SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Objective

To examine whether hydroxychloroquine (HCQ) usage is associated with a reduced risk of damage accrual in patients with systemic lupus erythematosus (SLE).

Methods

Patients (n = 518) meeting the American College of Rheumatology criteria for diagnosis of SLE and with ≤5 years disease duration at study entry were followed up annually. Socioeconomic, demographic, clinical, and serologic manifestations as well as disease activity (by the Systemic Lupus Activity Measure [SLAM]) and damage (by the Systemic Lupus International Collaborating Clinics damage index [SDI]) were measured. Propensity scores were calculated to adjust for confounding factors affecting treatment assignment. A Cox proportional hazards model was used to compare the risk of developing new damage according to HCQ use at enrollment into the study.

Results

Fifty-six percent of the patients were treated with HCQ at the time of study enrollment. Patients who were not treated with HCQ on enrollment had higher SLAM and SDI scores than patients who were treated. Untreated patients were significantly more likely to have major organ involvement such as renal disease (P < 0.0001) or central nervous system disease (P < 0.0025). Results of unadjusted analysis suggested that treated patients were less likely to accrue damage (hazard ratio [HR] 0.68). With adjustment for differences in treatment assignment, HCQ usage was still associated with a reduced risk of developing new damage, with an HR of 0.68 (95% confidence interval [95% CI] 0.53–0.93) (P = 0.014). With adjustment for differences in treatment assignment, HCQ usage was still associated with a reduced risk of developing new damage (HR 0.73 [95% CI 0.52–1.00]) (P = 0.05). However, patients receiving HCQ who had no damage at study entry had a statistically significant decrease in the risk of damage accrual (HR 0.55 [95% CI 0.34–0.87]) (P = 0.0111), whereas those receiving HCQ who had damage at study entry did not (HR 1.106 [95% CI 0.70–1.74]) (P = 0.6630).

Conclusion

These findings indicate that, after adjustment for propensity to receive HCQ, HCQ usage is independently associated with a reduced risk of damage accrual in SLE patients who had not yet accrued damage at the time of treatment initiation.

Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease of unknown etiology, which is characterized by a waxing and waning course. Disease manifestations are diverse, affecting every organ system in the body; the levels of severity of these manifestations vary from mild to life-threatening (1, 2). Although disease activity may be controlled with medication, organ damage may develop over time, as a consequence of the disease itself or medications used to treat it (3–8). Once damage has developed, it predicts the development of additional damage and higher mortality rates (9–13). Several medications that are used to treat active SLE may directly contribute to the development of damage. For example, corticosteroid use is associated with an increased risk of cataracts, myocardial infarction, strokes, osteoporosis, and avascular necrosis (4, 14–16). Identification of medications that not only treat disease activity but also prevent damage would be highly desirable. There is accumulating evidence that one such medication is hydroxychloroquine (HCQ) (17–23).

HCQ and several other related medications, originally used for management of malaria, have been used for many decades to treat rheumatic diseases (24, 25). In addition to their antimicrobial effects, these antimalarial medications exhibit antiinflammatory, antihyperlipidemic, antithrombotic, and immunomodulatory properties (24, 26). HCQ is the most commonly prescribed antimalarial medication for lupus in the US and is useful in the management of mucocutaneous manifestations, arthritis, and mild constitutional symptoms (24). HCQ has many additional health benefits in lupus patients. It has been shown to reduce serum cholesterol levels (18, 27–29), protect against osteoporosis in corticosteroid-treated patients (16), and decrease the frequency of lupus flares (30, 31). Use of HCQ has also been shown to be associated with lower pulse wave velocity in premenopausal women, suggesting a potential protective effect against future development of major vascular disease (32).

In the present investigation, we sought to examine the impact of HCQ use on the accrual of damage in patients participating in the LUMINA (LUpus in MInorities, NAture versus nurture) study, a longitudinal study of outcome in lupus patients. Since HCQ is traditionally used for the treatment of mild-to-moderate lupus manifestations and is not used as primary treatment for major organ system involvement such as renal or central nervous system disease, a traditional multivariable regression technique comparing damage accrual between HCQ users and nonusers would lead to unreliable estimates of risk, due to confounding by indication. Patients with milder disease, who are typically treated with HCQ, would naturally accrue less damage compared with those with severe multiorgan involvement. To address this concern regarding nonrandom treatment assignment, we used propensity score analysis (33) to adjust for potential known confounding factors that may influence the accrual of damage. To our knowledge, propensity score analysis has not been used previously to examine the impact of medications on a lupus cohort. Ultimately, a randomized controlled trial would be the ideal way to determine whether HCQ is truly protective against damage accrual. However, such a trial is not feasible given the widespread use of HCQ and the long-term followup necessary to adequately address this question.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Study population.

