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Review Article

Current Approach for the Diagnosis and Management of Noninfective Scleritis

Dutta Majumder, Parthopratim; Agrawal, Rupesh; McCluskey, Peter; Biswas, Jyotirmay§

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Asia-Pacific Journal of Ophthalmology: March-April 2021 - Volume 10 - Issue 2 - p 212-223
doi: 10.1097/APO.0000000000000341
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Abstract

Scleritis is a rare, sight-threatening inflammation of the sclera characterized by severe pain and redness of the eye. It is one of the important and critical differential diagnoses in a patient presenting with red eyes (Fig. 1). The classification proposed by Watson and Hayreh divides noninfective scleritis into 5 distinct clinical types and remains widely accepted (Fig. 2).1 Scleritis can be divided into 2 broad categories—anterior and posterior scleritis—with the ora serrata as an arbitrary boundary between these 2 subtypes.1,2 Anterior scleritis is further divided into necrotizing and nonnecrotizing. Necrotizing scleritis is subdivided into necrotizing scleritis with inflammation and without inflammation, whereas nonnecrotizing scleritis is further categorized into nodular and diffuse scleritis. Posterior scleritis refers to the inflammation of the sclera posterior to the ora serrata. Uncommonly, anterior scleritis can extend across ora serrata and involve the posterior sclera or vice versa. The term “panscleritis” has been used by many authors to denote scleritis in which both anterior and posterior scleritis were present together.3,4 Scleral inflammation can spread to contiguous ocular structures and in the absence of rapid and effective treatment, necrotizing scleritis may perforate the globe.5,6 In this review, we focus on 2 aspects of noninfective scleritis: first an overview of the various subtypes of scleritis and its systemic associations, and second an evaluation of current trends in the diagnosis and management of noninfective scleritis.

FIGURE 1
FIGURE 1:
Flow chart for approach to a patient with red eyes and to differentiate scleritis from other causes of red eyes.
FIGURE 2
FIGURE 2:
Classification of scleritis proposed by Watson and Hayreh1.

EPIDEMIOLOGY

The prevalence of scleritis varies between geographical regions. In a retrospective analysis of 354 scleritis patients from centers in Australia, Singapore, and India, regional differences were observed among patients in the Asia-Pacific region.7 Compared with patients from Singapore and Australia, the Indian cohort was characterized by younger age, male preponderance, and fewer bilateral cases.7 The majority of case series of scleritis across the world have reported a female preponderance. Scleritis typically affects the middle-aged, though patients from South-East Asian countries are younger when compared with western populations.3,7–10 Among all the subtypes of scleritis, necrotizing scleritis is commoner in older patients.11 Posterior scleritis is more common in younger patients.12 In a retrospective case series of children, posterior scleritis was the most common type of scleritis in patients ≤16 years.13 Posterior scleritis was diagnosed in patients as young as a 7-month-old baby,14 who was initially diagnosed as preseptal orbital cellulitis and endophthalmitis.14 Scleritis is bilateral in up to 50% of patients. Bilaterality is the most frequent in diffuse anterior scleritis, followed by necrotizing anterior scleritis, posterior scleritis, and nodular anterior scleritis.7,15,16Table 1 highlights the various demographic parameters and distribution of various subtypes of scleritis in various case series on scleritis across the world.

TABLE 1 - Epidemiological Perspective of Case Series on Scleritis
Authors No. Patients Age, y M:F Bilateral Diffuse Necrotizing Nodular Posterior
Watson and Hayreh1 207 1:1.5 45% 40% 14% 45% 2%
Yang et al3 293 39.4 (6–82) 1:1.4 35.20% 77.80% 1.70% 3.40% 2.70%
Tanaka et al6 123 57.8 (15–83) 1:1.2 41.50% 61.80% 8.10% 13.80% 16.30%
Sainz de la Maza et al15 500 53.7 (12–96) 1:2.4 41.20% 75% 5% 14.20% 6.20%
Keino et al11 83 51.1 (12–82) 1:1.2 47% 68.70% 9.60% 10.80% 10.80%
Erkanli et al133 114 48 (4–87) 1:2.6 31% 42% 6% 43% 9%
Jabs et al29 97 51 (6–81) 1:2.5 50.50% 59.80% 12.40% 20.60% 7.20%
Wieringa et al4 104 51.5 (18–91) 1:1.5 38.50% 34.60% 5.80% 19.20% 3.80%
Bin Ismail et al134 120 48.6 (16–83) 1:1.3 30.80% 62.50% 5.80% 20.80% 10.80%
Rahman et al8 79 42 (7–74) 1:1.03 40.50% 43% 15.20% 24.10% 17.70%
Xu et al135 77 48.8 1:1.08 9% 77.90% 1.30% 16.90% 3.90%
Abd El Latif et al136 303 46.1 (8–81) 1:2.9 23.40% 25.10% 21.40% 44.90% 8.30%
Lin et al92 119 49.4 (9–92) 1:2.2 32% 46.20% 12.60% 30.30% 13.40%
Ahn et al137 76 59.5 (11–81) 1:2.3 23.70% 23.70% 35.50% 40.80%

