Faculty Bibliography

The objective of this study was to define clinical and imaging characteristics of periaortitis prior to and after therapy with immunosuppressive drugs. Four consecutive patients with periaortitis (two secondary to atherosclerosis and two with rheumatic diseases) were studied with contrast-enhanced CT and magnetic resonance angiography (MRA), rheumatologic serologies, and acute-phase reactants. All were treated with corticosteroids and two patients received immunosuppressive agents. Patients were followed with serial MRA scans, CT scans, and clinical exams. Prior to treatment, all patients demonstrated a rind of periaortic tissue, which was enhanced with both contrast-enhanced CT as well as gadolinium-enhanced MRA. Clinical symptoms resolved and rind contracture occurred in all cases following therapy. Enhancement of the rind persisted despite the clinical improvement in all patients. No patient developed an aortic aneurysm or retroperitoneal fibrosis during the follow-up period. Corticosteroid/immunosuppressive treatment was continued for an average of 41 months. At 62 months of total follow-up, there has been no recurrence of periaortitis by clinical and/or radiologic exam. Treatment of periaortitis with corticosteroids and immunosuppression therapy leads to resolution of clinical symptoms and radiologic contracture of the periaortic rind. Patients responded to therapy without developing progressive fibrosis or aneurysm. MRA allows safe and repetitive imaging of periaortitis and provides excellent definition of lumenal abnormalities including plaque rupture

OBJECTIVE: To determine the frequency of unexplained reversible hypoxemia in patients with systemic lupus erythematosus and to assess the relation between hypoxemia and elevated plasma levels of complement split products. DESIGN: Cohort study. SETTING: Inpatient and outpatient facilities of the New York University Medical Center/Bellevue Hospital and the Hospital for Joint Diseases. PATIENTS: Case patients were 22 patients hospitalized with disease exacerbation and no evidence of parenchymal lung disease on chest roentgenogram. Four patients with stable disease were followed in the outpatient clinic, and five healthy normal volunteers served as controls. MEASUREMENTS: Plasma levels of complement split products (C3a, factor Bb fragment), alveolar-arterial (A-a) Po2 gradients, and pulmonary function were measured. MAIN RESULTS: Nine episodes of hypoxemia or hypocapnia (mean A-a gradient, 30.4 +/- 4.8 mm Hg) or both (despite normal chest roentgenogram results) were noted in six hospitalized patients (group 1). Gas exchange improved within 72 hours of steroid therapy (mean A-a gradient, 11.6 +/- 4.3 mm Hg; P less than 0.01). These patients had an elevated initial mean C3a level (938.4 +/- 246.8 ng/mL) that decreased within 72 hours (407.8 +/- 80.9 ng/mL; P less than 0.01), concomitant with improved oxygenation. Ventilation-perfusion scans, obtained for four of six group 1 patients, excluded pulmonary emboli. Four hospitalized patients (group 2) had a normal A-a gradient (mean, 7.5 +/- 2.7 mm Hg). The mean C3a level of this group (358.3 +/- 39.2 ng/mL) was lower than that of group 1 (P less than 0.05). Four patients with stable disease (group 3) had a mean A-a gradient and a mean C3a level of 3.3 +/- 2.7 mm Hg and 237.8 +/- 105.7 ng/mL, respectively, similar to values found in five normal volunteers, in whom the mean A-a gradient was 3.7 +/- 1.7 mm Hg and the mean C3a level was 124.8 +/- 9.2 ng/mL. CONCLUSION: A syndrome of reversible hypoxemia, unassociated with parenchymal lung disease, is unexpectedly common in acutely ill, hospitalized patients with systemic lupus erythematosus. The pathogenesis of this syndrome is unclear, although the data are compatible with the hypothesis that hypoxemia may be related to pulmonary leukoaggregation

Although commonly used to control a variety of inflammatory diseases, the mechanism of action of a low dose of methotrexate remains a mystery. Methotrexate accumulates intracellularly where it may interfere with purine metabolism. Therefore, we determined whether a 48-hr pretreatment with methotrexate affected adenosine release from [14C]adenine-labeled human fibroblasts and umbilical vein endothelial cells. Methotrexate significantly increased adenosine release by fibroblasts from 4 +/- 1% to 31 +/- 6% of total purine released (EC50, 1 nM) and by endothelial cells from 24 +/- 4% to 42 +/- 7%. Methotrexate-enhanced adenosine release from fibroblasts was further increased to 51 +/- 4% (EC50, 6 nM) and from endothelial cells was increased to 58 +/- 5% of total purine released by exposure to stimulated (fMet-Leu-Phe at 0.1 microM) neutrophils. The effect of methotrexate on adenosine release was not due to cytotoxicity since cells treated with maximal concentrations of methotrexate took up [14C]adenine and released 14C-labeled purine (a measure of cell injury) in a manner identical to control cells. Methotrexate treatment of fibroblasts dramatically inhibited adherence to fibroblasts by both unstimulated neutrophils (IC50, 9 nM) and stimulated neutrophils (IC50, 13 nM). Methotrexate treatment inhibited neutrophil adherence by enhancing adenosine release from fibroblasts since digestion of extracellular adenosine by added adenosine deaminase completely abrogated the effect of methotrexate on neutrophil adherence without, itself, affecting adherence. One hypothesis that explains the effect of methotrexate on adenosine release is that, by inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, methotrexate induces the accumulation of AICAR, the nucleoside precursor of which (5-aminoimidazole-4-carboxamide ribonucleoside referred to hereafter as acadesine) has previously been shown to cause adenosine release from ischemic cardiac tissue. We found that acadesine also promotes adenosine release from and inhibits neutrophil adherence to connective tissue cells. The observation that the antiinflammatory actions of methotrexate are due to the capacity of methotrexate to induce adenosine release may form the basis for the development of an additional class of antiinflammatory drugs