Heading into the unknown: autoimmune skin disorders (Proceedings)

The autoimmune skin disorders are a group of confusingly similar diseases. In this section the most common autoimmune skin diseases will be presented and they will be discussed from a clinical perspective. Most of the autoimmune skin diseases are treated similarly and this will be discussed in the last part of this section.

Clinical Presentation

Autoimmune skin diseases show great variation in cutaneous lesions; however, certain lesion patterns are consistently observed that include crusts, erosions, ulcers along with pustules, vesicles, bullae, and papules.

• Face - nasal planum, ear pinnae

• Foot pads

• Mucous membranes - oral, ocular, genital

Pemphigus Complex

Pathogenesis

Autoantibodies (usually IgG) are directed against components of the epidermal cell membrane responsible for cellular adhesion (desmoglein). The binding of anti-desmoglein antibodies initiates cellular events that eventually degrade the desmosomal components (cellular attachments) and results in acantholysis (release of the cellular attachments allowing the cells to float, or roundup, with subsequent cleft formation). Acantholytic cells (big, purple, fried egg cells) are immature, detached, keratinocytes that are the hallmark of pemphigus diseases. This is considered a Type II (Antibody-dependent) reaction with antibodies directed against tissue-bound antigens.

Pemphigus Foliaceus

• Most common autoimmune skin disease in small animals. Overrepresented in certain breeds, such as: Akitas, Chows, Dachshunds, Collies, ± Doberman Pinschers, Newfoundlands.

• Spontaneous form of the disease with no known cause.

• Drug/ tumor/ infection induced form - Some patients may have had chronic skin disease and thus have been exposed to many drugs in their past history.

     √ Lesions: Pustules and crusts that can wax and wane despite therapy

     √ Distribution: Nasal planum, pinnae, footpads, Can mimic pyoderma (pustules, crusts)

     √ ± pain/ pruritus - variable (not usually as pruritic as allergic patients).

     √ The pruritus is usually noted AFTER the development of crusted lesions, whereas an allergic patient is typically pruritic BEFORE the development of crusted lesions.

     √ Systemic signs uncommon

     √ Secondary pyoderma may be present, but the patient usually feels good

     √ Distribution may involve: Nasal planum - ± mucocutaneous junctions, Ear pinnae - not an otitis externa –lesions only affecting the pinnae, Footpads (hyperkeratotic) - may be the only sign.

     √ *oral mucosal involvement is usually not seen

     √ Diagnosis: Clinical signs- papules, pustules and crusts affecting primarily nasal planum, ear pinnae, foot pads

• Cytology - acantholytic cells, non-degenerate neutrophils; may observe bacteria (cocci)

• Histopathology - subcorneal vesicles or pustules containing acantholytic cells, neutrophils ± eosinophils

• CBC, Serum chemistries, UA – usually normal

• Occasionally some inflammatory changes will be present - hyperglobulinemia ± hypoalbuminemia, Leukocytosis due to neutrophilia. Antinuclear antibody test (ANA) - negative

Pemphigus Vulgaris

• No age, breed or sex predilections; rare disease with a very poor prognosis

• Oral lesions - High percentage of patients will present with oral lesions, often the chief complaint. Most severe form of because the lesions are deeper than those associated with Pemphigus foliaceus

• Primary lesions are rare - vesicles, bullae

• Secondary lesions are common - erosions, ulcers, crusts ± pain

• Deep lesions are painful and the secondary systemic signs are common due to the deep lesions and secondary infections (pyrexia, anorexia, depression).

• Sick animal on presentation

• Distribution may involve: nasal planum, ear pinnae, foot pads and the oral cavity (80% of cases)

• mucocutaneous junctions, claw folds, axillary and inguinal region—areas of friction especially.

• Diagnosis:Clinical signs - Erosions/ulcers affecting the nasal planum, ear pinnae, foot pads

• Oral lesions, mucocutaneous junctions along with axillary and inguinal areas

• Cytology - acantholytic cells, neutrophils, few bacteria

• Histopathology - suprabasilar vesicles or pustules containing acantholytic cells, neutrophils ± eosinophils

• CBC, Serum chemistries, UA, ANA - usually inflammatory changes associated with secondary infection; ANA - negative

Pemphigus Erythematosus

• Benign form of Pemphigus foliaceus with some similarities to Systemic Lupus Erythematosus

• ANA positive and UV aggravated similar to Lupus

• Lesions - similar to Pemphigus foliaceus

• Primary lesions are rare - papules and rare pustules

• Secondary lesions are common - erythema, oozing, crusts, scales, alopecia, erosions

• Depigmentation is common and typically occurs early in the disease process, thus photoaggravation contributes to some of the inflammation associated with this disease process.

