Review of etiopathgenesis and treatment including newer drugs

1. TITLE TEXT
DR C V GOPALA RAJU,
VISAKHA EYE HOSPITAL
VISAKHAPATNAM
Vernal Keratoconjunctivitis
New Drugs
stage. Limbal papillae tend to be
gelatinous and confluent (Fig. 3).
Bonini et al. (2000) graded the papil-
lae on the upper tarsal conjunctiva or
at the corneoscleral limbus as follows:
(1) Grade 0: no papillary reaction.
(2) Grade 1+: few papillae, 0.2 mm
widespread over the tarsal conjunctiva
or around the limbus.
(3) Grade 2+: papillae of 0.3–1 mm
over the tarsal conjunctiva or at the
limbus.
(4) Grade 3+: papillae of 1–3 mm all
over the tarsal conjunctiva or for 360°
around the limbus.
(5) Grade 4+: papillae of more than
3 mm over the tarsal conjunctiva or
gelatinous appearance at the limbus
covering the peripheral cornea.
Based on the predominant involvement
of either tarsal or limbal conjunctiva,
VKC can be divided into palpebral,
bulbar or mixed type with limbal forms
being prevalent in non-White patients
(Verin et al. 1999).
Photophobia, pain and foreign
body sensation are caused by involve-
ment of the cornea. Corneal changes
include punctate epithelial keratitis,
epithelial macro-erosions, shield ulcer,
plaque formation and late corneal
vascularization (Allansmith & Ross
1988; Buckley 1988). Coalescence of
punctate epithelial keratitis areas leads
to frank corneal epithelial erosion,
leaving Bowman’s membrane intact.
If untreated, a plaque containing
fibrin and mucus deposits over the
epithelial defect (Rahi et al. 1985).
Epithelial healing is then impaired,
and new vessel growth is encouraged.
The oval-shaped epithelial defects,
known as shield ulcers (Fig. 4), usu-
ally have their lower border in the
upper half of the visual axis. Healed
shield ulcers may leave a subepithelial
ring-like scar (Fig. 5). Corneal ulcer is
reported to occur in 3–11% of
patients. Corneal changes cause per-
manent reduction in visual acuity in
6% of patients suffering from VKC
(Neumann et al. 1959; Cameron 1995a;
Tabbara 1999). Pseudogerontoxon,
which resembles arcus senilis, is a wax-
ing and waning grey-white lipid deposi-
tion in the superficial stroma of the
peripheral cornea.
Signs of VKC are confined mostly
to the conjunctiva and cornea. The
skin of the lid and lid margin are rela-
tively uninvolved. The conjunctiva of
the fornices does not usually show
foreshortening and symblepharon
formation. Iritis is not reported to
occur in VKC. Ocular complications
of VKC have been reported to
include steroid-induced cataract and
glaucoma, corneal scarring, microbial
keratitis and limbal tissue hyperplasia
(Sridhar et al. 2003). Amblyopia seen
among VKC may be caused by cor-
neal opacity, irregular astigmatism
and keratoconus. Dry eye syndrome,
reported in patients suffering from
VKC, may be caused by unsupervised
use of topical corticosteroids (Tabbara
1999).
No precise diagnostic criteria have
been established for this disease.
Hyperaemia, itching, photophobia,
tearing and mucus discharge are
Fig. 1. Horner-Tranta’s dots.
Fig. 2. Cobble stone papillae.
Acta Ophthalmologica 2009

2. INTRODUCTION : DEFINITION
VERNAL KERATOCONJUNCTIVITIS
‣ Vernal keratoconjunctivitis (VKC) is a chronic, bilateral, at times
asymmetrical, seasonally exacerbated, allergic inflammation of
the ocular surface, involving tarsal and ⁄ or bulbar conjunctiva.
‣ Initially called as conjunctiva lymphatica - 150 years ago.
‣ spring catarrh, phlyctenula pallida, circumcorneal hypertrophy,
recurrent vegetative conjunctiva, verrucosa conjunctiva and
aestivale conjunctiva
‣ Although the allergic nature of this entity has been accepted for a
long time, its exact aetiology and pathogenesis is still unclear.

3. Geographical distribution
PREVALENCE
‣ It is more common in temperate zones of Mediterranean areas,
central and west Africa, the Middle East, Japan, the Indian
subcontinent and South America.
‣ VKC cases are also seen in Western Europe (including the UK
and Sweden), Australia and North America.
‣ After the recent decline of endemic trachoma, VKC is a leading
cause of outpatient ophthalmic morbidity.

4. Demography
AGE, GENDER, GENETICS AND ASSOCIATED DISEASES
‣ Starts before 10 years. (The earliest reported age is 5 months. Resolves after
puberty, usually around 4–10 years after onset (Bielory 2000; Leonardi
2002a).
‣ male to female ratio reported in the literature varying from 4:1 to 2:1
(Neumann et al. 1959; Beigelman 1965; Bonini et al. 2000).
‣ Atopic allergy, Nasal Allergy and Asthma. One third of VKC patients have
multiple atopic diseases (Bonini et al. 2000).
‣ In a gender- and age-matched study, a positive correla- tion between eyelash
length and severity of VKC has been reported.
‣ long lashes may represent the protective mechanism against physical agents
that might have an important role in the aetiopathogenesis of VKC, although
the chemical mediator responsible for lash growth was not identified (Pucci et
al. 2005).

