eMedicine Specialties > Ophthalmology > Sclera

Scleritis

Maite Sainz de la Maza, MD, PhD, Associate Professor, Division of Ocular Immunology and Uveitis, Department of Ophthalmology, Hospital Clinico y Provincial, Barcelona, Spain

Updated: Nov 8, 2007

Introduction

Background

Scleritis is a chronic, painful, and potentially blinding inflammatory disease that is characterized by edema and cellular infiltration of the scleral and episcleral tissues. Scleritis 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 and prolonging survival.

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. Posterior scleritis is characterized by flattening of the posterior aspect of the globe, thickening of the posterior coats of the eye (choroid and sclera), and retrobulbar edema.

Pathophysiology

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).

The following interact as part of the activated immune network, which can lead to scleral destruction: immune complex vessel deposition in episcleral- and scleral-perforating capillary and postcapillary venules (inflammatory microangiopathy) and cell-mediated immune responses. The autoimmune nature of scleritis also is supported by the frequent association with systemic autoimmune disorders and by the favorable response to immunosuppressive therapy.

Frequency

United States

The exact incidence is uncertain, although scleritis is not common. The reported prevalence 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.

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.

Mortality/Morbidity

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%). 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 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.

Sex

Women are more likely to have scleritis than men (1.6:1).

Age

Scleritis is most common in the fourth to sixth decades of life. The peak incidence is in the fifth decade.

Clinical

History

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 can include pain, tearing or photophobia, tenderness, and decreased visual acuity. The primary sign is redness.
- 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:
  - Severe, penetrating pain that radiates to the forehead, brow, jaw, or sinuses
  - Awakens the patient during the night
  - Exacerbated by touch; extremely tender
  - Only temporarily relieved by analgesics
- Tearing or photophobia without mucopurulent discharge, which is usually mild or moderate, may occur in about 25% of patients with scleritis.
- 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 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. 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:
- Connective tissue or vasculitic diseases
- Infectious diseases
- Miscellaneous diseases (eg, atopy, rosacea, gout, chemical injuries)
- Blunt or penetrating ocular trauma
- Drugs, such as pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronic acid (Zometa), and ibandronate (Boniva)
- Past ocular surgical procedures, especially within a year prior to the onset of scleritis, might be significant.
Past medical history is also important for discovering certain conditions (eg, gastric ulceration, diabetes, liver disease, 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:
- Dermatologic (eg, skin, hair, nails)
- Respiratory
- Cardiac
- Genitourinary
- Rheumatologic
- Gastrointestinal
- Neurologic
- Ear, nose, sinus, and throat

Physical

The head and extremities (eg, nose, mouth, external ear, skin, joints) examinations may reveal significant signs, which might be compatible with a particular underlying disease. An eye examination might detect and characterize scleral disease. Include scleral and general eye examinations.

Scleral examination
- 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 dark uvea to show.
  - A black, grey, 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 white sequestrum in the center that is surrounded by a well-defined black or dark brown circle. The slough may be removed gradually by granulation tissue, leaving the underlying uvea bare or covered by a thin layer of 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 is helpful to the following study areas:
  - Areas that have maximum vascular congestion
  - Areas that display new vascular channels
  - Areas that are totally avascular
General eye examination: Evaluate adjacent structures in scleritis at every follow-up visit, since involvement is an important reason for vision loss.
- Extraocular muscles
- Cornea
- Uvea
- Lens
- Intraocular pressure
- Dilated fundus

Causes

Scleritis may occur isolated (43%) or in association with several types of disorders (57%).

Autoimmune (48%)
- Connective tissue diseases and other inflammatory conditions include the following:
  - Rheumatoid arthritis
  - Systemic lupus erythematosus
  - Ankylosing spondylitis
  - Reactive arthritis
  - Psoriatic arthritis
  - Gouty arthritis
  - Inflammatory bowel diseases
  - Relapsing polychondritis
  - Polymyositis
  - Sjögren syndrome
  - Mixed connective tissue disease
  - Progressive systemic sclerosis
- Vasculitic diseases include the following:
  - Polyarteritis nodosa
  - Allergic angiitis of Churg-Strauss syndrome
  - Wegener granulomatosis
  - Behçet disease
  - Giant cell arteritis
  - Cogan syndrome
Infectious (7%) - Bacterial, fungal, viral, or parasitic
Miscellaneous (2%) - Atopy; rosacea; or secondary to foreign bodies, chemical injuries, or drugs (eg, pamidronate, alendronate, risedronate, zoledronic acid, ibandronate)

