AEROALLERGEN IMMUNOTHERAPY FOR ALLERGIC RHINITIS

Transcription

1 AEROALLERGEN IMMUNOTHERAPY FOR ALLERGIC RHINITIS Persia Pourshahnazari MD, FRCPC Clinical Immunology and Allergy November 4, 2018

2 OBJECTIVES Review indications and evidence for aeroallergen immunotherapy in allergic rhinitis Discuss practical issues that arise with administration of aeroallergen immunotherapy Identified gaps in our current knowledge of aeroallergen immunotherapy

3 GLOSSARY AIT allergen immunotherapy SCIT subcutaneous immunotherapy SLIT sublingual immunotherapy INCS intranasal corticosteroid sprays NSAH non-sedating antihistamines

4 CLINICAL CASE SCENARIO 20 year old female Symptoms of nasal congestion, rhinorrhea, ocular pruritus year round with worsening during the spring months. No lower respiratory tract symptoms. Tried INCS, antihistamine eyedrops, NSAH without adequate relief My friend got allergy shots and doesn t have allergies anymore. I want that too Referred to allergist

5 HISTORY AND EXAMINATION PMHx: Tonsillectomy/adenoidectomy age 7, otherwise healthy Meds: Nil Social/Environmental: Works in an office. Nonsmoker, social drinker. 1 dog at home, sleeps on her bed. No dust mite covers on the bedding. Lots of carpet. O/E: allergic shiners, nasal mucosal pallor without visible polyps, oropharyngeal lymphoid hyperplasia

6 PHYSICAL EXAMINATION IN ALLERGIC RHINITIS

7 INVESTIGATIONS Skin prick tests reveal large positive results to dust mites, dog, alder and birch The allergist advises allergen environmental avoidance measures (she is very definitely not getting rid of her dog anytime soon ) and aeroallergen immunotherapy

8 WHAT IS ALLERGEN IMMUNOTHERAPY? Administration of slowly increasing doses of relevant allergens to a sensitized patient Used in treatment of IgE-mediated allergic diseases Dose is increased until maintenance dosage achieved and/or patient is symptom-free

9 HOW DOES IT WORK? Mechanism(s) of action not yet fully understood Immunologic changes with AIT: Increased allergen-specific IgG Increased blocking IgG4 Neutralizing antibody Blocks inflammatory mediators released by activated mast cells and basophils Decreased specific and total IgE (follows an initial increase)

10 HOW DOES IT WORK? Immunologic changes with AIT: Increased allergen-specific IgA in secretions Shift from Th2 cytokines (allergic response) to Th1 cytokines (regulatory) Decreased mast cell, basophil, and eosinophil recruitment to tissues

11 Eifan et al, Curr Opin Allergy Clin Immunol (2011)

12 FORMS OF ALLERGEN IMMUNOTHERAPY Aeroallergens (inhalants) Subcutaneous immunotherapy (SCIT) Perennial (conventional) Preseasonal (available for pollens) Sublingual tablets (SLIT) Grasses (5 grass: Oralair, Timothy grass: Grastek) Short ragweed (Ragwitek) Dust mites (Acarizax)

13 OTHER FORMS OF ALLERGEN IMMUNOTHERAPY Venoms (Hymenoptera stinging insects) Perennial SCIT Rush and modified rush protocols often used to accelerate build-up Foods Limited clinical availability/active research area Oral immunotherapy (OIT) Epicutaneous immunotherapy (EPIT)

14 ALLERGEN IMMUNOTHERAPY Indications Allergic rhinitis/conjunctivitis Allergic asthma Stinging insect (venom) hypersensitivity Who to consider? Incomplete control with pharmacotherapy Intolerable side effects with pharmacotherapy Patient preference

15 ALLERGEN IMMUNOTHERAPY Contraindications Patients taking beta blockers Uncontrolled/severe asthma Typically won t consider AIT if FEV1<70% Significant comorbidities (e.g. cardiovascular disability) SLIT only: history of eosinophilic esophagitis Cautions Patients taking ACE inhibitors The very young and the very old No strict upper or lower age limits on SCIT Pregnancy Immune dysregulation: malignancy, autoimmunity, immunodeficiency

16 A BIT OF HISTORY 1911 Noon and Freeman report on prophylactic inoculation against hay fever in the Lancet

17 CROSS-DESENSITIZATION? Immunotherapy to one allergen will reduce symptoms elicited by another distinct allergen Eg. Immunotherapy to ragweed reducing symptoms to grasses in a patient sensitized to both Norman and Lichtenstein (1978) 3 year study, 42 patients Sensitized to both ragweed and grass pollens Consistent symptoms during the pollen seasons Intervention: Preseasonal or perennial SCIT to ragweed only No grass pollen administered

