Introduction
Sjögren’s syndrome (SS) is a multisystem autoimmune disease with B-cells and CD4+ cells infiltration and destruction of lacrimal glands, causing ocular dryness, photophobia, pain, blurred vision, and reduced life quality.[ 1 , 2 ] Hence, anti-inflammatory therapy forms an important component of treatment.[ 3 ] Cyclosporine A (CsA) is an immunomodulatory drug with such properties, having no serious adverse effects topically.[ 3 , 4 ] About 0.1% CsA was approved by the FDA in 2003 for dry eye management.
Few Indian studies have reported the efficacy of CsA eyedrop in 0.05% or 2% for SS, but not with 0.1%.[ 5-7 ]
This pilot study attempts to evaluate the effectiveness of 0.1% CsA eyedrop for primary SS in a tertiary care center.
Methods
This was a prospective observational consecutive case series conducted as per the tenets of the Declaration of Helsinki. Written informed consent was taken from each patient. The study protocol and informed consent were approved by our institutional review board.
Design of the study
Consecutive adult patients above 18 years of age, diagnosed in the rheumatology department with primary SS according to the 2016 ACR-EULAR classification, were enrolled for the study from July 1, 2021, to January 31, 2022, and referred to the ophthalmology department for dry eye assessment[ 1 ] [Table 1 ]. Complete ophthalmological assessment of anterior and posterior ocular segments with intraocular pressure and visual acuity was done for both eyes of each patient.
Table 1: Demographic features and baseline characteristics of study patients
Patients were required to have at least one symptom of ocular or oral dryness based on response to at least one of the following questions:
Daily, persistent, troublesome dry eyes >3 months?
Recurrent sensation of sand or gravel in eyes?
Use of tear substitutes >3 times/day?
Dry mouth daily >3 months?
Frequently drinking liquids for swallowing dry food?
Inclusion/exclusion criteria
Patients diagnosed as primary SS satisfying these inclusion and exclusion criteria were enrolled.[ 1 ]
Inclusion criteria ocular staining score (OSS) ≥5 and van Bijsterveld score (VBS) ≥4 in at least one eye after staining both eyes, and Schirmer ≤10 mm/5 min in at least one eye (after testing both eyes).
Exclusion criteria
Diagnostic tests
Minor labial salivary gland biopsy
It was performed if needed for diagnosis, based on clinical judgment. Diagnosis of SS was made if the focus score was ≥¼ mm².[ 1 ]
Van Bijsterveld score
Rose bengal 1% was used to score ocular surface in three zones: nasal bulbar conjunctiva, temporal bulbar conjunctiva, and cornea. The maximum score with this system was 9.
Ocular staining score
Fluorescein staining of cornea and lissamine green staining of interpalpebral bulbar conjunctiva were done using commercially available strips.[ 8 ] The maximum possible score for each eye was 12, graded separately on SICCA OSS form: (i) grade 0 = 0–9 dots, (ii) grade 1 = 10–32 dots, (iii) grade 2 = 33–100, and (iv) grade 3 > 100 dots.
Schirmer’s test
It was done on nonanesthetized eyes using sterile Whatman 41 paper to observe wetting of the strip at 5 min. Patients closed their eyes during the test. Values ≤10 mm were taken as moderate and ≤5 mm as severe dry eyes .
Antinuclear antibody
Serum samples were evaluated for ANA using immunofluorescence and immunoblot assay method (EUROLINE ANA Profile 3 IgG kit) for presence of SSA-A/Ro60, SSA-A/Ro52 and SS-B/La antibodies.
Study medications
Patients fulfilling inclusion criteria were started on CsA 0.1% eyedrop (Cyclomune 0.1% eyedrop, Sun Pharmaceuticals Industries Ltd, India), one drop in each eye twice daily for 3 months. Compliance and any adverse reaction were monitored by monthly telephonic conversation. Lubricating eyedrops were continued 6–8 times daily, 30 min after CsA eyedrop instillation.
At 3 months, tests for dry eye status repeated were questionnaire for symptoms, Schirmer’s test, OSS and VBS, and complete ophthalmological evaluation.
