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Cyclosporine A effective anti-inflammatory for dry eye disease
A new formulation adds chondroitin sulfate, dextran, glycerol and hydroxypropylmethylcellulose.
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The Dry Eye Workshop report in 2017 emphasized inflammation in dry eye disease and helped shift our traditional approach from treating the disease primarily with lubrication.
In conjunction with the pivotal work of the International Task Force of dry eye disease (DED) experts, it sparked the ophthalmic community’s interest in delivering more targeted anti-inflammatory therapy to return the unstable tear film to its homeostatic levels, thus, improving signs and symptoms.
Prescription treatment for DED
It took clinicians years to begin using Restasis (cyclosporine A 0.05% ophthalmic emulsion, Allergan) for treating DED after the FDA approved it in 2003 for increasing tear production, “in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.” The FDA then approved Xiidra (lifitegrast ophthalmic solution, Shire) in 2016 for treating the signs and symptoms of DED. The addition of this product to the market renewed awareness of the importance of treating ocular surface inflammation and delivered another effective treatment.
We are now embarking on our next steps in the journey to treat ocular surface inflammation: more offerings of the well-known anti-inflammatory, cyclosporine A (CsA).
CsA is a calcineurin inhibitor that interferes with T-cell function and was initially used clinically as a systemic immunosuppressive agent to prevent rejection after organ transplantation, Sall and colleagues reported. The anti-inflammatory impact of CsA on the ocular surface has been well studied and observed in clinical practice. For many years, we have used it as a fundamental component of mild to severe DED treatment. The most prescribed formulation of topical CsA, Restasis, is combined with Refresh Endura. Clinical studies comparing Restasis dosed two times a day with Refresh Endura alone demonstrated a significant improvement in Schirmer’s scores for the Restasis group (Sall et al.).
Ikervis (0.1% CsA emulsion, Santen) is currently used in Europe for the topical treatment of severe forms of immune-mediated ocular surface disease. Ikervis combines CsA with a cationic nano-emulsion formulation called Novasorb (Novagali) and is dosed once daily. In contrast to Restasis, which uses an anionic oil-in-water emulsion, Ikervis uses cationic emulsion (CsA CE) in an effort to deliver a longer-lasting presence of CsA in the tear film. It is thought that the bioavailability of CsA with the CsA CE formula is higher than with previous CsA formulations (Eroglus). In addition, 0.1% CsA CE has been well tolerated and shown to improve ocular inflammation, corneal damage and symptoms by Ocular Surface Disease Index score (Pisella et al.).
Klarity-C (Imprimis Pharmaceuticals Inc.) is a preservative-free eye drop available in the U.S. that contains 0.1% CsA, 0.25% chondroitin sulfate, 0.25% dextran, 1% glycerol and 0.1% hydroxypropylmethylcellulose (HPMC). It comes in a 5.5-mL bottle that contains at least 140 drops and allows drug delivery without contamination inside the bottle using a unidirectional valve.
Chondroitin sulfate (CS), used as a lubricant, has also been reported by Moon and colleagues to have anti-inflammatory effects in the treatment of osteoarthritis. It has been used as a lubricant in combination with other components such as sodium hyaluronate (HA) (Moon et al.) and xanthan gum (XG) (Pérez-Balbuena et al.) for treating dry eye. When compared to 0.05% CsA, the combination of CS and HA was also shown to improve tear film instability, increase aqueous tear production and improve ocular surface damage (Moon et al.). This study also demonstrated that goblet cell density was significantly higher in eyes treated with 0.05% CsA.
HPMC, CPMC
HPMC and carboxypropylmethylcellulose (CPMC) have similar properties. Post-application, the celluloid attributes of both HPMC and CPMC as water soluble molecules aid in extending the retention time on the ocular surface, resulting in decreased vision fluctuation from early tear break-up, according to Safarzadeh and colleagues. When applied to the ocular surface, HPMC and CPMC swell and absorb water and, because of this feature, they are typically used in various formulations to make a drop more viscous or create a gel. Refresh contains 0.5% CPMC, Celluvisc contains 1% CPMC, OcuCoat contains 2% HPMC, and Goniosol contains 2.5% HPMC. HPMC is often combined with dextran, a complex branched polysaccharide, and glycerin, a simple polyol, which forms the backbone of all lipids for additional lubricating effect on the ocular surface.
HPMC, dextran and glycerol have a long track record of safely supplementing the tear film by providing a lubricating effect to the ocular surface, Safarzadeh and colleagues reported. We are now able to prescribe this combination with 0.1% CsA in a preservative-free formulation in Klarity-C.
