KNOWLEDGE SUMMARY

Keywords: CATS; FELINE; FELINE CHRONIC GINGIVOSTOMATITIS; REFRACTORY; STEM CELL; TREATMENT

Effectiveness of mesenchymal stem cell therapy in cats with chronic gingivostomatitis

Omid Nekouei, DVM PhD^1*
San Tung Wong, BVM Student¹
Tiffany Ka Yi Leung, BVM Student¹
Qi An Ngai, BVM Student¹
Wing Sum Wong, BVM Student¹
Angel Almendros, DVM MVM PGCertSc MRCVS Dip. ABVP¹

¹ Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong
* Corresponding author email: omid.nekouei@cityu.edu.hk

Vol 9, Issue 1 (2024)
Submitted 15 May 2023; published: 07 Feb 2024; next review: 09 May 2025
DOI: https://doi.org/10.18849/ve.v9i1.680

PICO question

In cats with chronic gingivostomatitis, does using intravenous mesenchymal stem cell therapy, compared to not using it, lead to the improvement of clinical signs?

Clinical bottom line

Category of research

Treatment.

Number and type of study designs reviewed

Five interventional studies (clinical trials).

Strength of evidence

Moderate.

Outcomes reported

The reviewed studies indicate intravenous mesenchymal stem cell (MSC) therapy is safe to administer and can be effective in remission or alleviating the clinical signs of refractory, chronic gingivostomatitis in cats that have undergone full-mouth tooth extraction.

Conclusion

The collective evidence supports the intravenous administration of mesenchymal stem cell (MSC) therapy in cats with chronic gingivostomatitis following dental extraction. However, conducted clinical trials are prone to different degrees of bias due to the lack of independent control groups, the small number of subjects, and enrolling subjects with various severity of the disease. Therefore, more robust evidence can be obtained through well-designed randomised controlled trials to confirm the observed positive effects of the treatment in cats with a broader range of characteristics.

How to apply this evidence in practice

The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.

Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

Clinical scenario

Six months ago, you diagnosed a seven-year-old female domestic short-haired (DSH) cat with severe gingivostomatitis based on the presence of consistent clinical signs, a thorough oral examination, a complete blood work, and oral radiographs. You performed a full-mouth tooth extraction and administered supportive treatment, but the clinical signs persist, and the cat still suffers from pain and has not gained weight. Current treatment modalities, such as oral or injectable corticosteroids and oral cyclosporin were declined by the owner due to concerns of side effects in the unwell animal. You are now looking for alternative therapy options to improve the quality of this cat's life and the remission of clinical signs. A colleague suggests intravenous mesenchymal stem cell (MSC) therapy; however, you are uncertain about the clinical efficacy and safety of this option due to the limited evidence available.

The evidence

Following the eligibility criteria (see Methodology Section), five interventional studies were deemed relevant to the PICO question. Four clinical trials investigated the efficacy and safety of treating cats with feline chronic gingivostomatitis (FCGS) with autologous or allogeneic adipose-derived MSCs (Arzi et al., 2016; 2017; 2020; and 2021), and the other study included treatment with placenta-derived MSCs (Febre et al., 2022). Positive clinical responses to MSC therapy were found in all studies where cats had undergone previous full-mouth tooth extraction (Arzi et al., 2016; 2017; 2020; and Febre et al., 2022). However, in one study, MSC therapy appeared to lack efficacy when applied to affected cats prior to teeth extraction (Arzi et al., 2021). The appraised evidence moderately demonstrated that MSC therapy was safe and resulted in notable clinical improvement in most cats that did not respond to full-mouth tooth extractions. However, these studies had some limitations and were prone to different degrees of bias. The lack of an independent control group (consequently, no randomisation and blinding) and the small unjustified sample sizes (some labeled as pilots) reduced the robustness and generalisability of the findings. Spontaneous recovery from FCGS has never been reported, and cats that did not respond to medical interventions are often euthanised due to the debilitating nature of the disease, which can add to the value of the findings. All in all, our Knowledge Summary provides moderate support to MSC therapy to improve the clinical signs of FCGS-affected cats.

