Drug-induced lupus erythematosus following immunotherapy with anti-programmed death-(ligand) 1
Authors: Jean-Marie Michot, Mathilde Fusellier, Stephane Champiat, Charles Velter, Capucine Baldini, Anne-Laure Voisin, Francois-Xavier Danlos, Yolla El Dakdouki, Maxime Annereau, Xavier Mariette, Caroline Robert, Khadija Cherif, Aurélien Marabelle, Christine Mateus, Olivier Lambotte
Journal: Annals of the Rheumatic Diseases (2018)

Drug-induced lupus erythematosus following immunotherapy with anti-programmed death-(ligand) 1We read with interest the study of Kostine et al describing rheumatic immune-related adverse events (irAE), which occur in 6.6% of patients treated for cancer by anti-programmed death-(ligand) 1 (PDL1). 1 These new adverse effects pose significant challenges to patient care in terms of optimal management of these autoimmune damaging toxicities, while allowing effective antitumor therapy to continue.The PD(L)1 pathway is involved in the maintenance of immune tolerance, and the blockage of this axis by anticancer immunotherapy could trigger autoimmune diseases and especially lupus. 2 3 We then searched in the pharmacovigilance register of our institution-the 'Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC)'-whether cases of drug-induced lupus erythematosus (DI-LE) were reported following anti-PD(L)1 immunotherapies.Between October 2013 and July 2017, five cases of DI-LE were recorded in REISAMIC.Given the number of patients having received anti-PD(L)1 during the same period (n=1044), the estimated incidence of DI-LE was 0.48%.All patients gave their written informed consent for the use of their data in this report.The patients' characteristics are summarised in table 1.The patients had developed DI-LE at a median (range) age of 63 (48-80) years.None of the patients had a history of autoimmune disease before starting anti-PD(L)1.The most specific sign of DI-LE was subacute cutaneous lupus erythematous (SCLE) in four patients and chilblain lupus in the remaining patient.One patient having SCLE had also declared a systemic lupus erythematosus (SLE) according to the Systemic Lupus International Collaborating Clinics criteria. 4The DI-LE was revealed by a frank maculopapular rash in the four patients with SCLE (figure 1).The median time of DI-LE occurrence was 10 (range: 4-22) weeks after the initiation of immunotherapy.Antinuclear antibodies in serum were found positive for two (40%) out of the five patients and were specifically positive for anti-Sjögren's syndrome-related antigen A (SSA).These two SSA-positive patients had SCLE but no eye or mouth dryness symptoms suggestive of Sjögren's disease.A skin biopsy was performed in all cases except the chilblain lupus.The skin biopsies revealed a lymphocytic infiltrate of the dermis, predominantly around adnexal sites.Alcian blue staining revealed mucin deposits in all patients.Direct immunofluorescence assays for IgG or C3 in skin biopsy were positive in two of the four patients tested (50%).The treatment of DI-LE was based on topical corticosteroids in all cases, with the antimalarial hydroxychloroquine added in the SLE case, and the outcome was favourable with a resolution in all cases.This report is the first series of cases of lupus erythematosus induced by anti-PD(L)1 immunotherapy.A recent similar case report of pembrolizumab-related subacute cutaneous lupus erythematosus was provided. 5The DI-LE has been variously reported after drug exposure such as hydralazine, procainamide, quinidine, oestrogen, tumour necrosis factor inhibitors, chlorpromazine, isoniazid, practolol, penicillamine and minocycline. 6e believe that anti-PD(L)1 immunotherapies should also now be added to this list.Based on our experience and the present case series, DI-LE induced by anti-PD(L)1 was characterised by an extensive,