Among patients with allergy to grass pollen, 2 years of sublingual immunotherapy for allergic rhinitis are no more effective than placebo at relieving symptoms 1 year after the end of treatment, a new study shows.
The findings suggest that 3 years of treatment with sublingual immunotherapy are necessary for long-term control of moderate to severe allergic rhinitis, Guy W. Scadding, MBBS, PhD, and colleagues write in an article published in the February 14 issue of JAMA.
Given the negative results of the trial, "clinicians should be advised to follow established guidelines that recommend at least 3 years treatment," write Dr Scadding, from Imperial College and Royal Brompton and Harefield Hospitals NHS Foundation Trust, London, United Kingdom, and colleagues.
Subcutaneous immunotherapy (SCIT) is established as a highly effective treatment for rhinitis symptoms, whereas sublingual immunotherapy (SLIT) is a more recent alternative, the authors explain. "Three years of continuous treatment with immunotherapy via either delivery method modifies the underlying course of the disease with long-term remission of symptoms for several years after stopping treatment."
However, such a long treatment is expensive and inconvenient for the patient; thus, the researchers designed this randomized, double-blind, placebo-controlled trial to study the effects of 2 years of SLIT on the course of allergic rhinitis.
The authors randomly assigned patients to one of three groups: SLIT tablets plus placebo injections, SCIT injections plus placebo tablets, or placebo tablets plus placebo injections. Patients had to be 18 to 65 years of age with at least a 2-year history of moderate to severe grass pollen-induced allergic rhinitis, defined as symptoms that interfered with daily activities or sleep. The diagnosis was confirmed with a skin prick test, measurement of serum-specific immunoglobulin, and a grass allergen challenge.
The study ran from March 2011 to March 2015. Its primary end point was the difference between SLIT and placebo to a grass pollen allergen challenge 1 year after the end of treatment, as measured by the Total Nasal Symptom Score (TNSS), a questionnaire in which patients are asked to rate their symptoms, ranging from 0 (none) to 12 (maximum intensity), with scores of 7 or more out of 12 indicative of moderate to intense severity.
Secondary end points included other symptomatic measures such as peak nasal inspiratory flow and scores on the weekly Mini Rhinoconjunctivitis Quality of Life Questionnaire.
The use of rescue medications was monitored by giving patients packages containing desloratadine tablets, eye drops, and nasal spray before pollen season, with instructions to return all leftover medication to the investigators at the end of the study.
A total of 106 patients were enrolled in the study, of whom 92 continued to the primary end point evaluation 3 years later: 30 patients in the SLIT group and 31 each in the placebo and SCIT groups. They had a mean age of 33.5 years and included 34 women (32.1% of the original 106).
At baseline, the mean TNSS scores were 6.36 (95% confidence interval [CI], 5.76 - 6.96) among patients in the SLIT group, 6.06 (95% CI, 5.23 - 6.88) among patients in the placebo group, and 6.10 (95% CI, 5.32 - 6.89) for patients in the SCIT group.
At the 3-year follow-up examination 1 year after the end of treatment, mean TNSS scores among the 92 patients were 4.55 (95% CI, 3.67 - 5.43) in the SLIT group, 4.82 (95% CI, 3.90 - 5.74) in the placebo group, and 3.96 (95% CI, 3.21 - 4.71) in the SCIT group. There were no significant differences between the placebo group and the treatment groups, or between the two treatment groups.
In a primary outcome imputed intention-to-treat analysis that included the 106 original patients, the mean TNSS scores were 4.73 (95% CI, 3.97 - 5.48), 4.81 (95% CI, 3.97 - 5.65), and 3.89 (95% CI, 3.25 - 4.54), respectively, with the differences between groups still not attaining significance.
After 1 year of treatment, SCIT but not SLIT was associated with an improved TNSS area under the curve compared with placebo. However, by the end of the second treatment year, "both forms of immunotherapy performed better than placebo," the authors write.
During both treatment years, use of rescue medications was decreased with SLIT, but not SCIT or placebo, but both forms of therapy were associated with milder early and late skin responses to an intradermal allergen challenge, compared with placebo. Levels of allergen-specific immunoglobulin E were higher with SLIT and lower with SCIT compared with placebo, "and for [immunoglobulin G4], both forms of treatment resulted in increases over placebo." There were no serious treatment-related adverse events.
Study limitations included the lack of daily symptom diaries during pollen season and no comparison between 2 and 3 years of SLIT. Also, it was not powered to detect differences between active treatments, despite the finding that SCIT appeared to be more effective than SLIT at reducing TNSS after 1 year.
"These data highlight the need for a head-to-head clinical trial of sublingual and subcutaneous immunotherapy," the authors write.
In an accompanying editorial, Linda S. Cox, MD, notes that "the cumulative costs of symptomatic drug treatment for perennial or seasonal allergic rhinitis can be significant over time," because it is a chronic condition. Therefore, any analysis of allergen-specific immunotherapy must take into account its potential for long-term disease modification.
However, she warns, any cost-benefit assessment of allergen-specific immunotherapy must include "the duration of treatment required for optimal long-term efficacy. The time commitment requirement may be an important factor in patients' decisions to initiate therapy." Therefore, it is important to clarify the optimum duration of treatment.
The findings of this study suggest that "2 years is not sufficient for SLIT treatment to induce long-term clinical efficacy," writes Dr Cox, from the University of Miami Miller School of Medicine at Holy Cross Hospital, Fort Lauderdale, Florida.
What is more, the results "support current clinical practice guidelines recommending...at least 3 years of SLIT therapy...and provide an important contribution to the evidence regarding immunotherapy for allergic rhinitis," Dr Cox concludes.
Several study authors disclosed financial and research support from ALK, HAL Allergy, Merck, Stallergenes-Greer, the US Department of Health and Human Services, the National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Immune Tolerance Network, ALK-Abello A/S Hörsholm, Allergy Therapeutics, Regeneron, Biotech Tools, Anergis, Circassia, Biomay, and med Update GmBH. Dr Cox reported personal, speaker's, and consultation fees from MedImmune, Novartis, ASIT Biotech sa, Circassia, Biotech, Greer-Stallergenes, and Genentech.
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