In the 1970s, Hooks et al . at the National Institutes of Health noted the presence of interferon in the blood of approximately 70% of patients with active systemic lupus erythematosus (SLE). They concluded that interferon may play a role in the pathogenesis of SLE.1 Additional evidence linking interferon and SLE emerged in the form of isolated case reports.2 With the introduction of the interferon gene signature in the early 2000s, interferon science evolved to even greater heights.3 4 The burning clinical question was whether the interferon pathway could be inhibited and whether this would impact lupus disease activity. With the success of the anifrolumab development programme, additional strategies to subdue interferon pathway activation were explored.5–7 The plasmacytoid dendritic cell (pDC), a mass producer of type I and III interferons, was a very compelling target. Abundant in the skin as well as other organs in patients with SLE, development programs evolved with litifilimab and daxdilimab. The former monoclonal antibody binds blood cell dendritic antigen 2 (BDCA2), a protein selectively expressed on pDCs.8 BDCA2 ligation results in the suppression of type I and III interferon production as well as other proinflammatory cytokines and chemokines. Building upon the successes of the phase 2 programme,9 10 litifilimab is currently in phase III studies of both SLE and cutaneous lupus. Daxdilimab, a cytolytic antibody that targets Immunoglobulin-like transcript 7 (ILT7), is also in development for the treatment of SLE.11 Strategies to dampen SLE disease activity are incredibly eclectic, and the interferon pathway is no exception. Regardless of which approach rises to the top, the future is bright for our patients with SLE.
Hooks JJ, et al. Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med. 1979 Jul 5;301(1):5–8. doi: 10.1056/NEJM197907053010102.
Rönnblom LE, et al. Possible induction of systemic lupus erythematosus by interferon-alpha treatment in a patient with a malignant carcinoid tumour. J Intern Med. 1990 Mar;227(3):207–10. doi: 10.1111/j.1365-2796.1990.tb00144.x.
Bennett L, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003 Mar 17;197(6):711–23. doi: 10.1084/jem.20021553.
Baechler EC, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2610–5. doi: 10.1073/pnas.0337679100.
Furie R, et al. Anifrolumab, an anti-interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376–386. doi: 10.1002/art.39962.
Furie RA, et al. Trial of anti-BDCA2 antibody litifilimab for systemic lupus erythematosus. N Engl J Med. 2022 Sep 8;387(10):894–904. doi: 10.1056/NEJMoa2118025.
Furie RA, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 2019, 1(4), e208–e219.
Morand EF, et al. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med. 2020 Jan 16;382(3):211–221. doi: 10.1056/NEJMoa1912196.
Pellerin A, et al. Anti-BDCA2 monoclonal antibody inhibits plasmacytoid dendritic cell activation through Fc-dependent and Fc-independent mechanisms. EMBO Mol Med. 2015 Apr;7(4):464–76. doi: 10.15252/emmm.201404719.
Werth VP, et al. Trial of anti-BDCA2 antibody litifilimab for cutaneous lupus erythematosus. N Engl J Med. 2022 Jul 28;387(4):321–331. doi: 10.1056/NEJMoa2118024.
Karnell JL, et al. Depleting plasmacytoid dendritic cells reduces local type I interferon responses and disease activity in patients with cutaneous lupus. Sci Transl Med. 2021 May 26;13(595):eabf8442. doi: 10.1126/scitranslmed.abf8442.
Discuss the role of interferons in the pathogenesis of SLE
Describe strategies to inhibit interferons with a particular emphasis on plasmacytoid dendritic cells
Analyze litifilimab and daxdilimab SLE clinical trial data
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