Michael D. Lockshin

The Classification of Glomerulonephritis in Systemic Lupus Erythematosus Revisited

The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving <50% of total number of glomeruli) with subdivisions for active and sclerotic lesions; class IV for diffuse glomerulonephritis (involving > or =50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.

The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes

OBJECTIVE To develop a standardized nomenclature system for the neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE). METHODS An international, multidisciplinary committee representing rheumatology, neurology, psychiatry, neuropsychology, and hematology developed case definitions, reporting standards, and diagnostic testing recommendations. Before and after the meeting, clinician committee members assigned diagnoses to sets of vignettes randomly generated from a pool of 108 NPSLE patients. To assess whether the nomenclature system improved diagnostic agreement, a consensus index was developed and pre- and postmeeting scores were compared by t-tests. RESULTS Case definitions including diagnostic criteria, important exclusions, and methods of ascertainment were developed for 19 NPSLE syndromes. Recommendations for standard reporting requirements, minimum laboratory evaluation, and imaging techniques were formulated. A short neuropsychological test battery for the diagnosis of cognitive deficits was proposed. In the postmeeting exercise, a statistically significant improvement in diagnostic agreement was observed. CONCLUSION The American College of Rheumatology (ACR) Nomenclature for NPSLE provides case definitions for 19 neuropsychiatric syndromes seen in SLE, with reporting standards and recommendations for laboratory and imaging tests. It is intended to facilitate and enhance clinical research, particularly multicenter studies, and reporting. In clinical settings, consultation with other specialists may be required. It should be useful for didactic purposes but should not be used uncritically or as a substitute for a clinical diagnosis. The complete case definitions are available on the ACR World Wide Web site: http://www.rheumatology .org/ar/ar.html.

Anti-inflammatory and immunosuppressive drugs and reproduction

Rheumatic diseases in women of childbearing years may necessitate drug treatment during a pregnancy, to control maternal disease activity and to ensure a successful pregnancy outcome. This survey is based on a consensus workshop of international experts discussing effects of anti-inflammatory, immunosuppressive and biological drugs during pregnancy and lactation. In addition, effects of these drugs on male and female fertility and possible long-term effects on infants exposed to drugs antenatally are discussed where data were available. Recommendations for drug treatment during pregnancy and lactation are given.

Studies of twins with systemic lupus erythematosus: A review of the literature and presentation of 12 additional sets

To assess the role of genetic factors in systemic lupus erythematosus (SLE), 12 twon pairs (seven definitely monozygotic, three definitely dizygotic) of which one or both twins had SLE, were studied and compared to 17 twin pairs (12 definitely monozygotic) previously described. In the present series, four of seven (57 per cent) definitely monozygotic pairs were clinically concordant for SLE, satisfying the preliminary criteria of the American Rheumatism Association (ARA). Concordance for the presence of antinuclear factor (ANF) and hypergammaglobulinemia was 71 and tinuclear factor (ANF) and hypergammaglobulinemia was 71 and 87 per cent, respiectively. These data closely agree with those on the 12 definitely monozygotic sets previously described. All three of the dizygotic sets in the present series were discordant for clinical SLE, although one clinically well twin had marked serologic abnormalities. Comparison of these data with thos from other first degree relatives of out twins clearly suggests a strong genetic component in the pathogenesis of SLE. The relative contribution of nongenetic and environmental factors to the expression of the disease is discussed.

