Immunomodulators for Integumentary Disease in Animals

Glucocorticoids are the immunosuppressive agents most commonly used to treat immune-mediated skin disease. A range of other immunosuppressants may be used either concurrently with glucocorticoids or alone for the treatment of various immune-mediated dermatoses, including systemic lupus erythematosus (SLE), pemphigus complex, bullous pemphigoid, and vasculitis.

Azathioprine is converted to 6-mercaptopurine in the liver. It competes with purines in the synthesis of nucleic acids and prevents proliferation of rapidly dividing cells. It is used for treatment of pemphigus disorders, bullous pemphigoid, and SLE in dogs, ocular inflammation in the uveodermatologic syndrome, and histiocytomas. There is a 3- to 5-week lag period before its effects are evident, so it is often initially combined with glucocorticoids. In dogs the dosage is 2.2 mg/kg (50 mg/m²), daily for 2 weeks, and then reduced to every 48 hours. In horses, 2.5 mg/kg is administered once a day for two days and then reduced to every 48 hours for maintenance treatment. In dogs, it may be used in combination with metronidazole (10 mg/kg, PO, every 24 hours) for perianal furunculosis, although surgery may be necessary to remove residual scarring.

Gastrointestinal adverse effects (vomiting and diarrhea) may be avoided by administering azathioprine with food or lowering the dose. Bone marrow suppression may also develop. All three cell lines can be affected; however, leukopenia is the most common. The CBC should be monitored every 2 weeks during induction and at least every 4 months during maintenance treatment. Acute pancreatitis and hepatotoxicity has been reported in dogs. Azathioprine is contraindicated in cats because of rapid, lethal bone marrow suppression.

Cyclophosphamide is an alkylating agent used to treat a wide variety of cancers, especially lymphoreticular neoplasms, and is usually administered in combination with other drugs. It may also be used short-term in severe cases of SLE, rheumatoid arthritis, pemphigus complex, and vasculitis. The dosage for immunosuppression is 1.5–2.5 mg/kg, PO, every 48 hours. The dose should be administered in the morning so that it does not remain in the bladder overnight. Because most animals treated with cyclophosphamide also receive corticosteroids, polyuria induced by the steroids may be somewhat protective. The potential for hemorrhagic cystitis and bladder fibrosis limits the use of cyclophosphamide to no more than 3–4 months. Gastrointestinal tract toxicity, bone marrow suppression, alopecia, infertility, and teratogenic effects may also occur.

Chlorambucil is an alkylating agent similar to cyclophosphamide. However, it is slower acting and the least toxic of the group. It may be used for treatment of immune complex diseases in which azathioprine or cyclophosphamide are not tolerated, and it may be administered to cats. The dosage is 0.1–0.2 mg/kg, PO, every 24 hours, reduced to every other day once the patient responds. It is mostly used in combination with glucocorticoids but can be used with azathioprine in dogs only in particularly refractory cases. It may also be used to replace cyclophosphamide if hemorrhagic cystitis develops. Adverse effects are rare and include bone marrow suppression (which generally develops within 7–14 days of starting treatment and resolves in 7–14 days), gastrointestinal irritation, and seizures. Delayed hair regrowth has been reported in shaved dogs.

Gold salts (chrysotherapy) have anti-inflammatory, antirheumatic, immunomodulating, and antimicrobial (in vitro) effects. Parenteral and oral forms are available. Aurothiomalate is administered parenterally. It is absorbed rapidly and reaches peak levels in 4–6 hours. Rising serum values are noted for 5–10 weeks. Beneficial effects occur 6–12 weeks after the start of treatment. The oral form is auranofin. Only 25% is absorbed, and lower and more predictable plasma concentrations are found. The half-life is ~21 days; however, the retention and tissue accumulation are only 1% (parenteral gold 30%). Results with this compound are equivocal in dogs. Gold salts are indicated for canine and feline pemphigus unresponsive to glucocorticoids and feline plasma cell pododermatitis.