PATHOGENESIS

The etiology of scleritis remains unclear. Scleritis is commonly associated with systemic autoimmune disorders and systemic vasculitis. Histopathological specimens are rare and until recently have mostly been from blind eyes with end-stage scleritis enucleated for pain relief. More recently, episcleral and scleral biopsies have become available. Immunohistochemistry studies reveal that there is a localized scleral vasculitis, most likely secondary to deposition of circulating immune complexes, in patients with necrotizing scleritis.17 Many authors believe that scleritis associated with systemic autoimmune disorders is immune complex-mediated, and that scleritis unassociated with systemic diseases may be due to a local delayed hypersensitivity reaction.18 Histopathologically, scleritis is characterized by an inflammatory response of predominantly lymphocytes and plasma cells with fewer polymorphs.19 Necrotizing scleritis associated with rheumatoid arthritis (RA) has a zonal granulomatous inflammation with areas of tissue necrosis, whereas patients with idiopathic scleritis have a chronic inflammatory response with predominant macrophages, T and B cells, and the absence of scleral necrosis.17 Cytokines secreted by inflammatory cells such as interleukin-1 beta and tumor necrosis factor (TNF)-alpha induce secretion of matrix metalloproteinases (MMPs) from infiltrating inflammatory cells and stromal scleral fibroblasts.20,21 MMPs are a group of zinc-containing proteases that play a crucial role in the pathogenesis of scleritis by causing the breakdown of scleral collagen and proteoglycans leading to scleral necrosis. Increased levels of TNF-alpha and MMP-9 have been detected in tears of patients with necrotizing scleritis.22 There is a dysregulation of MMP secretion and that of their naturally occurring tissue inhibitors of MMP (TIMPs) in involved sclera in patients with scleritis leading to an overproduction of activated MMPs that break down proteoglycans and collagen, damage the sclera, and destroy the scleral wall in patients with necrotizing scleritis.21 Increased levels of proinflammatory cytokines detected patients with active scleritis decrease significantly with remission of scleritis highlighting the role of effective systemic therapy in the management of scleritis.23

No definite genetic predisposition has been identified in patients with scleritis. Though various systemic rheumatic diseases that can cause scleritis, have been linked with specific human leukocyte antigens (HLAs), there is no such association for scleritis. In a retrospective analysis of 5 patients with posterior scleritis, an association with HLA-B27 was reported by Anshu and Chee.24 In addition to other alleles or subtypes, RA, systemic lupus erythematosus (SLE), and antinuclear cytoplasmic antibody (ANCA)-associated vasculitis have been found to be associated with HLA-DR15.25 HLA-DR15, though not specific for scleritis, has been reported as a predisposing factor for corneal ulceration.26 Recently a study on the Chinese Han population reported 2 genes, cytotoxic T lymphocyte-associated antigen-4 and protein tyrosine phosphatase nonreceptor type 22, to confer genetic susceptibility to scleritis.27

SYSTEMIC ASSOCIATIONS

Approximately half of the patients with scleritis have an underlying systemic disorder, and the risk of association with systemic diseases varies with clinical subtypes.28,29 The majority of reports on the association between scleritis and systemic disease are from tertiary referral eye care centers. In a retrospective analysis of scleritis patients in a nontertiary community-based referral practice, 36% of the patients had associated systemic diseases.30 The common systemic diseases associated with scleritis are RA, granulomatosis with polyangiitis (GPA, previously known as Wegener granulomatosis), relapsing polychondritis (RP), polyarteritis nodosa, and SLE. RA remains the most common cause of systemic disease associated with scleritis.31,32

RA is associated with 10% to 19% of patients with scleritis, and conversely, scleritis occurs in 0.2% to 6.3% of patients with RA.15,33 In the majority of the patients, scleritis occurs after the diagnosis of RA and during the course of the disease.34 The diagnosis of scleritis, especially necrotizing scleritis with or without corneal involvement in RA, is of great concern as it may indicate the presence of systemic vasculitis and can be an important risk factor for increased mortality.35,36 Among all subtypes, necrotizing scleritis has the highest systemic association ranging from 70% to 95%.15 A small number of studies have reported higher associations of concurrent anterior and posterior scleritis (panscleritis) with systemic diseases.3,37 In a retrospective case series of 500 patients, scleritis was the first manifestation of an autoimmune disorder in 38.7% of patients, and diffuse scleritis was the most frequent type of scleritis in this case series.15

Scleritis secondary to a vasculitic disease tends to have a more severe clinical phenotype and a more aggressive course. GPA is the most common cause of vasculitis-associated scleritis and is an ANCA-associated vasculitis.34 Patients with ANCA-associated scleritis are at increased risk of developing severe scleritis with corneal involvement and visual impairment, and may require multiple immunosuppressive therapies.38,39 These patients should be thoroughly evaluated for an underlying systemic vasculitis. Scleritis can be the presentation of a localized form of GPA, making the clinical diagnosis of GPA more difficult.3 In a retrospective case series from India, tuberculosis (TB) was the underlying disease in 15% of the patients with ANCA-positive scleritis.39 The cross-reactivity of neutrophils with the mycobacterial cell wall can give rise to these autoantibodies, and TB should be ruled out in patients with ANCA-positive scleritis in endemic regions.39 It is unclear whether TB is a comorbidity or the cause of the scleritis in such patients, given the high background prevalence of TB in India. Scleritis associated with polyarteritis nodosa may have a clinical appearance similar to GPA, but is a much less frequent association.

