Fig. 5.16 Conjunctival biopsy, again demonstrating microangiopathy with inßammatory cells in the vessel wall and surrounding dense inßammatory inÞltration of the substantia propria

Fig. 5.17 Enucleation specimen from a patient who had posterior scleritis. Note the inßammatory cell inÞltrate in the sclera, but also the granulomatous inßammation of the choroid

Episclera

InÞltration of metabolically active Þbroblasts, lymphocytes, and plasma cells may involve the episclera in areas overlying active scleral inßammation. In some cases, episcleral necrosis with Þbroblast and extracellular matrix degradation may appear as a result of the extension of the scleral necrosis. Zonal granulomatous inßammation around necrotic areas may be seen. Neutrophils, lymphocytes, and plasma cells may localize around episcleral vessels. In some cases, episcleral vessel walls may reveal inßammatory microangiopathy [23, 41].

Conjunctiva

Destruction of the sclera often involves overlying conjunctiva, which displays an intense stromal inßammatory inÞltration and various degrees of epithelial derangements, ranging from squamous changes to epithelial loss. On occasion, the substantia propria may show a granulomatous inßammation with epithelioid cells and giant cells. Neutrophils, lymphocytes, eosinophils, plasma cells, and occasionally mast cells may be seen as perivascular accumulations. The walls of some vessels may be extensively inÞltrated by neutrophils (Fig. 5.16) [23, 41].

Iris, Ciliary Body, and Choroid

Anterior scleral inßammatory reactions may extend into the underlying uveal tract, sometimes

causing perivasculitis and a chronic granulomatous reaction with lymphocytes, plasma cells, giant cells, and epithelioid cells [11]. In posterior scleritis, the underlying choroid is also affected, giving rise to choroidal thickening (granulomatous inßammation) (Fig. 5.17) and less often to choroidal vasculitis [42, 43].

Cornea

Extension of the scleral inßammation into the cornea causes keratitis, which histologically may appear as an inÞltration of the corneal stroma by neutrophils, lymphocytes, and plasma cells. In the case of peripheral ulceration, necrotic epithelium can be seen at the overhanging edge [44].

Other Ocular Structures

Depending on the scleral area involved in scleritis, other ocular structures may also show morphological changes. Occasionally, scleritis is associated with an inßammatory inÞltration of the trabecular meshwork and intrascleral outßow channels [45]. Extraocular muscles and periorbital fat may show lymphocyte and plasma cell inÞltration [46]. Retinal pigment epithelium can be absent focally with surrounding inßammation in areas underlying choroiditis and scleritis [42]. Retinal and choroidal detachments, intravitreous or subretinal hemorrhages, perivasculitis of the retinal vessels, and central retinal vein occlusion may also appear. Optic nerve and macula may show inßammatory inÞltration [47].

Table 5.7 Vasculitic syndromes associated with scleritis

Noninfectious diseases

Primarily smalland medium-sized vessel vasculitic diseases

Primarily vasculitic (and/or granulomatous) diseases Polyarteritis nodosa

Allergic granulomatous angiitis (ChurgÐStrauss syndrome)

Granulomatosis with polyangiitis (Wegener) Beh•etÕs disease

CoganÕs syndrome SchšnleinÐHenoch purpura

Connective tissue diseases in which vasculitis may occur

Adult rheumatoid arthritis Systemic lupus erythematosus Relapsing polychondritis Juvenile rheumatoid arthritis SjšgrenÕs syndrome Dermatomyositis

Inßammatory conditions in which vasculitis may occur Arthritis and inßammatory bowel disease

Psoriatic arthritis

Primarily large-sized vessel vasculitic diseases

Inßammatory conditions in which vasculitis may occur Ankylosing spondylitis

Reactive arthritis Primarily vasculitic diseases

Giant cell arteritis TakayasuÕs arteritis

Infectious diseases

Clinicopathologic Correlates in Noninfectious Scleritis: Association with Systemic

Vasculitic Diseases

The clinical spectrum of systemic vasculitisassociated scleritis encompasses diseases thought to be primary vasculitic syndromes (PAN), diseases that are predominantly granulomatous (granulomatosis with polyangiitis [Wegener]), and diseases associated with underlying conditions, such as the acquired connective tissue disorders (rheumatoid arthritis) or other inßammatory conditions [48, 49]. A classiÞcation of vasculitic syndromes that can be associated with scleritis is shown in Table 5.7. In the following sections, we review the pathology of some of these conditions.

