Update on scleritis diagnosis and management: a narrative review

Introduction

Scleritis is a painful and potentially vision-threatening inflammatory disease of the sclera. It may arise idiopathically or be associated with systemic autoimmune disorders, most notably rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), relapsing polychondritis, and systemic lupus erythematosus (SLE), among others (1,2). Roughly half of cases are idiopathic, while autoimmune conditions account for around 40% of cases (3). Rarely, scleritis may be caused by other non-infectious processes, including malignancy, medication side-effects, or surgical trauma (1,2). It may also occur as a result of an infectious process, accounting for approximately 5–10% of cases (4).

Scleritis is a rare condition, with an estimated incidence ranging between 3.4 and 6.0 cases per 100,000 person-years and an estimated prevalence of approximately 5.2 per 100,000 individuals (5,6). It has a slight female predominance of 60–74% (5,7). Most patients are diagnosed between the ages of 40 and 60 years (5,7). Few pediatric cases have been reported, which are often severe and associated with systemic autoimmune disease (8).

Autoimmune scleritis is clinically classified into anterior and posterior forms, with anterior disease further subdivided into diffuse, nodular, and necrotizing subtypes (9). The diffuse and nodular forms are most common. Necrotizing scleritis is rare and carries the highest risk of ocular morbidity and mortality, particularly when associated with systemic vasculitis (2,9). Posterior scleritis is the less common form, accounting for 8–10% of autoimmune-mediated scleritis cases (1,10). However, it is frequently underdiagnosed due to its variable and sometimes subtle presentation (10).

Infectious scleritis, accounting for 5–10% of all scleritis cases, is most commonly caused by bacteria (Pseudomonas aeruginosa, Staphylococcus aureus), fungi (Aspergillus, Fusarium), mycobacteria, or herpesviruses. It is especially important to distinguish from immune-mediated disease given the need for antimicrobial therapy rather than immunosuppression (4).

The characteristic clinical feature of scleritis is severe, boring ocular pain that may radiate to the temple, brow, or jaw, often worsening at night and with eye movement. Associated findings include scleral edema, violaceous hue of the globe, episcleral vessel congestion that does not blanch with topical vasoconstrictors, thinning of the sclera and uveal exposure in advanced cases (1). Complications may include keratitis, uveitis, glaucoma, cataract, exudative retinal detachment, and even globe perforation, making timely recognition and treatment critical (1,2). Given the high rate of systemic disease association, a diagnosis of scleritis warrants careful systemic evaluation in collaboration with rheumatology and other subspecialists.

Management depends on severity, underlying etiology, and systemic associations. First-line approaches for autoimmune scleritis often include systemic corticosteroids and conventional immunomodulatory agents (11-13). Biologic therapies have emerged as effective options for refractory disease (14-17). Infectious scleritis requires targeted antimicrobial therapy, often combined with surgical debridement (4).

Although retrospective studies, case series, and uncontrolled clinical trials have provided insight into management strategies, there remains a lack of large, randomized, controlled studies to establish standardized treatment algorithms. Therapeutic decisions remain guided largely by clinician expertise, institutional experience, and underlying systemic conditions. Though traditional therapies such as steroids and conventional immunomodulators are still widely used, biologics, biosimilars, and novel treatment paradigms are rapidly changing the management landscape.

Several previous reviews have summarized the epidemiology, clinical features, and management of scleritis, most of which primarily focused on conventional immunosuppressive strategies or the general classification of scleritis (12,13,18,19). To our knowledge, there has been no updated comprehensive treatment paradigm for non-infectious scleritis published in the literature since 2022 (13). Furthermore, many reviews focus on either non-infectious or infectious scleritis, or one specific component of the treatment paradigm. This comprehensive updated review is therefore needed to synthesize new evidence, highlight the evolving landscape, and provide a mechanism-driven perspective that incorporates recent advances in the treatment of scleritis. Additionally, this review includes photos from our patients for clinical correlation with topics discussed. We present this article in accordance with the Narrative Review reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-2025-1-68/rc).

Methods

A structured narrative review of the literature was conducted to summarize current knowledge on the diagnosis, immunopathogenesis, systemic associations, and management of autoimmune and infectious scleritis. The PubMed/MEDLINE database was queried for peer-reviewed literature relevant to scleritis and related inflammatory scleral disorders. Search strategies incorporated a combination of free-text keywords and medical subject headings (MeSH) to ensure comprehensive thematic coverage.

Primary search terms included “scleritis”, “anterior scleritis”, “posterior scleritis”, “nodular scleritis”, “necrotizing scleritis”, “infectious scleritis”, and “autoimmune scleritis”. These were combined using Boolean operators (AND/OR) with secondary terms such as “rheumatoid arthritis”, “granulomatosis with polyangiitis”, “vasculitis”, “immunopathogenesis”, “diagnosis”, “imaging”, “treatment”, “management”, “immunomodulatory therapy”, “biologics”, “TNF inhibitors”, “rituximab”, “biosimilars”, “surgical management”, and more. Truncation operators (e.g., *) were used when appropriate to capture variations in terminology (Table 1).

The search was limited to publications accepted between January 1970 and May 2025, reflecting both foundational landmark studies and contemporary advances in imaging, immunology, and therapeutic approaches. Because this review is narrative rather than systematic, inclusion criteria were based on relevance to clinical presentation, diagnostic evaluation, systemic disease associations, and evolving management strategies for scleritis. Priority was given to original research articles, clinical trials, cohort studies, high-quality systematic reviews, consensus guidelines, and influential case series that shaped current clinical practice.

No language filters were used. Reference lists of published articles were hand-searched to identify additional studies not captured through database searches. Clinical trials and interventional studies were identified using ClinicalTrials.gov by searching under the condition “scleritis” and manually selecting for relevant trials.

