Discoid lupus erythematosus (DLE) is a variant of chronic cutaneous lupus erythematosus (CCLE), a relatively benign, non-life-threatening skin disease (10,13). Although the precise pathogenesis of DLE is unclear, it has been suspected that type 3 hypersensitivity reaction plays an important role (7). Predisposed breeds include German shepherds, Collies, Siberian huskies, Shetland sheepdogs, and their crosses (1,10). The age of the onset was 2.5-13 years, but the sex predilection has not been reported (1,8). The cutaneous lesions of DLE are characterized by erythema, depigmentation, scaling, and crusting that eventually progresses to erosion and ulceration (1). The lesions can be exacerbated by UV light exposure and are often more severe in summer and in sunny climates (1,11). The skin lesions are most commonly located on the nasal planum (10,11). On the other hand, ear pinnae, lips, oral cavity, periocular areas, perianal region, genitalia, and feet may also be involved (10,11). Canine DLE commonly requires persistent treatment (1). The traditional management of DLE is usually multifaceted, targeted at improving clinical signs while reducing adverse reactions from treatment (15). The treatments for canine DLE include oral glucocorticoids, azathioprine, chlorambucil, cyclosporine, tetracycline, niacinamide, and topical tacrolimus (1). Nevertheless, they should be used with careful monitoring because glucocorticoids, azathioprine, and chlorambucil may have severe systemic adverse effects for long-term use. Since 1992, combining the tetracycline family alone or with niacinamide has been reported to be effective for managing canine immune-mediated dermatosis, including DLE (1,3,14,17). This treatment has been used as a safer alternative to oral immunosuppressive drugs and as a steroid-sparing agent (4,11). This combination has various anti-inflammatory and immunomodulatory properties, but the precise mechanisms through which these two drugs affect DLE are not entirely understood (1,11). The topical calcineurin inhibitor pimecrolimus has high anti-inflammatory activity in animal models of skin inflammation (11). In human medicine, therapeutic use of topical pimecrolimus has been reported for DLE (16). However, there are no reports on the use of topical pimecrolimus in canine DLE.

This case report describes the successful treatment of a case of DLE with topical 1% pimecrolimus and minocycline-niacinamide combination.

A two-year-old, 22.5 kg, spayed female Pungsan dog was presented with a 17-month history of chronic crusts and erosion on the nose. The dog lived in an outdoor environment. The owner reported that the skin lesions on the nose worsened in the summer months. Before the initial visit, the dog had received an anti-inflammatory dose of oral glucocorticoids for five months and topical antimicrobial agents without meaningful improvement of the skin lesions. Therefore, the dog was referred to the Chungnam National University Veterinary Medical Teaching Hospital for accurate diagnosis and management.

The dermatological evaluation revealed a crust, depigmentation, erosion, and an erythematous lesion over the nasal planum with a loss of the normal cobblestone texture (Fig. 1A). The ear margins were seborrheic bilaterally with crust and scaling. Also, firm and multifocal plaques over the thigh, groin, axilla, and dorsum were detected. The cytology examination on the nose, thigh, groin, axilla, and dorsum revealed moderate neutrophilic inflammation and bacterial infection. Ectoparasites were not observed on the skin scrapping test, and fungal skin infections were ruled out by Wood’s lamp examination, trichogram, and fungal culture. Abdominal radiography and ultrasonography revealed subcutaneous calcified materials along the thigh, groin, axilla, and dorsum. Calcinosis cutis was suspected due to the adverse effect of previous prolonged corticosteroid therapy. Complete blood count (CBC) and serum biochemistry tests revealed no other abnormalities except for increased gamma-glutamyl transferase (14 U/L, reference interval 0-11). One 4 mm punch biopsy sample was collected from the nasal planum for a definitive diagnosis.

Figure 1. Skin lesions of discoid lupus erythematosus in a dog. (A) Skin lesions of the nasal planum at initial presentation. (B) Marked improvement of skin lesions after 12 weeks of treatment with minocycline, niacinamide, and 1% topical pimecrolimus cream. (C) Maintenance of clinical improvement with 1% topical pimecrolimus cream monotherapy for 5 months.