Polyarteritis Nodosa

The pathology of systemic PAN consists of nongranulomatous focal panmural necrotizing

vasculitis of smalland medium-sized muscular arteries, with a predilection for branching points and bifurcations. PAN may affect any smallor medium-sized artery of any organ, although there is less involvement of the pulmonary and splenic arteries [48, 50, 51]. Smalland medium-sized muscular arterial inßammation may extend to arterioles and, sometimes, to contiguous venules and veins. Skin, joints, peripheral nerves, gut, and kidney are the tissues most commonly involved [52]. Episcleritis or scleritis may be manifestations of ocular involvement [52, 53]; the latter may range from mild diffuse scleritis to severe necrotizing scleritis.

Histopathologically, systemic vascular lesions of affected organs are characterized by Þbrinoid necrosis and neutrophil inÞltration, which may extend to involve the full thickness of the arterial wall; less often, eosinophils and lymphocytes are present in and around the vessels. The arterial segment often thromboses or bulges in an aneurysmal fashion. As the lesions heal, there is proliferation of Þbrous tissue and endothelial cells of the affected arterial wall, which may lead to further occlusion of the vessel lumen. In any patient different arteries, or even separate branches of the same artery, may be seen in acute, chronic, or healed stages of arteritis [54]. Eosinophil tissue inÞltration and granulomas are not characteristically found [48].

The pathology of scleral involvement demonstrates an inßammatory microangiopathy of scleral vasculature that may lead to occlusion of some vessels. Choroidal vessels may also be involved [53, 55]. Unlike lesions elsewhere in the body, ocular involvement in PAN may show granulomatous changes in and around episcleral and choroidal vessels [9, 55Ð59].

In our past series [60], polyarteritis nodosa was diagnosed in two patients with scleritis, one with diffuse scleritis and the other with necrotizing scleritis; diagnosis conÞrmation was obtained after muscle and cutaneous nodule biopsy respectively. One of the cases is described as follows:

A 56-year-old white woman developed intermittent fever, chills, weight loss, fatigue, and low back pain. Discharge diagnoses after hospitalization at a community hospital were urinary tract infection and lumbar disk disease. Shortly

Fig. 5.18 Fifty-six-year-old woman with necrotizing scleritis and peripheral ulcerative keratitis. Note the intense scleritis and area of necrotizing scleritis, with a loss of approximately 85% of scleral thickness

Fig. 5.19 Subcutaneous nodule below the left elbow (same patient as in Fig. 5.18)

thereafter, she developed cervical pain, dizziness, and progressive lower extremity muscle weakness and, a few weeks later, she experienced pain in her right eye, noises in her right ear, and a grand mal seizure. At the time of the patientÕs Þrst evaluation by us, she exhibited a profound quadriceps muscle weakness and a heliotropic rash on the skin of the left eyelid. Her temperature was 39.5¡C and her pulse was 125 beats/min. Visual acuity was 20/50 OD (right eye), and 20/40 OS (left eye). Slit-lamp ocular examination disclosed a small area of anterior necrotizing scleritis and peripheral ulcerative keratitis (Fig. 5.18). Following admission to the hospital, laboratory tests showed a sedimentation rate of 120 mm/h, normal complete blood count (CBC) and muscle enzymes, and negative anti-nuclear antibody and rheumatoid factor tests. A few days later, a small nodule below the left elbow was detected (Fig. 5.19); biopsy showed nongranulomatous necrotizing vasculitis compatible with PAN (Fig. 5.20). Subsequent abdominal angiography disclosed arterial saccular aneurysms in the superior mesenteric artery. Systemic prednisone halted scleral inßammation and cleared systemic symptoms. Cyclophosphamide was instituted and prednisone tapered after 14 months of treatment because of steroid-induced myopathy.

Demonstration of necrotizing vasculitis on biopsy material of involved extraocular tissues conÞrms the diagnosis of systemic PAN in a patient

Fig. 5.20 Polyarteritis nodosa: subcutaneous nodular biopsy of the same patient as in Figs. 5.18 and 5.19. Note the enormous mononuclear cell inÞltrate in the arteriolar wall (MagniÞcation, ×40; hematoxylinÐeosin stain)

with compatible multisystem clinical Þndings. Inßammatory microangiopathy with or without granulomas in conjunctival and/or scleral specimens further strenghtens the diagnosis. Biopsy of symptomatic areas such as skin, testes, epididymis, skeletal muscle, and peripheral nerves provides the highest diagnostic yield [61, 62], whereas blind biopsy of asymptomatic organs is often negative. In cases with red cells, red cell casts, or proteinuria, renal biopsy will reveal focal necrotizing glomerulonephritis and, in about one half of the cases, a small vessel vasculitis will be demonstrated.