Routine protocols start with a test dose intramuscularly (1 mg if < 10 kg, 5 mg if >10 kg). The next week a second test dose is administered intramuscularly (2 or 10 mg), and if no adverse reactions occur, treatment continues at 1 mg/kg, IM, weekly until remission. Once in remission, the dose is administered every 2 weeks and may later be reduced to monthly injections. Occasionally, a higher dosage (1.5–2 mg/kg) may be required to induce remission. Treatment effects are not evident for 6–12 weeks, so other medications (commonly glucocorticoids) must be administered at therapeutic doses during this time. Gold salts should not be administered with other cytotoxic drugs because of the increased risk of toxic reactions. Adverse effects include allergic reactions (skin eruption, oral reactions), nephrotoxicity, and bone marrow suppression. Toxic epidermal necrolysis has been reported in dogs starting gold treatment immediately after azathioprine, so a 4-week washout period is recommended in these cases.

Cyclosporine impairs the proliferation of activated T cells by inhibiting transcription of interleukin (IL)-2, gene activation, and RNA transcription. This early inhibition of T cells also leads to reduced production of other cytokines, mast cells, and eosinophils, and inhibition of mononuclear cells, antigen presentation, histamine release from mast cells, neutrophil adherence, natural killer cell activity, and B-cell growth and differentiation.

Cyclosporine is used for treatment of atopic dermatitis and anal furunculosis. Extralabel use for the treatment of immune-mediated disorders (pemphigus and SLE) and epitheliotropic lymphoma has been less successful. Response has been good when used for sebaceous adenitis. The dosage for atopic dermatitis in dogs is 5 mg/kg, PO, every 24 hours for 30 days, after which the dosage may be reduced to alternate-day or even third-day dosing in some animals. The dosage for anal furunculosis is 7.5 mg/kg, PO, every 24 hours. The dosage for feline atopic dermatitis is 7 mg/kg, PO, every 24 hours for 30 days and then reduced to 7 mg/kg alternate-day dosing.

Adverse effects include gastrointestinal signs (nausea, vomiting, soft feces, and diarrhea), gingival hypertrophy, hirsutism, and papillomatosis (which generally decreases when the dose is decreased). Drugs that inhibit cytochrome P450 (eg, ketoconazole) potentiate cyclosporine toxicity notably. If ketoconazole (10 mg/kg, PO, every 12 hours) is also administered to animals with anal furunculosis, the dosage of cyclosporine can be reduced to 1 mg/kg, PO, every 12 hours. This induction dosage is maintained for 4 weeks and then reduced if the response is adequate or adverse effects (vomiting and lethargy) develop.

Oclacitinib is a Janus kinase (JAK) inhibitor and exerts its action via the inhibition of a variety of pruritogenic cytokines (eg, IL-31) and proinflammatory cytokines dependent on JAK 1 or JAK 3 enzyme activity. However, it may also exert effects on other cytokines (eg, involved in host defense or hematopoiesis) with the potential for adverse effects.

Oclactinib is rapidly absorbed and reaches peak plasma concentrations within 1 hour, leading to rapid onset of clinical effect. It is indicated for the treatment of pruritus associated with allergic dermatitis in dogs at a dosage of 0.4–0.6 mg/kg, PO, every 12 hours, for 2 weeks and then reduced to once-daily administration for maintenance treatment. In a blinded, placebo-controlled study for treatment of atopic dermatitis, the treatment success rate was 66% in reducing pruritus and 49% for Canine Atopic Dermatitis Extent and Severity Index (CADESI) scores.

Oclacitinib is not registered for use in cats, however, one blinded, randomized, methylprednisolone-controlled study has shown promising results in which 70% of the oclacitinib (0.7–1.2 mg/kg, PO, every 12 hours) and 75% of the methylprednisolone group (0.5–1 mg/kg, PO, every 12 hours) achieved 50% reduction in pruritus visual analogue scale and 60% and 80% reduction, respectively, in the SCORFAD (scoring feline allergic dermatitis) scale. The oral bioavailability is similar (87% vs 89%); however, the absorption and elimination are faster (time to maximal concentration, ~ 35 minutes; half-life, 2.3 hours) than in the dog (half-life, 3.45 hours). Thus, higher dosages (0.6–1.0 mg/kg, PO, every 12 hours) may be needed to achieve similar blood concentrations to those in dogs.

