Dr Lisa M. Nijm

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Ophthalmologists can now prescribe a corticosteroid for the treatment of dry eye disease (DED) with the confidence that they are doing so on-label, following the recent United States Food and Drug Administration (FDA) approval of a topical corticosteroid for short-term (up to 2 weeks’) use. Loteprednol etabonate ophthalmic suspension 0.25% (Eysuvis, Kala Pharmaceuticals) has a favourable adverse effect profile and a unique mechanism of action that is worth a closer look.

The drug product was studied in the largest clinical programme in DED to date, including more than 2,800 patients.

 In results from the STRIDE 1 and STRIDE 2 trials conducted by Kala Pharmaceuticals, it illustrated a beneficial safety profile, demonstrating similar intraocular pressure (IOP) levels to the vehicle arm. In treatment and vehicle groups, respectively, 0.2% and 0% of participants experienced a 10 mm Hg or greater increase from baseline, resulting in an IOP measurement of 21 mm Hg or greater at any post-baseline visit up to 29 days.

In the STRIDE trials, investigators observed statistically significant improvement in the measures of conjunctival hyperaemia and patient-reported ocular discomfort severity scores. Participants assigned to treatment with the loteprednol etabonate suspension product experienced rapid relief, with improvement in symptoms as early as Day 4.

The ophthalmic suspension has a novel formulation which utlises Kala Pharmaceuticals’ proprietary mucus-penetrating particle technology. These nanoparticles of approximately 300 nm in diameter are coated to facilitate their penetration through the mucus barrier.

This controlled delivery system enables the drug to spread more uniformly on the ocular surface to achieve longer retention and allow enhanced penetration to the target tissues, specifically the cornea and the conjunctiva.The formulation has demonstrated broad-spectrum anti-inflammatory action, leading to a more efficient and effective nanoparticle drug that rapidly reduces the symptoms and signs of DED, including in those patients with periodic acute exacerbations of worsening symptoms referred to as dry eye flares.

DED is an inflammatory disease in which an unstable and hyperosmolar tear film sets off a cascading sequence of inflammatory activity on the ocular surface.As with other chronic inflammatory conditions, such as asthma and rheumatoid arthritis, most patients with DED have chronic disease with dry eye flares.

The Tear Film & Ocular Surface Society Dry Eye Workshop II notes that patients can initially present with episodic dry eye in the absence of chronicity.

 Myriad triggers with varied intensity such as wind; low humidity; air conditioning; prolonged reading/visual tasks; and exposure to increased ozone concentrations have been shown to increase the incidence of flares.

 These inflammatory spikes occur in approximately eight out of 10 patients with dry eyes, and approximately half of patients with DED experience flares without continuous symptoms four-to-six times per year.

Particularly in relation to the COVID-19 pandemic, I have seen more patients presenting with acute dry eye symptoms who have never before been symptomatic. Many are spending 10–12 hours a day staring at computer screens. Additionally, the data show that there is an under-diagnosis and under-recognition of DED overall.

In general, I prescribe loteprednol etabonate ophthalmic suspension 0.25% for patients who have periodic exacerbations of dry eye, including those who are self-medicating with artificial tears, those with ocular allergies, or those with contact lens-associated issues; patients with chronic DED who need induction therapy to quell surface inflammation quickly in order to initiate chronic therapy; and patients with breakthrough dry eye flares who are on chronic therapy.

Two recent examples from my practice are discussed as follows.

A 42-year-old female contact lens wearer was referred to me for consultation for dry eye due to irritation from dust created by construction work on a nearby office. She had swelling in the left eye, with severe discomfort and complaints of dryness in both eyes for 5 weeks, and it was getting progressively worse.

The patient had initially been placed on tobramycin-dexamethasone 0.3%/0.1% twice a day and had a 95% improvement within the first week; however, on re-examination, her IOP had gone up to 35 mm Hg. She was then prescribed brimonidine-timolol 0.2%/0.5% (Combigan, Allergan) to decrease the pressure.

However, her symptoms worsened when she had an allergic reaction to the brimonidine-timolol 0.2%/0.5%. Although the drops were discontinued, her symptoms continued to worsen, with significant discomfort and redness, and she needed artificial tears every hour.

