How to deal with the difficult immune mediated diseases (Proceedings)

A variety of different diseases are in the category of what are referred to as autoimmune or immune mediated dermatologic diseases. The diseases typically have differing etiologies though a significant component in there pathogenesis is an abnormal or deleterious immune response that affect normal cutaneous structures, such as epidermal keratinocytes, basement membranes, blood vessels or adnexal structures. There is a wide variation in what is "wrong" with the immune system as well as what initiated the response. In some cases infectious agents such as bacteria or viruses may be the inciting etiology or the reaction may be in response to a drug. Some diseases, such as discoid lupus erythematousus and pemphigus erythematosus, are known to have a percentage of the cases photoaggraveted and control to UV exposure may alleviate or diminish the lesions and failure to control exposure may decrease the response to therapy. Therapies for autoimmune and immune mediated skin diseases often require immunonosuppressive or immunomodulating drugs. These drugs often effect different aspects of the immune response or function by different mechanisms. The differences between the diseases and treatments lead to variable responses to therapy with these drugs. There is no one routinely effective treatment and many different drugs and combinations of drugs may be used to manage these cases. The variable responses to treatment, expense of the drug or required monitoring and potential adverse effects all contribute to the treatment selected for each patient.

A specific diagnosis as possible should be made when using immune suppressive drug regimens. Even with a specific diagnosis there appears to be some controversy for some of these diseases regarding treatment success and the ultimate long-term prognosis of many of these disorders. For example in canine pemphigus, pemphigus vulgaris (PV) tends to be a more aggressive disease and more difficult to treat and manage than other forms of pemphigus. When pemphigus vulgaris occurs some cases are controllable but when it occurs as a result of a paraneoplastic syndrome it usually is non responsive and a fatal disease. Pemphigus foliaceus (PF) tends to warrant a better prognosis than pemphigus vulgaris but there is still variation in reported success. One report of 43 cases 39.5% were alive at the end of a 6-year study period. Of the dogs that had died 92% were dead by one year into treatment. Of these cases, 87% were euthanized due to drug side effects. These results are different from another report. Another study evaluated 91dogs with PF and had treatment follow up for 88 dogs with an average follow up of 18months. Only 12.5% had died while 46 were in remission and 31 significantly improved and one dog was completely tapered off drugs and stayed in remission. Eleven dogs were euthanized with 4 for refractory disease, 4 for unrelated problems, 2 for drug side effects and one the reason was unknown.

Since many patients are euthanized prior to reaching an acceptable level of improvement, the goal of therapy should not just be to stop the destructive immunologic response. Instead, the primary objective is to stop the inflammation and immunological destruction without causing side effects that the patient and client will not tolerate. This goal dictates how to approach the treatment of immune mediated skin disease and led to the following key principles of treatment as adapted for treatment of pemphigus from Griffin and Newton, 2011.

Key principles for treatment of immune mediated skin disease:

• Avoid doses of drugs that result in unacceptable side effects.

• Unacceptable side effects are partly determined by the client and the client's family.

• Severe cases initially need to be treated more aggressively.

• Combination drug therapy is generally more effective and has fewer side effects than monotherapy.

• Benefits are additive but differing side effects are not.

• Often not selected as the initial treatment because it is more costly than glucocorticoids alone.

• Mild or localized cases may initially be treated less aggressively.

• May mean relying on more topical therapy.

• Monotherapy with low immunosuppressive dose of glucocorticoids.

• When known, avoid triggering factors such as drugs or UV radiation.

• Persistent focal mild lesions should be acceptable only if their resolution requires higher drug doses that create more side effects or greater expense of therapy.

• Clients should be advised that some dogs may be cured or reach long-term remission, depending on the cause and even when no cause if found there may be some chance for cure, though controlled studies providing prognostic statistics are lacking for most immune mediated diseases.

