Autoimmune skin diseases (Proceedings)

The diagnosis of ANY skin disease is based on detailed history taking, clinical findings (identification of primary lesions, distribution of lesions), laboratory testing and therapeutic trials. For autoimmune skin diseases (AISD) the most beneficial laboratory procedure is histopathologic evaluation. However even that can cause confusion if appropriate samples for histopathologic testing are not collected.

Pemphigus

In pemphigus, the immune system is directed to inappropriately attack the desmosomes. Desmosomes are spot like sites of intercellular contact and attachment between keratinocytes.

PF is the most common form of pemphigus and is probably the most frequently diagnosed autoimmune skin disease (AISD) affecting cats and dogs. Other forms of pemphigus that will be seen in practice include pemphigus erythematosus (PE) and panepidermal pemphigus (PPP). In general, PF is a disease of young to middle aged animals with a mean age of onset of 4 years old. Sixty five percent of the dogs have the disease before 5 years of age. PF has been reported in numerous breeds with Chow Chows and Akitas being at increased risk in the authors practice. There is no gender predilection in dogs.

In the author's experience even though there are three forms of PF reported in the literature- spontaneous pemphigus, drug-related (both drug induced and drug triggered) and a form that is associated with chronic skin disease, it is rare to have cases in which the dog has had chronic skin disease. In fact, there is no evidence to support that claim. Cases that occur spontaneously are by far the most common presentation.

Historically, the owner may report that the lesions that wax and wane, that the progression was slow (especially cases with only facial involvement) or the owner may report that the dog developed acute eruptions (most commonly associated with generalized disease). With the generalized form the dogs frequently will be febrile, may have limb edema and have constitutional signs. Pruritus with any form varies from non-existent to moderately intense.

There are 3 primary distribution patterns of PF -facial (most common) form which involves the bridge of the nose, nasal planum, periorbitally, pinnae (especially CATS); a footpad form (cats may present only with paronychia) and a generalized form where lesions usually begin on the face and then spread (note -there is a subset of dogs with generalized disease from the onset). The lesions progress from an erythematous macule⇒ pustule⇒ collarettes⇒ erosions ⇒ yellow brown crusts. Because there is involvement of the hair follicles, multi-focal to diffuse alopecia is frequently present. The primary lesions of PF are large nonfollicular pustules (there are also follicular pustules present) especially involving the bridge of the nose, footpads, nasal planum or pinnae (cats may have lesions around the nipples). This is in contrast to pustules associated w/a bacterial pyoderma which are follicularly oriented, usually involve the ventral abdomen and/or trunk and are much smaller. Secondary lesions w/PF are more commonly seen than the pustules in cats and dogs. These lesions include epidermal collarettes, yellow brown crusts and erosions. These animals may be systemically ill, have distal limb edema, fever, lethargy and/or lymphadenopathy.

Differential diagnosis would include any pustular, crusting and scaling disease such as: pemphigus erythematosus; zinc responsive dermatosis (especially with foot pad involvement); metabolic epidermal necrosis (especially with foot pad involvement); bacterial and fungal (dermatophytosis) infections; demodicosis, DLE (facial/nasal form); erythema multiformae; mycosis fungoides; Leishmaniasis; and sebaceous adenitis.

Diagnosis

A cytologic prep of a pustule or crust should be performed. Microscopic findings would include acantholytic keratinocytes, either individually or in clusters, surrounded by NON-degenerative neutrophils and/or eosinophils- bacteria should not be seen. Histopathology is the only definitive means to diagnose pemphigus. An intact pustule (or if none are present, a crusted lesion) should be biopsied. Proteases, from either bacteria present in a pyoderma or from a dermatophyte (Trichophyton mentagrophytes), can breakdown the intracellular glycoproteins (desmoglein) leading to acantholysis. Because these infectious diseases mimic PF histologically, you should request special stains for both bacteria (gram stain) and fungi (GMS, PAS) anytime a diagnosis of PF is made from a biopsy. The author routinely cultures for dermatophytes in all cases of "PF".