Differential Diagnoses

Conjunctivitis, Allergic	Red Eye Evaluation
Corneal Melt, Postoperative	Squamous Cell Carcinoma, Conjunctival
Episcleritis	Squamous Cell Carcinoma, Eyelid
Gout	Uveitis, Anterior, Nongranulomatous
Herpes Zoster
Ocular Rosacea

Workup

Laboratory Studies

Based on the past history, review of systems, and physical examination, select appropriate diagnostic tests to confirm or reject the following suspected associated diseases:
- Rheumatoid factor - Rheumatoid arthritis
- Antinuclear antibodies - Systemic lupus erythematosus, rheumatoid arthritis, polymyositis, progressive systemic sclerosis, or mixed connective tissue
- Antineutrophil cytoplasmic antibodies (ANCA) - Wegener granulomatosis, polyarteritis nodosa, or microscopic polyangiitis
- Human leukocyte antigen (HLA) typing - Ankylosing spondylitis, reactive arthritis, psoriatic arthritis, or arthritis associated with inflammatory bowel disease
- Eosinophil count/immunoglobulin E (IgE) - Allergic angiitis of Churg-Strauss syndrome or atopy
- Uric acid - Gout
- Erythrocyte sedimentation rate (ESR) - Giant cell arteritis
- Hepatitis B surface antigen (HBsAg) - Polyarteritis nodosa
- Serologies - Infectious diseases, including syphilis
- Tuberculosis (TB) and anergy skin testing - Rare occurrence of TB or sarcoidosis

Imaging Studies

Chest x-ray - TB, Wegener granulomatosis, allergic angiitis of Churg-Strauss syndrome, or atopy
Sinus films - Wegener granulomatosis
Sacroiliac x-ray - Ankylosing spondylitis, reactive arthritis, psoriatic arthritis, or arthritis associated with inflammatory bowel disease
Limb joint x-ray - Rheumatoid arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, or gout
Ultrasonography (A- and B-scan) - Posterior scleritis; most helpful test to aid in diagnosing posterior scleritis, which is characterized by flattening of the posterior aspect of the globe, thickening of the posterior coats of the eye (choroid and sclera), and retrobulbar edema
CT scan - Posterior scleritis; a useful diagnostic tool to aid in detecting the following, which are important to differentiate posterior scleritis from orbital inflammatory diseases and orbital neoplasm: extraocular muscle or lacrimal gland enlargement, sinus tissue involvement, and posterior scleral thickening
MRI - Posterior scleritis
- MRI is used to differentiate localized inflammatory pseudotumor from posterior scleritis in proptosis or choroidal tumors from posterior scleritis in subretinal mass.
- Some orbital tumors, which cause choroidal folds and retinal striae, are also signs of posterior scleritis that are detected successfully by MRI.

Other Tests

Skin testing
- Intracutaneous tuberculin purified protein derivative (PPD) - TB
- Prick test - Atopy
Smears, cultures, and polymerase chain reaction (PCR) from conjunctival, corneal, episcleral, or scleral scraping - Infectious scleritis
- Scleral or corneoscleral biopsy is recommended if smears and culture results are negative at 48 hours, infectious scleritis is still the primary clinical suspicion, and the patient is worsening.
  - One third of tissue from a biopsy is sent to the microbiology department, where it is homogenized for smears, cultures, and PCR.
  - The middle third of tissue is transported to the pathology department for histopathology with special stains (eg, periodic acid-Schiff [PAS], Gomori methenamine-silver, acid-fast, calcofluor white).
  - The last third of tissue is sent to the immunology department for immunofluorescence studies with monoclonal antibodies (eg, anti–herpes simplex virus type 1, anti–varicella-zoster virus antibodies).
PCR of body fluids - Infectious scleritis

