A comprehensive medical and ophthalmic history, review of systems, and complete ocular and physical examination are essential to the diagnosis and management of scleral inflammatory disease.
Episcleritis, while most commonly idiopathic, may be associated with a variety of systemic vasculitic and connective tissue diseases and local ocular conditions in up to 36% of patients. These include atopy, rosacea, gout, herpes zoster, herpes simplex, syphilis, psoriasis, inflammatory bowel disease, systemic lupus erythematosus (SLE), myositis, relapsing polychondritis, erythema nodosum, Wegener granulomatosis, Cogan syndrome, and rheumatoid arthritis, the latter being the most common (Table 2). Other entities have been associated with episcleritis, such as drug reactions to pamidronate (Aredia), alendronate (Fosamax), and risedronate (Actonel). Episcleritis in childhood is rare, especially in children younger than 5; however, in older children, it is frequently associated with rheumatic disease.
Should the initial episode of episcleritis be evanescent and the medical review of systems and physical examination unrevealing, it is unnecessary to obtain extended diagnostic studies. Selective investigations should be performed to rule out specific diseases in patients with persistent or recurrent clinical course and symptoms suggestive of an associated systemic disease.
Scleritis may be the presenting clinical manifestation of a systemic disease. An associated systemic disease is present in approximately 40% to 57% of patients with scleritis; 30% to 48% have an associated connective tissue or vasculitic disease, 5% to 10% an infectious etiology, and 2% have atopy, rosacea, or gout (Table 2). Rheumatoid arthritis is by far the most common systemic association, followed by Wegener granulomatosis, relapsing polychondritis, systemic lupus erythematosus, and arthritis with inflammatory bowel disease. Necrotizing scleritis is most frequently identified in patients with Wegener granulomatosis, rheumatoid arthritis, polyarteritis nodosa, or relapsing polychondritis and is less likely to be seen in those with systemic lupus erythematosus, or the seronegative spondyloarthropathies. As with anterior scleritis, rheumatoid arthritis is the most common systemic disease association in posterior scleritis, followed by other connective tissue diseases (systemic lupus erythematosus, psoriatic arthritis) and systemic vasculitides (Wegener granulomatosis, polyarteritis nodosa, relapsing polychondritis); however, one must also consider infectious etiologies (Lyme disease, toxoplasmosis, herpes zoster) and neoplastic masquerade syndromes.
The diagnosis of a connective tissue or vasculitic condition in patients with scleritis carries a guarded systemic and ocular prognosis and demands prompt and aggressive systemic therapy. The mortality from vasculitic complications in patients with Wegener granulomatosis and polyarteritis nodosa is high in untreated patients, while the ocular morbidity and visual loss is more prevalent given the frequent occurrence of necrotizing scleritis and peripheral ulcerative keratitis with these diseases. The ocular prognosis of scleritis associated with connective tissue or vasculitic disease varies depending on the specific entity. Scleritis associated with spondyloarthropathies or systemic lupus erythematosus is usually a benign, self-limiting condition. That associated with rheumatoid arthritis or relapsing polychondritis is of intermediate severity. Scleritis associated with Wegener granulomatosis is a severe disease that can lead to permanent blindness or even loss of the eye.
Other entities have been associated with scleritis, such as drug reactions to pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronic acid (Zometa), and ibandronate (Boniva).
Infectious scleritis, either endogenous or exogenous, may be caused by the direct invasion of a microorganism or by the immune response to an infectious pathogen. Historical details that raise the index of suspicion of an infectious etiology include prior ocular trauma or surgery (especially a scleral buckling procedure, strabismus surgery, or pterygium excision), contact lens use, systemic or local immunosuppression, and local debilitating diseases (past history of recurrent keratitis caused by herpes simplex virus or herpes zoster virus). All classes of microorganisms, including bacteria, viruses, fungi, and parasites, can infect the sclera and produce a clinical picture identical to that seen with immune-mediated disease (Figure 9).
The presence of scleritis, even with the initial episode, requires a thorough diagnostic evaluation, guided by the patient’s clinical presentation, history, and review of systems. Typical initial investigations might include a chest radiograph, urine analysis, serum chemistries (which may indicate renal dysfunction in systemic vasculitides), syphilis serologies (FTA-ABS and RPR), and antineutrophil cytoplasmic antibody (ANCA) testing. ANCAs are specific markers for a group of related systemic vasculitides that include polyarteritis nodosa (PAN), Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and pauci-immune glomerulonephritis. Specifically, ANCAs are antibodies directed against cytoplasmic azurophilic granules of neutrophils and monocytes. These antibodies may be divided into 2 classes based on the pattern of staining seen on immunofluorescence. The cytoplasmic pattern, or c-ANCA, is both sensitive and specific for Wegener granulomatosis. The perinuclear pattern, or p-ANCA, is associated with PAN, microscopic polyangiitis, relapsing polychondritis, and renal vasculitis. All positive ANCA tests should be confirmed by testing for antibodies to proteinase-3 (PR3) and/or myeloperoxidase (MPO). Between 85% to 95% of all ANCA found in Wegener granulomatosis is c-ANCA with antigen specificity for PR3, which is highly specific for the disease, while the remainder is p-ANCA directed against MPO. In contrast, the diagnostic sensitivity of c-ANCA and p-ANCA for PAN is only 5% and 15% respectively, while in patients with microscopic polyangiitis, p-ANCA (anti-MPO) positivity is more common (50% to 80%) with a smaller percentage (40%) having the c-ANCA (anti-PR3) marker (Table 3).
Further testing in the appropriate clinical context might include:
- Rheumatoid factor or human leukocyte antigen (HLA)-B27 in the presence of polyarthritis or spondyloarthropathy
- Lyme serology in a patient with a history of a tick bite from an endemic area
- Antinuclear antibodies in individuals where SLE is suggested on history and physical exam
- Radiographic imaging of the sinus in the presence of sinus symptomatology
- Purified protein derivative (PPD) skin test or Quantiferon gold assay with a history of tuberculosis exposure
- Ultrasound examination in patients suspected of having posterior scleritis
Finally, scleral biopsy may be considered in cases where infectious scleritis, foreign body, or masquerade syndrome is suspected.