Erosive and ulcerative stomatitis in dogs and cats: which immune-mediated diseases to consider?

Petra Bizikova Department of Clinical Sciences, North Carolina State University, Raleigh, NC

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 MVDr, PhD, DACVD, DECVD
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Keith E. Linder Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC

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 DVM, PhD, DACVP
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Jamie G. Anderson Veterinary Oral Medicine, Dixon, CA
School of Dental Medicine, University of Pennsylvania, Philadelphia, PA

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 DVM, MS, DAVDC, DACVIM

Abstract

Immune-mediated and autoimmune diseases of the skin often present with oral cavity involvement. Autoimmune subepidermal blistering diseases and pemphigus vulgaris are classic examples. While the primary lesions (vesicles and bullae) are relatively specific, these fragile lesions evolve rapidly into erosions and ulcers, which are lesion types that overlap with many diseases. Furthermore, some immune-mediated diseases such as severe adverse drug reactions, lupus diseases, canine uveodermatological syndrome, and vasculitis, may or may not involve the oral cavity, and often nonoral clinical manifestations are more diagnostic. In these situations, disease knowledge combined with signalment, lesion distribution, and history help to narrow the differentials. Surgical biopsy is required for confirmation in most diseases, while immunosuppressive treatments most typically involve glucocorticoids with or without nonsteroidal immunosuppressants.

Abstract

Immune-mediated and autoimmune diseases of the skin often present with oral cavity involvement. Autoimmune subepidermal blistering diseases and pemphigus vulgaris are classic examples. While the primary lesions (vesicles and bullae) are relatively specific, these fragile lesions evolve rapidly into erosions and ulcers, which are lesion types that overlap with many diseases. Furthermore, some immune-mediated diseases such as severe adverse drug reactions, lupus diseases, canine uveodermatological syndrome, and vasculitis, may or may not involve the oral cavity, and often nonoral clinical manifestations are more diagnostic. In these situations, disease knowledge combined with signalment, lesion distribution, and history help to narrow the differentials. Surgical biopsy is required for confirmation in most diseases, while immunosuppressive treatments most typically involve glucocorticoids with or without nonsteroidal immunosuppressants.

Introduction

Many autoimmune and immune-mediated skin diseases can manifest with oral lesions (Table 1). While the most commonly seen lesions are deep erosions and ulcers, ulcerated masses can also have an immune-mediated origin.1 Unfortunately, these lesions are not diagnostically specific and are found in physiochemical (eg, radiation, pressure/mechanical, heat, caustic chemicals), infectious (eg, bacterial, viral, fungal, protozoal), congenital (eg, epidermolysis bullosa), metabolic (eg, uremic ulcer), and neoplastic diseases. Information about the breed, age of onset, treatment response, lesion extent, symmetry, preceding primary lesions, and concurrent haired skin and/or systemic involvement will narrow the list of differentials and, potentially, prioritize autoimmune/immune-mediated origin. Nonetheless, histopathological confirmation is often required to confirm the final diagnosis. Proper biopsy site selection and elimination of secondary bacterial infection, which can cause nonspecific erosions and ulcers, are critical aspects of the diagnostic process.

Table 1

Selected diseases with oral cavity involvement and their main lesion types.

Oral lesion types
Species/diseases Vesicles, bullae Deep erosions Deep ulcer with stromal involvement Mass Preceding depigmentation Atrophy/scarring
Dog
   Oral EM X
   MCLE X X X
   VCLE Rare X X X
   UDS X X
   Pveg X X
   Ischemic dermatopathy X X X X
   CCUS X X
   Wegener’s granulomatosis X X X
Dog and cat
   AISDBs: BP, EBA X X
   AISBD: MMP X X X
   PV X X
   PNP Rare X
   SLE X X X X
   Vasculitis X X X
   Uremic ulcer X X
   Physiochemical X X X X
   EM, SJS, TEN Rare X
   Eos granuloma X
   CTCL X X X
Cat
   Chronic gingivostomatitis X X X
   Herpesvirus X X X
   Calicivirus X X

AISBDs = Autoimmune subepidermal blistering diseases. BP = Bullous pemphigoid. CCUS = Canine chronic ulcerative stomatitis. CTCL = Epitheliotropic lymphoma. EBA = Epidermolysis bullosa acquisita. EM = Erythema multiforme. Eos = Eosinophilic. MCLE = Mucocutaneous lupus erythematosus. MMP = Mucous membrane pemphigoid. PV = Pemphigus vulgaris. Pveg = Pemphigus vegetans. PNP = Paraneoplastic pemphigus. SJS = Stevens-Johnson syndrome. SLE = Systemic lupus erythematosus. TEN = Toxic epidermal necrolysis. UDS = Uveodermatological syndrome. VCLE = Vesicular cutaneous lupus erythematosus.

Preceding depigmentation means a depigmentation observed prior to the development of any other skin lesion types (ie, vesicles, erosions, ulcers). The readers should bear in mind that postinflammatory/postinjury depigmentation (not discussed in the table) is common in many of these diseases.

