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OBJECTIVE: To review the occurrence of neurologic events suggestive of demyelination during anti-tumor necrosis factor alpha (anti-TNFalpha) therapy for inflammatory arthritides. METHODS: The Adverse Events Reporting System of the Food and Drug Administration (FDA) was queried following a report of a patient with refractory rheumatoid arthritis who developed confusion and difficulty with walking after receiving etanercept for 4 months. RESULTS: Nineteen patients with similar neurologic events were identified from the FDA database, 17 following etanercept administration and 2 following infliximab administration for inflammatory arthritis. All neurologic events were temporally related to anti-TNFalpha therapy, with partial or complete resolution on discontinuation. One patient exhibited a positive rechallenge phenomenon. CONCLUSION: Further surveillance and studies are required to better define risk factors for and frequency of adverse events and their relationship to anti-TNFalpha therapies. Until more long-term safety data are available, consideration should be given to avoiding anti-TNFalpha therapy in patients with preexisting multiple sclerosis and to discontinuing anti-TNFalpha therapy immediately when new neurologic signs and symptoms occur, pending an appropriate evaluation.

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PURPOSE: Our goal was to characterize the MR features of orbital Wegener granulomatosis (WG). METHOD: Twelve patients with pathologically proven WG were studied with MRI. Enhanced and unenhanced T1-weighted sequences with conventional and fat-suppressed techniques were used. T2-weighted images were also obtained. Signal intensity measurements were made in each orbital lesion on the T2-weighted images and compared with that of normal fat. The degree of enhancement was also evaluated by measuring the change in signal intensity of each lesion between the unenhanced and enhanced studies. RESULTS: Seventeen orbital lesions were identified in the 12 patients. Fifteen of the lesions examined by T2-weighted sequences demonstrated a marked decrease in signal intensity. The unenhanced, non-fat-suppressed T1-weighted sequences provided the best contrast between lesion and normal structures. All of the WG lesions enhanced, but the degree of enhancement varied. The enhancement characteristics were best appreciated on the fat-suppressed T1-weighted technique. CONCLUSION: MRI is an excellent imaging modality to evaluate orbital involvement in WG. A marked decrease in the T2 signal is a characteristic feature of this entity. The unenhanced, non-fat-suppressed T1-weighted sequence is the preferred method for lesion detection and for definition of the pattern of anatomic involvement when utilizing MRI.

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We describe a case of isolated Candida albicans arthritis in a non-intravenous drug-abusing, human immunodeficiency virus positive patient. This presentation is extremely unusual without other systemic features or risk factors for candidemia, as Candida septic arthritis normally reflects disseminated infection. In terms of diagnosis, this case also highlights the potential utility of magnetic resonance imaging for early detection of osteomyelitis.

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We identify and describe clinical findings in hypocomplementemic urticarial vasculitis syndrome (HUVS), an uncommon to rare illness related to systemic lupus erythematosus (SLE). A patient with recurrent, idiopathic urticaria-like lesions was diagnosed as having HUVS if a lesional biopsy showed leukocytoclastic vasculitis, the serum C1q was markedly decreased, and antibody to C1q was detected in the patient's serum. The clinical characteristics, serologic findings, and outcome of patients who met these criteria were determined from prospective and retrospective data, including hospital and office records, patient interviews, previously banked serum samples, and freshly drawn sera. Eighteen patients with HUVS were identified, and high incidences of angioedema, ocular inflammation, glomerulonephritis, and obstructive pulmonary disease were found. Renal and lung biopsies showed mesangial or membranoproliferative glomerulonephritis and severe pulmonary emphysema without vasculitis. Pulmonary function was measured in 17 patients, 11 of whom had dyspnea. All dyspneic patients had moderate to severe airflow obstruction, which progressed in all 11 and subsequently improved in only 1. Six of these 11 patients died of respiratory failure, 1 underwent lung transplantation, and 3 of the remaining 4 have moderately severe to life-threatening respiratory insufficiency. Treatment did not appear to alter the progression of obstructive lung disease. In contrast, renal insufficiency improved with treatment in 2 of 2 patients. Angioedema, ocular inflammation, obstructive lung disease, and glomerulonephritis appear to be common in HUVS, and lung disease causes substantial morbidity and mortality. The pathogenesis of HUVS may involve humoral autoimmunity, although it is not clear how autoimmunity would participate in development of obstructive lung disease. Cigarette smoking appears to be a risk factor for fatal lung disease in HUVS. All patients with HUVS should be made aware of this possibility and should be advised, encouraged, and helped to avoid tobacco smoke.

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We describe 4 patients with coagulopathy and vasculitis that demonstrated marked tissue ischemia and necrosis. In the clinical setting of rapid evolution of vascular insufficiency, the possibility of combined vasculopathic processes should be considered. This is especially so in patients with underlying connective tissue disease such as systemic lupus erythematosus or rheumatoid arthritis, in which both vasculitis and antiphospholipid antibodies are frequently present. Treatment of both pathologic processes may be required to prevent progressive tissue ischemia and necrosis. The use of antiplatelet and/or anticoagulation should be given consideration in addition to immunosuppressive agents.