5. Clinical features and diagnosis
SYMPTOMS
‣ Pruritus, hyperaemia, photophobia and watering.
‣ Bilateral in - 98%
‣ Minor differences in severity between the eyes are common
(Bonini et al. 2000).
‣ Several episodes of active inflammation throughout the year.
Initially seasonal may become perennial after a few years.
‣ Exacerbated by exposure to wind, dust, bright light, hot weather
or physical exertion associated with sweating.
‣ Tabuchi et al. (2004) reported Staphylococcus aureus to be one
of the exacerbating factors in VKC.

6. Clinical features and diagnosis
SIGNS
‣ Thick mucus hyper-secretion with sticky mucous filaments,
called ‘ropy discharge’, is a characteristic of VKC.
‣ Transient limbal or conjunctival yellow-white points or deposits,
known as Horner–Trantas’s dots are degenerating eosinophils
and epithelial cell debris.
‣ Asians show, perilimbal conjunctival pigmentation The extent of
pigmentation did not correlate with the severity of symptoms and
signs of VKC. The pigmentation persisted when the disease was
inactive (Rao et al. 2004).

7. Clinical features and diagnosis
SIGNS
‣ Limbal Papillae, Horner-Tranta’s Dots, Cobble stone Papillae
Based on the predominant involvement
of either tarsal or limbal conjunctiva,
VKC can be divided into palpebral,
bulbar or mixed type with limbal forms
being prevalent in non-White patients
(Verin et al. 1999).
Photophobia, pain and foreign
body sensation are caused by involve-
ment of the cornea. Corneal changes
include punctate epithelial keratitis,
epithelial macro-erosions, shield ulcer,
plaque formation and late corneal
vascularization (Allansmith & Ross
1988; Buckley 1988). Coalescence of
punctate epithelial keratitis areas leads
to frank corneal epithelial erosion,
leaving Bowman’s membrane intact.
If untreated, a plaque containing
fibrin and mucus deposits over the
epithelial defect (Rahi et al. 1985).
Epithelial healing is then impaired,
and new vessel growth is encouraged.
The oval-shaped epithelial defects,
known as shield ulcers (Fig. 4), usu-
ally have their lower border in the
upper half of the visual axis. Healed
shield ulcers may leave a subepithelial
ring-like scar (Fig. 5). Corneal ulcer is
reported to occur in 3–11% of
patients. Corneal changes cause per-
manent reduction in visual acuity in
6% of patients suffering from VKC
(Neumann et al. 1959; Cameron 1995a;
Tabbara 1999). Pseudogerontoxon,
which resembles arcus senilis, is a wax-
ing and waning grey-white lipid deposi-
tion in the superficial stroma of the
peripheral cornea.
Signs of VKC are confined mostly
to the conjunctiva and cornea. The
Fig. 1. Horner-Tranta’s dots.
Acta Ophthalmologica 2009
stage. Limbal papillae tend to be
gelatinous and confluent (Fig. 3).
Bonini et al. (2000) graded the papil-
lae on the upper tarsal conjunctiva or
at the corneoscleral limbus as follows:
(1) Grade 0: no papillary reaction.
(2) Grade 1+: few papillae, 0.2 mm
widespread over the tarsal conjunctiva
(3) Grade 2+: papillae of 0.3–1 mm
over the tarsal conjunctiva or at the
limbus.
(4) Grade 3+: papillae of 1–3 mm all
over the tarsal conjunctiva or for 360°
around the limbus.
(5) Grade 4+: papillae of more than
3 mm over the tarsal conjunctiva or
gelatinous appearance at the limbus
Fig. 1. Horner-Tranta’s dots.
Fig. 2. Cobble stone papillae.
Pathophysiology
Numerous cytological, immunohisto-
logical and molecular biological stud-
ies of allergic inflammation have
facilitated our understanding of the
pathophysiology of VKC. The ability
to measure cytokines in tears, along
with in-vitro analysis of the individual
or combined effects of these cytokines
on conjunctival mast cells, epithelial
cells and fibroblasts has facilitated our
understanding of specific processes
contributing to the pathogenesis of
VKC. The clear abundance of Th2
cytokines, upregulated expression of
their receptors and conspicuous pau-
city of T helper cell type 1 (Th1) cyto-
kines in tear and serum of VKC
patients confirm the crucial role
played by these factors in the onset
and perpetuation of the chronic aller-
gic inflammation observed in VKC. A
variety of cells, normally present or
illae.
mologica 2009

8. Clinical features and diagnosis
SIGNS : PAPILLAE
‣ Large (> 1 mm) papillae in VKC occur at the upper tarsus.
‣ Size of 7–8 mm are known as cobble- stone papillae.
‣ Papillae size correlate positively with the persistence or
worsening of symptoms over long-term follow-up (Bonini et al.
2000).
‣ These papillae become quite swollen during the active stage but
persist even during the quiescent stage.
‣ Limbal papillae tend to be gelatinous and confluent.

