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

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

2. 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”

3. Disclosures • none

4. 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

5. 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

6. SLIT History • H.H. Curtis treats hayfever with oral antigen drops in 1900  • Medical News, New York 1900; 77:16-19 • 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

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

8. 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

9. 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 1965:273:675-679

10. 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

11. Less blood, latex exposure Fewer office staff? Ability to use higher doses (?) Therapy of sensitive patients Lower barrier to therapy Why Sublingual Treatment ? • Convenience • Avoid needle anxiety • Expense (?) • Safety

12. SLIT Basic Science • Absorption • Does material get absorbed? • Immunologic Changes • What effect can be attributed to therapy?

13. 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

15. 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

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

17. 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

18. 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

19. 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 2003:14:216-221

20. 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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