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Subcutaneous and Sublingual Immunotherapy To Treat Allergic Rhinitis/Rhinoconjunctivitis and Asthma

Clinician Summary – Aug. 22, 2013

Subcutaneous and Sublingual Immunotherapy To Treat Allergic Rhinitis/Rhinoconjunctivitis and Asthma

Formats

Table of Contents

Research Focus for Clinicians

A systematic review was undertaken to summarize the evidence regarding the efficacy, comparative effectiveness, and safety of subcutaneous and sublingual immunotherapy for adult and pediatric patients. All included studies are randomized controlled trials (RCTs) and were published from January 1967 to May 2012. There are 74 RCTs on the efficacy and safety of subcutaneous immunotherapy (SCIT), 60 RCTs on the efficacy and safety of sublingual immunotherapy (SLIT), and 8 RCTs on head-to-head comparisons between both forms of immunotherapy. This summary is provided to assist clinicians in decisionmaking along with a patient’s values and preferences. Reviews of evidence should not be construed to represent clinical recommendations or guidelines. The full report can be accessed on the right side of this Web page.

Background

The medical management of patients with allergic rhinitis and allergic asthma includes allergen avoidance, pharmacotherapy, and immunotherapy. Daily use of pharmacotherapies for allergic rhinitis symptoms raises issues related to adherence, safety, and cost. Long-term use of inhaled steroids, long-acting bronchodilators, and leukotriene antagonists for asthma control have risks for moderate to severe adverse effects.

Allergen immunotherapy is typically used for patients whose allergic rhinoconjunctivitis and allergic asthma symptoms cannot be controlled by medication and environmental control, patients who cannot tolerate their medications, or patients who do not comply with chronic medication regimens. The U.S. Food and Drug Administration (FDA) has approved the use of allergen extracts for SCIT for treating allergic rhinitis and allergic asthma.

In the United States, a patient with allergies undergoing immunotherapy receives subcutaneous injections—in increasing doses—of an allergen-containing extract comprised of the relevant allergens to which he or she is sensitive in an attempt to suppress or eliminate allergy-related symptoms. There is considerable interest in using similar allergen extracts as SLIT as an alternative to SCIT. In the included studies, SLIT specifically refers to allergen extracts administered sublingually in the form of drops. Studies on sublingual tablets are not included here. Allergen extract drops are placed under the tongue for local absorption to desensitize the allergic individual over a period of months to years and to diminish allergic symptoms. SLIT is not currently FDA approved for use in the United States. However, some physicians are using subcutaneous formulations of allergens off-label for sublingual desensitization in the treatment of allergic respiratory conditions. This is largely based on products that have been researched for several years in the United States and Europe and are approved for use by European regulatory authorities.

Conclusions

  • There is sufficient evidence to support the overall effectiveness and safety of both SCIT and SLIT for treating allergic rhinoconjunctivitis and asthma (Tables 1 and 2).
  • However, there is not enough evidence to determine if either SCIT or SLIT is superior.
  • SCIT and SLIT are usually safe, although local reactions are commonly reported regardless of the mode of delivery (Table 3).
  • Serious, life-threatening reactions are rare, although they can occur (see SCIT, Table 3). SLIT studies mainly include patients with allergic rhinitis and/or mild asthma. Safety outcomes for SLIT should not be extrapolated to more severely affected patients.
  • Most studies use a single allergen for immunotherapy (Table 4). It may be difficult to extrapolate these results to the use of multiple-allergen regimens, which are commonly used in clinical practice in the United States.
  • Due to the wide variety of reported regimens, the target SLIT maintenance dose and the duration of therapy are unclear.