9. Clinical features and diagnosis
SIGNS : PAPILLAE GRADING - BONINI ET AL (2000)
‣ Grade 0: no papillary reaction.
‣ Grade 1+: few papillae, 0.2 mm widespread over the tarsal
conjunctiva or around the limbus.
‣ Grade 2+: papillae of 0.3–1 mm over the tarsal conjunctiva or at
the limbus.
‣ Grade 3+: papillae of 1–3 mm all over the tarsal conjunctiva or for
360° around the limbus.
‣ Grade 4+: papillae of more than 3 mm over the tarsal conjunctiva
or gelatinous appearance at the limbus covering the peripheral
cornea

10. Clinical features and diagnosis
CLASSIFICATION AND CORNEAL CHANGES OF VKC
‣ Palpebral, bulbar or mixed type
‣ Limbal forms prevalent in non-White patients (Verin et al. 1999).
‣ Photophobia, pain and foreign body sensation are caused by
involve- ment of the cornea.
‣ Corneal changes: punctate epithelial keratitis, epithelial macro-
erosions, shield ulcer, plaque formation and late corneal
vascularization (Allansmith & Ross 1988; Buckley 1988).
‣ Coalescence of punctate epithelial keratitis areas leads to frank
corneal epithelial erosion, leaving Bowman’s membrane intact.

11. Clinical features and diagnosis
SHIELD ULCER IN VKC
‣ If untreated, a plaque containing fibrin and mucus deposits over
the epithelial defect (Rahi et al. 1985). Epithelial healing is then
impaired, and new vessel growth is encouraged.
‣ The oval-shaped epithelial defects, known as shield ulcers,
usually have their lower border in the upper half of the visual
axis. Healed shield ulcers may leave a subepithelial ring-like
scar. Corneal ulcer is reported to occur in 3–11% of patients.
Pathophysiology
Numerous cytological, immunohisto-
logical and molecular biological stud-
ies of allergic inflammation have
facilitated our understanding of the
pathophysiology of VKC. The ability
to measure cytokines in tears, along
with in-vitro analysis of the individual
or combined effects of these cytokines
on conjunctival mast cells, epithelial
cells and fibroblasts has facilitated our
understanding of specific processes
contributing to the pathogenesis of
VKC. The clear abundance of Th2
cytokines, upregulated expression of
their receptors and conspicuous pau-
city of T helper cell type 1 (Th1) cyto-
kines in tear and serum of VKC
patients confirm the crucial role
played by these factors in the onset
and perpetuation of the chronic aller-
gic inflammation observed in VKC. A
variety of cells, normally present or
infiltrating the ocular surface, are
responsible for the profound expres-
sion of these cytokines in VKC. The
factors stimulating these varied cells
to increase their cytokine production
are still poorly defined. The immune,
nervous and endocrine systems seem
to interact with each other in the
pathogenesis of VKC (Bonini et al.
2004). Infective factors were thought
to contribute to the pathogenesis of
VKC but respiratory syncytial virus
and chlamydia were not detected in
conjunctival biopsies from patients
with VKC (Koulikovska et al. 2001).
Furthermore, serology for ocular chla-
mydial disease was also negative
(Montan et al. 1999).
Personal or family history of atopy,
elevated serum level of total and spe-
cific IgE, higher number of mast cells
Fig. 3. Limbal papillae.
Acta Ophthalmologica 2009
Mori et al. 2002). These findings
confirm that VKC has a mainly Th2
profile (Uchio et al.2000; Fujishima
et al. 2002).
Chemokines
Chemokines, a short term for chemo-
tactic cytokine (CC), are potent activa-
tors and chemoattractants. Chemo-
kines are produced not only by inflam-
matory cells but also by stimulated
epithelial cells, fibroblasts and vascular
endothelial cells in the conjunctiva.
Chemokines are involved in normal
trafficking of leukocytes and recruit-
ment during inflammation but their
role is not restricted to cell attraction.
These multipotent cytokines localize
and enhance inflammation by inducing
chemotaxis and cell activation of dif-
ferent types of inflammatory cells pres-
ent at sites of inflammation.
Chemokines bind to transmembrane
Acta Ophthalmologica 2009

12. Clinical features and diagnosis
OTHER SIGNS IN VKC
‣ Pseudogerontoxon, which resembles arcus senilis, is a waxing
and waning grey-white lipid deposition in the superficial stroma
of the peripheral cornea.
‣ The skin of the lid and lid margin may be thick and lax.
‣ Amblyopia seen among VKC may be caused by corneal opacity,
irregular astigmatism.
‣ Keratoconus.
‣ Dry eye syndrome,
‣ Cataract and glaucoma caused by unsupervised use of topical
corticosteroids (Tabbara 1999).

13. Pathophysiology
ALLERGEN AND MAST CELL REACTION,
‣ Starts before 10 years..

14. Pathophysiology
ALLERGEN AND MAST CELL REACTION,
The immune, nervous and endocrine systems seem to interact with each other in the pathogenesis of VKC (Bonini et al. 2004)
‣ Immune, nervous and endocrine systems interact with each other
in the pathogenesis of VKC (Bonini et al. 2004)
‣ VKC was primarily a type 1 hypersensitivity reaction
‣
‣ Abundance of Th2 cytokines
‣ Paucity of T helper cell type 1 (Th1) cytokines in tear and serum
‣ .