Scleritis is an uncommon but severe complication of SLE correlating with deterioration of the systemic disease.40 A recent comparative, retrospective analysis of 521 patients with SLE from Taiwan, such patients had a significantly higher risk of developing episcleritis and scleritis.41 Scleritis in SLE may manifest as nodular, diffuse, and posterior scleritis but rarely necrotizing.40,42

Scleritis is the most common ocular manifestation of RP and can be bilateral, diffuse, nodular, or necrotizing.43 Occasionally, there may be more than one systemic disease diagnosed in patients with scleritis.3 In a retrospective analysis of patients with RP-associated scleritis, 30% of the patients exhibited associations with other systemic vasculitis or autoimmune diseases.43 HLA-B27-associated seronegative arthritis can be associated with both anterior and posterior scleritis.3,24 In a retrospective case series of 500 patients with scleritis, HLA-B27-associated ocular inflammation without spondyloarthropathy was the second most common cause of the systemic disease after RA.15 Scleritis can also occur in association with various other conditions such as Crohn disease, Behçet disease, Vogt-Koyanagi-Harada disease, sarcoidosis, Takayasu disease, Cogan syndrome, and temporal arteritis.44 Immunoglobulin G4 (IgG4)-related immune-mediated process can involve sclera as either anterior or posterior scleritis.45–47 The clinical presentation in these patients can be variable, and ocular adnexal tissues are often involved in addition to scleritis.46 IgG4-related scleritis usually responds well to corticosteroids and immunosuppressives. B cell-directed biologic therapy with medication such as rituximab is the most effective therapy.

Drug-induced scleritis is very uncommon with bisphosphonates being the most strongly linked cause of scleritis (Naranjo score of 10).48 Bisphosphonate-associated scleritis may involve one or both eyes and usually responds to discontinuation of the drug.49,50 Various other drugs such as topiramate,50 procainamide,51 erlotinib,52 etanercept,53 and a combination of nivolumab and cabiralizumab54 have been reported to cause scleritis.

Surgically induced necrotizing scleritis occurs after surgical interventions and has been reported after extracapsular cataract extraction, trabeculectomy,55 retinal detachment surgery,56 strabismus surgery,57 pterygium surgery,58 and intravitreal injection.59 Surgically induced necrotizing scleritis is now a rare clinical phenotype of scleritis and this pattern of scleritis is now most frequently caused by infective scleritis, most often after pterygium surgery.60 A number of systemic diseases have been associated with surgically induced necrotizing scleritis.

CLINICAL CHARACTERISTICS

Patients with scleritis generally present with redness and severe ocular pain. Because of the rich sensory innervation of the sclera, scleritis is almost always painful. The ocular pain is classically described as dull, boring in nature and may radiate to the ear, scalp, forehead, and jaw.1 The pain is exacerbated by eye movement and worsens at night typically waking the patient from sleep in the early hours of the morning.1,32 It is often poorly responsive to analgesic therapy. The pain in scleritis is so severe that it may erroneously diagnosed as other conditions such as sinusitis, migraine, trigeminal neuralgia, or intracranial disorders.1 The severity of the pain in scleritis may vary with clinical subtypes. Ocular pain is most severe in patients with necrotizing scleritis; pain is not a feature of scleromalacia perforans (necrotizing scleritis without inflammation).1,15 Pain can be absent in posterior scleritis. In a case series of 114 patients of posterior scleritis, 64% of patients complained of periocular pain, and 13% of the patients complained of headache.42 In a case series by McCluskey et al,37 17.1% of the patients with posterior scleritis were asymptomatic other than having reduced vision.37 Diminution of vision has been described more commonly in patients with necrotizing scleritis and posterior scleritis.6

Scleral edema and congestion of the deeper episcleral vessels are a sine qua non physical sign of scleritis. The other critical sign is microvascular closure. Examination under natural daylight and use of red-free light during the slit-lamp examination may help appreciate the classical violaceous bluish color, and the pattern and depth of vascular engorgement.61 Blanching of vessels with 2.5% or 10% of phenylephrine is a useful clinical test to differentiate between episcleritis and scleritis. The phenylephrine blanches the conjunctival vascular plexus so that the deeper episcleral vascular plexuses can be differentiated and their relationship to the sclera determined. In patients with scleritis, the deep episcleral plexus is bowed out by oedematous sclera, in addition to the superficial vascular plexus. In episcleritis, only the superficial plexus is bowed outwards as only the episcleral tissue is inflamed and oedematous, although the underlying sclera is normal. It is also critical to carefully examine the episcleral vascular plexuses to determine whether there are areas of capillary and small vessel closure and occlusion. This finding means the patients are developing necrotizing scleritis.

