Scleritis is inflammation of the deep blood vessels, including the episcleral vascular plexus and the intrascleral vascular plexus, accompanied by scleral edema and cellular infiltration. The sclera is a fibrous tissue with sparse blood vessels, and deep scleritis is a rare disease. It can be unilateral or bilateral, and causes are broadly divided into idiopathic, associated with systemic disease, infectious, and postoperative.
The incidence is reported to be 1.6–5.5 per 100,000 person-years 5). It is more common in women. For non-necrotizing diffuse and nodular scleritis, the peak age is in the 40s; for necrotizing scleritis, it is in the 60s. The rate of bilateral involvement in necrotizing scleritis is about 60%. Non-infectious scleritis accounts for the majority and is often seen as an ocular manifestation associated with systemic inflammatory diseases. Infectious scleritis accounts for 5–10% of all cases and is rare but has a poor prognosis 7).
According to a multicenter survey based on the Japanese guidelines for uveitis management, among 3,810 patients seen at uveitis clinics, scleritis accounted for 235 cases (6.2%), making it the second most common condition after acute anterior uveitis (6.6%) 8).
The classic Watson classification (Watson et al., 1976) is widely used for classifying scleritis based on clinical findings. It broadly divides scleritis into anterior and posterior types, and anterior scleritis is further subdivided into three types based on morphology.
| Classification | Type | Features |
|---|---|---|
| Anterior scleritis | Diffuse | Most common. Diffuse hyperemia due to dilation and tortuosity of scleral vessels. |
| Anterior scleritis | Nodular | Dark red scleral nodule. Commonly occurs at the limbal palpebral fissure area. |
| Anterior scleritis | Necrotizing (inflammatory) | Risk of scleral necrosis, thinning, and perforation |
| Anterior scleritis | Necrotizing (non-inflammatory) | Scleromalacia perforans. Painless. |
| Posterior scleritis | — | Rare. Approximately 4% of all cases5) |
Diffuse scleritis is the most common, followed by nodular scleritis. Necrotizing scleritis and posterior scleritis are rare. Recurrences often present with the same disease type, but about 10% become more severe upon recurrence. If the underlying systemic disease is untreated, recurrences frequently occur at the same site of the sclera. About 10% of nodular scleritis cases progress to necrotizing scleritis over time.
A special type of necrotizing scleritis with almost no inflammatory symptoms is called scleromalacia perforans. It commonly occurs in patients with long-standing rheumatoid arthritis, and progresses slowly with scleral thinning without redness or pain. Although the English name includes “perforans” (perforating), in many cases the eyeball shape is maintained by a thin fibrous membrane.
Episcleritis is inflammation of the superficial vascular plexus, such as the Tenon’s capsule vascular plexus, with mild hyperemia, no pain, and no effect on vision. Scleritis is inflammation of the deep vessels, accompanied by severe eye pain and dark red hyperemia. The two can be differentiated by the fact that hyperemia in episcleritis subsides with 1:1000 epinephrine eye drops, while hyperemia in scleritis does not.
Diffuse Scleritis
Congestion: Severe congestion due to dilation and tortuosity of scleral vessels spreads diffusely. It is localized to the entire circumference or one or more quadrants.
Pain: Severe pain radiating to the face or temple is characteristic, and it can disturb sleep.
Notable findings: No nodules, elevations, necrosis, or thinning are present. It may be accompanied by conjunctival edema, eyelid swelling, anterior uveitis, or elevated intraocular pressure.
Nodular Scleritis
Nodules: Single or multiple dark red nodules. Commonly occur near the limbus in the palpebral fissure area.
Palpation: Nodules are immobile and tender to touch.
History: Many patients have a history of herpes zoster ophthalmicus. About 10% progress to necrotizing scleritis, but with early treatment, it heals leaving only small scars.
Necrotizing Scleritis
Scleral necrosis: Initially, localized white to yellow avascular areas (scleral necrotic foci). Accompanied by severe dilation, tortuosity, and melting of scleral vessels.
Thinning: The sclera becomes thin enough to see the uvea, and if it progresses further, it can lead to globe perforation. The thinned area remains even after inflammation subsides.
Prognosis: The age of onset is in the 60s, and bilateral involvement accounts for about 60%. Without early treatment, blindness and difficulty in preserving the eyeball may occur.
Posterior Scleritis
Epidemiology: The average age of onset is about 50 years, with a predilection for females, occurring about twice as often as in males. Bilateral involvement is 30–40%.
Fundus findings: Optic disc edema, choroidal folds, exudative retinal detachment, subretinal mass, and elevated intraocular pressure are observed. Uveal effusion and secondary angle-closure glaucoma have also been reported.