15. Pathophysiology
ALLERGEN AND MAST CELL REACTION,

16. Pathophysiology
DEGRANULATION PROCESS
‣ Degranulation process in allergy. Second exposure to allergen. 1 – antigen; 2 – IgE antibody; 3 –
FcεRI receptor; 4 – preformed mediators (histamine, proteases, chemokines, heparine); 5 – granules;
6 – mast cell; 7 – newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)

17. Pathophysiology
MEDIATORS
‣ Cytokines are small secreted proteins that mediate and regulate immunity and
inflammation.
‣ Chemokines, a short term for chemo- tactic cytokine (CC), are potent activa-
tors and chemoattractants.
‣ Histamine, an important inflamma- tory mediator in allergic eye disease, is
released by activated mast cells and basophils.
‣ Metalloproteinases (MMPs) are extra- cellular endopeptidases that selectively
degrade components of the extra- cellular matrix. Inflammatory cells,
particularly eosinophils, and structural cells like epithelial cells and conjuncti-
val fibroblasts are the probable cellu- lar source of these enzymes.
‣ Several growth factors, such as epider- mal growth factor, fibroblast growth
factor and transforming growth factor beta-1 (TGFb-1), were increased in
VKC.

18. Pathophysiology
MEDIATORS - CYTOKINES AND CHEMOKINES
‣ Cytokines are small secreted proteins that mediate and regulate immunity
and inflammation.
‣ Activated helper T cells (CD4), mast cells and eosinophils are the main
cytokine-producing cell types infiltrating the conjunctiva during chronic
allergic eye diseases.
‣ Chemokines, a short term for chemotactic cytokine (CC), are potent
activators and chemoattractants.
‣ Chemokines are produced not only by inflammatory cells but also by
stimulated epithelial cells, fibroblasts and vascular endothelial cells in the
conjunctiva.
‣

19. Pathophysiology
MEDIATORS - HISTAMINE, MMP AND GROWTH FACTOR
‣ Histamine exerts its biological effects by interacting with four G- protein coupled
receptors, classified as H1–H4. Vasodilatation, chemosis and itching of eye are
caused by histamine interaction with H1 receptors.
‣ Released by activated mast cells and basophils.
‣ Reduced inactivation by histaminase and increased production by specific or non-
specific activation of mast cells and basophils (Abelson et al. 1995).
‣ MMP: Increased production and activation of MMPs or imbalance between MMPs
and their natural tissue inhibitors (TIMPs) are all probably involved in the
pathogenesis of conjunctival inflammation, remodel- ling and corneal changes in
VKC.
‣ Growth factors, such as epidermal growth factor, fibroblast growth factor and
transforming growth factor beta-1 (TGFb-1), were increased in VKC. These factors
induce fibroblast growth and procollagen production (Leonardi et al. 1998).

20. Pathophysiology
CELLS IN VKC ,
‣ Mast cells
‣ Eosinophils
‣ T cells
‣ B cells
‣ Epithelial Cells
‣ Fibroblasts
‣ Natural Killer Cells

21. Pathophysiology
CELLS - MAST CELLS AND EOSINOPHILS
‣ Mast cells bind IgE on its surface. cross-linkage of this IgE by specific
allergens results in the release of pro-inflammatory mediators, including
histamine, proteases, prostaglandin D2 and leukotriene C4, into the local
extracellular environment.
‣ These mediators are responsible for causing ocular itching, hyperaemia,
lacrimation and chemosis in allergic conjunctivitis (McGill et al. 1998;
Church & McGill 2002).
‣ Eosinophils : 50–90% of cells in the tears during the active phase of VKC
are eosinophils (Leonardi 2002a).
‣ Activated eosinophils release cytokines, chemokines, leukotrienes and
epithelio- toxic proteins such as MBP, ECP, eosinophil peroxidase (EPO) and
eosinophil protein X ⁄ neurotoxin (EPX) (Tomassini et al. 1994; Leonardi et
al. 1995; Leonardi 2002a).

22. Pathophysiology
CELLS - T CELLS AND B CELLS
‣ T cell are mainly Th2 type (Maggi et al. 1991). Cytokine flow
cytometry has shown that 67% of VKC patients have Th2 cells in
tears, while Th1 cells are seen in the tears of only 8% (Leo- nardi et
al. 1999a).
‣ The predominance of Th2-like cells in tears and conjuncti- val biopsy
suggests a local Th2 response in VKC. Th2 lymphocytes, by virtue of
their cytokine profile, are responsible for increased production of
IgE, recruitment and activation of mast cells and eosinophils
(Umetsu & De Kruyff 1997; Bielory et al. 2002a).
‣ B lymphocytes expressing the ligands CD23, 21 and 40 in
conjunctiva speci- men from VKC may be a precursor of IgE
producing B cells (Abu El-Asrar et al. 2001d).

23. Pathophysiology
CELLS - EPITHELIAL CELLS AND FIBROBLASTS
‣ Epithelial cells not only act as a mechanical barrier, but also participate in
the regulation of allergic inflammation through expressing surface antigens
such as adhesion ⁄ effector molecules (ICAM-1, vascular cell adhesion
molecule-1 and HLA- DR) and releasing many cytokines (eotaxin, IL-8,
IL-6, RANTES).
‣ Histamine, released from the conjunctival mast cells, might stimulate the
synthesis of IL-6 and IL-8 by conjunctival epithelial cells and amplify the
allergic response (Irkec & Bozkurt 2003).
‣ Fibroblasts can modulate the functions of mast cells and eosinophils through
the membrane form of stem cell factor and GM-CSF, respectively.
‣ Fibroblasts can be affected by inflammatory mediators derived from mast
cells and eosinophils, such as TGFb and nerve growth factor and by the Th2
cytokines, IL-4 and IL-13 (Solomon et al. 2003).