By the time she saw me, it was her 11th visit to a doctor in 5 weeks and she was desperate for relief. I gave her a diagnosis of allergic conjunctivitis, contact lens over-wear and dry eyes. I discontinued all previous drops and put her on loteprednol etabonate ophthalmic suspension 0.25% every other day, four times a day, for 2 weeks; preservative-free tears four times a day; and extra-strength over-the-counter olopatadine 0.7% (Pataday, Alcon) twice a day.

Within 1 week, she had great improvement in all her symptoms and felt that her eyes were back to normal. She completed the treatment course with full resolution of her symptoms and, much to her relief (and that of her referring provider), no increase in IOP.

A 78-year-old woman with a variety of medical problems including multiple myeloma and colon cancer was referred for evaluation of severe dryness in both eyes. In particular, she was experiencing copious tearing from her right eye for the past several weeks, stating that her eye watered so much it felt as though she was looking through a “puddle”.

The patient had been taking cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan) for years, which she felt helped her, and recently had been given lifitegrast ophthalmic solution 5% (Xiidra, Novartis) to use in addition to Restasis, but she was still experiencing tearing. She was also using artificial tears, warm compresses and over-the-counter olopatadine 0.1% for allergic conjunctivitis.

On examination, the patient had evidence of chronic inflammation including conjunctivochalasis and corneal staining. I kept her on cyclosporine ophthalmic emulsion 0.05% and added loteprednol etabonate ophthalmic suspension 0.25% in both eyes four times a day for 2 weeks.

Within days, her tearing resolved and her vision improved from 20/40 to 20/25. The patient was very happy that she was no longer tearing and was thrilled with the improvement in vision.

When it comes to prescribing corticosteroids for DED, I am much more proactive and confident prescribing loteprednol etabonate ophthalmic suspension 0.25% for my patients because of its rapid onset and strong safety profile. I have had great success with the drop in many straightforward to complex cases, including patients with glaucoma, and have had no pressure increases measured at follow-up examination in my clinical experience so far. My patients and I are impressed by how quickly it works to quieten symptoms.

Having an on-label enhanced loteprednol formulation for short-term use in treating the signs and symptoms of DED is a welcome addition to our armamentarium. Dry eye can have a significant impact on patient quality of life and daily activities. Patients are extremely grateful and relieved to feel rapid relief from their DED symptoms, especially when they experience dry eye flares.

Dr Nijm is the founder and medical director of Warrenville EyeCare & LASIK, a clinical assistant professor of ophthalmology at the Eye and Ear Infirmary at UI Health in Chicago, Illinois, US, and creator of MDNegotiation.com and RealWorldOphthalmology.com. She is a consultant for Alcon, Allergan, Kala Pharmaceuticals and Novartis.

1. Gupta PK, Venkateswaran N. The role of KPI-121 0.25% in the treatment of dry eye disease: penetrating the mucus barrier to treat periodic flares. 

2. Korenfeld M, Nichols KK, Goldberg D, et al. Safety of KPI-121 ophthalmic suspension 0.25% in patients with dry eye disease: a pooled analysis of 4 multicenter, randomized, vehicle-controlled studies. 

3. Holland E, Nichols KK, Foulks GN, et al. Safety and efficacy of KPI-121 ophthalmic suspension 0.25% for DED in four RCTs. Presented at: American Academy of Ophthalmology virtual annual meeting. 13-15 Nov 2020; PO098.

4. Pflugfelder SC, de Paiva CS. The pathophysiology of dry eye disease: what we know and future directions for research. 

5. Lienert JP, Tarko L, Uchino M, et al. Long-term natural history of dry eye disease from the patient's perspective. 

6. Perez VL, Stern ME, Pflugfelder SC. Inflammatory basis for dry eye disease flares. 

7. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II definition and classification report. 

8. Rolando M, Zierhut M, Barabino S. Should we reconsider the classification of patients with dry eye disease? 

9. Amparo F, Dana R. Web-based longitudinal remote assessment of dry eye symptoms. 

10. Iyer JV, Lee SY, Tong L. The dry eye disease activity log study. 

11. Karakus S, Agrawal D, Hindman HB, et al. Effects of prolonged reading on dry eye. 

12. Kim Y, Paik HJ, Kim MK, et al. Short-term effects of ground-level ozone in patients with dry eye disease: a prospective clinical study. 