Prognosis

PF may be drug-induced or drug-triggered (i.e., the latent disease is unmasked by the drug exposure). The drug-induced form PF is caused by the drug and removal of the drug and short-term immunosuppressive treatment resolves the disease. Drug-triggered PF occurs when a drug stimulates a genetically predisposed individual to develop PF. Typically, this form of PF must be managed similar to idiopathic PF. Currently there is no way to identify which cases of drug related PF are drug induced and which ones are drug triggered. In fact there is no test that can be used to predict how well a case of PF will respond to treatment other than response to treatment itself.

A study at NCSU revealed that 6 of 51 dogs w/PF could be weaned off all medication and stayed in remission for >1 year. The author has seen many cases (that are NOT drug related) that when SLOWLY weaned off of medication stay in long term (life long) remission. This clinical observation is supported by a recent study in which 6 out of 51 dogs diagnosed w/PF were eventually able to develop to long-term remission, without drugs. Interestingly these dogs were from areas (NC or Sweden) w/high UV light exposure. In this group of dogs it took 1.5–5 months of therapy before the disease was remission. The drug(s) were then slowly tapered and then all therapy was stopped drugs. The total duration of immunosuppressive therapy varied between 3 and 22 months. These dogs stayed in remission for the entire follow up period (1.5–6 years after treatment).

A study performed at the University of Pennsylvania suggests that dogs with PF survived longer when given antibiotics (usually cephalexin) in addition to their immunosuppressive regimen. This is in contrast to the clinical observation that dogs w/PF don't develop concurrent pyodermas until AFTER being placed on immunosuppressive therapy. In addition, a recent study from CSU that reported no difference in survival when antibiotics were part of the initial treatment. In the study from University of Pennsylvania, survival rate was approximately 40% with 92% of the deaths by 1 year. They also reported that 10% of the cases went into long-term remission after weaning off medication. Other researchers report having a long-term survival rate of approximately 70%.

Cats may have a better prognosis than dogs with this disease. In the same report from the University of Pennsylvania, only 4/44 cats treated died (from their disease or therapy) during the study period. In the author's practice, survival at 1 year exceeds 90%. In addition a significant number of the dogs are eventually able to have all medications discontinued w/o subsequently having a relapse.

Treatment

Managing any AISD takes frequent rechecks and alertness to complications associated with immunosuppressive therapy such as demodicosis, dermatophytosis and bacterial pyodermas. Interestingly the author has rarely seen a dog w/PF that had a secondary pyoderma at initial presentation. It is more common to develop after beginning immunosuppressive therapy. If a patient was controlled and then has a relapse or a patient you getting trying to get into remission exacerbates there are really 2 possibilities. The PF (which does wax/wane) is flaring up OR another possibility is a secondary infection due to immunosuppression. If the new lesions are folliculocentric you must also rule the big 3 folliculocentric infections – bacteria, demodex and dermatophyte. Skin scrapings, Wood's light examination (screening test) and impression smears are the minimum that should be performed when the dog is presented w/these lesions. Whether or not you need to do a fungal culture at this time depends on the how frequently you see dermatophytosis in your practice and what is seen on cytology (acantholytic keratinocytes?, cocci?, demodex). If dermatophytosis is commonly seen in your practice then a fungal culture should be performed. Otherwise a fungal culture and a repeat skin biopsy can be considered a second tier test if the case is not responding appropriately.

In addition to the treatment options listed below, shampoo therapy should be included for symptomatic treatment of the crusting dermatitis. Since PF appears clinically the same as a superficial bacterial folliculitis, while awaiting the histopathology results, the author will also dispense cephalexin (10-15 mg/# bid-tid), unless there is a suspicion that it is a case of cephalexin induced PF.

