Clinical science Br J Ophthalmol: first published as 10.1136/bjophthalmol-2020-317907 on 9 March 2021. Downloaded from Real- world experience of using ciclosporin- A 0.1% (Ikervis) in the management of ocular surface inflammatory diseases Rashmi Deshmukh ,1 Darren Shu Jeng Ting,1,2 Ahmad Elsahn,1,2 2 1,2 1,2 Imran Mohammed , Dalia G Said, Harminder Singh Dua 1Ophthalmology, Nottingham ABSTRACT is being recognised.5 Many factors operate in the University Hospitals NHS Trust, Purpose To report the real- world experience of using aetiology and pathophysiology of DED of which Nottingham, Nottinghamshire, UK topical ciclosporin, Ikervis, in the management of ocular inflammation was first recognised as an important 2Academic Ophthalmology, surface inflammatory diseases (OSIDs). and consistent component in the report published Division of Clinical Methods This was a retrospective study of patients following a Delphi approach to treatment recom- Neurosciences, University of treated with Ikervis for OSIDs at the Queen’s Medical mendations in 20066 and substantiated in subse- Nottingham, Nottingham, Centre, Nottingham, between 2016 and 2019. Relevant 7 8 Nottinghamshire, UK quent reports. data, including demographics, indications, clinical Steroids have been the mainstay in the manage- Correspondence to parameters, outcomes and adverse events, were collected ment of most inflammatory conditions, including Professor Harminder Singh and analysed for patients who had completed at least 6 DED, allergic eye disease (AED), chemical eye Dua, Ophthalmology, University months follow-up . For analytic purpose, clinical outcome injury, ocular mucous membrane pemphigoid of Nottingham, Nottingham, was categorised as ’successful’ (resolved or stable Nottinghamshire, UK; (OMMP), Steven-Johnson syndrome (SJS) and disease), ’active disease’ and ’drug intolerance’. 9 harminder. dua@ nottingham. many others. However, over the last two decades, ac. uk Results 463 patients were included; mean age was non- glucocorticoid immune- modulators, especially 51.1±21.6 years, with a 59.0% female predominance. ciclosporin A (CsA), have gained prominence as RD and DSJT contributed Mean follow-up was 14.6±9.2 months. The most steroid- sparing topical therapy for DED.10 11 Oil- equally. common diagnosis was dry eye disease (DED; 322, based CsA preparations were in vogue (Optim- 69.5%), followed by allergic eye disease (AED; 53, Received 3 September 2020 mune 0.2%, licenced for dogs) and used off- label 11.4%) and ocular mucous membrane pemphigoid/ Revised 11 February 2021 in humans since the 1980s. Restasis (0.05% CsA, Accepted 17 February 2021 Steven- Johnson syndrome (OMMP/SJS; 38, 8.2%). Allergan, California, USA) was approved and Successful treatment was achieved in 343 (74.1%) licenced by the Food and Drug Administration patients, with 44 (9.5%) requiring additional treatment 12 and 76 (16.4%) reporting drug intolerance. The efficacy (FDA), USA, for treatment of DED in 2002. of Ikervis was highest in DED (264, 82.0%), followed by However the drug was not available in Canada OMMP/SJS (25, 65.8%) and post- and Europe including the UK, and the market keratoplasty (7, 50.0%; http://bjo.bmj.com/ p<0.001). Logistic regression analysis demonstrated authorisation application to the European Medi- age <70 years (p=0.007), AED (p=0.002) and OMMP/ cines Agency (EMA) was withdrawn by Allergan in 13 SJS (p=0.001) as significant predictive factors for Ikervis 2018. In 2015 Ikervis, a CsA eye- drop prepara- intolerance. AED and post- keratoplasty were 8.16 times tion (1 mg/mL or 0.1%) was approved by the EMA (95% CI, 2.78 to 23.99) and 13.98 times (95% CI, 4.22 for the treatment of severe DED in adults and by to 46.28), respectively, more likely to require additional the National Institute for Health and Care Excel- treatment compared with DED. lence, UK, for the treatment of severe keratitis of on September 26, 2021 by guest. Protected copyright. Conclusions Ikervis is a useful steroid-sparing topical DED not responding to treatment with tear substi- treatment for managing OSIDs in the real- world setting. tutes.14 15 In 2018, the same preparation of CsA Preparations with improved tolerability are needed to as in Ikervis (recommended once daily for DED) benefit a larger number of patients. was marketed with a different packaging, under the name of Verkazia (recommended four times a day) after being approved by EMA for treatment of 16 INTRODUCTION severe vernal keratoconjunctivitis (VKC). Dry eye disease (DED) is the most common disease As the only licenced steroid-sparing anti- © Author(s) (or their affecting the ocular surface (OS) in the young and inflammatory agent available for direct treatment at employer(s)) 2021. Re- use old, increasing with age, with a female prepon- the OS, the incentive and clinical pressure to use permitted under CC BY- NC. No derance.1 2 There are various reports on the inci- it for other inflammatory conditions was consider- commercial re- use. See rights able, and as often happens in clinical practice, off- and