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Feline Chronic Gingivostomatitis (FCGS)

Standard treatments fall short. A new therapeutic approach is on the horizon.

Disease State

Clinical definition

Feline Chronic Gingivostomatitis (FCGS), also known as chronic stomatitis, is a complex disease characterized by oral inflammation with an immune-mediated component and elusive etiology. Oral inflammation typically involves areas of the gingiva, alveolar and buccal mucosa, as well as the caudal oral mucosa, lateral to the palatoglossal folds. It is a painful, chronic, and debilitating inflammatory disease.

Etiology/cause

It is generally recognized that FCGS is the result of overactive and sustained T-cell expansion and T-cell exhaustion, both systemically and within the oral cavity. This was initially thought to be due to an abnormal response to plaque; however, it is now clear that the true cause is not completely elucidated, as the pathogenesis and progression differ from case to case.

Factors

Disease progression is multifactorial and often involves co-morbidity with infectious agents such as feline calicivirus, feline herpesvirus, feline leukemia virus, feline immunodeficiency virus, and Bartonella henselae, with feline calicivirus thought to be the primary infectious disease agent associated with FCGS. Additional co-morbidities include tooth resorption (feline odontoclastic resorption lesions/FORL), periodontal disease, food allergies, and hypersensitivity to plaque-forming bacteria.

Immune dysregulation

Immune dysregulation in FCGS occurs both locally and systemically. Locally, there is increased expression of mRNA for specific inflammatory mediators (IL-2, IL-4, IL-6, IL-10, IL-12, and IFN-γ). The predominant cells infiltrating the caudal oral mucosa in affected cats are primarily CD79a+ IgG isotype plasma cells, neutrophils (L1+ cells), and CD8+ (cytotoxic) T cells. Systemically, the cytokine expression profile mimics what is observed locally and is characterized by elevated circulating levels of IFN-γ, TNF-α, and IL-lβ, neutrophilia in 30-40% of patients, as well as CD8+ effector memory cells.

Medical management

Stimulation of the immune system by plaque bacteria appears to contribute to ongoing inflammation, and successful treatment of chronic stomatitis requires minimizing oral bacteria. Daily plaque removal by mechanical means (e.g., toothbrushing) is difficult in these painful cats, and reduction of plaque-retentive surfaces by extracting teeth has proven to be most effective in eliminating plaque and reducing oral inflammation. Antibiotics may be used as medically indicated.

Analgesics (opioids such as buprenorphine), gabapentin, non-steroidal anti-inflammatories, and immunosuppressive medications, including cyclosporine and corticosteroids (prednisone or prednisolone), are often used alone or in combination to manage pain and inflammation. Medical management without tooth extraction is likely to only temporarily alleviate clinical signs. Response to medical therapy alone is only observed in 23-45% of cases and is mostly transient.

Surgical management

The surgical approach to FCGS includes the removal of all teeth that have abnormalities on oral examination and imaging. Complete removal, including the roots, is important and should be confirmed with post-operative imaging.

Refractory FCGS

Of the cats with FCGS that have full-mouth extractions, 50-80% of cats will significantly improve. However, for the remaining 20-50%, abnormal clinical signs, loss of quality of life, and oral inflammation persist, requiring lifelong management. Continued clinical signs and oral inflammation despite the extraction of affected teeth (at least 2 months prior) and medical management are considered refractory (nonresponsive).

Unmet medical need

Cats suffering from refractory FCGS are often faced with lifelong anti-inflammatory and immunosuppressive drug therapy. There are no FDA-approved medications, and the medications that are currently used have no proven safety or effectiveness in the long-term management of FCGS and have highly variable clinical response rates.

Especially in cats, the available medications are also associated with potentially significant peripheral organ damage and toxicity, resulting in potential side effects that may not be well tolerated by the patient (examples include vomiting, bloody diarrhea, anorexia, frequent urination, vocalization, etc.). If the cats do not have some clinical control of inflammation and pain with these drugs, they may also experience reduced food intake, weight loss, lethargy, and overall ill thrift. The outcome for the unresponsive cat is a decreased quality of life and decreased life span due to death or euthanasia.

Many of these signs may make it difficult for the owner to be compliant with giving medications, which may require daily administration of oral medication, creating unwanted social behaviors and challenging the human-animal bond.

Why stem cells for the treatment of rFCGS

Mesenchymal stem cells, referred to as MSCs, are the body’s adult repair cells, allowing healing and restoration of damaged tissues naturally. MSCs are multipotent stem cells with differentiation limited to certain cell lineages and are capable of interacting with and modulating various immune cell subsets, such as T cells. Stem cells offer a therapeutic approach that targets the body’s natural healing mechanisms to heal diseased tissues rather than just control clinical signs. Stem cells work through mechanisms that spare organ damage in non-targeted tissues.

Diagnosis

Clinical signs/chief complaint

Signs of oral disease in cats

Cats present with clinical signs characteristic of oral disease, including bad breath (halitosis), poor or reduced grooming activities, difficulty eating, reduced appetite or inappetence, pain when eating or yawning, weight loss, and drooling. Additional clinical signs signaling reduced quality of life and general ill health include: irritability, hiding, vocalizing when eating, and reduced socialization with other pets and family members.

Differential diagnosis

There are a number of oral diseases that may mimic or have similar clinical signs to FCGS.

