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Comment on: Trial of Anti-BDCA2 Antibody Litifilimab for Cutaneous Lupus Erythematosus

Comment on Werth et al., N Engl J Med 2022;387:321-31.

DOI: 10.1056/NEJMoa2118024

Comment by Elisabet Svenungsson

In clinical practice it is often a challenge to treat cutaneous lupus erythematosus (CLE), especially the discoid and chronic lesions are commonly very resistant to treatment. These lesions cause irreversible damage, which has great impact on the quality of life for many patients. The anifrolumab studies(1, 2) have demonstrated improvement in CLE, and further hope for better treatments options for CLE is raised in this recent study, published in the New England Journal of Medicine by Victoria Werth and colleagues.(3)

It has been reported by several studies that type-1 IFN activity is high in CLE and the recent positive results from the anifrolumab studies, where the type-1 IFN receptor is blocked by a monoclonal antibody further demonstrate that type-I IFN is pivotal in CLE(1, 2).  The major source of type-1 IFN is believed to be the plasmacytoid dendritic cells (PDCs), although other cell types may also contribute. Almost 20 years ago in vitro experiments demonstrated that anti-BDCA2 antibodies could block IFN production in PDCs from SLE patients(4). In the present study the authors used a humanized monoclonal IgG1 antibody litifilimab to target the blood dendritic cell antigen 2 (BDCA2), which is uniquely expressed on the surface of PDCs.

The study is a phase 2 study performed over 16 weeks. It was initially designed to study the efficacy of litifilimab infusions at a dose of 450 mg given at week 0, 2 4, 8 and 12 weeks, versus placebo. However, during recruitment the design was changed to also include a dose-raising assessment. Thus, two additional groups, treated with lower doses 50 and 150 mg at the same intervals were added. The primary endpoint was evaluated by the percent change from baseline of skin lesions evaluated with the Cutaneous Lupus Erythematosus Disease Area and Severity index-Activity score (CLASI-A). Secondary endpoints were predefined reductions by percent or points in CLASI-A over 12 or 16 weeks.

Cutaneous lupus erythematosus (CLE) can occur isolated or as a manifestation of systemic lupus erythematous (SLE). Approximately half of the patients in this study had concurrent SLE. Our of 300 screened, 132 patients were with moderate-severe CLE were enrolled, 33 of whom received placebo. There were 26 in the 50 mg group, 25 in the 150 mg group and 48 in the 450 mg group. The 450 mg group was larger since it was started earlier. Essentially there were no important baseline differences between the three groups. 90% were on stable traditional background medication (hydroxychlorquine, steroids at a maximum dose of 15mg/day or immunosuppressants), approximately 80% were taking hydroxychlorquine. All three treatment groups obtained the primary endpoint versus placebo. The reduction in the CLASI scores ranged between 39 and 48 % in the three litifilimab groups, as compared to 15 % in the placebo group. However, the secondary endpoints were not met.

Viral infections were the side effects which most clearly differed the litifilimab groups from placebo, among them three cases of oral herpes infection, one case of herpes zoster infection and five cases of influenza. Treatment was withdrawn in 8 patients, in 3 of them due to hypersensitivity reactions. Injection site erythema occurred in 9 patients treated with litifilimab.

Though larger and longer trials are needed, it is promising that all three doses of litifilimab performed significantly better than placebo among patients with CLE. Results were not stratified for acute, subacte and chronic CLE, but approximately 70 % of participants were affected by chronic lesions, usually very difficult to treat with conventional treatments. From a more mechanistic viewpoint these results support a central role for type-1 IFN and for PDCs in the pathogenesis of CLE.

1.Furie RA, Morand EF, Bruce IN, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. The Lancet Rheumatology. 2019;1(4):e208-e19.

2.Morand EF, Furie R, Tanaka Y, et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med. 2020;382(3):211-21.

3.Werth VP, Furie RA, Romero-Diaz J, et al. Trial of Anti-BDCA2 Antibody Litifilimab for Cutaneous Lupus Erythematosus. New England Journal of Medicine. 2022;387(4):321-31.

4.Blomberg S, Eloranta ML, Magnusson M, et al. Expression of the markers BDCA-2 and BDCA-4 and production of interferon-alpha by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Rheum. 2003;48(9):2524-32.