Clinical Bottom Line

Table 1. Efficacy and Comparative Effectiveness of Subcutaneous and Sublingual Immunotherapy for Adult Patients*
Outcomes SCIT vs. Placebo or vs. Standard Therapy
(RCTs, No. of Patients) SOE
SLIT vs. Placebo or vs. Standard Therapy
(RCTs, No. of Patients) SOE
SCIT vs. SLIT
(RCTs, No. of Patients) SOE
* Reported scales or scoring systems were not uniform across studies. Followup ranged from one pollen season to 6 years. Standard therapy varied across trials and could include environmental control and/or medications such as topical nasal corticosteroid or cromolyn preparations, oral antihistamines, decongestants, beta-agonists, oral steroids, bronchodilators, ocular corticosteroids, and montelukast.
RCT = randomized controlled trial; RQLQ = Rhinoconjunctivitis Quality of Life Questionnaire; SCIT = subcutaneous immunotherapy; SF-36® = Short Form (36) Health Survey; SLIT = sublingual immunotherapy; SOE = strength of evidence
Improves asthma symptom score 17–84% greater improvement vs. controls (16 RCTs, n = 1,178) evidence high Significant improvement across all studies vs. controls (13 RCTs, n = 625) evidence high SCIT may improve asthma symptoms more effectively than SLIT (4 RCTs, n = 171) evidence low
Decreases use of asthma medications Decreased in 42% of studies vs. controls (12 RCTs, n = 1,062) evidence high evidence insufficient evidence insufficient
Improves combined asthma symptom and medication score Significant improvement in 83% of studies vs. placebo (6 RCTs, n = 196) evidence low evidence insufficient evidence insufficient
Improves rhinitis/ rhinoconjunctivitis symptoms Significant improvement in 73% of studies vs. controls (25 RCTs, n = 1,734) evidence high Significant improvement in 56% of studies vs. controls (36 RCTs, n = 2,658) evidence medium SCIT is superior to SLIT for improving allergic nasal and/or eye symptoms (6 RCTs, n = 412) evidence medium
Improves conjunctivitis symptoms Significant improvement in 43% of studies vs. placebo (14 RCTs, n = 1,104) evidence high Significant improvement in 46% of studies vs. placebo (13 RCTs, n = 1,074) evidence medium evidence insufficient
Decreases use of rhinitis/ rhinoconjunctivitis medications Significantly decreased in 70% of studies vs. controls (10 RCTs, n = 564) evidence medium evidence insufficient evidence insufficient
Improves combined symptoms (nasal, ocular, and bronchial Significant improvement in 67% of studies vs. placebo (6 RCTs, n = 591) evidence high evidence insufficient evidence insufficient
Improves combined rhinitis/ rhinoconjunctivitis symptom and medication score Significant improvement in 83% of studies vs. controls (6 RCTs, n = 400) evidence low evidence insufficient evidence insufficient
Improves asthma plus rhinitis/ rhinoconjunctivitis symptoms 21–68% greater improvement vs. controls (5 RCTs, n = 175) evidence medium Significantly improved in 80% of studies vs. controls (5 RCTs, n = 308) evidence medium evidence insufficient
Decreases use of asthma plus rhinoconjunctivitis medications 14–83% greater reduction in asthmabased studies vs. controls (5 RCTs, n = 203); significantly decreased in 91% of rhinitis-based studies vs. controls (11 RCTs, n = 768) evidence high Significant improvement in 47% of studies vs. controls (38 RCTs, n = 2,724) evidence medium There are no consistent differences between SCIT and SLIT (5 RCTs, n = 219) evidence low
Improves asthma plus rhinitis/ rhinoconjunctivitis symptom and medication score evidence insufficient Significant improvement in 68% of studies vs. controls (19 RCTs, n = 1,462) evidence medium SCIT is favored in 1 of 2 studies (2 RCTs, n = 65) evidence low
Improves disease-specific quality of life in patients with rhinitis/ rhinoconjunctivitis Significant improvement by the RQLQ or the SF-36® in 67% of studies vs. placebo (6 RCTs, n = 889) evidence high Significant improvement by the RQLQ in 75% of studies vs. controls (8 RCTs, n = 819) evidence medium evidence insufficient
Table 2. Efficacy and Comparative Effectiveness of Subcutaneous and Sublingual Immunotherapy for Pediatric Patients*
Outcomes SCIT vs. Placebo or vs. Standard Therapy (RCTs, No. of Patients) SOE SLIT vs. Placebo or vs. Standard Therapy (RCTs, No. of Patients) SOE SCIT vs. SLIT (RCTs, No. of Patients) SOE
* Reported scales or scoring systems were not uniform across studies. Followup ranged from one pollen season to 6 years. Standard therapy varied across trials and could include environmental control and/or medications such as topical nasal corticosteroid or cromolyn preparations, oral antihistamines, decongestants, beta-agonists, oral steroids, bronchodilators, ocular corticosteroids, and montelukast.
RCT = randomized controlled trial; RQLQ = Rhinoconjunctivitis Quality of Life Questionnaire; SCIT = subcutaneous immunotherapy;
SLIT = sublingual immunotherapy; SOE = strength of evidence
Improves asthma symptom score Significant improvement in 50% of studies vs. controls (6 RCTs, n = 550) evidence medium Significant improvement in all studies vs. controls (9 RCTs, n = 471) evidence high SCIT is favored in 67% of studies vs. SLIT (3 RCTs, n = 135) evidence low
Decreases use of asthma medications Significant reduction in 50% of studies (4 RCTs, n = 470) evidence low evidence insufficient evidence insufficient
Improves rhinitis/rhinoconjunctivitis symptoms Significant improvement in 67% of studies vs. placebo (3 RCTs, n = 285) evidence medium Significant improvement in 42% of studies vs. controls (12 RCTs, n = 1,065) evidence medium evidence insufficient
Improves conjunctivitis symptoms Significant improvement in 67% of studies vs. placebo (3 RCTs, n = 285) evidence low Significant improvement in 40% of studies vs. placebo (5 RCTs, n = 513) evidence medium evidence insufficient
Improves asthma plus rhinitis/rhinoconjunctivitis symptoms evidence insufficient Significant improvement with high-dose and low-dose SLIT vs. placebo (1 RCT, n = 98) evidence medium SCIT may be favored over SLIT for reducing nasal and/or eye symptoms (3 RCTs, n = 135) evidence low
Decreases use of asthma plus rhinoconjunctivitis medications Decreased in both studies vs. controls (2 RCTs, n = 80) evidence low Significantly reduced in 42% of studies vs. controls (13 RCTs, n = 1,078) evidence medium SLIT may decrease medication use more than SCIT, but results are inconsistent (3 RCTs, n = 135) evidence low
Improves combined asthma or asthma plus rhinitis/rhinoconjunctivitis symptom and medication score Significant improvement in both studies vs. placebo (2 RCTs, n = 85) evidence low Significant improvement in 50% of studies vs. controls (2 RCTs, n = 329) evidence low evidence insufficient
Improves disease-specific quality of life in patients with rhinitis/rhinoconjunctivitis Significant improvement measured by RQLQ in both studies vs. controls (2 RCTs, n = 350) evidence low evidence insufficient evidence insufficient
Strength of Evidence Scale