There is no "best" treatment that works for all PF patients so treatment must be individualized for each patient. This is why it is critical to physically recheck the dog or cat prior to any adjustment in medication and to monitor the progress of the disease closely. When planning a treatment be sure to consider the severity of the disease so that the treatment is not worse than the disease.

There may be regional differences in how aggressively PF needs to be treated. Some of this may be due to the differences in the gene pools of the patients. But since PF is a sunlight aggravated disease it also may be related to the differences in sun exposure. Regardless, sun avoidance is part of the treatment for PF.

Because diet has been implicated as a cause of PF (endemic) in humans, the author will review the dietary history and consider dietary modification if the initial response to therapy is poor. The ingredients implicated in human endemic PF contain thiols (eg garlic, onion), isothiocynates (mustard, horseradish), phenols (food additives) and/or tannins (tea, bananas, apples). Vitamin E (400-800 IU bid) and Essential Fatty Acids may be used as part of the treatment since these nutrients have anti-inflammatory properties and anti-oxidant activities.

Glucocorticoids (GC) are the main stay of therapy for AISD. They may be applied topically or administered systemically depending on the severity of the disease and the amount of the body involved. Since some cats can't metabolize inactive prednisone to the active form, prednisolone, only prednisolone should be used in cats. In dogs either prednisone or prednisolone may be used. The author has seen cases of feline PF, which were well controlled on prednisolone, but when prednisone was dispensed relapsed, only to go back into remission once the cat was placed back on prednisolone- all at the exact SAME dosage.

The most potent topical GC (veterinary product) is a product containing fluocinolone acetonide (Synotic). For localized disease the author will use this product applied bid until clinical remission (not to exceed 21 days) and then tapered slowly over the next few months. Be sure to have the owners wear gloves when applying this product.

In dogs w/more extensive disease, prednisone or prednisolone is administered at 1 mg/# bid for 4 days then ½ mg/# bid for another 10 days. The dog is rechecked every 14 days. If the disease is in remission, the dose is decreased 25% every 14 days. The author defines "remission" as the absence of any active lesions (no pustules and any crusts are easily removed with the underlying epidermis appearing pink rather than erosive). Don't taper the dose too quickly. The goal is to maintain the dog on 0.25 mg/# or less every other day. If this is not achievable, then azathioprine is added to the therapy (see below). Some dermatologist will use the combination therapy from the onset, but because at least 75% of the dogs in the author's practice can be maintained on just GC and there are additional risks and costs associated with this drug. Only if the dog fails to respond to GC, or can't be managed with every other day administration, will azathioprine be added to the therapy.

For cats, only prednisolone is used and in fact only prednisolone is stocked in the author's pharmacy- this is to avoid the inadvertent administration of prednisone to a cat. Dose for the cat is 1 mg/# bid for 14 days. From that point forward the management of the cat with prednisolone is the same as the dog. If the disease is not controlled with prednisolone then chlorambucil (see below) is added to the therapy not azathioprine!!!

If an animal fails to respond to prednisolone other immunosuppressive agents (see below) will be added to the therapy

Animals on chronic GC, regardless of dose should have a CBC, serum chemistry profile, urinalysis and urine culture (monitoring for asymptomatic bacteriuria) every 6 months.

Azathioprine (AZA) is an antimetabolite that is a competitive inhibitor of purine. Purine is necessary for DNA formation, so in the presence of AZA, defective DNA is formed preventing cell replication. It has a lag phase of four to six weeks before it reaches its full effectiveness. The drug is administered concurrently with GC. The initial dose of azathioprine is 1.0 mg/# sid. Once remission is achieved, and the dog is either off of GC, or the lowest dose of GC has been obtained, AZA is then tapered every 60-90 days. Usually the author will decrease the frequency, not the dose of azathioprine, first decreasing it to every other day and then if the disease is still in remission, to every 72 hours. A CBC, platelet count, serum chemistry profile are performed every 14 days for 2 months, then q 30 days for 2 months then q 3 months for as long as the dog is on azathioprine. Potential adverse effects include anemia, leukopenia, thrombocytopenia, hypersensitivity reactions (especially of the liver) and/or pancreatitis. AZA should not be used in cats- it may cause irreversible bone marrow suppression.