• Distribution = Face and ears - only (typically lesions are not present on the body or feet)** Some cases will have the footpads affected only**

• Oral cavity is not involved

• Diagnosis: Clinical signs - Face only; Exclusion of other dermatoses - Pemphigus foliaceus specifically

• Histopathology - Subcomeal vesicles or pustules containing acantholytic epidermal cells, neutrophils ± eosinophils (± basement membrane changes similar to Lupus). ANA may be positive

Bullous Pemphigoid

Pathogenesis

Autoantibodies (usually IgG) are directed against a component of the hemidesmosome (Bullous pemphigoid antigen, BPAG). Activation of complement with subsequent cellular infiltration causes loss of dermo-epidermal cohesion followed by epidermal separation and vesicle formation. The cellular infiltrates are essential for the pathogenesis of the lesions (unlike Pemphigus). Idiosyncratic drug reactions may also play a role in the pathogenesis of bullous pemphigoid. Acanthylosis is NOT a feature of this disease process.

• Lesions: Deep (clinically identical to Pemphigus vulgaris). Primary lesions are rare - vesicles and bullae, Secondary lesions are common - ulcers, crusts

• ± systemic signs due to severity of lesions and secondary infection. Patient is usually sick.

• Distribution may involve:

• Nasal planum, ear pinnae, foot pads

• Oral cavity (80% of cases), mucocutaneous junctions similar to Pemphigus vulgaris

• Nail beds (claw folds), Axillary and inguinal region (friction), Footpads (ulcers)

• Diagnosis: Clinical signs along with exclusion of other dermatoses

• Cytology = purulent inflammation ± bacteria, no acantholytic cells (only in pemphigus complex)

• CBC/Serum Chemistry, UA, ANA

• Histopathology -large subepidermal cleft and vesicle formation. The entire epidermis separates from the basement membrane.

Lupus Erythematosus

Lupus erythematosus refers to a group of diseases with distinctly different clinical presentations, however the histopathologic findings and development of auto-immune disease are very similar. Typically these diseases are divided into those with systemic symptoms and a poorer prognosis, in contrast to those with only cutaneous involvement, which are considered more cosmetic diseases.

Systemic Lupus Erythematosus

Pathogenesis

SLE is a generalized connective tissue disorder involving many organ systems and characterized by presence of antinuclear antibodies. Nuclear antigens become recognizable by the immune system, which causes immune response and subsequent tissue damage via circulation of antigen: antibody complexes. Since these nuclear antigens are not limited to the skin and are present within all nucleated cells, all tissues and organ systems are possible targets of the autoimmune reaction (joints, skin, bone marrow, kidney, etc.). This is considered a Type III (Arthus) reaction.

SLE is considered to be an uncommon multi-system disease affecting dogs and cats.

Cutaneous manifestations - lesions are extremely variable, thus this disease can "mimic" many other diseases and is often challenging to diagnose. Animals can develop any kind of skin lesion from chronic, mild skin lesions to severe, deep and potentially life threatening disease.

Seborrheic skin disease, Alopecia, Diffuse or regional erythema (cutaneous flushing), Footpad ulcers and hyperkeratosis, Claw growth disorders – onychodystrophy, Panniculitis, Refractory secondary pyoderma, Gingivitis/ulcerative stomatitis, Vesicular/bullous skin disorders, Variable pruritus, Vasculitis, Oral lesions - common (similar to PV and BP)

Some animals do not have skin lesions at all.

• Diagnosis: Polysystemic signs

• Polyarthritis (nonerosive) - most common clinical sign

• Pyrexia –constant or cyclical

• Cutaneous lesions - second most common clinical sign ~80% of SLE patients eventually have lesions.

     √ Renal disease, glomerulonephritis

     √ Pericarditis, myocarditis, Pneumonitis, pleuritis, Polymyositis

     √ Neurologic disorders, Lymphedema

     √ RBC, WBC, platelet abnormalities, Bone marrow abnormalities

Patient is usually sick

• CBC/Serum chemistries/UA - Evidence of renal failure ± pancytopenia (or any single cell line), ANA usually positive.

• Histopathology - variable changes can be seen. The most consistent findings include hydropic degeneration of basal cells, interface (lichenoid) dermatitis, subepidermal vacuoles (bubbles), and pigmentary incontinence (the pigment leaks from the epidermis into the underlying dermis). Unfortunately, the biopsies may be nondiagnostic in chronic cases or those without skin lesions.

• American Rheumatism Association Guidelines: Modified criteria for diagnosis:

     √ Erythema, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorders, neurologic disorders, hematologic disorders, immunologic disorders, antinuclear antibodies.

          o 4 modified criteria experienced during any observation period = SLE

          o 3 modified criteria with positive ANA = probable SLE

          o Helpful, but use cautiously when diagnosing SLE in dogs.

Discoid Lupus Erythematosus

Second most common autoimmune disease

• Similar to Systemic Lupus Erythematosus - These diseases cannot be differentiated based on histopathology findings.

