"Excuse me, but your basement membrane is showing": A review of common immune-mediated dermatoses (Proceedings)

While no day in veterinary practice is routine, there are weeks that are more filled with the usual offenders such as vomiting, diarrhea, and pets itching from allergies. You begin to yearn for an exotic diagnosis. In the dermatology world, diagnosing an immune mediated disease carries a sexier ambiance, shows your expansive knowledge, and gives you a swagger as you walk through the treatment room. Until, of course, your patient "crashes" from steroid side effects. This talk focuses on when to suspect an immune-mediated dermatosis, discussing the more common disorders, appropriate diagnostics, and therapy points.

What clinical signs (sort of) separate immune-mediated (IM) dermatoses from others?

          • Lesions focusing or starting on the face and / or feet

          • Very symmetrical lesions

          • New dermatosis in a pet over 3-4 years of age

          • Very aggressive or unusual lesions, especially if they do not respond to antibiotics

          • Concurrent mucosal and dermatologic lesions

          • Acute dermatitis while receiving a medication (secondary or drug-induced IM disease)

Diagnosing immune mediated dermatoses

There are some tenants of diagnosis common to IM dermatoses.

          • Biopsy of a primary lesion is key to making a diagnosis. Therefore, you have to have a clue what disease you suspecting and what its primary lesion is (e.g., primary lesion of pemphigus foliaceus is a pustule).

          • Good quality biopsies of representative areas, and as many as reasonable, are much more helpful in making a diagnosis than immunohistochemisty or immunofluorescence.

          • Biopsy more likely to yield a diagnosis if the pet is not receiving steroids or other immune suppressive therapy.

          • When taking punch biopsies, do not attempt "½ and ½." Center the punch over the suspected lesion. Wedge biopsies can include "normal" skin at the edges (which is often microscopically affected).

          • For lesions that are ulcerated and crusted, there may be secondary infection. This is not a good place to biopsy. The area of skin immediately adjacent to an ulcer is more likely to demonstrate the true pathology.

          • Specimens should be handled carefully and should be read by a pathologist with a special interest in dermatopathology. Give the pathologist a thorough history and clinical photos if possible.

Discoid Lupus Erythematosus (DLE)

DLE is listed in the derm "bible" as the second most common IM dermatitis in the dog. I am listing it first because I see more of this than pemphigus foliaceus (PF), what is accepted as the most common IM dermatitis. This disorder stays confined to the face, predominantly affecting the nasal planum, but there are reports of focal lesions on pinnae, lip margins, oral cavity, genitalia and distal extremities. We suspect this condition arises from a genetic predisposition and may be worsened by UV exposure. German Shepherds, collies, huskies seem predisposed.

Pathogenesis and primary lesion: IM destruction targeting the basal layer of the epidermis and the basement membrane zone. The early lesion of DLE is often depigmentation and loss of the normal architecture of the nasal planum (NP). As the condition progresses, there is ulceration and crusting. The dorsum of the NP is most often affected and the condition tends to "respect" the muco-cutaneous junction until later in the disease. In very severe cases, there is destruction of the rostal NP leading to arterial bleeding. Lesions often worsen after UV exposure. DLE is very rare in the cat.

Diagnosis Points: First, I recommend 3 weeks of cephalexin to rule out mucocutaneous pyoderma. If no improvement, then biopsy is indicated. NP biopsies require general anesthesia; you can easily take 4 – 6 mm punch biopsies from 2 or 3 affected areas. A diseased NP may not hold sutures well and I suggest using 3-0 or 2-0 suture on a taper needle.

Therapy points: Less severe cases of DLE may respond to tetracycline / niacinamide and / or topical tacrolimus. I have personally found oral cyclosporine to be effective in controlling DLE. Sun avoidance is important; I recommend sunscreen application daily when outdoors. Check out www.dognoseprotectors.com.

Systemic Lupus Erythematosus (SLE)

(A complete discussion of all clinical signs and the diagnosis of SLE are beyond the scope of this talk.) Pathogenesis, Primary Lesion and Clinical Signs: Approximately 50% of canine SLE cases have cutaneous signs. Because the etiology of SLE is multifactorial, the microscopic pathology and therefore clinical signs are quite varied. SLE can cause disruption of the basement membrane zone (hence bullae, vesicles, ulcers), and disruption in complement components (vasculitis). Multiple cellular and body sites are targeted. Cutaneous changes reported with SLE include mucocutaneous ulcerations; diffuse erythema, seborrhea, and / or alopecia; nasodigital hyperkeratosis; panniculitis, and vasculitis (ear tip necrosis; punctuate ulcers of foot pads and pressure points, ear magin necrosis). UV exposure often worsens lesions. SLE is rare in cats and cutaneous lesions present in fewer than 50% of the cases. Signs are varied but tend to commonly affect the face, where there is no favored body site in dogs.