Allergic Granulomatous Angiitis (Churg–Strauss Syndrome)

The association of asthma, eosinophilia, pulmonary inÞltrations, vasculitis, and extravascular

granulomas was termed Òallergic angiitis and granulomatosisÓ by Churg and Strauss in 1951 [63]. The pathology of this disease consists of small, necrotizing granulomas and necrotizing vasculitis involving predominantly small arteries, arterioles, venules, and veins rather than smalland medium-sized muscular arteries. Granulomas are composed of a central eosinophilic core surrounded radially by macrophages and giant cells. Inßammatory cells, predominantly eosinophils, are present; neutrophils and lymphocytes also may be found in smaller numbers. Chronic lesions are characterized by macrophages and giant cells and lesser numbers of eosinophils. Necrotizing vasculitis is characterized by segmental Þbrinoid necrosis and leukocytic (predominantly eosinophil) inÞltration, in and around the vessels; variable numbers of macrophages and giant cells also may be present around the necrotic areas. There may be thrombosis or aneurysmal dilatation at the site of the lesion. Healed areas show proliferation of Þbrous tissue and endothelial cells, which may lead to further narrowing of the vessel lumen [64Ð66].

Allergic granulomatous angiitis (ChurgÐ Strauss syndrome) may affect any organ in the body; however, unlike classic PAN, lung involvement is predominant, with gastrointestinal tract, skin, heart, kidney, and peripheral nerves also commonly involved [67, 68]. Scleritis may also occur [69]. Scleral tissue from patients with the ChurgÐStrauss syndrome and scleritis shows numerous eosinophils, granulomatous proliferation of epithelioid and giant cells, and vascular closure by inßammatory microangiopathy [69].

Demonstration of necrotizing small vasculitis and eosinophilic necrotizing intraand extravascular granulomas on biopsy material of involved extraocular tissues conÞrms the diagnosis of ChurgÐStrauss syndrome in a patient with compatible multisystem clinical Þndings and laboratory tests [62Ð66, 69, 70]. Involved tissues more commonly biopsied for diagnosis are lung, skin, and peripheral nerves. Demonstration of eosinophilic granulomas and inßammatory microangiopathy in conjunctiva and/or scleral specimens further strenghtens the diagnosis.

Granulomatosis with Polyangiitis (Wegener)

Complete (classic) granulomatosis with polyangiitis (Wegener) is characterized by necrotizing granulomatous lesions of the upper and lower respiratory tract (nose, sinuses, and lung), generalized small-vessel vasculitis in the lung and other organs, and focal or diffuse necrotizing glomerulonephritis [71Ð76]. Less extensive or limited forms of this condition also exist, in which case renal involvement is absent [77]. In highly limited forms of granulomatosis with polyangiitis (Wegener), ocular or orbital involvement is present in the absence of systemic manifestations [78].

In the complete form of granulomatosis with polyangiitis (Wegener), ophthalmic involvement may be present in up to 58% of the cases [53, 79Ð82]. In the limited form of granulomatosis with polyangiitis (Wegener), ocular manifestations, including scleritis, may constitute the major signs and symptoms, or indeed may be the only manifestation of the disease [81Ð89]. In the highly limited form of granulomatosis with polyangiitis (Wegener), ocular or orbital involvement, including scleritis, is the only objective Þnding of the condition [78].

Because granulomatosis with polyangiitis (Wegener) is predominantly a granulomatous disease rather than a form of primary vasculitis [90], necrotizing granulomas on involved organs are invariably present. Purely granulomatous disease without vasculitis may represent an early manifestation of granulomatosis with polyangiitis (Wegener) [91]. Granulomas contain a central area of necrosis surrounded by a zone of Þbroblastic proliferation with multinucleated giant cells, epithelioid cells, neutrophils, lymphocytes, and plasma cells [74]. Eosinophils are often present [78]. Vasculitis is frequently found. The vascular changes are similar to those of PAN; acute lesions show Þbrinoid necrosis with neutrophil and mononuclear cell inÞltration within and often adjacent to the vessel wall, which may lead to lumen narrowing and subsequent obliteration; healed lesions show Þbroblastic and endothelial proliferation, which may contribute to further vessel narrowing. Whereas both types of lesions are seen in some areas, only one type