Preclinical Carotid Atherosclerosis in Patients with Rheumatoid Arthritis

Context Patients with rheumatoid arthritis are prone to premature death from coronary heart disease despite few risk factors. Researchers have wondered if chronic inflammation is a trigger. Content The authors measured inflammatory markers and risk factors for coronary heart disease in 98 matched case-patients and controls (mean age, 48 years). Carotid ultrasonography revealed that 44% of case-patients and 15% of controls had atherosclerotic plaque. Independent predictors of plaque were age, smoking, and rheumatoid arthritis. In patients with rheumatoid arthritis, inflammatory mediators did not predict plaque. Limitations This cross-sectional study cannot prove that rheumatoid arthritis accelerates atherosclerosis. Interpretation Carotid atherosclerotic plaque is much more common in patients with rheumatoid arthritis than in controls. The mechanism remains unknown. The Editors Compared with the general population, patients with rheumatoid arthritis die prematurely (1, 2), primarily because of cardiovascular disease (1-3). Women with this disease have high rates of nonfatal myocardial infarction (4-6), even in the absence of traditional risk factors for atherosclerosis (4, 5, 7). Although markers of disease severity have been linked to an increase in overall mortality rates (1), researchers have not been able to clearly identify specific aspects of rheumatoid arthritis or its treatment that might heighten the risk for cardiovascular disease. Use of corticosteroids or disease-modifying antirheumatic drugs does not appear to increase the risk for cardiovascular events (2). In fact, a large longitudinal study recently reported that death rates from myocardial infarction among North American patients with rheumatoid arthritis had declined to the level seen in the general population (thereby yielding a greater magnitude of decline) in the setting of increased methotrexate use (8). In another U.S. study, methotrexate use was associated with lower all-cause mortality rates in rheumatoid arthritis, mostly because cardiovascular mortality rates were decreased (9). Early diagnosis of atherosclerosis in this population might trigger more aggressive prophylaxis, but we have not determined the prevalence of preclinical atherosclerosis or identified markers for the disease. In this study, we examined the prevalence of atherosclerosis in patients with rheumatoid arthritis by using ultrasonogram-defined carotid artery plaque as a direct measure and proxy for generalized atherosclerosis and as a surrogate for coronary atherosclerosis; we also examined those features of rheumatoid arthritis that predict plaque presence. Previous studies reported that plaque prevalence in rheumatoid arthritis is statistically similar to that of control populations (10, 11). However, in systemic lupus erythematosus, another autoimmune disease characterized by chronic inflammation, cross-sectional studies that were conducted by us and by others showed a marked increase in plaque compared with that seen in carefully matched controls (12, 13). The increased plaque rate in systemic lupus erythematosus is associated with chronic inflammation (not with treatment or with traditional atherosclerosis risk factors), suggesting that similar factors may be at work in rheumatoid arthritis. Preclinical disease may also be identified by using ultrasonography to determine carotid intimamedia thickness, an indirect measure of atherosclerosis. Intimamedia thickness was increased in 2 studies of East Asian patients with rheumatoid arthritis (14, 15) but not in a U.S. study (11). Intimamedia thickness varied more with disease duration (14, 15), but an association with serum C-reactive protein levels and erythrocyte sedimentation rate (2 markers of inflammation) has not been established because of conflicting reports (11, 15). Intimamedia thickness does not always correlate with atherosclerosis, particularly in relatively young individuals with chronic inflammatory disease (12, 13), and it may measure other aspects of vascular disease. Discrete atherosclerotic plaque is a potent independent predictor of incident cardiovascular disease, whereas intimamedia thickness in areas free of discrete plaque has limited value as a marker after traditional risk factors for cardiovascular disease are considered (16-18). Because of conflicting data regarding premature preclinical atherosclerosis in rheumatoid arthritis, we chose to use the direct measure of plaque to examine the prevalence of carotid atherosclerosis in consecutive unselected, nonhospitalized patients with rheumatoid arthritis and matched controls. For our other primary outcome, we sought to determine those clinical and biological measures that best predict the presence of plaque. Methods Study Sample We consecutively recruited patients who met the American College of Rheumatologys classification criteria for a diagnosis (possessing at least 4 of 7 criteria) of rheumatoid