The primary focus of this review will be on autoimmune/immune-mediated skin diseases with frequent oral cavity (buccal mucosa, tongue, gingiva, palate, labia) involvement with or without additional haired skin lesions. In these diseases, detailed information about the clinical picture, diagnostic approach, and treatment will be provided. Autoimmune/immune-mediated skin diseases in which oral cavity involvement is rarely seen will be briefly summarized. Finally, recently published immune-mediated diseases involving the oral cavity such as chronic ulcerative stomatitis (CCUS) and Wegener’s-like granulomatosis (WG) in dogs, gingivostomatitis/caudal stomatitis in cats, and eosinophilic granuloma in both dogs and cats will be listed for comparative purposes but not be discussed.1

Blistering Autoimmune Skin Diseases

The blistering autoimmune skin diseases are those that target the adhesion between epithelial cells (pemphigus diseases) or between the epithelium and its supporting stroma (autoimmune subepidermal blistering skin diseases [AISBDs]) and result in the primary lesions of vesicles and bullae (Figure 1; Table 1). Due to their fragility, vesiculobullous lesions will rapidly progress into deep erosions and shallow ulcers. The roof of a recently ruptured vesicle may be seen as a residual epidermal or mucosal flap, which may be the only evidence of a vesiculobullous origin. Stromal injury (ie, dermis or lamina propria) is not typical, but it can be seen as scarring in more chronic disease variants such as mucous membrane pemphigoid. Secondary infection can extend to the connective tissues and complicate the lesion’s appearance. Vesicles and bullae are particularly transient in the oral cavity due to constant movement and mechanical friction. While oral lesions are common, and often the first to be detected, most of these diseases will also exhibit lesions on mucocutaneous junctions, haired skin, and/or pawpads (Table 2).

Figure 1
Figure 1

Examples of lesions in various autoimmune/immune-mediated skin diseases in dogs. A—Buccal mucosa of a dog with autoimmune subepidermal blistering disease with intact vesicles (white arrows) and multifocal, recently ruptured vesicles with deep erosions and mucosal epithelium remnants (flaps) at the periphery (black arrows). B—A large deep erosion/shallow ulcer on the buccal mucosa and gingiva of a dog with epidermolysis bullosa acquisita. No overt stromal involvement can be appreciated clinically (courtesy of Dr. Natalie Gedon). C—Large, well-demarcated (punched-out) ulcer with stromal involvement in a dog with vasculitis. Smaller ulcers can be appreciated at the periphery. D—Diffusely eroded buccal mucosa and gingivae with a fibrin pseudomembrane (arrow) mimicking a recently ruptured vesicle in a dog with oral erythema multiforme.

Citation: Journal of the American Veterinary Medical Association 261, S1; 10.2460/javma.22.12.0573

Table 2

Selected diseases with oral cavity involvement and their lesion distribution.

Lesion distribution
Species/diseases Oral cavity Mucocutaneous junctions Haired skin
Dog
   Oral EM X X
   MCLE Rare X
   VCLE Rare Rare X
   UDS Uncommon X X
Pveg Variable Variable X
   Ischemic dermatopathy Uncommon X X
   CCUS X
   Wegener’s granulomatosis X
Dog and cat
   AISDBs: BP, EBA X X X
   AISBD: MMP X X Rare, minor
   PV X X X
   PNP X X X
   SLE X X X
   Vasculitis X X X
   Uremic ulcer X
   Physiochemical Depends on the source
   EM, SJS, TEN X X X
   Eos granuloma X X X
   CTCL X X X
Cat
   Chronic gingivostomatitis X
   Herpesvirus Uncommon X X
   Calicivirus X X

See Table 1 for key.

Pemphigus diseases

The classification of pemphigus depends on the depth of the blister formation, whether it is superficial pemphigus (ie, pemphigus foliaceus) and deep pemphigus (ie, pemphigus vulgaris, pemphigus vegetans, and paraneoplastic pemphigus). Only deep forms of pemphigus cause oral cavity lesions. Pemphigus foliaceus, in contrast, can present with perioral haired skin and nasal planum lesions, but involvement of the oral cavity is not a feature.2,3 All forms of deep pemphigus are very rare.4

Pemphigus vulgaris—Pemphigus vulgaris (PV) is a rare autoimmune disease of dogs and cats caused by anti-desmoglein-3 autoantibodies disrupting the adhesion between epithelial cells in the deep portion of the mucosa and skin. Vesicles and bullae are fragile and transient and quickly evolve into deep erosions or shallow ulcers. The disease onset is rapid or gradual and nonspecific systemic signs such as fever, hypo/anorexia, and lethargy are common. The oral cavity, in particular the gingiva and palate, is the most commonly affected body area, and, in rare patients, it may be the only affected area.4 Indeed, the most recent review4 reported an oral cavity involvement in 92% and 100% of dogs and cats with PV, respectively. Lesions are often symmetrical in their distribution, which is particularly noticeable on the haired skin (ie, paws, friction areas of axillae and groin, pinnae, etc).

In cats and dogs with intact vesicles or bullae, differential diagnoses include AISBDs (eg, mucous membrane pemphigoid, epidermolysis bullosa acquisita, or bullous pemphigoid), paraneoplastic pemphigus, and, in cats, also vesicles of calicivirus infection. Physiochemical burn and congenital blistering diseases with genetic mutations in adhesion proteins also cause blister formation. Exposure history or onset shortly after birth are clues in these situations. If only deep erosions/shallow ulcers are detected, then the differentials need to be expanded to other erosive/ulcerative stomatitides such as infection, oral erythema multiforme, CCUS, WG, gingivostomatitis/caudal stomatitis, etc. Biopsy is necessary to confirm the final diagnosis. Three to 5 (6- to 8-mm) punch and/or wedge biopsy samples should be collected from intact vesicles or from the margins of erosions (Figure 2). Selection of the technique depends on the lesion type and its size. For example, if an intact vesicle is too large to fit into a punch biopsy, an excisional wedge biopsy is recommended to collect the vesicle in its intact form with a small amount of a nonlesional skin/mucosa around it. Also, a wedge biopsy is often preferred for margins between eroded and intact skin/mucosa and in areas in which a circular excision would be more difficult to suture.

