**3. Novel therapies in allergic conjunctivitis**

Treatment of allergic conjunctivitis can be a challenge by the diverse immunological mecha‐ nisms of damage involved in ocular allergic diseases, reviewed in [38]. To date, a wide range of antiallergic drops treatments are available and can be confusing due to lack of improve‐ ment at the ocular surface in terms of avoiding anatomical changes in severe cases and con‐ trol of symptoms in the long time period, reviewed in [39, 40, 41]

Hence our primary goal for treating allergic patients should be preferently to recognize al‐ lergy background and ocular inflammation status at the time visit to better establish the type and source of antigenic stimuli. In this way, primary action such as avoidance and clearance of antigen with lubrication is recommended preferently in acute but also in the late stage of the chronic forms when dry eye could be implicated. Secondary treatment algo‐ rithm includes topical antiallergic agents, which are used towards the reaction characterized by mast cell activation, release of preformed and newly formed mediators such as hista‐ mine, prostaglandins, leukotrienes, production of chemokines and expression of adhesion molecules. The aim of treatment in seasonal allergic conjunctivitis and perennial allergic conjunctivitis is directed to symptom relief and control, whereas the objective in the chronic forms of vernal keratoconjunctivitis and atopic keratoconjuctivitis will be also to prevent visual complications or try to identify in early stages possible implication of cornea injury. Therefore the efficacy of therapeutic agents varies from patient to patient in terms of grade of severity at the ocular surface, reviewed in [38] and actual local and systemic status activi‐ ty of the immune system making the choice of treatment depending on multiple variables, each case must be individualized. In general ocular allergic diseases involve mast cell degra‐ nulation that will initiate through inflammatory mediators activation of enzymatic cascades, giving rise to pro-inflammatory mediators and in consequence antihistamines, mast cell sta‐ bilizers, non-steroidal anti-inflammatory agents, corticosteroids are agents of common use for acute and chronic conjunctivitis.

Nonetheless this wide range of drugs, management of allergic conjunctivits is still a chal‐ lenge and immune modulation could be the missing link in the therapeutical approach of ocular allergic diseases.

#### **3.1. Calcineurin inhibitors and atopic keratoconjunctivitis**

**Figure 2.** Clinical photographs of AMT in 67 year old female patient with a history of peripheral infectious keratitis secondary to trichiasis. Left, AMT covering the lower peripheral corneal defect. Amniotic membrane was folded sever‐ al times over the cornea to increase their anti-inflammatory properties. Right, Same patient, 15 days after AMT, clinical

Macrophage migration inhibitory factor (MIF) is an integral component of inflammatory re‐ sponses. MIF induces and sustains expression of several pro-inflammatory cytokines.[33] trough interaction with a receptor complex composed by CD74/CD44 [34] CD74 was first described as class II invariant chain, while CD44 is an adhesion molecule that binds hyalur‐ onic acid and other matrix metalloproteinases. Interaction of MIF with CD74/CD44 results in activation of Mitogen-Activated Protein Kinase (MAPK), production of PGE214 and further

Corneal infections by *Pseudomonas aeruginosa* are more difficult to treat and result in worse visual outcome than other bacterial corneal ulcers. Unfortunately the existing therapies fail to control the inflammation secondary to P. aeruginosa keratitis and novel interventions are needed to alleviate tissue damage resulting from local inflammation, recently two studies suggest that blockade of MIF-CD74 ligation ameliorate the disease-associated pathology by decreased proinflammatory mediators and reduced bacterial presence in the cornea [36, 37]

Treatment of allergic conjunctivitis can be a challenge by the diverse immunological mecha‐ nisms of damage involved in ocular allergic diseases, reviewed in [38]. To date, a wide range of antiallergic drops treatments are available and can be confusing due to lack of improve‐ ment at the ocular surface in terms of avoiding anatomical changes in severe cases and con‐

Hence our primary goal for treating allergic patients should be preferently to recognize al‐ lergy background and ocular inflammation status at the time visit to better establish the

photograph showing apparent control of hyperaemia and inflammation

induction of inflammatory mediators [35]

50 Common Eye Infections

**3. Novel therapies in allergic conjunctivitis**

trol of symptoms in the long time period, reviewed in [39, 40, 41]

**2.7. MIF-CD74 blockade in** *Pseudomona aeurginosa* **keratitis**

Calcineurin inhibitors are capable of inducing local immunosuppression more than immu‐ nomodulation. Topical [42] and systemic cyclosporine a (CsA) [43] have been suggested in the treatment of severe atopic keratoconjunctivitis. Cyclosporine is effective in controlling ocular allergic inflammation by blocking Th2 lymphocyte proliferation and IL-2 production. It also reduces eosinophils production via inhibition of IL-5 production. Use of CsA appears to be safe and the clinical goal for its use is to eliminate the need/dependence of steroids and favourably alter the long-term prognosis of patients with AKC.

Others calcineurins inhibitors that appears to be well tolerated by patients with severe atop‐ ic blepharoconjunctivitis [44] and severe atopic keratoconjunctivitis [45] and acceptable clin‐ ical outcome are tacrolimus and pimecrolimus, both of them were used first in atopic dermatitis treatment [46]. To date the real impact of anti-allergic treatment with calcineurin inhibitors is unknown.

#### **3.2. Mapracorat and eosinophils in ocular allergy**

Mapracorat is a novel selective glucocorticoid receptor agonist that maintains a beneficial anti-inflammatory activity but seems to be less effective in transactivation, resulting in a lower potential for side effect; it has been proposed for the topical treatment of inflammato‐ ry skin disorders. In vitro, Mapracorat inhibited eosinophil migration and IL-8 release from eosinophils or the release of IL-6, IL-8, CCL5/RANTES, and TNF-α from a human mast cell line with equal potency as dexamethasone, whereas it was clearly less potent than this glu‐ cocorticoid in inducing annexin I and CXCR4 expression on the human eosinophil surface; in other hand, animal model of allergic conjunctivitis showed that mapracorat was similar to dexamethasone eye drops in analogous reduction in clinical symptoms of allergic conjuncti‐ vitis and conjunctival eosinophil accumulation. [47] The authors suggest this novel gluco‐ corticoid receptor agonist as a candidate to be used in clinical trials of ocular allergy.

#### **3.3. Omalizumab and allergic diseases**

Omalizumab is a biological engineered molecule, targeting the Cε3 domain of the IgE mole‐ cule. It binds with free IgE and prevents free IgE from attaching to high-affinity IgE receptor (FcεRI) on effector cells such as mast cells, basophils and also on dendritic cells. An IgE-anti-IgE complex is formed, and as a result, free IgE is decreased. [48] Omalizumab has been well studied and used in treatment of asthma [49, 50, 51] and other allergic diseases such as uriti‐ caria and and stational rhinitis [52] Like other immunomodulators mentioned above, clinical trials with allergic conjunctivitis patients are needed to asses the real impact in ocular aller‐ gic diseases.