Summary of the evidence

Arzi et al. (2016)

 

Arzi et al. (2017)

 

Arzi et al. (2020)

 

Arzi et al. (2021)

 

Febre et al. (2022)

 

Appraisal, application and reflection

Feline chronic gingivostomatitis (FCGS) is a serious, immune-mediated, oral mucosal inflammatory disease in cats. While the majority of cats respond to total or sub-total dental extraction as the current standard treatment, approximately 30% of cats do not improve (Jennings et al., 2015). Palliative treatment before and/or after dental extraction includes the use of corticosteroids, interferon omega and cyclosporin for their anti-inflammatory and immunomodulatory effects (Hennet et al., 2011; and Lommer, 2013). However, these options often come with several side effects, such as immune suppression due to corticosteroids and gastrointestinal upset for interferon omega and cyclosporin. Mesenchymal stem cell (MSC) therapy is an emerging approach to treating cats with immune-mediated inflammatory disorders, such as FCGS. Mesenchymal stem cells have been used in several conditions where immunomodulation was intended, such as chronic kidney disease in cats (Vidane et al., 2017) and inflammatory bowel disease in dogs (Pérez-Merino et al., 2015). Additionally, other studies have assessed its efficacy and safety in dogs with periodontal disease (Inukai et al., 2013) and osteoarthritis (Huňáková et al., 2020), where no complications were reported. For FCGS, the available evidence on the safety and efficacy of MSC therapy in clinical settings is still scarce. This knowledge summary was prepared to address a critical question posed by feline practitioners regarding the efficacy of intravenous MSC therapy in cats with FCGS.

Following the eligibility criteria, five interventional studies were found relevant to the PICO question. Of which, four studies provided support for the safety and efficacy of MSC therapy toward complete remission or substantial improvement in the clinical signs of FCGS in cats that had undergone full-mouth tooth extraction (Arzi et al., 2016; 2017; 2020; and Febre et al., 2022). However, one trial indicated that MSC therapy prior to full-mouth dental extraction did not lead to substantial improvement (Arzi et al., 2021). Four studies investigated the treatment with two successive intravenous (IV) infusions of adult autologous or allogeneic MSCs (Arzi et al., 2016; 2017; 2020; and 2021), and one study applied a single IV infusion of placenta-derived MSCs (Febre et al., 2022). These five studies shared several outcome parameters in determining the efficacy of the treatment, including improvement in oral lesions, body weight, and behaviour of the subjects.

Although all five studies were clinical trials, they could not collectively provide a strong level of evidence in support of MSC therapy for FCGS in cats due to a number of limitations in their design and conduct. One of the key design issues was the lack of an independent control group of subjects to compare the treatment effect with untreated or other types of standard medical interventions in parallel. Therefore, all of these trials lacked randomisation and blinding, which are the most important components of good clinical trials. This issue makes the reviewed studies prone to different levels of bias. However, with respect to the progressive nature of refractory FCGC and the fact that spontaneous recovery has not been reported, these studies can still provide a moderate level of evidence in support of the treatment.

There were no sample size calculations or justifications in the reviewed studies. Four studies (Arzi et al., 2016;  2017;  2021; and Febre et al., 2022) had a small number of cats, mostly considered pilots. Therefore, several potential confounding factors, such as age, sex, weight, breed, and severity or stage of the disease, could not be considered. This can further limit the generalisability of the results with respect to the broad spectrum of factors affecting FCGS progress and complications in natural circumstances. For instance, concurrent diseases were not determined in these studies, which might have affected the clinical course of the disease and response to MSC therapy. Arzi et al. (2021) reported that the concurrent development of periodontitis in cats might have had a confounding effect on studying the clinical efficacy of MSC therapy. Moreover, the stomatitis disease activity index (SDAI) for each subject differed upon entry into the studies, further complicating the interpretations of their results. It is noteworthy that the study by Febre et al. (2022) was funded by Vetbiobank. Four of the authors were employees of Vetbiobank, and one author was a principal shareholder, which was declared in the conflict of interest statement.

From the five studies, intravenous autologous and allogeneic MSC therapy appear well-tolerated by cats with FCGS. Most side effects observed were mild to moderate, including transfusion reactions, increased respiratory rate, vomiting, and diarrhea which were resolved either spontaneously or therapeutically with no further complications (Arzi et al., 2016; and 2020). Skin necrosis requiring a skin graft was recorded only in one cat that developed oedema at the injection site (Arzi et al., 2020). Nevertheless, the small sample sizes and variable follow-up periods (6–24 months) hindered the long-term evaluations of the safety of MSC therapy in treating FCGS in cats. The potential detrimental consequences of stem cell therapy (e.g., tumorigenesis) have been documented in human patients (Bauer et al., 2018).

