Sublingual Allergy Immunotherapy (SLIT)

1
Understanding Sublingual Immunotherapy (SLIT)
Definitions, Indications, Alternatives and
Patient Selection

• Steven M. Houser, MD, FAAOA
• Assoc Prof Oto CWRU
• MetroHealth Medical Center
• Cleveland OH

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SLIT off label notice

• You need to be informed that SLIT drops are not
  accepted by the FDA
• No commercial antigens are specifically
  designated for SLIT drops
• Discussions on SLIT are inherently off label

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Disclosures

• none

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Lecture Objectives

• Define SLIT and how it differs from conventional
  subcutaneous immunotherapy (SCIT)
• Discuss the risks and benefits of SLIT as
  compared to SCIT
• Examine the evidence for SLIT
• Discuss insurance issues for SLIT
• Examine SLIT cost options for patients,
  physicians, and implications in patient selection

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Allergy History

• 3500 BC King Menses of Egypt dies of a wasp sting
• 1819 Bostock coins the term hayfever describing
  his own syptoms
• 1874 Blackley publishes that hayfever is caused
  by grass pollen
• 1902 Richet and Portier coin anaphylaxis
• 1906 Austrian pediatrician von Pirquet coins the
  term allergy to describe hypersensitivity
• 1911 Noon and Freeman perform ID ait v grass
  pollen in London
• 1915 Cooke publishes on allergy immunotherapy in
  US in Laryngoscope

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SLIT History

• H.H. Curtis treats hayfever with oral antigen
  drops in 1900 
• Medical News, New York 1900 7716-19
• French Hansel experiments with sublingual drops
  for dust mites at Mayo Clinic in the 1920s and
  published his results in 1936
• Hansel, F.  Allergy of the nose and paranasal
  sinuses.  CV Mosby.  1936

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SLIT History

• SLIT never embraced considered fringe medical
  therapy in US
• Insurance panels cover only SCIT
• Europeans begin researching SLIT in 1980s
• Success documented
• Monotherapy in Europe permits much higher
  SLIT/SCIT ratio
• US begins to readopt SLIT

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Definitions for this lecture

• Sub Lingual Immuno Therapy SLIT
• This term is imprecise there are several
  sublingual routes
• Sublingual spit
• Sublingual swallow
• Sublingual tablet
• Unless specified, SLIT is a generic term applied
  to all forms

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Subcutaneous ImmunotherapySCIT

• As the dominant therapy, most published reports
  evaluated SCIT
• 85-90 success rate for inhalants
• rhinitis, conjunctivitis and asthma
• Efficacy and safety well studied
• At expense of other routes
• Other routes of therapy received little attention
  for years
• Lowell FC, et.al. NEJM 1965273675-679

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Enter socialized medicine

• British Committee for the Safety of Medicine 1986
  report
• Based upon reports of fatalities
• questioned safety of immunotherapy
• significantly decreased British use of SCIT
• renewed interest in alternative IT routes
• Alternative methods became mainstream
• without prolonged outcomes studies
• fatalities later noted to be caused by avoidable
  errors

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Noninjection IT Routes

• Non-injection routes studied
• intranasal
• declared effective and safe by WHO
• oral
• noneffective
• bronchial
• marginal effectiveness, excessive risk
• sublingual (SLIT)
• spit and swallow techniques
• effective and safe
• Canonica 2003

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Why Sublingual Treatment ?

• Convenience
• Avoid needle anxiety
• Expense (?)
• Safety

• Less blood, latex exposure
• Fewer office staff?
• Ability to use higher doses (?)
• Therapy of sensitive patients
• Lower barrier to therapy

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SLIT Basic Science

• Absorption
• Does material get absorbed?
• Immunologic Changes
• What effect can be attributed to therapy?

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SLIT Absorption

• Mistrello 1993
• rats, sublingual absorption of allergen
• serum bioavailability only 1 compared to IV
  injection
• Bagnasco 1997 and 2001
• radioactive allergen
• no oromucosal penetration
• tracer found in serum after swallow
• tracer in mouth for at least 2 hours and as long
  as 20 hours after ingestion
• Sublingual / spit technique 70 of radioactivity
  retained in mouth
• Passalacqua 2004

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Immunologic Changes

• Mechanism of effectiveness not completely
  understood
• Immune system changes observed
• SCIT well studied
• less data available for SLIT
• most data comes from efficacy studies
• a few dedicated studies available

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Immunologic ChangesSLIT

• Decreased IgE
• Absence of post seasonal IgE rise
• IgG1 has early rise then tapers off
• IgG4 increases later and persists
• Tari 1994

