Session Information
Session Title: Muscle Biology, Myositis and Myopathies: Clinical and Therapuetic Aspects of Idiopathic Inflammatory Myopathies
Session Type: Abstract Submissions (ACR)
Background/Purpose: To evaluate downstream effects of an anti-IFN-α monoclonal antibody (mAb) in adult dermatomyositis (DM) and polymyositis (PM) patients using serum proteomics and gene expression profiling from patient blood and muscle samples.
Methods: A phase 1b randomized, double-blinded, placebo-controlled, multicenter clinical trial was conducted in adult patients with DM or PM. Whole blood, serum, and muscle specimens were procured both pre and 98 days post administration with an anti-IFN-α mAb, sifalimumab. Affymetrix whole genome arrays were used to measure transcript expression in whole blood and muscle, while a multiplex luminex immunoassay was used to measure serum levels of more than 130 proteins. Target modulation of type I IFN activity was measured using a 13 gene type I IFN gene signature in patients following administration with either sifalimumab or placebo.
Results: Serum levels of soluble interleukin-2 receptor (sIL-2R) were significantly higher at baseline in 19 DM and 18 PM patients showing an elevated blood type I IFN signature than in 6 DM and 5 PM patients without an elevated signature and 20 normal controls. Among patients with high baseline type I IFN gene signature, those expressing high levels of sIL-2R had lower manual muscle testing (MMT8) scores at baseline, compared to patients with only an elevated baseline type I IFN gene signature. Following administration with sifalimumab, whole genome transcript profiling identified the IL2 signaling pathway as among the top ten most suppressed pathway, along with several T cell-related signaling pathways. This result was not identified in placebo-dosed patients. Sifalimumab also down-regulated sIL-2R levels by more than 30% in 3 DM and 4 PM patients, with no significant change in 11 placebo dosed patients. Further, patients showing strong sIL-2R down-regulation post dosing of sifalimumab, also exhibited suppression of the type I IFN gene signature (target suppression > 80% in the blood).
Conclusion: Our results demonstrate that sIL-2R levels in the serum of myositis patients, in combination with a blood type I IFN gene signature, may correlate with disease activity in a patient subset better than a type I IFN gene signature alone. Sifalimumab down-regulated serum sIL-2R levels in a subset of myositis patients that also showed strong suppression of the type I IFN gene signature in blood. These results suggest the possibility to combine sIL-2R and type I IFN gene signature as a prognostic marker for myositis patients.
Disclosure:
X. Guo,
AstraZeneca,
1,
MedImmune,
3;
B. W. Higgs,
AstraZeneca,
1,
MedImmune,
3;
W. Zhu,
AstraZeneca,
1,
MedImmune,
3;
Y. Yao,
AstraZeneca,
1,
MedImmune,
3;
W. White,
AstraZeneca,
1,
MedImmune,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/proteomics-study-of-a-phase-1b-trial-with-an-anti-ifn-%ce%b1-monoclonal-antibody-indicates-association-of-soluble-interleukin-2-receptor-with-type-i-interferon-activity-in-patients-with-dermatomyositi/