The reviewed studies recommended two IV transfusions of 20 million MSCs, 1 month apart, following a lack of response to full-mouth or premolar-molar tooth extraction (Arzi et al., 2016; 2017; 2020; and 2021). Although it was generally demonstrated that both intravenous adipose-derived autologous and allogeneic MSCs were safe and efficacious for treating refractory FCGS, autologous MSCs might be preferred due to a faster response period and higher efficacy (Arzi et al., 2017; and 2021). An infusion rate of 2 million cells per minute was recommended to eliminate potential transfusion reactions (Arzi et al., 2016). Furthermore, a useful biomarker was suggested for predicting the response to adult MSC therapy, i.e., decreased CD8^lo (%) within the CD8+ T cells (Arzi et al., 2016; and 2020). Only one study investigated placenta-derived MSCs with a lower dose of 10 million cells and a single IV transfusion, which showed clinical efficacy despite the abovementioned limitations (Febre et al., 2022). One limitation in the present Knowledge Summary is the fact that 4/5 studies happened to be conducted by one group of researchers; therefore, the paucity of comparable evidence from other places regarding our PICO should be considered in using this summary. A recent descriptive survey conducted by the same research group (Soltero-Rivera et al., 2023) evaluated the long-term safety and efficacy of the intravenous MSC treatment of 38 FCGS patients, including some of the cases included in ‘Arzi et al., clinical trials’ (summarised here) and no adverse events were noted during the 2–9 years of follow-up. The results of this survey further lend support to using both autologous and allogeneic MSC as an efficacious and safe therapeutic option for refractory FCGS. We did not include the latter survey as an independent study in our current knowledge summary for multiple reasons: 1) not meeting one of our important inclusion criteria (i.e., ‘presented adequate details on the intervention’), 2) being at the lowest levels of the pyramid of evidence (as a descriptive survey), and 3) overlapping of cases with the trial subjects already included in our summary.

In conclusion, available studies collectively provide a moderate strength of evidence in support of using intravenous MSCs to treat cats with FCGS refractory to sub-total to total dental extraction. To enhance the strength of evidence and eliminate potential sources of bias, conducting randomised, double-blinded, controlled trials with a sufficient number of subjects is recommended. Nonetheless, the ethical considerations and complications of conducting such clinical trials are recognised.

Methodology

Search strategy

 

Exclusion / inclusion criteria

 

Search outcome

 

Author contributions

Omid Nekouei: Conceptualisation, Methodology (lead), Supervision, Validation, Formal analysis, Writing – Review & editing. San Tung Wong: Data curation, Formal analysis, Writing – Original draft preparation, Methodology. Tiffany Ka Yi Leung: Data curation, Formal analysis, Writing – Original draft preparation, Methodology. Qi An Ngai: Data curation, Formal analysis, Writing – Original draft preparation, Methodology. Wing Sum Wong: Data curation, Formal analysis, Writing – Original draft preparation, Methodology. Angel Almendros: Conceptualisation, Validation, Formal analysis, Writing – Review & editing.

ORCiD

Omid Nekouei: https://orcid.org/0000-0002-2427-4159
Angel Almendros: https://orcid.org/0000-0002-2441-7850

Conflict of interest

The authors declare no conflicts of interest.

