Introduction Immune related inflammatory disease in the oral cavity provides the clinician a diagnostic and treatment challenge. A tooth fracture is such and periodontal disease can be identified via Stages (1-4) with both probing and radiographic identification. However, immune oral pathology can mimic many processes. This lecture will review some of those processes and how to both identify and treat those conditions. I will be referencing three major pieces of literature (Frontiers in Veterinary Science, a lecture by Cindy Bell at the 2024 Veterinary Dental Forum and a recent article in JoVD regarding treatment of Canine Contact Ulcerative Stomatitis by Jamie Anderson)

Choosing an oral pathologist…and dermatologist
This is paramount. One must choose a pathologist that can help direct you clinically but a proper identification is necessary. Therefore, I HIGHLY RECOMMEND you take clinical images of the pathology and submit those along with intraoral radiographs when applicable with your sample. Historically, few pathologists are oral ‘specialists’ so please check with your laboratory and ask who within that group can read and help identify pathology. In addition, consulting a local boarded dermatologist will be helpful as they see many mucosal diseases.

Classification of inflammation
1. Plaque-associated contact mucositis and gingivitis
Oral mucositis (to also include ulcerations) can be a direct response to existing periodontal disease. Oral bacteria trigger a biological response of a variety of cells within the body such as interleukins (IL), mast cells, macrophages, osteoclasts. Therefore, plaque is the causative agent. This may occur with bacterial related to exposed necrotic bone and exposed roots in areas of gingival recession. Calculus can also lead to ulceration via a direct contact to the gingival mucosa (which occurs frequently in the caudal maxillary cheek teeth) as well. There could still be concurrent disease so in some case such cases where inflammation is more localized or proliferative, submission for pathology will help rule out neoplasia. A significant differentiation among these categories is with this condition, dermatological signs are not present. Histologically, they are generally lymphoplasmacytic, superficial and erosive.

Treatment is based on true identification of this condition but selective oral surgical extractions of affected teeth/area, followed by aggressive home care and repeated anesthetic dental assessment (supragingival/subgingival cleaning and polishing) every 3-6 months is warranted.

Doxycycline as a subantibacterial, anti-inflammatory agent at 2.0 mg/kg daily; fatty acid supplementation; daily brushing or usage of an enzymatic toothpaste along with water additive. (VOHC-approved) The usage of systemic antibiotics at normal dosages is contraindicated as well as the usage of corticosteroid therapy.

2. Canine Contact Ulcerative Stomatitis (CCUS)
CCUS is a clinical diagnosis, not a histopathological one, therefore, it is impossible to distinguish this from the above and can overlap with autoimmune diseases. Therefore, clinical presentation is paramount. Differential diagnoses for CCUS include autoimmune conditions such as pemphigus vulgaris, bullous pemphigoid, erythema multiforme, and lupus erythematosus, along with epitheliotropic T-cell lymphoma and uremic stomatitis.

Canine chronic ulcerative stomatitis (CCUS) is a spontaneously occurring, painful, and often debilitating condition of the oral cavity, with a suspected immune-mediated component. Ropey saliva with a fetid odor emanating from the mouth occurs. These pets are extremely painful to the touch and may experience weight loss, irritability and depression. This condition is seen with severe mucosal ulcerations related to contact to the tooth cusp and plaque formation that has occurred. Lesions may also occur on the lateral aspects of the tongue, mucocutaneous lesions of the lips, and glossopalatine folds of the palate. Breed association may be Maltese Terrier, Cavalier King Charles Spaniel, Labrador Retriever, Greyhound, and terrier breeds.

In some cases, medical management along with aggressive home care does help. A recent study used Cyclosporine and Metronidazole after oral care performed and periodontally compromised teeth were removed. Cyclosporine is an effective immunosuppressive agent that inhibits T-cell function, therefore inhibiting cell-mediated immunity.

Medical Management
Doxycycline 2.0-5.0 mg/kg daily; Niacinamide 250-500 mg po bid; Fatty acid supplementation; +/- pentoxifylline DOSAGE. Study Plan: Cyclosporine 5.0 mg/kg orally once daily (1 hr prior to or 2 hrs post meal) for 8 days. Cyclosporine assays were run on day 8 (pre pill and 2 hr post trough). Then added day 9 metronidazole @ 15-20 mg/kg orally once daily for 21 days. Frequency of cyclosporine was reduced in successful cases to every other day or twice weekly.