arthritis (19) and who were enrolled in the Rheumatoid Arthritis Registry at the Hospital for Special Surgery in New York. Patients were recruited at regular visits with their rheumatologists during a 15-month period (participation rate, 94%). Exclusion criteria were age younger than 18 years, serum creatinine level of 270 mol/L or greater (3.0 mg/dL) or creatinine clearance of 0.50 mL/s or less (30 mL/min), or current or recent (within the past 3 months) pregnancy. We quantified extent of disease by recording extra-articular manifestations (for example, the Sjgren syndrome, leg ulcers, and evidence of vasculitis, such as nail fold infarcts, splinter hemorrhages, and motor neuropathy), active joint count (number of tender or swollen joints), number of joints irreversibly damaged (fixed deformity or surgical replacement) (20), and the patients score on the Multidimensional Health Assessment Questionnaire (21). We recorded treatment by patient interview and chart review. Because treatment is often intermittent or at varying dosages, we tabulated medication use as never, former, or current. An 83-year-old woman had a previous stroke that was documented by magnetic resonance imaging, and a 45-year-old man had had coronary artery bypass surgery; we calculated our results both including and excluding these 2 patients. Patients were matched to controls on the basis of age (within 5 years), sex, and ethnicity. Controls were normotensive and hypertensive individuals who participated in longitudinal studies funded by the National Institutes of Health (22, 23) at the Hypertension Center of The New York Hospital and who underwent similar imaging protocols. We assessed patients for traditional cardiovascular disease risk factors: family history of myocardial infarction in first-degree male relatives younger than 55 years of age or first-degree female relatives younger than 65 years of age, smoking, hypertension (defined as blood pressure of 140/90 mm Hg or higher or the prescribed use of antihypertensive medications), diabetes mellitus (self-reported diagnosis), and fasting serum cholesterol levels. Hypertensive controls were studied after antihypertensive medications had been withheld for 3 or more weeks, whereas antihypertensive medications were not systematically withheld in hypertensive patients with rheumatoid arthritis. Brachial blood pressure was obtained at the end of the ultrasonographic studies after patients had remained in the supine position for 45 to 60 minutes in a quiet, darkened room. Of 100 patients with rheumatoid arthritis, a 74-year-old man was unable to be matched to a suitable control and a woman was excluded because she met diagnostic criteria for systemic lupus erythematosus. The institutional review board approved the study protocol, and all participants gave written informed consent. Carotid Ultrasonography All study participants underwent carotid ultrasonography, which was performed by experienced research sonographers who used an identical protocol. A single cardiologist, who was blinded to the identity of the study participants, interpreted the results. In brief, as previously described (22, 23), participants were studied in the supine position with slight hyperextension of the neck. Both extracranial carotid arterial systems were extensively scanned in multiple planes to optimize identification of atherosclerosis, which was defined as discrete plaque protruding into the lumen at least 50% beyond the diameter of the surrounding wall. Doppler interrogation was performed to evaluate the presence of significant (50% diameter reduction) obstruction. Intimamedia thickness was measured from end-diastolic (minimum dimension) M-mode images of the far wall of the distal common carotid artery. Intimamedia thickness was not measured in a location containing plaque. Mean values of right and left intimamedia thicknesses are presented. Reproducibility of intimamedia thickness and detection of plaque has been well documented (24-26). Carotid ultrasonographic studies were performed in the control group before 1999, whereas studies in the patients with rheumatoid arthritis were performed between 2000 and 2002. Laboratory Assessment Laboratory assessment of the patients with rheumatoid arthritis included routine chemistries and serum rheumatoid factor level. A high-sensitivity assay to determine serum levels of C-reactive protein was analyzed with a Cobas Integra system (Roche Diagnostics, Basel, Switzerland). Serum lipoprotein(a) levels were measured with an immunoturbidometric reagent (Diasorin, Stillwater, Minnesota) on a Roche Diagnostics Cobas Fara II system. Serum interleukin-6 levels were measured by automated enzyme immunoassay (Biosource International, Camarilo, California) on a Roche Diagnostics Cobas Core II analyzer. Serum levels of soluble intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 were measured by enzyme-linked immunosorbent assay (Caltag, Burlingame, California, and R&D Systems, Minneapolis, Minnesota,

