subcutaneous and sublingual immunotherapy to treat allergic rhinitis/rhinoconjunctivitis and asthma...

Subcutaneous and Sublingual Immunotherapy To Treat Allergic Rhinitis/Rhinoconjunctivitis and

AsthmaPrepared for:

Agency for Healthcare Research and Quality (AHRQ)

www.ahrq.gov

Agency for Healthcare Research and Quality Comparative Effectiveness Review (CER) Process

Background Clinical Questions Addressed in the CER Summary of CER Results Conclusions Gaps in Knowledge Resources for Shared Decisionmaking

Outline of Material

Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, the public, and others.

A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue.

The research questions and the results of the report are subject to expert input, peer review, and public comment.

The results of these reviews are summarized into a Clinician Research Summary and a Consumer Research Summary for use in decisionmaking and in discussions with patients.

The Research Summaries and the full report are available at www.effectivehealthcare.ahrq.gov/allergy-asthma-immunotherapy.cfm.

Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development

Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http://www.effectivehealthcare.ahrq.gov/allergy-asthma-immunotherapy.cfm.

The strength of evidence ratings are classified into four broad ratings:

Rating the Strength of Evidence From the Comparative Effectiveness Review

AHRQ Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Available at http://www.effectivehealthcare.ahrq.gov/methodsguide.cfm.Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http://www.effectivehealthcare.ahrq.gov/allergy-asthma-immunotherapy.cfm.Owens DK, Lohr KN, Atkins D, et al. J Clin Epidemiol. 2010 May;63(5):513-23. PMID: 19595577.

Allergic rhinitis is a common clinical problem affecting about 20 percent of the general population in North America.

Allergens such as tree, grass, and weed pollens characteristically cause seasonal rhinoconjunctivitis and/or asthma.

Allergens such as cat dander, cockroach, or dust mite may induce symptoms year-round and are associated with perennial rhinitis and/or asthma.

The prevalence of asthma in the general U.S. population is approximately 9 percent, and approximately 62 percent of individuals with asthma have evidence of atopy (i.e., the genetic predisposition to produce elevated immunoglobulin E [IgE] in response to environmental allergens).

Background:Allergic Rhinitis/Rhinoconjunctivitis and Asthma

Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http://www.effectivehealthcare.ahrq.gov/allergy-asthma-immunotherapy.cfm.Min YG. Allergy Asthma Immunol Res. 2010 Apr;2(2):65-76. PMID: 20358020.

The medical management of patients with allergic rhinitis and allergic asthma includes: Allergen avoidance Pharmacotherapy Immunotherapy

Daily use of pharmacotherapies for allergic asthma and 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 can have adverse effects.

Background: Management of Allergy Symptoms

Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http://www.effectivehealthcare.ahrq.gov/allergy-asthma-immunotherapy.cfm

Allergen-specific immunotherapy is typically used for: Patients whose allergic rhinoconjunctivitis and asthma

symptoms cannot be controlled by medication and environmental control

Patients who cannot tolerate their medications Patients who do not comply with chronic medication

regimens The U.S. Food and Drug Administration has approved

the use of allergen extracts for subcutaneous immunotherapy in treating seasonal and perennial allergic rhinitis and allergic asthma.

In the United States, a patient with allergies undergoing immunotherapy receives subcutaneous injections—in increasing doses until a maintenance dose is found—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.

Background:Subcutaneous Immunotherapy for Allergies


There is considerable interest in using similar allergen extracts as sublingual immunotherapy (SLIT) as an alternative to subcutaneous immunotherapy.

SLIT involves placing drops or tablets with the allergen extract under the tongue for local absorption to desensitize the allergic individual over a period of months to years and to diminish allergic symptoms.

In the United States, there currently are no sublingual forms of immunotherapy approved by the U.S. Food and Drug Administration.

However, some U.S. physicians are using subcutaneous aqueous extracts off-label for sublingual desensitization in the treatment of allergic respiratory conditions.