18 CROSS-DESENSITIZATION? Norman and Lichtenstein (1978) Both treatment arms (pre-seasonal and perennial): Significant improvement in symptom scores during ragweed pollen season No improvement in symptom scores during grass pollen season

19 CROSS-DESENSITIZATION? Dreborg et al (2012) 20 patients, perennial ARC symptoms, all sensitized to both dust mites and grass pollens Patients randomly assigned to 3 years of either dust mite or grass SCIT Conjunctival provocation testing and allergen-specific IgG testing at 3 years: Significantly changes in conjunctival provocation and allergen-specific IgG levels to treated allergen only Take away: Immunotherapy effects are clinically and immunologically specific

20 CHOOSING ALLERGENS Prescribing practice differs across the globe North America: often treat multiple allergens Europe: single or two allergens, chosen according to most clinically problematic allergy Passalacqua, Curr Opin Allergy Clin Immunol (2014)

21 CHOOSING ALLERGENS Other things to consider: Diluting allergen content in serum Limit each extract set to 4 types of allergens Pharmaceutical stability Mold and cockroach extracts have protease activity that degrade most pollens Need to separate treatment sets Clinical relevance Only treat allergens that are likely to be contributing to the patient s symptoms

22 HOW IS IMMUNOTHERAPY GIVEN? SCIT Perennial (conventional) Most appropriate option if treating multiple allergens Build-up: 6-8 months of once weekly injections Can be compressed into 3-4 months if patient comes in for injections twice per week Avoid back to back days Maintenance: monthly injections for 3-5 years Reduced relapse rate with 3 years of therapy Improved symptom scores with 5 years of therapy No evidence of added benefit with >5 years

23 EXAMPLE SCIT SCHEDULE

24 HOW IS IMMUNOTHERAPY GIVEN? SCIT Preseasonal 9 once-weekly injections immediately preceding the onset of the pollen season No long-term benefit; needs to be repeated annually Appropriate for patients who are only sensitized to one type of pollen

25 HOW IS IMMUNOTHERAPY GIVEN? SLIT One tablet under the tongue once daily First dose under medical supervision, remainder at home No eating/drinking/brushing teeth for 5-10 minutes Grass and ragweed pollens: Typically taken pre- and co-seasonally Can take year-round as well Target three consecutive years of treatment House dust mites: Taken perennially Optimal duration of therapy is currently unknown Most allergists targeting 3-5 years of treatment

26 COST OF IMMUNOTHERAPY SCIT Depends on company ordered from and pharmacy dispensing fees Typically 1 set costs ~$250 for 1 year 5 years of therapy: ~$1000 Double if patient needs 2 sets SLIT Grass pollen and ragweed ~$750 for 6 months 3 years of therapy: ~$2250 House dust mite ~$1500 for 1 year 4 years of therapy: ~$6000

27 EFFICACY OF AIT Evidence from systematic reviews for clinical benefit in ARC treated with AIT include: Symptom improvement (nasal and ocular) Reduced medication needs Improved quality of life In pediatric populations: Prevention of progression of AR to asthma Reduction of new sensitizations When do you start to see benefit? Perennial SCIT: shortly after reaching maintenance SLIT: by 12 weeks of treatment Jutel et al. International consensus on allergy immunotherapy. JACI (2015)

28 HOW DOES SLIT COMPARE TO SCIT? SLIT is more convenient, comfortable and safety profile is superior to SCIT Both are efficacious Head-to-head randomized trials are limited Weak evidence suggests SCIT is superior to SLIT SCIT has better evidence for persistence of benefit

29 A QUICK NOTE ON SLIT-DROPS 2013 JAMA systematic review (Lin et al) 63 studies (n = 5131) comparing SLIT-drops to placebo, pharmacotherapy or SLIT tablets Effective dose ranges not clarified in most studies Efficacy of multi-allergen SLIT drops NOT demonstrated Weak level evidence to support efficacy of singleallergen SLIT drops in ARC and asthma Take away message: Clinical benefit not yet consistently demonstrated for SLIT drops

30 MONITORING Patients on AIT should be seen by their allergist every 6-12 months for re-evaluation Assessment is clinical Symptoms, need for medications, adverse effects Skin prick tests? Currently no reliable diagnostic tools available to identify patients who will have a sustained clinical response to AIT New biomarkers being studied IgE binding by microarray, IgE binding peptides, allergen specific IgG4 Bush, R. Advances in allergen immunotherapy in JACI (2016)