24. Pathophysiology
CASCADE OF REACTIONS

25. Histopathology and Immunohistochemistry
TISSUE INFLAMMATION AND REMODELLING
‣ Histopathological studies of conjunctival tissue from VKC
patients show a prominent inflammatory cellular infiltration in
the epithelium and substantia propria and post-inflammatory
tissue remodelling.
‣ Tissue remodelling is more marked in tarsal than in bulbar
conjunctiva.
‣ Tissue inflammation
‣ Tissue remodelling

26. Histopathology and Immunohistochemistry
SUMMARY OF TISSUE REACTION IN VKC ,
‣ Infiltration of the conjunctiva by eosinophils, basophils, mast
cells, Th2 cells, monocyte ⁄ macrophages, dendritic cells, plasma
cells and B lymphocytes, frequently organized as small lymphoid
follicles without a germinative centre (Abu El-Asrar et al. 2001d;
Leonardi 2002a).
‣ Conjunctival thickening, subepithelial fibrosis, mucus
metaplasia, neovascularization and scarring are typical of
chronic VKC. Epithelial changes, connective tissue deposition,
oedema, inflammatory cell infiltration and glandular hypertrophy
all contribute in the tissue remodelling observed in VKC
(Leonardi 2002a).

27. Pathophysiology
CASCADE OF REACTIONS

28. End of part I
PART II
‣ Treatment
‣ New drugs

29. Treatment
PREVENTIVE MEASURES AND PATIENT EDUCATION
‣ Avoidance of sun, wind and salt water helpful but not enough.
‣ Contact with plants and flowers should be avoided.
‣ Use of sunglasses or any shading measures useful.
‣ Application of cold compresses and use of artificial tears
effective in the relief of symptoms by direct removal and dilution
of allergen from the ocular surface (Bielory 2002b).
‣ Cold compresses provide symptomatic relief, from ocular
pruritus.
‣ Frequent hand, face and hair washing – before going to bed may
be helpful (Leonardi 2002a).

30. Treatment
PHARMACOLOGICAL THERAPY

31. Treatment
PHARMACOLOGICAL THERAPY
‣ Anti-histamines,
‣ Mast-cell stabilizers,
‣ Dual acting agents,
‣ Corticosteroids
‣ Immunomodulators
‣ None is enough to treat all aspects of multifaceted
pathophysiology of VKC.

32. Treatment
PHARMACOLOGICAL THERAPY
‣ Why disease is regressing after 2 to 10 years ?
‣ Why disease is regressing after puberty?
‣ Why some cases are resistant to treatment ?
‣ Why recurrence of disease when the therapy is discontinued?
‣ Humoral, Endocrinal and Neurological elements in the disease
which we couldn't understand.
‣ Palliative and do not eliminate the complex immune response

33. Treatment - Pharmacotherapy
VASOCONSTRICTORS AND NON-SPECIFIC ANTI HISTAMINES
‣ Vasoconstrictor and non-specific anti- histamine combination
eyedrops like naphazoline or tetrahydrozoline and anti-
histamines like pyrilamine or pheniramine.
‣ These drops are safe and effective, at least temporarily.
‣ They relieve itching and reduce redness.
‣ Burning or stinging on installation and rebound hyperaemia are
common side-effects.
‣ Optihist and Optihist Plus Eye Drops

34. Treatment - Pharmacotherapy
MAST CELL STABILISERS
‣ Stabilize mast cells and prevent degranulation.
‣ Sodium cromoglycate (qid),
‣ Lodoxamide (qid),
‣ Nedocromil (bid)
‣ Pemirolast (qid)
‣ Cromal and Cromal Forte Eye Drops

35. Treatment - Pharmacotherapy
ANTI HISTAMINES
‣ Oral anti-histamines are a good choice when allergy involves the
eyes, nose or pharynx simultaneously.
‣ When allergic complaints are limited to eyes, focused therapy
with topical anti-histamines is efficacious and free of untoward
effects related to oral anti-histamines.

36. Treatment - Pharmacotherapy
SPECIFIC ANTI HISTAMINES - H1 RECEPTOR BLOCKERS
‣ Topical selective H1 blocker, emedastine and levocabasitne, are
better than vasoconstrictor ⁄ non-specific anti-histamine
combination eyedrops in controlling the signs and symptoms of
VKC.
‣ The anti-inflammatory effect seen with pure anti-histamines like
levocabastine and emedastine is attributed to the blocking of
histamine receptors, thus downregulating the expression of
ICAM-1 and limiting che- motaxis of inflammatory cells
(Bielory et al. 2005).

37. Treatment - Pharmacotherapy
DUAL ACTION - MAST CELL STABILISATION & ANTIHISTAMINE
‣ New generation of drugs such as olopatadine, epinastine, ketot-
ifen and azelastine has shown dual activity of mast-cell stability
and H1 receptor antagonism.
‣ The action of these drugs is not limited to mast-cell stabilization
and H1 receptor antagonism, they also exert anti-inflammatory
effects through several different mechanisms.
‣

38. Treatment - Pharmacotherapy
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
‣ Topical formulations of ketorolac and diclofenac have been
shown to diminish ocular pruritus and conjunctival hyperaemia.
‣ Prostaglandin E2 and I2 has been shown to be pruritogenic.
‣ Ketorolac may be a good alternative to topical steroid because it
reduces itching by inhibit- ing the synthesis of prostaglandins
(Sharma 1997).
‣ Stinging and burning sensation is the disadvantage.

