Since the New England Journal of Medicine publication on intravenous immune globulin (IVIG) for dermatomyositis late last year, the data have proved a major lift for patient care, offering crucial new insights into how best to manage patients and clues about how to minimize risks.1
The ProDERM trial results also seem to have opened up a new era of interest in dermatomyositis, leading to an array of work on potential targeted therapies for a condition that has been an understudied area of rheumatology, says Rohit Aggarwal, MD, MS, the lead investigator on the trial for Octagam, the IVIG treatment, and co-director of the University of Pittsburgh Medical Center Myositis Center, Pennsylvania. The trial “set a regulatory precedent that is huge for the field,” he says.
The primary end point was a Total Improvement Score (TIS) of at least 20. The score was calculated based on the consensus 2016 ACR/EULAR myositis response criteria—using muscle strength, physician’s global assessment of disease activity, patient’s global assessment of disease activity, a health assessment questionnaire, extramuscular disease activity and serum muscle enzyme levels.
Researchers randomized 47 patients to the IVIG group and 48 to a placebo group; 45 of the IVIG patients and 46 of the placebo patients completed the randomized phase. Those in the IVIG group received the drug, a 10% solution at 2.0 g/kg every four weeks. It was typically given in equal amounts over two days, but physicians could extend it to up to five days.
All of the patients, other than those who had a confirmed deterioration, were eligible for the open-label extension phase of the trial through week 40, in which those in the placebo group were switched over to the IVIG group.
Two patients ended up switching to the IVIG group in the randomized phase because of deterioration and another three were switched due to an error, researchers reported.
At week 16, at least minimal improvement—a TIS of at least 20—was seen in 79% of the IVIG patients and 44% in the placebo group (P<0.001). The average TIS at week 16 was 48 in the IVIG group and 21 in the placebo group.
The IVIG group did better regardless of disease severity. For those with mild disease activity, 73% receiving IVIG had at least a minimal response, compared with 27% in the placebo group; for those with moderate disease activity, 79% vs. 52%; and for those with severe disease activity, 86% vs. 50%. Researchers pointed out, though, that the trial was not powered to find differences between these subgroups.
At week 16, researchers found at least a moderate improvement—a TIS of at least 40—in 68% of the IVIG patients, compared with 23% of the placebo group. They found a major improvement—TIS of at least 60—in 32% of the IVIG group and 8% of the placebo group.
At the end of the open-label phase at week 40, the responses between the groups were similar, with 71% of those in the IVIG group who continued to receive IVIG having at least minimal improvement, and 70% of those who had received placebo but switched to IVIG having a response.
About 60% of patients in both groups had at least a moderate improvement at week 40, and more than 30% in both groups had a major improvement at week 40.
The time to at least minimal improvement was a median of 35 days in the IVIG group; to at least moderate improvement, 85 days for these patients; and to major improvement, 283 days in both trial groups.
During the randomized, placebo-controlled phase, deterioration was confirmed in three patients in the placebo group and no patients in the IVIG group. Researchers also found that, of the 85 patients taking concomitant glucocorticoids, 15 were able to reduce their dose or discontinue that treatment during the open-label extension phase. And among the 91 patients who entered the extension phase, eight had a reduction in the IVIG dose to 1 g/kg at 28 weeks or after.
Six thromboembolic events attributed to IVIG were seen in five patients, leading to a change in protocol—lowering the maximum infusion rate to 0.04 mL/kg per minute, from 0.12 mL/kg per minute. Afterward, the events were three times less frequent—the incidence fell from 1.54 per 100 patient-months before the change to 0.54 per 100 patient-months after.
What It Means
The findings have helped clinicians optimize how they use IVIG for dermatomyositis patients, Dr. Aggarwal says.
“We knew it works, but we did not know how quickly it works. What’s the plateau? What’s the safety? What’s the tolerability? All of that was extrapolated from the neurology literature, where most of the time the dose was 1 g/kg and not 2 g. So there was a significant lack of understanding of efficacy.”
Now clinicians have the data to know how long to keep trying IVIG. The trial found that it works within six to eight months, and typically within three to four months. So if it is not working after that, it might be best not to continue, Dr. Aggarwal says.
The trial also has allowed clinicians to use the drug more safely and to counsel patients more thoroughly, says Dr. Aggarwal. A total of 282 treatment-related adverse events were seen in 95 patients, most commonly headache, fever and nausea.
“It’s amazing to see that 92% of the reactions, or the side effects, are infusion related. That means they are going to happen, [but] they only are going to happen for the days you are in infusion and a couple of days after it. That’s it,” Dr. Aggarwal says. “When you tell the patient that, it makes a big difference.”
