1. The Pharmacology Of Allergies
Eric E. Schmidt, O.D.,F.A.A.O.
Omni Eye Specialists
Wilmington, NC

2. Ocular Allergic Disease Fun Facts!
50 million people suffer some type of allergic disorder
Incidence is way up over past 40 yrs
90% Of those have ocular involvement
32% involve only ocular tissue
40% Of population affected
Initial onset is trending younger
Warm, moist climate
SAC responsible for 85% of allergic eye disorders

3. Epidemiological research has confirmed that the prevalence of all types of allergy has been increasing since at least the 1980s. A number of potential causes of this phenomenon have been suggested, including increased industrialization and increased pollution. While estimates of the number of patients who suffer specifically from AC vary widely, we can say with some confidence that at least 20% or more of the general population suffer from AC at some point in the year. So AC is a very common complaint. 3

4.  Ocular vs. Nasal Complaints
Ocular symptoms are perhaps underappreciated relative to nasal symptoms.
A Swiss study of 509 patients seeking treatment for seasonal allergies found that in more than 2/3 of the patients, symptoms of allergic conjunctivitis were as severe or more severe than symptoms of rhinitis.
Reference
Wuthrich B, Brignoli R, Canevascini M, Gerber M. Epidemiological survey in hay fever patients: symptom prevalence and severity and influence on patient management. Schweiz Med Wochenschr. 1998;128:
Sneeze image 2006 JupiterImages Corporation
Ocular symptoms as severe or more severe than rhinitis symptoms in 70% of seasonal allergy patients
Wuthrich et al, Schweiz Med Wochenschr 1998;128:139 4

5. Ocular Symptoms Are Frequent
Eye Symptoms
Patients Aged 12 to 17 Years
Ocular symptoms are common in allergy patients, particularly watering, itching, and redness. The graph shows eye symptoms found concomitantly with allergic rhinitis. Symptom frequencies in this table are derived from a survey of 83 patients with seasonal allergic rhinitis, aged 12 to 17 years.
In another study of female patients, 70% of those (n = 310) with allergic conjunctivitis said that eye allergies affected their appearance. 65% said they were annoyed by lid swelling associated with allergic conjunctivitis. (n = 310). These results indicate that the impact of ocular allergy on personal appearance is significant and important, in addition to the physical misery associated with the disease.
References
Raizman MB. Recognizing and treating ocular allergy in women. The Female Patient. 2003;28:14-19.
Juniper EF, Guyatt GH, Dolovich J. Assessment of quality of life in adolescents with allergic rhinoconjunctivitis: Development and testing of a questionnaire for clinical trials. J Allergy Clin Immunol. 1994;93:
Juniper et al, J Allergy Clin Immunol 1994;93:413 5

6. Where in the US are allergies most prevalent?

7. This graph nicely illustrates the major peak in AC prevalence during the spring allergy season with another spike in early fall. Of course, these patterns of symptom prevalence vary significantly by region.
Also note that this pattern is specific to pollen triggers – other allergens may result in higher incidences of AC each month. 7

8. In our practices contact lens wearers are especially important and our early diagnosis and treatment of itching associated with allergic conjunctivitis can help the patient to get back into their lenses.
As a reminder, Patients should be advised not to wear a contact lens if their eye is red. BEPREVE should not be used to treat contact lens-related irritation. BEPREVE should not be instilled while wearing contact lenses. Remove contact lenses prior to instillation of BEPREVE. Lenses may be reinserted after 10 minutes following administration of BEPREVE. 8

9. While we all see peaks in visits for AC corresponding to our regional high pollen seasons – usually in Spring, Summer, and/or Fall – it is important to remember than many patients may have AC all year long because of allergies to mold or pet dander. Together, seasonal allergic conjunctivitis and perennial allergic conjunctivitis are the two most common forms of ocular allergy. They are identical type 1 or immediate hypersensitivity reactions, with the main difference being that Seasonal allergic conjunctivitis (SAC) involves an acute reaction to seasonal allergens while Perennial allergic conjunctivitis (PAC) is a chronic condition caused by household allergens that are always present (though seasonal pollens may exacerbate PAC). 9

