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OBJECTIVE: While work disability is common in patients with systemic lupus erythematosus (SLE), it is not known which lupus disease characteristics predispose toward work disability. We examined demographic, clinical, serological, and neuropsychological factors in a group of disabled and nondisabled patients with SLE. METHODS: Fifty patients meeting American College of Rheumatology criteria for SLE were assessed for work status, disease characteristics, fatigue, anxiety, depressive symptoms, and quality of life. All subjects underwent an abbreviated panel of neuropsychological tests. Subjects who had formal work disability (social security or longterm disability, n = 16) and subjects who self-reported work disability without formal recognition (n = 8) were compared to subjects denying work disability from lupus (n = 26). RESULTS: Education level, African-American race, and SLICC Damage Index score were significantly associated with formal work disability relative to other subjects. Neurocognitive impairment (OR 14.44, 95% CI 3.01, 68.20; p = 0.001), nephritis (OR 3.75, 95% CI 1.01, 13.9; p = 0.048), and discoid lupus (OR 19.93, 95% CI 3.51, 113.3; p = 0.001) were all associated with formal disability. Formally disabled patients had higher fatigue and anxiety scores and more impaired quality of life in many domains relative to nondisabled subjects. Subjects with self-reported work disability also had neurocognitive dysfunction, high fatigue scores, and poor quality of life, but in other respects appeared to have milder disease than formally disabled subjects. CONCLUSION: Neurocognitive dysfunction and fatigue are 2 manifestations that may contribute materially to work disability in lupus. Other associated factors include low education levels, SLICC Damage Index scores, discoid lupus, nephritis, and possibly African-American race.