Discoid lupus erythematosus (DLE) is a chronic variant of cutaneous lupus erythematosus, an autoimmune inflammatory disorder of the skin. Lesions are often localized to the scalp and can result in permanent scarring, disfiguration, and irreversible alopecia. Although DLE usually responds to topical or intralesional corticosteroids and/or oral antimalarials, some DLE is resistant to these treatments or adverse effects limit their effectiveness.
Three patients with treatment-refractory, biopsy-proved DLE were prescribed a novel, off-label preparation of tacrolimus lotion, 0.3%, in an alcohol base as an adjunct to oral antimalarial therapy. All 3 patients demonstrated improvement in lesion severity and hair regrowth with the use of this regimen after 3 months and continued improvement thereafter. We report a retrospective analysis of these 3 cases.
Conclusions and Relevance
This report is, to our knowledge, the first mention of tacrolimus being used in a lotion formulation to treat DLE lesions, resulting in hair regrowth. Topical tacrolimus lotion, 0.3%, in an alcohol base may be a potential therapeutic option for patients with DLE that is refractory to first-line therapies and who risk late-stage disease with permanent scarring alopecia.
Discoid lupus erythematosus (DLE) is a chronic variant of cutaneous lupus erythematosus characterized by well-defined erythematous plaques with scale, often predominantly featured on the face, ears, anterior neck, and scalp. More than half of patients with DLE first present with scalp involvement. Discoid lupus erythematosus is one of the most common causes of inflammatory cicatricial, or scarring, alopecia. Complications can include ulceration or permanent cosmetic disfigurement, with in situ squamous cell carcinoma occasionally seen in long-standing lesions. At later stages, the lesions may appear as smooth atrophic scars with central hypopigmentation and loss of follicular ostia, occasionally resembling lichen planopilaris or Brocq psuedopelade.
Although DLE is often managed successfully by topical or intralesional corticosteroids and/or oral antimalarials, some cases are refractory to these first-line therapies. Alternative therapies, such as methotrexate sodium, oral corticosteroids, thalidomide, and dapsone, may also be ineffective and/or limited by their risks and adverse effects. Among the topical therapies, corticosteroids and calcineurin inhibitors are most commonly used.
Topical and intralesional corticosteroids, however, have well-known adverse effects, including atrophy, telangiectasia, and rosacealike dermatitis. Although not approved by the US Food and Drug Administration for treatment of cutaneous lupus erythematosus, calcineurin inhibitors are often used to treat cutaneous lupus erythematosus variants.1- 10 Commercially available preparations include pimecrolimus cream, 1%, and tacrolimus ointment, 0.03% or 0.1%. No lotions are commercially available for topical use.
In our clinic, we used a novel off-label preparation of higher-potency tacrolimus, 0.3%, in an alcohol base as an adjunct therapy in 3 patients with recalcitrant alopecia secondary to biopsy-proved DLE. We herein retrospectively review their treatment responses.
We retrospectively reviewed the medical records of 3 patients with recalcitrant alopecia secondary to biopsy-proved DLE (Table 1) who demonstrated treatment success after being prescribed an off-label preparation of tacrolimus lotion, 0.3%. The patients had previously attempted prolonged trials of antimalarials and topical and intralesional corticosteroids. All 3 patients had a negative finding for antinuclear antibodies by indirect fluorescent antibody analysis.
The patients were prescribed thirty-six 5.0-mg tacrolimus capsules. We instructed the patients to add the contents of the capsules to 60 mL of 70% isopropyl alcohol and vigorously shake the mixture until the powder was completely in suspension. The patients applied the lotion twice daily and were counseled to shake the lotion thoroughly before each use. The lotion was used as an adjunct therapy to oral antimalarials.
At the 3-month follow-up, all patients demonstrated improvement in disease activity consistent with the Cutaneous Lupus Erythematosus Disease Area and Severity Index criteria, including a reduction in erythema, scale, pruritus, and surface area of the lesions.1 All patients also exhibited increased terminal hair regrowth within the center and the periphery of the lesions. They reported decreased pruritus and increased treatment satisfaction. No adverse events were noted. Patients 1 and 3 continued to use the lotion for 1 to 2 years, with continued hair regrowth and reduction of lesion surface area and pruritus. Representative photographs of patient 1 before and after use of the tacrolimus lotion are provided (Figure).