Diffuse anterior scleritis remains the most common type of scleritis in the majority of case series (Fig. 3A). It is characterized by diffuse involvement of the sclera with edema and congestion, though initially, it may begin with sectoral inflammation. Anterior uveitis can be seen in approximately 30% of patients with diffuse anterior scleritis.15,29 Diffuse anterior scleritis remains the second most common subtype of scleritis with peripheral corneal involvement.15

FIGURE 3
FIGURE 3:
Slit-lamp photographs of diffuse scleritis (A), nodular scleritis (B), necrotizing scleritis without inflammation (C), and necrotizing scleritis with inflammation (D).

Nodular scleritis is characterized by one or more distinct localized areas of swelling in the sclera (Fig. 3B). Nodules can be the initial presentation of a systemic infection, especially TB.8,62–64 Nodular scleritis was also found to be the most common subtype of anterior scleritis in a retrospective case series on scleritis in children.13

Necrotizing scleritis is a less common but the most severe form of scleritis. Necrosis of sclera can result from vasculitis and subsequent vascular occlusion with or without inflammation. Scleromalacia perforans is a rare form of necrotizing scleritis that occurs in the absence of clinical signs of inflammation (Fig. 3C). Scleromalacia perforans usually occurs in patients with long-standing RA and is characterized by the presence of extensive scleral thinning with uveal staphyloma and dilated scleral vessels.65,66 It is not painful and patients present with blurred vision from irregular astigmatism. Fortunately, scleromalacia perforans is now very rare due to greatly improved disease-modifying antirheumatic drugs and biologics to treat RA.15 Necrotizing scleritis is associated with an increased risk of complications. Among all subtypes of scleritis, anterior uveitis and peripheral ulcerative keratitis are most commonly seen in patients with necrotizing scleritis (Fig. 4). In addition, a combination of necrotizing scleritis with peripheral ulcerative keratitis is associated with a higher incidence of systemic rheumatic disease (Fig. 3D).67

FIGURE 4
FIGURE 4:
A, Color fundus photograph of left eye with posterior scleritis. One can note the hyperemic optic disc with blurring of disc margin, internal limiting membrane striae in the posterior pole, and exudative retinal detachment in the superotemporal quadrant. B, Fundus photograph of another patient with posterior scleritis. C, Ultrasound B-scan image of the same patient showing increased posterior scleral wall thickness and subtenon fluid collection resulting in T sign.

Posterior scleritis comprises up to 20% of scleritis cases (Fig. 5). This number may be higher, as posterior scleritis is often not diagnosed or missed due to its subtle clinical signs and protean manifestations. Posterior scleritis remains the most common cause of scleritis in children.13 In contrast to adults with posterior scleritis, pediatric patients with posterior scleritis showed male predominance, less association with systemic diseases, less frequent concurrent anterior scleritis, and more frequent disc swelling.68 Concurrent anterior scleritis is common in patients with posterior scleritis. In a case series of posterior scleritis by McCluskey et al,37 59.6% of the patients had developed anterior scleritis at some point in time during their course of inflammation. In another case series, the association of anterior scleritis was reported in 67.7% of the patients with posterior scleritis.15,16 Posterior scleritis can be bilateral and often idiopathic; diagnosis can be challenging because of similarities with other inflammatory conditions.16

FIGURE 5
FIGURE 5:
Slit-lamp photographs of peripheral corneal involvement in a patient with scleritis (A), scleral thinning in patient with necrotizing scleritis secondary to granulomatosis with polyangitis (B), and globe perforation in necrotizing scleritis (C).

Posterior scleritis can present as circumscribed scleral mass or elevation in approximately 12% of patients.2,37 Mass-like appearance in the form of giant nodular scleritis is the most challenging presentation of posterior scleritis.69 Many cases of posterior scleritis have been reported in literature where the diagnosis was made after the enucleation of the eye for suspected intraocular tumor. Posterior scleritis may present with a retinal pigment epithelium rip, where the rip is postulated to occur as a result of inflammation, exudation, and continuing pressure by the fluid or granuloma on the pigment epithelium.70 Inflammation of the posterior sclera can contiguously involve retinal artery and vein causing inflammation, and can lead to occlusion of the vessels.71,72 Posterior scleritis can involve optic disc by contiguous spread of inflammation or compression of the optic nerve due to increased sclerochoroidal thickening and manifest as optic disc edema.73 Posterior scleritis can cause secondary angle-closure glaucoma from rotation of ciliary body and anterior displacement of the lens-iris diaphragm caused by choroidal effusion and ciliary body edema from posterior scleritis.74–76 Fluid accumulation in the suprachoroidal and supraciliary space results from blockage of transscleral outflow of choroidal interstitial fluid due to disruption of bulk fluid flow across the sclera by thickened, inflamed sclera and/or raised episcleral venous pressure. The resultant inflammatory ciliochoroidal effusion syndrome is characterized by ciliochoroidal effusion, ciliary body edema, secondary angle-closure glaucoma, myopic shift, and shallow anterior chamber. Ikeda et al77 reported that ultrasound biomicroscopy is a valuable tool in the differentiation of angle-closure glaucoma due to ciliochoroidal effusion syndrome from pupillary block glaucoma. In another case report,78 a 64-year-old male, who presented with acute angle-closure glaucoma, later developed an exudative choroidal and retinal detachment. Posterior scleritis has been reported to present with annular choroidal detachment, internal ophthalmoplegia, and optic perineuritis.68