Diagnosis Points: Diagnosis is difficult. If varied cutaneous lesion with histopathology consistent with lupus are present along with other systemic signs associated with SLE such as fever, polyarthropathy, hematologic alterations, protein-losing nephropathy, etc., the suspicion of SLE should be high. References site the ANA as the most sensitive test for SLE. Unfortunately this has not been my experience. Recent glucocorticoid therapy will cause false negative results. Infectious diseases and some medications will cause false positive results. Histopathology and ruling out infectious causes is recommended to lead to a presumptive diagnosis of SLE.

Therapy points: Same approach as for PF and severe cases of DLE – start with glucocorticoids and move on to cytotoxic immune suppressive agents if response to g-corts is inadequate.

Pemphigus Foliaceus (PF)

PF is listed as the most common IM dermatosis of dogs and cats.

Pathogenesis, Primary Lesion and Clinical Signs: PF is the result of antibodies targeting a protein in the intercellular "glue" of the epidermis (desmosomes). This causes nucleated keratinocytes to let go of each other,"rounding up" and resembling a fried egg, becoming an acanthocyte. This happens within an intracorneal pustule. So the primary lesion is a pustule. Lesions usually start on the head / face ± feet (including foot pad hyperkeratosis) and then progress to a generalized state. Some cases of PF have eosiniophil-laden pustules and are extremely pruritic. In cats, PF often targets nail beds and skin surrounding the nipples.

Diagnosis Points: Biopsy of primary lesion is usually diagnostic. Here's the catch: it can be very hard to find an intact pustule. Because of this, I often include crusts in the formalin jar to be examined by the pathologist. Often they see layers of old neutrophils + acanthocytes and keratinocytes, demonstrating waves of the disease. Occasionally I will make a diagnosis of PF based on cytology of a pustule if my clinical suspicion is very high. In cats, triamcinolone may be more effective than the prednisone family.

Therapy Points: In my experience, about ½ of my PF cases will relapse before I've reached an acceptable dose of corticosteroids. My next favorite immune suppressive therapy is azathioprine for dogs and chlorambucil for cats.

Pemphigus Erythematosus (PE)

Pathogenesis, Primary Lesion and Clinical Signs: To me, this disease, both clinically and histologically, is a cross between lupus erythematosus and PF. The immune system is targeting the basement membrane zone, the basal layer, and the intercellular desmosomes. This causes the pustular (and eventually crusting) lesions typical of PF but also the depigmentation and ulceration (and eventual crusting) of lupus. Like DLE, lesions are often confined to the face and affect the nasal planum, but it also affects the haired muzzle. It spares the oral cavity. PE is uncommon in cats but more common in dogs.

Diagnostic Points: Same advice as for DLE and PF. Additionally, a caution: the fungal infection Trichophyton mentagrophytes can mimic PE. Fungal culture and fungal stains of biopsy specimens should be done.

Therapy points: Some cases of PE are fairly mild and do not warrant systemic immune suppressive therapies. For these I start with tetracycline or doxycycline + niacinamide, vitamin E, and omega 3 fatty acids. If lesions are localized, topical 0.1% tacrolimus or topical corticosteroids (alclometasone preferred) can be effective. In theory, cyclosporine will help manage these cases.

Sterile Nodular Panniculitis

Pathogenesis, Primary Lesion and Clinical Signs: This is, in my experience, a somewhat common problem of dogs but more rare in cats. Its clinical presentation is very different from disorders that target the epidermis / epidermal – dermal interface. This is immune destruction of the SQ fat, so the primary lesion is a nodule where there is a healthy amount of fat (trunk, proximal extremities). The nodules often ulcerate and drain a clear to serosanguinous viscid fluid (liquefied fat). Some more severe cases progress to serpiginous ulcerations that resemble a burn. Lesions may be singular or multiple and vary in size. This may be painful and the patient may be febrile and anorectic.

