JAK inhibition ‘promising,’ could reduce steroid use in dermatomyositis
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Earlier this year, a group of researchers published data from long-term extension study of tofacitinib in patients with dermatomyositis, demonstrating a “sustained response” to a pan-JAK inhibitor in this population.
Published in Arthritis & Rheumatology, it had been a follow-up to a first-of-its-kind study — a prospective, open-label clinical trial of tofacitinib (Xeljanz, Pfizer) for dermatomyositis that, for the first time, suggested strong clinical efficacy with a JAK inhibitor for this indication. Of particular note, the initial study found that the JAK inhibitor had improved Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) and Total Improvement Scores (TIS) as early as 4 weeks after treatment.
According to Julie J. Paik, MD, MHS, director of clinical trials and assistant professor of medicine at the Johns Hopkins Myositis Center, and lead author of both studies, these results open new, much-needed possibilities for dermatomyositis research and treatment.
“Many of the drugs in dermatomyositis take at least 3 months to kick in, and some can take as long as 6 months,” Paik told Healio. “In those cases, physicians often have to use steroids to stabilize patients until the immunomodulatory therapies begin to work. However, if JAK inhibitors work quickly, it can potentially minimize the steroid burden.”
In their initial, proof-of-concept study, also published in Arthritis & Rheumatology, Paik and colleagues assessed the efficacy and safety of tofacitinib in 10 patients with treatment-refractory active dermatomyositis over 12 weeks.
The study drug was administered in extended-release doses of 11 mg. Study protocols also called for all patients to have a “complete washout” of all steroid-sparing drugs.
Improvement, measured via the International Myositis Assessment and Clinical Studies group definition served, as the primary endpoint. In addition, the researchers evaluated patients based on the 2016 American College of Rheumatology/ EULAR myositis response criteria.
CDASI scores, chemokine levels, immunohistochemical analysis of STAT1 expression in the skin, RNA sequencing analysis and safety all underwent analysis as secondary outcome measures.
Results showed that all 10 patients met the primary endpoint criteria.
Half of the cohort experienced moderate improvement in disease activity, while the other half reported minimal improvement based on the 2016 ACR/EULAR parameter.
Regarding the mean change in CDASI activity score, results showed that the mean score of 28 (standard deviation ± 15.4) at baseline had improved to 9.5 (SD ± 8.5) at 12 weeks (P = .0005), which the researchers noted was a statistically significant improvement.
In addition, serum chemokine levels of CXCL9/CXCL10 also statistically significantly improved between baseline and 12 weeks.
The decrease in STAT1 signaling as a correlative factor with suppressing the interferon target gene expression was observed in three of nine biopsy samples from patients in the cohort.
Patients demonstrated creatine kinase levels of 82 (SD ± 34.8) IU/liter at baseline, which the researchers suggested indicates high disease activity in the skin.
Later, in the long-term extension study, all 10 patients continued treatment with tofacitinib through 20 weeks. Results showed that the response as assessed by the 2016 ACR/EULAR score at this timepoint was 35 (interquartile range, 32.5–37.5). The researchers suggested that this is a “sustained response” to a JAK inhibitor for this patient population.
Healio sat down with Paik to discuss the attractive features of JAK inhibition in this patient population and what directions future research might take.
Healio: Could you provide some background on JAK inhibitors in this population?
Paik: To my knowledge, the first case report of a JAK inhibitor, ruxolitinib (Opzelura, Incyte), being efficacious in dermatomyositis goes back to 2014. The case was published in the New England Journal of Medicine. Since then, there have been small retrospective case reports and series demonstrating its efficacy in dermatomyositis.
Healio: Where does your study fit into this body of evidence?
Paik: Our study is the first prospective, proof-of-concept clinical trial of tofacitinib in refractory dermatomyositis. We were able to perform assessments every 4 weeks until the endpoint at 12 weeks. We were also able to show pre- and post-treatment data to really answer the question of whether this drug is working effectively in our patients with refractory dermatomyositis.
Healio: To that point, your study had a relatively small population, with just 10 patients?
Paik: Yes, that is correct. We had two goals. The first was to conduct a rigorous study, but the second was to complete a study in a timely fashion to answer the simple question of whether JAK inhibitors had potential efficacy in dermatomyositis. That said, our exclusion and inclusion criteria were pretty restrictive, especially in terms of background immunomodulatory therapies. We required washout of all background immunosuppressant to assess the pure effect of tofacitinib.
In a bigger phase 2 or 3 study, you don’t have the luxury of doing that because, without background therapies, many patients would be flaring if there is a placebo group.
Healio: Regarding the monotherapeutic effect, could you talk a little more about how your study protocols called for a complete washout of steroid sparing agents?
Paik: Yes, everyone was washed out of everything, including intravenous Immunoglobulin (IVIG) and rituximab (Rituxan, Genentech). Only four of our patients were on steroids. Those patients were on a stable dose, with a maximum of 20 mg daily. Everyone else was able to manage without background therapies. The main disadvantage of doing the study this way was that we were unable to recruit patients who had significant muscle disease. Although it was not intended when the protocol was written, we ended up enrolling patients with skin-predominant dermatomyositis.
Healio: Were you surprised by the results?
Paik: The results were great in that all patients met the primary outcome measure. Most patients had at least a moderate improvement on the TIS. Furthermore, we saw a pretty quick improvement in the TIS and CDASI, as early as 4 weeks.
Healio: Could you discuss the findings from the long-term extension study?
Paik: The long-term extension study went out to 96 weeks, with seven of 10 patients continuing to that point. They all showed continued improvement. However, not everyone sustained a robust response. Still, many continued to show minimal improvement on the TIS and there was significant sustained response on the CDASI, which measures cutaneous improvement.
Healio: Could adherence issues be part of the reason the response was somewhat diminished over time?
Paik: Our patients informed us they were adherent. However, in the long-term extension study patients were not seen as regularly so it can also be a possibility.
Healio: What conclusions should rheumatologists draw from your findings?
Paik: The overall take-home message is that JAK inhibitors can be a promising therapeutic agent in dermatomyositis. They are attractive because of the potential early onset of action, and because it is an oral drug that can also be combined safely with other agents, such as methotrexate. The question still remains whether they are efficacious in treating muscle disease. As I mentioned, our study did not have many patients with muscle disease.
However, I believe that our work and other dermatology and rheumatology colleagues who have reported on the efficacy of JAK inhibitors in dermatomyositis have really laid the groundwork for larger phase 2 and 3 clinical trials that are underway in the United States and internationally.
Reference:
- Paik JJ, et al. Arth & Rheum. 2021;doi:10.1002/art.41602.
- Paik JJ, et al. Arth & Rheum. 2021;doi:10.1002/art.41944.
- Paik JJ, et al. Rheumatology. 2021;doi:10.1093/rheumatology/keab421.
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