LUMINA is a longitudinal study of outcome in SLE patients from the University of Alabama at Birmingham, the University of Texas Health Science Center at Houston, the University of Texas Medical Branch at Galveston, and the University of Puerto Rico Medical Sciences Campus. The cohort, study visits, and variables have been described in detail previously (34). Briefly, patients of defined ethnicity (Hispanic, African American, or Caucasian) who met at least 4 components of the American College of Rheumatology (ACR) criteria for SLE (35) and who had disease duration of ≤5 years at study enrollment were eligible to participate. After providing informed consent, patients completed a series of questionnaires and underwent physical examination and serologic testing. Demographic, socioeconomic, clinical, and immunologic data were obtained at the baseline visit (time 0), every 6 months for 1 year, and then annually thereafter. At time 0 and each subsequent visit, all available medical records were reviewed.

Definitions of variables.

The demographic characteristics recorded were age, sex, and ethnicity. Clinical variables included ACR criteria manifestations and other manifestations attributable to lupus, including Raynaud's phenomenon, arterial and/or venous thrombotic events, biopsy-proven renal disease, vasculitis, central nervous system manifestations, and cardiac disease. Immunologic variables included the presence of autoantibodies (antinuclear antibodies by indirect immunofluorescence [IIF], anti–double-stranded DNA antibodies by IIF against Crithidia luciliae, anti-Sm, anti-Ro/SSA, anti-La/SSB, anti–-small nuclear RNP by immunodiffusion, IgG and IgM antiphospholipid antibodies by enzyme-linked immunosorbent assay, and lupus anticoagulant by the Statclot test). Medications used to treat lupus, including corticosteroids, HCQ, methotrexate, azathioprine, mycophenolate mofetil, leflunomide, cyclophosphamide, and cyclosporine, were recorded. Disease activity during the month preceding the study visit was measured using the Systemic Lupus Activity Measure (SLAM) (36), a validated instrument for assessing disease activity.

In the LUMINA cohort, disease-related damage is measured using the Systemic Lupus International Collaborating Clinics damage index (SDI) (37, 38) and is assessed at each visit. This validated instrument measures the extent of irreversible organ damage caused either by the disease or by the treatments used for it from the time of diagnosis. A manifestation is recorded in the SDI if it has been present for at least 6 months and is (or is expected to be) irreversible. Manifestations from 9 organ systems (ocular, neuropsychiatric, renal, pulmonary, cardiovascular, peripheral vascular, gastrointestinal, musculoskeletal, skin), as well as premature gonadal failure, diabetes, and malignancy (if the latter 3 developed after the onset of SLE), constitute the domains of the SDI. The outcome of interest for the present study was the development of new damage, both overall and within specific domains, during the followup period. Patients who developed any new damage were, for the purpose of this study, considered to have the outcome of interest. The primary independent variable of interest in this study was HCQ use. Patients were divided into 2 categories: those who were taking HCQ at time 0 and those who were not.

Statistical analysis.

Socioeconomic, demographic, clinical, immunologic, and treatment characteristics were compared between patients who were HCQ users at the time of enrollment and those who were not, using t-tests and chi-square tests for continuous and categorical variables, respectively. To adjust for the inherent bias in grouping of patients based on use or nonuse of HCQ, propensity analysis was performed. Using a multivariable logistic regression model that includes the baseline demographic, clinical, immunologic, and treatment characteristics as the independent variables, the probability of HCQ use was determined. The specific variables included in the propensity score model are shown in Table 1. The study population was divided into quintiles according to the propensity score, and the probability of HCQ use was computed in each group. To adjust for heterogeneity between the 2 groups, the propensity score was then entered as a continuous variable in a Cox proportional hazards model along with the primary independent variable. A hazard ratio (HR) and its associated 95% confidence interval (95% CI), comparing the time to new damage among users and nonusers of HCQ, were computed. This was done for the occurrence of any new damage as well as for damage in specific domains.