3. Pemphigus vulgaris (PV), mucous membrane pemphigoid (MMP), Cytotoxic mucositis (EM, SJSA, TEN)
Pemphigus vulgaris is rare in dogs but is the most likely type to occur in the oral cavity. It is considered life threatening due to the loss of the epithelial barrier. Previous studies show 90% of dogs had oral lesions, and with 6%, the oral cavity was the only cavity involved. (Frontier). Areas of involvement are the areas of keratinized oral mucosa including hard palate, gingiva and dorsal tongue. Dogs experience oral pain with hypersalivation, lip smacking and halitosis. Lesions are flaccid vesicles and bullae, ulcerations and erosions. Many times the vesicles have already ruptured so you do not see them on oral exam. Histopathologically, one notices suprabasilar clefting with only a single layer of rounded basal cells and acantholysis. Therefore, histopathology alone may confirm a diagnosis. (Frontiers/Bell)

Mucous Membrane Pemphigoid
This is the most common AISBD (autoimmune subepidermal blistering disease) that occurs in 48% of cases of that category. German Shepherd dogs are highly represented. Interestingly, symmetrical lesions (vesicles and erosions on mucous membranes and mcj occurred in 90% of patients in a particular study. Oral sites are gingiva, hard and soft palate and tongue. The nasal planum can be the second most common site. Histological findings are large subepidermal clefts lacking inflammatory cells at the margin of the ulcer.

Treatment
Corticosteroids (prednisone, prednisolone) or immunomodulating drugs (doxycycline and niacinamide).

Erythema multiforme (EM)
Erythema multiforme encompasses a variety of clinical presentations that include Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN). TEN is identified as the most severe form. These are cytotoxic diseases that cause epithelial cell injury. Histopath is characterized by a distinctive pattern of interface inflammation with keratinocytes necrosis. Causes or most likely a ‘trigger’ may include chemotherapeutic agents, medication, bacterial / virus or an exposure to a toxin.

These dogs are quite ill with fever a common theme. CBC abnormalities are leukocytosis and neutrophilia; hypergammaglobulinemia may occur along with other biochemical abnormalities. Clinically, skin and mucosal lesions are typically macular erythema that progress to blisters/ulcers with exudation (Frontiers). Nikolsky’s sign (epidermis sloughs with minimal pressure)

Treatment
Removal of the causative agent (if found). Changing diet to a novel protein or hydrolyzed protein diet may be beneficial. Medical management may include one or more of the following: corticosteroids, azathioprine, cyclosporine, pentoxifylline. Niacinamide (vitamin B) and doxycycline have been used for synergistic immunomodulatory effects.

Immune Mediated Connective Tissue Diseases
Lupus erythematosus (LE) and Wegener’s Granulomatosis are in this category. With regard to LE, various forms can mimic paraneoplastic neoplastic syndromes, multicutaneous pyoderma, CCUS and plaque-associated mucositis. (Bell) These lesions, however, may mimic neoplasia due to the proliferative nature. (I can attest to this in many instances). Areas involved may be rostral labial mucosa, buccal mucosa, and sublingual mucosa. Tooth mobility (bone invasion) has been seen in many instances, giving the clinical appearance of an aggressive malignant neoplasia. The surface epithelium is usually smooth and non-lobulated, which may help differentiate this from neoplasia. Histologically, diffuse inflammatory disease that includes a missed leukocyte population of macrophages, plasma cells, lymphocytes and neutrophils.

Wegener’s Granulomatosis may be multifocal and one distinguishing characteristic seen clinically is dark red or purple lesions. Alveolar bone loss is common with gingiva being swollen. Histological differentiation from LE may be the added presence of eosinophils with the possibility of multinucleated giant cells.

 Treatment
Corticosteroid therapy

Conclusion
Immune-related oral diseases do occur in the canine and can be difficult to diagnosis and or find the causative agent. Proper biopsy techniques should be used and submission to an oral pathologist that has a knowledge of this category of disease. Images should be submitted to the pathologist when providing samples, and intraoral radiography should be performed to evaluate for bone loss.

References
• Bell, CM Histopathological Contributions to oral medicine: Autoimmune diseases and other immune-mediated inflammatory mucosal lesions in the dog. 2024 Veterinary Dental Forum Proceedings. Palm Springs, CA.
• Dosenberry C, Arzi B et al.. An update on oral manifestations of systemic disorders in dogs and cats. Frontiers in Veterinary Science. Jan 06, 2025. pp 01-15.
• Anderson, J. et al.. Medical management of Canine Chronic Ulcerative Stomatitis using cyclosporine and metronidazole. Journal of VetDent. Jan 2023 • Klug, W. et al.. Diagnosis and management of Wegener’s granulomatosis in the dog. Journal of VetDent. 2006.