CLINICAL RESEARCH: Use of cyclosporine for the treatment of refractory lymphocytic-plasmacytic gingivostomatitis in cats

OBJECTIVE: To evaluate clinical efficacy of cyclosporine in cats with lymphocytic-plasmacytic gingivostomatitis who have not responded to extraction of premolar and molar teeth.

DESIGN: Randomized, prospective, placebo-controlled, double-blind clinical trial.

RATIONALE: “Feline stomatitis” consists of a number of syndromes with the common presenting clinical symptom being severe inflammation of the gingiva (gums) and oral mucosa. Clinical signs may include bad breath, poor grooming, difficulty eating, pain when eating or yawning, irritability, and weight loss. Microscopic examination of affected tissues typically reveals infiltrates of lymphocytes and plasma cells^1,2, giving this complex the name “lymphocytic-plasmacytic gingivitis-stomatitis” (LPGS). The initiating cause is usually not identified, and may differ from case to case. Contributing factors may include viral infection (calicivirus, herpesvirus, feline leukemia virus and feline immunodeficiency virus), feline odontoclastic resorption lesions, periodontal disease, food allergies, and hypersensitivity to plaque bacteria^3,4,5,6,7,8. 

Approximately 80% of cats with LPGS will significantly improve following extraction of the premolar and molar teeth⁹. However, for the remaining 20%, continued administration of steroids is often required, with variable efficacy and potentially dangerous side effects.  

Cyclosporine, a medication which has long been used in both human and veterinary medicine to prevent organ rejection in transplant patients, inhibits the activity of T-lymphocytes. Because T-lymphocytes are involved in activating plasma cells (B-lymphocytes), suppressing the activity of T-lymphocytes may result in a decrease in inflammation caused by both T- and B-cells, such as is typical with LPGS. 

INCLUSION CRITERIA:

• Biopsy-confirmed diagnosis of LPGS*
• Previous extraction of all premolar and molar teeth
• Indoor-only
• FIV/FeLV negative
• Complete blood count, serum biochemistry profile, and urinalysis within 1 month of starting the study
• Fed a commercial feline diet which remains consistent throughout the study
• Absence of pre-existing immunosuppressive disease (e.g. diabetes) or liver disease
• Has not received injectable corticosteroids within 6 weeks of starting the study
• Has not received oral corticosteroids within 1 week of starting the study

 * If biopsy has not been performed prior to entrance into the study, tissue will be collected for histopathological analysis at the time of the initial evaluation, and the client will be charged for the cost of histopathological analysis ($128.75).

INFORMATION FOR CLIENTS: Cost and Long-term expectations: The initial examination costs $105. If the cat appears to be a candidate for inclusion in the study, anesthesia, full-mouth radiographs, and periodontal treatment will be performed on any remaining teeth at no charge. If full-mouth radiographs reveal significant periodontitis or odontoclastic resorption lesions at any remaining teeth, appropriate treatment will be performed at minimal charge to the client and the cat will be temporarily disqualified from the study. If root remnants are present and protruding from the gingiva, they will be extracted at a minimal charge and the cat will be temporarily disqualified from the study. If subsequent examinations at least 4 weeks post-operatively reveal persistent oral inflammation, these cats may then be enrolled in the study. If root remnants are present beneath the gingiva, they will not be extracted but their presence and location will be recorded.

Following initial evaluation under anesthesia, each patient's information will be submitted to Golden Gate Veterinary Pharmacy (including name, age, breed, weight, client's name and contact information). Cats will be randomly assigned to one of two groups based on a coin toss by Golden Gate Veterinary Pharmacy staff, and either cyclosporine or a placebo will be mailed to each client with appropriate instructions. Cats assigned to the treatment group will receive 2.5mg/kg cyclosporine (1.0ml of a custom-compounded Neoral®  suspension in a cod liver oil base with tuna flavoring) twice daily. Cats assigned to the control (placebo) group will receive 1.0ml of the same oil base with tuna flavoring twice daily. Neither the investigator (Dr. Lommer) nor the cat owners will be aware of each cat's assigned group (making this a "double blinded" trial). Medications will be provided to the clients at no charge.