As we develop new formulations of CsA, it is important to compare and contrast the chemical features, clinical performance and patient feedback regarding each offering. I often find that patient symptoms and clinical picture improve with the use of Restasis, Klarity-C and Xiidra.
Therapeutic choices
As we add more options to these currently available drops, the question becomes: Which of these is the best for mild to moderate DED? One thing that helps me determine this is to compare drops by using one drop in one eye and an alternate drop in the other eye of the same patient, while trying to keep all other variables the same. This situation can be a bit uncommon on some days, because there is often subjective or clinical asymmetry. But for those cases where you can isolate the drop as the primary adjustable variable and limit confounding variables, interestingly, patients will sometimes have a clear preference.
While some patients may need more of an anti-inflammatory effect, I see no disadvantage to prescribing 0.1% CsA twice daily. The study by Sall and colleagues compared 0.5% CsA twice daily to 0.1% CsA twice daily, both with Refresh Endura (Allergan) as the vehicle. The 0.1% group performed well compared to the 0.5% group, especially with corneal staining.
I also use 0.5% compounded CsA twice daily for patients with chronic inflammatory findings such as Thygeson’s, corneal neovascularization, superior limbic keratitis and conjunctival chalasis. In these cases, I have observed no toxicity, corneal abnormalities or increased irritation on administration of the higher CsA concentration. Given what we also know about the individual lubricants in Klarity, I expect it to perform well twice daily.
In my early experience with Klarity-C, I see that most patients find that it improves overall comfort and decreases vision fluctuation (due to improved tear break-up). It also clinically delivers the anti-inflammatory benefit I have come to expect from CsA, adding another excellent treatment for returning an altered tear film to its natural homeostatic state.
- References:
- Definition and Classification Subcommittee of the International Dry Eye Workshop. The Ocular Surface. 2007;doi 10.1016/S1542-0124(12)70081-2.
- Deveney T, et al. Clin Ophthalmol. 2018;doi:10.2147/OPTH.S115098/.
- Eroglus YI. Journal of Market Access and Health Policy. 2017;doi:10.1080/20016689.2017.1336043. eCollection 2017.
- Holland EJ, et al. Ophthalmology. 2017;doi 10.1016/j.ophtha.2016.09.025.
- Moon JW, et al. Korean J Ophthalmol. 2007;doi:10.3341/kjo.2007.21.4.189.
- Pérez-Balbuena AL, et al. BMC Ophthalmology. 2016;doi;10.1186/s12886-016-0343-9.
- Pisella PJ, et al. Clin Ophthalmol. 2018;doi:10.2147/OPTH.S150957.
- Safarzadeh M, et al. Journal of Optometry. 2017;doi:10.1016/j.optom.2016.11.002.
- Sall K, et al. Ophthalmology. 2000;doi:10.1016/S0161-6420(99)00176-1.
- Wilson SE, et al. Cornea. 2007;doi:10.1097/ICO.0b013e31802dffc7.
- For more information:
- Ahmad M. Fahmy, OD, FAAO, Dipl ABO, is in clinical practice at Minnesota Eye Consultants and is program chair of the Twin Cities Ocular Surface Disease Symposium. He can be reached at: amfahmy@mneye.com.
Disclosure: Fahmy reported no relevant financial disclosures.
Perspective
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Amy C. Nau, OD, FAAO
DEWS II continued to emphasize the importance of controlling the vicious cycle of chronic ocular surface inflammation in treating dry eye disease. Cyclosporine A 0.05% (Restasis) was a novel steroid-sparing approach to immunosuppression. CsA affects T cell activity by blocking calcineurin and reducing the function of effector T-cells and it also can influence mitochondrial activity in certain immune cells. While Restasis has enjoyed wide use in America, the effectiveness of this medication has recently been called into question (Schwartz et al.). Lifitegrast (Xiidra) is the second FDA-approved immunomodulator for dry eye. Xiidra blocks interaction between ICAM-1 and lymphocyte functional associated antigen-1, which may downplay the cell-mediated immune response and inflammation associated with DED. Whether higher concentrations of CsA embedded in alternative vehicles will prove superior to the original formulation and whether Xiidra provides an alternative – or possibly additive – therapy remains to be determined in clinical trials. With an expanding armamentarium of therapeutic targets, clinicians should be able to improve outcomes for our dry eye patients.
- Reference:
- Schwartz LM, et al. JAMA Intern Med. 2018;doi:10.1001/jamainternmed.2017.7904.
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