High: evidence high
High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.

Moderate: evidence medium
Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.

Low: evidence low
Low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the estimate.

Insufficient:evidence insufficient
Evidence is either unavailable or does not permit a conclusion.

Table 3. Adverse Effects*
Study Adults Pediatric Patients
* Not all studies reported adverse effects; due to the lack of a consistent reporting system across studies, a meta-analysis of adverse effects was not possible.
SCIT = subcutaneous immunotherapy; SLIT = sublingual immunotherapy
SCIT
SLIT
SCIT vs. SLIT

Table 4. Included Studies by Type of Allergen for Subcutaneous Immunotherapy (SCIT), Sublingual Immunotherapy (SLIT), and SCIT Versus SLIT
Allergen SCIT SLIT SCIT vs. SLIT
a Dust mites could include Dermatophagoides pteronyssinus or D. farinae or unspecified dust mites.
b Grass could include Bermuda grass, cocksfoot, meadow fescue, orchard grass, rye (Secale cereale or unspecified), Timothy grass, unspecified grass, or grass mix.
c Weeds could include English plantain, Kochia, mugwort, Parietaria, ragweed (short, Western, or unspecified), Russian thistle, or sagebrush.
d Mold could include Alternaria, Aspergillus, or Cladosporium.
e Tree could include American elm, bald cypress, birch, cottonwood, date sugar palm/wild date palm, Japanese cedar, London plane, maple, mountain cedar, olive, red/green ash, white birch, white oak, or tree mix.
Dust mitea 21 14 6
Grassb 11 15 -
Weedsc 9 7 -
Cat 5 2 -
Dog 1 - -
Moldd 6 2 -
Treee 6 13 2
Multiple allergens 15 7 -
 

Gaps in Knowledge

What To Discuss With Your Patients

  • The benefits and adverse effects of SCIT or SLIT for them or their child
  • Any comorbid conditions that they or their child may have that would affect their ability to take SCIT or SLIT
  • Other prescription or over-the-counter medications they are taking during SCIT or SLIT treatment
  • What adverse effects to look for and when to call their doctor
  • How often they should be taking SCIT or SLIT
  • How long they can expect to take SCIT or SLIT
  • The costs of SCIT and SLIT

Resource for Patients

Allergy Shots and Allergy Drops for Adults and Children, A Review of the Research is a free companion to this clinician research summary. It can help patients talk with their health care professionals about treatment options. It provides information about:

  • Allergies in general
  • How allergies are treated
  • Allergy shots and allergy drops
  • Benefits of allergy shots and allergy drops for adults and children
  • Possible side effects of allergy shots and allergy drops for adults and children
  • Questions to discuss with their doctor

Source

The information in this summary is based on Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review, Comparative Effectiveness Review No. 111, prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No. 290-2007-10061-I for the Agency for Healthcare Research and Quality, March 2013.

This summary was prepared by the John M. Eisenberg Center for Clinical Decisions and Communications Science at Baylor College of Medicine, Houston, TX. It was written by Andrea Humphries, Ph.D., Masayoshi Takashima, M.D., and Michael Fordis, M.D.

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