Background:Sublingual Immunotherapy for Allergies


Objective To evaluate the efficacy, effectiveness, and safety of

subcutaneous (SCIT) and sublingual (SLIT) immunotherapies that are presently available for use by clinicians and patients in the United States

Key Questions For patients with allergic rhinoconjunctivitis and/or

asthma: Efficacy and effectiveness of SCIT, SLIT, and SCIT versus

SLIT Safety of SCIT, SLIT, and SCIT versus SLIT

Safety and effectiveness of SCIT, SLIT, and SCIT versus SLIT in the pediatric subpopulation

Systematic Review: Objective and Key Questions

Lin SY, Erekosima N, Suarez-Cuervo C, et al. AHRQ Comparative Effectiveness Review No. 111. Available at http://www.effectivehealthcare.ahrq.gov/allergy-asthma-immunotherapy.cfm

Outcomes of Interest Primary Outcomes

Clinical endpoints: Symptom control Medication use Quality of life

Disease evolution/remission New allergen sensitivities Overall health care utilization Missed days of school/work

Secondary Outcomes Functional tests (pulmonary

function test‒forced expiratory volume)

Provocational test Adherence Convenience and compliance Biomarkers

Adverse Effects Local reactions

Skin, mouth, and throat (including irritation, itching, swelling, or pain in the oral cavity)

General symptoms (such as headache, fatigue, arthritis)

Systemic reactions Ocular Rhinitis/nasal Cutaneous Rash Gastrointestinal Respiratory/asthma Cardiovascular Anaphylaxis Death


142 studies were included in the review with these populations: adults only (52%), children only (24%), and adults and children (22%).

Studies on SLIT mainly included patients with allergic rhinitis and/or mild asthma.

All included studies were randomized controlled trials. Efficacy and safety of SCIT: n = 74 Efficacy and safety of SLIT*: n = 60 Comparisons of SCIT versus SLIT: n = 8

The types of scales/scoring systems used in the studies were not uniform.

Followup varied and ranged from one pollen season to 6 years. Standard therapy varied across trials. Due to heterogeneity in reported outcomes, results often only reflect

the percentage of trials in which a significant effect was seen for the immunotherapy arm versus controls and not the magnitude of effect.

Overview of Studies Included in theSystematic Review

*SLIT refers to allergen extracts that are administered sublingually in the form of drops. Studies on sublingual tablets are not included here.


Allergen SCIT SLIT SCIT vs. SLIT

Dust mite 21 14 6

Grass 11 15 ‒

Weeds 9 7 ‒

Cat 5 2 ‒

Dog 1 ‒ ‒

Mold 6 2 ‒

Tree 6 13 2

Multiple allergens

15 7 ‒

Included Studies by Type of Allergen for SCIT, SLIT, and SCIT Versus SLIT

SCIT = subcutaneous immunotherapy; SLIT = sublingual immunotherapy


74 articles were included with a total of 4,350 patients. The primary diagnoses were:

Asthma in 19 studies Asthma with rhinitis in 18 studies Rhinoconjunctivitis in 14 studies Asthma with rhinoconjunctivitis in 14 studies

Types of allergens evaluated: Seasonal allergens such as trees, grasses, weeds, and

seasonal molds in 59 percent of studies Perennial allergens in 38 percent of studies Seasonal and perennial allergens in 3 percent of studies

The heterogeneity of the data on clinical outcomes precluded pooling of the data for further analysis. Consequently, the results often only reflect the percentage of trials in which a significant effect was seen for the immunotherapy arm versus controls and not the magnitude of effect.

Included Studies for Subcutaneous Immunotherapy Versus Placebo or Standard Therapy


Primary Outcome Results*

No. of RCTs, No. of Patients

(n)

Strength of Evidence

Asthma symptom score

17‒84% greater improvement vs. controls

16 RCTs,n = 1,178

High

Use of asthma medications

Decreased in 42% of studies vs. controls

12 RCTs,n = 1,062

High

Combined asthma symptom and medication score

Significant improvement in 83% of studies vs. placebo

6 RCTs,n = 196

Low

Subcutaneous Immunotherapy Versus Placebo or Standard Therapy: Asthma Outcomes

RCT = randomized controlled trial


Primary Outcome

Results

No. of RCTs, No. of Patients (n)


Rhinitis/rhinoconjunctivitis symptoms

Significant improvement in 73% of studies vs. controls

25 RCTs, n = 1,734

High

Use of rhinitis/rhinoconjunctivitis medications

Significantly decreased in 70% of studies vs. controls

10 RCTs, n = 564

Moderate

Combined rhinitis/rhinoconjunctivitis symptom and medication score


6 RCTs,n = 400

Low

SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes (1 of 2)

RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy


Primary Outcome Results



Conjunctivitis symptoms


14 RCTs, n = 1,104

High

Combined symptoms (nasal, ocular, and bronchial)


6 RCTs,n = 591

High

Disease-specific quality of life in patients with rhinitis/ rhinoconjunctivitis

Significant improvement by RQLQ in 67% of studies vs. placebo

6 RCTs,n = 889

High

SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes (2 of 2)

RCT = randomized controlled trial; RQLQ = Rhinoconjunctivitis Quality of Life Questionnaire; SCIT = subcutaneous immunotherapy



No. of RCTs, No. of

Patients (n)

Strength of

Evidence

Asthma plus rhinitis/rhinoconjunctivitis symptoms

21‒68% greater improvement vs. controls

5 RCTs,n = 175

Moderate

Use of asthma plus rhinoconjunctivitis medications

• 14–83% greater reduction in asthma-based studies vs. controls

• Significantly decreased in 91% of rhinitis-based studies vs. controls

5 RCTs, n = 203

11 RCTs,n = 768

High

SCIT Versus Placebo or Standard Therapy: Asthma Plus Rhinitis/Rhinoconjunctivitis Outcomes



60 articles on sublingual immunotherapy (SLIT) that included 4,870 patients were eligible for inclusion.

Allergens evaluated included: Seasonal allergens (66%) Perennial allergens (31%) Both seasonal and perennial allergens (3%)

Comparators included: Placebo (71%) Another sublingual intervention without a placebo group (15%) Conventional treatment without placebo (pharmacotherapy or rescue

medications; 14%) Duration of treatment ranged from 3 months to 5 years. There was great heterogeneity in:

Dosages of maintenance or cumulative treatments The units to report dosing Standard therapy used across trials

Reported results often only reflect the percentage of trials in which a significant effect was seen for the immunotherapy arm versus controls and not the magnitude of effect.

Included Studies for Sublingual Immunotherapy Versus Placebo or Standard Therapy


Sublingual Immunotherapy Versus Placebo or Standard Therapy: Asthma Outcomes

Primary Outcome

Results


(n)



Significant improvement across all studies vs. controls

13 RCTs,n = 625

High



SLIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes






36 RCTs, n = 2,658

Moderate

Conjunctivitissymptoms


13 RCTs, n = 1,074

Moderate

Disease-specificquality of life in patients with rhinitis/ rhinoconjunctivitis

Significant improvement by RQLQ in 75% of studies vs. controls

8 RCTs,n = 819

ModerateRCT = randomized controlled trial; RQLQ = Rhinoconjunctivitis Quality of Life Questionnaire




(n)

Strength of

Evidence

Asthma plus rhinitis/ rhinoconjunctivitis symptoms

Significantly improved in 80% of studies vs. controls

5 RCTs, n = 308

Moderate



38 RCTs, n = 2,724

Moderate

Asthma plus rhinitis/ rhinoconjunctivitis symptom and medication score


19 RCTs, n = 1,462

Moderate

SLIT Versus Placebo or Standard Therapy: Asthma Plus Rhinitis/Rhinoconjunctivitis Outcomes





(n)

Strength of

Evidence

Improves asthma symptom score

SCIT may improve asthma symptoms more effectively than SLIT

4 RCTs,n = 171

Low

Improves rhinitis/rhinoconjunctivitis symptoms

SCIT is superior to SLIT for improving allergic nasal and/or eye symptoms

6 RCTs,n = 412

Moderate

Decreases use of asthma plus rhinoconjunctivitis medications

There are no consistent differences between SCIT and SLIT

5 RCTs,n = 219

Low

Improves asthma plus rhinitis/rhinoconjunctivitis symptom and medication score

SCIT is favored in 1 of 2 studies 2 RCTs,

n = 65Low

Subcutaneous Versus Sublingual Immunotherapy: All Outcomes

RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy; SLIT = sublingual immunotherapy


Thirteen studies on subcutaneous immunotherapy included 920 pediatric patients.

The pediatric population ranged in age from 3 to 18 years. Primary diagnoses included:

Asthma in 7 studies Asthma with rhinitis in 3 studies Asthma with rhinoconjunctivitis in 2 studies Rhinoconjunctivitis in 1 study

All studies allowed either conventional pharmacotherapy or rescue allergy medications during the study.