References

1. Arzi, , Clark, K. C., Sundaram, A., Spriet, M., Verstraete, F. J. M., Walker, N. J., Loscar, M. R., Fazel, N., Murphy, W. J., Vapniarsky, N. & Borjesson, D. L. (2017). Therapeutic Efficacy of Fresh, Allogeneic Mesenchymal Stem Cells for Severe Refractory Feline Chronic Gingivostomatitis. Stem Cells Translational Medicine. 6(8), 1710–1722. DOI: https://doi.org/10.1002/sctm.17-0035
2. Arzi, , Mills-Ko, E., Verstraete, F. J. M., Kol, A., Walker, N. J., Badgley, M. R., Fazel, N., Murphy, W. J., Vapniarsky, N. & Borjesson, D. L. (2016). Therapeutic Efficacy of Fresh, Autologous Mesenchymal Stem Cells for Severe Refractory Gingivostomatitis in Cats. Stem Cells Translational Medicine. 5(1), 75–86. DOI: https://doi.org/10.5966/sctm.2015-0127
3. Arzi, , Peralta, S., Fiani, N., Vapniarsky, N., Taechangam, N., Delatorre, U., Clark, K. C., Walker, N. J., Loscar, M. R., Lommer, M. J., Fulton, A., Battig, J. & Borjesson, D. L. (2020). A multicenter experience using adipose-derived mesenchymal stem cell therapy for cats with chronic, non-responsive gingivostomatitis. Stem Cell Research & Therapy. 11(1), 115. DOI: https://doi.org/10.1186/s13287-020-01623-9
4. Arzi, , Taechangam, N., Lommer, M. J., Walker, N. J., Loscar, M. R. & Borjesson, D. L. (2021). Stem cell therapy prior to full-mouth tooth extraction lacks substantial clinical efficacy in cats affected by chronic gingivostomatitis. Journal of Feline Medicine and Surgery. 23(6), 604–608. DOI: https://doi.org/10.1177/1098612X20967172
5. Bauer, G., Elsallab, M. & Abou-El-Enein, M. (2018). Concise Review: A Comprehensive Analysis of Reported Adverse Events in Patients Receiving Unproven Stem Cell-Based Interventions. Stem Cells Translational Medicine. 7(9), 676–685. DOI: https://doi.org/10.1002/sctm.17-0282
6. Febre, , Saulnier, N., Roux, P., Boutoille, F., Girard, N., Robert, C., Rakic, R., Rosset, E. & Maddens, S. (2022). Placenta-derived mesenchymal stromal cells as a treatment for refractory chronic gingivostomatitis in cats: eight cases (2018). Journal of Small Animal Practice. 64(4), 296–305. DOI: https://doi.org/10.1111/jsap.13583
7. Hennet, P. R., Camy, G. A. L., McGahie, D. M. & Albouy, M. V. (2011). Comparative efficacy of a recombinant feline interferon omega in refractory cases of calicivirus-positive cats with caudal stomatitis: a randomised, multi-centre, controlled, double-blind study in 39 cats (2011). Journal of Feline Medicine and Surgery. 13(8), 577–587. DOI: https://doi.org/10.1016/j.jfms.2011.05.012
8. Huňáková, K., Hluchý, M., Špaková, T., Matejová, J., Mudroňová, D., Kuricová, M., Rosocha, J. & Ledecký, V. (2020). Study of bilateral elbow joint osteoarthritis treatment using conditioned medium from allogeneic adipose tissue-derived MSCs in Labrador retrievers. Research in Veterinary Science. 132, 513–520. DOI: https://doi.org/10.1016/j.rvsc.2020.08.004
9. Inukai, T., Katagiri, W., Yoshimi, R., Osugi, M., Kawai, T., Hibi, H. & Ueda, M. (2013). Novel application of stem cell-derived factors for periodontal regeneration. Biochemical and Biophysical Research Communications. 430(2), 763–768. DOI: https://doi.org/10.1016/j.bbrc.2012.11.074
10. Jennings, M. W., Lewis, J. R., Soltero-Rivera, M. M., Brown, D. C. & Reiter, A. M. (2015). Effect of tooth extraction on stomatitis in cats: 95 cases (2000–2013). Journal of the American Veterinary Medical Association. 246(6), 654–660. DOI: https://doi.org/10.2460/javma.246.6.654
11. Lommer, M. J. (2013). Efficacy of Cyclosporine for Chronic, Refractory Stomatitis in Cats: A Randomized, Placebo-Controlled, Double-Blinded Clinical Study. Journal of Veterinary Dentistry, 30(1), 8–17. DOI: https://doi.org/10.1177/089875641303000101
12. Pérez-Merino, E. M., Usón-Casaús, J. M., Zaragoza-Bayle, C., Duque-Carrasco, J., Mariñas-Pardo, L., Hermida-Prieto, M., Barrera-Chacon, R. & Gualtieri, M. (2015). Safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells for treatment of dogs with inflammatory bowel disease: Clinical and laboratory outcomes. The Veterinary Journal, 206(3), 385–390. DOI: https://doi.org/10.1016/j.tvjl.2015.08.003
13. Soltero-Rivera, M., Hart. S., Blandino, A., Vapniarsky, N. & Arzi, B. (2023). Mesenchymal stromal cell therapy for feline chronic gingivostomatitis: Long term experience. Frontiers in Veterinary Science. 10:1171922. DOI: https://doi.org/10.3389/fvets.2023.1171922
14. Vidane, A. S., Pinheiro, A. O., Casals, J. B., Passarelli, D., Hage, M. C. F. N. S., Bueno, R. S., Martins, D. S., & Ambrósio, C. E. (2017). Transplantation of amniotic membrane-derived multipotent cells ameliorates and delays the progression of chronic kidney disease in cats. Reproduction in Domestic Animals, 52, 316-326. DOI: https://doi.org/10.1111/rda.12846