Dry eye disease (DED), also known as keratoconjunctivitis sicca, is a chronic condition requiring long-term treatment. It is defined by the Tear Film Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) II as a “multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles” [1,2,3,4,5,6,7]. Two primary categories of DED have been defined: aqueous deficient and evaporative dry eye . Meibomian gland dysfunction (MGD) is a key underlying cause of evaporative DED, while tear underproduction results in aqueous deficient dry eye . However, most people with DED display signs and symptoms in varying combinations that relate to both types of disease . Disruption of ocular surface homeostasis leads to the induction of pro-inflammatory pathways that cause ocular damage and neurosensory aberrations, resulting in a vicious circle of progressively worsening pathophysiology [1, 2, 3,4,5,6,7]. If left untreated, DED may progress in severity and result in permanent ocular damage [3, 7]. Symptoms include pain, ocular irritation and impaired/blurred vision as well as stinging, burning or scratching sensations, all of which can limit performance of daily tasks and quality of life (QoL) .
DED is typically cyclical in nature with episodic worsening (or flares) of signs and symptoms occurring over time, including prolonged ocular inflammation (usually indicated by the presence of eyelid and/conjunctival hyperemia) and discomfort [9,10,11]. Topical and systemic medications, environmental or lifestyle factors (e.g. air conditioning, use of screen-based technologies) and allergies can exacerbate symptoms [9,10,11,12,13,14]. DED represents a significant QoL and economic burden due to loss of productivity and psychological issues (e.g. anxiety, depression), and individuals with specific character traits are at higher risk of developing the condition [12,13,14,15,16,17]. Absenteeism and presentism (attendance at work while unwell or unable to be productive) alone cost an estimated $11,302 per person with DED .
Treatment traditionally focuses on the control of symptoms and reduction of complications, with the aim of restoring ocular surface homeostasis and preventing further symptomatic flares . Artificial tears (ATs) or tear substitutes offer protection and lubrication at the ocular surface, although treatment outcomes with ATs may be variable, and disease progression will invariably require the addition of topical anti-inflammatory treatments (e.g. corticosteroids, cyclosporine) to reduce inflammation and help to improve QoL [4, 6, 18,19,20,21,22,23,24,25,26,27,28]. The TFOS DEWS II and German Ophthalmology Society (DOG) guidelines and recent expert consensus recommendations advise that anti-inflammatory treatments should be used relatively early in the disease pathway (from stage 2), rather than being reserved for later stages of disease when the ocular surface may be less responsive to therapy [4, 29, 30]. Cyclosporine A (CsA) is a widely used anti-inflammatory treatment for DED that can be administered for long-term treatment of inflammation [4, 6, 18,19,20,21,22,23,24,25,26,27,28,29]. In contrast, corticosteroids are not recommended for long-term use due to a risk of ocular complications (e.g. ocular hypertension, cataracts and opportunistic infections) [4, 29]. Multicenter, randomized controlled trials (RCTs) have demonstrated efficacy and safety outcomes with CsA 0.05% anionic solutions or 0.1% cationic emulsion (CE) treatment, with significant improvement observed concerning the signs and symptoms of DED [20,21,22,23,24, 27]. In Europe, only CsA 0.1% CE is licensed for prescription and reimbursement . It is approved for the treatment of severe keratitis in adult patients with DED that has not improved despite treatment with tear substitutes . Two double-masked, randomized, parallel-group, vehicle-controlled phase III studies, SICCANOVE and SANSIKA, examined treatment outcomes with CsA 0.1% CE in people with moderate-to-severe and severe DED, respectively [21,22,23,24]. In both studies, CsA 0.1% CE was well tolerated, reduced corneal surface damage and lowered ocular surface inflammation [21,22,23,24]. Pooled analysis of SICCANOVE and SANSIKA outcomes confirmed that CsA 0.1% CE improved the signs and symptoms of DED, with a particular benefit to those with severe keratitis . An open-label 24-month extension study also showed that the majority of people demonstrating improvement in DED signs and symptoms during the SANSIKA study did not relapse and sustained lower corneal fluorescein staining (CFS) scores after CsA treatment had been discontinued . While CsA 0.1% CE has been shown to be generally well tolerated in clinical studies, some retrospective analysis and pre-clinical data indicate that tolerance may be reduced/low in certain populations (e.g. ocular graft vs. host disease), with pain/irritation at the site of installation being the main adverse event (AE) and reason for discontinuation reported [20,21,22,23,24, 28, 32,33,34].
Although RCTs are considered to be the gold standard approach for drug registration trials, strict inclusion and exclusion criteria mean that they are generally unable to accurately reflect the diverse patient population and situations typically encountered in clinical practice . RCTs usually require wash-out periods when examining the effects of treatment switches, which are unlikely to be implemented in real-life clinical situations. Real-world evidence is becoming increasingly important and accepted by regulators (alongside conventional randomized trials) for demonstrating the effectiveness of treatments in routine practice [36,37,38]. These data provide clinicians with an indication of the potential results they may observe in their own clinic as well as new insights concerning the treatment of disease and pharmacovigilance data .
Recently published real-world evidence indicates that patients with ocular surface inflammatory diseases (particularly those with dry eye) experience improved clinical outcomes with CsA 0.1% CE treatment, with reduced requirement for adjunctive steroids . The aim of the present study was to expand the evidence base regarding the use of CsA 0.1% CE in routine clinical practice. The PERSPECTIVE study examined, in a real-world clinical setting, the effectiveness, tolerability and safety of CsA 0.1% CE in controlling severe keratitis in adult patients with dry eye who had not improved despite treatment with tear substitutes. Although the approved label for CsA 0.1% CE states that it should be used in the treatment of severe keratitis and dry eye, no formal threshold for CFS score (using the Oxford Grade Scale) is stipulated in the licensed indication, and the literature in this area does not clearly define the way in which disease severity should be graded [1,2,3,4, 29,30,31]. In routine clinical practice, ophthalmologists may evaluate the severity of keratitis and DED using a combination of CFS score, other signs (e.g. eyelid and/or conjunctival erythema), patient-reported symptoms and QoL factors [1, 4, 29,30,31]. This approach reflects the complex and multifactorial nature of the disease [1, 4, 29,30,31]. The PERSPECTIVE study therefore aimed to reflect real-world clinical practice and only specified that treatment should be prescribed in accordance with the approved label for CsA 0.1% CE based upon the judgment of the investigator. This approach was designed to gain insights regarding the typical profile (in terms of ocular signs and symptoms) and treatment outcomes for those patients considered by the treating physician to have disease of sufficient severity to warrant CsA 0.1% CE therapy. The study provides important insights concerning the treatment of keratitis and dry eye in ophthalmology clinics across Europe and the treatment outcomes that clinicians and their patients may expect.