Generalized Canine Discoid Lupus Erythematosus Responsive to Tetracycline and Niacinamide Therapy

Introduction

Discoid lupus erythematosus (DLE) is a frequently reported canine autoimmune disease that classically presents as a facial-predominant form consisting of erythema, depigmentation, scaling, erosions/ulcers, and scarring of the nasal planum and craniodorsal muzzle.¹ There are only two published cases of a second phenotype of canine DLE, so-called generalized DLE, in which similar skin lesions are noted on the trunk and extremities without facial involvement.^2,3 In those cases, lesions were reported to respond successfully to either oral glucocorticoids or to a combination of topical glucocorticoids, topical tacrolimus, and oral hydroxychloroquine.^2,3 The latter is an immunomodulating antimalarial drug commonly used for the treatment of chronic cutaneous lupus erythematosus in humans.⁴

In this article, the authors describe the successful management of a third dog with generalized DLE using both oral tetracycline and niacinamide, an immunomodulating combination previously shown to be effective for treatment of dogs with the classic nasal-predominant variant of DLE.⁵

Case Report

An 11 yr old castrated male shih tzu weighing 10.7 kg presented with a 2 mo history of generalized, nonresolving, annular to polycyclic, erythematous papules and plaques with alopecia, hyperpigmentation, scaling, and centrally located atrophic scarring over the caudal dorsum, flanks, craniodorsal thorax, and lateroproximal extremities (Figure 1A). The dog did not exhibit other clinical signs, and there was no history of previous drug administration. There was no evidence of either oral or mucocutaneous involvement. Skin scrapings did not reveal any Demodex, and surface lesional skin cytology was unremarkable.

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Histopathology of lesional skin biopsy specimens revealed mild to moderate epidermal hyperplasia with compact to laminated orthokeratotic and parakeratotic hyperkeratosis. Multifocal, mild to moderate apoptosis of individual basal keratinocytes of the epidermis and of the hair follicle infundibula was also noted. Mild vacuolation and moderate jumbling of basal keratinocytes associated with a moderate amount of pigmentary dispersal to melanophages was noted in the superficial dermis. A mild to moderate number of lymphocytes infiltrated the basal epithelium, which led to blurring of the dermoepidermal junction. A patchy to near complete, mild to moderate, band-like (lichenoid) infiltrate of lymphocytes and plasma cells was found on the superficial dermis that hugged the epithelium (Figure 1C). The basement membrane appeared uniformly thickened throughout the specimen. Sebaceous glands were present and appeared unaffected. Direct immunofluorescence, performed on the same paraffin-embedded skin sections, confirmed the existence of a patchy, fine to thick, linear deposition of immunoglobulin (Ig) G, but not of IgM, IgA, or activated complement C3, along the dermoepidermal junction (i.e., a positive “lupus band”) as shown in Figure 1B.

A complete blood count, serum biochemical profile, and urinalysis were within normal limits. The clinical presentation, histopathology, laboratory values, and direct immunofluorescence findings supported the diagnosis of generalized DLE. There were no other clinical signs or laboratory values suggesting that the diagnosis of systemic lupus erythematosus (SLE) should be considered further.

The dog was prescribed a regimen of oral tetracycline^a and niacinamide^b (45 mg/kg of each drug q 8 hr), and the owner was instructed to limit the amount of sun exposure.⁶ Mild gastrointestinal disturbances consisting of vomiting and anorexia were noted initially, but quickly resolved. Re-examination 1 mo after initiating therapy revealed that the extent and severity of skin lesions had been reduced by ~80%. Weekly bathing with a benzoyl peroxide shampoo^c was also recommended due to its keratolytic properties. The dog was re-evaluated on a monthly basis. After 3 mo, the only lesions that remained were atrophic scars. Four months after starting treatment, omega-3 fatty acids^d (a total dose of 10 mg/kg eicosapentaenoic acid and 7 mg/kg docosahexaenoic acid once q 24 hr) were also added in to the treatment regimen for their proposed anti-inflammatory properties.^7,8 After 6 mo of therapy the atrophic scarring was no longer present. Attempts to reduce either the doses or frequencies of tetracycline and/or niacinamide administration at that time initially led to a rapid recurrence of skin lesions; however, a dose reduction 9 mo after beginning therapy no longer resulted in worsening of the disease. At the time this report was written, complete remission had been maintained for >1 yr with oral tetracycline (25 mg/kg q 8 hr), niacinamide (45 mg/kg q 8 hr), eicosapentaenoic acid (10 mg/kg q 24 hr), and docosahexaenoic acid (7 mg/kg q 24 hr).