Extension symptoms: When complicated by extraocular myositis, diplopia, pain on eye movement, proptosis, and ptosis may occur.
When inflammation extends from scleritis to the cornea, peripheral corneal infiltration and ulceration may occur. Anterior uveitis may also be complicated. Since scleritis almost invariably involves the episclera, findings of episcleritis are also mixed.
Posterior scleritis is often diagnosed late because the lesion is located deep in the fundus. It may occur simultaneously in the anterior and posterior segments, or with a time lag. About one-third of posterior scleritis cases are complicated by anterior scleritis, and during the course of posterior scleritis, anterior scleritis is observed in about 70% of cases1). Cases with anterior scleritis are more strongly associated with systemic diseases.
In posterior scleritis, anterior segment findings are scarce, and some patients present only with eye pain, headache, and decreased vision. Fundus findings such as choroidal folds and exudative retinal detachment are often definitively diagnosed only after B-mode ultrasonography reveals the T-sign or OCT shows choroidal thickening 1). It may also be mistaken for a choroidal tumor, so a comprehensive differential diagnosis is important.
Up to 50% of scleritis cases are associated with systemic autoimmune diseases. If the underlying systemic disease remains untreated, recurrence at the same site of the sclera is not uncommon. Necrotizing scleritis is often caused by rheumatic diseases, vasculitis, and hematologic disorders.
Collagen Vascular / Rheumatic Diseases
Rheumatoid arthritis (RA): The most frequently associated systemic disease. It can cause necrotizing scleritis and scleromalacia perforans. It is typical in patients on long-term treatment.
Systemic lupus erythematosus (SLE): Can be complicated by anterior scleritis.
Relapsing polychondritis: Can involve both anterior and posterior scleritis, with repeated remissions and exacerbations.
Vasculitis and Others
Granulomatosis with polyangiitis (GPA): Associated with necrotizing scleritis and scleromalacia perforans, leading to a severe course. As an ANCA-associated vasculitis, ocular involvement may be the initial manifestation 3).
Takayasu arteritis: Rarely complicated by scleritis, and may be the clue to diagnosing systemic vasculitis 4).
Polyarteritis nodosa (PAN): Can be complicated by necrotizing scleritis.
Other reported associations include sarcoidosis, Behçet’s disease, Crohn’s disease, ulcerative colitis, psoriatic arthritis, scleroderma, dermatomyositis, SAPHO syndrome, thyroid disease, aortitis syndrome, interstitial nephritis, Vogt-Koyanagi-Harada disease, and multiple sclerosis. Many patients with nodular scleritis have a history of herpes zoster ophthalmicus. Posterior scleritis may rarely present as an ocular manifestation of systemic lymphoma or multiple myeloma, requiring caution.
Infectious scleritis accounts for only 5–10% of all cases, but has an extremely poor prognosis 7). Approximately 50% of patients with infectious scleritis lose functional vision, and about 27% require enucleation or evisceration 7).
Most cases of infectious scleritis are caused by exposed sutures or scleral buckle materials after ophthalmic surgery, and are unilateral.
Ophthalmic surgery can trigger necrotizing scleritis. Typical triggers include pterygium surgery, cataract surgery, scleral buckling, strabismus surgery, and trabeculectomy. It occurs particularly frequently after pterygium excision with mitomycin C. The onset period ranges from a few days to several years after surgery, and cases occurring several years postoperatively are not rare.
The antimetabolites mitomycin C (MMC) and 5-fluorouracil (5-FU) have been used to prevent recurrence after pterygium surgery and to prevent scarring of glaucoma filtering blebs. MMC eye drops can cause scleral calcification or perforating scleral malacia months to years after use, so their use as eye drops was discontinued in the 1980s. Current glaucoma and pterygium surgeries mainly use a single intraoperative short-term application of low-concentration MMC (0.02–0.04%). However, postoperative pallor, vascular narrowing, and avascular zones may appear at the surgical site, which can predispose to future scleral malacia.
Rheumatoid arthritis is the most common, followed by other autoimmune diseases such as granulomatosis with polyangiitis (GPA), systemic lupus erythematosus, polyarteritis nodosa, relapsing polychondritis, Takayasu arteritis, and sarcoidosis. Up to 50% of scleritis patients have some systemic disease. In necrotizing scleritis, the rate of associated rheumatic disease, vasculitis, or hematologic disease is even higher.
The following tests are performed to search for systemic diseases.
In necrotizing scleritis or refractory cases, investigation for ANCA-associated vasculitis is particularly important 3). In regions with a high prevalence of tuberculosis, a tuberculin skin test should be performed before systemic treatment in scleritis resistant to topical steroid therapy.