Table 1. Demographic, socioeconomic, clinical, and serologic characteristics in SLE patients who were and those who were not treated with HCQ at the time of enrollment (time 0)*
VariableHCQ use at time 0 (n = 291)No HCQ use at time 0 (n = 227)P
  • *

    Except where indicated otherwise, values are the mean ± SD. SLE = systemic lupus erythematosus; HCQ = hydroxychloroquine; NS = not significant; CNS = central nervous system; ACR = American College of Rheumatology; SLAM = Systemic Lupus Activity Measure; SDI = Systemic Lupus International Collaborating Clinics damage index; anti-dsDNA = anti–double-stranded DNA; ER = emergency room; IBQ = Illness Behavior Questionnaire (75).

Age at time 0, years37.9 ± 12.535.1 ± 12.60.0132
Female, %9088NS
Ethnicity, %  <0.0001
 Hispanic (Texas) (n = 105)1626 
 Hispanic (Puerto Rico) (n = 73)5343 
 African American (n = 190)3222 
 Caucasian (n = 150)349 
Have medical insurance, %18270.0074
Highest education level, years13.1 ± 3.112.6 ± 3.10.0317
Below poverty line, %3235NS
Disease duration at time 0, years1.4 ± 1.31.5 ± 1.3NS
Clinical manifestations, %   
 Arthritis83710.0019
 Pleuritis or pericarditis40520.0034
 Pulmonary disease910NS
 Renal disease2553<0.0001
 Immune-mediated cytopenias77850.0275
 CNS involvement32450.0025
 Myositis9190.0014
 Fibromyalgia42NS
No. of ACR criteria met5.4 ± 1.35.6 ± 1.3NS
SLAM at time 08.2 ± 4.311.6 ± 7.0<0.0001
SDI at time 00.6 ± 0.91.07 ± 1.5<0.0001
Anti-dsDNA antibodies25320.0158
HLA–DRB*088140.0074
Hospitalizations due to SLE, %3235NS
ER visits due to SLE, %22370.0003
IBQ total at time 018.5 ± 6.718.7 ± 6.6NS
Corticosteroid use, %9088NS
Azathioprine use, %1216NS
Cyclophosphamide use, %527<0.0001

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Five hundred eighteen patients in the LUMINA study (178 Hispanic [105 from Texas and 73 from Puerto Rico], 190 African American, 150 Caucasian) were included in these analyses. The majority of the patients were women (89%). The mean ± SD age of the patients at time 0 was 36.5 ± 12.5 years. Detailed descriptions of the demographic, socioeconomic, clinical, and immunogenetic characteristics of the LUMINA cohort have been published previously (39, 40). Patients included in these analyses were comparable in their features with those included in previously reported studies from the LUMINA group (5, 10, 13, 40).

Baseline characteristics.

Of the 518 patients included in these analyses, 291 (56%) were taking HCQ at time 0; 67% of the patients were treated with HCQ at some point during the study followup period, and 33% were never treated with HCQ. Table 1 summarizes the differences in baseline characteristics by HCQ status. Patients who were not treated with HCQ were significantly more likely to have a higher SLAM score and SDI score at time 0. Nonusers were more likely to have serositis, renal disease, cytopenias, central nervous system involvement, and myositis than users of HCQ. Emergency room visits and hospitalizations due to lupus were more common in nonusers. The length of followup among users of HCQ versus nonusers was comparable (mean ± SD 2.47 ± 2.74 years and 2.42 ± 2.79 years, respectively).

The HR for new damage among all users of HCQ (prior to adjustment for the propensity score) was 0.68 (95% CI 0.53–0.93) (P = 0.014). Among patients who had no damage at time 0 and were being treated with HCQ, the HR was 0.57 (95% CI 0.37–0.88) (P = 0.0019). In contrast, patients who had damage at time 0 and were being treated with HCQ had a hazard ratio of 0.85 (95% CI 0.54–1.33) (P = 0.47). Figure 1 demonstrates the time to damage accrual in patients who were taking HCQ at time 0 compared with those who were not. The results suggest that patients who do not have damage early in their disease course are the ones who benefit the most from the protective effects of HCQ.

thumbnail image

Figure 1. Time to accrual of new damage (unadjusted for propensity score) in systemic lupus erythematosus patients who were and those who were not treated with hydroxychloroquine (HCQ) at time 0 (T0).

Download figure to PowerPoint

Propensity analysis.

