Abstract
Purpose
To report the clinical course of corneal ulceration/perforation in patients with Sjogren’s syndrome.
Methods
Retrospective descriptive study of patients diagnosed with Sjogren’s syndrome (primary and secondary) and corneal ulceration over past 8 years at tertiary eye care network. Assessed parameters were demographics, clinical details, microbiological profile, types of intervention and their outcomes.
Results
Forty-six eyes of 44 patients (11 males; mean age, 50 years) had corneal ulceration (28 eyes) or perforation (18 eyes) at the time of presentation. Of 46 eyes, 38 had sterile ulceration/perforation and rest 8 showed microorganism on microscopy or culture. The location was peripheral in 63% of eyes and it was the first presenting sign of Sjogren’s syndrome in 26% of patients. All 43 eyes (3 lost to follow-up after intervention) had successful management of corneal ulceration/perforation. Twenty-eight eyes with ulceration required medical management alone in 15 eyes, soft contact lens and isobutylcyanoacrylate in 12 eyes, and amniotic membrane grafting in one eye. Four eyes with ulceration worsened and required penetrating keratoplasty (n = 2), and amniotic membrane grafting (n = 2). Corneal perforations were successfully managed with isobutylcyanoacrylate patch and BCL (n = 15), corneal patch graft (n = 2) and multilayered amniotic membrane grafting (n = 1). The average time taken for ulcers to heal was 49 days over a mean follow-up duration of 10 months.
Conclusion
Corneal ulceration or perforation in Sjogren’s syndrome is often sterile and can be a presenting sign of undiagnosed SS. These patients usually respond to intensive medical therapy and bandage contact lens and isobutylcyanoacrylate patch application.
Subject terms: Eye manifestations, Eye diseases
Introduction
Corneal complications like ulceration or perforation can occur ~in 2.5–3.6% of Sjogren’s syndrome (SS) patients [1, 2]. These are usually vision threatening and require surgical interventions in a majority of patients. The reported data on corneal complications in SS is available from isolated case reports or small case series [3–9]. In SS, corneal ulceration or perforation is usually sterile [4–7]. Across published cases, majority of the SS patients developed corneal ulceration after the use of topical corticosteroid like following cataract surgery [4–7]. The association of scleritis or rheumatoid arthritis (RA) in these cases has been postulated to contribute to the collagenolytic process other than surface dryness [9, 10]. Our group recently published a big data analysis of 1938 eyes with SS where risk assessment for corneal complications (present in 46 eyes) was made [1]. Presence of scleritis and secondary SS were significant risk-factors for corneal complications in SS. Management of ulceration in SS is also variable across literature ranging from simple medical management with systemic immunosuppressives to surgical intervention in the form of glue application or amniotic membrane grafting [3–9]. It is unclear how many eyes with corneal complications in SS require surgical management and what can be the expected visual outcomes in them. The current paper reports the largest series of SS patients with corneal ulceration or perforation and describe their clinical features, extraglandular associations along with treatment outcomes.
Methods
Study design
This was a cross-sectional retrospective hospital-based descriptive study of patients diagnosed with SS (primary and secondary) and corneal ulceration at the time of presentation, between 1st January 2012 and 15th March 2020 to a network of tertiary eye centres of LV Prasad Eye Institute, Hyderabad. The study was approved by the Institutional Review Board (LV Prasad Eye Institute Ethics Committee) and conducted in accordance with the tenets of the Declarations of Helsinki. If a patient met any two of the three criteria formulated by the American College of Rheumatology (ACR) 2012, then a diagnosis of primary SS was made [1, 11]. Patients diagnosed with well-defined autoimmune connectivopathies in the absence of SS-related autoantibodies, and with objective documentation of dry eye signs (positive corneal staining or Schirmer <5 mm/5 min) were grouped into secondary SS [1].
Data retrieval and processing
A patient list with a diagnosis of “Sjogren’s syndrome” using ICD-9 coding H19.3 [SS with keratoconjunctivitis] made during any clinical visit was reviewed from an electronically generated database since 2012 and then checked for corneal ulceration or perforation or microbial keratitis. The retrieved parameters included demographics, ocular history, systemic diseases, history of RA, ocular findings, visual acuity at presentation and last follow-up, dry eye workup details, type of ulcer (sterile or infective), microbiological profile, types of intervention and their outcomes. Ulcers with clean base and without any associated stromal infiltrate or hypopyon were defined as sterile.