Systemic Lupus Erythematosus: Emerging Concepts: Part 1: Renal, Neuropsychiatric, Cardiovascular, Pulmonary, and Hematologic Disease

Systemic lupus erythematosus is an extraordinarily complex autoimmune disease that touches on nearly all medical subspecialties [1]. Evidence from a broad range of basic science studies indicates that the pathogenesis of this disease is equally complex and may vary from patient to patient. The diverse expression of the common lupus syndrome may result from variable abnormalities in intersecting genetic, immunologic, hormonal, and environmental pathways. Although many uncertainties about pathogenic mechanisms remain, recent advances in diagnosis and treatment have substantially improved the prognosis of patients with systemic lupus erythematosus. As mortality rates decrease, issues such as comorbidity, complications of therapy, and overall quality of life are receiving increased attention. We discuss recent advances in systemic lupus erythematosus. By necessity, this review is not comprehensive; we focus on changing concepts and new information. In this, the first part, we review issues related to the diagnosis and management of systemic lupus erythematosus with visceral involvement. In the second part, to be published in the 1 July issue, we examine selected topics related to dermatologic and joint disease, as well as issues related to the antiphospholipid antibody syndrome, pregnancy, hormonal therapy, and morbidity and mortality. We conclude with an overview of recent advances in the pathogenesis of the disease. Renal Disease The kidney is the viscus most commonly affected by systemic lupus erythematosus. With the use of sensitive light, electron, and immunofluorescence microscopy, at least modest abnormalities are seen in kidney biopsy specimens from almost all patients with lupus. Approximately 75% of renal biopsy specimens reported in several series have been classified as focal proliferative, diffuse proliferative, or membranous glomerulonephritis [2]. Pathogenesis Localization of immune complexes in the kidney appears to be the inciting event for the development of lupus nephritis. Autoantibodies that react with DNA and other cellular components are characteristic of human and murine systemic lupus erythematosus, but only a subset of the resulting immune complexes seems to be nephritogenic. Studies correlating the immunochemical properties of autoantibodies with the type and severity of nephritis have detected several features that may promote pathogenicity, including quantity, charge, class, isotype, idiotype, avidity for DNA, and efficiency of complement fixation [3]. Furthermore, cross-reactivity of anti-DNA autoantibodies with glomerular cell surface antigens, as well as with normal components of basement membrane and mesangial matrix, probably promotes glomerular immune complex formation and influences the location of these deposits within the glomerulus [4]. Thus, factors that lead to the deposition of many proinflammatory immune complexes in the subendothelial region of the glomerular capillary wall, adjacent to the circulation, are likely to induce (through release of complement components, cytokines, and other factors) cellular proliferation, an inflammatory response, necrosis, and eventually fibrosis [5]. Furthermore, a subset of autoantibodies may penetrate glomerular cells, bind to nuclei, and contribute to glomerular proliferation and proteinuria [6]. The subepithelial immune deposits characteristic of lupus membranous nephropathy probably evolve through the in situ interaction of autoantibodies with antigens, such as DNA or histones, that bind to glomerular basement membrane because of their affinity for basement membrane components such as fibronectin, collagen, laminin, and heparan sulfate [7]. Subepithelial immune complexes induce relatively little cellular proliferation or inflammatory response. Glomerular capillary wall injury appears to be induced by complement activation and formation of the membrane attack complex, C5b-9, that has been associated with this type of active immune complex-mediated injury [8]. Diagnostic Studies Laboratory Evaluation Serologic variables have been extensively evaluated as indicators of the activity of lupus nephritis. Serum complement abnormalities have correlated with the degree of renal histologic activity in several studies [9, 10]. Persistent C3 or CH50 complement depression has been associated with progression of kidney disease in some, but not all, groups of patients [10-12]. Antinuclear and anti-DNA antibody levels have been less consistently related to features of active glomerulonephritis [13]. Serologic abnormalities may develop many months before evidence of clinical renal involvement and should prompt close observation to detect changes in urinary sediment and protein excretion rate, which are frequently considered stronger indications for modifications of therapy. Standard kidney function variables (such as serum creatinine level and creatinine clearance) are insensitive