Figure 2
Figure 2

Examples of sites of biopsies depending on the lesion types. A—A punch biopsy (circle) of the entire small vesicle with adjacent mucosa to maintain the vesicle intact or a wedge biopsy (oval) of an erosion margin to capture the intact mucosa at the junction in a dog with an autoimmune subepidermal blistering disease. B—A wedge biopsy (ovals) at the junction of intact mucosa and erosion in a dog with vesicular cutaneous lupus erythematosus (courtesy of Dr. Natalie Gedon). C—A deep, punch biopsy (circle) of the entire ulcer or a large wedge biopsy (oval) that includes the deep ulcer center and the adjacent intact mucosa, if vasculitis is suspected. D—A wedge-shaped excisional biopsy of the ulcerated tongue (triangle) in a dog with vasculitis in an attempt to capture the injured vessels in the deep central area.

Citation: Journal of the American Veterinary Medical Association 261, S1; 10.2460/javma.22.12.0573

Treatment of canine and feline PV follows the general principles of immunosuppression outlined (Table 3). Immunosuppressive dosages of glucocorticoids are used until disease control is achieved. The dose is then gradually reduced (∼25% every 2 weeks). A nonsteroidal immunosuppressant is usually added early to act as a steroid-sparing agent or to replace glucocorticoids eventually. Various nonsteroidal immunosuppressants have been reported to control canine PV (eg, azathioprine, ciclosporin, cyclophosphamide, chlorambucil, aurothioglucose, oclacitinib), with azathioprine being the most frequently reported.4,5 Information about nonsteroidal immunosuppressants in feline PV is limited.

Table 3

General principles of immunosuppression and most commonly used immunosuppressants in dogs and cats with autoimmune/immune-mediated skin diseases.

Control/phase Glucocorticoids Nonsteroidal immunosuppressants
Disease control A period of intense therapy aimed to suppress the disease activity. As a result, new lesions cease to form, and old lesions start to heal.

Predniso(lo)ne*: 2–4 mg/kg/day

Triamcinolone: 0.2–0.6 mg/kg/day

Dexamethasone: 0.15–0.3 mg/kg/day

Azathioprine: 2 mg/kg/day (dog)

Ciclosporin: 5–8 mg/kg/day (dog); 5–10 mg/kg/day (cat)

Chlorambucil: 0.1–0.2 mg/kg/day to every other day (dog, cat)

MMF: 10–15 mg/kg twice a day (dog)

Oclacitinib: 0.6–1 mg/kg twice a day (dog)

Doxycycline (or minocycline) with niacinamide: 5 mg/kg and 250–500 mg/dog twice a day (dog)

Leflunomide: 2 mg/kg/day (dog); 2 mg/kg/day 2 days, then every other day (cat)

Consolidation phase Maintenance of the intense therapy until the majority (> 80%) of old lesions are healed and no new lesions are formed for the past 2 weeks.
Maintenance phase Gradual dose reduction until the lowest dose necessary to prevent disease activity is found or until drugs are completely stopped. Start with glucocorticoids. Dose reduction of about 25% every 2 weeks. Adjust the speed of reduction based on the disease activity and patient’s tolerance.

Dosages in table represent initial dosages used in autoimmune/immune-mediated skin diseases.

MMF = Mycophenolate mofetil.

*

Prednisolone in cats.

Pemphigus vegetans (Pveg) is an extremely rare form of PV with only a few veterinary cases reported so far, all of which were in dogs (reviewed by Tham et al).4 The best-documented case of canine Pveg exhibited deep erosions of the oral cavity, prepuce, and anus. Additionally, vesicles and pustules were seen on the abdomen, groin, and feet, while verrucous hyperkeratotic papules were found in the axillae and concave pinnae.6 Oral cavity involvement, however, was not seen in other cases. Biopsy from intact vesicles, margins of erosions, or the center of the hyperplastic and crusted lesions is necessary to confirm the final diagnosis. Treatment of canine Pveg follows the same principles as that of PV.

Paraneoplastic pemphigus—In people, paraneoplastic pemphigus (PNP) is a rare autoimmune blistering skin disease often associated with hematologic malignancies.7 Only 3 canine cases associated with thymoma, metastatic thymic lymphoma, and undifferentiated splenic sarcoma and 1 feline case with thymoma have been published (reviewed by Tham et al).4

Autoantibodies target keratinocyte-associated adhesion proteins (desmogleins, desmocollins, and plakins) and cytotoxic CD8+ lymphocytes cause epithelial cell death to induce lesion formation. Commonly seen lesions are extensive deep erosions/ulcers of the mucosae, oral cavity particularly, mucocutaneous junctions, and friction areas of haired skin. Intact vesicles/bullae are rarely captured. In 1 of the 3 dogs, only oral cavity involvement was reported (reviewed by Tham et al).4 In contrast, the single feline case only exhibited haired skin erosions.8 Nonspecific systemic signs are lethargy, hypo/anorexia, fever, and/or weight loss. Relevant differential diagnoses include PV, erythema multiforme, and AISBDs. Severe drug reactions (ie, Stevens-Johnson syndrome and toxic epidermal necrolysis) are considered less a relevant differential due to the lack of preceding acute-onset erythroderma, severe systemic involvement, and rapid progress.