of lesion is present in others [75]. Pathologically, lesions of granulomatosis with polyangiitis (Wegener) differ from extraocular lesions of PAN in that the former are characterized by granulomas that may be in, around, or clearly separated from the vessel walls. Pathosis in granulomatosis with polyangiitis (Wegener) differs often from that of ChurgÐStrauss syndrome in that in the former, the disintegrating cells in the center of the granuloma are neutrophils, usually not eosinophils [92]. However, although pathological Þndings are helpful in differentiating different entities, a speciÞc diagnosis can be conÞrmed only with the association of characteristic clinical Þndings [78].

Pathology of scleral lesions may demonstrate lesions similar to those found in other organs [9, 10, 44, 78, 84, 88, 93]. The constellation of histopathological features on conjunctival and scleral tissues include (1) collagen necrosis, (2) nuclear dust, (3) granulomatous foci with multinucleated giant cells surrounded by epithelioid cells, neutrophils, lymphocytes, and plasma cells, and frequently (4) inßammatory microangiopathy.

The diagnosis of granulomatosis with polyangiitis (Wegener) is based on the interpretation of clinical features and histological Þndings. Anti-neutrophil cytoplasmic antibody (ANCA) testing is an important adjunct in the diagnosis of granulomatosis with polyangiitis (Wegener) [94]. ANCAs are antibodies directed against cytoplasmic azurophilic granules of neutrophils and monocytes and may be divided into two classes based on the pattern of staining seen on immunoßuorescence. The cytoplasmic pattern, or c-ANCA (antigen speciÞcity for proteinase-3 [PR3]) is both sensitive and speciÞc for granulomatosis with polyangiitis (Wegener). The perinuclear ANCA, or p-ANCA (antigen speciÞcity for myeloperoxidase [MPO]), is associated with PAN, microscopic polyangiitis, relapsing polychondritis, and renal vasculitis. Between 85 and 95% of all ANCA found in granulomatosis with polyangiitis (Wegener) is c-ANCA while 5Ð5% is p-ANCA. Because of its high speciÞcity, a positive ANCA test is suggestive of granulomatosis with polyangiitis (Wegener), even in patients

without compatible clinical and histopathological Þndings. The sensitivity of ANCA testing is dependent on disease severity; whereas ANCA testing is positive in 95% of patients with active complete (classic) granulomatosis with polyangiitis (Wegener), it is positive only in 67% of patients with active limited disease and in 32% of patients in full remission after limited disease [95]. Therefore, a negative ANCA test does not exclude the diagnosis, especially in patients with limited clinical features and characteristic histological Þndings.

Pathologic detection of necrotizing granulomas with or without vasculitis in involved extraocular tissues conÞrms the diagnosis of granulomatosis with polyangiitis (Wegener) in a patient with compatible systemic clinical Þndings, such as chronic sinusitis, nasal ulceration, chronic cough, or hematuria, with or without positive ANCA testing [96, 97]. Pathologic detection of necrotizing granulomas with or without inßammatory microangiopathy in conjunctiva and/or scleral specimens in association with complete and, especially, limited clinical features, conÞrms the diagnosis of granulomatosis with polyangiitis (Wegener), even if ANCA testing is negative.

Biopsy of involved nasal mucosal, sinus tissue, skin, or sclera offers the best opportunity for obtaining a histological diagnosis [74, 84, 92, 96, 97]. Involved lung tissue, preferably through open biopsy, also may be obtained. Because renal involvement ranges from diffuse proliferative glomerulonephritis and interstitial nephritis to hyalinization of glomeruli, results of renal biopsy are rarely distinctive enough from other conditions to be deÞnitive [49].

Pathologic detection of necrotizing granulomas with or without inßammatory microangiopathy in sclera conÞrms the diagnosis of the highly limited form of granulomatosis with polyangiitis (Wegener) in a patient with scleritis and positive ANCA testing [78]. In the absence of characteristic ocular histological Þndings, a positive ANCA test is suggestive of highly limited granulomatosis with polyangiitis (Wegener), although not diagnostic. In the absence of a positive ANCA test, the

presence of characteristic ocular histological Þndings without systemic clinical features does not support the diagnosis of granulomatosis with polyangiitis (Wegener).

