Cyclosporine-induced psoriasiform-lichenoid dermatosis in four dogs: Successful treatment with antibiotics and cyclosporine dosage reduction
Abstract
Four dogs received cyclosporine at dosages of 8.6–17.5 mg/kg/day for 7–10 months to treat immune-mediated diseases. These dogs developed multiple, well-circumscribed lichenoid plaques with erythema and hyperpigmentation; additionally, thick scales appeared around the eyes, mouth and inside the auricles, and spread to almost the entire body. On the basis of histopathological examination and medication history, the four dogs were diagnosed with cyclosporin-induced psoriasiform-lichenoid dermatosis. Three of the four dogs exhibited marked improvement or disappearance of the skin lesions after systemic administration of antibiotics and reduction of the cyclosporine dosage; in the other dog, the lesions disappeared after systemic administration of antibiotics. Cyclosporine-induced psoriasiform-lichenoid dermatosis is believed to be multifactorial, involving the immune system and resident cocci on the skin.
BACKGROUND
Cyclosporine is a calcineurin inhibitor, which is an immunomodulator that exerts an inhibitory effect on T lymphocytes by inhibiting the production of cytokines such as interleukin-2. Cyclosporine (Atopica, Elanco) was approved in 2002 at a standard dosage of 5 mg/kg once daily for canine atopic dermatitis (CAD). International guidelines for CAD recommend the use of cyclosporine in the treatment of chronic CAD.1, 2 Cyclosporine also has reported efficacy against various inflammatory and immune-mediated diseases in dogs, and is often used at high dosages to treat these diseases. Common side effects of cyclosporine include mild to moderate gastrointestinal disturbances3, 4; however, rare side effects such as gingival thickening, hyperkeratosis of the paw pads, papillomatosis, psoriasiform-lichenoid dermatosis, verrucous dermatitis and hyperplastic skin lesions have also been reported.5-10 It has been suggested that dogs with psoriasiform-lichenoid dermatosis have cocci proliferation and response to infection,7, 8 while papillomavirus infection has been observed in the skin of dogs with verrucous dermatitis.6
Psoriasiform-lichenoid dermatosis is a rare skin condition that was reported to occur naturally in Springer spaniels in 1986.11 The disease was thought to primarily occur at a young age and have a strong predilection for certain dog breeds. Hence, it has been suggested that psoriasiform-lichenoid dermatosis is a genetic disease. However, the aetiology is unknown, and the condition repeatedly waxes and wanes. Multiple, clearly demarcated lichenoid plaques are formed mainly on the inside of the auricle, external auditory canal, ventral abdomen, foreskin and perineum. As the condition becomes chronic, the plaque becomes covered by sticky keratinous deposits. Plaques with well-demarcated and thick scales are formed, and histopathological findings reveal that the epidermis is irregularly thickened, often displaying downward projection that reach the dermis. Well-circumscribed circular microabscesses are observed within the epidermis. The condition is similar to psoriasis in humans. There are reports that the lesions disappear after the administration of antibiotics.12, 13
CASE PRESENTATION
Case 1
A 7-year-old, neutered, male Cavalier King Charles spaniel exhibited chronic eczema with hyperpigmentation and hair loss around the eyes, mouth and abdomen 2 months ago. The dog had been orally administered cyclosporine (17.5 mg/kg/day) and prednisolone for polyarthritis for 7 months, but the prednisolone had been discontinued for 5 days due to the onset of dermatitis.
The dog had multiple, well-circumscribed lichenoid plaques, hyperpigmentation, thick scales, erythema, papules, crusts and hair loss over the entire body.
Case 2
A 12-year-old, spayed, female Pomeranian was referred to our clinic for the investigation of hair loss accompanied by pruritus that had been present around its eyes for 2 months, and had gradually spread to the entire body. Cyclosporine was orally administered (at a dosage of 11.1 mg/kg/day) for 9 months to treat meningoencephalomyelitis. Prednisolone and cefovecin sodium (Convenia, Zoetis), itraconazole were systemically administered for dermatitis, but no improvement was observed.