The diagnosis of PNP is based on classic histopathological features and confirmation of a concurrent malignancy. Treatment and outcome information for canine PNP are lacking; in people and 1 cat, successful management of the malignancy and immunosuppression with glucocorticoids, with or without adjuvant nonsteroidal immunosuppressants, have shown promising outcomes.7,8

Autoimmune subepidermal blistering diseases

The main pathomechanism of AISBDs is an antibody-mediated attack on proteins in the basement membrane zone (BMZ), which is a complex adhesion structure between the epithelium and supporting stroma (ie, dermis, lamina propria).9,10 The 3 most common AISBDs in dogs and cats are mucous membrane pemphigoid (MMP), epidermolysis bullosa acquisita (EBA) and bullous pemphigoid (BP).9,10 Other rare conditions of this disease group include junctional EBA, mixed AISBD, linear IgA bullous disease, and bullous systemic lupus erythematosus. All AISBDs are known to cause vesiculobullous eruptions in the oral cavity, which rapidly progress to deep erosions and ulcers (Tables 1 and 2).10 Only MMP is predominately a disease of mucosae and mucocutaneous junctions, with oral cavity and lips being the most common. The remaining AISBDs will also present with lesions on haired skin.

While MMP can be diagnosed based on clinical and histopathological features alone, differentiation of the other AISBDs also requires confirmation of the depth of the dermo-epidermal separation and identification of the targeted protein (eg, by direct immunofluorescence, indirect immunofluorescence on salt-split mucosa, collagen IV immunohistochemistry, antigen-specific assays, etc). Unfortunately, no laboratories currently offer such immunotesting commercially and the diagnostic ability of veterinarians to further classify these cases is limited. As a result, the majority of recently published cases lack antigen confirmation and are correctly reported as AISBDs without further specification. While this limits further understanding of these diseases, it does not prevent clinicians from treating their patients. Indeed, the treatment approaches follow the general principles of immunosuppressive therapy and are similar among the different AISBDs in dogs and cats.10 This review will be limited to MMP only due to its predominantly mucosal and mucocutaneous junction involvement. Detailed information about other AISBDs, which usually present with both mucosal and haired skin lesions, can be found in a recent comprehensive review article.10

Mucous membrane pemphigoid—Mucous mem­brane pemphigoid, while rare, is the most common AISBD in dogs and cats.9,10 It is characterized by mucosal and mucocutaneous junction-dominant blistering lesions resulting from an autoantibody-mediated attack on BMZ proteins such as laminin-332, BP180, and/or BP230. Initial vesicles/bullae rapidly evolve to deep erosions/shallow ulcers. The oral cavity is the most commonly affected body area, specifically the gingivae and hard and soft palate. It can be the only area affected. Other commonly affected sites include the nasal planum and lips. Haired skin involvement, if present, is often detected on the concave pinnae. This was seen in about a third of MMP-affected dogs.11,12 Other haired skin areas, often pressure/trauma-prone areas, are involved less frequently and the severity and extent of the lesions are usually minor.11,12 Lesions are usually symmetric. Nondermatological signs such as lethargy, hypo/anorexia, and/or pain are reported in about half of the affected dogs and cats and are usually mild. In contrast to other blistering diseases of the oral cavity, MMP is more chronic with a waxing-and-waning course. Lesions often recur at the same locations, which can lead to scarring.

In patients with intact vesicles/bullae, relevant differential diagnoses include PV and PNP. Additionally, calicivirus should be considered in cats. As always, the list is longer in patients presenting only with deep erosions/shallow ulcers.

The diagnosis of MMP requires histopathological confirmation of a separation between the epithelium and supporting stroma (lamina propria or dermis) in a patient with the mucosal and mucocutaneous junction-dominant disease. Lesions suitable for biopsy are similar to those listed in the blistering diseases above (Figure 2). Because canine and feline MMP is immunologically heterogeneous, advanced immunotesting is not necessary to confirm the diagnosis.9,10

Treatment of MMP follows the general principles of immunosuppressive therapy applicable to other autoimmune skin diseases (Table 3). The owners should be warned that induction of disease control can be slow and flare-ups frequent. In 2 larger case series, tetracycline antibiotics and niacinamide alone, or in combination with a glucocorticoid or nonsteroidal immunosuppressant, were the most common drug combinations leading to disease control.11,12

Autoimmune/Immune-Mediated Diseases with Cytotoxic Tissue Patterns

In these diseases, cytotoxic lymphocyte-mediated attack leads to surface epithelial cell necrosis. As such, these diseases present with primary erosive mucosal and/or skin lesions with only rarely visible flaccid vesicles. Depigmentation, erythema, and/or loss of mucosal/epidermal surface architecture may be observed (Table 1). Stromal injury is not a feature.

Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis

Cytotoxic attack on epithelial cells by lymphocytes induces lesion formation in all 3 of these diseases. Erythroderma is often the only lesion before epithelial sloughing results in deep erosions.13 Canine and feline Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) and their overlap (OVE) syndrome are usually severe adverse drug eruptions that present true dermatological emergencies due to their rapid progression and severe systemic signs related to the epithelial loss (ie, hypothermia, dehydration, hypoalbuminemia/hypoproteinemia, sepsis, etc). Affected animals exhibit acute-onset, painful, nonpalpable lesions consisting of erythematous macules, patches, and/or more diffuse regions of erythroderma, which rapidly progress to deep erosions. Erythroderma involves > 50% of body surface area (BSA) and the degree of epithelial detachment dictates the diagnosis (SJS < 10%, OVE 10 to 30%, and TEN > 30% of BSA).13 Erosions can be created by physical friction of the erythematous skin (ie, positive pseudo-Nikolskiy sign). Mucosae, especially the oral cavity, are frequently affected. Cases without mucosal involvement have been reported in people and animals.14,15 The mortality rate is high and correlates with the percentage of epithelial detachment; shock and sepsis are common causes of death.13 Various drugs have been implicated (ie, trimethoprim-potentiated sulphonamides, cephalosporins, penicillin, levamisole, diethylcarbamazine, phenobarbital, flea dips, cannabidiol-containing hemp oil product)13,14,1618, although the causality was not always well documented. Infectious triggers are rare.13,14,19

Considering the acute erythroderma, epithelial detachment without stromal involvement, and marked systemic signs, clinically relevant differentials include PNP, severe PV, AISBDs, toxic shock syndrome, Sweet’s-like syndrome, and sterile pustular erythroderma of miniature schnauzers.