• Three phases of treatment are typical for most immune mediated skin diseases:

      1. Induction of remission

      2. Transition

      3. Maintenance

Induction phase

The initial therapy used in treating pemphigus is selected to stop the inflammation and suppress the immunologic response against the epidermis. Higher doses of drugs are usually needed for this phase of therapy. If the induction therapy is not effective in a timely manner for the chosen class of drugs, then the induction treatment should be immediately changed. For example, if 2.2 mg/kg q12h of prednisolone is not effective within 7-10 days, then a different induction treatment should be selected. Patients treated with azathioprine alone should show a good response within four weeks. Good response during the induction phase is characterized by drying and resolution of erosions with no development of new pustules or erosions; crusts may still be present but generally are found in the hair rather than at the skin surface. Also, patients that start treatment depressed, febrile, or otherwise systemically ill should show great improvement in attitude during the initial induction phase.

Transition phase

This phase involves tapering the drugs used to minimize the long-term side effects, risks of adverse reactions and cost. When combinations of medications are prescribed, the first drugs to be tapered are those with greater likelihood of adverse effects. When control of the disease and side effects have reached levels acceptable to both the client and clinician, then tapering of more expensive drugs or drugs that require more monitoring expenses can begin. All medications are slowly tapered until there is a recurrence of clinical signs.

Maintenance phase

Maintenance is reached after recurrence or exacerbation of the disease occurs in the transition phase. Once recurrence is noted, medication doses are raised again sufficiently to reinduce remission and then doses are maintained at the level reached prior to the recurrence. Thus, maintenance doses are the lowest doses that result in a stable degree of disease that is acceptable to the client and clinician. After one year of maintenance therapy, tapering is repeated, and some cases may remain cured even though they had flared at the end of the transition phase.

Common Therapeutics

While awaiting for test results and it is common to use relatively benign and inexpensive drugs such as vitamin E, doxycycline or tetracycline and niacinamide. Though efficacy as a sole treatment is low these drugs do sometimes benefit cases, potentially more with vasculitis, pemphigus erythematosus and discoid lupus. If a blood parasite or infectious agent has triggered or initiated the immunologic disease then these treatments are also unlikey to aggravate them, may even effectively treat them and have few side effects. In addition with cases of pemphigus, especially erythematosus and lupus sun avoidance and or sunscreen use is recommended.

Tetracycline and Niacinamide

The combination of tetracycline and niacinamide has been used with variable success in dogs and humans with pemphigus. The author will commonly use this therapy but usually finds it an adjunctive therapy at best for the pemphigus complex but can be more beneficial for localized cases such as pemphigus foliaceus limited to the face or pemphigus erythematosus. It has its best success for cases of discoid lupus erythematosus with one report showing 70% success[3]. It has also been used in idiopathic sterile pyogranulomatous dermatoses, histiocytic dermatoses, vasculopathies, and lupoid onychodystrophy. Tetracycline has anti-inflammatory properties affecting complement activation, antibody production, chemotaxis, prostaglandin synthesis, lipases and collagenases. Niacinamide inhibits mast-cell degranulation and phosphodiesterase. Adverse reactions include vomiting, diarrhea, anorexia and increased liver enzymes. When gastrointestinal complications occur, discontinuing the niacinamide may reduce or eliminate these problems. In rare cases the tetracycline may still produce beneficial results. The dosage recommendations are 500mg of each drug q 8h for dogs weighing more than 10kg and 250mg q 8h for dogs weighing less than 10kg. Tetracycline can be replaced with doxycycline at 5mg/kg a 12h. Clinical response may take 1 –2 months. If clinical response is seen the frequency can be reduced to twice or even once daily.

Glucocorticoids

More localized forms of autoimmune disease and vasculitis can be treated with topical glucocorticoids. Topical therapy is typically used as an early treatment in cases with milder less extensive lesions, while awating test results and most often in conjunction with other systemic therapy for focal persistent lesions. When utilized a potent glucocorticoid is often needed initially and then if adequate response is seen switching to a less potent topical glucocorticoid is recommended. Long term daily use of more potent topical glucocorticoids can create atrophy, alopecia and localized pyoderma. Systemic absorption by percutaneous absorption or ingestion via licking is also a concern. Iatrogenic hyperadrenocorticism has been well documented with potent glucocorticoids