• Unlike SLE - No systemic signs; only skin (usually only on face like PE)

• Lesions: Most often limited to the nose - Nasal depigmentation, Erosions, ulcers, erythema, alopecia, scaling, ± scarring, Patient feels good

• Diagnosis: Clinical signs - nose (erosions, depigmentation)

• Exclusion of other dermatoses - CBC, Serum chemistries, UA, ANA without evidence of systemic abnormalities, ANA = negative

• Histopathology - variable changes can be seen. The most consistent findings include hydropic degeneration of basal cells, interface (lichenoid) dermatitis, subepidermal vacuoles (bubbles), and pigmentary incontinence (the pigment leaks from the epidermis into the underlying dermis). Unfortunately, the biopsies may be non-diagnostic in chronic cases.

Once suspected, diagnosing autoimmune skin diseases is somewhat similar

1. Skin biopsies are essential and are the ONLY method to definitively diagnose these diseases.

2. This is only 1 piece of the puzzle, in addition to cytology findings and lab work, in many cases.

3. Histopathology results: Provide the pathologist with a clinical description and list of differential diagnoses. If the biopsy report is not diagnostic, consider calling the pathologist to discuss rule-out list.

4. This process is not fail proof. If a diagnosis was not made, consider repeating the biopsy procedure, consulting a specialist, or refer the case.

5. DO NOT treat without a diagnosis - the animal may be treated for life with immunosuppressive medications.

6. False negative results for histopathology are often seen due to: Absence of recent lesions, improper selection and handling of biopsies, prior steroid therapy—avoid this!

Treatment of Autoimmune Skin Disorders

• Prognosis - variable

• Treatment must be individualized for each patient

• Some patients do not respond well to any treatment and will require life long therapy - relapses common

• Treatment may be worse than the disease...

• Symptomatic Therapy, Antibiotic therapy, High Dose Steroid Therapy

• NOTE: Autoimmune diseases wax and wane and will flare up occasionally. Often, the medication dosages can be maintained allowing disease to diminish on its own; however, sometimes, the dosages must be increased to suppress the signs (predicting is the tricky part). Pyoderma can mimic a flare-up and must be ruled out. Alternative glucocorticoids: triamcinolone, dexamethasone , however the disadvantages include side effects of these steroids are often intolerable to the owner.

• Chemotherapy Drugs - cytotoxic agents: Used to lower dose of steroids required to keep disease in remission—steroid sparing therapy.

Azathioprine (Imuran)

• Used in dogs to minimize the dose of other immunosuppressive medications, thus avoiding undesirable side effects.

• Disadvantages-myelosuppressive (monitor CBCs every 2 weeks initially)

• ***Do not use in cats (extremely hepatotoxic and myelosuppressive)

• Predictable toxicity: Bone marrow suppression – neutropenia; Hepatotoxicity - TMPT enzyme detoxification.

• Dosing: 1mg/lb/24 hours (2.2mg/kg /24 hours)Often dosed Q 48 hours

• Slow onset of action-expect 3-6 weeks for skin lesions to respond, however side effects may be noted as soon as 2 weeks, thus CBC should be monitored every 2-3 weeks.

Chlorambucil (Leukeran)

• Good choice for cats and side effects less common.

• Myelosuppressive (monitor CBC) and possible GI upset

• 0.05 – 0.1 mg/lb/24 hours (0.1 – 0.22mg/kg/ 24-48 hours)

Alternative treatment options:

Tetracycline and Niacinamide

• < 10 kg dog - 250 mg of each every 8 hours; > 10 kg dog - 500 mg of each every 8 hours

• Lag phase of 1-2 months, Doxycycline 5-10 mg/kg BID (every 12 hours) if twice daily dosing desired.

• Chrysotherapy - Gold Salt Therapy (Aurothioglucose, Solganol)

• Dosage Regimen: 1 mg/kg IM weekly until response (6-12 weeks) then, 1 mg/kg IM every 2 weeks for 1-2 mos. then 1 mg/kg IM every month

• Do not combine with Azathioprine, Long lag phase - concurrent steroids may be used

• Side effects in dogs and cats include: anemia, thrombocytopenia (fatal), drug eruption/TEN (fatal).

Cyclosporine

Treating autoimmune skin disease with cyclosporine seems to be less predictable than the treatment of allergic dermatitis. In the author's experience, approximately 50% of patients with a variety of autoimmune skin disorders respond to cyclosporine therapy. Despite this less than ideal response rate, the limited adverse effect profile of cyclosporine compared to immunosuppressive steroids and chemotherapeutic agents make cyclosporine an extremely attractive treatment option for long-term control of autoimmune disorders. **However, cyclosporine is not a good option for induction of remission. It appears to be a good adjunct therapy in order to reduce the dose of other, more toxic, drugs. **We do not have long-term data as of yet for this drug in dogs and cats.