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Background: The clinical efficacy of sublingual immunotherapy (SLIT) in mite allergy and in mild disease is still a matter of debate, thus we performed a long-term clinical trial.
Methods: The study was randomized, double-blind and placebo-controlled. After a 1-year assessment, 68 patients with mild rhinitis with/without asthma due to mites were randomized to drugs + placebo or drugs + SLIT for 2 years. Sublingual immunotherapy was given as soluble tablets of monomeric carbamylated allergoid. Clinical scores for asthma and rhinitis (0, absent to 3, severe) and drug consumption were assessed by diary card in the period November–February. Quality of life was assessed before and after each observation period and pharmaco-economy data were evaluated as well.
Results: Fifty-six patients completed the study. The rate of dropouts was similar in the two groups. No relevant side effect was reported. There was a significant reduction of total clinical scores (P < 0.05) in the active group vs placebo at the first year, but not at the second whereas nasal obstruction significantly improved in both years (P < 0.05). The reduction of drug intake score was significant only at the first year. No change was observed concerning most of the Short Form-36 items, because at baseline all patients displayed a normal profile. A significant change in SLIT group was seen for the item ‘change in health status’. The need for extra visits was significantly lower in the active group (25%vs 43%).
Conclusions: Sublingual immunotherapy was clinically effective and safe in mite-induced mild disease.
Allergen-specific immunotherapy (IT) is a cornerstone in the management of respiratory allergy (1), and its clinical value is nowadays well recognized. In general, the clinical efficacy (reduction of symptoms and need for medications) of IT seems to be greater in pollen than in mite-induced allergy (1–4). This is probably due to the fact that in the case of dust mite allergy the continuous, although variable, exposure to an allergen sustains a chronic inflammation where the role of immunoglobulin E (IgE) and mast cells is less relevant than in pollinosis.
Starting from the earliest attempts, IT has been administered subcutaneously but due to safety aspects (5, 6) in the last 20 years new routes of administration have been investigated (7) and developed. Among these, the sublingual route (sublingual immunotherapy, SLIT) appeared to be the most promising alternative to the traditional IT. In 1998, the World Health Organization based on an extensive review of the literature, concluded that SLIT was a viable alternative to the injection route (1). These conclusions were subsequently confirmed in the recent ARIA (allergic rhintis and its impact on asthma) guidelines that extended the indication of SLIT to children also (8). Also in the case of SLIT, the effects in mite respiratory allergy were quantitatively less relevant than in pollen allergy, and statistically significant results were often obtained only with long-term treatments (9–11). Moreover, in children, SLIT proved effective only in those subjects with more severe rhinitis symptoms (12). Therefore, there are still some concerns about the indications and efficacy of SLIT in mild disease.
To date, it is recognized that the simple measurement of objective parameters or symptomatic changes does not provide a full evaluation of the effects of a given treatment, but the patients’ perception also plays a relevant role. This is the reason why the assessment of quality of life (QoL) is assuming a more and more important role in clinical trials, especially in allergy (13, 14). In association with the patients’ perception of the impact of disease on his/her life, there is an another parameter that can provide further information about the subject's well-being: the so-called ‘satisfaction’ that is the cognitive product of the comparison between expectations and reality (15, 16). In the case of IT in general, and SLIT in particular, there are few data concerning the QoL aspects (11). Aim of the present study was to evaluate the clinical efficacy and the safety of SLIT over a 2-year period in patients suffering from mild rhinitis due to dust mites. The effects on QoL were assessed as well.
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The use and indication of SLIT in mite allergy are less defined than in pollinosis. In fact, the results of clinical trials are less apparent in term of efficacy and need longer times to become measurable. Some clinical trials have provided positive results (9–11, 25), whereas in other studies the effects were marginal (26) or absent (27, 28). This may be due to the fact that with mites the allergenic exposure is extremely variable during the course of the year and therefore, prolonged periods of observation are needed. Furthermore, mite-induced allergy may provoke less severe symptoms, although long-lasting. It is difficult to carry out studies with mite allergy in adult patients. In fact, it is objectively difficult to keep many patients on a double-blind design, recording symptoms and drug intake continuously for years. We therefore chose to record the clinical scores only 4 months a year, from November to February, when the exposure to allergens was expected to be higher. With this method, we could demonstrate that allergoid SLIT induced a significant improvement of total clinical symptoms and drug consumption at the first year, whereas in the second year no significance was reached. This is consistent with the fact that all patients had a mild disease, and were allowed to use rescue medications for their symptoms. On the other hand, the symptom ‘nasal obstruction’ that is the most bothering symptom of persistent rhinitis, especially in patients allergic to perennial allergens like mites, was improved in both the observation periods. Obstruction in persistent forms is largely sustained by inflammation, and the improvement of obstruction is consistent with the previously demonstrated anti-inflammatory action of the allergoid IT (9). The nonsignificant difference between the two groups at baseline did not affect the final results as confirmed by a time-trend analysis.
Concerning QoL, all patients had QoL profiles not different from a control group of healthy subjects (15, 21–23), so it was not conceivable to obtain an improvement of normal values. Thus, we can deduce that a mild disease does not significantly affect the QoL of patients or, in other words, patients with mild symptoms cope with their disease and do not perceive an impact on daily functioning. This fact, indirectly confirms the validity of the ARIA classification of the severity of rhinitis. In addition, it has been previously shown that generic questionnaires (e.g. the SF-36) may be unable to detect changes in health status (29). On the other hand, a significant change in the item exploring the variation of the disease's status was found and a statistical projection showed that this change would have been maintained and would have become more and more significant in the next years. Of note, there was also a difference in extra visits and working absence in the active group, this indirectly testifying that a general effect on the disease severity has occurred. It remains to be ascertained whether a continuous SLIT treatment in mild disease can be proposed to all patients in clinical practice, although the adherence to treatment was shown not to represent a problem (30).
The clinical effect of SLIT also in mild disease should be considered in the light of the very favourable tolerability profile that would also allow small children to be safely treated (31). In this study, the safety aspect was further ensured by the use, as active principle, of a monomeric carbamylated allergoid, which has a reduced IgE-binding capacity. The monomeric carbamylated allergoid resulted to be very suitable for SLIT treatments because on the one hand its low molecular size (19) allows absorption at the mucosal level and on the other, the carbamylation improves its bioavailability by increasing the resistance to enzymatic degradation at the gastrointestinal level, as shown by biodistribution studies performed with the radiolabelled Der p 2 (32). In conclusion, SLIT with carbamylated allergoid exerts a measurable clinical effect even in mild rhinitis due to mites, and favourably affects the pharmaco-economic profile of the disease.