Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Rapid efficacy of anifrolumab across multiple subtypes of recalcitrant cutaneous lupus erythematosus parallels changes in discrete subsets of blood transcriptomic and cellular biomarkers.

Abstract

BACKGROUND: Observations with rituximab suggest B-cell independent mechanisms of cutaneous lupus (CLE) in SLE, especially discoid. Type-I interferon receptor blockade with anifrolumab shows efficacy in SLE but efficacy on cutaneous disease of specific morphologies has not been studied. Interferon has pleotropic immune effects and which of these are critical to therapeutic response is unknown. OBJECTIVE: We evaluated clinical efficacy and quality of life impact of type-I interferon-blockade in (i) rituximab-refractory CLE; (ii) discoid and other morphologies; (iii) transcriptomic and flow cytometric biomarkers. METHODS: We conducted a prospective single-centre study of anifrolumab in refractory mucocutaneous SLE. CLASI activity score, health related quality of life, 96-probe TaqMan gene expression analysis capturing key SLE blood transcriptome signatures, and 8-colour flow cytometry were undertaken at baseline, 1, 3 and 6 months. RESULTS: 7 patients (DLE n=5, chilblain LE n=1, SCLE n=1) were evaluated. Median (range) prior therapies was 6 (3, 15), including rituximab in 6/7. Median CLASI-A showed rapid and sustained improvement from 17 at baseline to 6 (p=0.016) at 1 month and 0 (p<0.001) by 3 months. Median percentage reduction in CLASI-A at 3 months was 60%. Significant improvements were observed in dermatology life quality index (DLQI; p<0.001), EQ5D-VAS (p=0.002) and LupusQoL fatigue, image and planning domains (p<=0.05). One patient discontinued treatment due to severe herpes zoster. Clinical responses paralleled discrete suppression of interferon stimulated genes (ISGs) from SLE blood transcriptome Module M1.2 with more varied downregulation in other IFN modules. Myeloid and inflammation-annotated genes remained upregulated throughout treatment. Intermediate monocytes (CD14++CD16+) reduced to normal levels during therapy (p=0.014) while other flow subsets showed no substantive changes. CONCLUSIONS: These data indicate rapid efficacy of anifrolumab in DLE and rituximab-resistant CLE. Response is associated with suppression of a subset of ISGs and decline in intermediate monocytes. Suppression of all ISGs or the wider SLE blood transcriptome is not required for response.