Subcutaneous Allergen Immunotherapy for Allergic Disease

Examining Efficacy, Safety and Cost-Effectiveness of Current and Novel Formulations

Linda Cox; Moisés Calderón; Oliver Pfaar

Immunotherapy. 2012;4(6):601-616.

Conclusion

Subcutaneous allergen immunotherapy has been shown in numerous clinical trials, systematic reviews and meta-analyses to be effective in reducing the clinical symptoms associated with asthma, AR/rhinoconjunctivitis and venom hypersensitivity. There is emerging evidence that it may be effective in other allergic conditions such as atopic dermatitis and venom sting large local reactions. Its benefits may persist long after treatment discontinuation and include prevention of allergic disease progression. Overall, if administered in an appropriate setting, SCIT is safe and well tolerated. However, systemic allergic reactions may occur and these have the potential to be life threatening. Studies suggest the incidence of SCIT SRs is approximately 0.1% of injections, with most being of a grade 1 severity. The financial burden of allergic disease to both society and patients is considerable. Studies comparing healthcare costs between SCIT and pharmacotherapy alone have demonstrated that SCIT may be associated with significant cost savings (as high as 80%). Only a small percentage of allergic patients subscribe to SCIT, probably due to the inconvenience and time involved in receiving this treatment in a medical facility. Investigations aimed at developing safer and more effective SCIT therapies have demonstrated promising results, which indicate that, in the near future, a single or ultrashort course SCIT vaccine may provide a 'cure' or long-term remission for allergic disease.

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Table 1. Injection allergen immunotherapy for seasonal allergic rhinitis: Summary of outcomes.
Outcome parameter	Number of studies	Participants (active/placebo)	SMD (95% CI)
Nasal symptoms	9	396/276	-1.28 (-2.03 to -0.54)
Bronchial symptoms	5	266/163	-0.59 (-1.06 to -0.11)
Ocular symptoms	3	226/119	-1.80 (-3.28 to -0.31)
RQLQ	5	332/239	-0.52 (-0.69 to -0.34)

RQLQ: Rhinoconjunctivitis Quality of Life Questionnaire; SMD: Standardized mean difference.
Adapted with permission from [18].

Table 2. Injection allergen immunotherapy for asthma: Asthma symptoms and medication scores by allergen.
Allergen	Asthma symptoms scores		Asthma medication scores
Allergen	Studies (participants)	SMD (95% CI)	Studies (participants)	SMD (95% CI)
Mite	12 (408)	-0.48 (-0.96 to 0.0)	12 (424)	-0.61 (-1.04 to -0.18)
Pollen	18 (663)	-0.61 (-0.87 to -0.35)	8 (324)	-0.52 (-0.9 to -0.13)
Others	5 (213)	-0.83 (-1.92 to -0.26)	1 (121)	-0.26 (-0.62 to 0.10)
Total	34 (1284)	-0.59 (-0.83 to -0.35)	20 (869)	-0.53 (-0.80 to -0.27)

SMD: Standardized mean difference.
Adapted with permission from [21].

Table 3. Injection allergen immunotherapy for asthma: Summary of allergen-specific bronchial hyper-reactivity indices.
Allergen-specific BHR index	Studies (participants)	SMD (95% CI)
Log PD₂₀ mite	6 (148)	-0.98 (-1.39 to -0.58)
Log PD₂₀ pollen	5 (202)	-0.55 (-0.84 to -0.27)
Log PD₂₀ animal dander	6 (153)	-0.61 (-0.95 to -0.27)
Log PD₂₀/PC₁₀₀ other allergens	2 (61)	-0.18 (-0.70 to 0.33)
Total	19 (564)	-0.61 (-0.79 to -0.43)

BHR: Bronchial hyper-reactivity; PC₁₀₀: Concentration required to produce a 100% increase in lung resistance; PD₂₀: Provocative dose required to produce a 20% fall in forced expiratory volume in 1s; SMD: Standardized mean difference.
Adapted with permission from [21].