While erythema multiforme (EM) in people is considered to be a separate disease entity from SJS and TEN, this distinction has not been well-documented in veterinary medicine, mainly because classic target lesions are rarely seen in animals and because histopathology has played an outsized role in diagnosing canine and feline EM.13 Indeed, depending on the biopsy site, histopathological changes of SJS and TEN may overlap with those of EM, and, therefore, histopathology alone cannot be used to distinguish EM from SJS and TEN.14 The potential triggers are more speculative and include drugs or, less often, infectious agents, or neoplasia.19,20 The spectrum of skin lesions reported in dogs and cats with EM includes discrete, round, ovoid, or serpiginous, palpable or nonpalpable erythematous lesions with central deep erosions/shallow ulcers. Crusting is variable and rare canine EM cases may exhibit marked hyperkeratosis.13,19,21 The trunk, in particular the axillae and groin, is commonly affected, as is the oral cavity and/or other mucosae and mucocutaneous junctions. Epithelial detachment is below 10% BSA in both EM minor and major and erythroderma, if present, does not exceed 50% of BSA. The number of mucous membranes (MM) involved differentiates between EM minor (≤ 1 MM) and EM major (> 1 MM).13,19 Exclusive oral cavity involvement has been reported under the name of oral EM, an entity that is also recognized in people.22,23 Systemic signs are absent or mild and the disease may exhibit slower progression.

For EM, clinically relevant differential diagnoses depend on the EM phenotype. For example, differentials for oral EM include PV, PNP, MMP, CCUS, vasculitis, or epitheliotropic lymphoma, while more generalized erosive variants also include other AISBDs, most forms of cutaneous lupus erythematosus, or even necrolytic migratory erythema. Differentials for proliferative and hyperkeratotic variants are still more numerous.13,24 In cats, thymoma-associated exfoliative dermatitis, calicivirus, herpesvirus stomatitis/dermatitis, and chronic gingivostomatitis/caudal stomatitis should be also added to the list.1,13

Confirmation of the diagnosis of EM, SJS, and TEN is based on a combination of clinical signs and histopathologic confirmation of lymphocyte-mediated cytotoxic dermatitis/mucositis. Multiple, 6- to 8-mm punch biopsies from erythematous erosion margins are ideal. Central areas of erosions are nondiagnostic, because the epidermis/mucosa with its diagnostic changes is lost.

Clinical management depends on the underlying cause (infection, drug reaction, idiopathic) and the disease severity. In milder cases of EM, the elimination of the trigger may result in spontaneous remission. More persistent EM cases require immunosuppression in addition to trigger elimination. Glucocorticoids alone or in conjunction with nonsteroidal drugs such as ciclosporin, oclacitinib, or azathioprine have shown efficacy.13,25 Some EM cases, hyperkeratotic and oral forms particularly, tend to flare once medications are tapered and may require long-term treatment.13,25 The prognosis is generally good and remission of the skin lesions with proper immunosuppressive treatment is expected. As the trigger is often unknown, a slow gradual withdrawal of the immunosuppressive treatment, once remission is induced, should be attempted.

In cases of SJS and TEN, an intensive supportive treatment (ie, pain, fluid, and electrolyte replacement, prevention of hypoalbuminemia, thermoregulation, nutrition, prevention of sepsis, wound care, etc) and elimination of the trigger are as important as the immunosuppressive treatment aimed to deactivate the lymphocyte-mediated epithelial damage. Due to these demands, rapid referral to a hospital intensive care unit is essential. Prognosis is guarded and the mortality rate is high, especially in cases of OVE and TEN.13,14

Lupus erythematosus

The current classification of cutaneous manifestations of lupus erythematosus in people has been recently adapted for dogs.26,27 This classification recognizes 2 main groups: (1) systemic lupus erythematosus (SLE), which can present with or without skin lesions, and (2) lupus erythematosus-related skin diseases, which include lupus-specific diseases (also known as, cutaneous lupus erythematosus [CLE]), and lupus-nonspecific skin diseases (eg, vasculitis, panniculitis, bullous SLE type I).27

Canine CLE preferentially affects haired skin and/or mucocutaneous junctions and true mucosal involvement is usually not a feature of this group of diseases. Nonetheless, rare cases of oral cavity involvement have been reported in dogs with vesicular CLE (VCLE) and mucocutaneous lupus erythematosus (MCLE).27 In such instances, the lesions are very minor compared to the classic annular to polycyclic erythema, erosions and ulcers on the glabrous skin of the abdomen, axillae, groin, and medial thighs in VCLE or erosions and ulcers at the mucocutaneous junctions of the anus, genitalia, oral cavity, and eyelids in MCLE.27 Detailed information about the various CLE forms can be found in a recent comprehensive review article.27

Presently, the only recognized CLE form in cats is the facial discoid lupus erythematosus, and oral cavity involvement has not been reported yet.2830 Confirmation of CLE requires histopathology of representative lesions such as early depigmentation with or without erythema and loss of epidermal/mucosal architecture. If erosions are sampled, the biopsies need to include the margin with intact skin/mucosa (Figure 2).

