Overview of the Issue

An immune-mediated disease is defined as a condition that lacks a definitive etiology but is characterized by inflammatory pathways resulting from, or triggered by, a dysregulation of the normal immune response.

Objectives of the Presentation

1.  To review common immune-mediated dermatologic diseases

2.  To review diagnosis and treatment options

Pemphigus Foliaceus

Pemphigus foliaceus (PF) is the most common disease that is part of the pemphigus complex. The complex is characterized by acantholysis, a breakdown of intercellular desmosomal components between keratinocytes.¹ In PF the major antigen targeted within the desmosome was originally thought to be desmoglein-1. More recently studies have shown that desmocolin-1 may also be a major autoantigen in PF.² PF can be triggered by an adverse drug reaction and there is also evidence to suggest that chronic skin disease, such as atopic dermatitis, can predispose to PF.³

Clinical signs include large, multi-follicle pustules and intense crusting. A facial presentation is the most common seen with PF including lesions on the nasal planum, dorsal muzzle, periocular region, and the pinnae. Lesions are most often symmetrical.¹ Occasionally the footpads can become hyperkeratotic and fissure. In cats, lesions are commonly noted around the nail beds as a sterile paronychia. The areolar region and the legs are more commonly affected in cats compared to dogs. A more generalized pustular form of the disease has also been documented. Pruritus with PF has been found to be variable depending on the individual.¹

Diagnosis

Cytology should be performed to diagnose any secondary infections. Acantholytic cells can be found on cytology but one must be aware that these cells are not pathognomonic for PF. Skin biopsy can provide a definitive diagnosis if lesions are selected appropriately.

If pustules are found on examination, these should be submitted as samples. Histopathology will reveal intra/subcorneal or intragranular pustules with acantholytic keratinocytes, “fresh” neutrophils and eosinophils.¹ Fungal stains will be negative and should be pursued to rule out trichophyton.

Treatment

The mainstay of treatment with PF is glucocorticoids administered at immunosuppressive dosages. These can then be tapered to the lowest effective dose that keeps clinical signs under control. If doses cannot be tapered or patients do not respond to glucocorticoids, then a second immunosuppressive agent should be added to the therapeutic regimen. Azathioprine (dogs), chlorambucil (dogs/cats) or mycophenolate mofetil (dogs) have been shown to be effective.^1,3 Cyclosporine is another treatment option. In this author’s opinion cyclosporine therapy is more effective in cats than dogs when treating PF. The prognosis for PF is fair. In a retrospective study by Gomez et al., the case fatality rate was 60.5%. Treatment times lasting more than 10 months correlated significantly with survival, as did the use of concurrent antimicrobials during initiation of immunosuppressive treatment.³

Discoid Lupus Erythematosus

Discoid lupus (DLE), is one of the forms of cutaneous lupus. This disease tends to be localized to the face and more specifically the nasal planum. In DLE, autoantibodies to antigens on epidermal basal cells are created leading to immune complex deposition at the level of the basal membrane.⁴

The age of onset for this disease is young to middle aged and no sex predilection has been documented. Dolichocephalic breeds are affected and some breed predispositions have been noted (German shepherd, Akita, Husky, etc.).⁴

Dogs can present with depigmentation of the nasal planum followed by a loss of cobblestone architecture, erythema, scaling, erosion, and ulceration. Lesions can extend up the dorsal muzzle and can sometimes affect the periocular region or the ear pinnae. Footpads are rarely affected.⁴

Diagnosis

Cytology in cases of DLE is unrewarding. Histopathology will show a lymphocyte-rich interface dermatitis with hydropic degeneration of basal cells and pigmentary incontinence. Both DLE and mucocutaneous pyoderma (MP) have overlapping histopathological changes so MP should be ruled out prior to beginning therapy for DLE.⁴

Treatment

DLE carries a good prognosis. Sunlight should be avoided to prevent UV damage to the skin. Treatment options can include systemic glucocorticoids, topical 0.1% tacrolimus, tetracycline/niacinamide, and vitamin E. Cyclosporine has been shown to be effective in some cases.⁴

Symmetrical Lupoid Onychodystrophy

Claw disease as the only manifestation of disease is uncommon and in one study accounted for 1.3% of dogs presented to a veterinary hospital.⁵ Symmetrical lupoid onychodystrophy (SLO) is a condition described in dogs. The exact cause and pathogenesis in unknown but based on response to therapy, an immune-mediated basis is suspected.