Treatment of scleritis is primarily with steroids, and a stepwise combination of topical therapy, systemic therapy, immunosuppressants, biologics, and surgical treatment is used depending on the type and severity. In cases with systemic disease, collaboration with rheumatology and collagen disease specialists is essential.
Oral NSAIDs (first-line)
Indication: Initial treatment for mild to moderate diffuse or nodular scleritis.
Example prescription: Celecoxib (COX-2 inhibitor) 100 mg twice daily, or indomethacin 50 mg three times daily. Often highly effective for pain and also useful for controlling inflammation.
Caution: Watch for gastrointestinal bleeding, renal dysfunction, and asthma attacks. If there are no contraindications such as asthma, use actively from the beginning.
Topical Steroid Therapy
Eye drops: Use 0.1% betamethasone sodium phosphate eye drops 4–6 times daily. Depending on the case, combine with betamethasone–fradiomycin ointment applied before sleep.
Subconjunctival injection: Triamcinolone acetonide 40 mg/mL, 0.1 mL once (up to once a month), or dexamethasone 3.3 mg/mL, 0.3 mL once, every 1–2 weeks for several times.
Caution: In necrotizing scleritis, avoid injecting into thin areas.
Systemic Steroid Therapy
Oral: Prednisolone 0.5–1 mg/kg/day (in mild cases where NSAIDs are ineffective, start with 20–30 mg divided into two doses and taper; in severe nodular, necrotizing, or posterior scleritis, start with 30–60 mg/day and taper).
Pulse therapy: Methylprednisolone 1,000 mg/day intravenously for 3 days, followed by tapering. Indicated for necrotizing scleritis and severe cases.
Caution: Tapering usually takes 1–2 weeks or more; in severe cases, continue over 2–3 months.
Immunosuppressants and Biologics
Cyclosporine: Start at 5 mg/kg/day divided into two doses orally, adjust trough level to around 100–150 ng/mL. Monitor renal function with regular blood tests.
Choice when systemic disease is present: Methotrexate is often chosen for rheumatoid arthritis, cyclophosphamide for systemic lupus erythematosus or systemic vasculitis. Azathioprine is less effective for scleritis.
Biologics: There are reports of using infliximab (anti-TNF-α antibody, Remicade®) and rituximab (anti-CD20 antibody, Rituxan®) in refractory cases3).
Treatment is initiated primarily with oral NSAIDs and 0.1% betamethasone eye drops. If the response is insufficient, immunosuppressive eye drops are added. If still inadequate, subconjunctival injection of 0.3 mL dexamethasone or 0.1–0.2 mL triamcinolone acetonide is performed, avoiding areas of scleral thinning. If local treatment is poorly effective, a tapering regimen of prednisolone 20–30 mg/day is continued for 1–2 weeks.
Because scleral thinning and perforation can occur in a short period, oral prednisolone 0.5–1 mg/kg/day is started from the initial treatment. For cases that respond poorly to oral steroids or have repeated relapses, the optimal immunosuppressive agent for the associated systemic disease is selected in collaboration with a rheumatologist. When cyclosporine 5 mg/kg/day in two divided doses is used, the blood trough level is adjusted to 100–150 ng/mL. Cyclosporine is contraindicated for scleritis associated with neuro-Behçet disease because it may worsen neurological symptoms. In severe cases, pulse therapy with methylprednisolone 1,000 mg/day intravenously for 3 days is performed after thoroughly ruling out infectious causes.
For scleritis resistant to immunosuppressive therapy, introduction of biologic agents is considered. TNF-α inhibitors have shown efficacy for sclerouveitis, but not all are effective for scleritis; etanercept has been reported to induce or exacerbate ocular inflammation including scleritis as a paradoxical reaction. Use of immunosuppressants and biologics requires systemic examination before and after initiation and collaboration with internal medicine.
Systemic administration of corticosteroids is the mainstay of treatment. Prednisolone is started at 30–50 mg/day and tapered, divided into 2–3 doses for pain control. If anterior segment inflammation is present, corticosteroid eye drops are used concomitantly. If oral therapy does not achieve inflammation control, steroid pulse therapy is performed after thoroughly ruling out infectious causes. If pulse therapy is ineffective or relapse occurs during tapering, active use of immunosuppressive agents is considered. Examples include azathioprine 1–2 mg/kg and methotrexate (Rheumatrex®) 6 mg/week. Necrotizing scleritis may require cyclophosphamide pulse therapy, and collaboration with an internist is particularly important.