10. Immunology 101
Basic function of immune system is to detect and eliminate any substance recognized as foreign
Antigens (allergens) are the foreign substances that trigger the immune response

11. Basic Immune Response Host recognizes a foreign body (antigen)
Host mobilizes a reaction
Self vs non-self

12. Allergies Exaggerated Immune Response
Body produces immunoglobulins (antibodies) specific to allergen (antigen)
Release of chemical mediators, e.g. histamine, cause allergy symptoms

13. Allergies & The Eye Allergen introduced into tear film
Allergen absorbed into conjunctiva
Allergen binds to IgE coated mast cells
Mast cell degranulates- allergic mediators released
Eyes swell and itch!

14. Sensitization, Early-phase and Late Phase.
Now, let’s look at the disease process itself. As with other Type 1 hypersensitivity reactions, there are 3 stages to Allergic Conjunctivitis:
Sensitization, Early-phase and Late Phase.
First, let’s review sensitization. 14

15. Sensitization, Early-phase and Late Phase.
Now, let’s look at the disease process itself. As with other Type 1 hypersensitivity reactions, there are 3 stages to Allergic Conjunctivitis:
Sensitization, Early-phase and Late Phase.
First, let’s review sensitization. 15

16. Sensitization, Early-phase and Late Phase.
Now, let’s look at the disease process itself. As with other Type 1 hypersensitivity reactions, there are 3 stages to Allergic Conjunctivitis:
Sensitization, Early-phase and Late Phase. 16

17. First, let’s review sensitization.
Now, let’s look at the disease process itself. As with other Type 1 hypersensitivity reactions, there are 3 stages to Allergic Conjunctivitis:
First, let’s review sensitization. 17

18. Produce histamine, which will cause the eye to itch and tear
In the sensitization phase, antibodies are created specific to the presenting allergen.
These IgE antibodies bind to the surface of mast cells. Sensitization is now complete. The mast cell then begins to
Produce histamine, which will cause the eye to itch and tear
Produce prostaglandins and leukotrienes, which are mediators for inflammation
The eye is now primed for the signs and symptoms of allergic conjunctivitis 18

19. The next step is the Early-Phase Response
The next step is the Early-Phase Response. In this stage, after contact with the allergen to which the eye has become sensitized, patients experience the hallmark symptom of itching associated with allergic conjunctivitis. 19

20. The allergens bind to IgE antibodies, that are bound to mast cells
If the eye encounters the same allergen that led to allergic sensitization, it will immediately begin the Early-Phase allergic reaction. During this process:
The allergens bind to IgE antibodies, that are bound to mast cells 20

21. The allergens bind to IgE antibodies, that are bound to mast cells
If the eye encounters the same allergen that led to allergic sensitization, it will immediately begin the Early-Phase allergic reaction. During this process:
The allergens bind to IgE antibodies, that are bound to mast cells 21

22. If the eye encounters the same allergen that led to allergic sensitization, it will immediately begin the Early-Phase allergic reaction. During this process:
The mast cells degranulate in response to the allergen-IgE antibody complex 22

23. If the eye encounters the same allergen that led to allergic sensitization, it will immediately begin the Early-Phase allergic reaction. During this process:
Within minutes, histamine prostaglandins, leukotrienes and other chemotactic factors/cell mediators, such as IL-5, are released 23

24. The Late-Phase allergic response is associated with the worsening and prolongation of symptoms.24

25. dendritic cells/monocytes
Anywhere from 2 to 6 hours or more after allergen exposure, the allergic reaction moves to the Late-Phase. The chemotactic factors released from mast cell degranulation attract, recruit, and activate:
Eosinophils
dendritic cells/monocytes
Neutrophils, which are another type of white cell capable of releasing cell mediators and engulfing/digesting foreign substances
Additional T cells 25

