0974: Rapid Efficacy of Anifrolumab Across Multiple Subtypes of Recalcitrant Cutaneous Lupus Erythematosus Parallels Discrete Changes in Transcriptomic and Cellular Biomarkers
Lucy Marie Carter1, Zoe Wigston1, Jack Arnold1 and Philip Laws2, 1University of Leeds, Leeds, United Kingdom, 2Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
Background/Purpose: Cutaneous lupus eyrthematosus (CLE) is frequently refractory to immunosuppressive therapies including B-cell depletion, but response varies by morphology with the chronic discoid (DLE) subtype being particularly resistant. Local production and response to type-I interferon (IFN-I) is implicated in all subtypes of CLE and therapeutic blockade of the IFN-I receptor with anifrolumab has shown benefit on mucocutaneous SLE in clinical trials.
Response to anifrolumab in recalcitrant CLE and by specific lesion subtype have not yet been described. It is also unclear whether cutaneous responses are dependent upon direct effects on IFN-I signaling or subsequent downstream effects on other immune functions regulated by IFN-I. We hypothesise that the efficacy of anifrolumab will differ dependent on the relative contribution of direct IFN-I effects vs. the downstream immunostimulatory effects of IFN-I on other immune functions. Here we evaluate the effect of anifrolumab on (i) rituximab-refractory CLE; (ii) on DLE; (iii) to compare clinical responses with IFN-specific biomarkers and transcriptomic evaluation of broader immune responses; (iv) to compare early and late immunophenotypic and clinical responses.
Methods: SLE patients with active recalcitrant CLE received anifrolumab 300 mg IV every 4 weeks and evaluated using the Cutaneous lupus erythematosus disease area and severity index (CLASI) and dermatology life quality index (DLQI). Fluorescence intensity of tetherin (CD317), a cell surface interferon biomarker, was evaluated by multiparameter flow cytometry of peripheral blood mononuclear cells (PBMCs). Validated IFN-Scores, in addition to gene expression scores annotated to Inflammation, Myeloid lineage and Plasmablasts modules, were measured in PBMCs using customised Taqman array at serial time points.
Results: 7 patients (DLE n=5, chillblain / nodular vasculitis n= 1, subacute CLE n=1) have commenced therapy. Median number of previously failed standard therapies is 6, including rituximab in 6/7 patients, belimumab in 2/7 and thalidomide in 4/7. Three patients required long-term oral prednisolone >10 mg daily. Median baseline CLASI activity score was 17 and DLQI was 17/30.
Rapid clinical responses were evident at 1 month, with more rapid effects observed in patients with SCLE and DLE compared with chillblain lesions. Median fall in CLASI activity score at 1 month was 6 points with a median percentage change from baseline of 31%. All had achieved as ≥50% reduction in CLASI activity score by 3 months. In all patients, a rapid and marked suppression of IFN-Score-A (mean difference 2.92, p< 0.01) and plasmablast tetherin (p=0.01), was evident by 1 month. Small and variable downward trends were observed in Inflammation- and IFN-Score-B (p=0.06), Myeloid (p=0.27) and Plasmablast (p=0.15) -annotated gene expression scores.
Conclusion: These preliminary results suggest that anifrolumab: (i) may be effective in highly recalcitrant and rituximab-resistant CLE, (ii) is effective in DLE; (iii) rapidly suppresses IFN-I response, but with lesser effects on non-IFN immune biomarkers and (iv) early direct effects on IFN-I are associated with rapid clinical response.
Disclosures: L. Carter, None; Z. Wigston, None; J. Arnold, None; P. Laws, Amgen, Celgene, Eli Lilly, Sanofi, Janssen, AbbVie/Abbott, Bristol-Myers Squibb(BMS), UCB.