A logistic regression model was used to generate a propensity score for the study population. The study population was divided into quintiles according to the propensity score, and the probability of HCQ use was computed for each group (Table 2). The propensity score and data on HCQ use were entered into a Cox proportional hazards model. As seen in Table 3, HCQ use was associated with a reduced risk of damage accrual. Analysis of the individual domains on the SDI was performed; however, due to the low number of events, no statistically significant decrease in damage accrual was demonstrated in the HCQ users (data not shown). After adjustment for the propensity score, the HR among patients without damage at time 0 was 0.55 (95% CI 0.34–0.87) (P = 0.0111), as compared with 1.106 (95% CI 0.70–1.74) (P = 0.6630) among patients with damage at time 0.

Table 2. Relationship between propensity score quintile and treatment with hydroxychloroquine
Propensity score quintileNo. of patients in quintileNo. of patients treatedObserved probability of treatment
130310
2842327
31358159
423316068
5363079
Table 3. Probability of developing new damage*
 HR95% CIP
  • *

    HR = hazard ratio; 95% CI = 95% confidence interval.

Hydroxychloroquine use0.730.52–1.000.05
Propensity score0.220.09–0.520.0006

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

HCQ has been used to treat SLE for many years. It is generally well tolerated and has a favorable risk-to-benefit ratio (25, 41). Utilization rates of HCQ in different cohorts of lupus patients range from 35% to 65% (18, 42–44). Over the last 15 years, evidence has accumulated to suggest that HCQ use may result in a myriad of health benefits in addition to treating those symptoms for which it is prescribed. The current study provides evidence that HCQ is associated with reduced risk of damage accrual. In particular, it appears that patients who do not have damage early in their disease course are the ones who benefit the most from HCQ. To adjust for the bias associated with nonrandom treatment assignments, propensity score analysis was performed. This technique allowed us to control for known factors that influence disease activity and/or damage accrual.

Although our analysis represents a unique approach to addressing the potential protective effect of HCQ in a well-characterized, diverse cohort, there are potential limitations to this study. Despite our use of propensity scores, there may still be residual confounding by unidentified factors. However, confounding by indication tends to deflate contrast in treatment efficacy, leading to a Type II error (33, 45) and thus making the positive findings observed in this study even stronger. We were unable to examine the dosage or duration of treatment with HCQ that is necessary to produce an impact on damage accrual, because these data were not collected as part of the routine study visits. In addition, our study did not have the statistical power to determine whether treatment with HCQ had a greater impact on certain domains of the SDI and whether it is useful in combination with other more potent immunosuppressive agents, such as cyclophosphamide.

What properties do antimalarial agents possess that would support their role in protecting against the development of damage in patients with SLE? In general, antimalarial medications exhibit a wide array of antiinflammatory, antithrombotic, and immunomodulatory properties. These agents inhibit antigen processing and presentation by macrophages and lymphoid dendritic cells (46, 47), phospholipase A2 activation (48), DNA and RNA synthesis (49), and secretion of several cytokines (interleukin-1, interleukin-6 [50–53], and tumor necrosis factor α [48,53]). In addition, they induce apoptosis in lymphocytes (54) and endothelial cells (55) and disrupt T cell receptor crosslinking–dependent calcium signaling (56). It may be postulated that interference with one or more of these mechanisms blunts the perpetuation of the immunologic response in lupus. Indeed, it has been shown that HCQ has a protective effect against major flares of disease (30, 57, 58). By decreasing the frequency of disease flares, the overall long-term risk of damage would also be decreased, since damage in lupus has been consistently found to be associated with higher degrees of disease activity in the LUMINA cohort (5) as well as in other studies (12, 59, 60). In addition to its direct biologic effects, HCQ may indirectly influence damage accrual by virtue of its corticosteroid-sparing properties.

Antimalarial medications inhibit lysosomal hydrolysis, decrease synthesis of cholesterol (61), inhibit secretion of very low-density lipoprotein (62), and increase hydroxymethylglutaryl-coenzyme A reductase activity (63). Indeed, HCQ usage has been associated with reduced serum cholesterol levels (18, 20, 27, 28, 64, 65), and this effect is enhanced in patients who are being treated with corticosteroids (29). HCQ has also been shown in some studies to affect platelet aggregation and adhesion (66). It has been used to reduce the risk of pulmonary embolism in patients who undergo hip replacement (67, 68). In patients with SLE and antiphospholipid antibody syndrome, treatment with HCQ decreases the risk of thrombotic events (69, 70).

