Use of cyclosporine A 0.05% ophthalmic emulsion for a distinctive intrapalpebral phenotype of anterior scleritis

Summary

Chronic scleritis poses a diagnostic and therapeutic challenge with multiple mimickers, underlying autoimmune conditions, diverse presentations and variable course. Treatment for mild forms includes topical corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs). For long-term control in patients with inadequate responses to steroids and NSAIDs, immunomodulators are employed. While oral cyclosporine has been used for inflammatory ocular conditions, research on topical cyclosporine for scleritis is limited. We present two cases: a man in his early 60s and a women in her late 20s, both with chronic, bilateral, intrapalpebral nodular scleritis with the clinical appearance of an inflamed pinguecula. After an initial poor response to conventional treatments, both patients responded positively to cyclosporine 0.05% ophthalmic emulsion as long-term monotherapy, likely due to cyclosporine’s inhibitory effects. These outcomes suggest topical cyclosporine as an effective additive therapy to steroids to maintain quiescence for this particular subset of nodular scleritis, especially when traditional therapies are inadequate.

Background

Scleritis is characterised by inflammation of the sclera. It is classified as anterior and posterior based on its position relative to ora serrata (figure 1). It is further divided based on presentation into diffuse, nodular and necrotising forms.¹ Symptoms of scleritis include redness, congestion of the deeper episcleral vessels, ocular pain exacerbating with eye movements, scleral oedema, diminution of vision and systemic vasculitis.¹ According to Smith et al,² the estimated global prevalence of scleritis is six cases per 10 000 population, while regional studies have yielded slightly lower estimates.³,⁵ Scleritis is bilateral in approximately 50% of the patients¹ and more common in elderly (>60 years of age) and white women.³,⁵

Figure 1. Flowchart showing the types, subtypes and common symptoms of scleritis.

Topical corticosteroids and oral non-steroidal anti-inflammatory drugs are commonly used to treat this condition.^{1 3} For more severe cases, short-term management may include oral corticosteroids¹; however, long-term oral corticosteroid use is discouraged due to adverse effects, including hyperglycaemia, weight gain, bone loss and impaired wound healing.⁶ In cases where corticosteroids are ineffective or cannot be tolerated, second-line treatments, including immunosuppressive agents such as methotrexate, azathioprine, mycophenolate and cyclophosphamide, can be administered.¹ Recently, biologics such as infliximab (anti-Tumor necrosis factor alpha), rituximab (anti-CD-20), tocilizumab (interleukin 6 (IL-6) antagonist) and tofacitinib (Janus kinase inhibitor) have been investigated for treating scleritis.^{1 7}

Cyclosporine, a calcineurin inhibitor that suppresses T-cell activation, is commonly used to treat ocular inflammation in conditions such as Behçet’s disease, uveitis and dry eye syndrome associated with Sjögren’s syndrome.⁸ Systemic application is also used to treat rheumatological conditions, including rheumatoid arthritis, systemic lupus erythematosus, polymyositis and antineutrophil cytoplastmic antibody-associated vasculitides.⁸ Evidence suggests that cyclosporine decreases the need for concomitant topical and oral use of corticosteroids in diseases with immune-system involvement,⁸ including ocular conditions such as keratoconjunctivitis.⁹

Several studies have reported successful treatment of scleritis with oral cyclosporine.¹⁰,¹⁴ However, the oral route of administration is associated with adverse effects of hypertension and potential nephrotoxicity.¹⁵ While the topical application may be associated with fewer systemic adverse effects,¹⁶ there are few reports of topical cyclosporine for treating scleritis.¹⁷,²⁰ This report presents two chronic bilateral nodular scleritis cases with a distinctive pinguecula-like overlay that responded to long-term therapy with 0.05% cyclosporine ophthalmic emulsion (Restasis, Abbvie).