Procedures

Low-dose anterior segment fluorescein angiography (FA) combined with anterior segment indocyanine green (ICG) angiography is recommended. 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.
- Diffuse scleritis
  - FA - Rapid filling, short transit time, extensive leakage, normal vascular pattern, and deep sclera leakage in early disease
  - ICG - Rapid filling, short transit time, no leakage except for local vascular damage, and occasionally late deep leakage
- Nodular scleritis
  - FA - Rapid transit time, abnormal leakage pattern, and staining nodules
  - ICG - Rapid filling, short transit time, and stained nodules
- Necrotizing scleritis
  - FA - Hypoperfusion and venular occlusion, increased transit time, new vessel formation, and deep staining
  - ICG - Hypoperfusion and venular occlusion, increased transit time, and late leakage from new or damaged vessels
- Scleromalacia perforans
  - FA - Virtually no perfusion
  - ICG - Leakage in area of necrotic tissue
- Posterior scleritis
  - FA - Retinal pigment epithelial detachments, serous retinal detachment, cystoid edema, choroidal folds, and hyperfluorescent and hypofluorescent areas
  - ICG - Diffuse zonal choroidal hyperfluorescence intermediate or late phase, pinpoint leakage, delayed choroidal perfusion, and hyperfluorescence in areas of maximal activity

Histologic Findings

Diffuse scleritis or nodular scleritis

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.

Necrotizing scleritis

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

Medical Care

Treatment almost always requires systemic therapy. Patients with an associated disease, such as rosacea, gout, atopy, or infection, need specific treatment.

Treatment of noninfectious scleritis: Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or immunomodulatory drugs are indicated. Topical therapy is routinely insufficient. This treatment must be individualized for the severity of the scleritis, response to treatment, adverse effects, and presence of the associated disease.
- Diffuse scleritis or nodular scleritis
  - The initial therapy consists of an NSAID; in case of therapeutic failure, 2 different NSAIDs should be tried in succession with 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.
  - In case of therapeutic failure of corticosteroids, immunosuppressive drugs should be added or substituted. Methotrexate can be the first choice, but azathioprine, cyclophosphamide, or cyclosporine may be helpful. Cyclophosphamide should be the first choice in treating patients with associated potentially lethal vasculitic diseases, such as Wegener granulomatosis or polyarteritis nodosa.
  - In case of therapeutic failure, other immunomodulatory drugs, such as the tumor necrosis factor alpha (TNF-alpha) inhibitor infliximab, may be effective, although further investigation is warranted.
- Necrotizing scleritis
  - The initial therapy consists of immunosuppressive drugs that are supplemented with corticosteroids during the first month; the latter is tapered slowly, if possible. Cyclophosphamide is the most effective drug.
  - In case of therapeutic failure, another immunomodulatory drug, such as infliximab, may be effective. Other alternatives are daclizumab and rituximab, although their efficacy awaits further study.
  - Periocular steroid injections should be applied with great caution in cases of necrotizing scleritis or peripheral ulcerative keratitis. 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.
Treatment of infectious scleritis: 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.

Surgical Care

Tectonic surgical procedures rarely may be required to preserve the integrity of the globe.
- Scleral grafts are fresh sclera or glycerin-preserved sclera that is 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.

Consultations

Rheumatology or internal medicine consultation for associated disease
Hematology, oncology, or internal medicine consultation for immunosuppressive therapy

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Orasone, Sterapred)

Inhibits phospholipase A and Fc receptor expression, reduces cytokine production, suppresses lymphocyte function, and redistributes circulating leukocytes. Also potent inhibitors of angiogenesis and potent stabilizer of cell membranes.

Dosing

Adult

1 mg/kg/d PO qd (single morning dose) with food

Pediatric

Not established

Interactions

Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Immunosuppressive drugs

Inhibit immune system activities.

Methotrexate (Folex PFS, Rheumatrex)

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.

Dosing

Adult

7.5-15 mg/wk PO divided tid or 15 mg/wk IM (once weekly) together with folic acid (1 mg/d)

Pediatric

Not established

Interactions

Oral aminoglycosides may decrease absorption and blood levels of concurrent oral MTX; charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX; coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase MTX plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity of MTX; may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor CBCs monthly, and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg, dehydration); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested)

Azathioprine (Imuran)

Interferes with DNA synthesis and inhibits lymphocyte proliferation.

Dosing

Adult

1-2 mg/kg PO qd

Pediatric

Not established

Interactions

Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Contraindications

Documented hypersensitivity; low levels of serum TPMT

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; check TPMT level prior to therapy; follow liver, renal, and hematologic function; pancreatitis rarely associated

Cyclophosphamide (Cytoxan, Neosar)

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.