indicators of change in glomerular filtration rate and are likely to underestimate the severity of glomerulonephritis [14]. More accurate assessments of glomerular filtration rate are obtained by using inulin or iothalamate clearances or by using creatinine clearance after blocking tubular secretion of creatinine by cimetidine [15]. Nonetheless, even these measures of kidney function may fail to detect the extent of renal parenchymal injury because of intrarenal hemodynamic compensatory mechanisms that have been shown in animal models to augment filtration in perfused glomeruli [16]. Renal Biopsy A classic clinical syndrome (for example, rapidly progressive glomerulonephritis) may, in some cases, obviate the need for a kidney biopsy to establish the type of lupus nephritis. Many patients, however, present with clinical features compatible with several of the classes of lupus nephritis for which different treatment strategies are usually recommended. In these patients, renal biopsy data may clarify an ambiguous situation and help to justify various therapeutic options. In the absence of significant proteinuria or urinary sediment abnormalities, we are usually reluctant to recommend renal biopsy outside the context of a research protocol. Deliberations about treatment usually include an assessment of prognosis. Hypertension has been associated with renal disease progression and death [17]. The contribution of kidney morphologic evaluation to estimates of prognosis has been debated vigorously. Detailed records of the duration of nephritis [18] or the rate of change of renal function [19] provide an indication of the balance of reversible and irreversible injuries that may have occurred. Kidney biopsy data provide a more direct appraisal of the type of renal disease and have enhanced outcome predictions based on clinical data in several [20-23], but not all [18, 24], studies. Variations in conclusions may relate to the salutary effects of contemporary treatments as well as to differences in patient selection criteria, prognostic factors, and outcome measures studied. Several investigators have observed the prognostic effect of markedly active histologic features (such as cellular crescents, fibrinoid necrosis, and subendothelial immune deposits) combined with chronic, irreversible morphologic attributes (such as interstitial fibrosis, tubular atrophy, and glomerular sclerosis) [22, 25, 26]. Treatment Glucocorticoids A mainstay of the treatment of systemic lupus erythematosus, glucocorticoids are often used alone as initial therapy for patients with lupus nephritis. Prednisone at low to intermediate doses is usually sufficient for patients with mesangial and mild focal proliferative glomerulonephritis. Studies now in progress are evaluating the effectiveness and toxicity of prednisone therapy given on alternate days and of other treatment strategies for patients with membranous lupus nephropathy [27]. Patients with diffuse proliferative or severe focal proliferative glomerulonephritis are candidates for vigorous immunosuppressive treatments intended to control intrarenal inflammation. In some cases, this control can be achieved by using daily, high-dose prednisone (1 mg/kg of body weight daily) for approximately 2 months and then tapering the dose to reduce the risk for glucocorticoid-associated toxicities. The systemic effects of glucocorticoids are well recognized. High-dose glucocorticoids may promote glomerular scarring by augmenting glomerular capillary perfusion pressures [28] and by elevating low-density lipoprotein (LDL) cholesterol levels, leading both to enhanced mesangial cell uptake of oxidized LDL cholesterol and to cellular injury [29]. Pulse intravenous methylprednisolone has been used as an intensive initial therapy for patients with lupus nephritis and other immune-mediated disorders. Favorable short-term results have been observed [19, 30], but this therapy has been less extensively studied as a maintenance therapy for chronic disorders such as lupus nephritis [31]. The effectiveness and toxicity of daily high-dose oral prednisone and pulse intravenous methylprednisolone therapy have not been rigorously compared in patients with lupus nephritis. Cytotoxic Drugs Immunosuppressive drug regimens that include cytotoxic drugs are more efficacious than prednisone alone in controlling clinical signs of active nephritis [32, 33], in preventing renal scarring [34], and ultimately in reducing the risk for end-stage renal failure, but they have not been shown to be more effective in reducing the risk for death [35, 36]. Among cytotoxic drug regimens, intermittent pulse cyclophosphamide therapy appears to have one of the most favorable therapeutic indexes [35-38]. Nonetheless, it has been recognized that intravenous pulse cyclophosphamide treatments are complicated, costly, inconvenient, uncomfortable, and potentially toxic. Given these concerns, additional studies have been done to address several questions. First, could an initial intensive immunosuppressive regimen sho

