June 21, 2011 — Newly released results of a 1-year pilot study of tumor necrosis factor α (TNF-α) blocker etanercept (Enbrel) in the treatment of dermatomyositis (DM), a subtype of inflammatory myopathy, shows that the drug is safe and well tolerated.
At the end of the trial, 4 of 11 subjects who were treated with etanercept were receiving only the study drug and met International Myositis Assessment Clinical Study (IMACS) recommended measures of improvement compared with none of the 5 patients treated with placebo.
The study showed that etanercept "is safe enough to proceed to a larger trial" and provided important information about which outcome measures might be useful to include in such a future trial, said principal investigator Anthony A. Amato, MD, professor of neurology, Harvard Medical School, and vice chairman, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts.
The study was published online June 17 in the Annals of Neurology.
Recruitment for the study proved to be problematic because clinicians preferred to refer only those patients in whom both prednisone and methotrexate had failed, making it difficult to enroll treatment-naive patients with newly diagnosed DM, said Dr. Amato. Many patients with DM, too, wanted to first try standard therapy.
"One of the valuable lessons learned during the trial is that it's going to be difficult to do any study on treatment-naive patients because most patients are going to want to have failed standard treatments even if they haven't been proven," he told Medscape Medical News.
For the study, 16 patients (10 women) were randomly assigned to receive etanercept, 50 mg (n = 11: 3 treatment naive, 8 refractory), or placebo (n = 5: 2 treatment naive, 3 refractory) once weekly by subcutaneous injection. Mean baseline prednisone dosage was 45 mg/day in the etanercept group and 39 mg/day in the placebo group.
The study included a unique prednisone-tapering component. Patients with newly diagnosed DM are typically prescribed a high dose of prednisone and then weaned off that drug when they "meet some marker of being completely normal," but there's no consensus on when to taper, said Dr. Amato. "Do you taper when the muscle enzymes are normal? Do you taper when the strength is normal? Do you taper when they're stable?"
In this study protocol, investigators mandated a "forced" taper into the design. "We kind of did the opposite; we tapered the patient unless they were getting worse," said Dr. Amato. That design should be useful for future research, he added. "I think we might be doing more of that kind of trial design — to try to lower the dose as long as the patient is not getting dramatically worse."
In the study, prednisone dosage from weeks 25 to 52 in the placebo group (median, 29.2 mg/day) was significantly higher than that in the etanercept group (median, 1.2 mg/day).
All 5 subjects in the placebo group underwent failed treatment (median time to treatment failure, 148 days). In contrast, 5 of the 11 subjects in the treatment group were successfully weaned off prednisone (median time to treatment failure, 358 days; P = .0002). Of the 6 treatment failures, 5 (83%) occurred in previously refractory subjects.
The study found no significant difference in adverse events between the 2 groups. No placebo-treated subject had an antinuclear antibody (ANA) at baseline, but 1 developed an ANA at the end of the study. Two of the 11 etanercept-treated subjects developed newly elevated ANAs. None developed systemic lupus erythematosus (SLE). Rash worsened in 5 patients in the etanercept and 1 in the placebo group.
"I don't know if the rash was a worsening of the DM or whether it was kind of a reaction to the medicine, like a lupus; it wasn't clear-cut and that's something we would be cautious about," said Dr. Amato.
In addition to infection and induction of SLE, potential adverse effects of etanercept include malignant tumors, but the 1 patient in the study who developed cancer was taking placebo.
At the end of the study, 6 subjects in the etanercept group met consensus criteria for improvement, that is, improvements in 3 of 6 core set measures by 20% or more, with no more than 2 worsening by at least 25%.
Of these, 4 continued not to take prednisone and had no additional treatment. One subject was weaned off prednisone and received no other treatment but did not meet any definitions of improvement (DOIs). The 5 etanercept subjects who were successfully weaned off prednisone had these improvements in a core set outcome measures:
Physician Global Activity score (mean, 54.3%);
Patient Global Activity score (mean, 55.3%);
Average manual muscle testing score (mean 5.2%);
Percentage of predicted normal maximum voluntary isometric contraction testing (mean, 39.2%);
Myositis Disease Activity Assessment Visual Analogue Scale extramuscular score (mean, 56.9%); and
Health Assessment Questionnaire score (mean, 40.3%).
Three placebo-treated subjects met recommended criteria for improvement at week 52, but each of them required increased prednisone and 2 also needed the addition of a second-line agent.
So although 4 of the 11 etanercept-treated subjects were receiving only the study drug and met IMACS DOI criteria, none of the placebo-treated patients reached this level of improvement.
Evaluating different outcome measures that could be used in future clinical trials was perhaps the most important objective of this pilot study, commented Dr. Amato. One of the obstacles in studying myositis, he said, has been establishing objective measures of improvement.
"If you're doing, say, an epilepsy study, you can count the number of seizures; in migraines you can count the number of migraines, or if someone has MS [multiple sclerosis], you can kind of track the lesions on an MRI [magnetic resonance imaging] scan of the brain, but in myositis you want to look at strength, but how do you measure strength objectively?"
Dr. Amato believes this is the first published blinded study on the use of an immune-modulating drug in patients with DM, a rare disorder affecting only a few people per 100,000 in the population. Patients receive treatment from a rheumatologist, dermatologist, or neurologist who specializes in muscle disease.
Recruitment Problems Not Unexpected
Carl F. Ansevin, MD, a neurologist in Boardman, Ohio, and a member of the American Academy of Neurology who specializes in neuromuscular medicine, thought that the study was extremely well designed under the circumstances.
"The authors did an excellent job of modifying their inclusion criteria to overcome initial recruitment problems," he told Medscape Medical News. "They used good common sense; they treated the patients well; they found out as much as they could, and they accomplished their goals — the safety goal, the goal to see if they could taper the steroids safely, and they demonstrated excellent test retest reliability in their outcomes measures goal."
More such studies are needed to find alternative agents to treat muscle diseases, Dr. Ansevin added. However, he thought that other neuromuscular disorders for which, unlike DM, there are currently no adequate treatments (eg, inclusion body myositis) might be amenable to a similar study.
He said that the recruitment problems encountered by the study organizers should not have been unexpected. "Getting patients to participate in studies like this when you have a treatment that works (usually but not always), albeit with significant adverse side effects, is very difficult."
Importantly, the pilot study showed that the treatment group could be maintained with lower doses of steroids, the so-called steroid-sparing effect, he added.
"There is definitely a population of patients that can use this drug if larger studies can be completed," Dr. Ansevin concluded. "They are to be congratulated on a study well done — and hopefully we will see more in the future."
Dr. Amato reports medical advisory board and consulting fees from MedImmune and royalties from Up to Date and McGraw-Hill. For conflict of information on other authors, please see the original paper.
Ann Neurol. Published online June 17, 2011.
Medscape Medical News © 2011 WebMD, LLC
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Cite this: Etanercept Safe, Well Tolerated in Dermatomyositis - Medscape - Jun 21, 2011.