Oclacitinib has been used in an extralabel fashion in horses.1,2

Lokivetmab is a caninized monoclonal antibody that binds to and inhibits the action of IL-31. Interleukin-31 activates peripheral nerves via the JAK pathway and is important mediator in chronic pruritus and has been shown to induce pruritus in dogs. It does not have anti-inflammatory or immunosuppressive activity. 

Lokivetmab is registered for the reduction of pruritus in canine atopic and allergic dermatitis. The dose varies (depending on country) and is either 1 or 2 mg/kg, SC. The degree and duration of response is variable between patients. One retrospective study (2 mg/kg) showed 50% reduction in pruritus visual analogue scale in 77% of dogs in the study; the frequency of administration was variable: < 4 weeks in ~20%, 4 weeks in 46% and >4 weeks in ~34%. Lokivetmab is eliminated via protein degradation pathways rather than xenobiotic metabolizing enzymes and no specific drug interactions have been reported.

Dapsone is an anti-inflammatory, antibacterial sulfone that inhibits neutrophil chemotaxis and adhesion to basement membrane zone antibodies, degranulation of mast cells, action of lysosomal enzymes, and activation of the alternative complement pathway. Dapsone also inhibits synthesis of IgG, IgA, and prostaglandins, as well as T-cell responses. Although it is used for a variety of diseases characterized by accumulation of neutrophils in humans, the results are more equivocal in dogs. However, it has been used for pemphigus foliaceus and erythematosus, subcorneal pustular dermatosis, leukocytoclastic vasculitis, and IgA dermatosis. The dosage is 1 mg/kg, PO, every 8 hours (dogs only) for 2–4 weeks or until a response is evident, then every 24–48 hours. Long-term treatment is not recommended. Mild anemia or severe leukopenia, blood dyscrasias, hepatotoxicity, or skin reactions may develop. Animals should be monitored by CBC, urinalysis, BUN concentration, and ALT activity every 2 weeks during induction. Cats are particularly sensitive to toxicity, and a dosage of 1 mg/kg, PO, every 24 hours is recommended. Concurrent use may allow the dosage of glucocorticoids to be reduced.

Although the precise mechanism of action is unknown, tetracyclines may inhibit in vitro lymphocyte blastogenic transformation and antibody production, activation of complement (component C3), prostaglandin synthesis, lipases and collagenases, and suppress leukocyte chemotaxis in vitro and in vivo. Niacinamide blocks IgE-induced histamine release, inhibits phosphodiesterases, and decreases protease release by leukocytes. The combination is indicated for discoid lupus erythematosus and pemphigus erythematosus. These diseases are characterized by leukocyte chemotaxis secondary to complement activation by antigen-antibody complexes and by release of proteases. Dogs weighing >10 kg should be administered 500 mg of each drug every 8 hours. If a clinical response is evident, the frequency may be decreased to once or twice daily. Vomiting, diarrhea, and anorexia are the most common adverse effects.

Pentoxifylline results in a range of immunologic and rheological effects, including increases in RBC and WBC deformability; decreases in RBC and platelet aggregation, leukocyte endothelial adherence, natural killer cell activity, neutrophil degranulation, and production of monocyte TNF-alpha, IL-1, IL-4, and IL-12; and inhibition of T- and B-cell activation. It has been used in limited numbers of animals for a variety of conditions, including vasculitis, canine familial dermatomyositis, ulcerative dermatitis of Shetland Sheepdogs and Collies, rabies vaccine–induced ischemic alopecia, ear margin dermatosis, contact allergy, and atopic dermatitis. The dosage is 10 mg/kg, PO, every 8 to 12 hours. Once a response is evident, the dosage may be tapered to once or twice daily. Gastrointestinal-related adverse effects have been reported (eg, nausea and vomiting).