The most common form of therapy used in immune mediated skin disease is systemic glucocorticoid though most often they are used in combination with other drugs. Which type of oral glucocorticoid therapy is selected depends on the individual case response and the side effects seen in that particular patient. Most commonly prednisone or prednisolone is utilized at immunosuppressive dosages. Initial dosages at 2.2 – 4.4 mg/kg q 24h can be used. My preference is to use 1.1mg/kg q12h for 4 days then switch to 2.2mg/kg q 24 hour for 3-7 days and if a response is seen then begin tapering by lowering the q48h dose at four day intervals. There are some cases that will respond more favorably to methylprednisolone, triamcinolone or dexamethasone than supposedly equipotent doses of prednisone or prednisolone. The dosing and tapering regime is the same as for prednisone or prednisolone. Oral triamcinolone (Vetalog, Fort Dodge) or oral dexamethasone (Azium, Schering-Plough and generics) are alternative glucocorticoids that can be utilized in more refractory cases or in cases that have profound polyuria and polydypsia or other behavioral or personality changes. These glucocorticoids are considered to be 6-10 times more potent than prednisone or prednisolone. Induction dosages for immune suppression with these drugs range from 0.2-0.6mg/kg q 24h for triamcinolone and 0.2-0.4 mg/kg q 24h for dexamethasone. As with prednisone therapy these dosages need to be reduced gradually and eventually tapered to a q 48 h to q 72h basis. As these glucocorticoids suppress the hypothalamic-pituitary-adrenal axis for 24-48 hours, it is optimal to give these drugs every 72 hours for maintenance. However the author has had many cases do very well long-term on an every 48 hour basis as maintenance. Maintenance dosages range from 0.1- 0.2 mg/kg q 48-72h for triamcinolone and 0.05 - 0.1mg/kg q 48-72h for dexamethasone. In severe cases of pemphigus foliaceus or vulgaris, the author has on occasion given shock dosages of prednisolone sodium succinate (10mg/kg/IV) or dexamethasone (1mg/kg/ IV) . This can be performed as a one-time treatment or given two days consecutively. This can be followed with a modification of other oral glucocorticoid therapy. This form of therapy has a higher incidence of gastrointestinal ulceration, in particular gastric hemorrhage. Concurrent use of gastric protectants is usually recommended when this form of therapy is utilized.

Side effects are common with long-term oral glucocorticoid therapy. The most common seen include: poor dull scaly hair coats, muscle atrophy, polyuria, polydipsia, polyphagia, weight gain, behavioral changes, panting and increased risk for infections. Secondary bacterial skin and bladder infections are common. Demodicosis and dermatophytosis are also more frequent in dogs on chronic glucocorticoid therapy. Ongoing cases that flare during their course of management should always be rechecked and screened for these secondary opportunistic infections. Other skin changes include atrophic skin, calcinosis cutis, atrophic scars, comedones and "milia" follicular cysts. Less common side effects include: gastrointestinal ulcerations, diarrhea, and pancreatitis. Steroid hepatopathy is a major concern and is one of the most important organs to monitor in long-term cases. Other endocrine concerns include the development of diabetes mellitus, adrenal gland suppression and reduced thyroid hormone production.

Monitoring should include semiannual complete blood counts, chemistry profiles, and urinalysis and urine cultures. If cases are non-responsive to glucocorticoids, fail to control on safe alternative day to every 72 hour dosing or have undesirable side effects, alternative or concurrent immunosuppressive drugs are indicated.

