A randomised trial suggests adding IVIG to prednisone delivers faster, greater improvement in newly diagnosed myositis, but safety concerns remain.
Patients with newly diagnosed idiopathic inflammatory myopathies may benefit from hitting the disease harder and earlier, say researchers.
A randomised trial has found intravenous immunoglobulin (IVIG) added to high-dose prednisone substantially improved outcomes within 12 weeks.
The double-blind, placebo-controlled TIME IS MUSCLE trial found patients receiving intravenous immunoglobulin achieved significantly greater improvement than those receiving prednisone alone, while reaching a moderate clinical response about eight weeks sooner.
The findings, published in JAMA Neurology, add to evidence challenging the traditional approach of starting patients with idiopathic inflammatory myopathies (IIMs) on high-dose glucocorticoids and escalating treatment later if needed.
“Small studies have suggested efficacy of IVIG as add-on or monotherapy directly after diagnosis,” the researchers wrote.
“The present trial provides evidence for efficacy of IVIG in IIMs in the first three months after diagnosis.
“This finding is in line with superior efficacy of more intensive (add-on) treatment in new-onset inflammatory bowel disease, rheumatoid arthritis, and myasthenia gravis.
“These strategies are applied on the premise that highly effective early control of autoimmune inflammation leads to better outcomes, and the present trial illustrates the feasibility of this approach in IIMs.”
The Dutch study randomised 44 adults with newly diagnosed IIMs to standard high-dose prednisone plus either IVIG or placebo. IVIG was given at 2g/kg at weeks zero, four, and eight. Forty-two patients reached a primary endpoint and were included in the main analysis.
At 12 weeks, the mean Total Improvement Score (TIS) was 60.0 in the IVIG group compared with 42.5 in the placebo group, a mean difference of 17.5 points (95% CI 4.4-30.6; P=0.01).
The TIS is a 100-point composite based on six measures of myositis disease activity, with higher scores indicating greater improvement.
The difference in TIS was also clinically substantial, the researchers said. Moderate improvement was achieved by 91% of patients receiving IVIG compared with 53% receiving placebo (P=0.01), while 70% versus 26%, respectively, achieved major improvement (P=0.005).
Response was faster as well. Median time to moderate improvement was four weeks with IVIG compared with 12 weeks with placebo (P=0.005).
Patients receiving IVIG also had better outcomes at week 12 for muscle strength, physical disability, muscle enzymes, and physician- and patient-rated disease activity, the researchers noted.
Mean Manual Muscle Test scores were 241 in the IVIG group and 220 in the placebo group (P=0.002), while mean Health Assessment Questionnaire Disability Index scores were 0.7 and 1.3, respectively (P=0.004).
The researchers said glucocorticoids, with or without subsequent immunosuppressive agents, had remained the cornerstone of initial IIM treatment for decades despite responses often being slow and incomplete.
Most previous trials of IVIG have focused on refractory disease, particularly dermatomyositis, but the researchers said their findings provided evidence for its efficacy during the first three months after diagnosis.
Exploratory analyses suggested the treatment effect may vary between IIM subtypes, the researchers said.
Among 13 patients with dermatomyositis, the mean TIS at 12 weeks was 69.2 with IVIG compared with 34.6 with placebo. Among 16 patients with immune-mediated necrotising myopathy, the corresponding scores were 49.4 and 34.4.
However, the trial was not powered to detect differences between subgroups, and the authors cautioned against drawing firm conclusions from those results.
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Safety remained an important caveat. There were 148 adverse events in the IVIG group and 104 in the placebo group, including five and four serious adverse events, respectively. One asymptomatic deep venous thrombosis was detected in a patient receiving IVIG.
The researchers also highlighted one sudden death that occurred outside the prespecified adverse-event monitoring period but directly after the patient received open-label IVIG following deterioration. No postmortem examination was performed, and the researchers said a causal relationship with IVIG was possible.
Given that both IVIG and glucocorticoids have been associated with thromboembolic events, the researchers said the events underscored the need for individual thromboembolic risk assessment and monitoring.
There were some limitations to the study, which was small and conducted at a single tertiary referral centre, with only 42 patients included in the primary analysis.
Follow-up for the reported efficacy endpoint was also limited to 12 weeks, with six- and 12-month outcomes to be reported separately.
Despite those limitations, the researchers said the results supported consideration of IVIG in patients with newly diagnosed IIM.
“In conclusion, the results of this randomised clinical trial may indicate that newly diagnosed patients with IIMs are substantially undertreated with prednisone monotherapy in the first months of their disease and that IVIG should be considered as an add-on to prednisone as initial treatment,” they wrote.