Two grading systems have been proposed for monitoring the severity of the scleral inflammation and response to the therapy. Using photograph-based methods, a grading system for assessing activity in scleritis was proposed by Sen et al.79 Grades are determined by the extent of redness and dilation of scleral vessels and divided on a 0 to 4+ scale. A quantitative scoring system, based on common clinical signs of scleritis, has been useful in grading the severity of scleritis and in predicting the response to systemic immunosuppressive therapy.80

COMPLICATIONS

Ocular complications are common in scleritis. In a study from Japan, complications were observed in 78% of all patients either at presentation or during the follow-up period.11 The same study reported complications in 100% of patients with either necrotizing or posterior scleritis, in 44% of patients with nodular scleritis, and in 77% of patients with diffuse anterior scleritis. Elevated intraocular pressure has been reported in up to 40% of patients with scleritis.6,11 Various mechanisms can cause a rise of intraocular pressure in posterior scleritis including inflammation of the outflow pathways, increased intraocular fluid viscosity, occlusion of trabecular meshwork by inflammatory cells and debris, peripheral anterior synechiae, neovascularization, secondary angle-closure, steroid response, and increased episcleral venous pressure.74,81 Raised intraocular pressure has been reported more frequently in patients with necrotizing scleritis.82 Another study found ocular hypertension more frequently in posterior scleritis and anterior necrotizing scleritis; in 78% of patients the ocular hypertension was steroid-induced.6 Cataract remains an important complication in patients with scleritis occurring in up to 50% in various studies.3,29 It can result from both scleral inflammation and corticosteroid therapy. A study that followed patients with scleritis for 11 years reported an incidence of 17% of cataract formation.28 In a retrospective review, necrotizing scleritis was the most common subtype of scleritis associated with cataract followed by diffuse and anterior scleritis, nodular scleritis.29,83 In a study by Tanaka et al,6 one-third of patients with necrotizing or posterior scleritis developed a decreased vision, most commonly from secondary glaucoma and optic neuritis.6 In another large studies of scleritis, severity of scleral inflammation, posterior and necrotizing phenotypes, ocular hypertension, and an associated systemic disease were the main risk factors for decreased vision in patients with scleritis.15 Sight-threatening complications such as perforation of the globe can occur in patients with necrotizing scleritis (Fig. 4C).5,6

ANCILLARY TESTS

Various imaging modalities have been used to aid in early diagnosis and evaluation of scleritis. As direct visualization of the posterior sclera is not possible, a number of imaging modalities have been utilized to obtain an early and accurate diagnosis of posterior scleritis. The diagnosis of anterior scleritis is almost always clinical. Anterior segment swept-source optical coherence tomography allows evaluation of the conjunctiva, Tenon capsule, episclera, and sclera with great detail and this novel noncontact technique has been used to analyze the depth of scleral inflammation and to quantify the extent of scleral involvement and thinning.84–86

Ultrasonography (USG) B-scan is considered the most helpful test in the diagnosis of posterior scleritis. It can demonstrate increased posterior scleral wall thickness, subtenon fluid collection resulting in a T sign (Fig. 5C) exudative retinal detachment, and the presence of scleral nodules and annular choroidal detachments. The T sign, though helpful for the diagnosis of posterior scleritis, is not pathognomonic and can be seen in up to 41% of the patients with posterior scleritis. 42,87 USG B-scan can be helpful in patients with posterior scleritis in the absence of classic clinical signs.37 However, USG B-scan often fails to pick up the diagnostic findings in posterior scleritis, especially in the early phase of the disease, and is of limited value in evaluating other intraorbital structures.2 Ultrasound biomicroscopy does not help in diagnosis per se but can be a valuable tool in cases of posterior scleritis with atypical presentations. For example, posterior scleritis can rarely manifest as secondary angle-closure glaucoma, and ultrasound biomicroscopy can help to detect suprachoroidal effusion and ciliary body edema, which are absent in primary angle-closure glaucoma.