A, Before application of topical tacrolimus lotion, 0.3%, the scalp demonstrates alopecia and signs of disease activity, including erythema and scale. B, After 6 months of tacrolimus therapy as an adjunct to chloroquine phosphate, the scalp shows a reduction in erythema and scale and increased hair regrowth.
Discoid lupus erythematosus is a common cause of scarring alopecia among patients with scalp involvement. The inflammatory cell infiltrate is especially prominent around the hair follicle at the level of the sebaceous glands and bulge, the location of the hair’s regenerative stem cells. In advanced DLE, many, if not all, of the hair follicles and sebaceous glands are destroyed, leaving residual fibrosis and atrophy. Early diagnosis and treatment are necessary because scarring can lead to irreversible alopecia and disfiguration.
Topical tacrolimus was one of the first nonsteroidal drugs approved for use in atopic dermatitis by the US Food and Drug Administration. Given its low adverse effect profile, the lower-potency formulations are considered safe in children as young as 2 years. Topical tacrolimus has many off-label uses, particularly for autoimmune and inflammatory conditions such as psoriasis, vitiligo, chronic actinic dermatitis, lichen planus, and pyoderma gangrenosum, among others.
As an immunomodulator, tacrolimus primarily targets intracellular signaling pathways implicated in T cell–receptor activation. Tacrolimus inhibits calcineurin, a serine-threonine phosphatase, by binding to an intracytoplasmic protein termed FK506 binding protein. Downstream, calcineurin inhibition by the tacrolimus–FK506 binding protein complex blocks the dephosphorylation of the nuclear factor of activated T cells, ultimately preventing entry of the factor into the nucleus. As a transcription factor, the nuclear factor of activated T cells would otherwise bind to the promoter region of various proinflammatory cytokine and chemokine genes to induce their synthesis, including those genes responsible for interleukin 2 (IL-2) (a T-cell growth and differentiation factor), tumor necrosis factor, interferon-γ, IL-4, and IL-10.
Targeting the calcineurin signaling pathways ultimately limits lymphocyte proliferation, which is a predominant feature of the scarring alopecia in DLE. In general, cutaneous lupus erythematosus lesions demonstrate a state of proinflammation, with increased expression of cytokines such as IL-2, interferon-γ, and tumor necrosis factor noted in biopsy samples.11 In contrast to corticosteroids—which nonselectively affect epidermal and dermal cells—topical tacrolimus spares keratinocytes, fibroblasts, and endothelial cells, precluding the more robust adverse effects seen with corticosteroids.12
Topical tacrolimus ointment has demonstrated mixed success in treating DLE lesions of the face and scalp as outlined in Table 2. Most of the clinical studies and case series3- 10 use ointment preparations of the commercially available, lower-potency tacrolimus, such as 0.1% or 0.03%. Two exceptions are the studies by Walker et al1 and Madan et al,2 in which a higher-potency tacrolimus ointment, 0.3%, was compounded with clobetasol propionate with a good clinical response. However, the inclusion of a corticosteroid obscures the precise role of tacrolimus and potentially begets a similar adverse effect profile to that of corticosteroids used alone.
Some authors13 have incorporated tacrolimus into other lotionlike vehicles, such as glycerine. To our knowledge, no studies have used higher-potency topical tacrolimus in lotion form with isopropyl alcohol. Moreover, the only study that notes hair regrowth is that by de la Rosa Carillo and Christensen,3 in which 1 patient had regrowth of terminal hair in the outer regions of her lesions with application of tacrolimus ointment, 0.1%, as monotherapy. The successful regrowth of hair among our 3 patients may be owing to enhanced delivery of tacrolimus to the site of inflammation and a subsequent reduction in disease activity mitigated by calcineurin inhibition. Thus, tacrolimus may prevent the lesions from entering a final scarred stage, thereby allowing an opportunity for the hair to regrow.