Sub-Tenon triamcinolone acetonide injection (STTA) is also used for posterior scleritis, but there is a rare risk of circulatory disturbance of the optic nerve and retinochoroid6). In elderly patients with vascular fragility or glaucoma, careful indication is necessary6).
In infectious scleritis, antimicrobial therapy based on identification of the causative organism and its sensitivity is fundamental2)7).
Necrotizing scleritis or perforating scleral malacia, and infectious scleritis unresponsive to medical treatment are indications for surgery. If scleral necrosis or malacia extends beyond a certain area, it becomes difficult to restore normal eye shape and maintain visual function, so early surgery while the necrotic area is still small is desirable.
The key points of surgery are the following three:
When extensive conjunctival necrosis or peripheral corneal ulcer is present, autologous conjunctival graft from the other eye or corneal epithelial transplantation is combined. Postoperative treatment includes oral cyclosporine and 1% Sandimmun® eye drops (hospital preparation) to promote graft survival and prevent recurrence of scleritis. Even in scleral malacia after MMC or 5-FU use, given the lack of confirmed efficacy of immunosuppressive eye drops or biologics, early preserved scleral grafting should be performed while the softened area is still small.
During long-term steroid and immunosuppressive therapy, it is necessary to regularly monitor intraocular pressure, liver and kidney function, blood glucose levels, and blood cyclosporine concentration. If blood glucose is elevated, systemic management in collaboration with an internist may be required, with steroid therapy under insulin use. For eye pain, analgesic and anti-inflammatory drugs are administered. Since scleritis may be triggered by infection or infectious allergy, initial treatment for first episodes should also include antibiotic eye drops and oral antibiotics.
Infectious scleritis has a poor prognosis, and early administration of antibiotics based on identification and sensitivity of the causative organism is essential. In Pseudomonas aeruginosa infection, the disease progresses rapidly, so prompt aggressive antibiotic therapy and surgical debridement are necessary 7). If exposed sutures or buckle materials are the cause, they should be removed promptly. Steroids carry a risk of exacerbating infection, so they should be used cautiously when infection is possible.
The sclera is a fibrous tissue with poor vascularity, and the incidence of deep scleritis is low. However, because the sclera has innervation, once inflammation occurs, it causes severe eye pain. The sclera is thinnest at the rectus muscle insertion, about 0.3 mm, and is a common site for necrosis and perforation. Since the sclera lacks a barrier structure, drugs injected subconjunctivally or into Tenon’s capsule can reach the intraocular space by diffusion, which is why subconjunctival steroid injection is a treatment option.
The pathology of scleritis associated with autoimmune diseases is characterized by zonal granulomatous necrosis. The center of the granuloma contains fibrinoid material, surrounded by epithelioid cells and multinucleated giant cells.
In scleritis, infiltration of inflammatory cells including T cells and macrophages increases. T cells and macrophages infiltrate the deep episcleral tissue, and clusters of B cells form around blood vessels. The increased expression of HLA-DR and IL-2 receptors on T cells suggests the involvement of cell-mediated immune responses.
Plasma cells are involved in the production of matrix metalloproteinases (MMPs) and TNF-α. In necrotizing scleritis, vasculitis with fibrinoid necrosis is observed, with neutrophil infiltration into the vessel walls. The pathogenesis of endogenous scleritis is suggested to involve immune mechanisms centered on cell-mediated immune responses.
A case series of 8 patients who developed posterior scleritis after COVID-19 vaccination or infection and were referred with a misdiagnosis of choroidal melanoma has been reported5). The average interval from the last vaccination to onset was 132 days, and from COVID-19 infection to onset was 14 days5). Most cases resolved spontaneously within 2 months, with minimal impact on vision5).
Cases have been reported where rituximab (anti-CD20 antibody) was effective for both induction and maintenance of remission in ANCA-associated necrotizing scleritis resistant to conventional immunosuppressive therapy (steroids + cyclophosphamide)3). Long-term follow-up studies are accumulating on the efficacy of rituximab for ocular lesions in granulomatosis with polyangiitis type of ANCA-associated vasculitis3).
There are reports of scleritis as an ocular manifestation of Takayasu arteritis, and attention is needed as it may be a diagnostic clue for systemic aortic inflammatory syndrome4). In young women with necrotizing scleritis, it is important to rule out Takayasu arteritis.
A case series of posterior scleritis after COVID-19 vaccination or infection has been reported5). However, a causal relationship has not been proven, and most cases follow a course of spontaneous resolution. COVID-19-related posterior scleritis may be mistaken for choroidal tumors, and recognition as a differential diagnosis is important5).