26. dendritic cells/monocytes
Anywhere from 2 to 6 hours or more after allergen exposure, the allergic reaction moves to the Late-Phase. The chemotactic factors released from mast cell degranulation attract, recruit, and activate:
Eosinophils
dendritic cells/monocytes
Neutrophils, which are another type of white cell capable of releasing cell mediators and engulfing/digesting foreign substances
Additional T cells 26

27. The presence of these additional immune cells and their by-products will prolong and exacerbate the symptoms of allergic conjunctivitis.
Eosinophils will release a variety of toxic proteins that can damage the epithelium
dendritic cells will engulf and digest any remaining allergens and dead cells
Neutrophils and other inflammatory cells will release secondary inflammatory mediators, which will cause more inflammation, redness and swelling. 27

28. Allergic Conjunctivitis
A Mast Cell mediated hypersensitivity reaction

29. Allergic Conjunctivitis Symptoms
Itching
Hyperemia
Mucus d/c
Filmy vision
Bilateral
Burning
Swelling
Tearing
FB sensation
Rhinitis

30. Allergic conjunctivitis objective findings
Papillae
Follicles
Increased lacrimal lake
Mucus strands
Conjunctival injection
Tear film debris
Lid edema
Conjunctival edema
*Symptoms often outweigh the signs*

31. Classification of Ocular Allergy
Seasonal allergic conjunctivitis
Perennial allergic conjunctivitis
Vernal keratoconjunctivitis
Atopic keratoconjunctivitis
Giant papillary conjnuctivitis

32. Here is the typical presentation of AC – the red, watery eye – with the patient’s principal complaint being ocular itch. Of course, many ophthalmic conditions may have a similar presentation, so the differential diagnosis of AC becomes important. Again, itching is usually considered a hallmark of allergy, and often helps differentiate it from ocular infection or dry eye. 32

33. Allergy Treatment Pearls
Prescription products safer and more effective than OTC?
Confirm symptoms, confirm diagnosis
Treatment depends upon severity
Treatment may be long term
Frequent follow-up necessary
Punctal occlusion?
CL question

34. What do we look for in a therapy?
Control symptoms
Work on intended targets
No toxicity
Comfort
No side effects
Rapid onset
Long duration
Easy to use dosing

35. Side effects of topical antihistamines
Surface drying
CL dehydration
Stinging

36. Bepotastine has two principal mechanisms of action.
It is a highly selective, direct histamine 1 (H1) receptor inverse agonist. The selectivity of this molecule is illustrate in this spider plot. Bepotastine has very low affinity for “off target” receptors such as serotonergic, adrenergic, or muscarinic receptors, which are associated with a variety of the adverse events, such as sedation and dryness, that we associate with older antihistamines. It is generally accepted that histamine plays a primary role in the itching associated with allergic conjunctivitis. Bepotastine has a very high affinity for the H1 receptor, thus blocking the primary trigger for itching, while potentially minimizing side-effects.
Bepotastine is also a mast cell stabilizer, which as we saw earlier is important in both the Early Phase and Late Phase allergic reaction. 36

37. Do Anti-histamines cause (or treat) dry eye?

38. Anti-histamine pharmacology
Reversible binding to H1 receptor sites
Prevent the binding of histamine
Thus the histamine effects cannot be released
Blocks further release of histaminic symptoms but has no effect on the histamine that is already bound!

39. TOPICAL Allergy drops 2016 Pataday/Patanol Bepreve Pazeo Lastacaft
Elestat?
Alaway

40. So why one drop over another?
Quicker onset
Less toxicity
Dosage
Longer duration
Action on eosinophils
More comfortable – (pH issue)
Less drying

41. So Does 1 Topical Antihistamine Work Better Than The Others?
Yes!!!

42. What to do about GPC???

43. Allergy Treatment
Are there any indications for
NSAID?
Steroid?

44. What about oral antihistamines?
Profound effects on both ocular and systemic allergies BUT…
Are the ocular effects superior to eyedrops?
Are the side effects worth the (perceived ) extra benefit?
Should we be treating systemic disease?
Is there an advantage to co-manage with an allergist?
Don’t forget about nasal steroids!!