Sublingual immunotherapy (SLIT) is a common treatment for allergic rhinitis in Europe, and allergists in the United States are becoming increasingly interested in this form of therapy.
However, several challenges need to be addressed before SLIT is readily available to the public, according to experts interviewed for this article.
For example, efficacy compared to subcutaneous immunotherapy (SCIT) and appropriate dosing need to be established, and a sublingual extract has yet to be approved by the Food and Drug Administration (FDA).
Despite these roadblocks, SLIT has the potential to help a number of patients with allergic rhinitis, including children and individuals who don’t want to undergo SCIT, according to experts.
“I think sublingual immunotherapy is going to fill an unmet need,” said Linda Cox, MD, an allergist in private practice at the Allergy and Asthma Center Ft. Lauderdale, Fla. and Chair of the American Academy of Allergy, Asthma and Immunology’s (AAAAI) Immunotherapy and Allergy Diagnostics Committee and the American College of Allergy, Asthma, and Immunology’s (ACAAI) Immunotherapy and Diagnostics Committee. She is also one of the authors of an AAAAI/ACAAI task-force report on the topic J Allergy Clin Immunol. 2006;117:1021–1035).
Investigating the Efficacy of SLIT
To help determine whether SLIT is a viable option for patients, the AAAAI/ACAAI task force conducted a meta-analysis of 47 SLIT studies.
“Every one isn’t positive, but it’s very clear that in majority of cases there is a clinical benefit,” said one of the analysis authors Harold Nelson, MD, Professor of Medicine at the National Jewish Medical and Research Center in Denver, Colo.
SLIT may be effective in patients because the oral cavity is an immunologically privileged site, said Samuele E. Burastero, MD, of the San Raffaele Scientific Institute in Milan, Italy, and author of a SLIT data review that found the therapy to be highly efficacious (Curr Opin Otolaryngol Head Neck Surg. 2006;14:197–201).
Data indicate dendritic cells in the oral mucosa, encountering antigen in the absence of “danger” signals, activate a prevalently regulatory, rather than Th2 (pro-allergic) immune response, explained Dr. Burastero. Recirculation of allergen-specific T regulatory lymphocytes to target organs of allergic inflammation can explain the clinically significant improvement of allergies affecting the upper respiratory tract, he said.
SLIT is not without side effects, said Dr. Nelson. They generally include local itching and swelling under the tongue and on the lips. Occasional gastrointestinal side effects will occur, but not with any great regularity, he said. There have been a few reports of wheezing or breaking out in hives, but no anaphylactic reactions or near fatal reactions have been reported.
Extended post-marketing studies have proven that SLIT is absolutely risk-free, in terms of severe side effects, said Dr. Burastero. SCIT has a low but not negligible and certainly immunotherapy-related rate of severe side effects, including death—about one occurrence out of 2 million injections, he added.
Effectiveness: SLIT vs. SCIT
SLIT appears to be half as effective as high-dose injected immunotherapy, at least during the first year of treatment, although the meta-analysis review did not analyze this, observed Dr. Nelson.
Only three controlled comparative studies of sublingual and subcutaneous immunotherapy have been published, noted Dr. Burastero. Only one study used an optimal placebo-controlled, double-blind, double-dummy, and randomized design. In all three studies, the reduction in disease severity was of the order of 50% with no significant difference between the two treatments.
One of the largest questions that needs to be addressed surrounding SLIT is dosing, said Dr. Nelson. “The trouble is there are reports of successful sublingual treatment when given at one half the cumulative dose given by injection as well as failures when given up to 500 times the customary injected dose,” he said. Researchers are also reporting huge dose ranges as being equally successful.
ALK Denmark, a manufacturer of immunotherapeutic extracts, conducted the first dose-response study in more than 850 people with grass-induced allergic rhinitis randomized to placebo, 2500, 25,000 or 75,000 units of Phleum pratense. Only the highest dose was effective, said Dr. Nelson.
Data from the meta-analysis indicate that optimal maintenance dosing frequency has not been established.
In Europe, dosing protocols vary according to physician habits and to manufacturer suggestions, said Dr. Burastero. The general trend is toward daily SLIT, without any induction phase. The extracts are obtained from a manufacturer using standardized preparative procedures and batch-to-batch controls, and contain known amounts of major allergen, he said. Data indicate efficacious daily doses start at roughly 2 μg of a major allergen(s) and range up to 100 times this amount. According to his data review, immunotherapy has to be continued for at least three and up to five years.
Dosing Studies in US and France
Stallergenes Laboratories in France has conducted dose-response studies of SLIT tablets in grass pollen rhinoconjunctivitis (J Allergy Clin Immunol. 2006;117:721), while ALK has begun phase 1 studies on ragweed tablets in the United States. Both studies suggest that the dose given in a once-a-month subcutaneous injection needs to be given daily via SLIT to be effective, said Dr. Cox.
