**4.5 Non-glucocorticoid immunomodulators (0.05–0.2% cyclosporin CsA, lifitegrast 5%, azithromycin, 0.03% tacrolimus)**

Cyclosporine is a fungal antimetabolite that inhibits IL-2 activation of lymphocytes. Lifitegrast is a small molecule integrin antagonist, which acts as a competitive antagonist to block binding between lymphocyte function-associated antigen 1 (LFA-1) and ICAM-1. Azithromycin and tacrolimus are macrolide antibiotics that have immunosuppressive activity.

All immunomodulators have been proven to provide some degree of positive impact in experimental, animal, and human studies in DED, which solely proves the role of inflammation in DED. The exact treatment dosage and duration are not fully established and this matter requires more randomized clinical trials, as underlined by the TFOS DEWS II committee [9].

#### **4.6 Oral diet supplementation**

Essential fatty acids (EFAs) are believed to modulate systemic inflammation; however, the exact impact on inflammation is complex and not fully understood. At present oral EFAs, supplementation is recommended by the guidelines and is believed to support the anti-inflammatory effect of DED [9].

### **4.7 Oral macrolides and tetracycline derivatives**

Both groups of oral antibiotics possess antibacterial and anti-inflammatory properties. The positive effect is reached by the inhibition of collagenase and also by the anti-chemotactic effects, which are believed to improve patients' symptoms by stabilizing the lipid layer of the tear film. This treatment is recommended, especially in chronic blepharitis and MGD along with lid hygiene and warm compresses of various types. MGD is considered to be the main cause of EDE, which is a predominant form of DE responsible for about 70% of cases. Thus, MGD treatment plays a crucial role in DED management.

The treatment regimen for azithromycin seems unified for all clinical studies (500 mg on day 1 and then 250 mg/day for 4 days), while there are significant differences among doxycycline regimens (20–200 mg/day for 2–6 months). Some studies have even proposed the use of a low dose of doxycycline (20 mg) on a long-term basis [30]. Currently, there is no consensus on the unified treatment schedule with doxycycline.

Based on the current knowledge oral macrolide or tetracycline antibiotics are recommended in DED treatment as a "step 2" option recommended by the TFOS DEWS II guidelines [9].