In the study, no pre-treatment was given routinely for infusion-related reactions, such as fever. Patients had to have two infusion reactions before they could receive pre-treatment. With pre-treatment, the drug is better tolerated, Dr. Aggarwal says.
The prime dermatomyositis candidates for IVIG are those with severe, refractory disease or significant dysphagia, as well as those who are pregnant or have a significant chance of becoming pregnant, who have a high risk of infection, who are undergoing treatment or evaluation for a malignancy and those with calcinosis, according to Dr. Aggarwal.
The data have also led clinicians to take greater precautions to prevent thromboembolic events seen with a thrombogenic disease, such as dermatomyositis, and a thrombogenic treatment, such as IVIG.
“Before this trial, I would not worry about somebody’s high risk of thromboembolic events. I would just give it to everybody not really considering the risk factors. But now I first ask: What are the risk factors?” With these study results in mind, Dr. Aggarwal says he would not give IVIG to a patient with a high thromboembolic risk or who has had thrombolic events.
For patients with an intermediate risk, he is likely to change the infusion rate. Instead of two days, Dr. Aggarwal may extend the infusion over three to five days.
The findings suggested that “doctors need to have a say in how fast an infusion can go. [If] they spend more time in giving their infusion, [they can] significantly decrease the side effects, [including] the serious side effects, [such as] thromboembolic events,” Dr. Aggarwal says. IVIG has also led his clinic to cut the tapering time for glucocorticoids in half, and the pace of tapering might increase even further, he says.
Perhaps even bigger than the guidance for patient management, he says, the trial has ignited new interest in developing new therapies for dermatomyositis. The TIS outcome measure and the disease activity measures were shown to be an acceptable measure that cleared regulatory hurdles.
“The classifications worked. The trial process worked. The time frame worked. The outcome measure worked. And that’s why the trial was positive,” Dr. Aggarwal says. “If any of these did not work then the trial would not have been positive…. This trial was, in certain people’s understanding, not proof that IVIG works. It’s proof that outcome measures and classification and the trial process worked.”
Myositis is no longer at the back of the line in terms of therapy development interest, according to Dr. Aggarwal.
“Previously what would happen is a drug would be tried in rheumatoid arthritis, maybe vasculitis, maybe lupus, and then people would pay attention to myositis,” he says. “That’s kind of changing.”
Another Perspective
Prateek Gandiga, MD, FACP, associate professor of medicine at Emory University, Atlanta, who specializes in treating myositis, says that, previously, he used IVIG only for those with severe disease or who had failed multiple medications.
“A big driver of that was, honestly, insurance coverage,” he says. With IVIG available more readily, more patients are able to benefit, with community physicians becoming more comfortable with it.
“I think people are shifting it earlier into the treatment paradigm and using it more often,” Dr. Gandiga says.
In one of his cases, a 65-year-old woman with dermatomyositis had persistent dysphagia, although her proximal muscle weakness and rash had resolved, and she had normal disease measures otherwise. To his surprise, the insurance provider allowed her to start on IVIG. Dr. Gandiga says he considered it a “Hail Mary pass,” but the woman’s dysphagia “completely turned around”—so much so that the lack of clarity of her speech, which he had initially thought was only her thick Southern accent, drastically improved.
He says the induction phase of treatment—the period of “trying to quickly get the fire as small as possible”—now involves IVIG more frequently, which can make treatment not as reliant on glucocorticoids.
A prior landmark trial of dermatomyositis, the RIM trial evaluating rituximab, failed to achieve the main study outcome designated by the researchers.2
Recently, the interest in myositis clinical trials has definitely increased, Dr. Gandiga says. Although he cautions that it’s hard to attribute this only to the ProDERM study, he believes the trial’s success in getting U.S. Food & Drug Administration approval using standardized International Myositis Assessment & Clinical Studies (IMACS) outcome measures has been extremely influential since you no longer have to guess what the FDA will allow.
“There’s been a definite explosion in the number of calls that I get from pharma companies saying, ‘Hey, we have an agent or a treatment that we’re really interested in and specifically we’d like to evaluate it for myositis,’” Dr. Gandiga says, “and a lot more effort into taking these things into phase 3 studies. I think it’s exciting because a lot of these preliminary trials look really promising.”
Thomas R. Collins is a freelance medical writer based in Florida.
References
- Aggarwal R, Charles-Shoeman C, Schessl J, et al. Trial of intravenous immune globulin in dermatomyositis. N Engl J Med. 2022 Oct 6;387(14):1264–1278.
- Oddis CV, Reed AM, Aggarwal R, et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum. 2013 Feb;65(2):314–324.