Higher dosing may be necessary because as radioactive labeling of a SLIT allergen has demonstrated only a small percentage of the allergen remains underneath the tongue up to 20 hours after administration and the remainder is rapidly degraded in the gastrointestinal tract into peptide fragments, she explained.
Another significant challenge of using SLIT is that in the US doctors desensitize a patient using polytherapy or a large number of antigens to which the individual reacts, said Bradley Marple, MD, Associate Professor and Vice Chairman of the Department of Otolaryngology–Head and Neck Surgery at the University of Texas Southwestern Medical Center at Dallas and an ENToday editorial board member. In Europe, physicians use monotherapy, which addresses only a few of the most pertinent antigens.
No FDA Approval or CPT Code
Another challenge to using SLIT is that there is no FDA-approved extract for this treatment, said Dr. Nelson. Package inserts state that extracts are only for injections and skin testing.
“The trouble is there are reports of successful sublingual treatment when given at one half the cumulative dose given by injection as well as failures when given up to 500 times the customary injected dose.” – —Harold Nelson, MD
One extract company, Greer Laboratories in Lenoir, NC, is pursuing the development of sublingual therapy using currently licensed standardized short ragweed pollen, grass pollen, house dust mite, and cat allergen extract/vaccines, according to Bob Esch, PhD, Executive Vice President of Research and Development there. The company hopes for a 2007 FDA submission.
Reimbursement for SLIT is another challenge that physicians face, because a CPT code for the therapy doesn’t exist. Acquiring a CPT code for billing generally takes about three years from a drug’s submission to the FDA, said Dr. Cox. “All major parties need to agree that we need one,” she said. If the AAOA, AAAAI, and ACAAI don’t all agree that a CPT is needed, the Centers for Medicare and Medicaid Services will not intervene. Physicians can use a nonspecific code, but the paper trail for these claims is time consuming, she said.
Studies are needed to address safety, appropriate escalation protocols, efficacy, impact upon markers of systemic immunologic modification, quality of life, identification of high-risk patients, optimal numbers of antigens to target, impact upon persistent allergic rhinitis symptoms, and stratification of patients to identify the best candidates for SLIT, said Dr. Marple.
More research of SLIT and food allergies needs to be conducted, added Dr. Cox. Some research has shown that SLIT can desensitize patients to hazelnut allergies, and plans for a sublingual peanut study have begun. “That would be a useful tool to have,” she explained.
Organizations such as the AAAAI, ACAAI, and the American Academy of Otolaryngic Allergy (AAOA) need to craft some practice guidelines for SLIT once FDA approval occurs, said Dr. Cox. “SLIT is a home therapy, so allergists need to know what kind of instructions to provide the patient,” she said.
Despite these challenges, SLIT holds potential for several patient populations. “We have a vast number of allergic individuals who are not receiving treatment,” said Dr. Cox.
I think sublingual immunotherapy is going to fill an unmet need.” – —Linda Cox, MD
For example, physicians generally aren’t treating children younger than age five for allergies, said Dr. Cox, adding that the 2003 allergen immunotherapy practice parameters recommend careful consideration in this age group (Ann Allergy Asthma Immunol. 2003;90(1 Suppl 1):1–40). Young children may not be able to report they are having a shot reaction and may not have the pulmonary reserves necessary if they have an asthmatic reaction, explained Dr. Cox.
However, some evidence indicates that that allergists and immunologists need to be intervening early to prevent the march from allergic rhinitis to asthma. In Europe, three studies have found that treatment of children with SLIT is reasonable and does not result in anaphylaxis or respiratory reactions, although gastrointestinal side effects such as abdominal pain and diarrhea may occur, said Dr. Cox.
Patients who do not have time to undergo SCIT may also benefit from SLIT, said Dr. Cox. A large deterrent for many people who are candidates for subcutaneous immunotherapy is the amount of time required for treatment, said Dr. Cox. “It takes a good hour to hour and a half by the time patients drive to the doctor’s office and get their shots,” she said.
“I think that the acceptance by the public is likely to be great,” said Dr. Marple. This would drive the demand for this form of therapy in appropriately selected patients. How this will impact SCIT remains to be seen, he said. “One should perhaps assume that clear-cut indications for SLIT and SCIT may emerge based upon treatment outcome data.”
Injection therapy will continue to be used, said Dr. Cox, adding that monthly injections of SCIT are less costly than the daily dosing of SLIT.
While research sorts out the questions surrounding SLIT, immunotherapy overall remains a remarkable option for allergic rhinitis patients, said Dr. Nelson. But clearly there have to be improvements in treatment, convenience, and safety, he concluded.
©2006 The Triological Society