When multiple publications addressed similar topics, preference was given to the most recent and methodologically rigorous studies. Data from heterogeneous sources, such as retrospective cohorts, prospective observational studies, randomized trials when available, and expert consensus statements, were synthesized qualitatively. Tables and figures were constructed to summarize classification systems, diagnostic criteria, complications, infectious etiologies, and emerging therapeutic approaches. No formal meta-analysis or quantitative synthesis was performed, consistent with the narrative design of this review.

Immunopathogenesis

Scleritis is characterized by immune dysfunction, with both humoral and cellular mechanisms contributing to scleral inflammation and tissue destruction. The structure of the sclera includes an extracellular matrix of collagen, elastin, and proteoglycans that resemble the makeup of joints, causing it to be susceptible to inflammatory conditions.

In autoimmune scleritis, immune complex deposition and complement activation lead to vascular injury and scleral necrosis (1). Autoreactive B cells produce pathogenic autoantibodies that deposit in scleral tissue, leading to complement activation and recruitment of neutrophils and macrophages (20). B-cell-mediated autoimmunity is increasingly recognized in autoimmune scleritis, supported by the clinical efficacy of B-cell-depleting therapy such as rituximab (20). T-cell activation also contributes to scleral inflammation. Activated CD4⁺ T cells infiltrate scleral tissue and secrete proinflammatory cytokines, including interferon-γ, interleukin (IL)-17, and tumor necrosis factor-α (TNF-α) (20). The involvement of Th17 cells and their downstream cytokine IL-17 suggest overlap with other systemic autoimmune vasculitides (21). The role of TNF-α in pathogenesis is supported by the therapeutic success of TNF-α inhibitors in refractory scleritis (14,15). These inflammatory mediators activate fibroblasts within the scleral stroma, leading to increased matrix metalloproteinase (MMP) activity, collagen degradation, and scleral thinning (22).

Genetic predisposition is less well defined in scleritis than in other ocular autoimmune diseases, though associations with human leukocyte antigen HLA-B27 and HLA-DR4 have been reported (23).

Infectious triggers may also lead to scleritis, with microbial antigens inducing a secondary immune response which may mimic the presentation of autoimmune scleritis (24). The pathogenesis of infectious scleritis is distinct, in that pathogens directly invade the avascular scleral stroma. Prior trauma, surgery, or systemic immunosuppression may trigger a robust neutrophil-dominated inflammatory response, allowing for invasion (24). Microbial toxins, enzymes, and biofilm formation further promote scleral necrosis and thinning (24). Unlike autoimmune scleritis, infectious scleritis represents a combined process of direct pathogen-mediated destruction and host inflammatory response.

Thus, the immunopathogenesis of scleritis can be characterized by either autoimmune inflammation driven by dysregulated B- and T-cell responses, or microbial invasion of scleral tissue. Both ultimately result in destruction and remodeling of the sclera, mediated by cytokine networks, neutrophil activation, and MMP-driven collagen degradation. Histopathologic studies demonstrate vasculitis with fibrinoid necrosis of scleral vessels and perivascular infiltration of lymphocytes, plasma cells, and macrophages. In necrotizing forms, obliterative vasculopathy with tissue ischemia is seen, contributing to structural complications including uveal exposure and risk of perforation (2).

Clinical features

Early recognition and initiation of systemic therapy are crucial in preventing ocular morbidity and vision loss in scleritis. The hallmark symptom is severe, deep, boring ocular pain, often radiating to the temple, brow, or jaw. The pain may worsen at night, waking patients from sleep, or with extraocular movements. In some cases, the pain may precede visible scleral inflammation, leading to delayed recognition or misdiagnosis as episcleritis, conjunctivitis, or sinus-related pain (1). However, scleritis may also present with minimal pain in some cases. Patients may also report redness, tearing, photophobia, and decreased visual acuity.

On examination, anterior and posterior types of scleritis typically differ in clinical presentation. Anterior scleritis generally presents with globe tenderness, scleral edema, and a violaceous hue due to congestion and dilation of deep scleral and episcleral vessels and prominent visibility of underlying uvea (2). Unlike what is seen with episcleritis, the scleral vessels are immobile and do not blanch with topical vasoconstrictors. In nodular scleritis, more localized scleral edema and tender nodules may be present. Necrotizing scleritis, associated with the highest risk of ocular morbidity, is characterized by avascular patches of scleral thinning, exposure of the underlying uvea, and risk of spontaneous globe perforation. Progressive tissue loss is often associated with severe pain and can be life-threatening when linked to systemic vasculitis (2,25). Though less common, scleritis may present posteriorly, manifesting with deep ocular tenderness, decreased vision, exudative retinal detachment, choroidal folds, or optic disc edema (10,26). Posterior scleritis is often under- or misdiagnosed, as it may mimic orbital or retinal pathology, and may be visualized with a B-scan or magnetic resonance imaging (MRI) of the orbits (26).

Once scleritis is diagnosed, careful differentiation between scleritis types is essential for guiding therapy. The Watson and Hayreh system, the most widely used classification system, classifies scleritis into anterior (diffuse, nodular, necrotizing) and posterior forms, based on clinical and imaging findings (Table 2) (1). Because disease progression can be asymmetric, each eye should be evaluated independently. Serial clinical photography, slit-lamp examination in ambient lighting, and imaging, including anterior segment optical coherence tomography (OCT), B-scan ultrasonography, or MRI for posterior involvement, are valuable tools for documenting disease evolution and treatment response (27).

