Stem Cell Therapy for FCGS
What is FCGS?
Feline Chronic Gingivostomatitis (FCGS), also known as chronic stomatitis, is a painful, debilitating disease characterized by inflammation of the gingiva, alveolar and buccal mucosa, and caudal oral mucosa lateral to the palatoglossal folds. There are two observed FCGS phenotypes: ulcerative/erosive and proliferative; some cats have a combination of both.
FCGS is characterized by local and systemic immune dysregulation. Oral mucosal mRNA expression is upregulated for several inflammatory mediators including IL-2, IL-4, IL-6, IL-10, IL-12 and IFN-γ.1,2 The predominant cells infiltrating the caudal oral mucosa in affected cats include CD79a+ IgG isotype plasma cells, neutrophils (L1+ cells), and CD8+ (cytotoxic) T cells.1,3,4 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 as well as CD8+ effector memory cells.3,5 Peripheral neutrophilia occurs in 30-40% of cats with FCGS.6
Cats with FCGS are most commonly infected with feline calicivirus (FCV); other associated infectious diseases include feline herpesvirus, feline leukemia virus (FeLV), feline immunodeficiency virus (FIV), and Bartonella henselae. Additional co-morbidities include tooth resorption (feline odontoclastic resorption lesions/FORL), periodontal disease, food allergies, and hypersensitivity to plaque forming bacteria.
Diagnosis and Clinical Signs
Cats present with clinical signs characteristic of oral disease including 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. A diagnosis of FCGS or chronic stomatitis may be suspected based on clinical presentation and can be confirmed with biopsy and histopathology. Proliferative lesions should be biopsied to rule out squamous cell carcinoma (SCC).
Differential Diagnoses
Periodontal disease and Gingivitis: FCGS may be differentiated from both periodontal disease and gingivitis by the presence of inflammatory lesions affecting tissues beyond the gingiva including the caudal oral mucosa.
Other forms of stomatitis: (i.e., autoimmune, paraneoplastic, electrical/thermal/chemical burn): These diagnoses can often be elucidated by clinical history and biopsy.
Eosinophilic granuloma complex: FCGS may be differentiated from eosinophilic granuloma complex histologically.
Neoplasia: FCGS may be differentiated form squamous cell carcinoma (SCC) and other oral neoplasia histologically. FCGS can be proliferative, therefore accurate diagnosis is important to direct treatment options and prognosis.
FCGS Management
Oral bacteria (plaque) may contribute to chronic immune stimulation and ongoing inflammation, and successful treatment of 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 tooth extraction has proven most effective in eliminating plaque and reducing oral inflammation.
Gabapentin, Burprenorphine, non-steroidal anti-inflammatories, and immunosuppressive medications including cyclosporine and corticosteroids are often used alone or in combination to manage pain and inflammation. Antibiotics may be used as medically indicated. Improvement with medical therapy alone without tooth extraction is observed in less than 50% of cats and is typically transient.
The surgical approach to FCGS includes removal of all abnormal teeth noted on examination and diagnostic imaging. Complete removal including the roots is crucial for clinical success and should be confirmed with post-operative imaging.
Refractory FCGS
50-70% of cats with FCGS significantly improve with dental extractions. The remaining 30-50% have persistent oral inflammation contributing to reduced quality of life, continued clinical symptoms, and chronic pain – necessitating long-term medication administration.6 These medications target the symptoms, but the disease process and oral lesions continue. Cats are considered “refractory” if they have persistent oral lesions and associated symptoms, are at least 2 months post dental extraction and need continued medical management.
Chronic anti-inflammatory and immunosuppressive medications can be associated with an increased risk for hepatotoxicity, renal toxicity, gastrointestinal upset, and risk for diabetes mellitus and cancer. Daily oral medication administration is often painful and stressful, putting a consistent strain on the cat, caregiver, and cat-caregiver bond. Chronic oral inflammation often results in reduced food intake, weight loss, lethargy, and overall ill thrift. In approximately 10% of cats with refractory FCGS, caregivers opt for euthanasia due to poor quality of life.7
Mesenchymal Stem Cell Therapy for FCGS
Mesenchymal stem cells (MSCs) have been shown in multiple studies to address not only the clinical symptoms but the underlying immune dysregulation and associated oral lesions. After intravenous administration, MSCs respond to cellular signals secreted by inflammatory cells that direct them to the site of inflammation, injury, or lesions.