Azathioprine

Azathioprine (Imuran, Glaxo Wellcome and generics) is the author's favorite and first choice immunosuppressive to use in canine pemphigus cases. It can also be used in a variety of other autoimmune diseases, sterile pyogranulomatous disorders, histocytic diseases and vasculitis cases. The author has not recognized any differences with brand name or generic therapy. There are anecdotal reports that generics have a higher incidence of idiopathic hepatic toxic reactions, but the author has not made this correlation. It can be used as a glucocorticoid-sparing agent in cases when glucocorticoids cannot be reduced to safe long-term levels, used in combination with glucocorticoids or other immunosuppressives in more refractory cases, or as a sole therapy. It is contraindicated in cats due to its more profound myelosuppression and potential for fatal reactions in cats. This may relate to the low levels of activity in cats of an enzyme called thiopurine methyltransferase (TPMT). A report suggests that there are variations in the activity levels of this enzyme between dog breeds, with Giant Schnauzers having much lower TPMT activity (and therefore being more susceptible to azathioprine adverse effects) and Alaskan Malamutes had much higher TPMT activity (and thus perhaps needing higher dosages of azathioprine) [. It is dosed at 1.5 – 2.5mg/kg q 24h - 48h. It is available is a 50mg scored tablet. It is an antimetabolite that interferes with the synthesis of nucleic acids and is cytotoxic to T cells. It has its greatest effect on T cell dependent antibody synthesis. It has a slow onset of action and usually takes 4-8 weeks to see clinical effects. Adverse reactions primarily include myelosuppression (lymphopenia, anemia and leukopenia) diarrhea and increased susceptibility to opportunistic infections when used long-term (pyoderma, demodicosis and dermatophytosis). The diarrhea that can be seen usually responds to dosage reduction, although it can be severe (hemorrhagic) and require drug discontinuation. Less common complications include vomiting, hepatotoxicity and possible pancreatitis. A rare azathioprine induced hepatotoxicity can be seen that usually responds to drug withdrawal. Dosage adjustments can be made based on the results of lab monitoring and clinical improvement. Starting at the lower end of the dosage range is generally recommended. Increasing the dosage after subsequent rechecks and lab monitoring can be performed as the case progresses. Complete blood counts with platelet counts are recommended every 2-3 weeks for the first 3 months of therapy. Initially periodic (every 2-3 months) monitoring of chemistry profiles is also recommended. Once cases are in remission monitoring can be reduced to every 6 months.

Chlorambucil

Chlorambucil (Leukeran, Glaxo Wellcome) is an alkylating agent that functions by affecting the cross linking of DNA. It is considered less toxic and slower acting than other alkylating agents. It is dosed at .1 -.2-mg/kg q 24h to 48h. It is available in a 2 mg non-scored coated tablet, making dosing in small dogs and cats easier. Myelosuppression is a concern and similar monitoring as listed with azathioprine should be performed. Other side effects include vomiting, diarrhea and anorexia.. The author will use chlorambucil in the canine as a glucocorticoid-sparing drug, as an alternative to azathioprine, in combination with glucocorticoids and azathioprine in more refractory cases or as a sole therapy in cases not tolerating other therapies. Indications are similar to azathioprine. It is also the authors' drug of choice in feline pemphigus when glucocorticoids do not work or are not tolerated .

