Scleral inflammation (scleritis) may occur in one or both eyes. Pain is a hallmark symptom.
Signs of scleritis include focal or diffuse redness or violaceous discoloration, initial scleral thickening, late scleral thinning, nodules, and scleral necrosis. It may be associated with keratitis, iritis, glaucoma, and exudative retinal detachment.
Scleritis commonly has an underlying cause, usually an autoimmune disease (rheumatoid arthritis, granulomatosis with polyangiitis, other vasculitic/connective tissue diseases).
Treatment include corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), immunosuppressives, and biologics.
Scleritis is a chronic, painful, and potentially blinding inflammatory disease that is characterized by edema and cellular infiltration of the scleral and episcleral tissues (outermost coat of the eye). Scleritis may be isolated to the eye, but is commonly associated with systemic autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, relapsing polychondritis, spondyloarthropathies, Wegener granulomatosis, polyarteritis nodosa, and giant cell arteritis.
Scleritis may be the initial or only presenting clinical manifestation of these potentially lethal disorders. The correct and rapid diagnosis and the appropriate systemic therapy can halt the relentless progression of both ocular and systemic processes, thus preventing destruction of the globe while prolonging survival and improving quality of life.
Scleritis may be classified into anterior and posterior. Anterior scleritis can be diffuse, nodular, necrotizing with inflammation (necrotizing), and necrotizing without inflammation (scleromalacia perforans). The most common clinical forms are diffuse scleritis and nodular scleritis. Necrotizing scleritis with or without inflammation is much less frequent, more ominous, and frequently associated with systemic autoimmune disorders, as well as peripheral ulcerative keratitis. Posterior scleritis is characterized by flattening of the posterior aspect of the globe revealed with imaging, thickening of the posterior coats of the eye (choroid and sclera), and retrobulbar edema.[1]
An autoimmune dysregulation in a genetically predisposed host is presumed to cause scleritis. Inciting factors may include infectious organisms, endogenous substances, or trauma. The inflammatory process may be caused by immune complex–related vascular damage (type III hypersensitivity) and subsequent chronic granulomatous response (type IV hypersensitivity).
Both immune complex vessel deposition in episcleral- and scleral-perforating capillary and postcapillary venules (inflammatory microangiopathy) and cell-mediated immune responses interact as part of the activated immune network, which can lead to scleral inflammation and destruction. The autoimmune nature of scleritis also is supported by the frequent association with systemic autoimmune disorders and by the favorable response to immunosuppressive therapy.[2]
United States
Although scleritis is uncommon, the exact incidence of scleritis is uncertain. The reported prevalence of scleritis is skewed by the somewhat selected referrals of the reporting institutions.
Approximately 2.6% of patients who were referred to the Immunology Service at the Massachusetts Eye and Ear Infirmary Hospital of Boston during an 11-year period had scleritis.
About 8.7% of patients who were referred to the Massachusetts Eye Research and Surgery Institute (MERSI) of Cambridge, MA, during a 5-year period had scleritis.
International
Approximately 0.08% of patients who were referred to the Department of Ophthalmology of Southern General Hospital and Victoria Infirmary of Glasgow during an 8-year period had scleritis.
Patients with scleritis are at risk for ocular complications and systemic disease association.
Ocular complications of scleritis, which cause vision loss and eye destruction, appear as a result of the extending scleral inflammation. Peripheral ulcerative keratitis (13-14%), uveitis (about 42%), glaucoma (12-13%), cataract (6-17%), and fundus abnormalities (about 6.4%) are all common. These complications are most common in necrotizing scleritis, the most destructive type of scleritis.
Disease association may be found in about 57% of patients with scleritis. Up to 48% of patients with scleritis present with a previously known connective-tissue or vasculitic disease. Some of these diseases are potentially lethal unless treated with prompt and aggressive therapy. Other patients may present with concomitant trauma, infection, or postsurgical inflammation. Systemic disease association is most common in cases of necrotizing scleritis. Scleritis may be the first manifestation of a potentially lethal systemic disease.
Women are more likely to have scleritis than men (1.6:1).
Scleritis is most common in the fourth to sixth decades of life, with the peak incidence occurring in the fifth decade.
Prognosis varies depending on the disease classification. It may range from a self-limited episode of inflammation to a severe necrotizing process with vision-threatening complication.
Ocular prognosis of scleritis with systemic autoimmune diseases varies, depending on the specific autoimmune disease.