In one of our past series [60], 13 patients with granulomatosis with polyangiitis (Wegener) underwent conjunctival and/or scleral biopsies; 1 patient had the complete form, 10 patients had the limited form, and 2 patients had the highly limited form (Table 5.8). In all but one patient, the ocular Þndings were the presenting manifestation that led to the diagnosis of granulomatosis with polyangiitis (Wegener). Detection of necrotizing granulomas and inßammatory microangiopathy by histopathology or immunoßuorescence conÞrmed the diagnosis of granulomatosis with polyangiitis (Wegener) in patients with the compatible clinical Þndings and positive ANCA testing. In patients with the highly limited form of granulomatosis with poly-

angiitis (Wegener), characteristic pathological Þndings conÞrmed the diagnosis in the context of positive ANCA testing. Prior to the development of ANCA testing, characteristic pathological Þndings conÞrmed the condition in patients with compatible clinical features. When clinical Þndings were nonspeciÞc (e.g., skin ulcer, patient no. 8, Table 5.8), necrotizing granulomas with vasculitis in other tissues (skin) established the diagnosis. One of the cases is described as follows:

A 41-year-old man developed pain, photophobia, and tearing in both eyes 6 months prior to his Þrst examination by us. Nodular scleritis in both eyes and marginal corneal thinning in the left eye were diagnosed and topical steroids and systemic nonsteroidal and steroidal antiinßammatory drugs were instituted. Review of systems disclosed an episode of fever and bilateral wrist swelling and pain associated with purpuric

Fig. 5.21 Forty-one-year-old man with necrotizing scleritis and peripheral ulcerative keratitis: left eye at the time of presentation. Note the areas of conjunctival erosion, disclosing loss of sclera underneath the conjunctiva

Fig. 5.23 Biopsied sclera of the same patient shown in Figs. 5.21 and 5.22: Note the granulomatous inßammation with epitheloid cells, multinucleated giant cells, and inßammatory microangiopathy (hematoxylinÐeosin stain)

Fig. 5.22 Left eye (same patient as in Fig. 5.21): Note the extensive ulcerative keratitis and associated necrotizing scleritis

rash on his lower extremities 2 months after the beginning of his ocular problem. Efforts to reduce the dosage of prednisone resulted in recurrent ocular pain and inßammation. Laboratory tests revealed an erythrocyte sedimentation rate (ESR) of 64 and red cells in the urinary sediment. The patient was referred to one of us (CSF) because of an increase in the extent of the marginal corneal thinning. At the time of his Þrst examination by us, photophobia and tearing were intense and visual acuity was 20/30 in both eyes. Necrotizing scleritis was present superiorly in both eyes and peripheral ulcerative keratitis was present superiorly in the left eye (Figs. 5.21 and 5.22). Review of systems disclosed chronic epistaxis in addition to the aforementioned posi-

tive historical features. Diagnostic possibilities considered were polyarteritis nodosa, rheumatoid vasculitis, systemic lupus erythematosus, and granulomatosis with polyangiitis (Wegener). Laboratory investigations included CBC, ESR, creatinine, urine analysis (UA), rheumatoid factor (RF), antinuclear antibodies (ANA), CICs (C1q binding and Raji cell assay), complement component survey (complement hemolytic 50% [CH50], components C3 and C4), hepatitis B surface antigen (HBsAg), ANCA, sinus and chest X-rays, and otorhinolaryngologic consultation. Resection of the conjunctiva overlying the area of scleral inßammation of the left eye was performed as a therapeutic maneuver for the peripheral ulcerative keratitis, and a scleral biopsy was also obtained. Otorhinolaryngologic consultation disclosed inßamed, friable tissue in the nasal mucosal, which was biopsied. Abnormal tests included a CIC (Raji assay) of 228 (0Ð50), an ESR of 20, microscopic hematuria, and left frontal sinus membrane thickening as revealed by sinus X-rays. ANCA testing was still pending. Biopsies of nasal mucosa and conjunctiva revealed nonspeciÞc inßammation with inÞltration of neutrophils, lymphocytes, and plasma cells. Biopsy of sclera showed granulomatous inßammation with epithelioid cells and scattered giant cells as well as neutrophil inÞltration of the vessel walls characteristic of an inßammatory microangiopathy (Fig. 5.23). ANCA testing by indirect immunoßuorescence was positive (136;