Cyclosporine and Tacrolimus

Cyclosporine (Neoral, Novartis) and tacrolimus (Prograf oral formulation and 0.03% and 0.1% Protopic topical preparation, Astellas Inc) are immunosuppressant agents that have been used extensively in human medicine, primarily to prevent organ transplant rejection . However these drugs have also been evaluated for the treatment of autoimmune diseases. Both of these drugs work similarly, however tacrolimus is much more potent and the oral formulations appear toxic in the canine. Currently due to the much greater potency and potential toxicity of tacrolimus and lack of adequate dosing regimes, systemic administration is not recommended in canine clinical cases. Both drugs become activated by binding to specific intracellular receptors, called immunophilins. Cyclosporine binds to cyclophilin and tacrolimus binds to FK506-binding proteins. Both drugs inhibit calcium-dependent pathways, particularly affecting the enzymatic actions of calcineurin, a calmodulin-dependent protein phosphatase. This results in blocking of regulatory proteins that upregulate activation genes of T-helper inducer and cytotoxic cells. Of the cytokines affected Interleukin-2 (IL-2) is most notably affected, although many other cytokines are affected . The initial studies of cyclosporine in the treatment of pemphigus and other cutaneous autoimmune diseases in dogs and cats has not been impressive and only limited responses have been seen . However these early studies utilized older formulations of cyclosporine. The author has seen some more recent responses utilizing the microencapsulated formulation (Neoral, Novartis). It is dosed at 5-10mg/kg q 24h with ketoconazole 5mg/kg q 24h. It is also common to use cyclosporine in conjunction with oral glucocorticoids. However, it may be used as a sole agent or as a glucocorticoids sparing agent. The author has also used cyclosporine in combination with other immunosuppressive agents including azathioprine. In one study three cases of well-documented canine PF which were failures on other medications or had side effects were treated with Cyclosporine (Atopica®, Novartis Animal Health, Greensboro, NC) in combination with glucocorticoids, azathioprine and ketoconazole. Ketoconazole at 2.5 – 5 mgkg-1 q24h was utilized to increase serum levels of CsA. Induction dosages of CsA and AZA ranged from 7.5 to 8mg kg-1 q24h and 1.5 – 2.5 kg-1 q24h, respectively. All drug dosages were tapered as clinical response was seen, with maintenance CsA ranging from 2.5 – 5 mg kg-1 q48h, AZA 1.5 – 2.5 mg kg-1 q48h and ketoconazole 2.5 – 5mg kg-1 q48h. Glucocorticoids were completely stopped within 3 – 12 weeks after the addition of cyclosporine. All cases were in remission (10 -18 mo) with no clinicopathological abnormalities on the combined azathioprine, cyclosporine and ketoconazole protocol [20]. Cyclosporine is also available as a topical 0.2% ointment (Optimmune, Schering-Plough). The author and his associates have seen some adjunctive effects utilizing this ointment for localized forms of pemphigus. Even more impressive are the responses seen from the topical administration of 0.1% tacrolimus. In a study at the authors practice 10 cases of discoid lupus erythematosus (DLE) and 2 cases for pemphigus erythematosus (PE) were treated. Eight of the ten dogs of DLE and both PE cases improved with therapy. In 6/8 cases no other medications were used except the topical tacrolimus. No adverse reactions were noted in any of the cases.

Side effects seen with cyclosporine most commonly include anorexia, vomiting or diarrhea. More serious side effects are rarely seen. Other side effects reported in limited cases include weight loss, nephrotoxicity, gingival hyperplasia, papillomatosis, lymphoplasmacytoid dermatitis, neoplasia, hirsutism and involuntary shaking. In humans there is an increased risk for malignancy with cyclosporine use, especially skin neoplasia . In the canine there is one poorly substantiated report of lymphoma developing in a dog treated with cyclosporine for perianal fistulas after 4 weeks of therapy. Another report looked at correlations of cyclosporine for use in atopic dermatitis and development of mycosis fungoides and leukemia. There were no correlations made however the average length of therapy was only 4.3 months, too short of a period to evaluate long-term effects. Longer-term studies will need to be evaluated to properly address this concern. Drugs that inhibit the hepatic microsomal isoenzyme P-450 system, increase blood cyclosporine levels thus ketoconazole is commonly used concurrently with cyclosporine. It allows for a lower cyclosporine dosage and thus cost, making cyclosporine more cost effective.. Severe side effects have been seen in dogs with oral tacrolimus as a sole or combined therapy. These side effects include anorexia, vomiting, diarrhea, weight loss, impaired glucose metabolism, marked hepatotoxicity and infections. Some of the gastrointestinal side effects can be controlled by using gastric protectants. Other side effects seen in humans include nephrotoxicity, neurotoxicity and hypertension . The topical preparation appears very safe in the cases treated at the author's practice and no side effects have been seen. However there are recent concerns associated with increase risk for neoplasia in humans. This is currently being further evaluated and warnings have been placed on products regarding this concern. Because of these recent concerns the author recommends that owners when applying this product use gloves. Monitoring serum levels of both cyclosporine and tacrolimus have been evaluated. In the authors experience the serum levels of cyclosporine generally do not correlate with clinical responses. However there may be some limited value to monitor these levels when clinical responses are not seen. If levels are still in the low therapeutic range dosages could be increased in an attempt to obtain a response. When topical tacrolimus therapy was utilized in the author's practice, there was no correlation with serum or whole blood tacrolimus levels and clinical improvement or adverse clinical effects or laboratory abnormalities.

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