Table 4. Injection allergen immunotherapy for asthma: Summary of allergen-nonspecific bronchial hyper-reactivity indices.
Nonspecific BHR index	Studies (participants)	SMD (95% CI)
Log PD₂₀ methacholine	12 (453)	Not evaluable
Log PC₂₀ histamine	4 (76)	-0.55 (-1.37 to 0.28)
Log PC₃₅ acetylcholine	1 (21)	-1.29 (-2.28 to -0.31)
δFEV₁ % cold air	1 (26)	-0.52 (-1.31 to 0.26)
Total	18 (576)	-0.35 (-0.59 to -0.11)

BHR: Bronchial hyper-reactivity; FEV₁: Forced expiratory volume in 1s; PC₂₀: Concentration required to induce a 20% fall in forced expiratory volume in 1s; PC₃₅: Concentration required to produce a 35% decrease in specific airway conductance; PD₂₀: Provocative dose required to produce a 20% fall in forced expiratory volume in 1s; SMD: Standardized mean difference.
Adapted with permission from [21].

Table 5. Injection allergen immunotherapy for asthma: Summary of lung function parameters.
Lung function parameter	Studies (participants)	SMD (95% CI)
Peak expiratory flow	11 (524)	0.14 (-0.33–0.61)
FEV₁	7 (199)	-0.32 (-0.96–0.31)
Thoracic gas volume	2 (81)	Not evaluable

FEV₁: Forced expiratory volume in 1s; SMD: Standardized mean difference.
Adapted with permission from [21].

Box 1. Allergen immunotherapy landmarks in the past 101 years: Bench to bedside.
1911–1930: Noon and Freeman reported successful immunization of hay fever patients with timothy grass pollen extract[1,3,97] 1921: Prausnitz and Kustner demonstrated that anaphylaxis sensitivity could be passively transferred by the serum of the sensitive patient (known as the Prausnitz–Kustner reaction)[98] 1935: Cooke demonstrated that blocking antibodies from patients treated with ragweed extract can confer protection on unvaccinated ragweed-allergic patients[98] 1954: Franklund and Augustin carried out the first placebo-controlled immunotherapy study of patients with grass pollen-induced hay fever[99] 1957, 1968: Johnstone demonstrated a preventive and dose–response effect of immunotherapy in terms of bronchial hypersensitivity and development of asthma[100,101] 1965: Lowell and Franklin demonstrated the specificity of immunotherapy in ragweed-allergic hay fever patients[102] 1967: Ishizaka identified IgE as the reaginic antibody[103,104] 1997: Des Roches et al. demonstrated that immunotherapy may prevent new allergen sensitizations[75] 1999: Durham et al. demonstrated the persistent benefits of immunotherapy after discontinuation of immunotherapy in grass pollen hay fever[54] 2002: Moller et al. demonstrated that immunotherapy may prevent progression of allergic rhinitis to asthma[70] 2003, 2004: Ewbank et al. and Nanda et al. demonstrated immunotherapy dose–response effect on immunological changes associated with cat SCIT with the effect at 5 weeks being predictive of the response at 1 year[105,106] 2006: Creticos et al. demonstrated efficacy of six weekly injections of vaccine containing CpG conjugated to the major ragweed allergen Amb a 1[92] 2007: Jacobsen et al. demonstrated that the asthma-preventive effect of SCIT was still significant 7 years after treatment discontinuation[69] 2008: Francis et al. demonstrated SCIT immunological changes occurred at different time points and allergen doses: IL-10 production at 2–4 weeks associated with low allergen doses and inhibition of late-phase skin responses[107]

SCIT: Subcutaneous immunotherapy.

Box 2. Evaluation of symptoms using a 4-digit score system as given by the Committee for Medicinal Products for Human Use.
0 = absent symptoms (no sign/symptom evident) 1 = mild symptoms (sign/symptom clearly present, but minimal awareness; easily tolerated) 2 = moderate symptoms (definite awareness of sign/symptom that is bothersome but tolerable) 3 = severe symptoms (sign/symptom that is hard to tolerate; causes interference with activities of daily living and/or sleeping)

Reproduced with permission from [202] and [206].

