In dogs with osteoarthritis, is intra-articular allogenic mesenchymal stem cell therapy more effective than placebo effect?

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Appraisal, application and reflection

The aim of osteoarthritis treatment is to decrease pain and increase limb function – enhancing the quality of life of the patient. The current treatment of choice for canine osteoarthritis (OA) is non-steroidal anti- inflammatory drugs (NSAIDs) alongside other conventional therapies including the use of polysulphated glycosaminoglycans, nutritional modifications, physical therapy and weight management (Pettitt & German, 2015). Although proven to be effective at combatting pain and lameness in dogs suffering with OA, owner compliance to daily administration of NSAIDs can be poor (Harman et al., 2016). New interventions such as platelet rich plasma (PRP) and mesenchymal stem cell injections are becoming increasingly popular for their reduced side effects and safety as long-term treatment (Singh, 2012). There are two forms of stem cell therapy available, allogenic and autologous. Most commercially available stem cell therapies for use in dogs are autologous. This Knowledge Summary looked into the efficacy of the use of allogenic stem cells for treatment of OA when compared to a placebo effect. The papers reviewed provided some moderate subjective evidence. No objective evidence was observed. One of the papers (Kim et al., 2019) showed no improvement in lameness based on both subjective and objective veterinary measurements thus indicating that allogenic stem cell treatment alone may have a limited effect on improvement of lameness.

Comparisons between the use of autologous and allogenic stem cells for OA in dogs are yet to be investigated. Both forms of stem cell therapy offer benefits and limitations. Allogenic stem cells offer the benefit of being available ‘off the shelf’ and appear to have a relatively long duration of action (Kim et al., 2019) however questions as to the safety of multiple dosages of allogenic stem cells should be considered. Studies of allogenic stem cell use in animals for other disease processes have identified complications due to graft-versus-host disease (Michálek et al., 2003; and Wi et al., 2021). All three papers reviewed only assessed single dose interventions and the longest time period studied in any of these papers was 6 months (Kim et al., 2019), meaning that long-term adverse effects and the total duration of improvement of a single intra-articular injection of stem cells is unknown. There is also consideration to be made as to the ethics of collecting allogenic stem cells. In two of the studies (Kim et al., 2019; and Maki et al., 2020) the stem cells were collected as a by-product from donor dogs that were already undergoing surgery for other procedures, however in the final study (Harman et al., 2016) it is not stated as to whether the donor dog was undergoing a general anaesthetic for any reason other than stem cell collection. Collection of allogenic stem cells carries all the risks of a general anaesthetic and does not benefit the donor in any way thus it poses a major ethical issue. Autologous stem cells pose less of a risk when considering the patients’ immune system (Khaddour et al., 2020) however they require harvesting from the patient themselves which poses a risk through the need for surgical collection. Autologous stem cells also pose an ethical issue as their production warrants the need for at least two general anaesthetics for the patient (RVC Canine Stem Cell Treatments Owners' Frequently Asked Questions, 2021). Further safety data is required for both forms of stem cell therapy to determine the risk, benefit ratio.

Mesenchymal stem cells can be obtained from a number of different tissues in the body (Hass et al., 2011). Both adipose and umbilical derived stem cells were used in these studies. One study (Kim et al., 2019) suggested that umbilical derived stem cells may be better than adipose derived as they are a population of younger stem cells with a greater ability to differentiate and proliferate. As well as stem cell lineage, the number of viable stem cells in the solution injected into the osteoarthritic joints differed amongst all three papers. One paper (Maki et al., 2020) compared intra-articular injection of different quantities of stem cells and did not identify any significant difference between lower and higher dosages in any of the measured outcomes. Increased volumes of stem cell did appear to have an increased level of IL-10 biomarker in the patients’ serum however, due to sample sizes this correlation was not significant. Age, lineage and quantity of the stem cells may well impact their efficacy and therefore it may be beneficial for future studies to compare these.

The sample size across all three studies was small. Only one of the papers (Kim et al., 2019) had done a pilot study to calculate a power analysis and even in this study the clinical trial sample size was smaller than that calculated therefore indicating a lack of power in the study. Not having a large enough study group could mean that the results were not true of the wider population and statistical analysis done on the results would have been invalid (Suresh & Chandrashekara, 2012).

All studies were blinded. The necessity for blinding was obvious in all three studies as there was a significant placebo effect noted in each. However, the effects of the stem cells went beyond that of the placebo.

The papers reviewed all used subjective primary measure outcomes which have a high potential for bias. This bias was mitigated through use of two well regarded subjective measures – Canine Brief Pain Inventory and Hudson Visual Analog Scale scores, both of which have been evaluated in multiple studies and are well accepted (Hudson et al., 2004; and Brown et al., 2008). Force plate gait analysis used in one paper (Kim et al., 2019) is an objective measure however it is very difficult to take accurately and has lots of room for error (McLaughlin, 2001).

In all of the papers the animals were client owned and taken home throughout the duration of the study and therefore there was a lack of environmental control. However, this provided a perspective on how the animal coped within their usual environment.

There was a potential limitation in the conflict of interest in two of the papers (Harman et al., 2016; and Kim et al., 2019). Both papers had input from employees of major stem cell research companies. This limitation was mitigated through the declaration of the remaining authors expressing that the research was conducted in the absence of any commercial or financial relationship however further funding is required for true independent studies to take place.

Overall, there is weak evidence to suggest that allogenic stem cell use in dogs with osteoarthritis is more efficacious than a placebo effect. However, consideration must also be taken when providing allogenic stem cell use as a treatment to owners such as donor, recipient, dosing, cell therapy formulation, route of administration and veterinary surgeon experience (Maki et al., 2020). Whilst these studies have suggested that allogenic stem cell use is effective as treatment for canine OA when compared to a placebo effect, it would be more useful to compare and recognise its uses to the current known treatments for canine OA, such as NSAIDs or intra-articular corticosteroids.

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