In contrast to CLE, ulcerative stomatitis has been reported in up to 20% of dogs and cats with SLE.31,32 Detailed descriptions are lacking, but both lupus-specific as well as lupus-nonspecific (ie, vasculitis, bullous SLE type I) lesions can be found in animals with SLE.27 As SLE is a multisystemic autoimmune disease, the diagnosis requires fulfillment of diagnostic criteria. In veterinary medicine, more than 1 unvalidated criterion can be found.33,34 In the most recent publication, at least 2 major signs with positive ANA test or at least 1 major and 2 minor signs with positive ANA test were required.33 One must remember that positive ANA has been demonstrated in dogs with Leishmania, Bartonella, and Ehrlichia infections, with other autoimmune/immune-mediated conditions, or even in healthy dogs.35,36 Similarly, positive ANA test results have been reported in about 30% of healthy cats and in cats suffering from FeLV.3739

Treatment of lupus erythematosus follows the general principles of immunosuppression, and a variety of treatment strategies can be found in the literature. In general, the initial drug selection and degree of immunosuppression depend on whether the patient suffers from SLE or CLE and the severity of clinical signs. More details on CLE treatment can be found in a recent review.27

Uveodermatological syndrome (also known as Vogt-Koyanagi-Harada-like syndrome)

Uveodermatological syndrome (UDS) is a rare syndromic condition believed to have a similar etiopathogenesis as its human counterpart in which an autoimmune targeting of melanocytes or melanocyte-associated antigens such as tyrosinase, gp-100, or KU-MEL-1 is suspected.40 So far, UDS has been recognized only in dogs.41 Dogs with UDS can suffer from concurrent granulomatous uveitis and depigmenting and/or erosive dermatitis often involving mucocutaneous junctions. Oral cavity involvement, which can vary from depigmentation to deep erosions/ulcers, has been reported in 23% of dogs.41 When involved, the palate appeared to be the most frequently affected region. Oral cavity changes usually accompany other, more typical skin lesions such as depigmentation with or without erosions on the nasal planum, eyelids, lips, or pawpads.41 Leukotrichia can also be seen. In most dogs (85%), ocular changes such as conjunctival congestion, corneal oedema, lacrimation, blepharospasm, photophobia, poor vision/blindness, or glaucoma are noticed first.41 Based on a recent review, the median time between the onset of ocular and dermatological signs was 12 weeks (range, 4 days to 3 years).41 Nonspecific systemic signs such as lethargy and hypo/anorexia are common, but signs of meningitis or dysacousia, as seen in people, are usually absent.

The most frequently affected breeds are Akitas, Siberian huskies, and Samoyeds, although a variety of other breeds are reported. Affected dogs are usually young adults (median age of onset 3 years), and males appear to be predisposed.

While the early depigmenting mucosal/cutaneous lesions may resemble vitiligo, the subsequent loss of epithelial surface architecture and erosions are more reminiscent of facial discoid lupus erythematosus (DLE), MCLE, epitheliotropic lymphoma, or leishmaniosis. A history of depigmentation followed by a loss of epidermal architecture and erosions and concurrent uveitis is usually sufficient to diagnose UDS. Histopathology is particularly helpful in dogs with early skin lesions, especially if they precede the ocular disease. Samples should be collected from the center of the erythematous and depigmented intact skin/mucosa as well as from actively depigmenting margins, and erosion margins, if present. All dogs with suspected UDS must undergo thorough ophthalmologic examination, because signs of uveitis may be subtle.

Immunosuppressive treatment should be initiated immediately after the diagnosis confirmation with the goal of rapidly reducing the disease activity to avoid blindness. Oral glucocorticoids together with a nonsteroidal immunosuppressant such as ciclosporin, mycophenolate mofetil, or azathioprine are used during the initial treatment phase. Topical ophthalmic glucocorticoids and cycloplegics are beneficial in dogs with anterior uveitis. Once disease control is achieved, a dose reduction, starting with glucocorticoids, is initiated (Table 3). Patients must be closely monitored, and regular ophthalmologic rechecks should be scheduled to detect early signs of a flare-up of uveitis.

Vasculitides/Vasculopathies

Vasculitis is an inflammatory reaction pattern associated with different causes varying from drug/vaccine reaction, infection, arthropod bites, and malignancy to autoimmunity.42,43 It occurs in dogs and cats and often immune-mediated mechanisms appear to play a role. The severity of the epithelial and stomal injury depends on the depth and number of vessels injured, the degree of vessel damage, and the timing. Lesions are variable and include pain, edema, swelling, petechiae/hemorrhages, eschar, erosions, and/or ulcers. Lesions can occur anywhere but extremities (ear tips, tail tips, noses, pawpads, and claws), and pressure points are predisposed. In 1 publication, oral cavity lesions occurred in 5% of dogs with vasculitis.42 Additionally, Wegener’s-like granulomatosis in a dog was reported to involve the oral cavity with vasculitis changes.44 Systemic signs are often present and differ depending on the underlying disease/trigger. Differential diagnoses depend on the stage of the disease and the lesions present. In later stages, the main differential diagnoses include infarctive thromboembolic disease, physiochemical injury, and deep bacterial or fungal infection (ie, necrotizing soft tissue disease). In the oral cavity, ulcers can also resemble CCUS or uremic ulcers; the latter can have vascular necrosis. Confirmation of vasculitis requires a biopsy, but it is often challenging to capture lesions. To increase the chances of capturing vasculitis, multiple biopsy samples must include the deep center of the ulcer and not the just superficial area (Figure 2). Additional diagnostic tests are usually required to determine the specific cause43 and treatment of vasculitis depends on the underlying cause.