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Immunologic ChangesSLIT

• Multiple efficacy studies have reproduced this
  data on immunoglobulin changes
• Smith 2004, Troise 1995, Tari 1990, Hordijk 1998,
  Canonica 2004
• Several studies reported either no change or a
  change in only one of the immunoglobulins
• Horak 1998, Nelson 1993, Pajno 2000 Mungan 1999,
  Tonnel 2004, Nelson 1993, La Rosa 1999

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Immunologic ChangesSLIT

• Reduction T cell proliferative response
• Reduction in ICAM-1 expression
• decreased local eosinophils and neutrophils
• nose and conjuctiva after allergen challenge
• decreased bronchial reactivity to methacholine

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Immunologic ChangesSLIT

• Decreased ECP, IL-13 and prolactin
• IL-13 is a TH2 cytokine
• promotes switch to IgE and IgG4 production
• involved in memory cell formation
• prolactin produced by activated T cells
• clonal expansion of immunocompetent cells
• ECP- produced by activated eosinophils
• Ippoliti Ped All Immunol 200314216-221

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Immunologic ChangesSLIT

• Marcucci 2003
• increase in nasal IgE and tryptase seen in
  placebo and not active group
• increased nasal tryptase with allergen challenge
  in placebo group only
• no changes in nasal or sputum ECP

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Immunologic ChangesSLIT

• Yuksel 1999
• decrease in urinary leukotrienes after SLIT
  compared to placebo controls
• significant in allergic rhinitis
• not significant in asthma subgroup
• urinary leukotrienes are associated with allergic
  asthma and rhinitis

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Clinical Science

• Efficacy
• Safety
• Dosing

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SLIT Efficacy
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SLIT Efficacy in Allergic Rhinitis

• Defining Efficacy
• Subjective, symptom based
• Medication scores
• QOL instruments
• Symptom logs/scores
• Objective
• Immunologic parameters
• Skin tests
• Provocation testing
• ?Correlation of objective/subjective data

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SLIT Efficacy in Allergic Rhinitis

• Comparisons/assessments of the literature, wide
  variance
• Study design dosing, schedule, duration, small
  numbers
• Endpoints/efficacy
• Outcome measures not uniform
• Subjective, validated?, objective

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SLIT Efficacy in Allergic Rhinitis

• Majority of SLIT efficacy studies done in Europe
• Lack of Ag standardization US vs. Europe
• Definitions units vary
• Translation to US dosing near impossible
• Lack of large scale US studies

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SLIT Meta-analysis

• Wilson DR 2005
• 22 DBPC studies, 979 patients
• Adult pediatric
• Literature to 2002
• Outcome measures
• Symptom scores
• Medication usage

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SLIT Meta-analysis

• Wilson DR 2005
• Results Significant reduction in symptom
  medication scores
• Large heterogeneity in studies
• Subgroup analysis seasonal/perennial, age,
  dose, duration, spit vs swallow
• No statistically significant differences
• Conclusion SLIT effective for allergic rhinitis

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SLIT Meta-analysis

• Radulovic 2007
• Added 19 studies to Wilsons prior study
• 39 DBPC, 2746 subjects
• Results
• Significant symptom medication reduction
• Effect increases as tx duration
• Conclusion SLIT effective for AR

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SLIT Efficacy Reviews

• Leatherman BD 2007
• 36 efficacy papers reviewed
• 30/36 found SLIT to be effective
• Cox L 2006
• Reviewed 64 studies
• SLIT effective
• More studies to determine dose duration

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SLIT Efficacy in Asthma

• NIU CK 2006
• 97 children 6-12, multicenter study
• Dust mite allergy plus mild/mod asthma
• SLIT 24 weeks
• Results significant decrease in asthma scores
• Significant improvement in spirometry
• Good tolerance, few minor AE
• Conclusion SLIT is clinically beneficial to mite
  sensitive asthmatic children.
• Ozdemir C 2007
• SLIT in DM allergic children
• Significant reduction in inhaled corticosteroid
  use

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SLIT Efficacy Pediatric

• Larenas-Linnemann 2009
• Updated review on SLIT for children
• Included 2007-8 literature
• Looked at meta-analysis systemic reviews
• Conclusion Evidence of effect in SLIT in
  children w/ AR or asthma caused by pollen. For
  DM asthma, evidence is still nonconcordant.