Multiple, well-circumscribed lichenoid plaques, hyperpigmentation, thick scales, erythema, crusting and hair loss covered almost the entire body of the dog, and hyperkeratosis was observed in the paw pads (Figure 1a–c).
Case 3
A 7-year-old, neutered, male Shih Tzu was referred to our clinic because of a papule that had developed on the right cheek 5 months previously; the papule had gradually enlarged, become hyperpigmented, and spread to the rest of the body. The dog was treated with cyclosporine (at a dosage of 8.6 mg/kg/day) for 10 months for immune-mediated thrombocytopenia. Prednisolone was administered orally for the dermatitis, but no improvement was seen.
LEARNING POINTS/TAKE-HOME MESSAGES
- Psoriasiform-lichenoid dermatosis should be considered as a differential diagnosis for dogs who are receiving cyclosporine and develop multiple well-defined lichenoid plaques or scales, with erythema or hyperpigmentation occurring on the inside of the auricle, around the eyes, mouth or abdomen.
- Cyclosporine-induced psoriasiform-lichenoid dermatosis can be diagnosed based on the clinical presentation, drug history and histopathological examination.
- Cyclosporine-induced psoriasiform-lichenoid dermatosis is likely to be a multifactorial disease.
- Antibiotic administration and cyclosporine dosage reduction or withdrawal were effective in treating cyclosporine-induced psoriasiform-lichenoid dermatosis.
Multiple, well-circumscribed lichenoid plaques, hyperpigmentation, thick scales, erythema and papules covered almost the entire body.
Case 4
An 8-year-old, neutered, male toy poodle/Maltese mixed breed dog developed papules on the abdomen and inside the auricles 3 months previously. The lesions had gradually become plaques, scales and crusts, and spread to the whole body. The dog also developed otitis externa accompanied by pruritus. The dog had been receiving cyclosporine (15.7 mg/kg/day) and prednisolone for 8 months to treat polyarthritis. The prednisolone was discontinued for 2 months for the dermatitis, and ear drops (Mimipure, Kyoritsu Seiyaku) were used to treat the otitis externa, but no improvement was observed.
Lichenoid plaques with clear borders, hyperpigmentation, thick scales and erythema were observed on almost all of the dog's body, and the auditory canal was swollen and erythematous (Figure 2a,b).
Table 1 summarises the clinical information of the four cases.
| Case | Breed | Age | Sex | Weight (kg) | Administered dose of cyclosporine (mg/kg/day) | Administered duration of cyclosporine (months) | Pinnae | Around the eyes | Around the mouth | Face/head | Back | Chest | Abdomen | Perineum/prepuce | Limb | Tail | Perianal | Paw | Pruritus |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Cavalier King Charles spaniel | 7 | MN | 5.7 | 17.5 | 7 | − | + | + | − | + | + | + | + | + | + | − | − | − |
| 2 | Pomeranian | 12 | FS | 1.8 | 11.1 | 9 | + | + | + | − | + | − | + | + | + | − | − | + | + |
| 3 | Shih Tzu | 7 | MN | 5.6 | 8.6 | 10 | + | + | + | + | + | + | + | − | + | + | + | − | − |
| 4 | Toy poodle/Maltese mixed breed dog | 8 | MN | 3.1 | 15.7 | 8 | + | − | − | + | + | − | + | + | + | + | − | − | + |
- Abbreviations: FS, spayed female; MN, neutered male.
INVESTIGATIONS
General blood and biochemical tests in Case 4 revealed hyperproteinaemia and hyperglobulinaemia. Skin scraping and cytology were performed in all cases, and bacterial culture and drug susceptibility testing were performed in Cases 2–4. In Cases 3 and 4, skin samples from the affected areas were collected and subjected to polymerase chain reaction testing for canine papillomavirus DNA (Graduate School of Agricultural and Life Sciences, the University of Tokyo). The test results are presented in Table 2.
| Case | Haematology and serum biochemistry | Skin scraping | Cytology of skin | Bacterial culture | PCR assay |
|---|---|---|---|---|---|
| 1 | Mild anaemia, mildly elevated BUN, Cre, P | Negative | Cocci | N/A | N/A |
| 2 | Mild anaemia, mildly elevated Glob, BUN | Negative | Cocci | Staphylococcus pseudintermedius | N/A |
| 3 | Mildly elevated TP | Negative | Cocci | S. pseudintermedius | Negative |
| 4 | Elevated TP, Glob | Negative | Cocci | S. pseudintermedius | Negative |
- Abbreviations: BUN, blood urea nitrogen; Cre, creatinine; Glob, globulin; N/A, not applicable; P, phosphorus; TP, total protein.
