negative, <20). The patient was diagnosed with granulomatosis with polyangiitis (Wegener) and treatment with cyclophosphamide was instituted. Ocular and systemic manifestations were brought under control and the patient is alive and well 5 years after the initiation of cyclophosphamide therapy.

Connective Tissue Diseases

Scleritis may be an ocular manifestation of several connective tissue diseases. Conjunctival and/ or scleral histopathological Þndings range from nonspeciÞc inßammation with neutrophils, lymphocytes, and plasma cells to granulomatous reaction with a central area of necrosis rimmed by a corona of epithelioid cells, in turn surrounded by giant cells, lymphocytes, and plasma cells. An inßammatory microangiopathy also may be found. Pathological detection of vascular inßammation in involved tissues, including conjunctiva and/or sclera, in connective tissue diseases should be regarded as an ominous sign, because it may indicate a more severe and widespread destructive process that markedly worsens life prognosis. The two connective tissue diseases in which vasculitis occurs most frequently are rheumatoid arthritis and systemic lupus erythematosus [48, 49].

1.Rheumatoid arthritis. Rheumatoid arthritis (RA) is a chronic, inßammatory disease characterized by a polyarthropathy that ranges from mild joint discomfort to severe, symmetric articular involvement. Although the diagnosis of RA is based on the basis of clinical criteria, approximately 70% of patients are positive for RF, as opposed to 1Ð5% of the general population [98]. Patients with a positive RF have a higher incidence of extraarticular manifestations than do patients without a positive RF. Extraarticular manifestations may be related to proliferative granulomas or to vasculitis. Antibodies to cyclic citrullinated peptide (anti-CCP) can also be used to evaluate patients with RA. Although these antibodies are most commonly found in RF-positive patients, on occasion they can be detected in the absence of RF. In addition, the anti-CCP test has a similar sensitivity and a better speci-

Þcity for RA than does RF, and, therefore, some have advocated its use to evaluate RA patients instead of RF. This is particularly the case in individuals with early RA, in whom assessment of anti-CCP may be the most useful to conÞrm the diagnosis and establish a likely prognosis. The presence of anti-CCP is most common in patients with aggressive disease, with a tendency for developing bone erosions. The development of anti-CCP is most frequent in individuals with an RA-associated HLA-b1 allele and in those who smoke cigarettes, and may occur before the development of clinical manifestations of RA. However, as with RF, the presence of anti-CCP is not useful to predict the future development of RA because it can be found in 1.5% of normal individuals, most of whom will not develop RA, and occasionally in patients with other rheumatic diseases. However, it is a useful test to conÞrm a diagnosis of RA and to estimate prognosis.

An example of proliferative granuloma in RA is the rheumatoid nodule, which is characterized by a central area of necrosis rimmed by palisading Þbroblasts that are surrounded by chronic inßammatory cells with occasional distinct giant cells. Although chronic changes are predominantly granulomatous, small-vessel vasculitis occurs early in the development of the rheumatoid nodule [99]. Immunoßuorescent staining of nodules shows small vessel walls containing immunoglobulins [100]. Vessel endothelium, histiocytes, Þbroblasts, lymphocytes, and plasma cells proliferate. Fibroblasts may release collagenase and proteoglycanase, resulting in a central necrosis [101]. A similar histology can be found in the sclera: a focus of scleral necrosis surrounded by a wall of epithelioid cells, neutrophils, lymphocytes, plasma cells, and occasional giant cells [102].

A superimposed systemic vasculitis may complicate RA. The spectrum of rheumatoid vasculitis ranges from a hypersensitivity vasculitis affecting small vessels to a severe, systemic necrotizing vasculitis syndrome similar to that seen in classic polyarteritis nodosa [103]. It is thought that the lesions are related to deposition

of circulating antigenÐantibodyÐcomplement complexes, because there are depressed serum complement levels [104, 105], immunoßuorescent staining of IgG, IgM, and C3 in the vessel wall [106], and large amounts of serum cryoimmunoglobulins [107]. Clinical vasculitis may manifest as cutaneous ulceration, peripheral neuropathy, pericarditis, or arteritis of the viscera (heart, lungs, bowel, kidney, liver, spleen, pancreas, lymph nodes, and testis). Patients with rheumatoid arthritis complicated by systemic vasculitis are more likely to have severe erosive joint disease and rheumatoid subcutaneous nodules than are patients with rheumatoid arthritis without vasculitis [108, 109]. Vasculitis may occur in rheumatoid arthritis patients who have had their disease for more than 10 years. Males are afßicted as commonly as females. Patients with rheumatoid arthritis-associated vasculitis usually have higher titers of rheumatoid factor, higher titers of circulating immune complexes, and lower titers of complement than do patients with rheumatoid arthritis without vasculitis [108Ð 118]. Patients with rheumatoid arthritis and widespread vasculitis have an alarmingly high mortality rate; frequent causes of death are related to mesenteric, coronary, and cerebral artery inßammation [119, 120]. Ferguson and Slocumb [114] reported that 8 of 19 (42%) rheumatoid arthritis patients with vascular involvement, manifested by sensorimotor neuropathy in three of four extremities, died of vasculitic events.

Pathological detection of inßammatory microangiopathy in conjunctiva and/or sclera in patients with connective tissue diseases and necrotizing scleritis may also indicate a manifestation of widespread vasculitis. In our past series [60], the ten patients (six females and four males) with RA, necrotizing scleritis, and inßammatory microangiopathy in scleral tissue had had the rheumatoid arthritis for more than 10 years. They had severe, often incapacitating, articular lesions, and had extraarticular manifestations, such as rheumatoid nodules, nailfold infarcts (Fig. 5.24), extremity purpuric lesions, peripheral neuropathies, nerve entrapment syndromes, cardiac conduction defects, cardiac valvulopathies, pneumonias, or pleural diseases. Rheumatoid factor titers were

Fig. 5.24 Periungual nailfold infarct in a patient with rheumatoid arthritis-associated vasculitis

high (mean titer, 1:3,157; normal, <60), as were circulating immune complexes (mean titer by Raji cell assay, 250; normal, 0Ð50). All ten patients required systemic immunosuppressive therapy to halt the progression of scleral destruction; four of these also underwent scleral grafting to maintain the integrity of the globe because of the advanced extent of scleral necrosis [33]. Jayson and Jones [121] found systemic vasculitis in 10 of 14 patients with rheumatoid arthritis and necrotizing scleritis; 6 of those patients died of vasculitic complications during the follow-up period. Foster et al. [122] reported that 7 of 20 patients with rheumatoid arthritis and necrotizing scleritis died of vascularrelated events within 8 years of the onset of the scleritis; aggressive treatment with systemic immunosuppressive therapy may favorably alter the ocular and the general outcome. These data suggest that inßammatory microangiopathy in scleral tissue in patients with connective tissue diseases and scleritis indicates a more destructive phase in the patientÕs clinical systemic course, worsening not only the ocular prognosis, but also the general prognosis as well. Early detection of these clinicopathological changes may lead to early aggressive treatment of both the ocular and the general conditions. One of our cases is described as follows:

A 55-year-old white woman with a 38-year history of rheumatoid arthritis developed pain and redness in both eyes 7 months prior her Þrst examination by us. She was diagnosed with bilateral nodular scleritis and treated with local and systemic steroidal and nonsteroidal antiinßammatory drugs. As the steroids were tapered, symptoms reappeared and she was sent to our