Dosing

Adult

1-3 mg/kg/d PO or pulsed IV 1 g/m² body surface area, in 250 mL of normal saline, piggy-backed onto the second half of one L 0.5% dextrose in water, infused over a 2-h period, q3-6wk

Pediatric

Not established

Interactions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life, while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis;
prehydration and copious oral intake of fluids (3 L/d) should be encouraged to minimize risk of hemorrhagic cystitis

Cyclosporine (Neoral, Sandimmune)

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.

Dosing

Adult

2-5 mg/kg/d PO divided bid

Pediatric

Not established

Interactions

Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin

Contraindications

Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis since it may increase risk of cancer

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

Mycophenolate mofetil (CellCept)

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.

Dosing

Adult

1 g PO bid

Pediatric

Not established

Interactions

In combination with either acyclovir or ganciclovir, may result in higher levels for both interacting drugs due to competition for renal tubular excretion; aluminum/magnesium present in some antacids and cholestyramine-containing products may decrease absorption, reducing levels (do not administer together); probenecid may increase levels of mycophenolate; salicylates and azathioprine may increase toxicity; may decrease levonorgestrel AUC; may decrease live virus vaccine immune response; when administered in combination with theophylline, may increase free fraction levels of theophylline

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Increases risk for infection (monitor blood count); severe renal impairment (CrCl <25 mL/min) may have increased adverse effects due to increase free MPA; caution in active peptic ulcer disease; incidence of malignancies and lymphoma consistent with that reported for other immunosuppressants (0.9%); commonly causes constipation, nausea, diarrhea, urinary tract infection, and nasopharyngitis; rare reports include interstitial lung disorders, colitis, pancreatitis, intestinal perforation, GI hemorrhage, gastric ulcers, duodenal ulcers, and ileus; do not chew, crush, or cut tab

Tacrolimus (Prograf)

Immunomodulator produced by the bacteria Streptomyces tsukubaensis. Mechanism of action similar to cyclosporine.

Dosing

Adult

0.15 mg/kg/d PO divided bid

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Skin can become photosensitive, and patients should use sunscreen and be cautioned about exposure to direct or artificial sunlight; excreted in human milk, discontinue either breastfeeding or drug, depending on importance of drug to mother (possible serious adverse reactions in breastfed infants); caution with immunosuppression (eg, AIDS, cancer); possible risk of lymph node cancer or skin cancer based on animal studies and small number of patients; may increase risk of viral infections; other adverse effects include headache, sore throat, flulike symptoms, fever, and cough

Monoclonal antibodies

Selective immunomodulators that affect specific aspects of the inflammatory pathways.

Infliximab (Remicade)

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 methotrexate in patients who have had inadequate response to methotrexate monotherapy.

Dosing

Adult

5 mg/kg IV (in combination with methotrexate therapy); follow by additional 5 mg/kg at 2 wk and 6 wk after first dose; repeat q8wk thereafter

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

TNF-alpha modulates cellular immune responses; anti-TNF therapies, such as infliximab, may adversely affect normal immune responses and allow development of superinfections; more cases of lymphoma were observed in TNF-alpha blockers compared to control groups; may increase risk of reactivation of tuberculosis in patients with particular granulomatous infections

Daclizumab (Zenapax)

Humanized monoclonal antibody that specifically binds to and blocks interleukin-2 (IL-2) receptor on surface of activated T cells.

Dosing

Adult

1 mg/kg IV over 15 min q2wk

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Manage patients receiving the drug in facilities with adequate supportive medical resources; severe, acute (onset within 24 h) hypersensitivity reactions, including anaphylaxis, observed with first exposure and upon re-exposure; studies in heart transplant recipients have shown increased mortality related to increased severe infection incidence

Blood products

Are used to improve clinical and immunologic aspects of the disease. They may decrease autoantibody production and increase solubilization and removal of immune complexes.

Immune globulin intravenous (Gammagard, Gammar-P, Gamunex, Sandoglobulin)

Neutralize 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%).

Dosing

Adult

2 g/kg IV over 2-5 d

Pediatric

Not established

Interactions

Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)

Contraindications

Documented hypersensitivity; IgA deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Check serum IgA before IVIG (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; lab result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Nonsteroidal anti-inflammatory drugs

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 may be effective in patients with noninfectious scleritis.