Skin biopsies were performed under local anaesthesia in all cases. The histopathological findings of the four cases were similar, with marked epidermal hyperkeratosis, degeneration and necrotic granular leukocytes, and numerous Gram-positive cocci and crusting. The epidermis was irregularly thickened with thickening of the granular layer, and in some portions, dermal papillae extended upward in a papillary shape, and epidermal projections extended toward the dermis (Figure 3a). The epidermis had micropustules containing neutrophils and eosinophils, and Gram-positive cocci were also present in some cases (Figure 3b). Partial liquefaction degeneration was observed on the basal side of the epidermis, accompanied by intraepithelial infiltration of granular leukocytes or lymphocytes, and a small number of individual necrotic keratinocytes. In the superficial layer of the dermis, there was vasodilation and a band-like dense infiltration of inflammatory cells just below the epidermis (Figure 3c). The infiltrating cells were primarily lymphocytes, plasma cells, histiocytes and mast cells, with particularly marked infiltration of lymphocytes and plasma cells; melanophages were scattered just below the epidermis. The examination revealed no ectoparasites and no fungi-like material positive for periodic acid–Schiff staining. The above histopathological findings were consistent with psoriasiform-lichenoid dermatosis.
DIFFERENTIAL DIAGNOSIS
Psoriasiform-lichenoid dermatosis, demodicosis, bacterial infection, papillomatosis, lichenoid keratosis, actinic keratosis, canine pigmented viral plaques and epitheliotropic T-cell lymphoma were the differential diagnoses.
OUTCOME AND FOLLOW-UP
Case 1
The dog received amoxicillin administered systemically (17.5 mg/kg twice daily) for 1 week, and was washed with shampoo containing salicylic acid (Keratolux, Virbac) and moisturiser (oats dermal calm, Zenoaq), with no obvious improvement. The dosage of cyclosporine was then reduced from 17.5 to 8.8 mg/kg/day. Three weeks later, hair growth occurred around the mouth and trunk, and 8 weeks after reduction of cyclosporin, the lichenoid plaques, scales and hyperpigmentation had almost disappeared.
Case 2
A drug sensitivity test demonstrated susceptibility to doxycycline. Two weeks after the dog began receiving systemically administered doxycycline (at a dosage of 8 mg/kg twice daily), there was hair growth around the eyes and a reduction in scales on the ears, bridge of the nose and back. Four weeks after initiating doxycycline administration, further improvement was observed. However, the dog's abdomen was pruritic, and cytology revealed cocci infection; hence, the antibiotic was changed to fosfomycin, which was administered systemically (18 mg/kg twice daily). A shampoo containing 2% chlorhexidine-miconazole (Malasecure, Fujita Pharm), moisturiser (Afloat dog moisturize, Qix) and topical antibiotics (Gentamicin ointment 0.1%, Takata Pharmaceutical) was also applied. Two weeks later, the skin lesions over the entire body improved and the pruritus resolved. The fosfomycin was continued, and the cyclosporine dosage was reduced from 11.1 to 5.6 mg/kg/day. The hyperpigmentation on the back and hyperkeratosis on the paws disappeared after 2 weeks (Figure 4a). The eruptions on the auricle and abdomen also improved (Figure 4b), and thus fosfomycin was discontinued. At 16 weeks after the cyclosporine dosage reduction, all skin lesions had disappeared (Figure 4c).