13. Ousler GW 3rd, Rimmer D, Smith LM, et al. Use of the controlled adverse environment (CAE) in clinical research: a review. 

14. López-Miguel A, Tesón M, Martín-Montañez V, et al. Dry eye exacerbation in patients exposed to desiccating stress under controlled environmental conditions. 

15. Tesón M, González-García MJ, López-Miguel A, et al. Influence of a controlled environment simulating an in-flight airplane cabin on dry eye disease. 

16. Fernández I, López-Miguel A, Enríquez-de-Salamanca A, et al. Response profiles to a controlled adverse desiccating environment based on clinical and tear molecule changes. 

17. Brazzell RK, Zickl L, Farrelly J, et al. Prevalence and characteristics of dry eye flares: a patient questionnaire survey. Presented at: American Academy of Ophthalmology 2019. 12-15 October 2019; San Francisco, California, US.

18. Brazzell RK, Zickl L, Farrelly J, et al. Prevalence and characteristics of symptomatic dry eye flares: results from patient questionnaire surveys. Program no. 195265. Presented at: American Academy of Optometry 98th annual meeting. 23-27 October 2019; Orlando, Florida, US.

Articles

Loteprednol etabonate suspension 0.25% demonstrates anti-inflammatory action and produces significant improvement in conjunctival hyperaemia and ocular discomfort.

Rethinking dry eye disease with acute steroid treatment

Ophthalmologists now can prescribe a steroid for treatment of dry eye disease (DED) with the confidence that they are doing so on-label. The FDA has approved a topical steroid for the short-term (up to 2 weeks) acute treatment of the signs and symptoms of DED. Loteprednol etabonate ophthalmic suspension 0.25% (Eysuvis; Kala Pharmaceuticals) has a favourable adverse effect profile and a unique mechanism of action that is worth taking a closer look.

Loteprednol etabonate ophthalmic suspension 0.25% was studied in the largest clinical program in DED to date—more than 2800 patients.

 In results from the STRIDE trials (NCT02813265, NCT02819284), loteprednol etabonate ophthalmic suspension 0.25% illustrated a beneficial safety profile with IOP similar between the vehicle and loteprednol etabonate ophthalmic suspension 0.25% arms. In treatment and vehicle groups, respectively, 0.2% and 0% of participants experienced a 10 mm Hg or greater increase from baseline, resulting in an IOP measurement of 21 mm Hg or greater at any postbaseline visit up to 29 days.

In the STRIDE trials, investigators observed statistically significant improvement in the measures of conjunctival hyperaemia and patient-reported ocular discomfort severity scores. Participants assigned to treatment with loteprednol etabonate ophthalmic suspension 0.25% experienced rapid relief with improvement in symptoms as early as day 4.

Further, loteprednol etabonate ophthalmic suspension 0.25% formulation has a novel formulation created utilizing AMPPLIFY, Kala’s proprietary mucus-penetrating particle technology. These nanoparticles of approximately 300 nm in diameter are coated to facilitate their penetration through the mucus barrier. This controlled delivery system enables the drug to spread more uniformly on the ocular surface to achieve longer retention and allow enhanced penetration to the target tissues, specifically the cornea and the conjunctiva.

Loteprednol etabonate suspension 0.25% formulated with AMPPLIFY technology has demonstrated broad spectrum anti-inflammatory action. This leads to a more efficient and effective nanoparticle drug that rapidly reduces the symptoms and signs of DED, including those patients with periodic acute exacerbations of worsening symptoms referred to as dry eye flares.

DED is a chronic inflammatory disease in which an unstable and hyperosmolar tear film sets off a cascading sequence of inflammatory activity on the ocular surface. As with other chronic inflammatory conditions, such as asthma and rheumatoid arthritis, most patients with DED typically have chronic disease with dry eye flares.

 Myriad triggers with varied intensity such as wind, low humidity, air conditioning, prolonged reading/visual tasks, and exposure to increased ozone concentrations have been shown to increase the incidence of dry eye flares.

 These inflammatory spikes occur in approximately 8 out of 10 patients with dry eyes, and approximately half of patients with DED experience flares without continuous symptoms between 4 to 6 times per year.

