**4. Anti-inflammatory potential of DED treatment methods**

#### **4.1 Eye lubricants**

Eye lubricants have different properties, which vary between formulas and significantly influence the final effectiveness of treatment. These are viscosity, pH, osmolarity, and electrolyte concentration. Additionally, eye lubricants may contain preservatives, osmotic agents, osmoprotectants, bioprotectants, antioxidants, lipids, amino acids, and inactive agents, such as buffers. Historically, DED was considered to be largely due to tear insufficiency and was treated by prescribing tear replacement products, but these products do not target the underlying pathophysiology of DED. The group includes natural polymers such as HPMC, synthetic polymers (PVP), carbomer gels, and paraffin ointments. To enhance lubrication and prolong the retention time on the ocular surface, a variety of viscosity-enhancing agents are frequently incorporated into such formulas. The main disadvantage of this group of eye drops is the short time of relief of symptoms for the patient, most of them also contain preservatives.

It is already well recognized that chronic exposure of the ocular surface to preservatives induces toxicity and adverse changes to the ocular surface. There are multiple *in vitro* and *in vivo* studies demonstrating that BAK can induce corneal and conjunctival epithelial cell apoptosis, damage the corneal nerves, delay corneal wound healing, induce squamous metaplasia, interfere with tear film stability, and also can cause loss of goblet cells [17–19].

Hyaluronic acid is worth mentioning because its viscosity depends on shear rate and due to its non-Newtonian properties, it mimics the tear film behavior. When open, the eye benefits from a higher tear viscosity to prevent tear film breakup, whereas a lower tear viscosity during blinking prevents damage to the epithelial surface. Moreover, by binding to the CD44 receptor Hyaluronic acid provides enhancement of corneal epithelium healing, improvement of the ocular surface function and protection, and also restoration of the morphology and distribution of goblet cells [20, 21].

The new formulas of eye lubricants usually have complex compositions and treat not only symptoms but are designed to aim at the causes of the disease—hyperosmolarity, inflammation, and ocular surface damage.

The trehalose properties are worth underlining because it is unique in terms of high water retention capabilities but also has the dual properties of both bioprotection and osmoprotection. Trehalose has a protective effect against inflammation in DED. It suppresses proinflammatory cytokines, such as IL-1, 2, 6, 17, TNF-α, as well as proteolytic enzymes (MMP-9), and cell keratinization, which was proved in vitro, in animal, and human studies [22–26].

#### **4.2 N-acetylcysteine (NAC)**

NAC is a mucolytic agent but also possesses antioxidant and anti-inflammatory properties. It inhibits cytokine release and suppresses adhesion molecule and nuclear factor kappa-B (NF-κB) expression. The most common concentration in clinical settings in patients with DED and MGD ranges from 5 to 10% topical [27].

#### **4.3 Serum eye drops**

In recent years, attention has been paid to autologous peripheral blood serum (PBS), umbilical cord serum (UCS), and platelet-rich plasma (PRP). In clinical

#### *Dry Eye Disease: Chronic Ocular Surface Inflammation DOI: http://dx.doi.org/10.5772/intechopen.114118*

settings, autologous serum eye drops are usually applied in concentrations ranging from 20 to 100%. The composition may be regarded to be similar to natural tears, by the content of factors, such as epidermal growth factor (EGF), nerve growth factor (NGF), fibronectin, and vitamins. It has a positive effect on the regeneration of epithelial cells and also has the potential to reduce the activity of inflammatory cytokines and increase the production of mucin and the number of goblet cells [9].

### **4.4 Topical steroids**

Topical corticosteroids are one of the most potent topically applied anti-inflammatory drugs to treat ocular inflammation. Topical corticosteroids are effective in reducing inflammation by stopping the inflammatory cascade at various levels, including (intercellular adhesion molecule 1) ICAM-1-mediated cell adhesion, reducing cytokines, chemokines, MMPs expression, induction of lymphocyte apoptosis, proliferation of fibroblasts, and collagen deposition. Corticosteroids increase the synthesis of lipocortins that block phospholipase A2 and inhibit histamine synthesis in mast cells. The drugs are widely used in all ocular diseases involving inflammation including keratitis, uveitis, ocular allergy, blepharitis, scleritis, and more. One should be aware of the differences among steroids related to the anti-inflammatory potential, drug duration of action, and the potential to incuse adverse events. There are several potential options in ophthalmic setting available such as hydrocortisone 3.35 mg/ml, 0.5% loteprednol etabonate, 0.1% fluorometholone acetate, 0.1% dexamethasone, 0.5% prednisolone acetate, and 0.05% difluprednate. However, soft corticosteroids (such as hydrocortisone 3.35 mg/ml, fluorometholone, or loteprednol 0.5%) may be ideal for the treatment of inflammatory flares in DED and may be considered mainstream anti-inflammatory therapy. Soft steroids have lower to no negative risks of ocular hypertension, cataracts, and infectious diseases, especially when used for a short duration (3–8 weeks).

The use of corticosteroids in DED has been shown to reduce the signs and symptoms associated with DES and prevent DES flares in many non-randomized trials in the clinical setting. Recently, two systemic reviews on the efficacy of topical administration of corticosteroids for the management of DED were published [28, 29]. The main conclusions are a good safety profile of topical steroids and the following benefits: provide small to moderate degrees of symptom relief beyond lubricants, small to moderate degrees of symptom relief beyond cyclosporin A (CsA), and less certain about the effects of steroids on improved tear film quality or quantity. Authors of both systemic reviews underline the need for randomized, controlled trials with larger sample sizes to provide higher-quality evidence to establish the role of steroids in DED.

Topical corticosteroid of limited duration is recommended in DED treatment as a "step 2" option recommended by the TFOS DEWS II guidelines [9].