  • Periodontal disease: FCGS may be differentiated from periodontal disease by the presence of inflammatory lesions affecting tissues beyond the gingiva, including the caudal oral mucosa.
  • Eosinophilic granuloma complex: FCGS may be differentiated from eosinophilic granuloma complex histologically.
Etiology of FCGS
  • Neoplasia: FCGS may be differentiated from squamous cell carcinoma (SCC) and other oral neoplasia histologically. It is possible for FCGS to present as proliferative and can transform into SCC, therefore, accurate diagnosis in these cases with a fine needle aspirate or biopsy is important for prognosis and treatment.
  • Gingivitis: Similar to periodontal disease, FCGS may be differentiated from gingivitis by the presence of inflammatory lesions affecting tissues beyond the gingiva, including the caudal oral mucosa. Other tissues in the oral cavity are affected in FCGS.
  • Other stomatitis (i.e., autoimmune causes, paraneoplastic, electrical/thermal/ chemical burn)

These diagnoses may require additional diagnostics to confirm, and a good clinical history may rule out additional causes.

Diagnostics

Oral exam:

  • An oral examination should identify inflammation that crosses the mucogingival junction, involving the gingiva and extending to the buccal and caudal oral mucosa, lateral to the palatoglossal folds.
  • Lesion scores.

Two observed phenotypes:

  • ulcerative/erosive, and/or
  • proliferative

A combination of both is possible.

Ellipse 17
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CLINICAL PATHOLOGY
Complete blood count, serum biochemistry panel, and urinalysis should be performed to assess the patient’s overall health status and as a pre-operative health assessment if surgical care is recommended.

Ellipse 18
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INFECTIOUS DISEASE TESTING
Viral disease testing to assess FeLV, FIV, and FCV status should be performed due to the potential prognostic significance and to document potential causative factors.

Ellipse 19
Created in https://BioRender.com

HISTOPATHOLOGY
Histological characteristics of FCGS include Infiltrates of lymphocytes and a cells, with varying numbers of neutrophils.

Lesion Scoring Chart

Score the inflammation of oral cavity sites:
0 = none; normal pink, healthy tissue
1 = mild; mild erythema, likely no ulceration or proliferation
2 = moderate; moderate erythema, superficial erosion or ulceration, moderate proliferation, no spontaneous hemorrhage
3 = severe; extreme erythema with spontaneous hemorrhage, deep ulceration and/or significant proliferation of tissues

table@2x

TOTAL SCORE (MAXIMUM = 24):

Mechanism of Action

Mechanism of Action of MSCs

Stem cells are administered intravenously, where they are introduced into the bloodstream and can recognize and react to the microenvironment, particularly inflammation, both directly, through cellular interactions with immune cells (T-cells, macrophages, B cells), and indirectly through paracrine signaling (interleukins, TGF, etc). The investigational uterine-derived MSCs do not elicit an immune response in the recipient animal because they do not express MHC II on their cell surface.

Once administered, the MSCs are capable of homing to sites of inflammation as a response to chemotactic cytokines secreted by inflammatory cells such as TNF-alpha and interferon-gamma. In response to their environment, the cells produce several anti-inflammatory paracrine factors to mitigate excessive inflammation, mainly prostaglandin-E2 and indoleamine 2,3 dioxygenase, but also hepatocyte growth factor, tumor necrosis factor-stimulated gene 6, interleukin-6, and tumor growth factor-β. These secreted factors limit immune cell expansion. The cells also act to restore the balance of dysregulated T-helper cell subtypes so that the Th-2 cells are no longer dominant.

In addition, a few pathogens have been shown to be concomitant with FCGS, particularly feline calicivirus or FCV but also feline leukemia virus and feline foamy virus. The investigational uterine-derived MSCs appear to aid in viral clearance of FCV-positive cats, likely due to enhancement of the cytotoxicity capability of CD8+ T cells.

Cellular Interactions Specific To FCGS

Cellular Interactions Specific To Fcgs

Uterine derived MSCs

The endometrium is the lining of the uterus, and it undergoes cyclic regeneration during each estrous cycle. As a result, it is a readily accessible and renewable source of stem cells. Obtaining allogeneic uterine-derived MSCs is less invasive and less complicated than other sources, making this cell source more feasible for therapeutic applications. Uterine-derived MSCs have also been found to possess potent immunomodulatory properties. They can regulate the immune response and reduce inflammation, crucial for treating chronic oral inflammatory diseases.

FCGS Uterine Derived

Additionally, MSCs derived from the uterustend to have low expression of major histocompatibility complex (MHC) antigens, which makes them less likely to be recognized and attacked by the recipient’s immune system.

Consequently, this treatment may improve the success rate of extractions and become a more readily available source for these cells. This approach will revolutionize the treatment options for cats with feline chronic gingivostomatitis (FCGS), enhance their quality of life, and expand cell therapy to a broader range of diseased cats. The stem cells under investigational use for refractory FCGS are feline allogeneic uterine-derived from the perivascular area and the endometrial layer of the uterus from a healthy FDA-qualified donor.

A deeper look into the life organ

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Manufacturing and Potency

Cell Flask

The investigational stem cells being studied are collected from a FDA-qualified feline (cat) donor during a routine spay procedure. The cells are intended to be used in other cats (same species) as an allogeneic ready-to-use product. The uterine-derived MSCs have been demonstrated in a matrix of assays to be potent (functional) and directed at the relevant clinical factors in FCGS. Each batch of stem cells is manufactured according to Current Good Manufacturing Practices (CGMP) and is released with established specifications demonstrating key quality attributes for identity, purity, safety and potency of the drug product.

Allogeneic cells from a FDA qualified donor

Created in https://BioRender.com

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