Even in advance of the results of an ongoing phase 3 trial in patients with cutaneous lupus erythematosus (CLE), anifrolumab — a monoclonal antibody targeting interferon — might not be best reserved as an option of last resort.

With the intention of preventing the irreversible disfigurement associated with uncontrolled disease, “I have moved this way up on my therapeutic ladder,” reported Ruth Ann Vleugels, MD, MPH, chair in dermatology and director of the connective tissue disease clinics at Brigham and Women’s Hospital, Boston. 

Initial results of the phase 3 trial with anifrolumab in adults with chronic and/or subacute CLE, called LAVENDER, are not expected until the end of 2026, but case reports support off-label use when patients with discoid lupus erythematosus (DLE) are not adequately responding to first- or second-line therapies, Vleugels said.

Early Treatment Proposed to Prevent Scars 

“Why? The severe disfigurement that accumulates over time is not reversed” even by the most effective therapies, she explained. “If we intervene aggressively, we can prevent this damage, and this is what I want for all my discoid lupus patients.”

Speaking on January 26 at Maui Derm Hawaii 2026, Vleugels addressed several emerging therapies for the cutaneous manifestations of connective tissue diseases. Like anifrolumab, the excitement about these coming therapies is based in part by evidence of activity on fundamental pathways of pathogenesis.

To connect the CLE benefit provided by anifrolumab, which is already approved for systemic lupus erythematosus (SLE), Vleugels cited a 2024 paper published in Nature. She characterized this study as a “landmark” because it connects interferon to promotion of CXCL13+ T cells that, in turn, drive lupus.

The same paper demonstrated that when anifrolumab blocks this pathway, it correlates with disease control. In the case of CLE, the inhibition of interferon and of CXCL13+ T cells correlated with improvement in the Cutaneous Lupus Erythematous Disease Area and Severity Index - Activity (CLASI-A) score.

The first to publish on discoid lupus response to anifrolumab in a series of cases, Vleugels described how she moved from reserving this therapy for those who had failed everything else to her current position. Some of the case studies were drawn from a published series of seven adolescents with DLE, of which she was the senior author. When treated early, several achieved complete clearance of skin lesions.

“Anifrolumab is off label in children even with SLE. The current indication is only for adults,” Vleugels said. But she indicated that it is reasonable to consider aggressive therapies even in this age group when the goal is to prevent irreversible skin damage.

Anifrolumab is not the only therapy on the horizon. Deucravacitinib, a TYK2 inhibitor, also produced marked improvements in CLASI-A scores in a phase 2 trial presented at the 2025 American Academy of Dermatology. Ongoing studies are evaluating this agent in SLE with or without CLE, but this is another drug Vleugels considers for off-label use for cutaneous expression in selected patients.

Phase 3 Brepocitinib Data Available 

Phase 3 data are already available for the TYK2/JAK1 inhibitor brepocitinib in dermatomyositis, another connective tissue disease. The data, acquired from the VALOR study, were presented at the 2025 meeting of the European Academy of Dermatology and Venereology. “It was the first ever positive phase trial for dermatomyositis,” according to Vleugels.

“Ideally, this will be the first agent with a novel mechanism of action approved for dermatomyositis,” said Vleugels, who said regulatory approval might be granted this year. She noted that the efficacy reported last September was impressive.

“The 30 mg dose of brepocitinib achieved statistical significance for all 10 of the ranked endpoints,” she said, including a rapid onset of skin response relative to placebo (P = .0003).

This disease, too, is driven by interferon but specifically by the interferon beta subtype, according to studies of gene signatures in which Vleugels was involved. This led directly to the development of dazukibart, an interferon-beta specific monoclonal antibody that is also now the focus of a phase 3 global trial after highly positive results were observed in a phase 2 trial published early in 2025, according to Vleugels.

For a case of highly recalcitrant dermatomyositis in an adolescent, the interferon- implicated pathway provided Vleugels with a rationale for a trial of anifrolumab after all else — including an array of the most potent anti-inflammatory therapies available — had failed.

Within 72 hours, this individual, who Vleugels believes was the first dermatomyositis patient to receive anifrolumab, had “striking improvement.” The benefit was sustained with lesions largely resolved within a year. Vleugels reported that she has subsequently offered this agent to adults and has observed similar types of responses.

Intravenous immunoglobulin (IVIG) was first used for dermatomyositis in 1992, but it did not receive regulatory approval until recently, according to Vleugels. She expressed concern that not all dermatologists are aware of how easy this drug is to obtain and administer now that its use in dermatomyositis is within labelling. 

However, while Vleugels considers it effective in dermatomyositis, she warned that it is often best combined with additional therapy, including JAK inhibitors, which are rapidly being adopted for the skin and systemic symptoms of many connective tissue diseases.

She suggested that until brepocitinib is made available for dermatomyositis as expected, there is no evidence to support off-label use with commonly available JAK inhibitors, including tofacitinib.

JAK Inhibitors Attractive Off-Label Option for DM 

Aware that many dermatologists remain cautious about using drugs with a boxed warning, Vleugels said this concern is misplaced and inconsistent with the already large number of drugs that dermatologists prescribe with boxed warnings, including botulinum toxin, IVIG, many antibiotics, and all TNF inhibitors. 

She does counsel patients about JAK inhibitors and questions them about predisposing risks, but she does not hesitate to use them in the absence of relative contraindications and when the evidence supporting use for the indication is strong.

“JAK inhibitors are now commonly being used in patients with concomitant skin and joint diseases as well as in sclerosing diseases,” Vleugels said. For these types of severe diseases, the benefit-to-risk ratio of advanced targeted therapies is often favorable for intervention even in advance of phase 3 trials.

The standard therapies for connective tissue diseases have serious limitations, according to Joseph F. Merola, MD, MMSc, a rheumatologist and chair of the Department of Dermatology at the University of Texas Southwestern School of medicine, Dallas, who was asked to comment on the topic.

“Our traditional therapies for connective tissue disease and cutaneous lupus carry substantial monitoring burden, and frequently fall short for patients,” he said citing such drugs as methotrexate, mycophenolate, and thalidomide.

“We are increasingly enthusiastic about targeted therapies with improved therapeutic windows and higher efficacy,” he told Medscape, specifically singling out anifrolumab and deucravacitinib, which he said “are supported by emerging data and our own very positive off-label experience.”

In addition to the therapies mentioned by Vleugels, he said there are others, such as the subcutaneous pyruvate dehydrogenase complex inhibitor litifilimab, which is in phase 3 development, and oral drugs such as Enpatoran (Merck). 

Together, these represent “a potentially transformative moment for patients with CLE and SLE,” he said.

Vleugels reported financial relationships with AbbVie, Apogee, AstraZeneca, Lilly, and Priovant. Merola reports financial relationships with AbbVie, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, Eli Lilly, Incyte, Johnson & Johnson, Leo, MoonLake, Novartis, Pfizer, Sanofi-Regeneron, Sun, and UCB.