Diagnostic Points: The primary lesion is deep and a wedge biopsy will be more demonstrative than a punch biopsy. It is also advised to do cultures for bacteria, mycobacteria, deep fungal organisms (if in fungal-endemic area), as well as making sure pathologist does special stains for infectious agents, including acid-fast staining. The primary differentials for this condition are infectious diseases (mycobacteria, atypical mycobacteria, fungi).

Therapy Points: Many cases, after control with immune suppressive medications, can be tapered drugs without relapse of the condition. Cases with marked ulceration will have scars. Milder cases may respond to tetracycline / niacinamide; cyclosporine may be effective. In cases of a singular lesion, surgical excision can be curative, though I warn the owner more lesions may develop.

Symmetric Lupoid Onychodystrophy (SLO)

Pathogenesis, Primary Lesion and Clinical Signs: This is a somewhat common condition of dogs of dogs. This condition is characterized histologically by lupoid changes at the claw matrix (i.e., damage of basal layer / basement membrane zone of the claw). This causes weakening of the attachment of the claw and sometimes intra-nail hemorrhage (purple color inside the claw. The first symptom noted in the acute phase is often sloughing of a claw. This may be interpreted as a "gee whiz" by the client but soon other nails start to fall off. Eventually most nails are affected. As nails regrow, they are misshapen, brittle, and soft. In my experience this is painful in the acute phase and less painful in the chronic phase (when there is regrowth of nails after initial sloughing). Dogs are otherwise healthy with no other dermatologic signs. Most cases of SLO are idiopathic; there are a few reports of SLO associated with food hypersensitivity, which makes us wonder if SLO should not be considered a diagnosis but rather a reaction pattern of the nail to various immunologic insults (such as drug reaction, food hypersensitivity, etc).

Diagnosis Points: 1) There are not many conditions that will cause "20 nail dystrophy" in an otherwise healthy pet than SLO. Infectious causes and neoplasia affected 1 or sporadic claws; if PF affects the nails, it will cause other dermatologic changes. 2) Diagnosis is made by amputating an affected P3 and submitting for histopath. 3) Every time I have done this, my path report reads: "changes consistent with but not diagnostic for SL)." 1+2+3 = I've stopped doing biopsies on these cases.

Therapy Points: The cornerstone of therapy is use of fatty acids (omega 3's and 6's). Cases that do not respond to FA's can be tried on tetracycline + niacinamide. There are reports of very refractory cases that are eventually treated by surgical removal of all nails. These dogs will respond to steroids but often the side effects are worse than the disease and surgery offers a chance to cure.

Points on clinical management of immune mediated diseases

The cornerstone treatment of most IM diseases is corticosteroid therapy. The initial dosing of steroids should be high (see table below) and should not be tapered until the disease is at least 75% improved.. My preferred tapering regime is to decrease the dose by about 25% every 2 weeks, with my first goal being to get to alternate day therapy to minimize side effects. I would rather have a patient on 40 mg of prednisone every other day than 20 mg once a day. Patients receiving higher steroid doses, especially daily, need to be monitored for UTI via urine cultures. Owners need to be instructed to monitor for signs of GI ulceration.

Some of my colleagues prefer to hospitalize patients and give very high doses of corticosteroids for the first five days (such as >/= 5 mg / kg prednisone) and quickly taper to alternate day treatment at 1 mg / kg or less.

If a patient relapses at greater than 0.5 mg / kg q 48 hrs of prednisone (or equivalent dose of stronger corticosteroid), or the patient has unacceptable side effects at this dose or lower, I will start add in cytotoxic agents such as azathioprine (dogs) or leukeran (cats). Cyclosporine is another less cytotoxic option (for both dogs and cats) but is expensive in larger dogs and has been associated with fatal toxoplasmosis in cats. Once I've started a steroid-sparing medication, after 3 weeks I again taper the steroid dose and / or frequency.

Selected References

Preziosi DE, Goldschmidt MH, Greek JS, et al. Feline pemphigus foliaceus: a retrospective analysis of 57 cases. Veterinary Dermatology 2003, 14, 313–321.

Blackwell Publishing Ltd.

Scott, Miller and Griffen: Small Animal Dermatology, 6th Ed. WB Saunders, 2001.

Morris DO. Immunomodulatory Drugs in Veterinary Dermatology. In Proceedings of the Western Veterinary Conference, 2004.