Infectious scleritis may present as any subtype and should especially be considered in patients with a history of ocular trauma or surgery. Surgically induced necrotizing scleritis may occur months to years after inciting surgeries such as pterygium excision with mitomycin C (Figure 5), strabismus, trabeculectomy or retinal surgeries. Therefore, it is important to obtain a detailed ocular history and look for clinical findings suggestive of prior surgeries. Infectious scleritis is typically described by etiology (bacterial, fungal, viral, parasitic), location (anterior, posterior), and morphology (diffuse, nodular, necrotizing). Associated corneal ulcer, scleral necrosis with mucopurulent discharge, or scleral abscess may often be seen at the site of infection (4,28,29).

Figure 5 Infectious necrotizing scleritis. Slit lamp photograph showing culture-positive Pseudomonas aeruginosa necrotizing scleritis nasally in a patient status post pterygium excision many years prior to presentation

If untreated, infectious scleritis can lead to progressive scleral thinning, secondary corneal and intraocular complications, and irreversible vision loss. Necrotizing scleritis associated with systemic vasculitis carries particularly poor prognosis, with increased risk of both ocular morbidity and systemic mortality (25). Thus, prompt recognition, systemic evaluation, and appropriate immunomodulatory or antimicrobial therapy are essential.

Figure 1 Diffuse anterior scleritis. Slit lamp photograph of a patient presenting with severe eye pain, diagnosed with idiopathic diffuse anterior of the right eye (A) Image taken on upgaze. (B) Image taken on downgaze.

Figure 2 Nodular scleritis. Slit lamp photograph of a patient with RA, on methotrexate, presenting with nodular scleritis superior nasally in the left eye. RA, rheumatoid arthritis.

Figure 3 Necrotizing scleritis with inflammation. (A) Slit lamp photographs revealing significant nasal injection with scleral thinning. (B) Satellite lesion superior nasally and adjacent scleral thinning in a patient with no prior history of auto-immune conditions.

Figure 4 Necrotizing scleritis without inflammation. (A) Slit lamp photographs of a patient presenting with no eye pain showing circumferential scleromalacia with uveal show of the right eye. (B) Focal area of thinning nasally.

Complications

Scleritis can result in significant ocular morbidity due to severe inflammation and tissue necrosis. A wide range of complications may occur depending on severity and associated conditions. Chronic or necrotizing disease may lead to scleral thinning or melting, with progression to scleral ectasia, staphyloma, perforation, and possible globe deformation and rupture. Adjacent structures, including the cornea and anterior chamber, may be involved, causing keratitis, corneal thinning, uveitis, or cataract. Ocular hypertension may occur, leading to secondary glaucoma (1). Vitritis, macular edema, and exudative retinal detachment (Figure 6) are also potential complications, most commonly due to chronic posterior disease (10).

Figure 6 Inferior exudative retinal detachment. Fundus photograph from the same patient shown in Figure 1A,1B, demonstrating inferior exudative retinal detachment in setting of idiopathic anterior diffuse scleritis. Resolution was achieved after treatment with oral prednisone and methotrexate.

Possible complications of scleritis:

• Decreased visual acuity;
• Scleral thinning;
• Keratitis (peripheral ulcerative keratitis, interstitial keratitis);
• Peripheral corneal thinning;
• Anterior uveitis;
• Cataract;
• Ocular hypertension;
• Glaucoma;
• Vitritis;
• Cystoid macular edema;
• Exudative retinal detachment;
• Globe deformation.

Diagnosis and stratification

The diagnosis of scleritis and monitoring of disease progression and treatment response are based primarily on clinical features, with attention to scleral appearance on physical exam and ocular pain as described by the patient.

To describe the severity of scleritis, Sen et al. developed a standardized grading system to standardize research and clinical care (Table 3). Following the application of 10% phenylephrine, scleral inflammation may be described with an ordinal scale from 0 (none) to +4 (necrotizing) (30).

Laboratory tests, imaging, and scleral biopsies are not essential to diagnose scleritis, but they are essential to identify associated systemic diseases and differentiate between types of scleritis to guide management approach.

Laboratory investigations

In some cases, scleritis may be the first symptomatic manifestation of an underlying autoimmune, systemic, or infectious process. In 7–18% of cases, the patient manifests with a systemic disease after the onset of scleritis (3). When an underlying cause of scleritis is not identified from a patient’s history, the following relevant laboratory evaluations are performed.

• General and inflammatory markers:
• Complete blood count with differential;
• Basic metabolic panel;
• Liver function test;
• Erythrocyte sedimentation rate;
• C-reactive protein;
• Autoimmune and systemic disease evaluation:
• Antinuclear antibody—evaluation for SLE;
• Rheumatoid factor—evaluation for RA;
• Anti-cyclic citrullinated peptide antibody—evaluation for RA;
• Anti-neutrophil cytoplasmic antibodies [ANCAs, including proteinase 3 (PR3) and myeloperoxidase (MPO)]—evaluation for GPA;
• HLA-B27—evaluation for spondyloarthropathy;
• Infectious serologies:
• Syphilis serology;
• Lyme disease serology;
• QuantiFERON;
• Herpes simplex virus (HSV) types 1 and 2;
• Sarcoidosis evaluation:
• Serum angiotensin-converting enzyme;
• Serum lysozyme;
• Urinalysis—assessment for renal involvement or systemic vasculitis.

Imaging

Imaging modalities are tailored to the subtype and severity of disease. B-scan ultrasonography is essential for diagnosing posterior scleritis, revealing scleral or choroidal thickening, classic T-sign, optic nerve involvement, choroidal folds, or exudative retinal detachment (10,12). MRI of the orbits may be performed if the B-scan is non-conclusive, or if optic neuritis is suspected based on clinical exam (27). Computed tomography (CT) of the orbits can be considered to rule out other orbital pathologies (27). Anterior segment OCT can detect scleral thickening, and macular OCT can reveal associated macular edema or subretinal fluid (31,32). Fluorescein and indocyanine green angiography may be employed to visualize areas of necrosis (9). Lastly, chest X-ray or CT of the chest without contrast may be performed when there is high clinical suspicion for sarcoidosis (7).