Computerized tomography scan can show thickening of the posterior scleral coat with increased uptake on contrast. McCluskey et al80 found no advantages of computerized tomography scan over USG B-scan in cases where the latter failed to confirm the diagnosis of posterior scleritis. Magnetic resonance imaging has been reported as a useful adjunct for diagnosis of posterior scleritis because of its excellent soft-tissue resolution.88 Orbital magnetic resonance imaging can differentiate sclera from the other ocular layers and can be used as an important tool to differentiate posterior scleritis from idiopathic orbital inflammation syndrome.88

Fundus fluorescein angiography can show early pinpoint leaks with late pooling of the dye in patients with subretinal fluid secondary to posterior scleritis.2 This pattern of fundus fluorescein angiography is not specific for posterior scleritis and can be seen in many conditions. Additionally, one can have disc leakage and vascular staining in patients with posterior scleritis. Posterior scleritis may also cause choroidal folds which appear as alternating light and dark bands on fundus fluorescein angiography. Indocyanine green angiography in posterior scleritis may show diffuse zonal choroidal hyperfluorescence reflecting vascular hyperpermeability in the choroid.89 Indocyanine green angiography can sometimes help delineate more subclinical areas of choroidal inflammation in patients with posterior scleritis.90 Optical coherence tomography (OCT) is useful in the evaluation of adjacent choroid and retina during the course of posterior scleritis. OCT can show associated neurosensory detachment and monitor responses to the therapy. Using enhanced depth imaging, thickening of choroidal in response to scleral inflammation in posterior scleritis was studied and marked thinning of choroid has been observed in patients with recurrent attacks of inflammation.91

LABORATORY INVESTIGATIONS

The evaluation of a case of scleritis needs a multidisciplinary approach. There is no single biomarker for the diagnosis of systemic rheumatic diseases and targeted laboratory investigations to rule in or rule out specific diseases is important in patients with scleritis. Investigations are based on the results of clinical assessment by a thorough history, complete ocular examination, and a careful review of systems. In common clinical practice, rheumatoid factor, antinuclear antibody, and ANCA are obtained in patients with scleritis along with complete blood count, erythrocyte sedimentation rate, C-reactive protein, urine analysis, and HLA-B27. An extensive array of investigations can be performed to rule out associated infections, and further serological tests such as complement levels and autoantibodies to exclude autoimmune conditions can be ordered depending on the clinical picture. Chest imaging is helpful when GPA, TB, or sarcoidosis is suspected. A retrospective study found that investigating for rheumatoid factor and ANCA in patients with idiopathic scleritis is useful in identifying patients who are at risk for the development of RA and GPA.92 The patients with idiopathic scleritis who tested positive for rheumatoid factor in the same study were found to be at much higher risk of developing RA at follow-up, even in the absence of joint symptoms. In another study, ANCA was found to be both sensitive and specific for GPA-associated scleritis.93 There is no definitive laboratory test for the diagnosis of IgG4-associated scleritis and serological tests often have a limited role. A high index of suspicion, exclusion of other etiologies, and histopathological analysis of the specimen obtained through scleral biopsy may help confirm the diagnosis of IgG4-associated scleritis.94

DIFFERENTIAL DIAGNOSIS

One of the important steps of scleritis management is early identification of infective scleritis and prompt initiation of antimicrobial therapy as the scleral infections are rapidly progressive and destructive. Scleritis is primarily a noninfective immune-mediated inflammation and infection of sclera is less common. As a result, in majority of the cases, a diagnosis of infective scleritis is not considered initially. As the treatment with systemic immunomodulators will result in further progression of infective scleritis, one must rule out the possibility of infection before initiating aggressive immunosuppressive therapy. A history of surgical or accidental trauma in a sceritis patient should be considered as red-flag sign, as trauma is a major risk factor for infective scleritis. Additionally, contiguous spread or extension of infective keratitis or rarely severe endophthalmitis can cause infective scleritis (panophthalmitis). Absence of any underlying systemic autoimmune disease in cases with necrotizing scleritis should also raise suspicion of an infective etiology. Infective scleritis due to Pseudomonas aeruginosa, Staphylococcus, Proteus, or herpes zoster can manifest as necrotizing scleritis, and can mimic necrotizing scleritis secondary to autoimmune etiologies.18,95Pseudomonas aeruginosa remains the most common cause of infective scleritis and often results from corneal infections.96 Infective scleritis can also occur in patients with immunosuppression, especially with the use of long term immunomodulators, and in patients with a septic foci elsewhere in the body.97 In TB-endemic areas, one must screen and rule out tuberculous scleritis that can have plethora of clinical manifestations. Sclerokeratitis and nodular scleritis not responding to conventional therapies should be evaluated for TB.8,98 Posterior scleritis secondary to ocular TB, though uncommon, can occur.90