31 DOC, WHY ISN T IT WORKING? Factors to consider if the patient is at maintenance dose and not improving: Ongoing allergenic exposures (eg. cat in the home) High allergen level exposures Ongoing exposure to non-allergenic triggers (eg. cigarette smoke) Untreated clinically relevant allergens Inadequate doses of each allergen Cox et al. AAAAI Practice Parameter. JACI (2011)

32 AEROALLERGEN IMMUNOTHERAPY: ADVERSE REACTIONS - SCIT Local reactions Very common Up to 80% of patients will have some sort of local reaction over the course of their treatment Most are fairly mild Vary from small wheals to large local reactions Swelling larger than the palm of the patient s hand considered a large local reaction Usually an indication to slow down if patient is still in the build-up phase Typically responds well to non-sedating antihistamines Can take prophylactically, typically 1 hour prior to injection

33 AEROALLERGEN IMMUNOTHERAPY: ADVERSE REACTIONS - SCIT Systemic reactions 1-4% of all patients on inhalant SCIT Range of presentations from generalized urticaria to anaphylaxis Risk never goes away doesn t matter if patient is building up or on maintenance Near-fatal reactions (severe hypotension and/or respiratory failure) in 1:1,000,000 injections Fatalities are extremely rare but not negligible Always encourage patients to wait the full 30 minutes of monitoring after their injections!

34 AEROALLERGEN IMMUNOTHERAPY: ADVERSE REACTIONS - SCIT Factors associated with severe systemic reactions: Prior history of systemic reactions Large local reactions do not predict future systemic reactions Asthma Especially if severe or if symptoms are not well controlled Clerical errors Wrong dose Wrong patient s serum Cofactors Exercise, intercurrent illness, medications

35 AEROALLERGEN IMMUNOTHERAPY: ADVERSE REACTIONS - SLIT Safety profile superior to SCIT Systemic adverse reactions in <1% of patients Anaphylaxis considered uncommon to rare Higher risk if oral mucosa is not intact USA: patients are prescribed an epinephrine autoinjector No similar standard of care in Canada Oropharyngeal symptoms are common Tingling, pruritus, mild swelling Typically resolve after 1-2 weeks Very rare: eosinophilic esophagitis (EoE) Contraindicated in patients with past history of EoE

36 AEROALLERGEN IMMUNOTHERAPY IN PREGNANCY SCIT Women counselled not to build-up during pregnancy and lactation Can continue to receive monthly maintenance if previously well tolerated SLIT Published data still lacking No reported fetal harm to date Would not start during pregnancy and lactation, but could perhaps consider continuing if woman becomes pregnant while on therapy

37 KEY POINTS Aeroallergen immunotherapy is a safe and effective treatment for ARC Patients are treated to relevant aeroallergens based on local aerobiology and clinical relevance Type of immunotherapy used depends on patient s sensitizations and preference SCIT should only be administered in facilities equipped to deal with emergency situations

38 QUESTIONS? Thank you!

39 REFERENCES 1. Moote W and Kim H. Allergen-specific immunotherapy. Allergy, Asthma and Clinical Immunology (Suppl 1):S5 2. Cox et al. Allergen immunotherapy: A practice parameter third update. JACI. 127:1 S Norman PS, Lichtenstein LM. The clinical and immunologic specificity of immunotherapy. JACI Jun;61(6): Dreborg S et al. Immunotherapy is allergen-specific: a double-blind trial of mite or timothy extract in mite and grass dual-allergic patients. Int Arch Allergy Immunol. 2012;158(1): Passalacqua, G. The use of single versus multiple antigens in specific allergen immunotherapy for allergic rhinitis: review of the evidence. Curr Opin Allergy Clin Immunol Feb;14(1): Nelson, H. Allergen immunotherapy (AIT) for the multiple pollen sensitive patient, Expert Review of Clinical Pharmacology :11, CSACI Immunotherapy Manual 8. D.M. Smith and C.A. Coop / Ann Allergy Asthma Immunol 116 (2016) 188e Jutel et al. International consensus on allergy immunotherapy. JACI 2015 Sep;136(3): Calderon MA, et al. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database of Systematic Reviews 2007, Issue Tabar et al. Three years of specific immunotherapy may be sufficient in HDM respiratory allergy. JACI Tworek et al. Perennial is more effective than preseasonal SCIT in the treatment of seasonal allergic rhinoconjunctivitis. Am J Rhinol Allergy Radulovic et al. Systematic reviews of sublingual immunotherapy (SLIT). Allergy. 2011;66(6): Larenas-Linnemann, D. How does the efficacy and safety of Oralair compare to other products on the market? Therapeutics and Clinical Risk Management 2016: