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BACKGROUND: Epicutaneous allergen administration using a patch may be an alternative to subcutaneous or sublingual immunotherapy. OBJECTIVE: To optimize treatment dose and to demonstrate the efficacy and safety of epicutaneous immunotherapy. METHODS: This monocentric, placebo-controlled, double-blind trial included 132 patients with grass pollen-induced rhinoconjunctivitis. In February 2008, patients were randomly allocated to receive placebo or 3 different doses of allergen. Before and during the pollen season 2008, patients received 6 weekly patches. Efficacy was assessed 4 to 5 months later (n = 110) and during the pollen season of the treatment-free follow-up year in 2009 (n = 93). The primary outcome was patient-reported changes in hay fever symptoms assessed by a visual analog scale. Secondary outcome measures were weekly visual analog scale symptom scores during pollen season, use of rescue medication, changes in conjunctival and skin reactivity, as well as safety. RESULTS: Hay fever symptoms during the pollen season were reduced by more than 30% in 2008 and by 24% in 2009 in the high-dose group as compared with that in the placebo group, and the alleviation of symptoms in the follow-up year was dependent on the treatment dose. Higher allergen doses were associated with drugrelated adverse events (AEs), predominantly manifested by pruritus, erythema, wheal, or eczema. Eleven systemic AEs of grades 1 to 2 required treatment and led to study exclusion. The dropout rate due to AEs was 8.3%. No drug-related serious AE was recorded. CONCLUSION: Epicutaneous immunotherapy is safe and efficacious in a dose-dependent manner after 6 patches only.

The results of our third trial on epicutaneous allergen-specific immunotherapy (EPIT) will be presented and discussed in the context of our previous trials. This monocentric, placebo-controlled, double-blind phase I/IIa trial included 98 patients with grass pollen rhinoconjunctivitis. Prior to the pollen season 2009, patients received six patches (allergen extract: n = 48; placebo: n = 50) with weekly intervals, administered onto tape-stripped skin. Allergen EPIT produced a median symptom improvement of 48% in 2009 and 40% in the treatment-free follow-up year 2010 as compared to 10% and 15% improvement after placebo EPIT (P = 0.003). After allergen EPIT but not placebo EPIT, conjunctival allergen reactivity was significantly decreased and allergen-specific IgG4 responses were significantly elevated (P < 0.001). In conclusion, our three EPIT trials found that allergen EPIT can ameliorate hay fever symptoms. Overall, treatment efficacy appears to be determined by the allergen dose. Local side-effects are determined by the duration of patch administration, while risk of systemic allergic side-effects is related to the degree of stratum corneum disruption.

To cite this article: Senti G, von Moos S, Kündig TM. Epicutaneous allergen administration: is this the future of allergen‐specific immunotherapy? Allergy 2011; 66: 798–809. Abstract IgE‐mediated allergies, such as allergic rhinoconjunctivitis and asthma, have become highly prevalent, today affecting up to 30% of the population in industrialized countries. Allergen‐specific immunotherapy (SIT) either subcutaneously or via the sublingual route is effective, but only few patients (<5%) choose immunotherapy, as treatment takes several years and because allergen administrations are associated with local and, in some cases, even systemic allergic side‐effects because of allergen accidentally reaching the circulation. In order to resolve these two major drawbacks, the ideal application site of SIT should have two characteristics. First, it should contain a high number of potent antigen‐presenting cells to enhance efficacy and shorten treatment duration. Secondly, it should be nonvascularized in order to minimize inadvertent systemic distribution of the allergen and therefore systemic allergic side‐effects. The epidermis, a nonvascularized multilayer epithelium, that contains high numbers of potent antigen‐presenting Langerhans cells (LC) could therefore be an interesting administration route. The present review will discuss the immunological rational, history and actual clinical experience with epicutaneous allergen‐specific immunotherapy.

Opinion statementIgE-mediated allergies today affect up to 30 % of the population in industrialized countries. Allergen immunotherapy is the only disease-modifying treatment option with a long-term effect. However, very few patients (<5 %) choose immunotherapy, due to the long treatment duration (between 3–5 years) and possible local and systemic allergic side effects of the allergen administrations. The latter occur when an allergen accidentally reaches the blood circulation. Therefore, the ideal application route for allergen immunotherapy should be characterized by two hallmarks: firstly, by a high number of potent antigen-presenting cells, which enhance efficacy and thus shorten treatment duration. Secondly, the allergen administration site is ideally non-vascularized, so that inadvertent systemic distribution of the allergen and consequent systemic allergic side effects are minimized. The epidermis contains high numbers of potent antigen-presenting Langerhans cells and, as an epithelium, is non-vascularized. Therefore, the epidermis represents an interesting administration route. Historical evidence for the clinical efficacy of epicutaneous allergy immunotherapy (EPIT) has now been strengthened by a number of recent double-blinded placebo-controlled clinical trials performed by independent groups. We review the immunological rationale, history and clinical experience with epicutaneous allergy immunotherapy.

Background and objectivesIn patients with kidney failure due to IgA nephropathy, IgA deposits can recur in a subsequent kidney transplant. The incidence, effect, and risk factors of IgA nephropathy recurrence is unclear, because most studies have been single center and sample sizes are relatively small.Design, setting, participants, & measurementsWe performed a multicenter, international, retrospective study to determine the incidence, risk factors, and treatment response of recurrent IgA nephropathy after kidney transplantation. Data were collected from all consecutive patients with biopsy-proven IgA nephropathy transplanted between 2005 and 2015, across 16 “The Post-Transplant Glomerular Disease” study centers in Europe, North America, and South America.ResultsOut of 504 transplant recipients with IgA nephropathy, recurrent IgA deposits were identified by kidney biopsy in 82 patients; cumulative incidence of recurrence was 23% at 15 years (95% confidence interval, 14 to 34). Multivariable Cox regression revealed a higher risk for recurrence of IgA deposits in patients with a pre-emptive kidney transplant (hazard ratio, 3.45; 95% confidence interval, 1.31 to 9.17) and in patients with preformed donor-specific antibodies (hazard ratio, 2.59; 95% confidence interval, 1.09 to 6.19). After kidney transplantation, development of de novo donor-specific antibodies was associated with subsequent higher risk of recurrence of IgA nephropathy (hazard ratio, 6.65; 95% confidence interval, 3.33 to 13.27). Immunosuppressive regimen was not associated with recurrent IgA nephropathy in multivariable analysis, including steroid use. Graft loss was higher in patients with recurrence of IgA nephropathy compared with patients without (hazard ratio, 3.69; 95% confidence interval, 2.04 to 6.66), resulting in 32% (95% confidence interval, 50 to 82) graft loss at 8 years after diagnosis of recurrence.ConclusionsIn our international cohort, cumulative risk of IgA nephropathy recurrence increased after transplant and was associated with a 3.7-fold greater risk of graft loss.

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