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Cutaneous vasculitis and vasculopathic processes continue to be difficult to define, diagnose, and treat. Historically, the complexity of these disorders has been compounded by imprecision in terminology and classification and the presence or absence of underlying systemic illness. Approaching the literature with consistent diagnostic constraints and accepted terminology can, it is hoped, eliminate some of the ambiguity. During the past year, several case reports and brief communications regarding cutaneous vasculitis or vasculopathies have appeared, as well as thoughtful basic science reports whose authors have attempted to further the understanding of the underlying pathophysiology. Recent technologic advances have produced recombinant cytokines, growth factors, and thrombolytics that have been used therapeutically for a variety of medical illnesses. The role of these agents in the treatment of cutaneous vasculitis and vasculopathies has varied from provocative in some to therapeutic in others. A number of these reports are discussed.

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Glucocorticoids are pleiotropic hormones that at pharmacologic doses prevent or suppress inflammation and other immunologically mediated processes. At the molecular level, glucocorticoids form complexes with specific receptors that migrate to the nucleus where they interact with selective regulatory sites within DNA; this results in positive and negative modulation of several genes involved in inflammatory and immune responses. At the cellular level, glucocorticoids inhibit the access of leukocytes to inflammatory sites; interfere with the functions of leukocytes, endothelial cells, and fibroblasts; and suppress the production and the effects of humoral factors involved in the inflammatory response. Clinically, several modes of glucocorticoid administration are used, depending on the disease process, the organ involved, and the extent of involvement. High doses of daily glucocorticoids are usually required in patients with severe diseases involving major organs, whereas alternate-day regimens may be used in patients with less aggressive diseases. Intravenous glucocorticoids (pulse therapy) are frequently used to initiate therapy in patients with rapidly progressive, immunologically mediated diseases. The benefits of glucocorticoid therapy can easily be offset by severe side effects; even with the greatest care, side effects may occur. Moreover, for certain complications (for example, infection diathesis, peptic ulcer, osteoporosis, avascular necrosis, and atherosclerosis), other drug toxicities and pathogenic factors overlap with glucocorticoid effects. Minimizing the incidence and severity of glucocorticoid-related side effects requires carefully decreasing the dose; using adjunctive disease-modifying immunosuppressive and anti-inflammatory agents; and taking general preventive measures.

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The immune responses to hepatitis B virus envelope antigen were investigated in 16 vaccine recipients after immunization with a recombinant yeast-derived preS2 + S (adw) vaccine for hepatitis B virus. After the completion of the three-slot immunization series, all vaccine recipients developed antibody to the S domain and anti-preS2 antibody. In vitro proliferative responses to preS2 (120-174) peptide were demonstrated in 10 of 16 vaccine recipients. Although reactivity could be demonstrated through the length of the preS2 peptide, the principal site of proliferative activity was contained within the preS2 (146-165) region of the peptide. The principal T cell reactive site coincides with a region of significant amino acid variability of the different hepatitis B virus serotypes. Cross-reactivity with a serotype (ayw) not present in the preS2 + S vaccine could not be demonstrated at this widely recognized T cell epitope. The low level of cross-reactivity demonstrated in a limited subset of the vaccine recipients was mediated through nondominant T cell reactive sites contained in the relatively conserved preS2 (120-146) region of the molecule. The identification of widely recognized but serotype-specific T cell epitopes in the preS2 region of the hepatitis B virus envelope antigen may be an important consideration in future vaccine development.

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Wegener's granulomatosis (WG) is frequently associated with retroorbital involvement, which typically responds slowly to the standard therapy of oral corticosteroids and cytotoxic agents. We describe the case of a 61-year-old man with WG, who developed marked retroorbital granulomatous inflammatory tissue and experienced a dramatic clinical and radiographic response to the administration of high dose intravenous (iv) methylprednisolone. We believe that high dose iv methylprednisolone may have distinct advantages over standard therapies in the treatment of retroorbital WG.

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Among the pathologic findings affecting the eye during pregnancy, microvascular abnormalities affecting both choroidal and retinal circulation have been reported in cases of complicated pregnancy. We report a case of papillophlebitis and arteriolar occlusion in a pregnant woman without any complications throughout her pregnancy. The patient was placed on glucocorticoids and her vision, visual fields and funduscopic appearance improved almost to normal. Despite the improvement with treatment, the contributing role of glucocorticoids in this case could not be fully determined. Papillophlebitis and arteriolar occlusion should be included among gestational-related vasculopathies.

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Fewer than 40 cases of vasculitis have been described in the setting of human immunodeficiency virus infection. We describe a patient with the acquired immunodeficiency syndrome (AIDS), a heavy smoker, who developed a syndrome of constitutional symptoms, eosinophilia and digital gangrene. Vasculitis of the digital arteries was documented by angiography. He responded to high dose corticosteroid therapy with arrest of the ischemic process. After steroids were discontinued, he suffered a relapse of the vasculitis documented by skin biopsy. In patients with AIDS with this serious, potentially steroid responsive condition, steroid therapy should be considered in spite of the preexisting immunodeficiency state.