Arterial Stiffness in Chronic Inflammatory Diseases

Chronic inflammatory diseases are associated with premature atherosclerosis; however, it is unknown whether arterial stiffness is increased in this setting, possibly as a manifestation of vascular disease preceding and/or independent of atherosclerosis. Carotid ultrasonography and radial applanation tonometry were performed in 101 patients with systemic lupus erythematosus, 80 patients with rheumatoid arthritis, and 105 healthy control subjects. The 3 groups were comparable in age, gender, and carotid artery absolute and relative wall thickness. Atherosclerotic plaque was more common in lupus (46%) and rheumatoid arthritis (38%) patients than in controls (23%) (P<0.003). Although control subjects had higher central and peripheral blood pressures, arterial stiffness was increased in patient groups compared with controls (lupus, rheumatoid arthritis, controls, respectively: &bgr;: 3.36 versus 3.22 versus 2.60, P<0.001; Young’s modulus: 441 versus 452 versus 366 mm Hg/cm, P=0.004; Peterson’s elastic modulus: 278 versus 273 versus 216 mm Hg, P<0.001) after adjustment for differences in mean brachial pressure. In multivariate analysis involving the entire population, arterial stiffness was independently related to age, serum glucose, and the presence of chronic inflammatory disease. In multivariate analysis restricted to the patients, arterial stiffness was independently related to age at diagnosis, disease duration, serum cholesterol, and C-reactive protein (and IL-6, when substituted for C-reactive protein). When analyses were repeated in the 186 study subjects without carotid plaque, arterial stiffness remained significantly elevated in patient groups after adjustment for differences in age and mean brachial pressure. In conclusion, arterial stiffness is increased in chronic inflammatory disorders independent of the presence of atherosclerosis and is related to disease duration, cholesterol, and the inflammatory mediator C-reactive protein and the cytokine that stimulates its production, IL-6.

Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody.

Effects of therapy, antibody titer, and pregnancy history on pregnancy outcome were evaluated in pregnancies of women with antiphospholipid antibody. Prior fetal death and a high antiphospholipid antibody titer (greater than 40 IgG phospholipid units) contributed independently, in an additive manner, to current fetal loss. Twenty-one pregnancies occurred in asymptomatic women who had both prior fetal death and a high IgG antiphospholipid antibody titer. In this very high-risk group, 9 of 11 (82%) of pregnancies treated with prednisone, 10 to 60 mg/day, ended in fetal death, compared with 5 of 10 (50%) not treated with prednisone (p approximately 0.01, life-table analysis). Of pregnancies treated with aspirin, 80 mg/day, 9 of 14 (64%) treated and 5 of 7 (71%) not treated with prednisone had a fetal death (difference not significant). Prednisone does not improve, and may worsen, current fetal outcome in asymptomatic pregnant women with a high antiphospholipid antibody titer and prior fetal death.

Lupus pregnancy. Case-control prospective study demonstrating absence of lupus exacerbation during or after pregnancy.

To assess whether pregnancy is associated with exacerbation of systemic lupus erythematosus (SLE), a variety of clinical markers of disease activity in 28 pregnant patients with SLE (33 pregnancies) were compared with the same markers in age-, race-, organ system-, and disease severity-matched nonpregnant women with SLE. Both groups were followed up for periods of up to one year after delivery. Eight patients elected abortion for nonmedical reasons. In all patient groups, there were no differences between pregnant and nonpregnant patient groups in frequency of any disease activity marker studied including therapy. However, new proteinuria occurred in four pregnant patients compared with one nonpregnant patient, and thrombocytopenia attributable to SLE occurred in five pregnant patients and one nonpregnant patient. Renal disease, when it occurred, more closely resembled pregnancy-induced hypertension than lupus nephritis. It is concluded that pregnancy complications are frequent, but the assertion that pregnancy causes exacerbation of SLE remains unproved.

Vasculitis With Hepatitis B Antigenemia: Long-term Observations in Nine Patients

The development of generalized necrotizing vasculitis in association with hepatitis B antigenemia is the first example in man of a chronic rheumatic disease presumably caused by a viral infection. This report reviews the experience in nine biopsy-proven cases of hepatitis B-associated necrotizing vasculitis followed for up to six years. The natural history of the disease is emphasized and the manifestations of patients with vasculitis who carry hepatitis B antigen are compared with those of vasculitis patients who are antigen negative.