Case presentation

Patient A

Patient A (man, in his early 60s) had a history of bilateral intrapalpebral scleral injection with an overlying, frothy, yellowish appearance. At presentation, this was suspected to be a pinguecula secondary to chronic dry eye syndrome. He had a history of multiple flare-ups with waxing and waning course treated with a variety of medications, including artificial tears eye, lubricating eye ointment, tobramycin–dexamethasone combination and prednisolone eye drops.

In 2014, his disease flared up and presented with redness and irritation in the right eye. His symptoms were managed with the tobramycin–dexamethasone combination (four times a day) and prednisolone eye drops (four times a day). As we suspected the patient of having pingueculitis, we added topical 0.05% cyclosporine ophthalmic emulsion to the treatment regime. During the follow-up visit, he stated that 0.05% cyclosporine ophthalmic emulsion alleviated the symptoms.

The patient experienced flare-ups again in 2015, 2016 (figure 2A), 2018 and 2019. These flare-ups were successfully managed with prednisolone and 0.05% cyclosporine ophthalmic emulsion with a 2-year disease-free period. Upon deeper inquiry, it was revealed that flare-ups were associated with poor drug compliance and resolved with improved compliance.

Figure 2. (A) Early documentation of patient A’s condition showing the initial presentation of chronic ocular issues such as pingueculitis of both eyes or nodular scleritis. (B) The scleritis returned with a corneal melt after a mandated switch to lifitegrast (Xiidra) by insurance. (C) The patient’s condition was significantly improved, although with mild scleral thinning, which was evident 5 weeks after reinstating 0.05% cyclosporine ophthalmic solution as a long-term monotherapy. (D) Patient B presented with a similar area of bilateral scleritis with a phenotypic pinguecula-like overlay as patient A. (E) To avoid chronic immunosuppression, she started 0.05% cyclosporine ophthalmic solution, eliciting a similar significant inflammatory response as seen in patient A. (F) She remains controlled on 0.05% cyclosporine ophthalmic solution as a long-term monotherapy for the last 14 months. OD, right eye; OS, left eye.

The patient’s condition deteriorated again in 2021 after an insurance-mandated switch from 0.05% cyclosporine ophthalmic emulsion to a 5% lifitegrast ophthalmic solution. This was followed by the development of peripheral ulcerative keratitis with corneal melting in the left eye (figure 2B), thus highly indicative of scleritis. Therefore, the diagnosis was finally established at this visit. The patient was managed using topical lubrication, lifitegrast ophthalmic solution 5% in both eyes, prednisone (30 mg tablet daily), ciprofloxacin (four times a day; right eye), ketotifen (two times per day) and oral doxycycline (100 mg, two times per day) with minimal alleviation of symptoms.

Patient B

Patient B was a woman in her late 20s. She had a history of idiopathic panuveitis since childhood (onset around age 5–6 years), which was controlled with oral methotrexate and topical steroids.

In 2019, at age 25, she was diagnosed with Burkitt lymphoma, which required her to discontinue oral methotrexate and initiate chemotherapy. She underwent four cycles of chemotherapy along with intrathecal methotrexate injection to achieve remission with no evidence of disease. She also remained symptom free of any ocular inflammation.

In November 2021, during a comprehensive eye exam, we noticed patches of scleral redness with a frothy yellow material in the palpebral fissure of both eyes. Phenotypically, the appearance was of an inflamed pinguecula. However, the administration of phenylephrine did not blanch the injected vasculature, indicating the involvement of scleral tissue. The scleral inflammation responded to prednisone acetate 1% ophthalmic suspension (four times a day) but would immediately recur at lower doses. Naproxen, 500 mg by mouth two times per day, was trialled but was discontinued as it did not have a steroid-lowering effect.

In June 2022, the patient continued to flare when she tapered her prednisolone drops. On examination, like patient A, she had a reddish, inflamed lesion with a yellowish overlay affecting the right eye more severely than the left initially (figure 2D). She also developed symptoms of dry eye syndrome. Schirmer testing revealed 5 mm of tear production in the right eye and 6 mm in the left eye.

