Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose
Discoid Lupus Erythematosus (DLE), the most common chronic cutaneous form seen in LE, includes inflammation leading to scarring, telangiectasias, atrophy, and/or dyspigmentation. Elevated levels of IFN-γ mRNA have been described in DLE skin biopsy specimens, and patients with DLE have an IFN transcriptional signature in both blood and skin. AMG 811 is a human monoclonal antibody that selectively targets and neutralizes human IFN-γ, and results from a randomized, placebo-controlled, crossover study in DLE subjects have been previously reported (NCT01164917; Werth et al, 2013). The primary results demonstrated acceptable safety and PK profiles without apparent clinical benefit. Evidence of a pharmacodynamic effect in the blood (e.g. inhibition of IFN-γ) was apparent; however, heterogeneity in skin samples prevented definitive conclusions about the effects of AMG 811 in diseased skin.
Methods
This multi-center clinical study included 16 subjects with DLE enrolled in a randomized, single-dose crossover study. DLE subjects required a history of skin biopsy consistent with the diagnosis of DLE (Gilliam and Sontheimer classification); a diagnosis of SLE (ACR criteria) was not required, however 14 of 16 subjects had both DLE and SLE. Microscopic histopathology was performed on punch biopsies obtained from discoid lesional and non-lesional areas, and the abundance of CD3+, CD4+, CD8+, CD68+ and Ki67+ cells were quantitated by laser scanning cytometry. Whole blood and skin RNA and serum proteins were analyzed by microarray and ELISA, respectively.
Results
The baseline CLASI activity and damage scores ranged from 10 to 34 and 6 to 35, respectively (maximum 70), reflecting heterogeneity in the anatomic location and severity of the DLE skin involvement in this cohort. A range of microscopic pathology findings was observed including acanthosis, keratinocyte apoptosis, inflammatory cell infiltrates and dermal mucinosis. As with psoriasis, there was a wide range of elevated numbers of CD3+, CD4+, CD8+ T cells, CD68+ macrophages and as well as Ki67+ proliferating cells in the lesional skin compared to non-lesional skin. The AMG 811 PD score, a microarray signature described previously, was significantly higher in DLE lesional skin compared with non-lesional skin. Histopathology and RNA transcript analysis revealed substantial intra- and inter-subject heterogeneity between skin biopsies from DLE subjects as compared to published results from subjects with psoriasis. Pathway analysis of the transcriptome suggested differential activation of both the interferon and IL-17 pathways.
Conclusion
Discoid subjects in this small clinical study demonstrated a high level of clinical, histologic and molecular heterogeneity at baseline, creating hurdles for measuring response to therapy. Analysis of clinical and/or skin biomarkers may improve understanding of the heterogeneity within DLE, and may better enable subgroup selection for assessment of response to therapeutic treatments.
Disclosure:
B. Sullivan,
Amgen,
3,
Amgen,
1;
R. Guzman,
Amgen,
3,
Amgen,
1;
C. B. Russell,
Amgen,
3,
Amgen,
1;
G. Arnold,
Amgen,
3,
Amgen,
1;
M. Boedigheimer,
Amgen,
3,
Amgen,
1;
C. Ma,
Amgen,
3,
Amgen,
1;
J. Chung,
Amgen,
3,
Amgen,
1;
V. P. Werth,
UV Therapeutics,
1,
Amgen, Rigel, Janssen, Novartis, Invion ,
2,
Philadelphia VAMC and University of Pennsylvania,
3,
Medimmune, Genentech, Novartis, Pfizer, Cephalon, UV Therapeutics, Rigel, Biogen, Lupus Foundation of America, Sanofi-Aventis, Stiefel, Merck, RPS, Idera, Canfield, Celgene,
5,
Head MAB, International Pemphigus and Pemphigoid Foundation,
6,
CLASI, CDASI,
7;
D. A. Martin,
Amgen,
3,
Amgen,
1.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/molecular-cellular-and-histopathologic-assessment-of-baseline-characteristics-of-sixteen-subjects-with-discoid-lupus-erythematosus-prior-to-treatment-with-amg-811-anti-ifn%ce%b3/