Ibuprofen (Motrin, Ibuprin)

DOC for patients with mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Dosing

Adult

800 mg PO tid

Pediatric

Not established

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy

Indomethacin (Indocin)

Rapidly absorbed. Metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation. Inhibits prostaglandin synthesis.

Dosing

Adult

75 mg SR PO bid

Pediatric

Not established

Interactions

Contraindications

Documented hypersensitivity; GI bleeding; renal insufficiency

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Category D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; reversible leukopenia may occur (discontinue if persistent leukopenia, granulocytopenia, or thrombocytopenia)

Naproxen (Naprosyn, Naprelan)

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.

Dosing

Adult

250-500 mg PO tid

Pediatric

Not established

Interactions

Contraindications

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Category D in third trimester of pregnancy; acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

Piroxicam (Feldene)

Decreases activity of cyclooxygenase, which, in turn, inhibits prostaglandin synthesis. These effects decrease formation of inflammatory mediators.

Dosing

Adult

20 mg PO qd

Pediatric

Not established

Interactions

Contraindications

Documented hypersensitivity; active GI bleeding

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Celecoxib (Celebrex)

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.

Dosing

Adult

200 mg PO qd; alternatively, 100 mg PO bid

Pediatric

Not established

Interactions

Coadministration with fluconazole may cause increase in celecoxib plasma concentrations because of inhibition of celecoxib metabolism; coadministration of celecoxib with rifampin may decrease celecoxib plasma concentrations

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause fluid retention and peripheral edema; caution in compromised cardiac function, hypertension, and conditions predisposing to fluid retention; caution in severe heart failure and hyponatremia because may deteriorate circulatory hemodynamics; NSAIDs may mask usual signs of infection; caution in the presence of existing controlled infections; evaluate therapy when symptoms or lab results suggest liver dysfunction

Follow-up

Further Inpatient Care

In cases of pending scleral perforation, peripheral ulcerative keratitis perforation, or positive Seidel test, admit for scleral patch grafting.

Further Outpatient Care

Patients should have a scleral examination 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 other specialists for associated systemic disease and/or immunosuppressive therapy follow-up care is recommended.

Inpatient & Outpatient Medications

Systemic medications include NSAIDs, corticosteroids, or immunomodulatory agents, depending on the type of scleritis and/or associated disease.

Complications

Keratopathy - Peripheral corneal thinning, acute stromal keratitis, sclerosing keratitis, or peripheral ulcerative keratitis
Uveitis - Anterior or posterior
Glaucoma
Cataract
Fundus abnormalities - Choroidal folds, subretinal mass, disk edema, macular edema, annular ciliochoroidal detachment, or serous retinal detachment

Prognosis

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 Wegener granulomatosis 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.

Patient Education

For excellent patient education resources, visit eMedicine's Eye and Vision Center. Also, see eMedicine's patient education article Eye Pain.

Miscellaneous

Medicolegal Pitfalls

Failure to inform patient and family of the adverse effects of NSAIDs, corticosteroids, or immunomodulatory agents
Failure to treat with immunosuppressive agents in cases of scleritis associated with Wegener granulomatosis or polyarteritis nodosa
Failure to establish or attempt to identify an underlying infectious or autoimmune etiology in severe, recurrent, or recalcitrant cases of scleritis

