Antimalarials and Mortality in Lupus
Antimalarials and Mortality in Lupus
Shinjo SK, Bonfá E, Wojdyla D, et al; Grupo Latino Americano de Estudio del Lupus Eritematoso (Gladel)
Arthritis Rheum. 2010;62:855-862
Antimalarial agents (hydroxychloroquine and chloroquine) are commonly used to treat lupus, particularly the articular and cutaneous manifestations of the disease. In fact, hydroxychloroquine is one of the 3 drugs approved by the US Food and Drug Administration (FDA) for treatment of lupus; the other two are prednisone and aspirin. For years it has been known that patients with lupus have a higher mortality than patients without lupus, largely due to cardiovascular disease (CVD), but studies of lupus have mainly focused on treatment of acute disease activity, such as nephritis. As such, we know little about the effects of treatment on longer-term outcomes, such as mortality, although some studies have already suggested that hydroxychloroquine may improve survival in lupus. In this long-term prospective observational study, as part of the Grupo Latino Americano de Estudio del Lupus Eritematoso (GLADEL) project, researchers from 9 Latin American countries investigated the relationship between antimalarial use and mortality in lupus.
For this study, the GLADEL cohort consisted of 1480 patients with lupus (by American College of Rheumatology criteria), 77% of whom had used antimalarials (hydroxychloroquine and/or chloroquine) for lupus for a mean of 48.5 months. All patients (antimalarial users and nonusers) were followed for a median of 55 months (range, 1-102), with 89 (6%) of patients dying during follow-up. In unadjusted Kaplan-Meier survival analysis, overall mortality rates (per 1000 person-months) were lower in antimalarial-treated patients (4.4% vs 11.5%, P < .001). There were several significant differences between antimalarial users and nonusers: First, antimalarial users had more cutaneous and arthritic manifestations of lupus than nonusers, although renal disease was less frequent in users (28.4%) vs nonusers (42.5%) (P < .001). Second, a higher proportion of antimalarial users had insurance than nonusers (P < .001). Third, follow-up time was less in nonusers (31 months vs 60 months, P < .001). Finally, users were less likely to have received azathioprine than nonusers (3.6% vs 7.1%, P = .01). Also, several important factors were similar between users and nonusers, including corticosteroid and cyclophosphamide use and the presence of anti-dsDNA antibodies. However, in their final analysis after adjustment for several variables (age at diagnosis, medical coverage, and neurologic disorder but not renal disease, which apparently did not affect the model), antimalarial use for ≥ 6 months was associated with a significant 38% reduction in mortality rate. In terms of deaths from CVD or thrombotic disease, there was no significantly lower rate in users vs nonusers. The study authors concluded that there may be a time-dependent protective effect against death of antimalarials in patients with lupus.
There are several important limitations to the findings of this study: First, because this was an observational study, there may have been factors other than antimalarial use (including disease severity) that were not adequately accounted for that contribute to mortality. Second, the levels of inflammation (measured by erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]) that may be important factors in disease activity and mortality in lupus were not analyzed. Third, an alternative model that did account for medication use and renal manifestations did not show statistically significant differences in mortality between antimalarial users and nonusers. Fourth, due to small numbers, power to investigate mortality from specific processes, such as CVD, was limited. However, overall these results are interesting, and in concert with prior studies, they suggested that antimalarials may improve mortality in lupus, perhaps outside of protection from CVD events. Ultimately, we need randomized controlled trials to show us what therapies are most likely to improve both disease-specific manifestations of lupus and overall mortality, although these studies will be very difficult to perform given the rarity of lupus and significant disease heterogeneity. As a take-home point, however, this work is another piece of data suggesting that antimalarials may have benefit beyond treatment for specific disease manifestations of lupus.
Abstract
Antimalarial Treatment May Have a Time-Dependent Effect on Lupus Survival: Data From a Multinational Latin American Inception Cohort
Shinjo SK, Bonfá E, Wojdyla D, et al; Grupo Latino Americano de Estudio del Lupus Eritematoso (Gladel)
Arthritis Rheum. 2010;62:855-862
Introduction
Antimalarial agents (hydroxychloroquine and chloroquine) are commonly used to treat lupus, particularly the articular and cutaneous manifestations of the disease. In fact, hydroxychloroquine is one of the 3 drugs approved by the US Food and Drug Administration (FDA) for treatment of lupus; the other two are prednisone and aspirin. For years it has been known that patients with lupus have a higher mortality than patients without lupus, largely due to cardiovascular disease (CVD), but studies of lupus have mainly focused on treatment of acute disease activity, such as nephritis. As such, we know little about the effects of treatment on longer-term outcomes, such as mortality, although some studies have already suggested that hydroxychloroquine may improve survival in lupus. In this long-term prospective observational study, as part of the Grupo Latino Americano de Estudio del Lupus Eritematoso (GLADEL) project, researchers from 9 Latin American countries investigated the relationship between antimalarial use and mortality in lupus.
Study Summary
For this study, the GLADEL cohort consisted of 1480 patients with lupus (by American College of Rheumatology criteria), 77% of whom had used antimalarials (hydroxychloroquine and/or chloroquine) for lupus for a mean of 48.5 months. All patients (antimalarial users and nonusers) were followed for a median of 55 months (range, 1-102), with 89 (6%) of patients dying during follow-up. In unadjusted Kaplan-Meier survival analysis, overall mortality rates (per 1000 person-months) were lower in antimalarial-treated patients (4.4% vs 11.5%, P < .001). There were several significant differences between antimalarial users and nonusers: First, antimalarial users had more cutaneous and arthritic manifestations of lupus than nonusers, although renal disease was less frequent in users (28.4%) vs nonusers (42.5%) (P < .001). Second, a higher proportion of antimalarial users had insurance than nonusers (P < .001). Third, follow-up time was less in nonusers (31 months vs 60 months, P < .001). Finally, users were less likely to have received azathioprine than nonusers (3.6% vs 7.1%, P = .01). Also, several important factors were similar between users and nonusers, including corticosteroid and cyclophosphamide use and the presence of anti-dsDNA antibodies. However, in their final analysis after adjustment for several variables (age at diagnosis, medical coverage, and neurologic disorder but not renal disease, which apparently did not affect the model), antimalarial use for ≥ 6 months was associated with a significant 38% reduction in mortality rate. In terms of deaths from CVD or thrombotic disease, there was no significantly lower rate in users vs nonusers. The study authors concluded that there may be a time-dependent protective effect against death of antimalarials in patients with lupus.
Viewpoint
There are several important limitations to the findings of this study: First, because this was an observational study, there may have been factors other than antimalarial use (including disease severity) that were not adequately accounted for that contribute to mortality. Second, the levels of inflammation (measured by erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]) that may be important factors in disease activity and mortality in lupus were not analyzed. Third, an alternative model that did account for medication use and renal manifestations did not show statistically significant differences in mortality between antimalarial users and nonusers. Fourth, due to small numbers, power to investigate mortality from specific processes, such as CVD, was limited. However, overall these results are interesting, and in concert with prior studies, they suggested that antimalarials may improve mortality in lupus, perhaps outside of protection from CVD events. Ultimately, we need randomized controlled trials to show us what therapies are most likely to improve both disease-specific manifestations of lupus and overall mortality, although these studies will be very difficult to perform given the rarity of lupus and significant disease heterogeneity. As a take-home point, however, this work is another piece of data suggesting that antimalarials may have benefit beyond treatment for specific disease manifestations of lupus.
Abstract
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