Chlorambucil (CAL) is used in cats, in dogs who failure to respond to azathioprine or can't tolerate it. The protocol/ precautions/monitoring for CAL is the same as w/AZA. The induction dose is 0.1-0.2 mg/KG/day.

Because tetracycline and niacinamide (T/N) have a variety of anti-inflammatory & immunomodulating properties the combination has been used in treating a variety of immune mediated skin diseases, such as discoid lupus erythematosus, vesicular cutaneous lupus erythematosus (idiopathic ulcerative dermatosis of collies and Shelties), lupoid onychodystrophy, pemphigus erythematosus, German Shepard Dog metatarsal fistulae, sterile panniculitis, sterile periadnexal granulomatous dermatitis (idiopathic sterile granuloma-pyogranuloma syndrome), vasculitis, dermatomyositis and cutaneous histiocytosis. The author may use this combination for any of the previous mentioned diseases if the disease is relatively mild. If any of these diseases fail to respond well to immunosuppressive therapy, T/N may also be added to the therapy in dogs.

The dosage for tetracycline and niacinamide in dogs <10 kg is 250 mg of each, q 8 hours. For dogs >10kg - 500 mg of tetracycline and 500 mg of niacinamide q 8 hours are administered. If there is clinical response, which may take a few months, T/N are slowly decreased from tid, to bid to sid. Side effects are rare but when they occur as usually due to niacinamide. These side effects include vomiting, anorexia, lethargy, diarrhea and elevated liver enzymes. Tetracycline may lower seizure threshold in dogs. In cats doxycycline 5 mg/kg s-bid is use rather than tetracycline. If doxycycline is administered to a cat, be sure to use a liquid form or administer 5 cc of water after "pilling" the cat. Esophageal strictures have occurred as a sequele to doxycycline use in cats!!!

CSA, a calcineurin inhibitor, has been used orally at a dose of 5 mg/KG sid in cases of PF w/poor results in dogs. There have been anecdotal reports of successful treatment of PF in cats (especially nail bed form). Recently topical tacrolimus has been reported to be effective in the treatment of facial PF and PE. The author has limited experience with this product.

Specific treatment approach- for mild cases of facial PF (or cases of pemphigus erythematosus), a topical glucocorticoid is used and/or T/N. For generalized forms, or in cases with severe facial and/or footpad involvement, prednisolone should be used as described above. As long as the disease is in remission at each recheck, the steroids are tapered as previously described. If the disease is not in remission at the 14 day recheck or it can't be kept in remission with steroids at a dose of <0.25 mg/# q 48 hrs, then either azathioprine (dogs) or chlorambucil (cats) is added to the treatment.

If the disease is not responding to the above treatment, confirm that the diagnosis is correct (be sure to have ruled out dermatophytosis, demodicosis and bacterial pyoderma) then, changing to either dexamethasone or triamcinolone may be helpful. Use 0.05-0.1 mg/# bid as the starting dose and then taper as previously discussed.

As a "rescue" treatment for refractory cases of PF, high dose GC pulse therapy has been reported to be successful. Pulse therapy is followed by ½ mg/# bid of prednisolone and then taper as described previously. There are 2 protocols for pulse therapy:

     1. 11 mg/kg of methylprednisolone sodium succinate (mixed w/250 ml of D5W) IV sid x 3-5 days

     2. 11 mg/kg once daily for 3 days of prednisone orally

Discoid lupus erythematosus (DLE)

The approach to diagnosing DLE is the same as PF- signalment, detailed history, physical findings, histopathology changes and response to therapy. In the dog, DLE is the 2nd most common autoimmune skin disease. The author has never recognized it in a cat. It has been reported that there is no age predilection, but in the author's experience it seems to be more common in young to middle aged-dog. Collies, Shelties, German shepherd dogs, Siberian huskies and Brittany spaniels have been reported by some dermatologists to be at increased risk.