Microbiologic testing

Scrapings for smear, bacterial and fungal culture, and polymerase chain reaction (PCR) from sclera, episcleral, conjunctiva, or cornea should be obtained when infectious etiology is considered (33).

Histology

Scleral biopsy is not often performed and is reserved for atypical, antimicrobial-resistant, or culture-negative cases to rule out other inflammatory conditions, neoplasm, or sarcoidosis. Pathology results may reveal necrosis, vascular occlusion, and inflammatory infiltrates including macrophages and T cells (34).

Related underlying conditions

Autoimmune scleritis underlying conditions (in order of prevalence) (3):

• RA;
• GPA;
• Relapsing polychondritis;
• SLE;
• Polyarteritis nodosa;
• Sjögren’s syndrome;
• Mixed connective tissue disease;
• Inflammatory bowel disease;
• Psoriatic arthritis;
• Sarcoidosis;
• Immunoglobulin G4 (IgG4)-related disease.

Differential diagnosis

Several conditions can mimic scleritis, making accurate diagnosis essential. Scleritis may be mistaken for episcleritis, which is defined by inflammation of the superficial episcleral plexus only and may present with redness, discomfort and foreign body sensation (2). To distinguish between the two, a topical vasoconstrictor (typically 2.5% or 10% topical phenylephrine) is applied. The vessels will blanch with episcleritis, but not with scleritis (1,2). This distinction is clinically important, as episcleritis is typically self-limited, while scleritis requires systemic immunosuppressive or antimicrobial therapy (2).

Other potential mimickers include conjunctivitis, keratitis, orbital inflammation, conjunctival lesions, foreign body and referred ocular pain.Accurate differentiation relies on assessment of pain severity, depth of redness, ocular findings, and response to therapy (1,9). Imaging (B-scan, anterior segment OCT) and laboratory evaluation aid in excluding mimickers.

Management

Treatment of scleritis requires stratification by etiology (autoimmune vs. infectious), severity (mild vs. moderate vs. necrotizing), and anatomic subtype (anterior vs. posterior). Early distinction between infectious and non-infectious causes is essential because immunosuppression can worsen infectious disease (24).

Immune-mediated scleritis

Stepladder approach

1^st line: nonsteroidal anti-inflammatory drugs (NSAIDs)

Clinical practice and cohort data support starting treatment for mild to moderate non-necrotizing anterior scleritis with NSAIDs (7,12,13). Comparative randomized controlled trials are limited, and recommendations are largely based on consensus, endorsed in major ocular inflammation reviews and clinical guidelines. Common agents include naproxen (500 mg twice daily), indomethacin (25–50 mg three times daily), and ibuprofen (600–800 mg three to four times daily) (11,35). Naproxen is often the first NSAID tried, though choice may reflect local practice and tolerability. Patients who fail to respond may try switching to another NSAID before escalating therapy. If symptoms persist after an adequate trial (commonly 1–2 weeks), escalation is indicated. Observational series show a minority of patients respond to NSAIDs alone (~30–50%), and many require escalation to systemic steroids or immunomodulatory therapy (IMT) (11,36). Even if NSAIDs alone are able to provide adequate disease control, long-term use may be limited by gastrointestinal, renal, or cardiovascular adverse effects. Patients unable to tolerate one NSAID may need trial of an alternative prior to escalation (37).

2^nd line: corticosteroids

Systemic corticosteroids are the next line of therapy if NSAIDs are inadequate. They are also considered the first-line therapy for acute immune-mediated necrotizing scleritis, often in combination with or rapidly followed by systemic immunosuppressive therapy.

Oral prednisone is commonly initiated at 1 mg/kg, with doses ranging from 40 to 60 mg daily, with gradual tapering by 10 mg once inflammation is controlled (11,37). In cases of severe immune-mediated scleritis, intravenous methylprednisolone sodium succinate (e.g., 1 g/day for 1–3 days) followed by an oral prednisone taper may be employed to gain rapid control (11,37). If no improvement is seen by one month or if inflammation is not fully controlled or recurrence of scleritis is noted with steroid tapering, then treatment should be escalated to IMT with anti-metabolites or biologic agents for long-term management.

Though systemic corticosteroids offer potential for rapid control, prolonged use may lead to significant systemic side effects, including hypertension, diabetes, osteoporosis, and increased infection risk (7,11,36). Patients should be thoroughly counseled about these potential risks and monitored carefully in collaboration with primary care.

Topical corticosteroids, such as difluprednate 0.05% or prednisolone acetate 1%, may sometimes be used as adjunctive therapy (11). Difluprednate is typically preferred as the more effective option of the two. However, given limited scleral penetration, topical corticosteroid monotherapy is typically insufficient for treatment of scleritis (11,38).

Sub-Tenon (periocular) triamcinolone steroid injections can also be used to treat non-necrotizing anterior scleritis as an adjunct or steroid-sparing strategy in patients with severe comorbidities who are not eligible for systemic treatment (38,39). Although earlier reports raised concern about scleral thinning and perforation, more recent studies suggest improved safety when carefully avoided in necrotizing scleritis cases or actively infected eyes (11,38).

