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Show EDITORIAL What is Vasculitis? Stephen E. Nadeau, MD This issue of the Journal of Neuro- Ophthalmology includes two articles on temporal arteritis that emphasize problematic issues in the pathogenesis, diagnosis, and treatment of vascular inflammation. Cockerham et al ( 1) describe a patient with nonspecific orbital inflammation associated with biopsy- documented temporal arteritis whose ocular manifestations responded to radiation therapy. This article reminds us that vasculitis in general, temporal arteritis included, is a final common pathway of poorly understood immunopatho-logic processes that reflect the nature of the inciting antigen( s) and the immunogenetic profile of the patient ( 2). Kim et al ( 3) describe two episodes of late ipsilateral ischemic optic neuropathy caused by temporal arteritis in an apparently adequately treated patient, highlighting the uncertainties in our approach to treatment of this condition. Our current approach to the diagnosis and treatment of vasculitis has its roots in the pathologically- based classification system developed by Zeek and Knowles ( 4,5) in the early 1950s. This nosology fortuitously corresponded to recognizable clinical syndromes. However, as science has advanced, the " lumps" defined by Zeek and Knowles have been successively split. The splits have had important therapeutic implications, as in the example of polyarteritis nodosa ( PAN). Early on, Churg- Strauss disease, once classified as a PAN subtype, was split from the PAN group because of its distinctive features of prominent pulmonary manifestations, a history of allergies and crescendo asthma, an eosinophilic vascular infiltrate, peripheral eosinophilia, and high serum levels of IgE. Later, it was recognized that 30% of cases of ' typical' PAN are related to chronic hepatitis B infection ( a figure reduced to 10% since the advent of hepatitis B vaccine). More recently, it has become evident that many cases of PAN, including the form limited to nerve and muscle, are related to hepatitis C infection ( typically in association with cryoglobulinemia), HIV infection, or a paraneoplastic disorder. Originally considered a vascular inflammation stemming from the deposition of antigen- antibody complexes in vascular walls with activation of complement and leukocyte chemotaxis, PAN is now recognized as considerably more complicated and variable, often involving cell- mediated immune processes. Most recently, it has been subdivided into a classic form and a far more prevalent form- microscopic polyangiitis ( MPA). MPA is marked by prominent pulmonary involvement ( with pulmonary hemorrhage), glomerulonephritis, association with p- ANCA ( perinuclear pattern of antibodies to neutrophil cytoplasmic antigens), and a particularly malignant and refractory course requiring prolonged and aggressive immunosuppressive treatment. The high morbidity and even mortality ( intercurrent infection and secondary neoplasia) associated with corticosteroid and daily cyclophosphamide treatment of PAN pioneered by Fauci et al ( 6) in the early 1970s has led to a search for more specific therapies. Monthly pulsed intravenous cyclophosphamide treatment is now acknowledged to be as effective as daily cyclophosphamide in the treatment of idiopathic PAN, and it has lower morbidity. PAN related to hepatitis B, C, or HIV is best treated primarily with antiviral therapy. Geriatric Research, Education and Clinical Center, the Brain Rehabilitation Research Center, and the Rehabilitation Outcomes Research Center, Malcom Randall DVA Medical Center, and the Department of Neurology, University of Florida College of Medicine, Gainesville, Florida. Address correspondence to Stephen E. Nadeau, MD, GRECC- 182, Malcom Randall DVA Medical Center, 1601 SW Archer Road, Gainesville, FL 32608- 1197, USA; E- mail: snadeau@ ufl. edu Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. J Neuro- Ophthalmol, Vol. 23, No. 2, 2003 113 JNeuro- Ophthalmol, Vol. 23, No. 2, 2003 EDITORIAL This nosologic splitting process has also affected giant cell arteritis to the extent that temporal arteritis is differentiated from Takayasu's arteritis, a disorder with identical vascular pathology and spectrum of vascular involvement. Unlike temporal arteritis, Takayasu's arteritis predominantly affects the young, is particularly prevalent in Asia, and produces symptoms related to aortic branch arterial stenoses rather than inflammation of external carotid artery branches. These two disorders could reflect essentially the same immunopathologic process as it affects subjects with fundamentally different immunophenotypes. Cases such as that reported by Cockerham et al ( 1) remind us that the vascular pathology of temporal arteritis may occur in a variety of settings. It is quite possible that their patient did not have precisely the same disease as the patient with more typical temporal arteritis, or that the immunologic process leading to nonspecific orbital inflammation in this patient led, in addition, to temporal arteritis, or