DISCUSSION
To the authors’ knowledge, this was the first study to implement an EPIT protocol for allergens in veterinary medicine and to evaluate its impact on CAD treatment.
Inspired by encouraging human reports27,29,31,32,35-38and engaged with the idea of finding a practical, needle-free, owner- and pet-friendly AIT route, recognising the skin’s unique immunological features, this pilot was designed as a proof-of-concept clinical trial, to primarily investigate the feasibility, effectiveness, and safety of EPIT in spontaneous, nonseasonal, mite-sensitive CAD. Although small and uncontrolled, this study demonstrates the safety and practicability of EPIT in dogs and provides promising initial evidence of its efficacy in CAD management.
Sixteen atopic dogs of two CAD predisposed breeds were recruited for once-weekly, 12-hour patch application over six months. The inclusion of two common breeds with high CAD prevalence was meant to avoid breed-related differences in treatment response that might exist if only one breed were selected. Conversely, including more breeds would require several sample groups and dogs, which at this research stage was not feasible. Therefore, French bulldogs, with an empirically assumed background of poor response to general CAD treatments, and Labrador retrievers, with a perceived good treatment response, were screened (unpublished data). The belief of a breed-related EPIT response was not confirmed as no statistical breed effect was observed for all parameters. As the immune response depends on the allergen contact time with skin’s immune cells, and periods of 8 to 48 hours have proven efficacious in EPIT human studies for environmental allergies31,32,35, 12 hours was deemed sufficient to trigger the desired immune response and plausible for application in dogs. Alike previous EPIT studies31,32,35, a weekly protocol was applied.
Considering the AIT long treatment duration and delay until clinical improvement (typically three to twelve months)7,8, six months could be insufficient to show significant effects. Strikingly, this study shows significant clinical improvement within only one month of EPIT, for both pruritus (p=0.003) and skin lesions’ scores (p=0.009) (figure 3), supporting EPIT’s potential to induce a rapid clinical response. Over six months, both PVAS and 2D-IGA mean scores decreased monthly (table 3), reaching a significant improvement at the study end (PVAS: p=0.000015; 2D-IGA: p=0.006) (figure 3).
Notwithstanding the more stringent outcome measures used in this study, compared with ≥ 50% reduction of baseline pruritus/skin lesion scores45, success rates of 73.3% and 66.7% were achieved, respectively, in the pruritus and skin lesion evaluation, after 6-month EPIT. Although the different outcome measures used in this study do not allow direct comparison with other canine AIT routes11-18, the results of this study suggest a similar or even better response rate for EPIT, which aligns with previous EPIT human studies31,32,35-38 and preliminary 3-month EPIT results on CAD47.
Noteworthy, all dogs showed improved pruritus scores after both three (56.1% mean improvement) and six months (63.1% mean improvement). Additionally, after three months, all dogs had improved pruritus severity level, including the two that were initially moderate-to-severe at enrolment, normal-to-mild at three months, but moderate-to-severe again after six months. As the 6-month observation occurred in spring and one of these dogs was pollen sensitised, the acute CAD flare at six months may have been triggered by a clinical development of a seasonal CAD strand. For the other dog, there was no evidence of reported flare factors.
The success rate of skin lesions’ outcome (66.7%) was slightly lower than that for pruritus (73.3%), which is coherent in a clinical context, as complete resolution of skin lesions can be hard to achieve and often requires prolonged treatment. Furthermore, 60% of dogs were normal-to-mild at the study start (table 2) and improving an already mild lesion condition is challenging. Nevertheless, at 6-month EPIT, 93.3% of dogs presented a normal-to-mild status (table 2).
After 6-month EPIT, 93.3% of owners rated the response to EPIT as good-to-excellent, which captures the owner’s perceived EPIT benefit. While the protocol was time-consuming and required strong owner’s commitment, which for dogs with a less tolerant character may have rendered weekly application more demanding, EPIT improved QoL for 93.3% of dogs and families (58.4% mean improvement), and for 66.7% of them by more than 50%. The significant decrease in mean QoL scores throughout six months (table 3, figure 3) and the QoL improvement in 86.7% of dogs at 3-month EPIT also mirror the owner’s perceived efficacy and reinforces EPIT’s potential for rapid clinical response. As CAD meaningfully impacts the well-being of those involved, QoL assessment was a valuable research topic for this study.
EPIT was able to engage the immune system, producing IgE changes already noticeable at three months. Partial desensitisation to at least one mite occurred in 40% of dogs after three months and in 46.7% at 6-month EPIT, while full desensitisation to all mites was achieved by 13.3% of dogs at both timepoints. These findings are consistent with previous human48,49,50 and canine16,26,51studies, reporting decreased serum IgE levels during AIT. Although no further conclusions could be drawn due to the wide IgE values’ variation, the observed immune modulation suggests EPIT’s objective effect. However, similarly to previous studies26,51, mite desensitisation and IgE values’ changes did not correlate with clinical improvement in this study, possibly due to CAD’s complex and multifactorial nature.
EPIT was practicable, well-tolerated, and safe, as no systemic or severe local reactions were observed. Self-limiting local pruritus was the most common side-effect, alike reported in literature5,6. Even so, it remains unclear the bodysuit contribution for pruritus. Although recorded as adverse effects, local skin reactions under the patch indicate that EPIT was able to pulse and activate skin dendritic cells for antigen presentation.
Adherence to chronic therapeutics is a critical challenge for clinical research, especially for AIT, owing to high withdrawal rates5,17,18,22,24. We report a 93.8% adherence rate for EPIT, which is higher than that published for other routes14,17,18,22,51. Despite the encouraging compliance, this study only followed patients for six months. It is possible that longer trials would result in higher dropout rates.
This pioneer approach suggests that a simple, practical innovation as EPIT can be safe, effective, and improve AIT adherence, which may facilitate its future broad application.
Several limitations can be pointed to this study. Firstly, as a pilot trial, it was open-labelled, neither blinded nor placebo-controlled, as other dog studies11,13,15,17,18,26. We faced ethical concerns justifying a control group in a six-month study on a distressing and QoL-disruptive syndrome as CAD. Nevertheless, clinical assessment scales were used to minimise potential bias. Secondly, this was a small-scale study, and it is likely that six months cannot show EPIT’s full clinical and immunological potential. Therefore, scientifically sound, prospective, larger, and longer-lasting trials are needed to confirm these findings and assess the long-term EPIT benefits. Thirdly, some dogs were on antipruritic medication with considerable effects on the immune system, which is controversial during AIT, despite poorly studied in dogs6,18. Medication-limiting criteria were set to minimise this interference in EPIT success evaluation, so changes in posology before and during EPIT or introduction of new generalised treatments were not allowed. Noteworthy, although focal treatment with topical products was allowed, only one dog required such intervention with an antibacterial product, due to localised pyodermitis. Thus, significant clinical improvement is unlikely to be due to concurrent medication. Moreover, we found ethically questionable to stop dogs’ supportive medication, as they would suffer unnecessarily, and owner’s compliance could be compromised. Finally, this study used a new validated skin lesions’ globally assessment tool (2D-IGA), which overcomes certain limitations of other instruments44. However, to guide observers in their lesion extent evaluation, a German shepherd dog silhouette is supplied, which is less suitable for brachycephalic breeds as French bulldogs44.
This proof-of-concept study demonstrates EPIT’s feasibility, effectiveness, and safety in CAD treatment. Promising six-month results emphasise EPIT’s potential as a non-invasive, safe, effective, compliance-enhancing, and at-home easy-to-use route. Encouraged by this pilot study, a novel, design- and formulation-improved EPIT project is underway.