Outcome measures
Primary outcome measure was OSS and VBS comparison, whereas the secondary outcome measures were Schirmer’s test comparison and subjective improvement of ocular symptoms.
Statistical analysis
This was a time-bound study of standard of care with consecutive patients, hence sample size calculation was not applicable.
Continuous variables were expressed as mean and standard deviation. Categorical data were expressed as n (%). For comparing pre- and posttest variables, paired t -test was used. For comparing categorical data, we used Fisher’s exact test. P < 0.05 was considered to be statistically significant.
Results
A total of 20 patients (40 eyes) were recruited for the study and followed up for 3 months with 100% treatment compliance. The demographic details are given in Table 1 .
Primary outcome measures
VBS and OSS for each patient showed a statistically significant improvement for either eye [Table 2 ].
Table 2: Results of van Bijsterveld score, ocular staining score , and Schirmer’s test
Secondary outcome measures
Schirmer’s test improved for each eye, which was statistically significant [Table 2 ].
Moreover, there was a subjective improvement of symptoms for around 90.5% of patients.
No patient reported any ocular or systemic discomfort during treatment.
Discussion
Inflammation in SS is not addressed by lubricating eyedrops and punctal occlusion.[ 9 ] Hence, topical anti-inflammatory and lacrimogenic therapy is important in management.[ 9 ]
Efficacy and safety of 0.1% CsA eyedrop have been studied for varied dry eye conditions.[ 5 , 6 ] CsA is a lipophilic product of the fungus Tolypocladium inflatum .[ 10 ] It inhibits T-lymphocyte activation and mitochondrial permeability transition pore opening, thereby preventing cell apoptosis and increasing tear production.[ 11 ]
Around 50% of patients with SS develop extraglandular features such as peripheral neuropathy, arthritis, interstitial lung disease, renal involvement, and vasculitis. The risk of lymphoma makes early diagnosis of dry eye in these patients very crucial.[ 12 ]
Systemic therapy (glucocorticoids, disease-modifying antirheumatic drugs [DMARDs], and biologics) has not shown much improvement in ocular sicca in SS. Topical therapy has been found to be more effective and safe.
The role of CsA eyedrops in dry eye management for primary SS has been studied along with other dry eye conditions in varying concentrations (0.05%–2%).[ 3-7 ] However, multiple studies have shown higher efficacy with 0.1% of CsA.[ 4 , 13 ] In the Indian context, although 0.1% CsA is widely used for dry eyes , there is no study which has studied its efficacy in primary SS. In this pilot study, we were able to demonstrate its efficacy and safety for such patients.
Demographic features showed a 100% female preponderance, which correlates with previous data in primary SS.[ 9 ]
The questionnaire on ocular and oral sicca in ACR-EULAR classification showed a statistically significant improvement in dry eye symptoms, which agrees with previous studies.[ 3 , 4 ]
Schirmer’s test in our patients demonstrated a significant improvement at 3 months, comparable with previous studies using CsA 0.05% or 0.1%.[ 3 , 4 , 13 ] Studies using a higher concentration of CsA (2%) have given varied results, with Gündüz and Ozdemir reporting a significant improvement, while Jain et al . showed no improvement, with an increase in ocular surface discomfort.[ 5 , 14 ] Increased dosing (3–4 times daily) of 0.05% formulation has shown an improvement in 68% of patients, albeit with compliance issues.[ 15 ]
Ocular surface staining showed a significant improvement in our patients. As compliance was good, the results reinforce the effectiveness of this formulation. Such improvement is reported in previous studies.[ 3 , 4 ] Stevenson et al . did not find a difference in corneal staining between 0.05% and 0.1% formulation.[ 4 ] However, no Indian studies of 0.1% CsA usage have measured ocular surface scoring.
Limitations of our study include small sample size, lack of control group, and short follow-up. We have not included extraglandular manifestations of SS as their treatment does not alter the severity of sicca symptoms.[ 15 ] The aim is to conduct a larger randomized study with either 0.05% or 0.1% CsA in primary SS with a longer follow-up duration to enable us to understand the efficacy of this formulation in ameliorating chronic ocular sicca refractory to glucocorticoids and DMARDs.
Conclusion
The encouraging results of this study help us to understand the effect of 0.1% CsA on ocular sicca in primary SS patients.