The histopathology examination of the lesion revealed moderate to severe degenerative or apoptotic changes of the basal layer and lymphoplasmacytic interface dermatitis (Fig. 2A, D). The mild pigmentary incontinence and indistinct dermal-epidermal junction were also identified (Fig. 2B, C). FDLE was diagnosed based on the history and clinical, cytological, and histopathological results. In addition, firm and multifocal plaques over the thigh, groin, axilla, and dorsum were detected during the physical examination. Radiography revealed subcutaneous calcification. Calcinosis cutis was suspected due to the adverse effects of previous prolonged corticosteroid therapy.

Figure 2. Histopathology of canine DLE. (A) A marked band-like lymphoplasmacytic interface dermatitis (arrows) is observed. (B) The indistinct dermal-epidermal junction is associated with basal cell degeneration. (C) Mild pigmentary incontinence (arrows) is present. (D) Some basal cell apoptosis (arrow) is also identified (H&E; (A) 40×, (B) 200×, (C, D) 400×).

Treatment was commenced with minocycline at 7 mg/kg orally twice daily (Minocin^®, SK chemicals, Korea) and niacinamide at 500 mg/dog orally twice daily (Niacinamide^®, Now Foods, USA). Dimethyl sulfoxide (DMSO, DMSO cream^®, Natures Gift, USA) was also applied twice daily to treat the calcinosis cutis. Glucocorticoids were not administered due to the presence of calcinosis cutis induced by previous long-term corticosteroid treatment. After six weeks of treatment, the clinical signs on the nose were mildly improved, but skin lesions of calcinosis cutis were not improved. At this time, topical 1% pimecrolimus cream (Elidel^®, Menarini, Italia) twice daily was initiated as an adjuvant therapy, while DMSO, minocycline and niacinamide were continued at the same dose and frequency. After 6 weeks of additional treatment, skin lesions on the nasal planum were markedly improved (Fig. 1B), and mild regression of calcinosis on the dorsum was identified. On the other hand, the dog exhibited urinary incontinence, which resulted from the DMSO application. Therefore, DMSO was discontinued, and the urinary incontinence improved after two weeks. Fourteen weeks after starting treatment, minocycline and niacinamide were eventually discontinued, and the dog was continued solely on topical 1% pimecrolimus as a long-term therapeutic option. Topical 1% pimecrolimus cream was continued because skin lesions on the nasal planum were not completely improved. The dog’s skin lesion on the nasal has been maintained in clinical remission with topical 1% pimecrolimus twice daily for more than 5 months (Fig. 1C). Additionally, there was also improvement in skin lesions of ear margins, but calcinosis cutis on the thigh, groin, axilla, and dorsum remained without meaningful improvement.

DLE is a relatively common canine autoimmune skin disease with no systemic manifestations (8,11). Recently, DLE has been classified as a subtype of chronic cutaneous lupus erythematosus (CCLE) and further subdivided into FDLE and generalized DLE (GDLE) (14). In FDLE, skin lesions are limited to the face and neck, whereas the skin lesions in GDLE also appear below the neck (14). The initial skin lesions in FDLE include depigmentation, erythema, and scaling that progress into ulcerations, erosions, and crusts. These usually appear on the nasal planum, ear pinnae, periocular areas, and lips (14). The skin lesions in GDLE consist of discoid plaque with adhesive scaling, dyspigmentation, follicular plugging, erythematous margin, and central alopecia (3). These lesions were multifocal or generalized and predominate on the neck, dorsum, thorax, and abdomen (3). The diagnosis of canine DLE requires history, clinical signs, and compatible histopathology findings (2). The histopathology of canine DLE is characterized by a band-like lymphoplasmacytic infiltrate in the dermis, with pigmentary incontinence and basal cell vacuolation (8,14). In canine FDLE, histopathology is featured by a prominent band-like pattern of inflammation with dermal infiltrate of lymphocytes and plasma cells (14). Vacuolar degeneration, apoptosis, loss of basal cells, pigmentary incontinence is often subtle or mild (14). In the present case, the history of sun exposure, location and the presence of crust, depigmentation, erosion, and erythematous lesions along with histopathological findings of degenerative changes of basal layer and lymphoplasmacytic interface dermatitis were most consistent with the FDLE variant.