Investigations

Patient A

During the 2019 flare-up, serological testing revealed a weakly positive speckled antinuclear antibody (ANA), titre 1:50 (normal <1:50). The following autoantibodies were negative: SSA, SSB, double-stranded DNA, smith, ribonucleoprotein, SCL-centromere, histone, cyclic citrullinated peptide, anti-neutrophil cytoplasmic antibody, proteinase-3 and myeloperoxidase. Testing was also negative for syphilis antibody, interferon-gamma release assay, rheumatoid factor and the presence of human leucocyte antigen B27. ACE and muramidase were in the normal range.

Patient B

Serologic workup revealed an elevated ANA titre of 1:640 with a homogeneous pattern. Lactate dehydrogenase was 359 (reference range 122–214 U/L). The following autoantibodies were negative: SSA, SSB, double-stranded DNA, smith, ribonucleoprotein, SCL-centromere, histone, cyclic citrullinated peptide, anti-neutrophil cytoplasmic antibody, proteinase-3 and myeloperoxidase. Testing was also negative for syphilis antibodies, interferon-gamma release assay, Lyme antibodies, rheumatoid factor, and human leucocyte antigen B27. ACE and muramidase were in the normal range. In addition, vitamin D deficiency (9 ng/mL, normally >20 ng/mL) was noted for which a vitamin D supplement was prescribed.

Given the patient’s cancer history and borderline lactate dehydrogenase levels, an excisional biopsy of the right nasal intrapalpebral lesion was performed. The conjunctival biopsy revealed chronic subepithelial granulomatous inflammation accompanied by capillary telangiectasia and fibrosis, with the overlying conjunctival epithelium displaying reactive inflammation and exclusive squamous metaplasia with foci of early epidermalisation, including focal keratosis (figure 3). The capillaries entrapped in this granulomatous process were mixed, vascular and lymphatic. CD163 staining highlighted the large groups of histiocytes. There was no morphologic evidence of actinic elastotic degeneration, vasculitis, necrosis, goblet cell infiltrations, conjunctival dysplasia or epithelial/lymphoproliferative malignancy. Special stains for microbiological profile (Gram, periodic acid-Schiff, Gomori methenamine silver and acid-fast bacilli) returned negative. These findings were consistent with nodular scleritis rather than malignancy or pingueculitis.

Figure 3. Nodular scleritis. (A) Scattered subepithelial groups of histiocytes with intervening lymphocytic infiltration and overlying conjunctival epithelium with reactive changes. (B) Dispersed clusters of histiocytes highlighted by CD163 staining.

Treatment

Patient A

After reassessing the complete history, it was decided to reinitiate 0.05% cyclosporine ophthalmic emulsion instead of lifitegrast ophthalmic solution. Due to the history of flare-ups associated with poor compliance, the patient was counselled in detail regarding the importance of compliance on clinical outcomes.

Patient B

Given the similar symptomatic presentation and non-responsiveness to conventional therapy as patient A, 0.05% cyclosporine ophthalmic emulsion (two times per day) in both eyes was added to her regimen.

Outcome and follow-up

Patient A

Shortly after starting 0.05% cyclosporine ophthalmic emulsion eye drops and its regular use along with an oral corticosteroid taper, the patient’s disease went into remission. There was a marked improvement in the symptoms after 2 weeks, and the disease fully responded in 5 weeks (figure 2C). A repeat serologic workup was unrevealing.

Prednisone was discontinued after 11 weeks, and the inflammation has remained controlled with 0.05% cyclosporine ophthalmic emulsion monotherapy for the last 22 months.