In a subset of vascular diseases, called ischemic dermatopathies, evidence of ischemia can be found in biopsies, but a distinct vasculitis is absent. The diseases with presumed immune-mediated mechanisms include canine familial dermatomyositis (DM) of collies and shelties, generalized ischemic dermatopathy (idiopathic or vaccine-associated), and localized vaccine-associated panniculitis; the latter being localized at the site of injection and without additional skin or mucosal involvement.45 These conditions have not been recognized in cats. Characteristic skin lesions include scarring alopecia, hyperpigmentation and hypopigmentation, erosions, and crusts. In DM and generalized ischemic dermatopathy, lesions are often present on the ear and tail tips, periocular, nasal planum, dorsal muzzle, face/head, pawpads, digits, claws, and/or pressure points. Mucocutaneous junctions and mucosal lesions (lips and oral cavity particularly) are less common (28% and 8%, respectively) and always in conjunction with the typical skin lesions.46 Rare dogs show evidence of muscle injury, especially the masticatory group. Megaesophagus has been also reported.45

Diagnosis of ischemic dermatopathy is based on a characteristic clinical picture, history of vaccination (in some dogs), and biopsy. Multiple samples should be collected from central areas of scarring alopecia or from epidermal margins of erosions or ulcers. Treatment depends on the severity of the disease. A spectrum of drugs has been reported to be effective in treating milder cases including pentoxifylline (25 to 30 mg/kg twice daily)47 with or without vitamin E (200 to 800 IU twice daily) or tetracycline/niacinamide.43 More severe cases are usually treated with an immunosuppressive dose of glucocorticoids (ie, predniso(lo)ne 2 to 4 mg/kg/day) in conjunction with a nonsteroidal immunosuppressant such as ciclosporin, mycophenolate mofetil, or azathioprine. Rapid disease remission was achieved with oclacitinib (0.4 to 0.7 mg/kg twice daily) in severe refractory cases of a vaccine-induced ischemic dermatopathy.48

Clinically Relevant Points

  • Many diseases can manifest with oral lesions, including several autoimmune and immune-mediated skin diseases.

  • Primary lesions such as vesicles/bullae or masses are more specific and can help to narrow down the list of differential diagnoses (also known as, vesicles/bullae in blistering diseases), while lesions such as deep erosions and ulcers are seen in many diseases.

  • Signalment, history, lesion distribution, and symmetry may narrow the list of differential diagnoses.

  • A list of relevant differential diagnoses is important for collecting appropriate biopsy samples, which are usually necessary to confirm the final diagnosis.

  • Biopsies should be collected from active lesions representative of the suspected disease (biopsies collected from chronic lesions often do not reflect the primary disease process and are not likely to yield diagnostic information).

  • Clearance of secondary bacterial infection should be attempted prior to the biopsy.

  • Whenever possible, biopsy specimens should be taken when the animal is not under the effects of glucocorticoids or other immunosuppressive therapy.

  • Treatment guidelines for specific autoimmune and immune-mediated skin diseases have not been established and, therefore, general principles of immunosuppression apply to most conditions.

Acknowledgments

The authors declare that there were no conflicts of interest or external funding in the preparation of this manuscript.

The authors thank Dr. Natalie Gedon for sharing her clinical photos with us.

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  • Figure 1

    Examples of lesions in various autoimmune/immune-mediated skin diseases in dogs. A—Buccal mucosa of a dog with autoimmune subepidermal blistering disease with intact vesicles (white arrows) and multifocal, recently ruptured vesicles with deep erosions and mucosal epithelium remnants (flaps) at the periphery (black arrows). B—A large deep erosion/shallow ulcer on the buccal mucosa and gingiva of a dog with epidermolysis bullosa acquisita. No overt stromal involvement can be appreciated clinically (courtesy of Dr. Natalie Gedon). C—Large, well-demarcated (punched-out) ulcer with stromal involvement in a dog with vasculitis. Smaller ulcers can be appreciated at the periphery. D—Diffusely eroded buccal mucosa and gingivae with a fibrin pseudomembrane (arrow) mimicking a recently ruptured vesicle in a dog with oral erythema multiforme.

  • Figure 2

    Examples of sites of biopsies depending on the lesion types. A—A punch biopsy (circle) of the entire small vesicle with adjacent mucosa to maintain the vesicle intact or a wedge biopsy (oval) of an erosion margin to capture the intact mucosa at the junction in a dog with an autoimmune subepidermal blistering disease. B—A wedge biopsy (ovals) at the junction of intact mucosa and erosion in a dog with vesicular cutaneous lupus erythematosus (courtesy of Dr. Natalie Gedon). C—A deep, punch biopsy (circle) of the entire ulcer or a large wedge biopsy (oval) that includes the deep ulcer center and the adjacent intact mucosa, if vasculitis is suspected. D—A wedge-shaped excisional biopsy of the ulcerated tongue (triangle) in a dog with vasculitis in an attempt to capture the injured vessels in the deep central area.

  • 1.

    Anderson JG, Hennet P. Management of severe oral inflammatory conditions in dogs and cats. Vet Clin North Am Small Anim Pract. 2022;52(1):159184. doi:10.1016/j.cvsm.2021.09.008

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Olivry T. A review of autoimmune skin diseases in domestic animals: I–superficial pemphigus. Vet Dermatol. 2006;17(5):291305. doi:10.1111/j.1365-3164.2006.00540.x

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Bizikova P, Burrows A. Feline pemphigus foliaceus: original case series and a comprehensive literature review. BMC Vet Res. 2019;15(1):22. doi:10.1186/s12917-018-1739-y

    • Search Google Scholar
    • Export Citation
  • 4.

    Tham HL, Linder KE, Olivry T. Deep pemphigus (pemphigus vulgaris, pemphigus vegetans and paraneoplastic pemphigus) in dogs, cats and horses: a comprehensive review. BMC Vet Res. 2020;16(1):457. doi:10.1186/s12917-020-02677-w

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Martinez N, McDonald B, Crowley A. A case report of the beneficial effect of oclacitinib in a dog with pemphigus vulgaris. Vet Dermatol. 2022;33(3):237-e65. doi:10.1111/vde.13063

    • Search Google Scholar
    • Export Citation
  • 6.

