Efficacy and Safety of Deucravacitinib for Cutaneous Lupus Erythematosus

INTRODUCTION

Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease with various subtypes characterised by their onset and clinical features.^[1] CLE can present independently or as a manifestation of systemic lupus erythematosus (SLE).^[2] Current systemic treatments for CLE are immune-modulating agents.^[3] However, treatment options are limited, and patients refractory to or unable to tolerate these medications have limited options.^[3] CLE-specific clinical trials are limited, and SLE-specific trials often exclude CLE patients who do not have concurrent SLE.^[3] However, SLE trials often report skin-specific outcome measures, which can be used to determine a medication’s efficacy for CLE.^[3] Nevertheless, there remains a lack of research on targeted CLE treatment.^[3]

Deucravacitinib is the first oral, allosteric inhibitor of tyrosine kinase 2 (TYK2). Its allosteric mechanism allows deucravacitinib to lock TYK2 in an inactive state, and this mechanism of inhibition may be long-lasting.^[4] Deucravacitinib was first approved in the US in September 2022 for treating moderate-to-severe plaque psoriasis in adults.^[4] TYK2 mediates the signalling of type I interferons, IL-10, IL-12, and IL-23, key cytokines involved in lupus pathogenesis.^[5] TYK2 expression has also been significantly associated with an increased risk of CLE and SLE.^[5] TYK2 inhibition may also be a promising drug mechanism for CLE control.

A recent randomised controlled trial (RCT) named PAISLEY evaluated deucravacitinib as a treatment for SLE.^[6]It concluded that deucravacitinib had higher response rates than placebo in SLE patients and had an acceptable safety profile.^[6] This RCT demonstrated statistically significant improvements in the Cutaneous Lupus Erythematosus Disease Area and Severity Index 50 (CLASI-50; a decrease of ≥50% from baseline), a widely used outcome measure for CLE.^[6] Additionally, there are sparse case reports of deucravacitinib treating CLE.^[7–10] Our study aimed to systematically review the literature to analyse the efficacy and safety of deucravacitinib for treating CLE.

METHODS

This study was exempt from Institutional Review Board approval, as data was gathered from published literature. The following databases were searched for articles: PubMed, Cochrane Library, MEDLINE, EMBASE, and Scopus. The search terms used were “deucravacitinib” and “lupus.” No limits or restrictions were used for the search strategy.

Clinical studies or case reports of male or female patients of any age with CLE (population) were included if they compared deucravacitinib (intervention) as a treatment for CLE to placebo or prior to deucravacitinib initiation (comparison) and reported clinical response (outcome). All articles published online, in print, or press, in any language, were included. Two reviewers (A.P. and L.H.) independently performed the title and abstract reviews, with conflicts resolved through discussion. Studies were excluded based on the title or abstract if there was no clear indication that they were clinical studies evaluating deucravacitinib as a treatment for CLE. The remaining articles were thoroughly reviewed for inclusion through full-text review, with non-English articles translated for review. Articles that summarized findings from a study already included in the search were excluded.

Two reviewers (A.P. and L.H.) independently evaluated full texts for inclusion and extracted data from the selected articles. The following outcomes were gathered from each study: study type, demographic information (number of subjects, age, gender, and ethnicity), intervention, efficacy data, and safety data.

RESULTS

Literature Search

Our initial search strategy identified 96 distinct citations. The title and abstract review excluded 58 citations, while the full-text review excluded an additional 33. As outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram [Figure 1], we included five studies in this systematic review.

Close

Figure 1:

PRISMA flow diagram. PRISMA: Preferred reporting items for systematic reviews and meta-analyses. n represents number of articles.

Export to PPT

DISCUSSION

CLE patients need additional treatment options with limited drug toxicity for effective disease management. Newer treatments for SLE include agents targeting the Janus kinase (JAK) pathway, type I interferons, and B-lymphocyte stimulators.^[12] Deucravacitinib, via TYK2 inhibition, has shown benefits in SLE.^[6] TYK2 plays a role in the immune signalling of type I interferons, which are upregulated in CLE lesions.^[5] This process may explain why deucravacitinib is effective for CLE patients.^[5] Recent reports and data from an SLE trial also show benefits for CLE with deucravacitinib.^[6] In the PAISLEY trial, 69.9% of study patients receiving deucravacitinib 3 mg twice a day achieved a CLASI-50 response.^[6] In comparison, only 16.7% of study patients on placebo achieved the same outcome (p < 0.001).^[6]This systematic review of the existing literature supports deucravacitinib as a potentially efficacious treatment for CLE. CLE patients treated with deucravacitinib saw objective improvement in <1 month.^[6,9–11]

The most common adverse effects of deucravacitinib are upper respiratory tract infections, nasopharyngitis, headache, and urinary tract infections.^[6] Cutaneous adverse events include rash and acne.^[6] However, most patients in the PAISLEY trial who experienced these adverse effects chose to continue deucravacitinib.^[6] During the PAISLEY trial, patient levels of anti–double–stranded DNA antibodies decreased after treatment. In patients with low baseline levels of complement C3 (<0.9 g/L) or C4 (<0.1 g/L), levels of C3 and C4 increased over the follow-up period.^[11] All dosages of deucravacitinib, but not placebo, were associated with reduced IFN-regulated gene expression through 44 weeks of treatment, with suppression evident as early as week 4.^[11] It should be noted that the PAISLEY trial participants were all primarily SLE patients, and the study reported results on cutaneous manifestations as well.^[6] On the other hand, the four case reports^[7–10] in this review primarily involved CLE patients, and none reported cutaneous adverse effects, suggesting that the side effect profiles for deucravacitinib may vary depending on the condition being treated.

There are limitations to consider in this study. The PAISLEY trial studied deucravacitinib as a treatment for SLE, not CLE specifically, so adverse effects or responses noted may differ in patients with primarily CLE.^[6] Only four other reports^[7–10]could be found with relevant data for CLE patients, and some of these reports did not detail adverse effects. Confounding factors include patients on concomitant medications that could affect their response to deucravacitinib. Further research and lab investigations are needed in patients with primarily CLE to quantify efficacy and characterise adverse effects with thorough evidence.

CONCLUSION

Our review provides a consolidation of evidence for deucravacitinib as a treatment for CLE, which has limited treatment options. Deucravacitinib may be an effective treatment option for CLE, which is currently treated mainly with antimalarials, glucocorticoids, biologics, and immunosuppressants. Patients who cannot tolerate these treatments or have other contraindications could benefit from using deucravacitinib as an effective alternative. Patients can also be reassured that no deucravacitinib-associated safety signals have been identified. However, further randomised controlled trials of deucravacitinib for CLE-specific patients and skin-specific outcome measures are warranted.