Once MSCs have reached the diseased tissue, they act both directly through cellular interactions with immune cells (T-cells, macrophages, B cells), and indirectly through cell-to-cell signaling (prostaglandin-E2, cytokines, growth factors) to reduce inflammation, limit immune cell expansion, restore the balance of T-helper cell subtypes, and promote natural healing mechanisms.8–10 Uterine-derived MSCs (UMSCs) may also aid in viral clearance in FCV positive cats.8
Studies using Gallants UMSCs have shown that approximately 75% of cats with refractory FCGS improve clinically by 60 days post treatment and approximately 50% have improvement in the oral lesions by 90 days, with continued improvement beyond that.11 The lag in the improvement lesion scores is due the natural time it takes to repair and heal tissue with maximum effect seen after 180 days post-treatment. Some cats have experienced clinical cure and remission of the refractory FCGS.
UMSCs have been shown to be well tolerated in multiple studies in cats with rFCGS. There is no known toxicity profile associated with organs and tissues and repeated doses do not appear to increase the risk of side effects. Most side effects are short lived and respond to treatment if needed. The most common observations included vomiting, diarrhea, and increased respiratory rate in less than 8% of cats considered probably related to the drug around the time of administration. There is always the possibility for serious reactions. All decisions regarding treatment should be a risk:benefit decision. UMSCs are not FDA approved for use but are still under investigation by the FDA-CVM. Conditional approval is being targeted for 2026.
1. Harley R, Helps CR, Harbour DA, Gruffydd-Jones TJ, Day MJ. Cytokine mRNA Expression in Lesions in Cats with Chronic Gingivostomatitis. Clin Diagn Lab Immunol. 1999;6(4):471-478. doi:10.1128/CDLI.6.4.471-478.1999
2. Dolieslager SMJ, Lappin DF, Bennett D, Graham L, Johnston N, Riggio MP. The influence of oral bacteria on tissue levels of Toll-like receptor and cytokine mRNAs in feline chronic gingivostomatitis and oral health. Vet Immunol Immunopathol. 2013;151(3-4):263-274. doi:10.1016/j.vetimm.2012.11.016
3. Arzi B, Mills-Ko E, Verstraete FJM, et al. Therapeutic Efficacy of Fresh, Autologous Mesenchymal Stem Cells for Severe Refractory Gingivostomatitis in Cats. Stem Cells Transl Med. 2016;5(1):75-86. doi:10.5966/sctm.2015-0127
4. Harley R, Gruffydd-Jones TJ, Day MJ. Immunohistochemical Characterization of Oral Mucosal Lesions in Cats with Chronic Gingivostomatitis. J Comp Pathol. 2011;144(4):239-250. doi:10.1016/j.jcpa.2010.09.173
5. Arzi B, Clark KC, Sundaram A, et al. Therapeutic Efficacy of Fresh, Allogeneic Mesenchymal Stem Cells for Severe Refractory Feline Chronic Gingivostomatitis. Stem Cells Transl Med. 2017;6(8):1710-1722. doi:10.1002/sctm.17-0035
6. Soltero-Rivera M, Goldschmidt S, Arzi B. Feline chronic gingivostomatitis: current concepts in clinical management. J Feline Med Surg. 2023;25(8):1098612X231186834. doi:10.1177/1098612X231186834
7. Soltero-Rivera M, Hart S, Blandino A, Vapniarsky N, Arzi B. Mesenchymal stromal cell therapy for feline chronic gingivostomatitis: Long term experience. Front Vet Sci. 2023;10:1171922. doi:10.3389/fvets.2023.1171922
8. Rivas IL, Soltero-Rivera M, Vapniarsky N, Arzi B. Stromal cell therapy in cats with feline chronic gingivostomatitis: current perspectives and future direction. J Feline Med Surg. 2023;25(8):1098612X231185395. doi:10.1177/1098612X231185395
9. Taechangam N, Iyer SS, Walker NJ, Arzi B, Borjesson DL. Mechanisms utilized by feline adipose-derived mesenchymal stem cells to inhibit T lymphocyte proliferation. Stem Cell Res Ther. 2019;10(1):188. doi:10.1186/s13287-019-1300-3
10. Park SG, An JH, Li Q, et al. Feline adipose tissue-derived mesenchymal stem cells pretreated with IFN-γ enhance immunomodulatory effects through the PGE2 pathway. J Vet Sci. 2021;22(2):e16. doi:10.4142/jvs.2021.22.e16
11. Gallant data on file.