3^rd line: immunosuppressive agents

Steroid-sparing IMT is recommended in severe and refractory cases, or when long-term corticosteroid use is contraindicated. Methotrexate (10–25 mg weekly, oral or subcutaneous) is the most commonly prescribed antimetabolite, typically combined with folic acid supplementation. Retrospective cohorts and pilot studies have reported improved disease control and potential for steroid reduction (40,41). Mycophenolate mofetil (1–3 g/day) is an alternative for patients refractory to or intolerant of methotrexate, supported by robust cohort data (15,42).Azathioprine (1–2.5 mg/kg/day) is another alternative, of particular importance when methotrexate is contraindicated for patients with hepatic dysfunction or women of childbearing potential, given its proven safety in these populations (14). Though less commonly used, calcineurin inhibitors such as cyclosporine or tacrolimus remain options for refractory disease.

Each immunosuppressive agent has unique advantages and limitations. Methotrexate offers effective steroid-sparing control but carries hepatotoxicity and teratogenic risks (40,41). Mycophenolate may be preferred in methotrexate-intolerant patients but can cause gastrointestinal side effects and leukopenia (14,15). Azathioprine is generally safe in select populations but requires monitoring for myelosuppression (7,11). Calcineurin inhibitors can be effective in refractory disease but require frequent monitoring due to nephrotoxicity (7,11). Close monitoring of patients on immunomodulators is needed to assess for tolerance and possible side effects.

Several other agents are known to have some efficacy in the treatment of scleritis but are not routinely used. Historically, alkylating agents such as cyclophosphamide were used in severe vasculitis-associated cases such as GPA; however, their use has declined due to toxicity and the emergence of biologic agents (41,43). In 2014, an open-label prospective study showed that sirolimus [mammalian target of rapamycin (mTOR) inhibitor] subconjunctival injections have potential for reducing scleral inflammation, though recurrences occurred requiring reinjection (44).

4^th line: biologic therapies

Biologic therapies are increasingly utilized in refractory or systemic autoimmune-associated scleritis. TNF-α inhibitors such as adalimumab and infliximab have demonstrated efficacy, particularly in RA-associated and refractory scleritis, with some patients showing dramatic clinical improvement (Figure 7). Multiple case series, systematic reviews, and meta-analyses have shown benefit and rapid disease control (45-48). Adalimumab is administered subcutaneously with a loading dose, followed by 40 mg every other week. The interval may be decreased to weekly dosing if no improvement is noted. Infliximab is administered intravenously at a starting dose of 5 mg/kg every 4 weeks followed by maintenance infusions. The dosing and time intervals may be adjusted based on clinical response. The patient may receive these infusions at infusion centers or at home infusions with appropriate nursing care. Because many scleritis patients may already have an underlying autoimmune diagnosis, they may already be on biologic therapy. In such cases, therapy choice should be optimized for ocular outcomes. Patients previously on etanercept for RA are often transitioned to adalimumab or infliximab given their efficacy for both ocular and joint-related disease manifestations.

Figure 7 Slit lamp photograph from the same patient with rheumatoid scleritis and nodular scleritis shown in Figure 2 after addition of infliximab infusions to weekly oral methotrexate, showing complete resolution of nodular scleritis and localized area of scleromalacia.

Rituximab (administered intravenously at a dose of 1,000 mg on days 1 and 15, with repeat infusion every 6 months based on clinical response) is an anti-CD20 agent, which has shown promising results, particularly in severe, necrotizing, or GPA-associated scleritis. Case series and small prospective cohorts demonstrate success in refractory or GPA-associated scleritis. Comparative studies of rituximab vs. cyclophosphamide in systemic ANCA-vasculitis support rituximab for induction of remission in vasculitis with ocular involvement (17,43,49,50).

Several TNF-α inhibitor and rituximab biosimilars have been approved in the United States (adalimumab-atto, adalimumab-abda, adalimumab-adbm, adalimumab-aqvh, infliximab-dyyb, infliximab-abda, infliximab-axxq, rituximab-abbs). However, data on biosimilar effectiveness for ocular endpoints is currently limited, and the utility of biosimilars for scleritis is under active investigation. Observational studies have shown biosimilars to be safe and effective in non-infectious uveitis, however, the role of biosimilars in scleritis management needs to be further explored (51,52). Further research is needed to determine comparative efficacy and cost-effectiveness in this specific clinical context.

Other biologics common in the treatment of RA have been noted as effective for inflammation control and steroid sparing for refractory non-infectious scleritis, though evidence remains sparse. Tocilizumab (IL-6 inhibitor) and abatacept (recombinant fusion protein) have been noted as effective for inflammation control and steroid sparing in retrospective case series (53,54). Gevokizumab (anti-IL-1β) has been shown to reduce inflammation in a phase I/II open-label trial (55). Janus kinase (JAK) inhibitors such as tofacitinib, baricitinib, and upadacitinib have had promising outcomes in small retrospective case series, and tofacitinib is currently being further investigated in a phase II trial (56-58).

5^th line: surgical intervention

Surgical intervention may be required in necrotizing scleritis with scleral melt or perforation once inflammation is adequately controlled. Procedures include scleral patch grafting or tectonic reinforcement to preserve globe integrity (59).

Infectious scleritis

Infectious scleritis can result from a variety of bacterial, viral, fungal, or parasitic organisms, each with potentially distinct clinical features (Table 4). Infectious scleritis requires prompt initiation of pathogen-specific antimicrobial therapy. It is important to distinguish infectious scleritis from autoimmune scleritis early on to avoid using immunosuppressive therapy in infectious disease (24). Initiation of therapy should proceed in parallel with diagnostic testing in suspected infectious cases.

A high level of suspicion for an infectious cause should be maintained in patients with prior trauma, ocular surgery, necrotizing disease, or immunosuppressant-refractory disease (4). Key clinical features suggesting infection include scleral necrosis, hypopyon, unifocal or multifocal scleral abscesses, and mucopurulent discharge (4). Important historical clues include previous ocular surgery (especially pterygium excision, cataract, and vitreoretinal surgeries), ocular trauma, poor contact lens hygiene, eye-whitening procedures, and subtenon triamcinolone injections (4).