39. Treatment - Pharmacotherapy
CORTICOSTEROIDS
‣ Loteprednol is highly effective in the acute and prophylactic treatment of
allergic conjunctivitis.
‣ In a retro- spective study, loteprednol etabonate was shown to be safe and
effective when used for 12 months or more for the treatment of seasonal or
perennial allergic conjunctivitis (Ilyas et al. 2004).
‣ Fluorometholone is a soft cortico- steroid and is effective in controlling the
signs and symptoms of VKC.
‣ Supratarsal injection of dexamethasone sodium succinate, triamcinolone
acetonide and hydrocortisone sodium succinate is effective in the temporary
suppression of inflammation associated with VKC (Saini et al. 1999; Singh et
al. 2002; Lisanework 2003).
‣ Although corticosteroids are the most efficacious drugs, steroid-resistant
forms of VKC are not unusual and may necessitate an alternative therapy.

40. Treatment - Pharmacotherapy
IMMUNE MODULATORS - CYCLOSPORINE
‣ Cyclosporine (2%) eyedrops were effective and safe in the treat-
ment of severe VKC (Pucci et al. 2002; Kilic & Gurler 2006).
‣ Most of the therapeutic effect was achieved 2 weeks after
commencing the treatment and was maintained during the next 3
months by continuous medication (Pucci et al. 2002).
‣ Main inhibition - cost
‣ Main confusion - preparation and concentration

41. Treatment - Pharmacotherapy
IMMUNE MODULATORS - CYCLOSPORINE
‣ Cyclosporine, a fungal metabolite, decreases the signs and
symptoms of VKC. BenEzra et al. (1986)
‣ Cyclosporine 0.05% eyedrops in oil solution to treat severe VKC.
‣ Cyclosporine is lipophilic so it must be dissolved in an alcohol–oil
base, which causes ocular irritation.
‣ Immunomodulating effect on components of cell-mediated and
humoral immune response. (Abu El-Asrar et al. 1996).
‣ Cyclosporine blocks Th2 lymphocyte proliferation and IL-2
production. Furthermore, it inhibits histamine release through a
reduction in IL-5 production (Ben- Ezra et al. 1988; Secchi et al.
1990). It accelerates apoptosis in fibroblast.

42. Treatment - Pharmacotherapy
CYCLOSPORINE - DRUG DELIVERY IS A CHALLENGE
‣ Cyclosporine is a Lipophillic drug
‣ Currently available systems using oils to deliver CsA topically are
poorly tolerated and provide a low bioavailability.
‣ CsA water solubility (e.g. cyclodextrins), or those designed to
facilitate tissue drug penetration using penetration enhancers.
‣ The use of colloidal carriers (micelles, emulsions, liposomes and
nanoparticles) as well as the approach using hydrosoluble prodrugs
of CsA have shown promising results. Solid devices such as
shields and particles of collagen have been investigated to enhance
retention time on the eye surface.
‣ None of these formulations are ideal.

43. Treatment - Pharmacotherapy
CYCLOSPORINE EYE DROPS - DRUG INTERACTIONS
‣ Pregnancy or planning to become or breast feeding
‣ Herpes Simplex corneal infection
‣ Patients with punctal plugs
‣ Topical Anti-inflammatory drugs like Ketorolac reduces the
effect of cyclosporine.

44. Treatment - Pharmacotherapy
CYCLOSPORINE EYE DROPS - META ANALYSIS
29/10/15 11:25 pmTopical cyclosporine in the treatment of allergic conjunctivitis: a meta-analysis. - PubMed - NCBI
PURPOSE:
DESIGN:
PARTICIPANTS:
METHODS:
MAIN OUTCOME MEASURES:
Ophthalmology. 2013 Nov;120(11):2197-203. doi: 10.1016/j.ophtha.2013.03.044. Epub 2013 Jun 3.
Topical cyclosporine in the treatment of allergic conjunctivitis: a meta-
analysis.
Wan KH , Chen LJ, Rong SS, Pang CP, Young AL.
Abstract
To assess the efficacy and safety of topical cyclosporine versus placebo in the
treatment of allergic conjunctivitis.
Systematic review and meta-analysis.
Seven qualified studies incorporating 306 eyes of 153 patients were analyzed.
Searches of randomized controlled trials were conducted in MEDLINE, EMBASE, the
Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the World Health
Organization International Clinical Trials Registry Platform.
We assessed the methodologic quality of individual included trials
and performed meta-analyses using the random effects model if P<0.1 in the test for
heterogeneity, or otherwise used the fixed effects model. We assessed scores of composite signs
and symptoms, reduction in steroid eye drop use in steroid-dependent patients, and safety
outcomes (i.e., stinging or burning sensation).
Abstract
1
Author information
Full text links
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45. Treatment - Pharmacotherapy
CYCLOSPORINE EYE DROPS - META ANALYSIS
Page 1 of 2http://www.ncbi.nlm.nih.gov/pubmed/23743438
MAIN OUTCOME MEASURES:
RESULTS:
CONCLUSIONS:
Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the World Health
Organization International Clinical Trials Registry Platform.
We assessed the methodologic quality of individual included trials
and performed meta-analyses using the random effects model if P<0.1 in the test for
heterogeneity, or otherwise used the fixed effects model. We assessed scores of composite signs
and symptoms, reduction in steroid eye drop use in steroid-dependent patients, and safety
outcomes (i.e., stinging or burning sensation).
At 2 weeks of follow-up or longer, evidence suggests a statistically significant
improvement in the composite signs (standardized mean difference [SMD], -1.21; 95% confidence
interval [CI], -1.80 to -0.62; I(2) = 71%) and symptoms (SMD, -0.84; 95% CI, -1.51 to -0.16; I(2) =
80%) after topical cyclosporine treatment for allergic conjunctivitis regardless of the dosage of
treatment. There was a significant reduction (mean difference, -61.16; 95% CI, -101.61 to -20.72;
I(2) = 58%) in the use of steroid eye drops in patients with steroid-dependent allergic
conjunctivitis. Stinging or burning sensation (odds ratio, 2.56; 95% CI, 0.19-35.06; I(2) = 73%) was
common in both the cyclosporine and placebo groups.
This systematic review and meta-analysis suggests topical cyclosporine could
be an effective and safe treatment method for allergic conjunctivitis. Further randomized controlled
trials with larger sample sizes and standardized outcome measurements, follow-up periods, and
cyclosporine concentrations are warranted to determine the short- and long-term efficacy and
safety and the minimal effective dosage of topical cyclosporine for allergic conjunctivitis.
Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights

