Methodology and quality of immunotherapy trials

The tradition of basing the clinical efficacy of immunotherapy on controlled studies is only 55 years old (1). The risk of not comparing the advantage of active treatment with placebo has been illustrated for Hymenoptera venom allergy showing that whole-body extract was as effective as placebo (2). In the evidence-based thinking of modern medicine, it is crucial that treatments proposed to patients fulfill at least the criterium that the clinical efficacy could not be questioned, i.e. there is a solid scientific documentation of the benefit of intervention (3). During the last 10 years the international recognition of efficacy of sublingual immunotherapy is reflected in position papers and meta-analysis. In the 1993 EAACI position paper (4) only two studies supported efficacy. In 1998 (5) the number was doubled, and in the 2001 ARIA document (6) increased to 13 studies. The latest Cochrane analysis (7) identifies 22 studies fulfilling criteria to conclude on efficacy, identical to another review (8). Another review published in 2002 identified 23 studies of which 26% were categorized as unequivocally effective, 35% possible effective (significant improvement in either symptom or medication scores), and 39% without statistically documented efficacy (9). In the latter review eight studies investigating the efficacy of house dust mite allergy documented clinical efficacy in half of the studies. The study in this issue of Allergy (10) further adds to the documentation of efficacy in house dust mite allergy. The immunotherapy study included 32 patients divided in two study groups, and during the 2-year treatment period a steady decrease in rhinitis score was observed. At termination of the study the symptoms in actively treated were reduced to about one-third of placebo-treated. The medication score did not differ significantly between the two groups probably caused by a general low intake of drugs. The study is interesting as it only considered immunotherapy in those patients with residual symptoms after application of mite-reducing intervention (anti-mite mattress cover). Only about 25% of 120 screened patients using mattress cover fulfilled the inclusion criteria of residual symptoms of >40% of the possible maximal symptom score indicating that, in contrast to the general opinion (11) rigorous house dust mite avoidance and exposure control will control most of the clinical symptoms in the majority of house dust mite allergic patients. Like the problem in many immunotherapy studies the level of allergen exposure varies during the treatment period and the initial beneficial effect of intervention seems partly to wean-off during the treatment period reinforcing that the reduction in clinical symptoms is indeed caused by active immunotherapy. Some years ago an editorial on sublingual immunotherapy (12) raised reservations on the quality of published studies. Studies included insufficient number of patients, the drop out rate was unacceptably high, and the randomization process was hampered by no baseline assessment. The conclusion of this editorial was that future studies should be large, properly randomized, and controlled. Baseline symptom levels should be prospectively assessed to ensure precise balancing of the groups for all relevant major end points . In order to bring the documentation for clinical efficacy to modern standard, to ensure that patients are offered treatment based on scientific evidence, and to minimize the risk of misuse of the limited financial resources for scientific evaluations on inconclusive studies, it may be time for scientific journals to reconsider their policy for accepting scientific studies. Several journals (Lancet, New England Journal of Medicine, etc.) only accept studies conducted according to the Consort guidelines (13). Hans-Jørgen Malling Allergy Clinic, National University Hospital, Copenhagen, Denmark