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Immunomodulators for Integumentary Disease

By Michael Shipstone, BVSc, FACVSc, DACVD, Queensland Veterinary Specialists

Immunostimulants

Immunostimulation is used to enhance a deficient immunologic response; however, animals that appear to benefit from these agents are not severely immunosuppressed. The most common use of immunostimulants in dogs is for chronic, recurrent staphylococcal pyoderma. For primary therapy, immunomodulatory bacterins should not be substituted for antibiotics; they should be used concurrently with an appropriate antibiotic until the infection has been resolved. The immunomodulator is then continued and success judged on the time to and severity of any infection relapse. They are clearly helpful as adjunct agents or for maintenance therapy for some dogs with recurrent pyoderma but have no benefit in other cases.

Staphage lysate is a preparation of Staphylococcus aureus and polyvalent staphylococcus bacteriophage. When given concurrently with antibiotics, staphage lysate (0.5 mL, SC, twice weekly, or 1 mL, SC, weekly) has improved the response of dogs with superficial staphylococcal pyoderma compared with antibiotics alone. The mechanism of action is believed to be stimulation of T lymphocytes and activation of phagocytic cells. Deficient IgM levels—but not IgA or IgG levels—may be normalized with treatment.

S aureus bacterin-toxoid, used for prevention of staphylococcal mastitis in cattle, has been used with some success in cases of canine bacterial hypersensitivity. Various treatment protocols have been advocated. One schedule consists of 0.1 mL, intradermally, daily for 5 days, then weekly for 1 mo, then at monthly intervals. At corresponding times, doses given SC increase from 0.15 mL to 1.9 mL. Local swelling at the injection site, fever, and malaise are common adverse effects in dogs.

Propionibacterium acnes bacterin is labeled for use in dogs (0.25–2 mL, IV, 1–2 times/wk) and appears to have some benefit as adjunct treatment for recurrent pyoderma.

Many other immunostimulants have been described for use; however, responses in dermatologic disorders have been equivocal.

Immunosuppressants

Glucocorticoids:

Glucocorticoids are the immunosuppressive agents most commonly used to treat immune-mediated skin disease (see Autoimmune Skin Disorders). 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:

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-wk lag period before its effects are evident, so it is often initially combined with glucocorticoids. The dosage is 2.2 mg/kg (50 mg/m2), daily for 2 wk, and then reduced to every 48 hr. In dogs, it may be used in combination with metronidazole (10 mg/kg/day) for perianal furunculosis, although surgery may be necessary to remove residual scarring.

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

Cyclophosphamide:

Cyclophosphamide is an alkylating agent used to treat a wide variety of cancers, especially lymphoreticular neoplasms, and is usually given 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, every 48 hr. The dose should be given 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 mo. GI tract toxicity, bone marrow suppression, alopecia, infertility, and teratogenic effects may also be seen.

Chlorambucil:

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 given to cats. The dosage is 0.1–0.2 mg/kg/day, reduced to every other day once a response is seen. 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), GI irritation, and seizures. Delayed hair regrowth has been reported in shaved dogs.

Crysotherapy:

Gold salts have anti-inflammatory, antirheumatic, immunomodulating, and antimicrobial (in vitro) effects. Parenteral and oral forms are available. Aurothiomalate is given parenterally. It is absorbed rapidly and reaches peak levels in 4–6 hr. Rising serum values are noted for 5–10 wk. Beneficial effects are seen 6–12 wk 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, but 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 IM (1 mg if <10 kg body wt, 5 mg if >10 kg body wt). The next week a second test dose is given IM (2 or 10 mg), and if no adverse reactions are seen, treatment continues at 1 mg/kg, IM, weekly until remission. Once in remission, the dose is given every 2 wk 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 seen for 6–12 wk, so other medications (commonly glucocorticoids) must be given 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 therapy immediately after azathioprine, so a 4-wk washout period is recommended in these cases.

Cyclosporine:

Cyclosporine impairs the proliferation of activated T cells by inhibiting transcription of interleukin-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. Extra-label use for the treatment of immune-mediated disorders (pemphigus, 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/day for 30 days, after which the dose may be reduced to alternate-day or even third-day dosing in some animals. The dosage for anal furunculosis is 7.5 mg/kg/day. The dosage for feline atopic dermatitis is 7 mg/kg/day for 30 days and then reduced to 7 mg/kg alternate-day dosing.

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

Oclacitinib

Oclacitinib is a Janus kinase (JAK) inhibitor and exerts its action through the inhibition of a variety of pruritogenic cytokines (eg, IL-31) and pro-inflammatory 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.

It is rapidly absorbed and reaches peak plasma concentrations within 1 hr, 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, bid, for 2 wk and then reduced to once daily administration for maintenance therapy. In a double-blind, placebo-controlled study for treatment of atopic dermatitis, the treatment success was 66% in reducing pruritus and 49% for Canine Atopic Dermatitis Extent and Severity Index (CADESI) scores.

Sulfones:

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 people, 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, tid (dogs only) for 2–4 wk or until a response is seen, then every 24–48 hr. Longterm therapy is not recommended. Mild anemia or severe leukopenia, blood dyscrasias, hepatotoxicity, or skin reactions may develop. Animals should be monitored by CBC, urinalysis, BUN, and ALT every 2 wk during induction. Cats are particularly sensitive to toxicity, and a dosage of 1 mg/kg/day is recommended. Concurrent use may allow the dosage of glucocorticoids to be reduced.

Tetracycline and Niacinamide:

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 are given 500 mg of each drug tid. If a clinical response is seen, the frequency may be decreased to once or twice daily. Vomiting, diarrhea, and anorexia are the most common adverse effects.

Pentoxifylline:

Pentoxifylline results in a range of immunologic and rheologic 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-α, 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, bid-tid. Once a response is seen, the dosage may be tapered to once or twice daily. GI-related adverse effects have been reported (eg, nausea, vomiting).