Scleritis in spondyloarthropathies or in systemic lupus erythematosus, usually a relatively benign and self-limiting condition, is diffuse scleritis or nodular scleritis without ocular complications.
Scleritis in granulomatosis with polyangiitis is a severe disease that can lead to permanent blindness; it is usually necrotizing scleritis with ocular complications.
Scleritis in rheumatoid arthritis or relapsing polychondritis is a disease of intermediate severity; it may be diffuse, nodular, or necrotizing scleritis with or without ocular complications.
Scleritis without systemic disease association is often more benign than scleritis accompanied by infection or autoimmune disease. These cases of idiopathic scleritis may be mild, shorter in duration, and more likely to respond to topical steroid drops alone.
It is important for patients with signs and symptoms of scleritis to undergo an accurate eye evaluation to ensure proper treatment, to determine prognosis, and to exclude differential diagnoses with less vision-threatening potential.
For excellent patient education resources, visit eMedicineHealth's Eye and Vision Center. Also, see eMedicineHealth's patient education article Eye Pain.
When interviewing the patient, investigate the following: the major complaint; a history of the present illness; the past history, including infection, injury, or surgery; and the review of systems.
Symptoms of scleritis can include pain, tearing or photophobia, ocular tenderness, and decreased visual acuity. Pain is the most common symptom for which patients seek medical assistance, and it is the best indicator of active inflammation. Pain results from both direct stimulation and stretching of the nerve endings by the inflammation.
The following pain descriptions are characteristic of scleritis:
The primary sign of scleritis is redness. Tearing or photophobia without mucopurulent discharge, which is usually mild or moderate, may occur in about 25% of patients with scleritis.
Unfortunately, many patients with scleritis first present to the emergency room or urgent care clinic, where a diagnosis of conjunctivitis is typically treated inappropriately with topical antibiotics. This practice generally leads to a significant delay in the initiation of anti-inflammatory therapy and a prolonged clinical course and more guarded prognosis.
Upon palpation, the patient may describe tenderness that is diffuse with possible radiation to other parts of the head.
Decreased visual acuity may be caused by extension of scleritis to the adjacent structures, leading to reactive blepharitis, myositis, keratitis, uveitis, glaucoma, cataract, and fundus abnormalities.
Redness gradually increases over several days. It has a bluish red tinge, which is seen best when the examination is performed in natural light, not through the slit lamp. It may be localized in one sector or involve the whole sclera; most frequently, it is in the interpalpebral area. This discoloration does not blanche after topical applications of routine sympathomimetic dilating agents (Neo-Synephrine 2.5%).
Past medical and ocular histories may elucidate systemic diseases, trauma, drugs, or surgical procedures that might cause scleritis:
Past medical history is also important for discovering certain conditions (eg, gastric ulceration, diabetes, liver disease, anemia, renal disease, hypertension) that eventually might modify future therapy.
Past and present therapies and responses to these interventions should be investigated.
Because scleritis can be associated with systemic disorders, make a routine inquiry that covers various bodily systems, as follows:
Examination of the head and extremities (eg, nose, mouth, external ear, skin, joints) may reveal significant signs, which might be compatible with a particular underlying disease. An eye examination might detect and characterize scleral disease. Ocular examination should include a complete general eye examination with a specific focus on the sclera.
Daylight
The sclera may appear diffuse, deep bluish red, or violaceous. After several attacks of scleral inflammation, areas of scleral thinning and translucency may appear, allowing the darkness of the uvea to be appreciated through the thin sclera.
A black, gray, or brown area that is surrounded by active scleral inflammation indicates a necrotizing process. If tissue necrosis progresses, the scleral area may become avascular, producing a central white sequestrum surrounded by a well-defined black or dark brown circle. The slough may be replaced gradually by granulation tissue, leaving the underlying uvea bare or covered by a thin layer of Tenon and conjunctiva.
Slit lamp light
In scleritis, maximum congestion is in the deep episcleral network with some congestion in the superficial episcleral network. The posterior and anterior edges of the slit lamp beam are displaced forward because of underlying scleral and episcleral edema.
In scleritis, topical application of 2.5% or 10% phenylephrine only blanches the superficial episcleral network without significant effect on the deep episcleral network.