even vice versa. Temporal artery biopsy should not be regarded as a convenient and effective approach to the tissue diagnosis of any and all kinds of vasculitis. The temporal artery may be involved by nearly any arteritis. However, biopsy of sural nerve, muscle, or viscera ( such as the kidney or lung), or visceral angiography in the case of PAN, have far greater sensitivity and specificity than temporal artery biopsy for other vasculitides. Furthermore, the finding of inflammation in a temporal artery might lead to an incorrect diagnosis of temporal arteritis and exclusive reliance on corticosteroids when treatment with antiviral agents or cyclophosphamide is actually indicated. Advances in the molecular biology of immune function are beginning to shed light on the pathogenesis of temporal arteritis and the closely related disorder, polymyalgia rheumatica ( PMR) ( 7- 12). Sixty percent of patients with temporal arteritis or PMR express the HLA- DR4 haplotype ( defining a specific glycoprotein antigen receptor), compared with 30% of controls, and HLA- DR4- negative patients share an increased frequency of HLA- DR3, DR8 and DR13 haplotypes. Temporal arteritis, PMR, and rheumatoid arthritis share a strong association with certain allelic variants at the third hypervariable region on one of the genes ( HLA- DRBl) that defines the shape of the HLA-DR4 antigen binding site- HLA- DRBl* 0401 and * 0404/ 8. However, the serologic specificity of HLA- DR4 in temporal arteritis and PMR is determined by sequence polymorphisms ( allelic variants characterized by certain specific nucleotide sequences) at another hypervariable region within the HLA- DRBl gene, one that defines the shape of another part of the HLA- DR4 antigen binding site. Patients expressing HLA- DR4 who have temporal arteritis or PMR exhibit specific allelic variants that produce characteristically shaped pockets within the antigen- binding cleft of the HLA- DR4 molecule. These pockets accommodate only antigens bearing very specific side chains. Once a macrophage encounters an antigen of the requisite shape and binding properties, it is able to present both that antigen and the CD80 or CD86 molecules on its surface to helper T- cells. These T- cells have an antigen receptor; they also have a receptor for CD80/ 86 ( the CD28 molecule). Only when the macrophage presents the appropriate molecule to both T- cell receptors will a T- cell produce interleukin 2 ( IL- 2) and other cytokines that then induce the lymphoprolif-erative clonal expansion that begins the immune response. In temporal arteritis and PMR, this response appears to be entirely T cell- mediated. Unfortunately, the inciting antigen has not yet been identified. Topographic studies of the immune process within the arterial wall of temporal artery biopsies in patients with temporal arteritis and PMR are providing information that may lead to identification of the antigen and are clarifying the inflammatory response. Among patients with both temporal arteritis and PMR, the majority of monocytes in the peripheral circulation are activated, as are the CD4 helper T- cells in arterial walls. However, only in the presence of actual arteritis is there evidence of further differentiation of these CD4 helper T cells, accompanied by the secretion of interleukin- 2 ( IL- 2) and interferon- 7 ( IF7). IL- 2 induces clonal expansion of T cells and IF- y is a potent macrophage activator. The activation of these T cells apparently occurs through cytokine- mediated cross talk with local macrophages that have bound and presented the inciting antigen. The difference between the activated T cells in the arterial walls of patients with PMR and temporal arteritis is that in PMR, the T cells do not secrete IF- y. In temporal arteritis, these T cells are located primarily in the adventitia ( apparently having migrated from the vasa vasorum), implicating the adventitia as the source of the inciting antigen. The cytokines produced by these cells, most particularly 1F7, attract another type of macrophage, which congregates in the media about the internal elastic lamina and secretes matrix metalloproteinases, which play a major role in tissue destruction. In some patients, macrophages expressing inducible nitric oxide synthetase are attracted to the intima; nitration may contribute to tissue injury through lipid peroxidation. Multinucleated giant cells, which develop in the media through unknown mechanisms, produce platelet derived growth factor ( PDGF), which is chemotactic for the adventitial fibroblasts and medial myoblasts that generate intimal proliferation, and vascular endothelial growth factor, which induces angiogenesis. Intimal proliferation ( without thrombosis) is the principal factor responsible for ischemic symptoms in temporal arteritis. Production of large amounts of arterial PDGF has been correlated with ischemic events such as visual loss, jaw claudication, and Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 114 © 2003 Lippincott Williams & Wilkins EDITORIAL JNeuro- Ophthalmol, Vol. 23, No. 2, 2003 stroke. Temporal