Case 3
Urea cream (Urea cream 20%, Ikeda Medical Industrial) was applied twice daily for 2 weeks, but no obvious improvement was seen. A shampoo containing 2% chlorhexidine and miconazole (Malaseb, Kirikan) improved the lichenoid plaques and scales on the back, abdomen, extremities, tail and perianal area. A more significant improvement was observed after 1 week of systemic administration of ampicillin sodium. Thereafter, prednisolone was systemically administered (0.5 mg/kg once daily) to treat immune-mediated thrombocytopenia, and the dosage of cyclosporine was reduced from 8.6 to 4.6 mg/kg/day. Two weeks after the cyclosporine dosage reduction, all lesions showed improvement; 10 weeks after reduction, all lesions had disappeared.
Case 4
After 2 weeks of systemic administration of cephalexin (24 mg/kg twice daily), the plaques, erythema, scales and swelling of the ear canal had improved, and the pruritus in the ear had disappeared. At 5 weeks after the initiation of washing with a shampoo containing 2% chlorhexidine and miconazole (Malasecure, Fujita Pharm) in combination with the cephalexin, there was a significant improvement in the lichenoid plaques, scales and hyperpigmentation (Figure 5a,b). However, as pustules, papules and crusts were observed on the abdomen, and cytology revealed a cocci infection, the antibiotic was changed to doxycycline administered systemically (8.1 mg/kg twice daily), along with a moisturiser containing chlorhexidine (Oats spot foam, Zenoaq). Two weeks later, only slight scales and hyperpigmentation were present. The lesions disappeared completely 4 weeks after administration of doxycycline. Thereafter, the dosage of cyclosporine was reduced from 15.7 to 7.5 mg/kg/day, and doxycycline was discontinued.
In Cases 2–4, there was no recurrence of lesions 1–2 years after the first visit, Case 1 died 3.5 months later of unrelated cause, but had no recurrence during that time.
Table 3 shows the clinical response to systemic antibiotics and cyclosporine dosage reduction.
| Case | First, systemic antibiotics | Next, cyclosporine dosage reduction |
|---|---|---|
| 1 | No response | Almost resolution |
| 2 | Improvement | Resolution and no recurrence |
| 3 | Improvement | Resolution and no recurrence |
| 4 | Resolution | No recurrence |
DISCUSSION
On the basis of clinical symptoms, dermatological examination, histopathological findings, medical history and response to treatment, four dogs were diagnosed with cyclosporine-induced psoriasiform-lichenoid dermatosis accompanied by cocci proliferation and infection. Spontaneous psoriasiform-lichenoid dermatosis has been reported to occur frequently in young English Springer spaniels. However, the four dogs with cyclosporine-induced psoriasiform-lichenoid dermatosis in this report were of various breeds and were aged between 7 and 12 years. Furthermore, five previously reported cases of cyclosporine-induced psoriasiform-lichenoid dermatosis involved two West Highland white terriers, one Shetland sheepdog, one labrador retriever and one collie dog with ages ranging from 2 to 7.5 years.7-9 Therefore, our cases and previous reports suggest that no dog breed is prone to psoriasiform-lichenoid dermatosis, which is believed to be induced by cyclosporine, and that the condition occurs in a wide range of dog breeds of various ages.
The four dogs in the present cases were treated with 8.6–17.5 mg/kg/day of cyclosporine for 7–10 months to treat immune-mediated diseases. Multiple, clearly demarcated lichenoid plaques with erythema, hyperpigmentation and scaling initially appeared around the eyes, mouth and inside the auricles, and gradually spread to the entire body. In previous reports of cyclosporine-induced psoriasiform-lichenoid dermatosis, four of five dogs were treated with cyclosporine at a dosage of 5 mg/kg/day or less for 2 weeks to 2 years to treat the skin disease,7-9 while one dog received 10 mg/kg/day of cyclosporine for 4 weeks. Psoriasiform-lichenoid dermatosis may develop in dogs receiving high dosage or long-term administration of cyclosporine, but our cases and past reports show that there is no clear relationship between the dosage of cyclosporine and the period until onset.