The conventional treatment of canine DLE involves systemic and topical corticosteroids, tetracycline and niacinamide combination, vitamin E, fatty acids, and topical tacrolimus (10,11). Azathioprine, chlorambucil, and cyclosporine can be used in refractory cases (3,10). The prognosis in canine DLE is considered good after diagnosis and appropriate treatment (11,14). On the other hand, recurrence is common after tapering of the medication dosages (2,3). The present case showed an insufficient clinical response to anti-inflammatory dose of corticosteroid treatment before referral, and the patient showed calcinosis cutis as an adverse effect of corticosteroid treatment. Therefore, the minocycline-niacinamide combination was started as an alternative and topical 1% pimecrolimus was used as a long-term and adjuvant therapy.

The use of tetracycline and niacinamide together has been suggested for the treatment of discoid lupus erythematosus, pemphigus erythematosus, and pemphigus foliaceous in dogs (11). A retrospective study indicated that this therapy may be effective in up to 70% of canine DLE but has a slow onset and requires 2 months to reach maximal therapeutic effect (1,4,11). Gastrointestinal upset, including anorexia, vomiting, and diarrhea, are commonly observed adverse effects of this treatment (1,11,15,17). Minocycline is a tetracycline antibiotic that is characterized as a broad-spectrum bacteriostatic antibiotic (6). In addition to its antimicrobial effects, minocycline not only possesses anti-inflammatory properties but also chelates calcium and directly inhibits collagenolytic enzymes such as matrix metalloproteinases (MMPs), elastase, and cathepsins (6,9). In previous studies, the therapeutic use of minocycline has been reported for canine calcinosis cutis (6,9). In the current case, minocycline was used in combination with niacinamide not just for the treatment of DLE but also in conjunction with DMSO because of its proven efficacy in canine calcinosis cutis. No side effects were observed during minocycline-niacinamide administration.

Pimecrolimus, like tacrolimus, is a topical immunomodulator whose major mechanism of action is calcineurin inhibition (13). Calcineurin inhibitors block the T-lymphocyte activation by binding to immunophilins and then lead to a decrease in cytokine expression, such as tumor necrosis factor α (TNF-α), interferon-γ (INF-γ), and interleukin 2, 3, and 4 (5,13). Although pimecrolimus and tacrolimus share a similar molecular weight and mechanism of action, pimecrolimus penetrates less through the skin than tacrolimus (5,12,13). Therefore, pimecrolimus has a lower risk of systemic effects after topical administration (12). The most common adverse events of topical pimecrolimus and tacrolimus in humans are skin burning at the site of application, and pimecrolimus shows a lower rate of skin burning than tacrolimus (3,13). The authors believed that pimecrolimus might be helpful for the treatment of canine DLE because pimecrolimus has advantages over tacrolimus, shares a similar mechanism of action with tacrolimus. In the present case, the improvement of skin lesions was maintained with topical pimecrolimus after minocycline-niacinamide discontinuation, and no adverse cutaneous reaction at the areas in contact with topical pimecrolimus was observed.

The present case has some limitations as follows. First, biopsy samples were not collected from the lesions of calcinosis cutis. However, while definitive confirmation might have been obtained through histological examination, we could sufficiently infer the diagnosis of calcinosis cutis based on physical examination, and radiological tests. Second, the ANA test was not performed due to the lack of systemic signs such as polyarthritis which is one of the major clinical signs of systemic lupus erythematosus. In addition, among the 104 dogs diagnosed with classic FDLE included in the four extensive series of cases, there were no reported cases of progression to SLE (14).

This paper reported a case of FDLE treated and well-managed with topical 1% pimecrolimus in combination with minocycline-niacinamide. No drug-related adverse effects were identified, and the dog was maintained with pimecrolimus alone. Therefore, pimecrolimus can be considered a safe long-term management therapeutic option for canine FDLE.

The authors have no conflicting interests.