Particularly in relation to the COVID-19 pandemic, I have seen more patients presenting with acute dry eye symptoms who have never before been symptomatic. Many are spending 10 to 12 hours a day staring at computer screens. Additionally, the data show that there is an underdiagnosis and under-recognition of DED overall.

In general, I prescribe loteprednol etabonate ophthalmic suspension 0.25% for patients who have periodic exacerbations of dry eye, including those self-medicating with artificial tears, those with ocular allergies, or those with contact lens–associated issues; patients with chronic DED who need induction therapy to quell surface inflammation quickly in order to initiate chronic therapy; and patients with breakthrough dry eye flares who are on chronic therapy.

Below are 2 recent examples from patients in my practice.

A 42-year-old female contact lens wearer was referred to me for consultation for dry eye due to irritation from dust created by construction on a nearby office. She had swelling in the left eye with severe discomfort and complaints of dryness in both eyes for 5 weeks that was getting progressively worse. She had initially been placed on tobramycin-dexamethasone 0.3%/0.1% twice a day and had a 95% improvement within the first week; however, on re-examination, her IOP went up to 35. She was then prescribed brimonidine-timolol 0.2%/0.5% (Combigan, Allergan) to decrease the pressure. However, her symptoms worsened when she had an allergic reaction to the brimonidine-timolol 0.2%/0.5%. Although the drops were discontinued, her symptoms continued to worsen with significant discomfort and redness, and she needed artificial tears every hour.

By the time she saw me, it was her 11th visit to a doctor in 5 weeks and she was desperate for relief. I gave her a diagnosis of allergic conjunctivitis, contact lens overwear, and dry eyes. I discontinued all previous drops and put her on loteprednol etabonate ophthalmic suspension 0.25% every other day, 4 times a day, for 2 weeks; preservative-free tears 4 times a day; and extra-strength over-the-counter olopatadine 0.7% (Pataday, Alcon) twice a day. Within 1 week, she had great improvement in all her symptoms and felt her eyes were back to normal. She completed the treatment course with complete resolution of her symptoms and, much to her relief (and her referring provider’s), no increase in IOP.

A 78-year-old woman with a variety of medical problems including multiple myeloma and colon cancer was referred for evaluation of severe dryness in both eyes. In particular, she was experiencing copious tearing from her right eye for the past several weeks, stating that her eye watered so much it felt as though she was looking through a “puddle.” The patient had been taking cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan) for years, which she felt helped her, and recently had been given lifitegrast ophthalmic solution 5% (Xiidra, Novartis) to use in addition to Restasis, but she was still experiencing tearing. She also was using artificial tears, warm compresses, and over-the-counter olopatadine 0.1% for allergic conjunctivitis.

On examination, the patient had evidence of chronic inflammation including conjunctivochalasis and corneal staining. I kept her on cyclosporine ophthalmic emulsion 0.05% and added loteprednol etabonate ophthalmic suspension 0.25% in both eyes 4 times a day for 2 weeks. Within days, her tearing resolved and her vision improved from 20/40 to 20/25. The patient was very happy that she no longer was tearing and was thrilled with the improvement in vision.

When it comes to prescribing steroids for DED, I am much more proactive and confident prescribing loteprednol etabonate ophthalmic suspension 0.25% for my patients because of its rapid onset and strong safety profile. I have had great success with the drop in many straightforward to complex cases, including patients with glaucoma, and have had no pressure increases measured at follow-up examination in my clinical experience so far. My patients and I are impressed by how quickly it works to quiet symptoms.

Nijm is the founder and medical director of Warrenville EyeCare & LASIK, a clinical assistant professor of ophthalmology at the Eye and Ear Infirmary at UI Health in Chicago, and creator of MDNegotiation.com and RealWorldOphthalmology.com. She is a consultant for Alcon, Allergan, Kala Pharmaceuticals, and Novartis.

 2021;13:25158414211012797. doi:10.1177/25158414211012797

2. Korenfeld M, Nichols KK, Goldberg D, et al. Safety of KPI-121 ophthalmic suspension 0.25% in patients with dry eye disease. 

