BUENOS AIRES – Clinicians facing cases of severe refractory cutaneous lupus erythematosus – including in patients who smoke – have several treatment options, according to a prominent CLE researcher.

Dr. Victoria P. Werth, professor of dermatology at the Hospital of the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Affairs Medical Center, shared clinical strategies for treating CLE that is resistant to topical or intralesional treatments, and even systemic therapy with antimalarials.

"In terms of systemic therapy there are very few randomized placebo-controlled trials, and recommendations are based on expert opinion and retrospective case series. However, this is beginning to change," Dr. Werth said at an international congress on systemic lupus erythematosus. With the validated CLASI (CLE Disease Area and Severity Index) measure, which Dr. Werth and her colleagues introduced in 2005, "it’s been possible to prospectively follow patients who are being put on treatment."

Antimalarials are the established first-line systemic treatment for CLE, with studies showing hydroxychloroquine to be effective in 50%-70% of patients (Curr. Rheumatol. Rep. 2011;13: 300-7). "It’s worth it to give antimalarials to smokers," Dr. Werth said, citing findings from a prospective cohort study she coauthored (n = 218). She and her colleagues found that even though smoking was associated with more severe disease activity, current smokers requiring treatment with antimalarial agents alone actually improved more than nonsmokers treated with only these agents (Arch. Dermatol. 2012;148:317-21). When skin disease was refractory to antimalarials, the smokers responded less well than nonsmokers to additional therapies such as immunosuppressants.

Dr. Werth noted that patients who do not respond to hydroxychloroquine tend to be those with generalized discoid lupus. In her clinic, she said, patients are started with hydroxychloroquine at less than 6.5 mg/kg per day and given 6-8 weeks to respond. If they do not, quinacrine 100 mg/day is added. At another 6-8 weeks, if no improvement is seen, "stop the hydroxychloroquine and consider starting chloroquine at a dose of less than 3.5 mg/kg per day," Dr. Werth advised, noting that chloroquine has more eye toxicity than hydroxychloroquine.

Immunosuppressants are the usual next step after treatment failure with antimalarials; mycophenolate mofetil (MMF) has been shown in small, uncontrolled studies to be effective in CLE. Dr. Werth discussed a yet-unpublished open-label study (n = 13) that her group conducted in which azathioprine tended to be less effective than MMF in patients who had failed antimalarials.

Thalidomide is effective for refractory CLE, Dr. Werth noted, citing a Spanish study (n = 60) in which nearly all patients treated with 100 mg daily achieved a clinical response, as assessed by CLASI scores, with a complete response seen in 85% (Br. J. Dermatol. 2012;166:616-23).

"Many patients not responsive to antimalarials do respond to thalidomide, and sometimes a lower maintenance dose – as much as 25-50 mg/day or even once a week – can be helpful," she said. Patients, particularly those with discoid forms of CLE, can relapse when taken off thalidomide, but do respond when started again, she said, and kept on low-dose aspirin or hydroxychloroquine to prevent thrombotic events.

Thalidomide is used cautiously in CLE because of its serious adverse effect profile, which includes teratogenicity, amenorrhea, stroke, and peripheral neuropathy. And about 10% of patients, mostly smokers, prove refractory to immunosuppressives and/or thalidomide. For severely refractory patients, the thalidomide analog lenalidomide may have a role.

In Dr. Werth and her colleagues’ case series of lenalidomide in five severely refractory CLE patients, four improved, but one developed systemic lupus erythematosus, leading to speculation that the drug could activate T cells and trigger systemic disease (J. Am. Acad. Dermatol. 2012;66:571-82). In a Spanish open-label study evaluating 5-10 mg/day of lenalidomide in 15 patients, a complete response occurred in 12, and there were no reports of systemic lupus developing after a mean 15 months’ follow-up (Arthritis Res. Ther. 2012;14:R265). Dr. Werth called the lenalidomide findings "encouraging," but warned that the thalidomide derivatives "have complex mechanisms that need to be studied."

The biologic agents belimumab and rituximab offer other options for patients who fail thalidomide. Post-hoc analyses of randomized clinical trials of belimumab "showed that there seemed to be dose-dependent improvement in rash in patients relative to baseline – so there’s hope that further study will demonstrate that skin may benefit from treatment with belimumab," Dr. Werth said.

Rituximab also may be indicated for patients with bullous lupus that is unresponsive to treatment with dapsone or steroids. "It would make sense because this is clearly an autoantibody-driven process," Dr. Werth said. "There have been a number of reports of rituximab helping patients with refractory bullous lupus."

The CLASI copyright is owned by the University of Pennsylvania, Dr. Werth’s institution. Dr. Werth disclosed financial relationships with Pfizer, Novartis, Cephalon, Rigel, and Medimmune, and grant support from Celgene and Amgen.

Strategy outlined for treating severe refractory cutaneous lupus