Red-free light
Red-free light is helpful to the following study areas:
Evaluate adjacent structures in scleritis at every follow-up visit, since involvement is an important reason for vision loss, as follows:
Scleritis may occur in isolation (43%) or in association with several types of disorders (57%), as follows:
See the list below:
Based on the past history, review of systems, and physical examination, select appropriate diagnostic tests to confirm or reject the following suspected associated diseases:
See the list below:
See the list below:
Low-dose anterior segment fluorescein angiography (FA) combined with anterior segment indocyanine green (ICG) angiography is recommended.[9] ICG distinguishes totally occluded vessels from the temporary obstruction caused by high endothelial venules or vascular spasm seen as nonperfusion with FA. FA identifies new corneal vessels and leakage, whereas ICG does not. ICG locates the site of maximum inflammation and is more valuable in assessing the effects of treatment and when to withdraw that treatment. These anterior-segment imaging techniques require specific expertise and training and are not available in most facilities or academic departments.
A nongranulomatous inflammatory reaction occurs that is characterized by infiltration of mononuclear cells, such as macrophages, lymphocytes, and plasma cells. In the most severe cases, mononuclear cells may organize into granulomatous lesions. Mast cells, neutrophils, and eosinophils may also be present.
A granulomatous inflammatory reaction occurs that is characterized by a central area of fibrinoid necrosis, surrounded by epithelioid cells, multinucleated giant cells, lymphocytes, and plasma cells. Neutrophils, mast cells, and eosinophils are dispersed throughout the inflamed tissue and around vessels. Inflammatory microangiopathy, which is characterized by neutrophilic infiltration in and around the episclera and sclera that perforates the vessel walls with or without fibrinoid necrosis, is frequently seen.
Treatment of scleritis almost always requires systemic therapy. Patients with an associated disease, such as rosacea, gout, atopy, or infection, need disease-specific treatment. Systemic therapy complements aggressive topical corticosteroid therapy, generally with difluprednate, prednisolone or loteprednol etabonate. Use of both topical and systemic modalities reduces the dose requirements of each. This combination therapy mitigates, to some extent, the inherent risks of systemic steroids, including hypertension and diabetes, among many others; the risks of GI and renal morbidity caused by oral nonsteroidal anti-inflammatory drugs (NSAIDs); and the risks of elevated IOP and cataractogenesis due to topical steroids.
Treatment of noninfectious scleritis: Systemic NSAIDs, corticosteroids, or immunomodulatory drugs are indicated.[10] Topical therapy is routinely insufficient. This treatment must be individualized for the severity of the scleritis, response to treatment, adverse effects, and presence of associated disease.
Systemic dosing information is as follows:
The initial therapy consists of a systemic NSAID; in case of therapeutic failure, 2 additional successive different NSAIDs should be tried following the first drug. In high-risk patients, consider appropriate gastrointestinal protection with misoprostol or omeprazole.
If NSAIDs are not effective or have untoward complications, oral corticosteroids can be substituted. Remission may be maintained with continued NSAIDs.
Periorbital and subconjunctival steroid injections have been reported to be efficacious as adjunctive therapy. Caution should be observed, particularly when a comorbid infectious etiology such as toxoplasmosis or syphilis cannot be completely ruled out.[11]
In case of therapeutic failure of systemic corticosteroids, immunosuppressive drugs should be added or substituted. Methotrexate (MTX) can be the first choice, but azathioprine, mycophenolate mofetil, cyclophosphamide, or cyclosporine may also be helpful.[12, 13, 14] Cyclophosphamide should be the first choice in treating patients with associated potentially lethal vasculitic diseases, such as granulomatosis with polyangiitis or polyarteritis nodosa.
In case of therapeutic failure, biologic response modifiers, such as infliximab or adalimumab, may be effective.[15, 16, 17, 1, 6] Other alternatives include golimumab, certolizumab, tocilizumab, and rituximab, although further investigation is warranted.[18, 19, 20]
The initial therapy consists of immunosuppressive drugs that are supplemented with corticosteroids during the first month; the latter is tapered slowly, if possible. Cyclophosphamide should be the first choice in treating patients with an underlying systemic vasculitis such as granulomatosis with polyangiitis or polyarteritis nodosa.
In case of therapeutic failure, biologic response modifiers, such as infliximab or adalimumab, may be effective. Other alternatives are golimumab, certolizumab, tocilizumab, and rituximab, although their efficacy awaits further study.[20, 21]
Periocular steroid injections should not be applied in cases of necrotizing scleritis or peripheral ulcerative keratitis but could be very helpful in diffuse or nodular scleritis as an adjunctive therapy. Some authors believe that depot steroids actually may exacerbate necrotizing disease.
Pulse intravenous cyclophosphamide with or without pulse intravenous corticosteroids may be required for urgent cases and may be followed by maintenance therapy.