Standard therapy varied across studies. Due to heterogeneity in reported clinical outcomes, results

often only reflect the percentage of trials in which a significant effect was seen for the immunotherapy arm versus controls and not the magnitude of effect.

Included Studies for SCIT Versus Placebo or Standard Therapy in the Pediatric Population




(n)




6 RCTs,n = 550

Moderate

Use of asthma medications

Significant reduction in 50% of studies

4 RCTs,n = 470

Low

Pediatric Patients—SCIT Versus Placebo or Standard Therapy: Asthma Outcomes



Primary Outcome

Results


(n)




3 RCTs,n = 285

Moderate



3 RCTs,n = 285

Low

Disease-specific quality of life in patients with rhinitis/rhinoconjunctivitis

Significant improvement in both studies vs. controls

2 RCTs,n = 350

Low

Pediatric Patients—SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes

RCT = randomized controlled trial ; SCIT = subcutaneous immunotherapy


Primary Outcome

Results


(n)

Strength of

Evidence


Decreased in both studies vs. controls

2 RCTs,n = 80

Low

Improves combined asthma or asthma plus rhinitis/rhinoconjunctivitis symptom and medication score

Significant improvement in both studies vs. placebo

2 RCTs, n = 85

Low

Pediatric Patients—SCIT Versus Placebo or Standard Therapy: Asthma Plus Rhinitis/Rhinoconjunctivitis Outcomes



18 studies including 1,583 pediatric patients (≤ 18 years of age) Primary diagnoses:

Asthma (n = 3 studies) Rhinitis (n = 2 studies) Rhinoconjunctivitis (n = 4 studies) Asthma and rhinitis (n = 4 studies) Asthma with rhinoconjunctivitis (n = 5 studies)

Perennial and/or seasonal allergies were included Comparator groups included:

Placebo (n = 15 studies) Sublingual immunotherapy (SLIT) comparator group (n = 3 studies) Pharmacotherapy/symptomatic therapy (n = 2 studies)

Due to heterogeneity in reported clinical outcomes, results often only reflect the percentage of trials in which a significant effect was seen for the immunotherapy arm versus controls and not the magnitude of effect.

Included Studies for SLIT Versus Placebo or Standard Therapy in the Pediatric Population




(n)

Strength of

Evidence


Significant improvement in all studies vs. controls

9 RCTs,n = 471

High

Pediatric Patients—SLIT Versus Placebo or Standard Therapy: Asthma Outcomes

RCT = randomized controlled trial; SLIT = sublingual immunotherapy


Primary Outcome

Results


(n)




12 RCTs,n = 1,065

Moderate



5 RCTs,n = 513

Moderate

Pediatric Patients—SLIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes





(n)

Strength of

Evidence

Asthma plus rhinitis/rhinoconjunctivitis symptoms

Significant improvement with high- and low-dose SLIT vs. placebo

1 RCT, n = 98

Moderate


Significantly reduced in 42% of studies vs. controls

13 RCTs, n = 1,078

Moderate

Asthma plus rhinitis/rhinoconjunctivitis symptom and medication score


2 RCTs, n = 329

Low

Pediatric Patients—SLIT Versus Placebo or StandardTherapy: Asthma Plus Rhinitis/Rhinoconjunctivitis Outcomes





(n)

Strength of

Evidence

Improves asthma symptom score

SCIT is favored in 67% of studies vs. SLIT

3 RCTs, n = 135

Low

Improves asthma plus rhinitis/ rhinoconjunctivitis symptoms

SCIT may be favored over SLIT for reducing nasal and/or eye symptoms

3 RCTs, n = 135

Low

Decreases use of asthma plus rhinoconjunctivitis medications

SLIT may decrease medication use more than SCIT, but results are inconsistent

3 RCTs, n = 135

Low

Pediatric Patients—SCIT Versus SLIT:All Outcomes

RCT = randomized controlled trial; SCIT = subcutaneous immunotherapy; SLIT = sublingual immunotherapy


Local reactions (such as redness, swelling, pruritus, or induration at the injection site) were usually mild and occurred in 5 to 58 percent of patients and 0.6 to 54 percent of injections and were more common than systemic reactions.