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SLIT Efficacy Protective Effect in Children

• Marongna M 2008
• 213 allergic children intermittent asthma
• Randomized SLIT vs meds for 3 years
• Conclusion
• SLIT reduced onset of mild persistent asthma
• SLIT decreased bronchial hyperreactivity
  (methacholine)
• SLIT decreased the onset of new sensitizations

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SLIT Long term effects in children

• Di Rienzo V 2003
• 35 children SLIT for 4-5 years
• 25 children meds
• SLIT group improved asthma
• No difference in new sensitizations
• Clinical effects maintained on asthma 4-5 years
  after SLIT discontinued.

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Recent Large Scale Studies of Efficacy

• Wahn 2009
• Multicenter DBPC
• 278 Children 5-17
• Grass tablet vs placebo
• Results significant symptom reduction
• Decrease in medication use

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Recent Large Scale Studies of Efficacy

• Bufe 2009
• 253 children 5-16
• Multicenter DBPC
• Grass tablet vs placebo
• Given pre and in-season
• Results Significant symptom medication
  reduction
• Immunologic changes
• Asthma improved

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Recent Large Scale Studies of Efficacy

• Durham 2006
• Multicenter DBPC
• Timothy grass tablet
• Given 18 weeks pre and in season
• Results at highest dose (15 microgram)
• Significant reduction in symptoms medication
• Improve RLQL
• Increased efficacy if given pre-season
• Increase in IgG blocking Ab

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Efficacy SLIT vs SCIT

• Kinchi 2004
• 71 pt in DBPC study
• Birch
• Both decreased symptom/medication scores compared
  to placebo
• Non-significant greater improvement in SCIT
• ? Insufficient numbers
• SLIT higher safety profile

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SLIT versus SCIT
Reference Patients Allergen Main Results
Ongari 1995 5 controls 8 SLIT 7 SCIT Grass Treatments equally effective on symptoms
Bernardis 1996 12 SLIT 11 SCIT Alternaria Symptoms and drug intake improved with both treatments
Piazza 1993 17 SCIT 14 SLIT 12 Nasal IT 14 Controls Dustmite Symptoms improved with all treatments IgE IgG4 change only with SCIT
Mungan 1999 15 SLIT 11 SCIT 10 PLA Dustmite Rhinitis symptoms improved with both Asthma symptoms only with SCIT
Quorino 1996 10 SLIT 10 SCIT Grass Equally effective SLIT better tolerated
Kinchi 2004 21 SCIT 18 SLIT 19 PLA Birch Rate of symptoms 50 with SLIT and 66 with SCIT versus baseline Both better than placebo SLIT safer/fewer SE
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Efficacy SLIT vs SCIT

• only one DBPC
• Few studies
• Most show SLIT and SCIT equivalent in symptom
  control
• More studies needed

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Efficacy SLIT vs Pharmacotherapy

• Maronga 2009
• 51 pts SLIT vs inhaled budesonide
• Grass pollen
• SLIT effective and superior to budesonide
• Upper lower airway sx
• Year 3 and 5

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SLIT Efficacy Single vs Multi-antigen

• SLIT-most studies focus on single antigen
• SCIT-lack of multi-antigen studies
• US multi-Ag prevaling method
• SLIT few multi-Ag studies in US

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Single Antigen vs. Multiple Antigen
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SLIT Efficacy Single vs Multi-antigen

• Maronga 2007
• 58 pts, grass birch allergy
• Single, multi, or pharmacotherapy
• Symptoms, med use, nasal eosinophils
• Results multi-antigen SLIT most effective

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SLIT Efficacy Single vs Multi-antigen

• Saporta 2007
• SCIT and SLIT multi AG observational study
• 66 pts
• SLIT only group 70 substantial sx improvement
• SCIT -gt SLIT group
• 75 equally effective
• 17 SLIT more effective
• 8 SCIT more effective
• 64 substantial sx improvement

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SLIT Efficacy Single vs Multi-antigen

• Wise SK 2009
• 15 pts multi Ag SLIT
• M-RLQL before and maintenance (2.9 months)
• Results Significant improvement 12/14 domains

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SLIT Efficacy Single vs Multi-antigen

• Koepp (presented AAOA 2008)
• Multi Ag SLIT
• 2-3 yrs maintenance cont clinical improvement
• Demographics/skin testing
• Not predictive of SLIT outcomes

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SLIT Efficacy Conclusions

• SLIT is effective in the treatment of allergic
  rhinitis.
• SLIT improves asthma symptoms.
• Further large scale studies are required to
  determine optimal effective U.S. dosing and
  duration.