A standardized protocol for evaluating all cases of corneal ulceration, as described in detail previously, was followed [12]. Briefly, under topical anaesthesia (0.5% proparacaine hydrochloride) corneal scrapings were obtained from the base and edge of the ulcer using a sterile surgical no. 15 blade mounted on a Bard Parker handle by cornea specialists under slit-lamp magnification. The samples were evaluated for microscopic examination of smears on glass slides and directly inoculated onto culture media. The corneal smears were assessed using gram stain, Giemsa stain, and potassium hydroxide (plus calcofluor white) mount. The culture media used were sheep blood agar, chocolate agar, non-nutrient agar, Sabouraud’s dextrose agar (SDA), potato dextrose agar (PDA), thioglycollate broth, and brain heart infusion broth. All culture media were incubated for 7 days, except for SDA and PDA, which were incubated for 2 weeks. Positive microbiology was defined as the presence of bacteria or fungi (reported as the number of organisms per high-power field) on smears or culture positivity (morphological correlation to the organism identified on smears, and/or if the same organism grew in more than one medium, and/or if there was growth on at least two streaks on blood agar). If the smears were negative for the presence of microorganism and the culture also showed no growth, then the corneal ulcers were termed “sterile” or “non-infectious/infective”.
Results
Demographics
A total of 46 eyes of 44 SS patients (33 females: 11 males) had corneal ulceration or perforation at presentation. The mean age at presentation was 50±12.6 years (range, 18 to 74). Majority (34/44; 78%) had secondary SS. Thirty-three patients were carrying the diagnosis of SS (diagnosed by rheumatologist elsewhere) at the time of presentation. Corneal ulceration/perforation was the first presenting sign of SS in 10/44 (26%) patients. These ten patients were referred to rheumatologist based on the clinical suspicion of SS from the ophthalmic perspective and were then confirmed by treating rheumatologist. Majority (34/44, 77%) of patients had RA. Also, scleritis was present in four eyes, of which three had central corneal perforation along with scleromalacia perforans. All patients had Schirmer values of less than 10 mm and mean value was 3.7 mm (SD, 3.5). Xerostomia was present in 82% of patients. Twenty-four patients (54.5%) were taking immunosuppression in the form of oral hydroxychloroquine and methotrexate. Of 44 patients, five were diabetic (mean HbA1c of 7.25), seven were hypertensives and one patient had hypothyroidism.
Ulcer details and microbiology
Table 1 summarizes the clinical details of ulcers (size, location and types) and their treatment outcomes. Of 46 eyes, 28 eyes (61%) had corneal ulceration alone and 18 eyes (39%) had corneal perforation as well. The location of corneal ulcerations was peripheral in 63% of eyes. Two patients had bilateral involvement, and in both eyes, ulcers were located in the peripheral cornea. Perforation was located centrally in 7 and peripherally in 11 eyes. All cases had stromal thinning, with ulcer depth extending up to mid-stroma in 46 eyes (100%) and deep stromal tissue in 12 eyes (26%). Hypopyon was present in four eyes. (Fig. 1). Two patients, one of whom had undergone cataract extraction and the other pterygium excision, had perforations in the postoperative period while using topical steroids. There were no cases of sequential ulceration in the other eye. Nineteen eyes with clinical suspicion of infective ulceration had corneal scraping reports. No organism could be found in 11 out of 19 eyes. The underlying microorganisms in the rest 8 eyes were Staphylococcus aureus (n = 3), Streptococcus pneumoniae (n = 2), Serratia marcescens (n = 2) and Fusarium (n = 1).
Table 1.
Summary of clinical details of corneal ulcers and their treatment outcomes.
| Corneal ulceration/perforation, No. of eyes (%) | |
|---|---|
| Mean age, years (Range) | 50 (18 to 74) |
| Gender, women | 33 (75) |
| Scleritis | 4 (8.6) |
| Presence of RA | 34 (77) |
| Clinical details | |
| Median VA at presentation | 20/200 |
| Type of ulcer | |
| Sterile (%) | 38 (82) |
| Infective (%) | 8 (18) |
| Ulcer Location | |
| Involving visual axis | 20 (43.5) |
| Ulcer Depth | |
| Mid stromal | 16 (34.8) |
| Deep stromal | 12 (26) |
| Full thickness perforation | 18 (39.2) |
| Size of ulcer | |
| Mean maximum width (range, in mm) | 3.9 (2 to 9) |
| Dry eyes (Schirmer <10 mm, positive fluorescein staining) | 46 (100) |
| Treatment outcomes* | |
| Medical alone | 15 (32.6) |
| Surgical | |
| Soft contact lens and isobutylcyanoacrylate | 27 (58.7) |
| Amniotic membrane grafting | 4 (8.7) |
| Corneal patch grafting | 2 (4.3) |
| Tectonic penetrating keratoplasty | 4 (8.7) |
| Mean follow-up (in months) | 10.3 ± 10.2 |
RA rheumatoid arthritis; *denotes the overall treatment given to 46 eyes including repeat treatment for worsening eyes.
Fig. 1. Corneal ulceration and perforation in Sjogrenʼs syndrome.
First row, Slit-lamp photograph of the right cornea shows sterile central 2 mm perforation with iris plugging (A), which resolved with isobutylcyanoacrylate and contact lens application (B, C). Second row, Slit-lamp photograph of the right cornea of another patient shows 9 mm wide sterile corneal ulceration with stromal involvement (D) that shows healing with BCL and medical management alone (E, F).
Treatment outcomes
All 43 eyes (3 lost to follow-up after intervention) had successful management of corneal ulceration/perforation (reepithelialization of the corneal defect, restoration or maintenance of the a.nterior chamber, and stromal scarring) at final follow-up. Of 28 eyes with ulceration alone, 15 eyes (53.6%) were treated with medical management alone, 12 eyes (42.8%) with soft bandage contact lens (BCL; Fig. 1D–F) and isobutylcyanoacrylate patch for severe thinning, and amniotic membrane grafting in one eye (3.6%). Medical management for sterile ulceration included topical cyclosporine drops, intense lubricants, topical steroids and antibiotics. Those who were not on any systemic immunosuppression were referred to physician for starting the same. Four out of 29 eyes worsened and required penetrating keratoplasty (n = 2) and amniotic membrane grafting (n = 2).
Perforated corneal ulcers were managed with isobutylcyanoacrylate patch and BCL (n = 15), corneal patch graft (n = 2) and multilayered amniotic membrane grafting (n = 1) (Fig. 1A–C). Of 18 patients, three were lost to follow-up after surgical intervention. In the rest except two eyes, the anterior chamber was restored, and the perforation site healed with eventual scarring. Two eyes managed with isobutylcyanoacrylate patch and BCL progressed to corneal melt, which required penetrating keratoplasty (infective melt) in one and conjunctival flap in another patient (sterile melt). Penetrating keratoplasties did not require repeat surgery in any of the eyes. The average time taken for ulcers to heal was 49 days (range, 9 to 120). Twenty-six eyes had visual acuity of <20/200 at presentation whereas 23 eyes had <20/200 at last visit. The mean visual acuity (in LogMAR) improved to 1.24 ± 1.19 from 1.66 ± 1.19 at presentation. The mean follow-up duration was 311 days (SD, 307). The numbers requiring tectonic keratoplasty were so small that we could not perform statistical analysis of risk factors associated with poor outcomes.
Discussion
The majority of corneal ulceration or perforation in eyes with SS is sterile (82%). Rheumatoid arthritis is the most common (77%) extraglandular association found in these patients and can be associated with scleritis in up to12% of patients. Corneal ulceration/perforation can occur de novo in SS without the history of topical corticosteroid use. Application of bandage soft contact lens with or without tissue adhesive arrests and heals the ulcerative process in a majority of eyes (56%) and remains the mainstay of therapy. Only 11% eyes require penetrating keratoplasty for severe thinning or perforation. The reepithelialization process takes a long time, sometimes lasting up to 3 months.
Corneal ulceration in SS is usually sterile and responds to aggressive immunosuppressives [13]. The incidence of perforations is high in sterile ulcers seen in SS patients as they can be painless and get noticed late [14]. In the current series, 83% of corneal perforations were sterile. Management options for sterile corneal perforations include tissue adhesive glue, amniotic membrane transplantation, conjunctival flaps or tectonic corneal grafts depending upon the extent of perforation. The current study had 39% of perforated eyes that is similar to the earlier reports [15]. The majority of these perforations were managed successfully with tissue adhesive, BCL and intensive medical treatment. When we reviewed the relation between ulcer size and management option, corneal perforations associated with melt area measuring more than 7 mm usually required surgical intervention in the form of AMG or tectonic grafting. One of the cases with sterile perforation and melt area measuring 8*5 mm diameter was managed with BCL and medical therapy, which progressed and required AMG. There is a single case report of sterile corneal perforation managed with AMG, autologous serum drops and a regenerating agent (Poly-carboxymethylglucose sulphate) along with systemic immunosuppressives in a newly diagnosed SS [16]. Regenerating agents are not used widely and none of our cases were managed with it. Penetrating keratoplasty is offered in situations where AMG has failed or the perforation size is large (two eyes with 9*8 mm of corneal melt in current series). Penetrating keratoplasty in eyes with necrotizing keratitis due to RA (though without SS) has a poor prognosis [10]. In the current series, the outcomes of penetrating keratoplasty, which was performed in 4 eyes, were good and devoid of any graft rejection, melt or perforation. They were kept on topical cyclosporine and steroids following corneal grafting along with systemic immunosuppressive for SS.