The most common systemic reactions were respiratory reactions, occurring in up to 46 percent of patients and in up to 3 percent of injections.

General symptoms (such as headache, fatigue, and arthritis) occurred in up to 44 percent of patients and were usually mild or unspecified.

Gastrointestinal reactions were reported in only one study. Thirteen anaphylactic reactions were reported in four trials. No deaths were reported in the included studies.

Adverse Effects:Subcutaneous Immunotherapy in Adults


Local reactions (such as irritation, itching, swelling, or pain in the oral cavity) were common and usually mild and occurred in 0.2 to 97 percent of patients receiving sublingual immunotherapy (SLIT).

Systemic reactions occurred more frequently in the SLIT arm versus controls and included ocular, rhinitis/nasal, respiratory/asthma, cutaneous, gastrointestinal, and cardiovascular adverse effects.

No life-threatening reactions, anaphylaxis, or deaths were reported in the included trials.

SLIT studies mainly include patients with allergic rhinitis and/or mild asthma. Safety outcomes should not be extrapolated to more severely affected patients.

Adverse Effects:Sublingual Immunotherapy in Adults


The recording and reporting of the adverse events was neither uniform nor comparable across studies.

Local reactions were common and were all of mild or moderate severity.

There was one report of anaphylaxis with subcutaneous immunotherapy.

There were no reported deaths in the included studies.

Adverse Effects: Subcutaneous Versus Sublingual Immunotherapy in Adults


Local reactions were the most common adverse reactions in the pediatric population receiving subcutaneous immunotherapy.

There were no reports of anaphylaxis or deaths.

Adverse Effects: Subcutaneous Immunotherapy in Pediatric Patients


Local reactions (such as irritation, itching, swelling, or pain in the oral cavity) were common but mild.

No life-threatening reactions, anaphylaxis, or deaths were reported in these trials.

The strength of evidence for all other adverse effects is insufficient.

Adverse Effects: Sublingual Immunotherapy in Pediatric Patients


Local reactions were reported in both patient groups.

No systemic reactions were reported in patients receiving sublingual immunotherapy.

In the pediatric population taking subcutaneous immunotherapy, one anaphylaxis event and three respiratory systemic reactions were reported.

Adverse Effects: Subcutaneous Versus Sublingual Immunotherapy in Pediatric Patients


There is sufficient evidence to support the overall effectiveness and safety of both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) for treating allergic rhinoconjunctivitis and asthma.

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.

Overview of Conclusions (1 of 2)


Serious, life-threatening reactions are rare, although they can occur. Studies of sublingual immunotherapy (SLIT) mainly include

patients with allergic rhinitis and/or mild asthma. Safety outcomes should not be extrapolated to more

severely affected patients.

Most of the studies in the review used a single allergen for immunotherapy, and 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 duration of therapy are unclear.

Overview of Conclusions (2 of 2)


Additional studies are needed on: The efficacy and safety of multiple-allergen subcutaneous

(SCIT) and sublingual (SLIT) immunotherapy The effectiveness of single-allergen versus multiple-allergen

SCIT and SLIT for desensitization The efficacy and safety of SCIT and SLIT in specific

subpopulations (pregnant women, monosensitized vs. polysensitized patients, patients with severe asthma, and urban vs. rural patients)

Whether or not SCIT and SLIT can prevent or modify the atopic march in pediatric patients at high risk for allergic rhinitis and asthma, as well as the optimal age to initiate therapy

Determining the target maintenance dose, dosing strategies, and the necessary durations of treatment for SCIT and SLIT

Direct comparisons of SCIT to SLIT in pediatric and adult patients

Optimizing allergen standardization for subcutaneous and sublingual regimens

Gaps in Knowledge


The benefits and adverse effects of subcutaneous (SCIT) or sublingual (SLIT) immunotherapy 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

Shared Decisionmaking: What To Discuss With Your Patients


Resource for Patients Allergy Shots and Allergy

Drops for Adults and Children, A Review of the Research is a free resource that 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 The 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


subcutaneous and sublingual immunotherapy to treat allergic rhinitis/rhinoconjunctivitis and asthma...

Documents

allergic asthma

healthcare research

asthma lin sy

peer review

systematic review

research questions

prevalence of asthma

research summaries