permissions. Published dence and prevalence of DED, which is estimated by BMJ. to affect 15%–33% of individuals aged over 65 label use of Ikervis became an option in a variety of years but younger individuals are increasingly clinical scenarios where previous oil- based prepa- To cite: Deshmukh R, being affected.2–4 DED is traditionally classified as rations of CsA were used with some or significant Ting DSJ, Elsahn A, et al. 17 18 Br J Ophthalmol Epub ahead aqueous deficient DED (resulting from affection of benefit. We report our real- world experience of print: [please include Day the lacrimal gland) or evaporative DED (primarily with licenced and off-label use of Ikervis in the Month Year]. doi:10.1136/ due to meibomian gland dysfunction), though management of chronic non- infective OS inflam- bjophthalmol-2020-317907 increasingly a considerable overlap between the two matory diseases (OSIDs). Deshmukh R, et al. Br J Ophthalmol 2021;0:1–6. doi:10.1136/bjophthalmol-2020-317907 1 Clinical science Br J Ophthalmol: first published as 10.1136/bjophthalmol-2020-317907 on 9 March 2021. Downloaded from MATERIALS AND METHODS Table 1 Summary of the characteristics of patients treated with A list of patients who received a prescription of Ikervis (topical topical ciclosporin (Ikervis) in Nottingham, UK CsA 0.1%) from April 2016 to October 2019 was obtained from the hospital pharmacy database. All the charts were retrospec- Total n=463 tively analysed and patients who had a follow-up of more than Parameters n (%) 6 months were included in the study. An Excel spreadsheet was Age, years created to standardise the data collection, which included the 0–18 34 (7.3) demographic profile, diagnosis, clinical parameters, dose and >18 to 30 44 (9.5) duration of Ikervis treatment and clinical outcome. Diagnosis >31 to 50 98 (21.2) was based on clinical examination, characteristic findings and >51 to 70 152 (32.8) biopsy (where applicable). Patients were categorised into DED, >70 135 (29.2) AED including VKC and atopic keratoconjunctivitis (AKC), Gender OMMP, SJS and post- keratoplasty cases. Diagnoses other than these were categorised as ‘others’. These patients included non- Female 273 (59.0) specific chronic conjunctivitis, limbal stem cell deficiency, neuro- Male 190 (41.0) trophic keratopathy, inflammatory keratitis like superior limbic Diagnosis keratitis, inflamed pterygium or pseudopterygium, peripheral Dry eye diseases 322 (69.5) ulcerative keratitis and scleritis/episcleritis. Clinical parameters AED 53 (11.4) noted included best corrected visual acuity at baseline and final OMMP 28 (6.0) follow- up visit or at the time of discontinuing Ikervis, whichever Post- corneal graft 14 (3.0) was sooner, intraocular pressure, conjunctival findings, corneal SJS 10 (2.2) findings, dry eye parameters like tear-film breakup time and Others* 36 (7.8) Schirmer’s test II values were recorded. A note was made when CDVA, logMAR patients presented with burning sensation or ocular discomfort Baseline 0.24±0.45 affecting compliance. When Ikervis was discontinued by the Final 0.23±0.47 treating physician within a duration of 6 months, owing to the Clinical outcome† side effects or patient intolerance, patients were not excluded Resolved 119 (25.7) but were categorised under the intolerant group when evaluating Stable 224 (48.4) the clinical outcome. Active 44 (9.5) Clinical outcome was defined based on clinical parameters Intolerant to Ikervis 76 (16.4) on follow- up as: (1) resolved: when the signs and symptoms Treatment frequency subsided completely for at least 1 month with no requirement Once a day 286 (61.8) of further Ikervis treatment; (2) stable: when the disease did not resolve nor worsened with ongoing Ikervis and the OS (defined Twice a day 173 (37.4) as the conjunctiva, cornea and lacrimal apparatus) was free from >Twice a day 4 (0.9) visibly detectable inflammation and/or graft rejection (in post- Follow- up duration, months 14.6±9.2 keratoplasty cases); (3) active: flare up of condition or active *Included cases of inflammatory keratitis (n=9), non- specific chronic conjunctivitis inflammation requiring additional treatment such as topical (n=7), scleritis/episcleritis (n=4), limbal stem cell deficiency (n=3), neurotrophic http://bjo.bmj.com/ steroids and (4) intolerant: when patient on Ikervis experienced keratopathy (n=2), pseudopterygium (n=2), peripheral ulcerative keratitis (n=2), superior limbic keratoconjunctivitis (n=2), uveitis (n=2), epithelial ingrowth (n=1), burning sensation and discomfort necessitating discontinuation conjunctival granuloma (n=1) and giant papillary conjunctivitis (n=1). of the drug. The treatment was considered a ‘success’ if outcome †Clinical outcome is defined as: (1) resolved: resolution of disease without further 1 (resolved) or outcome 2 (stabilised) were achieved. need of Ikervis; (2) stable: stable disease with ongoing Ikervis; (3) active: active disease requiring additional treatment such as topical steroids and (4) intolerant: Ikervis discontinued due to intolerable side effects.