Diagnostic testing is essential before excluding infection. Scleral biopsy with culture and histopathology, which remains the gold standard for microbiological diagnosis. Common pathogens include Pseudomonas aeruginosa, fungi, and HSV. Other organisms include Nocardia, Actinomyces, Haemophilus, and gram-positive cocci. Tuberculosis-related scleritis should be considered in recurrent cases with positive QuantiFERON testing, particularly when associated with prior uveitis (4,29).

Bacterial scleritis is treated with topical, subconjunctival, oral, and intravenous antibiotics. Topical fortified antibiotics are first line, often combined with subconjunctival injections. When infectious scleritis is suspected, topical fortified broad-spectrum antibiotics will be initiated immediately (e.g., cefazolin 50 mg/mL, tobramycin 14 mg/mL, vancomycin 25 mg/mL) and then will be modified depending on smear results and culture sensitivity results (4,29). Frequent dosing (hourly) is often required. Topical antibiotic agents may be combined, and subconjunctival antibiotic injections may be initiated concurrently in severe or necrotizing cases. If no improvement is noted, or in necrotizing or refractory cases, systemic oral antibiotics may be added to the regimen. In severe cases or immunocompromised patients, patients may be admitted for intravenous antibiotic administration (4,29). An example of the resolution of necrotizing scleritis following targeted antibiotic therapy is shown in Figure 8.

Figure 8 Resolution of necrotizing scleritis due to Pseudomonas aeruginosa. Slit lamp photograph of the same patient shown in Figure 5 after treatment with fortified tobramycin drops, subconjunctival ceftazidime injections and systemic antibiotics including intravenous cefepime followed by oral ciprofloxacin. Scleral injection and necrosis have resolved and nasal area of scleromalacia is visualized.

Viral scleritis, most frequently associated with HSV or VZV, is managed with systemic antiviral therapy such as acyclovir or valacyclovir (4,29). A representative case of herpes zoster ophthalmicus (HZO)-associated nodular scleritis is shown in Figure 9.

Figure 9 HZO-associated nodular scleritis. Slit lamp photograph demonstrating nodular scleritis inferior temporally in a patient with history of HZO with vesicular lesions in V1 distribution 1 month prior to scleritis onset. HZO, herpes zoster ophthalmicus.

Fungal scleritis, typically due to Aspergillus, Fusarium, or Candida spp., requires prolonged treatment with topical and systemic antifungals such as natamycin or voriconazole. Subconjunctival injections may be considered in severe cases (4,29).

Antiparasitic therapy is initiated in rare cases of parasitic scleritis based on organism identification, described in case reports (61-66).

In necrotizing scleritis cases, early surgical debridement is recommended to remove devitalized tissue and enhance drug delivery, since antimicrobial penetration into necrotic scleral tissue is limited. Studies support improved outcomes when medical management is combined with surgical intervention (29,66,67).

Prognosis

The prognosis of scleritis is highly variable and depends on the underlying etiology, disease severity, response to therapy, and associated conditions. Early intervention is associated with improved outcomes (1-3). In patients with mild to moderate scleritis who respond well to treatment, visual outcomes are generally favorable (7). Necrotizing scleritis and posterior scleritis carry a higher risk of vision-threatening complications, necessitating more aggressive therapy and close monitoring (9,24,26). Infectious scleritis typically has a guarded prognosis due to delayed diagnosis, scleral necrosis, and limited antimicrobial penetration into avascular scleral tissue (4,28,29).

Close long-term follow-up for at least 2 years is essential for all patients (11,35). For active disease, follow-up may be as frequent as every 2–6 weeks to monitor treatment response and detect complications early. Once scleritis is controlled and there is no evidence of active scleritis, follow-ups may occur every 3 months to monitor for relapse (7). In cases of effective IMT, where scleritis has been controlled for 2 years, patients may gradually be tapered off and followed for any recurrences (37,41,42). It is essential to emphasize to patients the chronic nature of scleritis, and the importance of adhering to treatment plans and follow-up schedules. It is also important to reassess for systemic manifestations for those patients with idiopathic scleritis, since autoimmune conditions may manifest after scleritis onset.

Optimal management frequently requires multidisciplinary collaboration with rheumatology for autoimmune etiologies and infectious disease specialists for infectious scleritis to guide therapy and monitor systemic involvement (6).

Discussion and future directions

Stepladder vs. early biologic therapy: a persistent clinical controversy

The management of immune-mediated scleritis has evolved significantly over the past two decades, reflecting advances in understanding disease pathophysiology and the emergence of novel therapeutics. While corticosteroids and NSAIDs were the primary treatments for immune-mediated scleritis with immunosuppressive therapy reserved for steroid-refractory or necrotizing cases, the “stepladder” paradigm of NSAIDs → systemic corticosteroids → immunomodulators → biologics gradually gained traction and has increasingly been supported by literature in the 2000s and beyond (1,61).

As awareness of long-term complications from systemic corticosteroids increased in the mid 2000s and more emerging data linked scleritis to systemic autoimmune disease, early introduction of steroid-sparing IMT became acceptable (7,11). Increased co-management with rheumatology allowed for focus to shift from suppressing ocular inflammation towards treating the underlying autoimmune cause (46,47).

In the 2010s, biologics became utilized increasingly earlier in management. In particular, anti-TNF agents (adalimumab and infliximab) and later rituximab showed strong efficacy in vasculitic and rheumatoid-associated scleritis (14,15,43). As a result, early targeted immunomodulation became the general approach to autoimmune scleritis (61).

