In the past 60 years, no drug has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of cutaneous lupus erythematosus (CLE), following the approval of hydroxychloroquine and corticosteroids under regulatory standards that predate current clinical trial requirements. As such, in patients who are refractory to or experience adverse effects from these treatments, management has relied on extrapolating therapeutic responses in other organs affected by systemic lupus erythematosus (SLE) to the skin. Numerous therapies have been used off-label in CLE, including methotrexate, mycophenolate mofetil, dapsone, retinoids, thalidomide, and lenalidomide, among others.1 Recently, two new biologic agents have been added to the therapeutic arsenal: rituximab and belimumab. The former, an anti-CD20 monoclonal antibody, is generally used to treat severe forms of SLE, such as cardiopulmonary, neuropsychiatric, or renal involvement, while its efficacy profile in CLE is less well defined and supported by limited evidence.2 In contrast, belimumab is another monoclonal antibody that inhibits B cells by specifically binding to the B-lymphocyte stimulator protein (BLyS). It has demonstrated efficacy over placebo in treating mucocutaneous signs of lupus and reducing disease flares, although its maximum therapeutic effect may take up to a year to manifest.3

In a recent article, the group led by Victoria P. Werth reviewed the latest advances in clinical trials for CLE.1 In addition to the above-mentioned drugs, several promising agents for the treatment of SLE and CLE were highlighted (Table 1). Anifrolumab, a selective inhibitor of the type I interferon receptor subunit 1, has recently been approved by both the FDA and the European Medicines Agency (EMA) for the treatment of moderate-to-severe SLE, following the results of its phase III trials TULIP-1 and TULIP-2. The latter specifically evaluated cutaneous involvement using the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and found a significant ≥50% improvement in CLASI activity vs placebo (49% vs 24%, respectively; p=0.04). A phase II/III trial specifically assessing this drug in CLE is currently underway.1 These results have been corroborated in numerous recent case series in real-world clinical practice.4 Deucravacitinib, a selective tyrosine kinase 2 (TYK2) inhibitor approved for the treatment of plaque psoriasis, showed promising results in the phase II PAISLEY trial: a higher proportion of patients treated with deucravacitinib 3mg/day achieved a ≥50% improvement in CLASI activity vs placebo (69.6% vs 16.7%, respectively; p<0.001), prompting the launch of further trials.1 Finally, two novel agents – lifitilimab and daxdilimab – have shown promising results in early-phase clinical trials for both SLE and CLE.1 These drugs selectively inhibit plasmacytoid dendritic cells, which play a key role in initiating and sustaining the inflammatory cascade in lupus through the production of various types of interferons and other cytokines.5

The broad heterogeneity of mucocutaneous signs in SLE and CLE, as well as variability in treatment response, largely depends on the relative contribution of different interleukins, inflammatory mediators, and cellular components involved in disease pathogenesis. This concept, known as the inflammatory phenotype in CLE, may help explain the success or failure of the therapies discussed in this update.2,3 With advances in understanding the pathophysiology of this disease, new therapeutic options are expected to emerge in the coming years for patients with SLE and, particularly, CLE – both of which have lacked novel treatments for the past six decades.