Patient B

Patient B’s ocular symptoms improved significantly after 5 weeks (figure 2E) of starting 0.05% cyclosporine ophthalmic emulsion based on our prior experience treating patient A. Control of inflammation allowed us to taper the dosage of topical steroids to once per week after 21 weeks of treatment initiation. Her scleral inflammation remains controlled with 0.05% cyclosporine ophthalmic emulsion as a long-term monotherapy for the last 14 months (figure 2F). There has been no reactivation of her uveitis.

Discussion

The symptoms and severity of scleritis vary between types.²¹ Diffuse scleritis causes redness and pain but more significant inflammation than nodular scleritis.^{1 21} Nodular scleritis is characterised by deep red, immobile nodules that lift the vessels and the overlying episcleral and conjunctival tissues.^{1 21} It features distinctive avascular necrotic sclera and significant pain, typically associated with underlying scleral inflammation.^{1 21}

Both patients were diagnosed with nodular scleritis. However, their clinical presentation and the existence of a yellowish pinguecula-like structure overlying scleral nodules seem atypical compared with standard descriptions and presentations of nodular anterior scleritis. Yet, there are clear similarities in the symptomology of the two patients. We considered episcleritis^{22 23} or pingueculitis²⁴ as alternative diagnoses but feel that the correct diagnosis is scleritis, perhaps a very anterior variant. Patient A presented with peripheral ulcerative keratitis during the clinical course, which is typically associated with scleritis and not episcleritis.²⁴ Patient B had the absence of vessel blanching with phenylephrine and a biopsy confirming scleritis. Patient A was not biopsied as his condition came under control with therapy.

Our eventual realisation that patient A had scleritis and that the topical cyclosporine was the effective treatment modality took time and several rounds of recurrent inflammation. However, our experience with patient A was crucial for diagnosing and treating patient B, whose similar clinical appearance and symptom constellation prompted quicker initiation of topical cyclosporine use.

The three previously reported cases of scleritis treated by topical cyclosporine (table 1) involved patients with necrotising scleritis. Hoffmann and Wiederholt¹⁷ and Rosenfeld et al¹⁸ reported complete remission of necrotising scleritis of the right eye with 2% topical cyclosporine after 6 weeks in an 83-year-old woman and 4 weeks in a 68-year-old woman, respectively, after multimodal conventional therapy failed. Gumus et al¹⁹ reported successful treatment of orbital myositis with scleritis in a 35-year-old woman with 0.05% topical cyclosporine without recurrence after a 6-month follow-up. A case series found that topical cyclosporine A alone was ineffective in four out of five scleritis patients but was effective in combination with oral corticosteroids and azathioprine, allowing the tapering and discontinuation of all medications over 6 months.²⁰ One patient discontinued cyclosporine A due to severe discomfort. However, the case series lacked details on the type of scleritis and patient histories.

Table 1. Summary of previous case reports of scleritis treated by topical cyclosporine.

Study	Patient	Diagnosis(s)	Initial treatment modality	Cyclosporine dose	Clinical course	Follow-up
Hoffmann and Wiederholt17	83/F	Cachexia Rheumatoid arthritis (onset 23 years prior to presentation) Necrotising scleritis of the right eye that started 6 months before presentation	Multimodal therapy with 1% atropine eye drops, Polyspectran eye drops, indomethacin eye drops, cysteine gel, chlorambucil and vitamin A ointments for 3 months	2% topical cyclosporine A in castor oil (two times per day)	All symptoms improved in 3 weeks, with almost complete symptom resolution within 6 weeks of treatment	No recurrence over 13 months of follow-up
Rosenfeld et al18	68/F	Inflamed right eye with large superonasal scleral nodule with reactive ptosis Developed a 5×3 mm zone of scleral necrosis 5 months after initial presentation	Topical prednisolone acetate, flurbiprofen sodium (0.03%), and oral indomethacin (25 mg; three times a day) The patient responded to oral sulindac (150 mg; two times per day) with topical prednisolone but was discontinued due to adverse reactions Oral prednisone (30 mg/day for 2 weeks, then 25 mg for 3 months) provided symptomatic relief but no improvement in scleral necrosis	2% topical cyclosporine in corn oil (four times a day)	Necrotising scleritis resolved after 4 weeks. Treatment tapered off completely over 12 weeks	No recurrence over 12 months of follow-up
Gumus et al19	35/F	Ocular myositis with scleritis on her left eye	Fluocortolone and a synthetic pure glucocorticoid (1 mg/kg body weight) for 8 months Oral cyclosporine (150 mg two times per day) for 6 months; discontinued due to adverse effects	0.05% topical cyclosporine A for 6 months plus dexamethasone for 1 month (both four times a day)	Symptom resolution within 1 month of treatment	No recurrence over 6 months of follow-up
Holland et al20	45/F60/F49/M78/F60/F	Scleritis	Not reported	Not reported	No effect of cyclosporine A alone in four patients, but adding it to the treatment regime comprising oral corticosteroids and azathioprine allowed tapering and discontinuation of all medications over 6 monthsCyclosporine A was discontinued in the 49/M patient due to severe discomfort.	Not reported