Examinations will be performed every 2 weeks for 6 weeks following initiation of treatment. At each of the three follow-up visits, cats will be graded on a scale of 0-3 in the following categories: client’s evaluation (appetite, activity level, grooming behavior, and perceived comfort), weight gain or loss, and a visual inspection by Dr. Lommer. At the second recheck (4 weeks after starting treatment), blood will be collected and submitted for evaluation of serum cyclosporine levels. Results will not be revealed until all rechecks have been completed and scores recorded for that individual. At the final recheck, photographs will be obtained (under sedation if necessary). There will be no charge for these follow-up visits, blood tests, or sedation.

At the end of the 6 week evaluation period, owners of cats who had been receiving placebo will be given the opportunity to try cyclosporine at no charge for 6 weeks if they agree to return for 3 follow-up visits and grading as described above. Cyclosporine testing will be performed on these cats four weeks after initiating treatment, at a cost of $156 to the clients.

Owners who wish to maintain their cats on cyclosporine long-term after completion of the study will be responsible for the costs associated with this treatment. Cyclosporine solution for an average cat will cost approximately $75 for a one-month supply. Cyclosporine levels should be performed 2-4 weeks after initiating treatment and whenever necessary to calibrate a patient's dosing; this test costs $156 if performed by Aggie Animal Dental Service; family veterinarians may also perform this testing, although fees may vary. Complete blood count and serum biochemistry profile should be performed every 6 months when patients are receiving cyclosporine; these tests generally cost about $95-110 and can be performed by the patient's family veterinarian.

STUDY DESIGN:

Cats will be randomly assigned to either a treatment or control (placebo) group based on a coin toss by personnel at Golden Gate Veterinary Pharmacy. Assignment will be recorded by pharmacy personnel and kept confidential until the study's completion: neither the investigator nor the cats’ caretakers will be aware of each animal’s assigned group. The medication will be mailed directly from Golden Gate Veterinary Pharmacy to the clients.

At the initiation of the study, each cat will be anesthetized, photographs will be taken, and full-mouth radiographs will be obtained using bisecting angle, parallel, and near-parallel extra-oral techniques. Periodontal treatment will be performed on any remaining teeth. If full-mouth radiographs reveal significant periodontitis or odontoclastic resorption lesions at any remaining teeth, appropriate treatment will be performed at no charge and the cat will be temporarily disqualified from the study. If root remnants are present and protruding from the gingiva, they will be extracted and the cat will be temporarily disqualified from the study. If subsequent examinations at least 4 weeks post-operatively reveal persistent oral inflammation, these cats may then be enrolled in the study. If root remnants are present beneath the gingiva, they will not be extracted but their presence and location will be recorded.

Cats assigned to the treatment group will receive 2.5mg/kg cyclosporine (1.0ml of a custom-compounded Neoral® suspension in a cod liver oil base with tuna flavoring) twice daily. Cats assigned to the control (placebo) group will receive 1ml of the same oil base with tuna flavoring twice daily. 

Examinations will be performed every 2 weeks for 6 weeks following initiation of treatment. At each of the three follow-up visits, cats will be graded according to the Stomatitis Disease Activity Index.  At the second recheck (4 weeks after starting treatment), blood will be collected and submitted for evaluation of serum cyclosporine levels. Results will not be revealed until all rechecks have been completed and scores recorded. At the final recheck, photographs will be obtained (under sedation or anesthesia if necessary).

Stomatitis Disease Activity Index used for scoring:

Owner evaluation:  Initial: 0 = comfortable: normal appetite, activity level, and grooming behavior   1 = slight discomfort: slight reduction in appetite, activity level and/or grooming 2 = significant discomfort: significant reduction in appetite, activity level, and/or grooming   3 = extreme discomfort: lethargic, unable to eat, grooming very little or not at all.  Follow-up: 0 = significant improvement    1 = mild improvement   2 = no change   3 = worse

Weight: 0 = gain >0.5kg   1 = gain >0.25kg but <0.5kg   2 = stable or <0.25kg gain   3 = weight loss

Inflammation of oral cavity sites: 0 = none   1 = mild   2 = moderate   3 = severe

STATISTICAL ANALYSIS: Cats in each group will be graded according to the Stomatitis Disease Activity Index above. Data from the two groups will be compared using 95% confidence intervals (Wilson procedure without correction for continuity) as well as a t-test. A p-value of <0.05 will be considered significant. ANOVA tests may be performed to determine whether presence of root remnants, age, breed, or other factors affected outcome.

