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.
Type I interferon (IFN) dysregulation is a major contributory factor in the development of several autoimmune diseases, termed type I interferonopathies, and is thought to be the pathogenic link with chronic inflammation in these conditions. Anti-neutrophil cytoplasmic antibody (ANCA)-Associated Vasculitis (AAV) is an autoimmune disease characterised by necrotising inflammation of small blood vessels. The underlying biology of AAV is not well understood, however several studies have noted abnormalities in type I IFN responses. We hypothesised that type I IFN responses are systemically dysregulated in AAV, consistent with features of a type I interferonopathy. To investigate this, we measured the expression of seven interferon regulated genes (IRGs) (ISG15, SIGLEC1, STAT1, RSAD2, IFI27, IFI44L and IFIT1) in peripheral blood samples, as well as three type I IFN regulated proteins (CXCL10, MCP-1 and CCL19) in serum samples from AAV patients, healthy controls and disease controls. We found no difference in type I IFN regulated gene or protein expression between AAV patients and healthy controls. Furthermore, IRG and IFN regulated protein expression did not correlate with clinical measurements of disease activity in AAV patients. Thus, we conclude that systemic type I IFN responses are not key drivers of AAV pathogenesis and AAV should not be considered a type I interferonopathy.
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