The symptoms of cyclosporine-induced psoriasiform-lichenoid dermatosis have been proposed to be an atypical response to staphylococcal infection, and there are reports that the administration of antibiotics is effective.7, 8 Histopathological examination of skin of the four dogs in the present report confirmed the Gram-positive cocci in the surface layer of the epidermis or within microabscesses of the epidermis in all cases. In the three cases in which bacterial culture and drug susceptibility tests were performed, Staphylococcus pseudintermedius was isolated and identified. When systemic antibiotics were administered, three of four dogs showed significant improvement in the skin lesions within 1–2 weeks of administration. In addition, although there were no previous reports of pruritus, it was observed in two of four dogs in the present report. In these two dogs, pruritus disappeared after the administration of antibiotics; thus, we believe that the pruritus was due to the proliferation of cocci or infection. The test results and response to antibiotic administration in our cases suggest that, as previously reported,14 the cyclosporine-induced psoriasiform-lichenoid dermatosis is a unique response to staphylococcal infection and proliferation. The culprit coccus was thought to be S. pseudintermedius, the main pathogen in canine pyoderma.
For the treatment of cyclosporine-induced psoriasiform-lichenoid dermatosis in dogs, it has been reported that cyclosporine withdrawal or administration of antibiotics and cyclosporine dosage reduction are effective.7-9 In Cases 1–3, systemic administration of antibiotics and cyclosporine dosage reduction proved effective. The reduction in cyclosporine, in all cases, was around 50%, and the optimal reduction levels still need to be established. In Case 1, it was suggested that a significant response was achieved merely by cyclosporine dosage reduction. However, to our knowledge, no report has demonstrated resolution of the skin lesions after antibiotic administration alone. In Case 4, the adequate response to the antibiotic may be due to the use of doxycycline, which is known to have immunomodulatory activity. This was the first case in which the lesions disappeared after the systemic administration of antibiotics or topical therapy, even before the reduction of the cyclosporine dosage. Human psoriasis is a multifactorial disease, with autoimmune responses triggered by bacterial superantigens potentially playing a central role in its pathogenesis, and interactions between the immune system, keratinocytes and the associated skin microbiome.15, 16 Cyclosporine-induced psoriasiform-lichenoid dermatosis in dogs is expected to be a multifactorial disease involving the immune system and resident Staphylococcus on the skin. Depending on the case, some instances can be managed with systemic antibiotics and topical therapy, some with a reduction in cyclosporine dosage, and others may require both systemic antibiotics and a reduction in cyclosporine dosage. It was also surmised that reducing the dosage of cyclosporine might be effective in preventing recurrence.
AUTHOR CONTRIBUTIONS
Junko Ike and Toshiroh Iwasaki wrote the paper. Maiko Sekiguchi evaluated histopathological examination. Ryosuke Ueda and Takeshi Mukosaka provided the cases.
ACKNOWLEDGEMENTS
We thank Kelly Zammit, BVSc, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
CONFLICT OF INTEREST STATEMENT
The authors declare they have no conflicts of interest.
FUNDING INFORMATION
The authors received no specific funding for this work.
ETHICS STATEMENT
The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. No ethical approval was required.
REFERENCES
IMAGE QUIZ
Figure 1c
A 12-year-old Pomeranian presented with multiple, well circumscribed, hyperpigmented lichenoid plaques with thick scales on the abdomen. The dog had been receiving high doses of cyclosporine for an extended period to treat an immune-mediated disease.
MULTIPLE-CHOICE QUESTION
What is the likely diagnosis?
POSSIBLE ANSWERS TO MULTIPLE-CHOICE QUESTION
1. Pyoderma
2. Canine pigmented viral plaques
3. Cyclosporine-induced psoriasiform-lichenoid dermatosis
4. Lichenoid keratosis
5. Lentigo
CORRECT ANSWER
3. Cyclosporine-induced psoriasiform-lichenoid dermatosis.
Cyclosporine-induced psoriasiform-lichenoid dermatosis can be diagnosed based on the clinical presentation, drug history and histopathological examination. Polymerase chain reaction testing for canine papillomavirus DNA is useful for differential diagnosis of canine pigmented viral plaques.