Contributorship
Swapnali Sabhapandit – Conception and design of the study, data collection, manuscript preparation and analysis, and final approval of the manuscript
Madhuri Radhakrishnan – Conception and design, manuscript analysis, and final approval
Anumula Shireesha – Data collection, manuscript preparation, and analysis
Arifa Tummala – Data collection
Perumalla Solomon – Data collection
Sahithi Venapally – Manuscript preparation.
Ethical approval
This study was approved by the Institutional Ethics Committee–Asian Institute of Gastroenterology (IEC-AIG) (ECR/346/Inst/AP/2013/RR-19). The approval number is AIG/IEC-BHandR 16(a)/07.2021-01.
Financial support and sponsorship
Nil.
Conflicts of interest
All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf
Acknowledgments
We acknowledge the support of Dr. VV Ravikanth, Senior Research Scientist, Genetics Department, Asian Institute of Gastroenterology Hospitals, Hyderabad, in helping out with the statistical analysis of the data.
References
1. Shiboski CH, Shiboski CS, Seror R, Criswel LA, Labetoulle M, Lietman TM, et al. ACR-EULAR classification criteria for primary Sjögren's syndrome: A consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol 2017;69:35–45.
2. Miljanovic B, Dana R, Sullivan DA, Schaumberg DA, Impact of dry eye syndrome on vision-related quality of life. Am J Ophthalmol 2007;14:409–15.
3. Aragona P, Giannaccare G, Mencucci R, Rubino P, Cantera E, Rolando M, Modern approach to the treatment of dry eye, a complex multifactorial disease: A P. I. C. A. S. S. O. board review. Br J Ophthalmol 2021;105:446–53.
4. Stevenson D, Tauber J, Reis BL, Efficacy and safety of cyclosporin A ophthalmic emulsion in the treatment of moderate-to-severe dry eye disease: A dose-ranging, randomized trial. The Cyclosporin A Phase 2 Study Group. Ophthalmology 2000;107:967–74.
5. Jain AK, Sukhija J, Dwedi S, Sood A, Effect of topical cyclosporine on tear functions in tear-deficient
dry eyes . Ann Ophthalmol (Skokie) 2007;39:19–25.
6. Goel U, Desai D, Lavingia B, Gokhale N, Jadhav S, Gogtay J, Efficacy and safety of 0.05% cyclosporine ophthalmic microemulsion for the treatment of moderate to severe dry eye disease – An Indian experience. Delhi J Ophthalmol 2015;25:238–41.
7. Patil A, Sabnis M, A comparative study between efficacy of cyclosporine 0.1% and rebamipide 2% eye drops in moderate to severe dry eye cases. J Adv Med Dent Sci Res 2019;7:86–92.
8. Bron AJ, Evans VE, Smith JA, Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea 2003;22:640–50.
9. Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. TFOS DEWS II epidemiology report. Ocul Surf 2017;15:334–65.
10. Henrich CF, Ramulu PY, Akpek EK, Association of dry eye and inflammatory systemic diseases in a tertiary care-based sample. Cornea 2014;33:819–25.
11. Kunert KS, Tisdale AS, Stern ME, Smith JA, Gipson IK, Analysis of topical cyclosporine treatment of patients with dry eye syndrome: Effect on conjunctival lymphocytes. Arch Ophthalmol 2000;118:1489–96.
12. Vivino FB, Sjogren's syndrome: Clinical aspects. Clin Immunol 2017;182:48–54.
13. Duran BL, Palafox MJ, Quintella HE, Alcazar JL, Aleniz-de la O LF, A comparative clinical trial of the efficacy of two different aqueous solutions of cyclosporine for the treatment of moderate-to-severe dry eye syndrome. Br J Ophthalmol 2010;94:1312–5.
14. Gündüz K, Ozdemir O, Topical cyclosporin treatment of keratoconjunctivitis sicca in secondary Sjögren's syndrome. Acta Ophthalmol (Copenh) 1994;72:438–42.
15. Dastjerdi MH, Hamrah P, Dana R, High-frequency topical cyclosporine 0.05% in the treatment of severe dry eye refractory to twice-daily regimen. Cornea 2009;28:1091–6.