arteritis is thus the emergent product of a complex interaction between specific immune events involving T- cells and several different types of macrophages and the microanatomic structure of the arterial wall. The complexity of the immunopathologic process underlying temporal arteritis makes it easy to imagine how allelic variations, particularly in the HLA region, could lead to differences in clinical presentation, association with other disease processes, and treatability. The specificity of this clinical- immunopathologic link has recently been dramatically demonstrated in the delineation of a subtype of temporal arteritis that predominantly involves branches of the aortic arch and produces symptoms of upper extremity claudication rather than manifestations of ischemia and infarction in branches of the external carotid artery ( 13). This disorder affects the elderly, women more often then men ( as in typical temporal arteritis), and it is as often associated with PMR ( that is, it is not Takayasu's arteritis). However, temporal artery biopsy is negative in 42% of these patients, and the course is more insidious and less marked by tissue infarction as large vessel collaterals have time to develop. These clinical differences correspond to immunopathologic differences. The aortic arch variant is characterized by higher arterial levels of IL- 2 RNA and it is associated with the HLA- DRB 1* 0404 haplotype, whereas typical temporal arteritis is more often associated with the HLA-DRB 1* 0401 haplotype. These discoveries start to explain the inconsistent clinical manifestations of temporal arteritis and the mediocre sensitivity of temporal biopsy- about 70% ( 14), which make diagnosis so difficult. Treatment of temporal arteritis has also been tendentious. In general, this condition is exquisitely corticoste-roid- sensitive; there is evidence that starting prednisone doses as low as 20 mg daily may be adequate ( 15). However, it is equally clear that treatment must be very prolonged- up to 5 years in 40% of cases ( 16). The need for prolonged treatment may be related to the fact that corticosteroids suppress macrophage function but they do not suppress IL-- y producing T cells, which are instrumental in instigating the disease process. Relapse may occur with apparently adequate corticosteroid dosage, as reported by Kim et al ( 3), but 90% of relapses occur with prednisone doses of less than 10 mg/ day. There is emerging evidence of differences in corticosteroid requirements that may reflect underlying pathogenic mechanisms ( 17). Levels of the proinflammatory cytokine IL- 6, which is released by antigen- presenting macrophages in arteritic lesions, may be a more sensitive marker of disease activity than the sedimentation rate ( 18). Unfortunately, this assay is not widely available. Although it is less toxic, alternate- day corticosteroid treatment has been shown to be less effective than daily treatment ( 19). Corticosteroid- sparing agents such as aza-thioprine can usefully supplement but not replace corticosteroid treatment ( 20). Corticosteroid complications vary markedly from patient to patient, reflecting sex, comorbid conditions ( weight, osteoporosis, hypertension, diabetes, peptic ulcer disease, infection), and individual idiosyncrasies. Treatment must involve a careful balancing of degree of confidence in diagnosis, awareness of possible diagnostic alternatives, individual corticosteroid side effects, and the probability of relapse. Where this balance is struck will remain a matter of clinical judgment until we have more sensitive and specific markers of the disease process. Cockerham et al ( 1) used orbital radiation as an alternative to corticosteroid treatment in their patient with nonspecific orbital inflammation. This would not be the first time that radiation has been used to treat a local inflammatory or even vasculitic condition; it is the recommended treatment of lethal midline granuloma, likely a cross between Wegener granulomatosis and lymphomatoid granulomatosis, a type of lymphoma. The wisdom of this action will only be revealed as Cockerham et al ( 1) follow their patient to see if systemic corticosteroids need to be reinsti-tuted and if there are long- term complications of radiation. Advances in the management of temporal arteritis over the past 30 years have been based on earlier case ascertainment as a result of more widespread awareness of its prevalence and protean manifestations and by the emergence of an appreciation for its chronicity. Further advances will depend on understanding the full spectrum of temporal arteritis variants, which reflect a complex and variable immunopathogenesis, and the development of treatments specifically linked to discrete immunologic mechanisms. REFERENCES 1. Cockerham KP, Cockerham GC, Brown HG, et al. Radiosensitive orbital inflammation associated with temporal arteritis. J Neuro- Ophthalmol 2003; 23( 2): 117- 121. 2. Nadeau SE. Neurologic Manifestations of Vasculitis and Connective Tissue Disease. 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