Effectiveness of mesenchymal stem cell therapy in cats with chronic gingivostomatitis

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.