Clinical findings include depigmentation, erythema, erosions, crusts and alopecia. When the nasal planum is affected there is loss of its cobblestone appearance and it develops a slate gray appearance. DLE usually begins on the nasal planum and may process to involve the bridge of the nose. It may also involve the lips, periocular region, pinnae, and genitalia. Dogs affected with DLE are not clinically ill. Differential diagnoses would mucocutaneous pyoderma, pemphigus complex, cutaneous drug reaction, erythema multiformae, cutaneous lymphoma, uveodermatologic syndrome, SSC, solar dermatitis/collie nose and systemic fungal infections.

Mucocutaneous pyoderma (the author feels a better name is "antibiotic responsive dermatitis" since bacteria are not seen histologically) is a crusting disease that may affect the lips, nasal planum (exclusively), the bridge of the nose, periocular region, genitals or anus. Clinically it is indistinguishable from DLE. There is no identifiable cause for this disease and the diagnosis is based on the signalment (adult dog, most commonly in German Shepard Dogs (or mixes)), clinical appearance and distribution of the lesions and most importantly response to antibiotic therapy. In the past it was differentiated from DLE based on histopathologic findings. DLE was diagnosed when a lichenoid lymphocytic to lymphoplasmacytic interface dermatitis with hydropic degeneration and/or individual necrotic keratinocyte involving the basal cell layer, pigmentary incontinence and a thickened basement membrane was present. Mucocutaneous pyoderma would be diagnosed histologically when a lichenoid plasmacytic to lymphoplasmacytic infiltration was present without an interface change and without basal cell damage. However, this criterion has been called into question with a recent study that reported that histologically mucocutaneous pyoderma and DLE may be indistinguishable! In that study, dogs were separated, based on histologic findings, into 3 groups, ones with lymphocytic lichenoid interface dermatitis with hydropic degeneration; ones with plasmacytic lichenoid dermatitis, and lastly ones with a mixture of the first 2 patterns- lymphoplasmacytic lichenoid, interface dermatitis with hydropic degeneration. The authors then evaluated whether the group responded to antibiotics or immunomodulating therapy. There was no statistical difference when histopathologic features were compared between the 2nd and 3rd groups! The author now believes that all cases of canine nasal dermatitis should have a 30 day course of cephalexin prior to immunomodulating therapy- in fact prior to biopsy a 3-4 week course of a cephalosporin is appropriate and may establish a diagnosis without needing to biopsy the lesion!

Diagnosis

Dogs with DLE are clinically healthy and are normal hematologically and serologically (including a negative ANA). Historically the histopathologic changes consistent w/DLE included a lymphocytic to lymphoplasmacytic lichenoid interface dermatitis w/hydropic degeneration of basal keratinocytes. Scattered apoptotic keratinocytes may also be present.

Treatment

In treating dogs w/DLE it is important to recognize that it is primarily a cosmetic disease. Occasionally dogs will be pruritic and the lesions seem to bother the dog. It is therefore important to treat cases in proportion to the severity of the symptoms. Be sure that the therapy is not worse than the disease. The author treats this disease in a stepwise progression with each step added to the previous therapy except where noted. The steps are as follows: Cephalexin 10-15 mg/# bid- tid for 30 days (since DLE and MCP are indistinguishable); if the dog does not respond to the cephalexin, then the cephalexin is discontinued and the following treatment is begun, sun avoidance, sun screens and vitamin E and omega 3 fatty acids. Niacinamide and tetracycline are as begun as previously described. If after 60 days the dog doesn't respond to this treatment the next step is topical GC (beginning with a moderately potent GC). If after 60 days there is no response then stop the tetracycline and niacinamide and begin systemic prednisolone (anti-inflammatory doses) that is slowly weaned over a period of months to achieve the lowest possible dose.

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