In SS, the necrotic process in cornea is considered to be an immune-mediated effect, hence use of immunosuppressives is recommended. In the current series, 54% of patients were on immunosuppressive therapy and still developed corneal complications. The exact etiopathogenesis of corneal ulceration in SS is unknown. The use of topical corticosteroids has been implicated in causing corneal perforations after cataract surgery or when used in undiagnosed SS patients [4, 7]. In one of the series, all six patients of secondary SS with severe corneal thinning were using topical corticosteroid therapy [3]. Of six, four had perforated corneas. Only two patients in the current series were using topical steroids and subsequently developed corneal perforation. Our previously published multivariate analysis of these 46 eyes with corneal ulceration or perforation had identified the presence of scleritis (8.7% vs. 1.3%) and secondary SS to be statistically significant risk-factors associated with corneal complications [1]. Of 44 patients, 78% had secondary SS, and was associated with RA in all cases. However, degree of dryness, duration of arthritis, presence of RA, and extraglandular ocular involvement did not influence the risk of getting corneal ulceration in SS. Whatever may be the inciting factor, the pathogenic process involves collagenolysis, either due to a lack of defence against collagenase or an increase in collagenolytic enzymes activity. A majority (77%) of patients in the current series had RA. In patients with RA, sterile ulceration is believed to be a T cell-mediated antigen-antibody immune reaction. Hence, there has been a speculation about the role of topical cyclosporin in prompt healing of sterile ulcers in patients with RA [17]. All patients with sterile ulceration in the current series were using topical cyclosporine. Immunosuppression is usually started if it is a newly diagnosed SS with corneal ulceration. However, the isolated effect of immunosuppression in healing the corneal ulceration in SS could not be ascertained with published studies and current study. The strengths of this study are large sample size, long-term follow-up, and uniformity in data available for all patients. The possible limitation could be the retrospective nature and unavailability of specific data about type of systemic immunosuppressives.
In conclusion, corneal ulceration or perforations in SS are usually sterile and require bandage soft contact lens and isobutylcyanoacrylate application for ulcer healing. Progressive melt or large perforations do well with penetrating keratoplasty but require systemic immunosuppression.
Summary
What was known before
Corneal ulceration or perforation can occur in 2.5–3.6% of Sjogren’s syndrome (SS) patients.
Corneal ulceration or perforation is usually sterile in SS.
Majority of published cases were due to topical corticosteroid use like following cataract surgery.
What this study adds
About 82% of corneal ulceration in SS are sterile and require bandage soft contact lens with isobutylcyanoacrylate application for ulcer healing.
Progressive melt or large perforations require systemic immunosuppression along with tectonic keratoplasty.
The reepithelialization in SS ulcers takes long time, even up to 3 months.
Acknowledgements
We thank Dr Zarin Modiwala, MBBS for her support in data collection and Dr Savitri Sharma, MBBS, MD, Dr Joveeta Joseph, MBBS, DNB, Mr. Venkateshwara Rao, Mr. Balakrishna, Mrs. Renuka, Mr. Gorappa, Laboratory technicians, Jhaveri Microbiology Centre, L V Prasad Eye Institute, Hyderabad for microbiological data.
Author contributions
SS and SB were responsible for designing the study protocol, writing the protocol and IRB, conducting the literature review and writing the manuscript along with interpreting results, and creating tables. SC and AVD were responsible for extracting the data from electronic records and analysing data and interpreting results.
Funding
Hyderabad Eye Research Foundation (HERF), India.
Data availability
Raw data is available with authors and can be shared upon reasonable request.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
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Data Availability Statement
Raw data is available with authors and can be shared upon reasonable request.