HCQ has been shown to have antihyperglycemic properties in patients with type 2 diabetes mellitus (71, 72). It has been demonstrated that chloroquine stabilizes intracellular lysosomes, thereby retarding the breakdown of the internalized insulin receptor complex (73). Among SLE patients, mean glucose levels in those who are taking HCQ have been shown to be lower than in those not receiving this treatment (18). HCQ is protective against abnormal glucose tolerance and is associated with lower fasting insulin levels (74).

In summary, the results of this study, using propensity score analysis of data accumulated in a longitudinal study of SLE patients, indicate that HCQ usage is associated with a reduced risk of damage accrual. The precise mechanisms by which HCQ influences damage accrual are unknown, but most likely involve its effects on inflammation, lipid and serum glucose levels, and platelet aggregation, as outlined above. A randomized controlled trial would be needed in order to prove that HCQ is truly protective against damage accrual in patients with SLE. Unfortunately, it is unlikely that such a trial will ever be conducted. The numbers of patients and the length of followup necessary to demonstrate differences in damage accrual, especially in specific domains on the SDI, would be prohibitively expensive. In addition, based on the available clinical data, it would be unethical to perform a placebo-controlled trial of HCQ. In the absence of such a randomized controlled trial addressing the critical question of whether HCQ is protective against damage, and the unlikeliness that such a trial would be performed due to these practical barriers, our present findings can be used to lend further support for the routine use of HCQ in the treatment of SLE.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The authors wish to thank William J. Koopman, MD, and Kenneth Saag, MD, MSc, for their critical review of the manuscript. We would also like to thank current and past LUMINA investigators and, most importantly, the patients who participated in this study.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  • 1
    Boumpas DT, Austin HA, Fessler BJ, Balow JE, Klippel JH, Lockshin MD. Systemic lupus erythematosus: emerging concepts. I. Renal, neuropsychiatric, cardiovascular, pulmonary and hematologic disease. Ann Intern Med 1995; 122: 94050.
  • 2
    Boumpas DT, Fessler BJ, Austin HA, Balow JE, Klippel JH, Lockshin MD. Systemic lupus erythematosus: emerging concepts. II. Dermatologic and joint disease, the antiphospholipid antibody syndrome, pregnancy and hormonal therapy, morbidity and mortality and pathogenesis. Ann Intern Med 1995; 123: 4253.
  • 3
    Zonana-Nacach A, Camargo-Coronel A, Yanez P, de Lourdes Sanchez M, Jimenez-Balderas FJ, Aceves-Avila J, et al. Measurement of damage in 210 Mexican patients with systemic lupus erythematosus: relationship with disease duration. Lupus 1998; 7: 11923.
  • 4
    Zonana-Nacach A, Barr SG, Magder LS, Petri M. Damage in systemic lupus erythematosus and its association with corticosteroids. Arthritis Rheum 2000; 43: 18018.
  • 5
    Alarcon GS, McGwin G Jr, Bartolucci AA, Roseman J, Lisse J, Fessler BJ, et al, for the LUMINA Study Group. Systemic lupus erythematosus in three ethnic groups. IX. Differences in damage accrual. Arthritis Rheum 2001; 44: 2797806.
  • 6
    Illei GG, Takada K, Parkin D, Austin HA, Crane M, Yarboro CH, et al. Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: long-term followup of a cohort of 145 patients participating in randomized controlled studies. Arthritis Rheum 2002; 46: 9951002.
  • 7
    Yee CS, Hussein H, Skan J, Bowman S, Situnayake D, Gordon C. Association of damage with autoantibody profile, age, race, sex and disease duration in SLE. Rheumatology (Oxford) 2003; 42: 27679.
  • 8
    Gladman DD, Urowitz MB, Rahman P, Ibanez D, Tam LS. Accrual of organ damage over time in patients with SLE. J Rheumatol 2003; 30: 19559.
