT) event and another patient’s death from unknown causes highlighted pre-existing concerns about thromboembolic risks with IVIG.

Overall, however, Raaphorst and colleagues indicated that “IVIG should be considered as an add-on to prednisone as initial treatment” in IIMs, although “prophylactic anticoagulant therapies” to accompany IVIG could make sense as well.

IIMs are a group of neuromuscular conditions that result from autoimmune attack, with skeletal muscle the primary focus although the skin, lungs, heart, and joints may also be affected. Unlike most other autoimmune diseases, IIMs hit men and women equally. Current initial therapy consists of corticosteroids, usually prednisone. Refractory cases are now seen as a potential target for chimeric antigen receptor (CAR) T-cell therapy or related treatments that could actually be curative, but the expense and risks are too great for it to be considered for newly diagnosed patients.

Recognizing that steroids alone don’t reliably induce remission, clinicians have tried IVIG as an add-on to boost the response. Encouraging results have been reported in case series and open-label studies, but efficacy and safety have not been documented in a rigorous, placebo-controlled trial until now.

Raaphorst and colleagues recruited 44 patients for the trial, which began in 2021, but two dropped out early and were excluded from the analysis. Mean participant age was 59 and half were men. Time from symptom onset averaged nearly 6 months (reflecting the difficulty in reaching a diagnosis for many patients). Besides muscle pain and weakness, most patients experienced symptoms in other tissues, mostly the skin, heart, and lungs.

Prednisone was started at 1 mg/kg with a maximum daily dose of 80 mg, lowering by 10 mg/day each month. IVIG was administered at 2 g/kg, given at weeks 0, 4, and 8. Placebo was plain saline. Participants and most study personnel were blinded as to assignments, except for the nurses who actually administered IVIG or placebo, because of the immediate on-site preparation needed for IVIG. They were told to maintain patients’ blinding.

TIS served as the trial’s primary endpoint. It’s a composite of scores on the following instruments, with a range of 0-100:

• Manual Muscle Test
• Physician Global Activity
• Patient Global Activity
• Health Assessment Questionnaire Disability Index
• Extramuscular disease activity
• Serum levels of creatine kinase, lactate dehydrogenase, aldolase, alanine, and aspartate aminotransferase

Because TIS reflects change over time, all patients started at zero. By week 4, those randomized to IVIG already had improved more than the placebo group (39 vs 30 points). At week 12, the mean difference had increased to 17.5 points (P=0.01).

Secondary outcomes included “moderate” and “major” improvement, defined as TIS increases of at least 40 and 60 points, respectively. These were achieved in the two arms as follows at week 12:

• Moderate improvement: 91% IVIG, 53% placebo
• Major improvement: 70% IVIG, 26% placebo

Individual TIS components were also tracked, along with a dermatomyositis-specific measure for the 13 participants with that form of IIM. All of these also favored IVIG, significantly in each case except for extramuscular disease activity (P=0.06).

Adverse event totals were 148 in the IVIG group and 104 with placebo. All but eight were rated as nonserious. Two patients in each group developed serious infections; myocarditis was seen in two IVIG patients and one given placebo; and one IVIG patient experienced DVT though without symptoms.

Additionally, one participant in the IVIG group died suddenly with no autopsy performed. This patient had formally withdrawn from the trial after receiving two doses because of “clinical deterioration,” Raaphorst and colleagues indicated, but then received a third open-label dose at what would have been week 8 and died the following day. Therefore, IVIG could not be ruled out as precipitating the fatal event.

Since its suddenness is consistent with thromboembolism, that, plus the DVT episode, underscore the need to take such risks seriously, the investigators wrote. “An increased risk of thromboembolic events has been reported for both IVIG and glucocorticoids, particularly in patients with known other risk factors,” they noted. They recommended that IIM patients treated with IVIG be monitored for these events, and use of preventive therapies could be considered.

Limitations to the study included the small sample and the short trial duration, as well as the trial’s conduct in the Netherlands; results therefore may not be fully applicable to other populations.