 2021 1;40(5):564-570. doi:10.1097/ICO.0000000000002452

3. Holland E, Nichols KK, Foulks GN, et al. Safety and efficacy of KPI-121 ophthalmic suspension 0.25% for DED in rour RCTs. Presented at: AAO 2020; Nov 13-15, 2020; virtual.

2017;124(suppl 11):S4-S13. doi:10.1016/j.ophtha.2017.07.010

5. Lienert JP, Tarko L, Uchino M, Christen WG, Schaumberg DA. Long-term natural history of dry eye disease from the patient’s perspective. 

 2016;123(2):425-433. doi:10.1016/j.ophtha.2015.10.011

6. Perez VL, Stern ME , Pflugfelder SC. Inflammatory basis for dry eye disease flares. 

. 2020;201:108294. doi:10.1016/j.exer.2020.108294

 2017;15(3):276-283. doi: 10.1016/j.jtos.2017.05.008

 2021;29(3):521-523. doi:10.1080/09273948.2019.1682618

10. Amparo F, Dana R. Web-based longitudinal remote assessment of dry eye symptoms. Ocul Surf. 2018;16(2):249-253. doi:10.1016/j.jtos.2018.01.002

11. Iyer JV, Lee SY, Tong L. The dry eye disease activity log study. 

 Published online October 24, 2021. doi:10.1100/2012/589875

12. Karakus S, Agrawal D, Hindman HB, Henrich C, Ramulu PY, Akpek EK. Effects of prolonged reading on dry eye. 

 2018;125(10):1500-1505. doi:10.1016/j.ophtha.2018.03.039

13. Kim Y, Paik HJ, Kim MK, et al. Short-term effects of ground-level ozone in patients with dry eye disease: a prospective clinical study. 

 2019;38(12):1483-1488. doi:10.1097/ICO.0000000000002045

14. Ousler GW, Rimmer D, Smith LM, Abelson MB. Use of the controlled adverse environment (CAE) in clinical research: a review. 

 2017;6(2):263-276. doi:10.1007/s40123-017-0110-x

15. López-Miguel A, Tesón M, Martín-Montañez V, et al. Dry eye exacerbation in patients exposed to desiccating stress under controlled environmental conditions. 

 2014;157(4):788-798. doi:10.1016/j.ajo.2014.01.001

16. Tesón M, González-García MJ, López-Miguel A, et al. Influence of a controlled environment simulating an in-flight airplane cabin on dry eye disease. I

 2013;54(3):2093-2099. doi:10.1167/iovs.12-11361

17. Fernández I, López-Miguel A, Enríquez -de-Salamanca A, et al. Response profiles to a controlled adverse desiccating environment based on clinical and tear molecule changes. 

 2019;17(3):502-515. doi:10.1016/j.jtos.2019.03.009

18. Brazzell RK, Zickl L, Farrelly J, et al. Prevalence and characteristics of dry eye flares: a patient questionnaire survey. Presented at: AAO 2019: October 12-15, 2019; San Francisco, California.

19. Brazzell RK, Zickl L, Farrelly J, et al. Prevalence and characteristics of symptomatic dry eye flares: results from patient questionnaire surveys. Presented at: AAOPT 2019: October 23-27, 2019; Orlando, Florida.

20. 2018 Study of Dry Eye Sufferers. Conducted by Multi-sponsor Surveys, Inc.

21. 2020 Study of Dry Eye Sufferers. Conducted by Multi-sponsor Surveys, Inc.

Patients can benefit from short-term, on-label treatment with a novel loteprednol formulation.

Using acute steroid treatment for dry eye disease

My clinic is busier than ever managing dry eye, as our already-strong demand for services has swelled in response to patients’ COVID-19-era increased screen time, work-from-home arrangements and elevated stress. People need help. During this past year, I have implanted more punctal plugs, prescribed more dry eye medications and scheduled more in-office dry eye procedures than ever before.

Cyclosporine is a well-established stalwart of long-term management for dry eye disease (DED). Ophthalmologists have trusted it for years as an effective immunomodulator that alleviates dry eye symptoms without major negative side effects.

We have several options for cyclosporine: Cequa (0.09%, Sun Ophthalmics), Restasis (0.05%, Allergan) and the compounded Klarity-C Drops (0.1%, Imprimis). Several more are in the pipeline, including generic Restasis, CyclASol (0.1%, Novaliq), Ikervis (0.1%, Santen Pharmaceutical) and OTX-CSI ophthalmic insert (0.36 mg, Ocular Therapeutix).