Rarely ocular tumors can masquerade as scleritis. Ocular surface squamous neoplasia, especially nodulo-ulcerative variant, can mimic necrotizing scleritis or sclerokeratitis.99 Posterior scleritis, particularly nodular posterior scleritis, can mimic intraocular tumor and there are many instances where an eye with posterior scleritis had been enucleated over a suspicion of melanoma.100 However, there are reports of choroidal melanoma masquerading as scleritis there by delaying the diagnosis.101 Scleral inflammation can be the initial presentation of choroidal melanoma that may initially respond to systemic corticosteroids. A high index of suspicion and ultrasound evaluation can help in such scenario. Metastatic carcinoma can mimic posterior scleritis and rarely masquerade as necrotizing scleritis.101

TREATMENT

Topical corticosteroid and oral nonsteroidal antiinflammatory drug are considered the first-line therapy for nonnecrotizing scleritis by many authors. In a retrospective case series of 392 patients with noninfective anterior scleritis, nonsteroidal antiinflammatory drugs were found to be effective in young patients with unilateral scleritis, with anterior nodular scleritis, with a short delay of presentation, and without associated systemic diseases.102 In a retrospective analysis of 126 patients with nonnecrotizing scleritis, flurbiprofen, a nonselective cyclo-oxygenase inhibitor, was found to be a safe and effective drug for the management of nonnecrotising anterior scleritis.103 A large number of patients with the mild and moderate disease eventually need an alternative treatment regimen, most commonly with oral corticosteroids.

The use of topical immunosuppressives, namely topical ciclosporin, and topical tacrolimus, has been reported by various authors with the variable results.6,104 In a prospective, single-arm study, 0.1% of topical tacrolimus has been reported to reduce clinical signs and ocular pain in 9 patients of noninfectious, nonnecrotizing anterior scleritis, who are unresponsive to a course of topical steroid.105 Using 0.02% of topical tacrolimus ointment, 3 of 4 patients with necrotizing and nodular scleritis could achieve complete resolution of scleral inflammation and reduction in the steroid use with no recurrence over 1 year.106 Subconjunctival injections of depot corticosteroid have been used in patients with noninfectious, nonnecrotizing anterior scleritis with rapid resolution of inflammation in the majority of the patients and few side-effects.107,108 This method of delivery of corticosteroid reduces the need for systemic therapy.109 A multicenter, retrospective study reported improvement of signs and symptoms of scleritis in 89.7% of patients after a single injection and effect sustained in 50% of the patients up to 48 months.108 The feared complications of scleral melt or necrosis has led to a reluctance to use this modality of treatment in the past.110

Oral corticosteroids remain the mainstay of the short-term management of scleral inflammation. Usually, a starting dose of prednisolone 1 mg/kg/d with weekly reduction, depending on the clinical response is advocated.32 However, though oral corticosteroid is beneficial, its long-term use is limited by numerous side effects. Pulse intravenous corticosteroid therapy is administered in cases with vision-threatening emergencies, necrotizing scleritis, and posterior scleritis, where rapid control of inflammation is required and infection has been excluded.

Immunosuppressives have emerged as a useful addition in the management of scleritis. Indications of immunosuppressive therapy in scleritis are inadequate response or failure to respond to oral corticosteroid therapy, recurrence of scleritis on a dose of more than 7.5 to 10 mg/d of oral corticosteroid, and serious side effects with corticosteroid therapy.29,102 In a questionnaire-based survey that studied the treatment preferences in the management of idiopathic scleritis among uveitis specialists and rheumatologists, methotrexate was the most selected first-choice treatment before equalization of cost/insurance factors.111 Convenience of weekly dosage and flexibility of dosage depending on the clinical response and patients tolerance were the main reasons for the increased use of methotrexate in the management of scleritis. Using methotrexate as monotherapy for ocular inflammatory diseases, a retrospective review of 384 patients including 56 scleritis patients within the Systemic Immunosuppressive Therapy for Eye Disease (SITE) cohort study reported corticosteroid-sparing success in 37.3% of patients with scleritis at or before 6 months and in 58.3% of patients with scleritis at or before 12 months of methotrexate therapy.112 Successful corticosteroid-sparing was defined as resolved inflammation at ≥2 visits for ≥28 days after tapering the corticosteroid to ≤10 mg/d in the study. Treatment with azathioprine in a cohort of scleritis patients in SITE study was reported to control inflammation in 20% of patients within 6 months and in 11.1% of patients in 12 months.113 However, azathioprine has been found to be very useful in the management of scleritis associated with RP.43,114,115 Mycophenolate is an effective and well-tolerated corticosteroid-sparing agent for the treatment of scleritis. In a cohort of 51 eyes of 33 patients with scleritis in the SITE study, treatment with mycophenolate mofetil led to the resolution of scleritis in 25.5% of patients at 6 months and in 49.5% of patients at 12 months.116 In a comparative analysis of cohorts of patients taking methotrexate and mycophenolate mofetil in the SITE study, both the drugs were noted to have similar corticosteroid-sparing effect at 9 months; however, mycophenolate mofetil achieved corticosteroid-sparing effect more rapidly than methotrexate, the latter reducing the chances of corticosteroid-associated side effects. In a recent randomized controlled trial on patients with uveitis, the use of mycophenolate mofetil compared with methotrexate as first-line corticosteroid-sparing treatment did not observe superior control of inflammation.117 Cyclophosphamide is an established therapy in patients with systemic vasculitis and in patients with scleritis associated with such systemic diseases.39 The efficacy of cyclophosphamide was evaluated in a cohort of 76 eyes of 48 patients with scleritis in the SITE study, and 47.9% of the patients were treated with another immunosuppressant initially. A total of 30.2% and 60.5% of patients achieved a corticosteroid-sparing effect at 6 months and 12 months respectively.118 In a retrospective, multicenter study from Korea, the efficacy of cyclophosphamide in the treatment of necrotizing scleritis was comparable with that of other immunosuppressives, namely azathioprine, ciclosporin, methotrexate, and mycophenolate mofetil.119 The study did not observe a significant difference in remission, relapse, vision-loss, and corticosteroid-sparing effect between the 2 groups, though the rate of discontinuation of therapy due to side effects was much higher in the patients taking cyclophosphamide.119