Commercially available tacrolimus ointments are minimally absorbed, with a bioavailability of less than 0.5%. The distinctly significant hyperkeratosis of DLE likely leads to even lower penetration of compounds. Our preparation of tacrolimus in an alcohol base may enhance percutaneous drug absorption and delivery to the dermis, in which the lymphoid infiltrates responsible for DLE lesions reside. The contents of oral tacrolimus capsules are lipophilic, and the scalp’s abundant hair follicles provide a lipid-laden path for drug absorption in addition to being the target of interest. Moreover, 70% isopropyl alcohol is favored as a solvent because it is safe, readily dissolves lipophilic compounds, and enhances permeation of the stratum corneum barrier (particularly in areas of decreased skin integrity, such as DLE lesions), and its evaporation after application provides a cooling relief. Secondary advantages of the tacrolimus lotion are that it leaves little to no residue on the scalp and does not require occlusion, both of which increase patient burden and dissatisfaction with treatment. Similar products, including oral suspensions of tacrolimus, have been shown to be stable for approximately 60 days at room temperature. The adverse effects of topical tacrolimus not experienced by our patients but reported elsewhere include peeling and burning.4 Although the degree of systemic absorption was not assessed in our 3 patients, we have tested the same topical tacrolimus preparation, 0.3%, for the diagnosis of lichen planopilaris in another patient (A.G.F., unpublished data, March 2015). Her serum tacrolimus level was undetectable after using the lotion on a large region of her scalp for many months. The same was true for another patient using a tacrolimus mouthwash for oral lichen planus despite mucosal exposure (S.R., unpublished data, 2014). Moreover, a veterinary study14 using tacrolimus lotion, 0.3%, for canine atopic dermatitis demonstrated mean blood concentrations below toxic levels among the 8 dogs receiving large doses for 4 weeks.
Of note, the US Food and Drug Administration has placed a black box warning on calcineurin inhibitors owing to the theoretical risk for hematologic cancers after long-term use, with observations of increased incidence in murine models.15 The available evidence in humans is not supportive at this time. As a chronic hypertrophic and scarring disease, DLE lesions demonstrate an increased risk for neoplastic transformation. Thus, a reduction of disease activity is essential to avoid irreversible damage and these long-term complications.
Although further studies are required, our limited observations support the use of topical tacrolimus lotion, 0.3%, in an alcohol base in treatment-resistant cases of DLE-associated alopecia. The results support a new potential therapeutic option for this disease.
Accepted for Publication: April 8, 2015.
Corresponding Author: Andrew G. Franks Jr, MD, Ronald O. Perelman Department of Dermatology, New York University School of Medicine, 240 E 38th St, 12th Floor, New York, NY 10016 (firstname.lastname@example.org).
Published Online: June 3, 2015. doi:10.1001/jamadermatol.2015.1349.
Author Contributions: Drs Ramachandran and Franks had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Ramachandran, Franks.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Ramachandran, Franks.
Administrative, technical, or material support: All authors.
Study supervision: Ramachandran, Franks.
Conflict of Interest Disclosures: None reported.
Funding/Support: The Carl J. Herzog Foundation awards a fellowship stipend that supports the annual salary of junior faculty (Dr Ramachandran).
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Previous Presentations: A portion of this study was presented at the 2014 annual meeting of the Society for Investigative Dermatology; May 8, 2014; Albuquerque, New Mexico; and the 2014 annual meeting of the Rheumatologic Dermatology Society; November 14, 2014; Boston, Massachusetts.
Correction: This article was corrected June 25, 2015, to fix a label and the caption for the Figure.
Milam EC, Ramachandran S, Franks AG. Treatment of Scarring Alopecia in Discoid Variant of Chronic Cutaneous Lupus Erythematosus With Tacrolimus Lotion, 0.3%. JAMA Dermatol. 2015;151(10):1113-1116. doi:10.1001/jamadermatol.2015.1349