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. 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.
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 [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.
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?
Patients diagnosed as primary SS satisfying these inclusion and exclusion criteria were enrolled.
Inclusion criteria included labial salivary gland with focal lymphocytic sialadenitis and focus score ≥¼ mm², anti-SSA (Ro) positive, 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 included ocular pathology (history of infection, surgery, injury, lid abnormalities, or inflammation in preceding 3 months), history of head-and-neck radiation, active hepatitis C infection (confirmation by PCR), AIDS, sarcoidosis, amyloidosis, graft-versus-host disease, IgG4-related disease, and usage of systemic or topical medications that may interfere with outcome of the study (immunomodulators, steroids, antihistamines, cholinergic agents, antimuscarinics, beta-blockers, tricyclic antidepressants, phenothiazines, hormone replacement therapy, topical medications other than assigned study medication, and artificial tears); patients with a score of ≥4 were then included in the study.
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.
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. 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.
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.
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.
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.
Primary outcome measure was OSS and VBS comparison, whereas the secondary outcome measures were Schirmer’s test comparison and subjective improvement of ocular symptoms.
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.
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].
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.
Inflammation in SS is not addressed by lubricating eyedrops and punctal occlusion. Hence, topical anti-inflammatory and lacrimogenic therapy is important in management.
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. It inhibits T-lymphocyte activation and mitochondrial permeability transition pore opening, thereby preventing cell apoptosis and increasing tear production.
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.
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.
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.
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. 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. 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.
The encouraging results of this study help us to understand the effect of 0.1% CsA on ocular sicca in primary SS patients.
- 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.
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
Conflicts of interest
All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf. All authors have no potential conflict of interest to declare.
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.
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