Box 3. Clinical indications for allergen immunotherapy.
*Indications for allergen immunotherapy in patients with allergic rhinitis, allergic conjunctivitis or asthma* Allergen immunotherapy should be considered for patients who have demonstrable evidence of specific IgE antibodies to clinically relevant allergens. The decision to begin allergen immunotherapy may depend on a number of factors, including but not limited to: Patient preference/acceptability Adherence Medication requirements Response to avoidance measures Adverse effects of medications Coexisting allergic rhinitis and asthma Possible prevention of asthma in patients with allergic rhinitis Potential indication: atopic dermatitis if associated with aeroallergen sensitivity
*Indications for allergen immunotherapy in patients with reactions to Hymenoptera stings* Patients with a history of a systemic reaction to a Hymenoptera sting (especially if such a reaction is associated with respiratory symptoms, cardiovascular symptoms or both) and demonstrable evidence of clinically relevant specific IgE antibodies Patients older than 16 years with a history of a systemic reaction limited to the skin and demonstrable evidence of clinically relevant specific IgE antibodies (patients ≤16 years of age who present with a history of only cutaneous reactions to Hymenoptera stings usually do not require immunotherapy) Adults and children with a history of a systemic reaction to imported fire ant stings and demonstrable evidence of clinically relevant specific IgE antibodies Potential indication: for large local reactions in patients who have frequent and disabling large local reactions

Adapted with permission from [32].

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Executive Summary

Assessment of Immunotherapy Outcomes

The most accepted primary outcome is evaluation of improvement in symptoms and medication use or a combined symptom–medication score.
No validated method for assessing symptoms or medication but 4-point rating scale (3 = most severe) widely accepted for symptoms; Rhinoconjuctivitis Total Symptom Score (range 0–18).
Recognizing the interdependence between allergic symptom and use of antiallergy medication, guidelines recommend evaluating both outcomes separately but calculating a combined score (i.e., weighted sum of symptoms and medication scores).
Secondary outcomes include Quality of Life questionnaires, allergen provocation tests and immunological parameters such as specific IgG and IgE.

Systematic Reviews & Meta-analyses

Efficacy: systemic reviews and meta-analyses are instruments for synthesizing clinical trial data to determine if there is a beneficial effect of a treatment over placebo:
- Allergic rhinitis: significant reductions in symptoms scores (standardized mean difference: -0.73) and medication scores (standardized mean difference: -0.57);
- Asthma: significant reductions in symptoms scores (standardized mean difference: -0.59), numbers needed to treat to prevent deterioration in asthma symptoms and increased medication use; 3 and 4, respectively. No consistent effect on pulmonary function;
- Venom hypersensitivity: symptoms prevented in 79% of patients receiving venom immunotherapy versus 36% of those who did not.

Safety:
- Mild systemic reaction: 22% of subcutaneous immunotherapy (SCIT) versus 8% of placebo;
- Moderate to severe: 7% of SCIT versus 1% of placebo;
- Adverse reaction severe enough to require epinephrine occurred in one in 770 injections.

Potential Indications for SCIT in Addition to Allergic Rhinitis, Asthma & Hymenoptera Sensitivity

Frequent and disabling large local venom insect sting reactions and atopic dermatitis.
Conflicting evidence on efficacy in oral allergy syndrome.
SCIT therapeutic safety index for food allergy not favorable with currently available unmodified extracts.

Preventive & Persistent Effect of SCIT

Prevention of progression from allergic rhinitis to asthma has been demonstrated in some open-label and randomized controlled trials.
Prevention of the development of new allergen sensitivities has been demonstrated in monosensitized individuals.

Cost–effectiveness of SCIT

Studies comparing the healthcare costs between patients treated with SCIT and pharmacotherapy alone have demonstrated that SCIT may be associated with significant cost savings (as high as 80%).

Novel SCIT Formulation

Novel approaches to SCIT such as T-cell-directed peptide fragments or adjuvants conjugated to modified vaccines may offer shorter, more effective and safer treatment, which in turn may increase the number of allergic individuals subscribing to this treatment.

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Subcutaneous Allergen Immunotherapy for Allergic Disease

Examining Efficacy, Safety and Cost-Effectiveness of Current and Novel Formulations

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