Discussion

Canine DLE is a common autoimmune skin disease that has been recognized for >30 yr.^1,9 A predilection of the classic nasal-predominant form has been reported for the collie, Shetland sheepdog, German shepherd dog, and Siberian husky breeds.¹⁰ Lesions of canine DLE have been found not only on the face (i.e., nasal planum, pinnae, muzzle, periorbital region) but also on the trunk and on the limbs; however, those cases are extremely rare, and lesions typically occur in conjunction with more classic lesions on the nose.⁹

In comparison, cutaneous lupus erythematosus in humans is divided into acute, subacute, and chronic cutaneous lupus variants. DLE appears as the most common form of chronic cutaneous lupus erythematosus, which in itself is a subcategory of lupus erythematosus-specific skin disease. Early lesions result in sharply demarcated, coin-shaped (i.e., discoid), erythematous plaques most commonly encountered on heavily sun-exposed areas, including the face, scalp, ears, V area of the neck, and extensor aspects of the arms.¹¹ As in dogs with this disease, the majority of humans with DLE are otherwise healthy. Studies pertaining to the prevalence of DLE in humans are lacking, although all forms of lupus erythematosus are more common in women of childbearing age.¹²

The current standard for diagnosing DLE in both dogs and humans is based on clinical signs suggestive of the disease, exclusion of clinical signs that would be suggestive of SLE, and the histopathological demonstration of a lymphocyte-rich interface dermatitis with prominent basal keratinocyte vacuolar degeneration and apoptosis.^1,13 In the patient described herein, a positive lupus band (i.e., a deposition of Igs and/or complement at the dermoepidermal junction) was noted using direct immunofluorescence, which helped differentiate DLE from other similar skin conditions. It should be emphasized that the lupus band test is a laboratory procedure that should always be interpreted in conjunction with clinical findings and other serological and immunopathological parameters because positive results have been found in other connective tissue disease as well as normal sun-exposed skin.¹³ Another consideration is that there is very high diagnostic specificity when there are three or more immunoreactants present in a sample.¹⁴ In this case, only deposition of IgG was noted along the basement membrane; however, when used in conjunction with the appropriate history and suggestive clinical signs, it supported the diagnosis of generalized DLE.

An antinuclear antibody (ANA) titer is commonly performed when there is high suspicion of SLE in both human and canine patients. That test was not performed in this patient because there were no signs suggestive of systemic involvement/SLE. In a case series published in 1992 (n = 75), the most common clinical signs of canine SLE were polyarthritis (91% of cases), renal involvement (65%), and mucocutaneous disorders (60%).¹⁵ The patient in the current case had no evidence of either systemic disease or of mucocutaneous involvement at the time of diagnosis or during the ensuing 1 yr of therapy. In addition, the previously mentioned serum biochemical profile and urinalysis did not reveal any renal abnormalities. Those findings, along with the clinical presentation, made the probability of diagnosing SLE in this patient very low. It should also be noted that a positive ANA is rarely seen in human and canine DLE cases, and that the test has a low specificity for the disease.^1,16,17 Therefore, ANAs are neither sensitive nor specific for the diagnosis of DLE and are of no use in the absence of signs suggestive of SLE.

The traditional treatment of canine DLE is usually multifaceted, aimed at reducing clinical signs while limiting adverse side effects from medication. Treatment regimens normally include systemic and/or topical glucocorticoids, oral tetracycline, oral niacinamide, and topical tacrolimus.^1,5,18 The patient described herein is the third reported case of a dog with a generalized variant of DLE and the first dog with this phenotype that achieved complete remission of clinical signs with the combination of oral tetracycline and niacinamide. Classic nasal predominant DLE has been treated with tetracycline and niacinamide in the past, but the excellent response using this generalized variant resembles that obtained in many dogs with classic nasal DLE that have been treated with this regimen.^5,9 The fact that clinical signs of the disease recurred in this patient after lowering the dose and frequency of the medications argues against the possibility of spontaneous remission.

Tetracycline is broad-spectrum polyketide antibiotic that has significant anti-inflammatory properties. It can affect complement activation, antibody production, chemotaxis, prostaglandin synthesis, lipases, and collagenases.¹⁹ A common adverse event seen with tetracycline is gastrointestinal upset, such as anorexia, vomiting, and diarrhea. The tetracycline was likely the source of the gastrointestinal disturbances noted during treatment in this patient. As the availability of tetracycline is diminishing, oral doxycycline (at a dose of 5–10 mg/kg q 12 hr) may be considered as an alternative therapeutic, although treatment responses are anecdotal at this time.

Niacinamide, an amide of nicotinic acid, also has anti-inflammatory properties and has been used for >50 yr in humans to treat conditions, such as acne and rosacea.²⁰ It is suspected to act by inhibiting mast cell degranulation and phosphodiesterases.²¹ In dogs, the immunomodulating combination of niacinamide and tetracycline has been used for >20 yr as corticosteroid substitute/sparing agents for several proven or suspected autoimmune diseases, such as DLE, pemphigus foliaceus, and lupoid onychodystrophy (idiopathic onychitis).^5,22,23 It is worth noting that the listed combination of drugs was not reported as a treatment option for any cutaneous lupus variants of humans.^4,24

Finally, omega-3 fatty acids have been suggested to have substantial anti-inflammatory properties via their conversion to resolvins and protectins, which work in conjunction with peroxisome proliferator-activated receptor gamma and the G protein-coupled receptor, GPR120.²⁵ Those properties could make omega-3 fatty acids helpful supplements for controlling autoimmune diseases. They were used in the dog described in this report in conjunction with the tetracycline and niacinamide therapy; however, it is unlikely that benefit was provided because clinical signs of the disease recurred with alteration of the tetracycline/niacinamide doses.

Conclusion

The above-described regimen of safe and inexpensive immunomodulating drugs should be considered as the first line of therapy for dogs affected with this variant of DLE. The combination of therapeutics is also beneficial if glucocorticoids and/or antimalarials are either contraindicated or need to be avoided.