Oral cyclosporine has been well studied for its therapeutic benefits on scleritis.

Cyclosporine ophthalmic emulsion likely attenuates scleritis symptoms by inhibiting calcineurin, which inhibits IL-2 transcription and downstream T-cell activation.²⁵ Cyclosporine also impairs T helper type 17 cell differentiation by suppressing IL-17, which has been implicated in scleritis pathogenesis and corticosteroid resistance.^{8 26 27} It suppresses transforming growth factor β, IL-1 and IL-4 in fibroblasts,⁸ potentially reducing necrosis and fibroblast-induced angiogenesis in scleritis,²⁷ as nodular scleritis can progress to necrotising forms.²¹ Cyclosporine’s anti-inflammatory effects on the lacrimal gland may increase tear production, which can help maintain ocular surface health and alleviate discomfort.²⁸,³⁰

Interestingly, the elevated ANA in both of our patients suggests systemic inflammation, although the symptoms were only observed in the interpalpebral area. Asymptomatic cases of, for example, Crohn’s disease,³¹ gout³² and synovitis³³ with systemic inflammation have been reported, where local symptoms emerge due to additional physiological and physical stress limited to that region. Likely, such stress can push an already primed immune system over the edge. In our cases, it is plausible that the ocular surface disease was an instigating factor that led to increased inflammation and ultimately tipped the immune system into an overactive state that proliferated into scleritis. Topical immunosuppressants like cyclosporin may reduce these local triggers and relieve the symptoms in some patients. However, topical treatment alone might not be sufficient in other patients, but it may reduce the dosage of systemic therapies. Hence, although these two cases provide preliminary evidence suggesting that 0.05% cyclosporine ophthalmic emulsion may effectively manage anterior scleritis with a characteristic pinguecula-like overlay, we are limiting our recommendation at this time to patients of this specific phenotype and not advocating for a broader application of cyclosporine ophthalmic emulsion in patients with scleritis. Nonetheless, our findings warrant further investigation on topical cyclosporine as a potential modality for patients who prefer to avoid, do not respond to or cannot tolerate traditional therapies.

Learning points.

• A 0.05% cyclosporine ophthalmic emulsion was effective in managing nodular scleritis with pinguecula-like overlay in these cases, particularly in patients with a history of recurrent inflammation despite standard therapies, such as topical corticosteroids and non-steroidal anti-inflammatory drugs.

• This observed benefit of 0.05% cyclosporine ophthalmic emulsion seen here is specific to the phenotype described and should not be generalised to all cases of scleritis.

• Recognising specific ocular disease phenotypes may help tailor inflammatory treatment strategies.

• Larger studies are still needed to confirm the clinical utility, broader applicability and long-term efficacy of cyclosporine ophthalmic emulsion for managing nodular scleritis with this distinct phenotypic presentation.