Biologics providing selective targeting of the immune mediators of the inflammation cascade have become very useful therapies to treat noninfective uveitis and scleritis. In a questionnaire-based survey among uveitis specialists and rheumatologists that studied treatment preferences in the management of idiopathic scleritis, 83.3% of the rheumatologists chose a biologic as their first-choice agent, and 90% of the uveitis specialists chose a biologic as their second choice.111 TNF-alpha is one of the important modulators of inflammation and induces MMPs, making TNF blocking biologic drugs such as infliximab and adalimumab, attractive treatment options for scleritis. Increased amounts of MMP in necrotic and inflammed scleral tissue indicates that therapies targeting inhibition of MMP may be helpful in scleritis.20 In a single-center prospective, nonrandomized study of 5 patients with anterior scleritis, resolution of scleral inflammation could be achieved by week 14 with no additional immunosuppressive. However, the study reported transient systemic side effects of infliximab therapy in 2 patients, and 1 patient developed intraocular inflammation that did not respond to the reinduction of the therapy.120 From an 8-year follow-up prospective cohort of 43 patients, which also included 4 patients of scleritis, Sharma et al121 reported successful, sustained remission in 91% of the patients and a sustained corticosteroid-sparing effect in 3 quarters of the patients with TNF inhibitors. TNF-alpha blockers have shown promising results in the management of treatment-resistant cases of scleritis.121 Recently, a multicenter, retrospective case series reported TNF-alpha inhibitors effective in the treatment of scleritis although allowing a corticosteroid-sparing effect and preserving visual acuity.122

Rituximab is a chimeric monoclonal antibody against CD-20, a B cell surface antigen that has been used successfully for the treatment of scleritis. Rituximab is given as intravenous infusions in 2 doses 6 to 8 weeks apart. In a prospective randomized double-masked trial by Suhler et al,123 rituximab was effective in controlling scleral inflammation in 9 of 12 enrolled patients with refractory, noninfective scleritis at 24 weeks. The drug is usually well-tolerated in majority of the patients. Recurrence of inflammation is common and requires repeated infusions.123–125

Several newer biologics have been used in the management of treatment-resistant cases of scleritis. Tocilizumab is a recombinant humanized monoclonal antibody that prevents interleukin-6-mediated signaling by blocking both transmembrane and soluble interleukin-6 receptors.126 Tocilizumab is a useful alternative in the management of noninfective scleritis.127–129 Tocilizumab has been reported to be beneficial in the management of severe systemic rheumatoid vasculitis complicated by the involvement of multiple extra-articular organs with scleritis and necrotizing crescentic glomerulonephritis.130 However, paradoxical worsening in the form of a scleral nodule has been described in a 48-year-old patient after the second dose of tocilizumab therapy.131 Janus kinases inhibitor such as tofacitinib has been described as an effective steroid-sparing agent in the management of scleritis.132 Recently, a retrospective analysis reported the efficacy of various biologics including rituximab, anakinra, tocilizumab, abatacept, and tofacitinib in 19 eyes of 14 patients with refractory scleritis.133 Resolution of scleritis was achieved in 10 out of 19 eyes, and the authors reported a significant decrease in the number of relapses with these agents.134

Scleritis is a severe, vision-threatening inflammation of the sclera, which often poses significant diagnostic and therapeutic challenges for the treating ophthalmologists. In the absence of rapid and effective treatment, the inflammation can spread to adjacent structures and can be progressively destructive, leading to vision loss. The management of scleritis usually requires a multidisciplinary approach, and a patient with noninfective scleritis should be carefully screened for an underlying systemic rheumatic disease or other associated systemic diseases. Biologic agents are increasingly used in the management of scleritis, not responding to the conventional therapies; however, there is a need for clinical trials evaluating the efficacy of these biologic agents to the conventional therapies for scleritis.

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        Keywords:

        biologicals; necrotizing scleritis; posterior scleritis; scleritis; systemic rheumatic diseases

        Copyright © 2020 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.