Despite advances in IMT, the optimal sequencing of systemic treatment for severe and necrotizing scleritis remains controversial. Traditional management has favored the “stepladder” paradigm, due to historical practice patterns, cost and safety concerns of biologics, and the lack of randomized controlled trials directly comparing treatment strategies (11,37,43,45,46,61). However, increasing clinical experience and observational data have challenged the adequacy of a delayed escalation strategy, particularly in aggressive necrotizing disease (25,68). In such cases, prolonged reliance on corticosteroids and sequential conventional immunosuppressants may expose patients to cumulative toxicity while allowing ongoing disease progression (15,37,61).

Recent literature increasingly supports a tiered but accelerated step-up approach, sometimes skipping steroids as long-term therapy. Earlier use of biologic agents, most notably tumor necrosis factor inhibitors such as adalimumab, infliximab, and as well as B-cell targeting agents such as rituximab, are increasingly being opted for in patients with rapidly progressive disease or underlying systemic vasculitis (17,43,45,46,48,49,51,69). Proponents of this “top-down” approach argue that early targeted immunomodulation may more effectively suppress pathogenic immune pathways, reduce steroid dependence, and prevent irreversible structural complications (20,48-50). However, in real-world practice, the use of biologic agents is often limited by non-clinical factors such as cost and insurance coverage.

The basis for the “top-down” strategy mirrors evolving treatment paradigms in other immune-mediated inflammatory diseases, such as RA and inflammatory bowel disease, where early biologic intervention has been associated with improved long-term outcomes (6). However, the generalizability of these models to scleritis remains uncertain, given the rarity and heterogeneity of the disease, and evidence supporting early biologic therapy is derived mainly from retrospective cohorts, small case series, and extrapolation from uveitis or systemic autoimmune disease literature (17,43,45,46,51,69). Additionally, biologic therapy carries risks of increased infection rate, malignancy, and immunogenicity, which must be weighed against disease severity and comorbidities (46,48,49). There is a need for head-to-head comparative trials between biologic agents and conventional immunosuppressants. Studies that stratify treatment response based on underlying systemic disease subtypes, such as RA or IgG4-related disease, could facilitate personalized, phenotype-driven treatment paradigms. Furthermore, longitudinal registry-based studies are warranted to define prognostic biomarkers and correlate systemic inflammatory burden with ocular disease course and relapse risk.

The role of biosimilars in the treatment of scleritis

Another major area of need is the evaluation of biosimilars, particularly for TNF-α inhibitors (adalimumab, infliximab) and B-cell-targeting agents (rituximab). Biosimilars approved for immune‑mediated inflammatory diseases have demonstrated comparable effectiveness and safety to their reference biologics in rheumatologic conditions, and real‑world experience in other ocular inflammatory diseases such as non‑infectious uveitis suggests clinical efficacy (4,52,70,71). However, transition to biosimilars are often driven by insurance-mandated cost considerations rather than clinical factors. While biosimilars may broaden access to biologic therapy, high-quality multicenter data are needed to validate their effectiveness, safety, and long-term outcomes in scleritis. Such evidence is critical to inform widespread adoption, particularly in resource-limited settings.

Current state of therapeutic advancement

As shown in Table 5, recent interventional trials in scleritis remain limited in number and scale compared to other ocular conditions, reflecting both the rarity and heterogeneity of the condition.

Since 2016, prospective investigations have been early-phase investigator-initiated studies evaluating biologic and small-molecule immunomodulators and novel delivery of agents in non-infectious scleritis. In 2016, gevokizumab (anti-IL-1β) was shown to be effective in the control of non-infectious non-necrotizing scleritis in a phase I/II open-label trial (55). Most recently, JAK inhibitors have presented a promising addition to the therapeutic landscape for refractory non‑infectious scleritis. Case series and systematic case‑report reviews indicate that agents such as tofacitinib, baricitinib, and upadacitinib can achieve disease control after failure of conventional and biologic therapies in non-infectious scleritis, with generally tolerable safety profiles (56-58).At this time, a small cohort phase II single-arm interventional trial is underway (NCT03580343). Prospective clinical evaluation and randomized comparisons against established therapies will define the optimal role of JAK inhibitors in severe or refractory disease.

Overall, while recent trials signal a shift toward targeted immunotherapy and biosimilars, the field remains constrained by small sample sizes, non-standardized endpoints, and a lack of phase III data, highlighting the need for multicenter collaboration and standardized outcome measures in future scleritis research.

Further translational research focusing on local immunologic pathways, cytokine expression, and scleral fibroblast activation may reveal novel therapeutic targets and support the development of localized sustained-release and other novel drug delivery systems. In 2018, a phase I trial was completed for EGP-437, a non-invasive iontophoresis treatment to deliver corticosteroids directly to the eye using a low-level electrical current, which showed meaningful improvement in severity of non-infectious anterior scleritis with low systemic absorption (72). Adrenocorticotropic (ACTH) hormone is another option which is currently being used in steroid-dependent or refractory scleritis patients, which is also under concurrent investigation for scleritis in a phase II open trial (ATLAS study, NCT03465111) (73). ACTH gel is used in various inflammatory conditions, including lupus, multiple sclerosis, and nephrotic syndrome, with proposed benefit for scleritis due to its mechanism through blocking multiple inflammatory pathways (74). However, it is of note that in a previous trial for its use in nephrotic syndrome, approximately 25% of patients experienced adverse effects similar to steroids, including weight gain, fluid retention, hypertension, hyperglycemia, mood disturbances, and increased susceptibility to infection (75).