46. Treatment - Pharmacotherapy
IMMUNE MODULATORS - MYTOMYCIN-C
‣ Mitomycin-C is an inhibitor of fibroblast proliferation.
‣ Mitomycin-C (0.01%) eyedrops were shown to decrease the
mucous discharge, conjunctival hyperaemia and limbal oedema
in VKC patients refractory to topical steroids and mast-cell
stabilizers (Akpek et al. 2000; Jain & Sukhija 2006).
‣
‣

47. Treatment - Pharmacotherapy
IMMUNE MODULATORS - TACROLIMUS
‣ Used in Sever atopic dermatitis.
‣ Topical Immunosuppressant
‣ VKC and KCS - Ophthalmic use - Ointment form
‣ Emulsion, Solution or Suspension or gel form are also available
‣ Strength - 0.01% to 0.03%
‣ In Severe cases and as a loading dose BD and maintenance OD

48. Treatment - Pharmacotherapy
IMMUNE MODULATORS - TACROLIMUS - REVIEW OF LITERATURE
31/10/15 6:30 amLong-term follow-up of tacrolimus ointment for treatment of atopic keratoconjunctivitis. - PubMed - NCBI
PURPOSE:
DESIGN:
METHODS:
RESULTS:
Am J Ophthalmol. 2014 Feb;157(2):280-6. doi: 10.1016/j.ajo.2013.10.006. Epub 2013 Oct 19.
Long-term follow-up of tacrolimus ointment for treatment of atopic
keratoconjunctivitis.
Al-Amri AM .
Abstract
To evaluate the long-term clinical outcomes of 0.1% tacrolimus dermatologic ointment
(Protopic) in cases of refractory atopic keratoconjunctivitis (AKC).
Prospective, nonrandomized, noncontrolled case series.
Twenty-two eyes from 11 patients with severe AKC who were treated with 0.1%
tacrolimus ointment were followed prospectively. The mean age of the patients was 32.27 ± 12.7
years (range, 19-61 years). Each patient completed a follow-up period of at least 48 months,
during which the signs and symptoms of AKC were assessed. Changes in the total scores of signs
and symptoms from baseline were recorded at each visit, and the main outcome measure was the
clinical response to topical tacrolimus treatment.
Dramatic improvements in clinical signs and symptoms were achieved 1 week after
starting topical tacrolimus treatment, and complete clinical resolution was observed in almost all
patients 6 weeks after starting treatment. Treatment was gradually reduced, with increasing
intervals between applications. Eight patients remained asymptomatic for up to 3 years, although
recurrence occurred in 3 patients who attempted to discontinue treatment. All patients complained
Abstract
1
Author information
Full text links
PubMed
PURPOSE:
DESIGN:
METHODS:
RESULTS:
CONCLUSIONS:
Am J Ophthalmol. 2014 Feb;157(2):280-6. doi: 10.1016/j.ajo.2013.10.006. Epub 2013 Oct 19.
Long-term follow-up of tacrolimus ointment for treatment of atopic
keratoconjunctivitis.
Al-Amri AM .
Abstract
To evaluate the long-term clinical outcomes of 0.1% tacrolimus dermatologic ointment
(Protopic) in cases of refractory atopic keratoconjunctivitis (AKC).
Prospective, nonrandomized, noncontrolled case series.
Twenty-two eyes from 11 patients with severe AKC who were treated with 0.1%
tacrolimus ointment were followed prospectively. The mean age of the patients was 32.27 ± 12.7
years (range, 19-61 years). Each patient completed a follow-up period of at least 48 months,
during which the signs and symptoms of AKC were assessed. Changes in the total scores of signs
and symptoms from baseline were recorded at each visit, and the main outcome measure was the
clinical response to topical tacrolimus treatment.
Dramatic improvements in clinical signs and symptoms were achieved 1 week after
starting topical tacrolimus treatment, and complete clinical resolution was observed in almost all
patients 6 weeks after starting treatment. Treatment was gradually reduced, with increasing
intervals between applications. Eight patients remained asymptomatic for up to 3 years, although
recurrence occurred in 3 patients who attempted to discontinue treatment. All patients complained
of a mild burning sensation upon application of the ointment. No additional medications were
required to provide relief, and no patient discontinued treatment because of adverse drug effects.
No drug-related ocular complications were encountered, and no significant changes in visual
acuity or refraction were documented.
Tacrolimus dermatologic ointment is a potentially safe and effective treatment for
AKC cases refractory to standard treatment and may substitute for steroid treatments aimed at
controlling disease activity.
1
Author information

