leukotriene-e4 and Lupus-Erythematosus--Systemic

This is a pilot study of zileuton, a selective 5-lipoxygenase inhibitor in systemic lupus erythematosus (SLE).. Forty patients with SLE received zileuton 600 mg qid or placebo in an 8 week, randomized prospective, double blind trial. Disease activity was manifested largely by constitutional, articular, and skin manifestations with no evidence of active renal, cardiac, or neurologic involvement. Concomitant administration of nonsteroidal antiinflammatories, corticosteroids, or antimalarials was not permitted. Disease activity was determined at baseline and at Days 15 and 57 by assessment of arthritis severity, the Systemic Lupus Activity Measure (SLAM), investigator and patient global ratings, hematologic indices, and serologic measures including autoantibody titers, complement levels, and interleukin 2 receptors (IL-2R). Total body sulfidopeptide leukotriene synthesis was measured by urinary leukotriene E4 (LTE4) concentrations.. Overall SLAM (the primary measure of efficacy in this study) was significantly improved with zileuton compared with placebo (-2.1 +/- 1.3, compared with an increase of 2.3 +/- 1.3 with placebo by Day 57, p = 0.048). Changes in individual SLAM subscores, arthritis severity, global ratings, and IL-2R levels compared with baseline did not achieve statistical significance, but were generally decreased from baseline with zileuton (indicating trends towards improvement) and increased from baseline with placebo (indicating trends towards clinical worsening). Urine LTE4 levels at Day 57 had increased from baseline in the placebo group (indicating worsening) and decreased in the zileuton group (indicating improvement).. Selective 5-lipoxygenase inhibition may be beneficial in mild SLE.

Topics: Adult; Aged; Double-Blind Method; Female; Humans; Hydroxyurea; Leukotriene Antagonists; Leukotriene E4; Lipoxygenase Inhibitors; Lupus Erythematosus, Systemic; Male; Middle Aged; Pilot Projects; Prospective Studies; Treatment Outcome

The peptidoleukotrienes, leukotriene (LT) C4 and its metabolites LTD4 and LTE4, cause diverse physiologic effects and have been implicated in several disease processes. A potential role for enhanced peptidoleukotriene synthesis in the pathogenesis of autoimmune disease in general and systemic lupus erythematosus (SLE) in particular has been suggested by animal studies. Therefore, we measured the urinary levels of LTE4 in patients with active and inactive SLE as well as in patients with rheumatoid arthritis (RA), scleroderma (Scl), and in healthy controls. Comparisons were made to other standard clinical tests in assessing individual patient disease activity. A marked increase in urinary LTE4 levels in patients with active SLE was noted (319 +/- 49 pg/mg creatinine, n = 20) relative to patients with inactive SLE (80 +/- 8 pg/mg creatinine, n = 7 [p less than 0.02]), patients with RA (86 +/- 8 pg/mg creatinine [p less than 0.01]), and healthy controls (68 +/- 4.3 pg/mg creatinine, n = 6 [p less than 0.01]). Patients with Scl also had elevated urinary LTE4 levels (188 +/- 33 pg/mg creatinine, n = 7) relative to controls (p less than 0.02), while values from patients with RA were not significantly different from controls. Using the Systemic Lupus Activity Measurement as a gauge of clinical activity, a rise in urinary LTE4 levels was noted during stages of active disease with a subsequent decline following the resolution of these symptoms. Our data indicate that increased synthesis of leukotrienes is associated with active SLE and Scl and suggest that these leukotrienes may mediate certain symptoms associated with these diseases.

Topics: Adult; Arthritis, Rheumatoid; Creatine; Female; Humans; Leukotriene E4; Lupus Erythematosus, Systemic; Male; Middle Aged; Scleroderma, Systemic; SRS-A