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A patient with chronic systemic Weber-Christian disease who was treated with hydroxychloroquine developed cardiac dilatation with congestive heart failure. Endomyocardial biopsy demonstrated myocyte degeneration and interstitial fibrosis, but no typical features of chloroquine induced cardiomyopathy. Clinical symptoms of congestive heart failure also were recognized in 7 of the 11 reported autopsy cases of Weber-Christian disease having cardiac involvement. This involvement can affect the pericardium and the myocardium.

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We examined the ability of human natural killer (NK) cells to modualte pokeweed mitogen (PWM)-induced polyclonal antibody production. Highly purified NK cells inhibited plaque-forming cell (PFC) responses and this suppression could be substantially increased by preincubation of NK cells with the known enhancers of NK cell lytic activity, interferon (IFN)-alpha, IFN-gamma, and interleukin-2. Additionally, costimulation of NK cells with two anti-CD2 antibodies (9-1 and 9.6), which recognize different epitopes on the CD2 molecule, also augmented the inhibitory effect. When subpopulations of NK cells were assayed for suppressor cell activity, this activity was primarily mediated by NK cells bearing Leu-7 but not Leu-2 (CD8) antigens. Thus, alteration of NK cell lytic activity may have significant effects on the immunoregulatory functions of these cells, which may have important implications for the in vivo manipulation of cytotoxic responses.

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This study evaluated the in vitro immune responses to different components of the hepatitis B surface antigen (HBsAg) over the course of acute hepatitis B virus (HBV) infection. Early in the convalescent phase of infection, while HBsAg was present in the serum, peripheral blood mononuclear cells (PBMCs) were stimulated with preS2 peptide or hepatitis B surface protein. Specific IgG directed to different components of HBsAg was produced without a polyclonal increase in total IgG production. Stimulation with preS2 peptide produced IgG to the preS2 peptide (anti-preS2) and to the S antigen (anti-HBs). Hepatitis B surface protein stimulation produced anti-HBs but not anti-preS2. After this initial reactive phase, the PBMCs did not produce specific antibody when stimulated with either component of HBsAg; this effect lasted greater than 1 year. At some time 1-2 years after acute infection, the pattern of in vitro S antigen- and preS2 antigen-stimulated anti-HBs response reemerged in the PBMCs. Reemergence of sustained preS2 peptide-stimulated anti-preS2 response was not observed.

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An antigen-inhibitable Ab-2 that exhibits internal image activity will selectively stimulate the in vitro production of anti-HBs in individuals with remotely established immunity to hepatitis B virus. This response is seen (1) in the absence of a polyconal increase in total IgG, (2) with the F(ab')2 component of the Ab-2, (3) in cultures depleted of T-cells, and (4) in the absence of stimulation by antigen. This observation demonstrates that the Ab-2-mediated stimulation of specific IgG production may be an important regulatory function in man.

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In this report we evaluate the human immune response to hepatitis B surface antigen (HBsAg) following remote infection with hepatitis B virus (HBV). HBsAg-reactive lymphocytes can be readily demonstrated in the peripheral blood of individuals with established immunity following infection with HBV. In vitro stimulation with small doses of plasma-derived HBsAg, yeast-derived HBsAg (S region) or pre-S2 peptide will induce specific IgG to HBsAg (anti-HBs) in the absence of a polyclonal increase in total IgG. The pre-S2 peptide will stimulate, in a T cell-dependent fashion, the in vitro production of anti-HBs with specificity for the S domain. This anti-HBs production is mediated by pre-S2-stimulated soluble T-cell factors. Peripheral blood mononuclear cells from individuals with established immunity proliferate to the yeast-derived HBsAg but not to the plasma-derived HBsAg or pre-S2 peptide. The chronic HBsAg carriers do not produce anti-HBs following stimulation with HBsAg regardless of the source or component of antigen used. Different study protocols failed to demonstrate HBsAg-specific responses in the peripheral blood mononuclear cells of chronic carriers.

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In addition to lytic activity against malignant and virally transformed target cells, recent evidence has suggested that natural killer (NK) cells can modulate immune activities such as the suppression of B cell responses through noncytotoxic means. Using human B cells and highly purified autologous NK cells, we have demonstrated that NK cells can substantially augment the proliferative responses of B cells stimulated with the surface immunoglobulin crosslinking agents anti-IgM or Staphylococcus aureus Cowan strain I (SAC). This "enhancer" activity of NK cells was quite potent and was observed at an NK:B cell ratio as low as 0.05. Peak blastogenic responses of B cells cocultured with NK cells in the presence of B cell activators were observed at 2-3 days, similar to the responses of B cells in the absence of NK cells. Using the inhibitor of DNA synthesis mitomycin C, we determined that B cells and not NK cells were proliferating in cocultures of these lymphocytes stimulated with SAC. Activated B cells neither prevented the lysis of the isotope-labeled NK-sensitive target cell line K562 nor formed conjugates with NK cells, suggesting that cell contact was not a prerequisite for the effect. These studies have further expanded the functional repertoire of NK cells to include enhancer as well as suppressor and lytic activities.

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