Lastly, emerging advanced imaging modalities hold promise for improving diagnostic precision and monitoring. Recent advances in anterior segment OCT, enhanced depth imaging OCT, ultrasound biomicroscopy, and swept-source OCT have improved the precision of scleritis diagnosis. Throughout management, such advanced imaging modalities should be used for early detection of posterior involvement, quantification of scleral thickness, and objective monitoring of treatment response (31,32). Fluorescein and indocyanine green angiography may further aid in identifying necrotizing changes before clinical thinning becomes apparent (76). Clinical monitoring, in conjunction with imaging, should guide timely escalation through therapeutic tiers, optimizing outcomes while reducing cumulative corticosteroid exposure and treatment-related toxicity. Future integration of artificial intelligence–based image analysis may provide automated, reproducible disease severity scoring, supporting earlier risk stratification, more tailored therapy, and standardized outcomes in future studies.

Future scleritis research should prioritize comparative efficacy trials, validation of biosimilars, integration of advanced imaging-based diagnostics, and biomarker-driven treatment stratification. Collaborative, multicenter clinical networks and standardized outcomes will be critical to advancing precision medicine approaches and improving long-term visual outcomes.

Updated management approach

Patients with non-necrotizing anterior scleritis may still be appropriately managed with a traditional escalation strategy, whereas those with necrotizing disease, vision threatening posterior scleritis, or associated systemic vasculitis may benefit from earlier introduction of biologic therapy under close multidisciplinary supervision.

Figure 10 illustrates the updated current evidence-supported stepwise approach to non-infectious scleritis. This tiered approach integrates current evidence, patient-specific risk stratification, and emerging therapeutics, and should be individualized for patients based on severity, anatomic subtype, and systemic associations.

Figure 10 Treatment algorithm for non-infectious scleritis (61). ANCA, anti-neutrophil cytoplasmic antibody; IMT, immunomodulatory therapy; IV, intravenous; JAK, Janus kinase; NSAID, nonsteroidal anti-inflammatory drug; TNF, tumor necrosis factor.

For mild, non-necrotizing anterior scleritis, initial therapy typically involves NSAIDs such as naproxen, indomethacin, or ibuprofen, with choice guided by patient comorbidities and tolerability. If patients fail to respond or cannot tolerate NSAIDs, therapy is escalated to systemic corticosteroids. Oral prednisone is commonly initiated, with gradual tapering once inflammation is controlled, while intravenous methylprednisolone may be reserved for acute or severe presentations such as necrotizing scleritis. Adjunctive strategies, including topical corticosteroids or periocular triamcinolone injections, may be used selectively in non-necrotizing cases to limit systemic exposure.

Patients with persistent, recurrent, or severe disease, or those at high risk for steroid-related complications, are escalated to IMT. First-line IMT agents include methotrexate, mycophenolate mofetil, and azathioprine. The specific agent should be selected based on patient-specific factors, including comorbidities, contraindications, and tolerability, and requires careful laboratory monitoring. For cases refractive to IMT, associated with systemic autoimmune disease, or with severe necrotizing pathology, biologic therapies should be initiated as early as possible. The initial biologic therapy of choice is often adalimumab or infliximab (TNF-α inhibitors), with rituximab (B-cell-targeting) selected for patients with ANCA-vasculitides. Other biologics (tocilizumab, abatacept, gevokizumab) and JAK inhibitors (tofacitinib, baricitinib, upadacitinib), as well as repository corticotropin injection, may be considered for patients who are already on TNF-α inhibitors or are intolerant or refractory to other biologic options.

Surgical interventions of scleral patch grafting and tectonic reinforcement remain options for necrotizing scleritis with scleral melt or risk of perforation, once inflammation is controlled.

Infectious scleritis continues to be managed with a dual approach combining aggressive antimicrobial therapy and surgical intervention. Empiric broad-spectrum topical and systemic antibiotics should be initiated immediately while awaiting culture results. Based on sensitivities, prompt pathogen-directed therapy should be initiated, combining topical, subconjunctival, and systemic antibiotics (4,29). For refractory cases, subpalpebral antibiotic lavage systems can deliver high concentrations of antibiotics directly to infected tissue (77). Retrospective studies indicate that rapid initiation of therapy improves globe salvage and limits scleral destruction, though prospective trials are lacking. Early surgical debridement is recommended in necrotizing cases (66,78). Surgical options include cryotherapy, lamellar or penetrating corneoscleral grafting, and conjunctival recession (4,29). Despite advances in understanding, no consensus exists on standardized management protocols for infectious scleritis. The rarity of the condition and heterogeneity of causative organisms make large-scale trials challenging. Current evidence supports aggressive early management, though there is a need for further studies to define optimal therapeutic timing and combination strategies.

Ultimately, there is no rigid treatment algorithm for scleritis. Rather, the approach to management should be individualized and risk stratified.

Conclusions

The management of scleritis is evolving from a corticosteroid-based stepwise paradigm toward more individualized, mechanism-driven strategies. While conventional immunosuppressive agents are effective for many patients, accumulating evidence supports the earlier use of biologic therapies in high-risk cases, particularly necrotizing scleritis or scleritis cases associated with systemic vasculitis. The absence of randomized controlled trials underscores the need for prospective, collaborative studies to define optimal treatment sequencing, comparative efficacy, and long-term safety. Until data are available, treatment decisions should balance disease severity, systemic involvement, and patient-specific risk factors, emphasizing early control of inflammation to prevent irreversible structural ocular complications and vision loss.

Acknowledgments

We appreciate the slit lamp and fundus photographs taken by the ophthalmic technicians in the Department of Ophthalmology and Visual Sciences at Montefiore Medical Center.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Roy S. Chuck, Joan J. Kang, and Viral V. Juthani) for the series “Inflammatory Disorders of the Cornea and Ocular Surface”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-2025-1-68/rc

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-2025-1-68/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-2025-1-68/coif). The series “Inflammatory Disorders of the Cornea and Ocular Surface” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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