FURTHER INFORMATION:

• Aggie Animal Dental Service is an independent specialty practice. Neither of our affiliated hospitals, Madera Pet Hospital or Pets Unlimited, is associated with this research project.

• No guarantee is implied as to the results that may be obtained.

• Enrollment in this study involves examination and possible surgical procedures under general anesthesia. The administration of any anesthetic agent and the performance of any surgical procedure carries a small but realistic possibility of complications, which can include death.

• There are no FDA-approved cyclosporine formulations for cats, so its use is “off-label”. Side effects of cyclosporine may include stomach upset (decreased appetite, vomiting, diarrhea). In addition, animals receiving cyclosporine are more susceptible to infections (including bacterial, viral, fungal and parasite infections) and should not be fed raw meat or exposed to other animals from unknown backgrounds. Fatal Toxoplasmosis and disseminated Mycobacterium avium infection have been reported in cats receiving cyclosporine^10,11.

• Aggie Animal Dental Service receives no financial support from, and does not have a vested or proprietary interest in Novartis, the manufacturer of Neoral®.

• This research project is partially funded by a grant from the Academy of Veterinary Dentistry.

REFERENCES:

1. Diehl K, Rosychuk RA. Feline gingivitis-stomatitis-pharyngitis. Vet Clin North Am Small Anim Pract. 1993 Jan;23(1):139-53.

2. Johnessee JS, Hurvitz AI. Feline plasma cell gingivitis-pharyngitis. J Am Anim Hosp Assoc 1983: 19: 179–181.

3. Pedersen NC. Inflammatory oral cavity diseases of the cat. Vet Clin North Am Small Anim Pract 1992: 22: 1323–1345.

4. Reubel GH, George JW, Higgins J, Pedersen NC. Effect of chronic feline immunodeficiency virus infection on experimental feline calicivirus-induced disease. Vet Microbiol 1994: 39: 335-351.

5. Reubel GH, Hoffmann DE, Pedersen NC. Acute and chronic faucitis of domestic cats. A feline calicivirus-induced disease. Vet Clin North Am Small Anim Pract 1992: 22: 1347-1360.

6. Tenorio AP, Franti CE, Madewell BR, Pedersen NC. Chronic oral infections of cats and their relationship to persistent oral carriage of feline calici-, immunodeficiency, or leukemia viruses. Vet Immunol Immunopathol 1991: 29: 1-14.

7. Waters L, Hopper CD, Gruffydd-Jones TJ, Harbour DA. Chronic gingivitis in a colony of cats infected with feline immunodeficiency virus and feline calicivirus. Vet Rec 1993: 132: 340-342.

8. Lommer MJ, Verstraete FJM. Concurrent oral shedding of feline calicivirus and feline herpesvirus 1 in cats with chronic gingivostomatitis. Oral Microbiol Immunol 2003: 18: 131–134.

9. Hennet PR. Chronic gingivo-stomatitis in cats: long term follow up of 30 cases treated by dental extractions. J Vet Dent 1997; 14(1): 15-21.

10. Last RD, Suzuki Y, Manning T, Lindsay D, Galipeau L, Whitbread TJ. A case of fatal systemic toxoplasmosis in a cat being treated with cyclosporin A for feline atopy.Vet Dermatol. 2004 Jun;15(3):194-8.

11. Griffin A, Newton AL, Aronson LR, Brown DC, Hess RS. Disseminated Mycobacterium avium complex infection following renal transplantation in a cat.J Am Vet Med Assoc. 2003 Apr 15;222(8):1097-101, 1077-8.
     

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