  • 9
    Rahman P, Gladman DD, Urowitz MB, Hallett D, Tam LS. Early damage as measured by the SLICC/ACR damage index is a predictor of mortality in systemic lupus erythematosus. Lupus 2001; 10: 936.
  • 10
    Alarcon GS, McGwin G Jr, Bastian HM, Roseman J, Lisse J, Fessler BJ, et al, for the LUMINA Study Group. Systemic lupus erythematosus in three ethnic groups. VIII. Predictors of early mortality in the LUMINA cohort. Arthritis Rheum 2001; 45: 191202.
  • 11
    Nived O, Jonsen A, Bengtsson AA, Bengtsson C, Sturfelt G. High predictive value of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for survival in systemic lupus erythematosus. J Rheumatol 2002; 29: 1398400.
  • 12
    Mok CC, Ho CT, Wong RW, Lau CS. Damage accrual in Southern Chinese patients with systemic lupus erythematosus. J Rheumatol 2003; 30: 15139.
  • 13
    Alarcon GS, Roseman JM, McGwin G Jr, Uribe A, Bastian HM, Fessler BJ, et al. Systemic lupus erythematosus in three ethnic groups. XX. Damage as a predictor of further damage. Rheumatology (Oxford) 2004; 43: 2025.
  • 14
    Mok CC, Lau CS, Wong RW. Risk factors for avascular bone necrosis in systemic lupus erythematosus. Br J Rheumatol 1998; 37: 895900.
  • 15
    Boyanov M, Robeva R, Popivanov P. Bone mineral density changes in women with systemic lupus erythematosus. Clin Rheumatol 2003; 22: 31823.
  • 16
    Lakshminarayanan S, Walsh S, Mohanraj M, Rothfield N. Factors associated with low bone mineral density in female patients with systemic lupus erythematosus. J Rheumatol 2001; 28: 1028.
  • 17
    Wallace DJ. Antimalarials: the ‘real’ advance in lupus. Lupus 2001; 10: 3857.
  • 18
    Petri M. Hydroxychloroquine use in the Baltimore Lupus Cohort: effects on lipids, glucose and thrombosis. Lupus 1996; 1 Suppl: S1622.
  • 19
    Petri M. Thrombosis and systemic lupus erythematosus: the Hopkins Lupus Cohort perspective. Scand J Rheumatol 1996; 25: 1913.
  • 20
    Petri M, Lakatta C, Magder L, Goldman D. Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis. Am J Med 1994; 96: 2549.
  • 21
    Petri M. Hydroxychloroquine prevents later damage in SLE [abstract]. Arthritis Rheum 2001; 44 Suppl 9: S280.
  • 22
    Fessler BJ, McGwin G Jr, Alarcon GS, Roseman JM, Bastian HM, Friedman AW, et al. Hydroxychloroquine (HCQ) usage is associated with decreased renal and cardiovascular damage in patients with systemic lupus erythematosus [abstract]. Arthritis Rheum 2001; 44 Suppl 9: S201.
  • 23
    Molad Y, Gorshtein A, Wysenbeek AJ, Guedj D, Majadla R, Weinberger A, et al. Protective effect of hydroxychloroquine in systemic lupus erythematosus: prospective long-term study of an Israeli cohort. Lupus 2002; 11: 35661.
  • 24
    Wallace DJ. Antimalarial agents and lupus. Rheum Dis Clin North Am 1994; 20: 24363.
  • 25
    Rynes RI. Antimalarial drugs in the treatment of rheumatological diseases. Br J Rheumatol 1997; 36: 799805.
  • 26
    Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum 1993; 23: 8291.
  • 27
    Wallace DJ, Metzger AL, Stecher VJ, Turnbull BA, Kern PA. Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids. Am J Med 1990; 89: 3226.
  • 28
    Hodis HN, Quismorio FP Jr, Wickham E, Blankenhorn DH. The lipid, lipoprotein and apolipoprotein effects of hydroxychloroquine in patients with systemic lupus erythematosus. J Rheumatol 1993; 20: 6615.
  • 29
    Rahman P, Gladman DD, Urowitz MB, Yuen K, Hallett D, Bruce IN. The cholesterol lowering effect of antimalarial drugs is enhanced in patients with lupus taking corticosteroid drugs. J Rheumatol 1999; 26: 32530.
  • 30
    The Canadian Hydroxychloroquine Study Group. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N Engl J Med 1991; 324: 1504.
  • 31
    Tsakonas E, Joseph L, Esdaile JM, Choquette D, Senecal JL, Cividino A, et al, and The Canadian Hydroxychloroquine Study Group. A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. Lupus 1998; 7: 805.
