Management of inflammation in dry eye disease: Recommendations from a European panel of experts

**Background:** Dry eye disease (DED) is a common heterogeneous ocular surface disease affecting approximately 11–30% of individuals in Europe. It has a substantial impact on vision, quality of life, and work productivity. The pathophysiology involves a self-reinforcing inflammatory cycle (the 'vicious circle') driven by tear hyperosmolarity, immune activation, and neurogenic inflammation. Early initiation of anti-inflammatory therapy with topical corticosteroids and/or ciclosporin A (CsA) is recommended by the 2017 TFOS DEWS II report, especially when tear substitutes are insufficient. However, there is limited guidance on practical aspects of CsA use, such as when to start, how to measure treatment effects, and how to taper or discontinue therapy. This consensus document was developed to address these unmet needs and provide clinical recommendations for managing inflammation in DED, with a focus on topical CsA.

**Methods:** A steering committee (SC) of seven European DED experts developed a questionnaire to gather information on unmet needs and management practices in DED. The questionnaire was based on an initial literature review and distributed online to the SC and an expanded panel of 22 additional ophthalmologists from 15 European countries. Based on the questionnaire results, the SC developed 18 recommendation statements covering four areas: disease severity and progression; patient management (including treatment initiation, tapering, and discontinuation); efficacy, safety, and tolerability of CsA; and patient education. All 29 experts voted remotely on these statements using a nine-point scale (1 = strongly disagree; 9 = strongly agree). Consensus was defined as ≥75% of experts scoring a statement ≥7. Only one round of voting was needed, and the entire process took place from 1 October 2020 to 10 May 2021.

**Key Results:** Consensus was achieved on all 18 statements. Key findings include: - **Disease severity and progression:** 100% agreement that severity should be measured by symptom severity, corneal and conjunctival staining, low tear production, short tear film break-up time (TBUT), and meibomian gland pathology. Corneal and conjunctival staining and low tear production help differentiate severe DED keratitis from other forms of keratitis. Important risk factors for progression include small fibre neuropathy, primary Sjögren's syndrome, rheumatoid polyarthritis, systemic lupus erythematosus, and others (e.g., diabetes, autoimmune disease, cicatrising conjunctivitis) (89.7% agreement). - **Patient management:** A stepwise approach is recommended for patients with moderate corneal staining, using environmental control, artificial tears (ATs), lid hygiene, topical corticosteroids, and/or topical CsA (86.2% agreement). Early initiation of CsA should be considered in patients with clinical risk factors for severe DED (79.3% agreement). Important indicative markers of inflammation include corneal staining, conjunctival staining, conjunctival hyperaemia, and reduced aqueous tear production (89.7% agreement). The absence of severe corneal staining should not prevent CsA initiation if other risk factors are present (89.7% agreement). Patients should be examined within 3 months of initiating CsA, ideally after 1 month and then every 3 months (93.1% agreement). ATs should be used with CsA, applied regularly and ideally 15 min before and/or after CsA (86.2% agreement). Bridging CsA with corticosteroids can offset the slow onset of CsA; CsA can be started simultaneously with corticosteroids or up to a week afterwards, and the corticosteroid dose tapered by reducing applications by 1 drop every 7–14 days (89.7% agreement). There is no fixed interval for examinations during combined therapy; frequency should be based on steroid type, concentration, instillation frequency, and comorbidities (96.6% agreement). CsA may be continued indefinitely if well tolerated and effective, but tapering and stopping should be considered if sustained improvement is achieved; discontinuation is recommended for poor tolerance, lack of efficacy, or patient choice (89.7% agreement). CsA does not need to be stopped when a patient requires surgery (e.g., cataract or glaucoma surgery) (93.1% agreement). - **Efficacy, safety, and tolerability of CsA:** Treatment efficacy can be assessed from as early as 1–3 months after initiation, with improvements in blurred vision, reduced ocular surface staining, and improved TBUT as main indicators (86.2% agreement). A small proportion of patients may need to stop CsA due to adverse events; additional steps (e.g., use of ATs and topical corticosteroids, refrigerating the drug) can alleviate discomfort (96.6% agreement). - **Patient education:** Patient education before and during treatment is critical for optimising adherence (96.6% agreement). Topics include the delay in noticeable response, possible adverse events (e.g., burning sensation that lessens over time), the need for corticosteroids at the start and during flare-ups, continued use of ATs, and the minimal systemic effect of CsA.

**Clinical Implications:** This consensus provides practical, expert-driven guidance for clinicians managing DED, particularly regarding the use of topical CsA and corticosteroids. Key recommendations include early initiation of CsA in patients at risk for severe disease, a stepwise treatment approach, regular monitoring (at 1 month and every 3 months), and the importance of patient education to improve adherence. The bridging approach with corticosteroids can help manage the delayed onset of CsA efficacy. CsA can be continued long-term, even during surgery, and discontinuation should be considered only if sustained improvement is achieved or if tolerance/efficacy issues arise. These recommendations aim to improve patient outcomes by addressing gaps in previous guidelines and providing actionable strategies for clinical practice.