Sublingual or injection immunotherapy: the final answer?
Authors: G. Passalacqua, G. W. Canonica
Journal: Allergy (2003)

The history of sublingual immunotherapy (SLIT) is a matter of the last 15 years only, but it parallels that of subcutaneous immunotherapy (SCIT) (1), since the earliest studies were only aimed at demonstrating the clinical efficacy. Subsequently, data about the mechanisms of action (2–4), postmarketing surveillance studies (5, 6), and results concerning the long-lasting efficacy (7) appeared. Finally, a metaanalysis (8) confirmed as an evidence A the efficacy of SLIT in allergic rhinitis. This historical pathway lead to the acceptance of SLIT, that is now recognized as a viable alternative to the injection route in the official documents (9). Despite the number of studies and the overall weight of the evidence, some concerns about the use of SLIT still remain (10, 11). For instance, it has been correctly highlighted that the self-administration of the treatment might pose adherence problems. Moreover, there are still uncertainties about the optimal maintenance dose to be administered, as in the positive studies, dosages ranging from three to 375 times greater than with SCIT (12, 13) were employed, and there is still no evidence of a defined dose–response relationship. Probably, one of the most controversial aspects of SLIT is the direct comparison against injection immunotherapy as far as the magnitude of the clinical efficacy (and the safety) are concerned. From a practical viewpoint, allergists could ask why they should use a new form of immunotherapy when a well-established treatment is already available. In this sense, they should be assured, with experimental evidence, that the new treatment is better or, at least, equivalent to the old one. In the case of specific immunotherapy it is difficult, for practical reasons, to provide a final answer to the question. In fact, clinical studies with immunotherapy are intrinsically time-consuming and expensive, a correct selection of homogeneous patients is difficult to make and the mandatory inclusion of a placebo arm further complicates the problem. Moreover, as two different ways of administration are to be compared, a double dummy design is definitely the more appropriate method to provide an objective evaluation. Indeed, there have been in the past few studies attempting to compare SCIT and SLIT, only one of them was double blind and double dummy (14), but not placebo controlled. It involved 20 grass pollen allergic patients for two pollen seasons. The trial showed that SLIT and SCIT had equivalent clinical efficacy (symptoms and need for drugs). Ongari et al. (15) demonstrated in open fashion that the two routes had similar efficacy, again in 20 patients with grass allergy and that both treatments were significantly more effective than pharmacological treatment alone. Bernardis et al. (16) performed another open study with an Alternaria tenuis vaccine, and found a significant clinical improvement with both SLIT and SCIT after 12 months. A study by Piazza et al. (17), assessed in an open way the clinical efficacy of SLIT, SCIT and local nasal IT in 43 patients with rhinitis because of mites, but in this study only the immunological changes were emphasized. The authors evidenced the good tolerability of SLIT, but SCIT resulted more effective and able to induce systemic immunological changes. The most recent comparative study was placebo controlled, but open and not randomized (18). In 36 mite-allergic patients, it was shown that SLIT well controlled rhinitis symptoms, but only SCIT was effective on asthma. The aforementioned studies, including the double dummy one, had remarkable methodological limits: the number of subjects was small and, in some studies, there was or no baseline evaluation or no randomization or no placebo control. These facts, in addition to the controversial results, made those studies not conclusive. In the present issue of Allergy, Khinchi et al. (19) report the results of a clinical trial comparing SLIT and SCIT. The study was randomized, double blind, double dummy and placebo-controlled, therefore three parallel arms were planned. Clinical scores (symptoms of rhinitis and asthma), medication intake, side effects and quality of life were the evaluation parameters. Seventy-one patients were randomized to SLIT, SCIT or placebo. The patients were followed-up for two consecutive birch pollen seasons after the baseline one. By taking into account the baseline conditions, the Authors found no significant difference between SLIT and SCIT in term of symptom load and drug intake. Both active treatments proved superior to placebo. Looking at the results, SCIT appeared slightly more effective: the overall disease severity was reduced by 50% in the SLIT group and by 66% in the SCIT group vs baseline. This aspect was counterbalanced by the superior safety profile of SLIT (no grade 3–4 side effect with SLIT, one grade 4 and five grade 3 with SCIT). No change in quality of life could be detected and, unfortunately, the low pollen count did not allow performing evaluations in the third year of the study. This clinical trial has several distinctive merits, thus representing a significant advance with respect to the previous studies in the field. First, the correct design that involves also a placebo arm; secondly, there was a baseline (before randomization) assessment; thirdly, the baseline evaluation allowed balancing the distribution of patients accordingly to severity of symptoms; fourthly, a preliminary estimation of the required dimension of the sample was correctly carried out. Therefore, the evidence provided by this study is strong. Taking into account both the magnitude of the effect and the safety, we can conclude that SLIT and SCIT are almost equivalent, when they are compared through a rigorous enough study design. It can be argued that the results obtained with birch pollen cannot be extended to all allergens, but there is also no reason to believe that immunotherapy works with different mechanisms for different allergens. Thus, the study by Khinchi et al. represent a cornerstone, and enhances our confidence in the clinical role of SLIT.