  • 32
    Selzer F, Sutton-Tyrrell K, Fitzgerald S, Tracy R, Kuller L, Manzi S. Vascular stiffness in women with systemic lupus erythematosus. Hypertension 2001; 37: 107582.
  • 33
    Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997; 127: 75763.
  • 34
    Alarcon GS, Roseman J, Bartolucci AA, Friedman AW, Moulds JM, Goel N, et al, for the LUMINA Study Group. Systemic lupus erythematosus in three ethnic groups. II. Features predictive of disease activity early in its course. Arthritis Rheum 1998; 41: 117380.
  • 35
    Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 12717.
  • 36
    Liang MH, Socher SA, Larson MG, Schur PH. Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 1989; 32: 110718.
  • 37
    Gladman D, Ginzler E, Goldsmith C, Fortin P, Liang M, Urowitz M, et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum 1996; 39: 3639.
  • 37
    Gladman DD, Urowitz MB, Goldsmith CH, Fortin P, Ginzler E, Gordon C, et al. The reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index in patients with systemic lupus erythematosus. Arthritis Rheum 1997; 40: 80913.
  • 39
    Reveille JD, Moulds JM, Ahn C, Friedman AW, Baethge B, Roseman J, et al, for the LUMINA Study Group. Systemic lupus erythematosus in three ethnic groups. I. The effects of HLA class II, C4, and CR1 alleles, socioeconomic factors, and ethnicity at disease onset. Arthritis Rheum 1998; 41: 116172.
  • 40
    Alarcon GS, Friedman AW, Straaton KV, Moulds JM, Lisse J, Bastian HM, et al. Systemic lupus erythematosus in three ethnic groups. III. A comparison of characteristics early in the natural history of the LUMINA cohort. Lupus 1999; 8: 197209.
  • 41
    Maksymowych W, Russell AS. Antimalarials in rheumatology: efficacy and safety. Semin Arthritis Rheum 1987; 16: 20621.
  • 42
    Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003; 82: 299308.
  • 43
    Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al, and the European Working Party on Systemic Lupus Erythematosus. Morbidity and mortality in systemic lupus erythematosus during a 5-year period: a multicenter prospective study of 1,000 patients. Medicine (Baltimore) 1999; 78: 16775.
  • 44
    Pistiner M, Wallace DJ, Nessim S, Metzger AL, Klinenberg JR. Lupus erythematosus in the 1980's: a survey of 570 patients. Semin Arthritis Rheum 1991; 21: 5564.
  • 45
    D'Agostino RB Jr. Propensity score methods for bias reduction in comparison of treatment to a non-randomized, controlled group. Stat Med 1998; 17: 226581.
  • 46
    Fox RI, Kang HI. Mechanism of action of antimalarial drugs: inhibition of antigen processing and presentation. Lupus 1993; 1 Suppl: S912.
  • 47
    Fox R. Anti-malarial drugs: possible mechanisms of action in autoimmune disease and prospects for drug development. Lupus 1996; 5 Suppl: S410.
  • 48
    Bondeson J, Sundler R. Antimalarial drugs inhibit phospholipase A2 activation and induction of interleukin 1β and tumor necrosis factor α in macrophages: implications for their mode of action in rheumatoid arthritis. Gen Pharmacol 1998; 30: 35766.
  • 49
    Cohen SN, Yielding KL. Inhibition of DNA and RNA polymerase reactions by chloroquine. Proc Natl Acad Sci U S A 1965; 54: 5217.
  • 50
    Wallace DJ, Linker-Israeli M, Hyun S, Klinenberg JR, Stecher V. The effect of hydroxychloroquine therapy on serum levels of immunoregulatory molecules in patients with systemic lupus erythematosus. J Rheumatol 1994; 21: 3756.
  • 51
    Salmeron G, Lipsky PE. Immunosuppressive potentials of antimalarials. Am J Med 1983; 75: 1924.
  • 52
    Sperber K, Quraishi H, Kalb TH, Panja A, Stecher V, Mayer L. Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1α (IL-1α) and IL-6 in human monocytes and T cells. J Rheumatol 1993; 20: 8038.
  • 53
    Van den Borne BE, Dijkmans BA, de Rooij HH, le Cessie S, Verweij CL. Chloroquine and hydroxychloroquine equally affect tumor necrosis factor α, interleukin 6 and interferon-γ production by peripheral blood mononuclear cells. J Rheumatol 1997; 24: 5560.