    Heimann M, Beco L, Petein M, Nishifuji K, Amagai M, Olivry T. Canine hyperplastic intraepidermal pustular and suprabasal acantholytic dermatosis with features of human pemphigus vegetans. Vet Pathol. 2007;44(4):550555. doi:10.1354/vp.44-4-550

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Kartan S, Shi VY, Clark AK, Chan LS. Paraneoplastic pemphigus and autoimmune blistering diseases associated with neoplasm: characteristics, diagnosis, associated neoplasms, proposed pathogenesis, treatment. Am J Clin Dermatol. 2017;18(1):105126. doi:10.1007/s40257-016-0235-z

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Hill PB, Brain P, Collins D, Fearnside S, Olivry T. Putative paraneoplastic pemphigus and myasthenia gravis in a cat with a lymphocytic thymoma. Vet Dermatol. 2013;24(6):646649. doi:10.1111/vde.12086

    • Search Google Scholar
    • Export Citation
  • 9.

    Olivry T. An autoimmune subepidermal blistering skin disease in a dog? The odds are that it is not bullous pemphigoid. Vet Dermatol. 2014;25(4):316318. doi:10.1111/vde.12152

    • Search Google Scholar
    • Export Citation
  • 10.

    Bizikova P, Olivry T, Linder K, et al. Spontaneous autoimmune subepidermal blistering diseases in animals: a comprehensive review. BMC Vet Res. In press.

    • Search Google Scholar
    • Export Citation
  • 11.

    Olivry T, Chan LS. Spontaneous canine model of mucous membrane pemphigoid. In: Chan LS, ed. Animal Models of Human Inflammatory Skin Diseases. CRC Press; 2004:241249.

    • Search Google Scholar
    • Export Citation
  • 12.

    Tham HL, Olivry T, Linder KE, Bizikowa P. Mucous membrane pemphigoid in dogs: a retrospective study of 16 new cases. Vet Dermatol. 2016;27(5):376-e94. doi:10.1111/vde.12344

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Yager JA. Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis: a comparative review. Vet Dermatol. 2014;25(5):406-e64. doi:10.1111/vde.12142

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Banovic F, Olivry T, Bazzle L, et al. Clinical and microscopic characteristics of canine toxic epidermal necrolysis. Vet Pathol. 2015;52(2):321330. doi:10.1177/0300985814537530

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Schneider JA, Cohen PR. Stevens-Johnson syndrome and toxic epidermal necrolysis: a concise review with a comprehensive summary of therapeutic interventions emphasizing supportive measures. Adv Ther. 2017;34(6):12351244. doi:10.1007/s12325-017-0530-y

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Sartori R, Colombo S. Stevens-Johnson syndrome/toxic epidermal necrolysis caused by cefadroxil in a cat. JFMS Open Rep. 2016;2(1):2055116916653616. doi:10.1177/2055116916653616

    • Search Google Scholar
    • Export Citation
  • 17.

    Cornelis I, Vandenabeele S, Dunon D, Van Ham L. Presumed phenobarbital-induced Stevens-Johnson syndrome in a 4-year-old female Great Dane. Vet Q. 2016;36(4):242246. doi:10.1080/01652176.2016.1182231

    • Search Google Scholar
    • Export Citation
  • 18.

    Simpson AC, Bradley CW, Schissler JR. Probable cutaneous adverse drug reaction due to a cannabidiol-containing hemp oil product in a dog. Vet Dermatol. 2020;31(5):404e108. doi:10.1111/vde.12876

    • Search Google Scholar
    • Export Citation
  • 19.

    Hinn A, Olivry T, Luther P. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis in the dog: clinical classification, drug exposure, and histopathologic correlations. J Vet Allergy Clin Immunol. 1998;6:1320.

    • Search Google Scholar
    • Export Citation
  • 20.

    Scott D, Miller HM. Erythema multiforme in dogs and cats: literature review and case material from the Cornell University College of Veterinary Medicine (1988–96). Vet Dermatol. 1999;10(4):297309. doi:10.1046/j.1365-3164.1999.00143.x

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Banovic F, Olivry T, Artlet B, et al. Hyperkeratotic erythema multiforme variant in 17 dogs. Vet Dermatol. Published online December 12, 2022. doi:10.1111/vde.13141

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Ayangco L, Rogers RS III. Oral manifestations of erythema multiforme. Dermatol Clin. 2003;21(1):195205. doi:10.1016/S0733-8635(02)00062-1

  • 23.

    Nemec A, Zavodovskaya R, Affolter VK, Verstraete FJ. Erythema multiforme and epitheliotropic T-cell lymphoma in the oral cavity of dogs: 1989 to 2009. J Small Anim Pract. 2012;53(8):445452. doi:10.1111/j.1748-5827.2012.01230.x

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Anderson JG, Peralta S, Kol A, Kass PH, Murphy B. Clinical and histopathologic characterization of canine chronic ulcerative stomatitis. Vet Pathol. 2017;54(3):511519. doi:10.1177/0300985816688754

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    High EJ, Linder KE, Mamo LB, Levy BJ, Herrmann I, Bizikova P. Rapid response of hyperkeratotic erythema multiforme to oclacitinib in two dogs. Vet Dermatol. 2020;31(4):330-e86. doi:10.1111/vde.12852

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Sontheimer R. The lexicon of cutaneous lupus erythematosus–a review and personal perspective on the nomenclature and classification of the cutaneous manifestations of lupus erythematosus. Lupus. 1997;6(2):8495. doi:10.1177/096120339700600203

    • PubMed
    • Search Google Scholar
    • Export Citation
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