To be fair, the Dutch study is a worst-case scenario for SLIT, according to Dr. Nelson. There are data showing adherence to SLIT is best when patients are routinely seen in the office every 3 months, apparently not the case in the Dutch study.
In a soon-to-be-published report, Dr. Nelson has reviewed 11 randomized head-to-head-comparison studies of SLIT versus SCIT and found them consistently uninformative. Most often, the deck was stacked against SLIT because it was given only three times per week and/or in too-low doses. In his view, there is only one enlightening comparative study, a recent randomized trial in which 40 Danish patients allergic to grass pollen received optimally dosed SLIT, SCIT, or neither for 15 months, with the same company’s standardized injectable and tablet Timothy grass preparations being used.
After 15 months, both treatments were effective, clinically as well as immunologically, compared with the no-treatment controls, with the benefits becoming significant in the first 1-3 months. However, the improvements in IgG4, IgE-blocking factor, facilitated antigen presentation, and the basal activation test were generally twice as great in the SCIT group. Moreover, the symptomatic response to nasal challenge – the only measure of clinical response utilized in the study was significantly better than in controls only with SCIT (Clin. Exp. Allergy 2014;44:417-28).
"This is the best comparative study we have, and it may be the best we’ll get. Here both treatments are being given optimally, and it’s very clear that at least in the first year, SCIT beats SLIT. It looks as though SLIT is trying to catch up late but doesn’t quite get there through 15 months. The investigators have stored frozen cells, so we can look forward to data on changes in regulatory T cells and suppression of Th2 cells in further publications," Dr. Nelson said.
Of note, an analysis of seven phase III clinical trials totaling nearly 2,700 adults and children showed that roughly half of them experienced transient local adverse reactions to grass SLIT. The reactions usually began on day 1, lasted 30-60 minutes, and recurred with the first seven or so daily doses. The reactions predominantly involved itching of the mouth or throat. About 10% of patients reported a sensation of swelling in the mouth that wasn’t visible to observers and tended to last longer than a week.
"Some people are surprised at the high incidence of these local, transient adverse reactions," he commented.
A common practice among American allergists is off-label sublingual administration of mixtures of eight or more pollen extracts. But a randomized, double-blind, placebo-controlled clinical trial in which Dr. Nelson was senior coinvestigator suggested this may be counterproductive when such mixtures are given in conjunction with Timothy pollen extract. A SLIT combination of Timothy pollen and nine additional pollen allergen extracts performed significantly worse than Timothy alone at the same dose; in fact, it failed to outdistance placebo in most endpoints (J. Allergy Clin. Immunol. 2009;124:150-6).
"This was a small, 56-patient study that clearly needs to be replicated, but there’s no financial backing for it. This is rather critical, since many people doing off-label sublingual immunotherapy using multiple allergen extracts think that they know what they’re doing. I hope I’ve made the point that they don’t know what dose to use, and there’s no evidence that multiple allergen mixes are really effective," Dr. Nelson said.
Grass allergies are the most common seasonal allergies in the United States. The three standardized SLIT products under FDA review, all of which have been approved in Europe for years, are Grastek, a Timothy grass extract, and Ragwitek, both developed by Merck in partnership with ALK of Denmark, and Oralair, a five-grass product developed by the French company Stallergenes. Oralair, to be marketed in the United States by Greer, contains Timothy grass allergen as well as extracts of four other temperate pasture grasses. Of note, Bermuda and Bahia grasses, common causes of seasonal allergy, aren’t included in Oralair or Grastek.
The companies have pursued different dosing strategies. ALK recommends taking Grastek continuously year-round. Stallergenes recommends starting Oralair a few months before the start of grass allergy season and stopping when the pollen season is over. In one 3-year study, 633 grass-allergic patients were randomized to Oralair or placebo starting 2 or 4 months prior to the pollen season. The reduction in adjusted symptom scores was similar with 2 vs. 4 months of therapy in advance of the allergy season (J. Allergy Clin. Immunol. 2011;128:559-66). That’s an important finding because it means preseasonally treated patients can purchase 8 weeks fewer tablets, the allergist noted.