The disease is generally noted in young to middle aged dogs with no sex predilection. Predisposed breeds include German shepherd dogs and Gordon setters.⁵ Another common breed presenting with this disease is the Rottweiler. In a study by Wilbe et al., DLA class II alleles have been found in Gordon setters indicating a possible genetic predisposition.⁶

Dogs are otherwise healthy. In a retrospective study of 30 dogs and literature review, 17% of dogs with SLO were also diagnosed with hypothyroidism.⁷ It is thought that antithyroid antibodies could be binding to the claw matrix causing a lupoid reaction. Many patients in this study had well-controlled hypothyroidism prior to developing SLO so the direct association is not clear. This author continues to recommend thyroid evaluation in SLO patients. In the above study, there was one dog with a confirmed cutaneous adverse food reaction (CAFR), so CAFR have also been proposed as a possible factor in development of SLO.⁷ Dogs will show licking of the paws, dry/brittle claws, sloughing of claws, exudate from the claw bed, misshapen claws, and pain (lameness). It is common for dogs to have secondary infections at the claw base. A feature of the disease is that multiple claws on multiple feet will become affected.

Diagnosis

Cytology of the claw beds should always be performed to assess for any secondary infections. If digits are swollen, radiographs should be taken to rule out a tumour or boney changes. Thyroid testing may be indicated as well as a complete blood count and serum biochemistry as a baseline for overall health and prior to treatment.

Most dermatologists will diagnose SLO based on clinical signs, history, and examination. Very few diseases affect the claws and SLO should be at the top of your differential list if multiple claws are affected. The diagnosis of SLO can be confirmed via biopsy and histopathology if required. To collect a biopsy sample, the 3rd phalanx of an effected digit must be amputated so that the entire claw and base can be assessed. If possible, a dewclaw should be selected for biopsy. Histopathology will show a hydropic and lichenoid interface dermatitis similar to that seen in cases of discoid lupus. However, there is concern that these changes may be just a reaction pattern to an insult on the claw.

Treatment

Treatment options include supplementation with omega 3 and 6 fatty acids, tetracycline and niacinamide, cyclosporine, pentoxifylline and glucocorticoids.^5,8 Patients should receive pain medications if required and claws should be trimmed every two to three weeks. Improvement is generally noted within three to four months, at which time medications can be tapered to the lowest effective dose.

Each time the dose is tapered, no further adjustments should be made for at least six to eight weeks. At rechecks, new claw growth should be assessed by looking at the base of the claw.

Summary including 5 Key “Take Home” Points

1.  Immune-mediated disease is due to dysregulation of the immune response.

2.  Histopathology paired with clinical signs is the best way to diagnose an immune-mediated skin disease.

3.  Treatment is often long term if a trigger factor cannot be identified.

4.  Treatment revolves around either topical or systemic immunosuppressive/immunomodulating agents.

5.  Most immune-mediated dermatologic diseases are treatable.

References

1.  Miller WH, Griffin CE, Campbell KL. Muller and Kirk’s Small Animal Dermatology. 7th ed. Toronto, ON: Elsevier; 2013:438–448.

2.  Bizikova P, Dean GA, Hashimoto T, Olivry T. Cloning and establishment of canine desmocollin-1 as a major autoantigen in canine pemphigus foliaceus. Vet Immunol Immunopathol. 2012;149(4):197–207.

3.  Gomez S, Morris DO, Rosenbaum MR, Goldschmidt MH. Outcome and complications associated with treatment of pemphigus foliaceus in dogs: 43 cases (1994–2000). J Am Vet Med Assoc. 2004;224(8):1312–1316.

4.  Miller WH, Griffin CE, Campbell KL. Muller and Kirk’s Small Animal Dermatology. 7th ed. Toronto, ON: Elsevier; 2013:453–461.

5.  Miller WH, Griffin CE, Campbell KL. Muller and Kirk’s Small Animal Dermatology. 7th ed. Toronto, ON: Elsevier; 2013:731–739.

6.  Wilbe M, Ziener ML, Aronsson A, et al. DLA Class II alleles are associated with risk for canine symmetrical lupoid onychodystropy (SLO) PLoS ONE. 2010;5:e12332.

7.  Mueller RS, Rosychuk RA, Jonas LD. A retrospective study regarding the treatment of lupoid onychodystrophy in 30 dogs and literature review. J Am Anim Hosp Assoc. 2003;39:139–150.

8.  Ziener ML, Nødtvedt A. A treatment study of canine symmetrical onychomadesis (symmetrical lupoid onychodystrophy) comparing fish oil and cyclosporine supplementation in addition to a diet rich in omega-3 fatty acids. Acta Veterinaria Scandinavica. 2014;56:66.