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SLIT Adverse Events

• Local irritation not uncommon
• 11 rate of systemic reaction
• Rodriguez Allergy Asthma Immunol 2008
• 3 case reports of anaphylaxis from SLIT
• No reported deaths
• Leatherman Oto Clin N Am 2008

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SLIT currently

• FDA approved SLIT product tabs, not drops
• Grass, ragweed (dust and cat in development)
• No CPT code for drops
• General allergists were reluctant to adopt
• Only 5.9 used SLIT in 2008
• Allergy Asthma Immunol 2008
• SLIT tabs may have spurred an about face
• AAOA continues to move forward on SLIT
• AAOA consensus SLIT dosing protocol
• AAOA Today, Winter 2007
• AAOA dosing paper, IFAR 2015

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Sublingual Immunotherapy (SLIT)

• Daily drops below the tongue
• Typically 3-500x the SCIT dose
• Held in place for 2 minutes prior to swallow
• Main issues
• Safety
• Patient convenience

Leatherman OtoHNS 2007
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Whom to place on SLIT?

• Children
• Shots can work in lt7yo, but difficult on office
• Drops acceptable to child, parents
• Competitive athletes
• Cannot tolerate arm swelling/irritation
• Patients fearing needles
• Patients that cannot come to office weekly

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Incorporate into practice

• Outlay
• nursing (AAOA basic course)
• space flow of office
• refrigerator, syringes, bottles
• does the general allergist send patients?
• SLIT requires more antigens
• Join AAOA for fellowship (reimbursement?)

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Older SLIT recipe

• Escalation dropper bottles (5mL)
• Make these 4 at one time, reverse numbering
• Bottle 4
• 0.2mL concentrate each Ag
• Add 50 glycerine to make 5mL
• Bottle 3
• 1mL 4 4mL 50 glycerine
• Bottle 2
• 1mL 3 4mL 50 glycerine
• Bottle 1 (patient starts with this dilute
  bottle)
• 1mL 2 4mL 50 glycerine

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Older SLIT recipe

• Maintenance bottle (10mL)
• 0.4mL concentrate of each Ag
• Add 50 glycerine to make 10mL volume
• Limited to 25 Ag per bottle
• Note that proteolytic enzyme issue still exists
• Molds and pollens separate

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Older SLIT recipe
Bottle 1 Bottle 2 Bottle 3 Bottle 4
162,500 112,500 12,500 1500
1 drop qd x 7d 1 drop qd x 7d 1 drop qd x 7d 1 drop qd x 7d
2 drops qd x 7d 2 drops qd x 7d 2 drops qd x 7d 2 drops qd x 7d
3 drops qd x 7d 3 drops qd x 7d 3 drops qd x 7d 3 drops qd x 7d
Maintenance bottle 3 drops qd continued
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SLIT Houser personal recipe

• Build up dropper bottles (5mL)
• 0.034mL/drop Greer
• 3 drops approximate 0.1mL
• Final bottle (10mL)
• 0.05mL/drop Greer
• 3 drops approximate 0.15mL

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Current SLIT recipe

• Maintenance dropper bottle (10mL)
• Bottle 2 maintenance
• Initial vial made (patient uses 2nd)
• 1mL each concentrate 50 glycerine to total
  10mL
• Up to 10 antigens can be treated
• Escalation dropper bottle (5mL, or smaller)
• Bottle 1 (patient starts with this dilute
  bottle)
• 1mL of bottle 2 4mL 50 glycerine
• Can use smaller volume as well
• 5-fold dilution of maintenance vial
• E.g., 0.5mL of 2 2mL 50 glycerine

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Current SLIT recipe
Bottle 1 Bottle 2
150 110
1 drop x 3d 1 drop x 3d
2 drops x 3d 2 drops x 3d
3 drops x 3d 3 drops daily as maintenance
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Comparison of SCIT v current SLIT Ag dose

• SCIT
• 0.5mL/week 0.02mL per Ag per week
• SLIT
• 0.015mL/d x7 0.105mL per Ag per week
• 0.105/0.02 5.25
• SLIT maint dose is 5.25x the SCIT weekly maint
  dose for any individual Ag
• Can only use up to 10 Ag in a SLIT vial

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Anaphylaxis

• head down / legs up
• call for help
• Epinephrine 0.3cc 1/1000 IM, SQ
• touniquet above test / injection site
• Secure airway, give O2
• Place IV, give fluids
• diphenhydramine, vasopressor, brochodilator
• All patients should have epinephrine pen
• Reaction up to 2 hours after injection