References

Ahmadi-Simab K, Lamprecht P, Nölle B, Ai M, Gross WL. Successful treatment of refractory anterior scleritis in primary Sjögren´s syndrome with rituximab. Annals of Rheumatic Diseases. 2005;64:1087-1088. [Medline].
Cazabon S, Over K, Butcher J. The successful use of infliximab in resistant relapsing polychondritis and associated scleritis. Eye. Feb 2005;19(2):222-4. [Medline].
Cheung CMG, Murray PI, Savage COS. Successful treatment of Wegener´s granulomatosis associated scleritis with rituximab. Br J Ophthalmol. 2005;89:1542-1543. [Medline].
Fong LP, Sainz de la Maza M, Rice BA, Kupferman AE, Foster CS. Immunopathology of scleritis. Ophthalmology. Apr 1991;98(4):472-9. [Medline].
Hakin KN, Ham J, Lightman SL. Use of orbital floor steroids in the management of patients with uniocular non-necrotising scleritis. Br J Ophthalmol. Jun 1991;75(6):337-9. [Medline].
Murphy CC, Ayliffe WH, Booth A, Makanjuola D, Andrews PA, Jayne D. Tumor necrosis factor alfa blockade with infliximab for refractory uveitis and scleritis. Ophthalmology. 2004;111(2):352-356. [Medline].
Murphy CC, Ayliffe WH, Booth A, Makanjuola D, Andrews PA, Jayne D. Tumor necrosis factor alpha blockade with infliximab for refractory uveitis and scleritis. Ophthalmology. Feb 2004;111(2):352-6. [Medline].
Nieuwenhuizen J, Watson PG, Emmanouilidis-van der Spek K, Keunen JE, Jager MJ. The value of combining anterior segment fluorescein angiography with indocyanine green angiography in scleral inflammation. Ophthalmology. Aug 2003;110(8):1653-66. [Medline].
Papaliodis GN, Chu D, Foster CS. Treatment of ocular inflammatory disorders with daclizumab. Ophthalmology. Apr 2003;110(4):786-9. [Medline].
Sainz de la Maza M, Foster CS, Jabbur NS. Scleritis associated with rheumatoid arthritis and with other systemic immune-mediated diseases. Ophthalmology. Jul 1994;101(7):1281-6; discussion 1287-8. [Medline].
Sainz de la Maza M, Foster CS, Jabbur NS. Scleritis associated with systemic vasculitic diseases. Ophthalmology. Apr 1995;102(4):687-92. [Medline].
Sainz de la Maza M, Jabbur NS, Foster CS. An analysis of therapeutic decision for scleritis. Ophthalmology. Sep 1993;100(9):1372-6. [Medline].
Sainz de la Maza M, Jabbur NS, Foster CS. Severity of scleritis and episcleritis. Ophthalmology. 1994;101(2):389-396. [Medline].
Sainz de la Maza M, Tauber J, Foster CS. Scleral grafting for necrotizing scleritis. Ophthalmology. Mar 1989;96(3):306-10. [Medline].
Sobrin L, Kim EC, Christen W, Papadaki T, Letko E, Foster CS. Infliximab therapy for the treatment of refractory ocular inflammatory disease. Arch Ophthalmol. Jul 2007;125(7):895-900. [Medline].
Tuft SJ, Watson PG. Progression of scleral disease. Ophthalmology. 1991;98(4):467-471. [Medline].
Wakefield D, McCluskey P. Cyclosporin therapy for severe scleritis. Br J Ophthalmol. 1989;73(9):743-746. [Medline].
Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol. Mar 1976;60(3):163-91. [Medline].

Keywords

scleromalacia perforans, necrotizing scleritis, brawny scleritis, diffuse scleritis, sectorial scleritis, nodular scleritis, scleromalacia, scleral inflammation, anterior scleritis, posterior scleritis

Contributor Information and Disclosures

Author

Maite Sainz de la Maza, MD, PhD, Associate Professor, Division of Ocular Immunology and Uveitis, Department of Ophthalmology, Hospital Clinico y Provincial, Barcelona, Spain
Maite Sainz de la Maza, MD, PhD is a member of the following medical societies: American Academy of Ophthalmology and American Uveitis Society
Disclosure: Nothing to disclose.

Medical Editor

John D Sheppard, Jr, MD, MMSc, Associate Professor of Ophthalmology, Microbiology and Immunology, Director for Thomas R Lee Center for Ocular Pharmacology, Director, Uveitis Service, Eastern Virginia School of Medicine; Consulting Staff, Virginia Eye Consultants
John D Sheppard, Jr, MD, MMSc is a member of the following medical societies: American Academy of Ophthalmology, American Society for Microbiology, American Uveitis Society, Association for Research in Vision and Ophthalmology, and Contact Lens Association of Ophthalmologists
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

R Christopher Walton, MD, Professor, Director of Uveitis and Ocular Inflammatory Diseases Service, Assistant Department of Ophthalmology, Assistant Dean for Graduate Medical Education and Continuing Education, University of Tennessee College of Medicine; Consulting Staff, Regional Medical Center, Memphis Veterans Affairs Medical Center, St Jude Children's Research Hospital
R Christopher Walton, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Healthcare Executives, American Uveitis Society, Association for Research in Vision and Ophthalmology, and Retina Society
Disclosure: Nothing to disclose.

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

Further Reading