49. Treatment - Pharmacotherapy
IMMUNE MODULATORS - TACROLIMUS - DRUG INTERACTION
‣ Ultraviolet light therapy on skin
‣ Herpes or Chickenpox
‣ Precancerous skin conditions
‣ weakened Immunesystem
‣ Avoid in
‣ Lymphoma or skin cancers
‣ Pregnant or planning to become, breast feeding
‣ Swollen Lymph nodes or Mononucleosis

50. Treatment - Pharmacotherapy
IMMUNE MODULATORS - CYCLOSPORINE & TACROLIMUS
31/10/15 6:36 amTopical immunomodulators in the management of allergic eye diseases. - PubMed - NCBI
PURPOSE OF REVIEW:
Curr Opin Allergy Clin Immunol. 2014 Oct;14(5):457-63. doi: 10.1097/ACI.0000000000000089.
Topical immunomodulators in the management of allergic eye diseases.
Erdinest N , Solomon A.
Abstract
Allergic eye diseases comprise a spectrum of diseases, with each
condition being characterized by a complex immunopathology. The more severe and chronic
conditions, such as vernal keratoconjunctivitis and atopic keratoconjunctivitis, involve
predominantly mast cells and eosinophils, while also being associated with a preponderance of T
cells. Treatment with topical antihistamines or mast cell stabilizers is often unsatisfactory, and
therapy depends on topical corticosteroids. Corticosteroids have significant side-effects with long-
term use; therefore, they appear to be more appropriate for short-term pulse therapy.
Immunomodulatory agents can also be used to inhibit T-cell activation and show encouraging
results among patients with severe allergic eye conditions. The present review is an attempt to
present a coherent picture of the recent investigations of topical immunomodulatory agents'
therapy in severe allergic eye diseases, especially cyclosporine A and tacrolimus, and their
mechanisms of action.
Abstract
1
Author information
Full text links
PubMed

51. Treatment - Pharmacotherapy
IMMUNE MODULATORS - CYCLOSPORINE & TACROLIMUS
RECENT FINDINGS:
SUMMARY:
conditions, such as vernal keratoconjunctivitis and atopic keratoconjunctivitis, involve
predominantly mast cells and eosinophils, while also being associated with a preponderance of T
cells. Treatment with topical antihistamines or mast cell stabilizers is often unsatisfactory, and
therapy depends on topical corticosteroids. Corticosteroids have significant side-effects with long-
term use; therefore, they appear to be more appropriate for short-term pulse therapy.
Immunomodulatory agents can also be used to inhibit T-cell activation and show encouraging
results among patients with severe allergic eye conditions. The present review is an attempt to
present a coherent picture of the recent investigations of topical immunomodulatory agents'
therapy in severe allergic eye diseases, especially cyclosporine A and tacrolimus, and their
mechanisms of action.
Immunomodulatory agents are commonly indicated for the treatment of
severe and prolonged allergic conjunctivitis. This article reviews the recent studies of these drugs
and the development of immunomodulatory treatments for severe allergic eye diseases.
Cyclosporine A and tacrolimus are currently available for the treatment of severe
allergic conjunctivitis. These agents have led to improved therapeutic results for patients with
severe and chronic allergic eye diseases.
PMID: 25054831 [PubMed - indexed for MEDLINE]
Publication Types, MeSH Terms, Substances
LinkOut - more resources

52. Treatment
SURGICAL TREATMENT
‣ Surgical excision of giant papillae is recommended if they cause corneal
lesions.
‣ Excision or cryocoagulation of large papillae helps in the early resolution
of corneal epitheliopathy or ulcer, although papillae regrow in most
patients.
‣ Debridement of ulcer base, surgical removal of plaque or excimer laser
phototherapeutic keratectomy helps in early re-epithelialization of vernal
shield ulcer refractory to medical treatment. (Cameron et al. 1995b; Sol-
omon et al. 2004; Ozbek et al. 2006).
‣ Amniotic membrane implantation leads to complete re-epithelialization of
persistent corneal epithelial defects and vernal plaques recalcitrant to con-
ventional medical treatment (Rouher et al. 2004; Pelegrin et al. 2008).

53. Treatment
FUTURE CHALLENGES
‣ Despite the development of newer drugs in the last decade, the
statement of Professor Lightman – ‘at present however, the
current situation for those with severe VKC remains a disturbing
dependence upon topical steroids, with all the attendant risks’,
emphasizing the need for more selective drugs for better and
long-lasting control of VKC – is still appropriate (Hingorani &
Lightman 1995)

54. Thank you for your patient hearing
THANK YOU