How do we choose which one to use? Although the concentrations range from 0.05% to 0.1%, I have found cyclosporine to be efficacious at all levels, with some subtle differences. The choice usually comes down to tolerability of the formulation and affordability with patients’ insurance.

As a topical ophthalmic agent, cyclosporine poses several challenges. Firstly, it is a hydrophobic, lipophilic molecule, which makes it difficult to penetrate the aqueous layer and reach the eye. Secondly, cyclosporine can cause burning or stinging on instillation.

As a result, manufacturers need to formulate a vehicle that achieves the penetration required for efficacy, produces minimal side effects and feels comfortable for chronic use – a notoriously difficult set of challenges. The tolerability of different cyclosporine formulations hinges primarily on the vehicle, which varies among different products.

Although I tend to favour products with an established track record of comfort, some patients might tolerate one better than another. Therefore, I offer samples to let them find what works best.

Because I have used Restasis—which has an anionic castor oil-in-water emulsion vehicle

—for many years, I know to expect patients to be comfortable with its long-term use. As it has been around a long time, Restasis is also covered by most insurance plans, making it easier for patients to obtain and resulting in fewer call backs to the office.

My patients also have tolerated Cequa well, which has a nanomicelle-based solution. Commercial patients can obtain Cequa at its lowest price through a specialty pharmacy, so we check with patients in advance to see if that is a convenient arrangement.

The third current option, Klarity-C Drops, has a chondroitin sulfate, glycerin and dextran-based solution.

 This compounded option can be the most cost-effective choice for some patients. However, in my limited experience, it also seems to be more difficult for patients to tolerate, with greater burning and stinging upon instillation than the other options available.

Looking at the pipeline, I do not yet know which vehicle generic cyclosporine will use. But my general concern with generics is always how true they are to the original formulation.

I use both cyclosporine and lifitegrast (Xiidra, Novartis) as part of long-term management plans for dry eye. With cyclosporine, my best candidates have chronic dry eye symptoms and possibly wear contact lenses, so they need long-term relief from inflammation.

It can take up to 3 months for cyclosporine to build up the concentration required for full efficacy, so I tend to choose it for patients who can patiently await some improvement. For more severe cases, I also utilise a steroid during the cyclosporine induction period, such as loteprednol etabonate ophthalmic suspension 0.25% (Eysuvis, Kala Pharmaceuticals) which can be used on-label for short term treatment of dry eye signs and symptoms.

In addition, my patients who have dry eye secondary to autoimmune conditions such as Sjogren’s syndrome or rheumatoid arthritis tend to respond very well to cyclosporine. From a clinical standpoint, it has been great to see an emphasis on DED result in options for long-term treatment. 

Whether we get the long-lasting effects of a dry eye procedure, prescribe an immunomodulator or, optimally, offer some combination of both therapies, the options allow ophthalmologists to tailor effective, economical and comfortable care to every patient.


Dr Nijm is a corneal surgeon and medical director of Warrenville Eye Care and LASIK, Warrenville, Illinois, United States, founder of MDNegotiation.com and an assistant clinical professor of ophthalmology at the University of Illinois Eye and Ear Infirmary, Chicago, Illinois. She is a consultant for Allergan, Kala Pharmaceuticals, Novartis, Ocular Therapeutix and Sun Pharmaceuticals.

de Oliveira RC, Wilson SE. Practical guidance for the use of cyclosporine ophthalmic solutions in the management of dry eye disease. Clin Ophthalmol. 2019;13:1115-1122.

Klarity-C Drops (cyclosporine 0.1% ophthalmic emulsion PF). Imprimis. Accessed June 28, 2020. https://www. imprimisrx.com/formulation/kcdrops/

Cyclosporine for dry eye disease appears to be efficacious at all levels and the choice of which formulation to use usually depends on tolerability and affordability. Tolerability hinges primarily on the vehicle, which varies among different products.

Author | Dr Lisa M. Nijm

Articles

Rethinking dry eye disease with acute steroid treatment

Using acute steroid treatment for dry eye disease

Cyclosporine options for dry eye relief have varying tolerabilities