Systemic treatment with or without topical antimicrobial therapy always is required. Differentiating infectious scleritis from noninfectious scleritis is important because corticosteroid therapy and immunosuppressive therapy (often used in noninfectious autoimmune scleritis) are contraindicated in active infections.
Tectonic surgical procedures rarely may be required to preserve the integrity of the globe.
Scleral grafts from fresh donor sclera or glycerin-preserved sclera are available through eye banks. Grafts may be performed in cases of pending perforation during the time before the effects of systemic immunosuppressive agents manifest.
Corneal tissue may be used for associated corneal disease.
See the list below:
Patients should undergo a room-light scleral examination, a slit-lamp evaluation, and general eye examination at every follow-up visit.
Carefully monitor medication type, dose, and adverse effects. In case of therapeutic failure, change the medication type.
Consultation with a rheumatologist for associated systemic disease and/or immunomodulatory therapy follow-up care is recommended.
Drug precautions are as follows:
In cases of pending scleral perforation, peripheral ulcerative keratitis perforation, or positive Seidel test, admit for scleral patch grafting.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Clinical Context: Inhibits phospholipase A and Fc receptor expression, activates the glucocorticoid receptor, reduces cytokine production, suppresses lymphocyte function, and redistributes circulating leukocytes. Also potent inhibitors of angiogenesis and potent stabilizer of cell membranes.
Clinical Context: Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body. Alternative corticosteroids may be used in equivalent dosage.
Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Clinical Context: Inhibits DHFR, causing a block in the reduction of dihydrofolate to tetrahydrofolate. This inhibits the formation of thymidylate and purines; arrests DNA, RNA, and protein synthesis. Patients should take adjunctive folic acid therapy up to 1000 mg per day to avoid hematopoietic complications.
Clinical Context: Interferes with DNA synthesis and inhibits lymphocyte proliferation.
Clinical Context: Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross linking of DNA, which may interfere with growth of normal and neoplastic cells. Drug of choice for granulomatosis with polyangiitis or polyarteritis nodosa.
Clinical Context: Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity. For children and adults, base dosing on ideal body weight.
Clinical Context: Inhibits purine synthesis and proliferation of human lymphocytes. Promising published case report of 3 patients with resistant disease treated with mycophenolate mofetil. Reduced toxicity makes this regimen an attractive alternative.
Clinical Context: Subcutaneous recombinant human IgG1 monoclonal antibody specific for human TNF. Indicated to reduce inflammation and inhibit progression of structural damage in moderate-to-severe rheumatoid arthritis. Reserved for those who experience inadequate response to one or more DMARDs. Can be used alone or in combination with MTX or other DMARDs. Binds specifically to TNF-alpha and blocks interaction with p55 and p75 cell-surface TNF receptors.
Clinical Context: Intravenous chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-alpha and inhibits its binding to TNF-alpha receptor. Reduces infiltration of inflammatory cells and TNF-alpha production in inflamed areas. Used with MTX in patients who have had inadequate response to MTX monotherapy.
Clinical Context: Indicated to reduce signs and symptoms for moderately-to-severely active rheumatoid arthritis in combination with MTX. For use in adults who have experienced an inadequate response to one or more TNF antagonist therapies. Antibody genetically engineered. Chimeric murine/human monoclonal antibody directed against the CD20 antigen found on surface of B lymphocytes. Focal leukoencephalopathy is a lethal rare side effect that must be considered.
Selective immunomodulators that affect specific aspects of the inflammatory pathways.
Clinical Context: DOC for patients with mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.
Clinical Context: Rapidly absorbed. Metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation. Inhibits prostaglandin synthesis.
Clinical Context: For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.
Clinical Context: Decreases activity of cyclooxygenase, which, in turn, inhibits prostaglandin synthesis. These effects decrease formation of inflammatory mediators.
Clinical Context: Primarily inhibits COX-2. COX-2 is considered an inducible isoenzyme, induced by pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited, thus incidence of GI toxicity, such as endoscopic peptic ulcers, bleeding ulcers, perforations, and obstructions, may be decreased when compared to nonselective NSAIDs. Seek lowest dose for each patient.
Neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%).
Has a sulfonamide chain and is primarily dependent upon cytochrome P450 enzymes (a hepatic enzyme) for metabolism.
Have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known but may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may exist, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions. Systemic therapy with NSAIDs, corticosteroids, and immunosuppressive agents, alone or in combination, may be effective in patients with noninfectious scleritis.