  • 54
    Meng XW, Feller JM, Ziegler JB, Pittman SM, Ireland CM. Induction of apoptosis in peripheral blood lymphocytes following treatment in vitro with hydroxychloroquine. Arthritis Rheum 1997; 40: 92735.
  • 55
    Potvin F, Petitclerc E, Marceau F, Poubelle PE. Mechanisms of action of antimalarials in inflammation: induction of apoptosis in human endothelial cells. J Immunol 1997; 158: 18729.
  • 56
    Goldman FD, Gilman AL, Hollenback C, Kato RM, Premack BA, Rawlings DJ. Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties. Blood 2000; 95: 34606.
  • 57
    Rudnicki RD, Gresham GE, Rothfield NF. The efficacy of antimalarials in systemic lupus erythematosus. J Rheumatol 1975; 2: 32330.
  • 58
    Canadian Hydroxychloroquine Study Group. A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. Lupus 1998; 7: 805.
  • 59
    Stoll T, Sutcliffe N, Mach J, Klaghofer R, Isenberg DA. Analysis of the relationship between disease activity and damage in patients with systemic lupus erythematosus: a 5 year prospective study. Rheumatology (Oxford) 2004; 43: 103944.
  • 60
    Karlson EW, Daltroy LH, Lew RA, Wright EA, Partridge AJ, Fossel AH, et al. The relationship of socioeconomic status, race, and modifiable risk factors to outcomes in patients with systemic lupus erythematosus. Arthritis Rheum 1997; 40: 4756.
  • 61
    Benyen AC. Can chloroquine be of value in the treatment of hypercholesterolemia? Artery 1986; 13: 34051.
  • 62
    Rustan AC, Nossen JO, Tefre T, Drevon CA. Inhibition of very low density lipoprotein secretion by chloroquine verapamil and monensin takes place in the Golgi complex. Biochim Biophys Acta 1987; 930: 3119.
  • 63
    Chen HW, Leonard DA. Chloroquine inhibits cyclization of squalene oxide to lanosterol in mammalian cells. J Biol Chem 1984; 259: 815662.
  • 64
    Tam LS, Gladman D, Hallett D, Rahman P, Urowitz MB. Effect of antimalarial agents on the fasting lipid profile in systemic lupus erythematosus. J Rheumatol 2000; 27: 21425.
  • 65
    Borba EF, Bonfa E. Longterm beneficial effect of chloroquine diphosphate on lipoprotein profile in lupus patients with and without steroid therapy. J Rheumatol 2001; 28: 7805.
  • 66
    Espinola RG, Pierangeli SS, Ghara AE, Harris EN. Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies. Thromb Haemost 2002; 87: 51822.
  • 67
    Carter AE, Eban R, Perrett RD. Prevention of post operative deep venous thrombosis and pulmonary embolism. Br J Med 1971; 1: 3124.
  • 68
    Loudon JR. Hydroxychloroquine and postoperative thromboembolism after total hip replacement. Am J Med 1988; 85: 5761.
  • 69
    Wallace DJ. Does hydroxychloroquine sulfate prevent clot formation in systemic lupus erythematosus? [letter]. Arthritis Rheum 1987; 30: 14356.
  • 70
    Erkan D, Yazici Y, Peterson MG, Sammaritano L, Lockshin MD. A cross-section study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology (Oxford) 2002; 41: 9249.
  • 71
    Quatraro A, Consoli G, Magno M, Caretta F, Nardozza A, Ceriello A, et al. Hydroxychloroquine in decompensated, treatment-refractory noninsulin-dependent diabetes mellitus: a new job for an old drug? Ann Intern Med 1990; 112: 67881.
  • 72
    Gerstein HC, Thorpe KE, Taylor DW, Haynes RB. The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas: a randomized trial. Diabetes Res Clin Pract 2002; 55: 20919.
  • 73
    Bevan AP, Krook A, Tikerpae J, Seabright PJ, Siddle K, Smith GD. Chloroquine extends the lifetime of the activated insulin receptor complex in endosomes. J Biol Chem 1997; 272: 2683340.
  • 74
    Petri M, Yoo SS. Predictors of glucose intolerance in systemic lupus erythematosus [abstract]. Arthritis Rheum 1994; 37 Suppl 9: S323.
  • 75
    Pilowsky I. Dimensions of illness behavior as measured by the Illness Behavior Questionnaire: a replication study. J Psychosom Res 1993; 37: 5362.