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(unpublished data).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.