Acropulpitis in systemic lupus erythematosus is associated with high type 1 interferon signature.

Abstract

Digital skin lesions in systemic lupus erythematosus (SLE) may be due to vascular changes (thrombosis or vasculitis) or specific lupus skin lesions mainly chilblain lupus or discoid lupus.1 Severe clinical changes of the digits observed in type 1 interferonopathies (IFNpathies) such as Aicardi-Goutières syndrome and familial chilblain lupus include purpura, oedema, periungual and pulp erythema, and violaceous papules. Type I interferon (IFN)–mediated genes have been shown to be overexpressed in the skin of cutaneous lupus erythematosus (CLE)2 and in the blood and target organs of SLE.3 This study describes the digital lesions in 15 SLE patients with similar clinical features to those seen in type 1 IFNpathies, defined as acropulpitis, and analysed type 1 IFN skin signature in two of them. Patients included had to fulfil SLE criteria according to the American College of Rheumatology revised in 1997 and/or the 2012 SLICC4 and to have skin digits lesions similar to type 1 IFNpathies (including oedema, periungual and pulp erythema, and violaceous papules sometimes atrophic). The expression of 7 IFN-stimulated genes (ISG; MX1, IFIT1, IFI44, IFI27, ISG15, IFI44L, SIGLEC) named as IFN score was studied by reverse transcriptase polymerase chain reaction on formalin-fixed paraffin-embedded cutaneous tissue, and skin IFN score was calculated, as previously described5 in two SLE patients with acropulpitis, 10 non-digital discoid lupus patients and 22 dermatomyositis (DM) patients, included as controls (Appendix S1). Out of the 15 patients, 14 were women, with a median age at diagnosis of 27 (range: 16–41 years). All patients had bilateral digital lesions with violaceous papules associated with periungual and pulp inflammatory and purpuric oedema (see example in Figure 1A). Lesions frequently affected the toes (n = 11/15). All patients had associated extra-digital cutaneous lesions: chronic CLE (CCLE; n = 8), discoid (n = 7) and panniculitis (n = 2), acute CLE (ACLE; n = 7) and subacute CLE (n = 3). Twelve patients had at least one associated extra-cutaneous lupus involvement, most often concomitant (n = 11), articular (n = 12), renal (n = 7), haematological (n = 3), seritis (n = 2), neurological (n = 1), cardiac (n = 1) and pulmonary (n = 1). Nine patients had a severe form of SLE (renal (class II, III, IV and V nephritis), neurologic, seritis, myocarditis, autoimmune cytopenia). Severe systemic flares were always concomitant with acropulpitis flares. Most patients had positive anti-Sm (n = 12), anti-DNA (n = 13) and interestingly anti-RNP antibodies (n = 12). Two digital biopsies were performed in two patients of 25 and 24 years old. Both patients had extra-digital cutaneous lesions (CCLE and ACLE), systemic involvement (articular and haematological; and articular and class IV lupus nephritis) and anti-DNA, anti-Sm and anti-RNP antibodies. The skin biopsies showed interface dermatitis with superficial and deep dermal lymphoid infiltrate, interstitial mucin deposit, without vasculitis (Figure 1B). Relative mRNA levels of all seven ISG measured were increased in the two patients' biopsies compared with healthy skin (Figure 1C). Skin IFN scores of the two patients analysed (186 and 171) were increased compared with a control cohort of lupus discoid patients (median = 149, range: 134–202) and close to a control cohort of DM patients (median = 173, range: 65–659). The median follow-up was 2.91 years (range: 3 months–18 years). Four patients relapsed of acropulpitis during the follow-up, three of them concomitantly of a systemic flare. This study describes an original form of SLE-associated acral skin lesions, similar to lesions encountered in type 1 IFNpathies. Acropulpitis and severe systemic flares and relapses were most often concomitant, suggesting that acropulpitis seems associated with SLE activity and severity. The type 1 IFN pathway was analysed in a sample too small to draw firm conclusions; therefore, a prospective study evaluating skin IFN signature in these lesions in multiple patients and the prognostic value of this clinical symptom should be considered. None. The authors have no conflicts of interest to declare. G.S., C.C., F.C., M.B., H.L-B., M.Bagot., A.S., A.D-M., M.J., J-D.B. provided data and contributed to the preparation of the manuscript; J.M., J-D.B. supervised the study and analyzed the data; G.S., C.C., M.B. performed the experiments; H.L-B., J.L-C. provided methods and technical advice and G.S., M.J., and J-D.B wrote the manuscript. Data can be shared by contacting corresponding author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.