Research ArticleArticle

The Early Protective Effect of Hydroxychloroquine on the Risk of Cumulative Damage in Patients with Systemic Lupus Erythematosus

Pooneh S. Akhavan, Jiandong Su, Wendy Lou, Dafna D. Gladman, Murray B. Urowitz and Paul R. Fortin
The Journal of Rheumatology June 2013, 40 (6) 831-841; DOI: https://doi.org/10.3899/jrheum.120572

Abstract

Objective. To assess whether hydroxychloroquine (HCQ) prevents early damage in patients with systemic lupus erythematosus (SLE).

Methods. We updated an existing systematic review of literature on clinical effects of HCQ in patients with SLE. We conducted a nested case-control study embedded in an inception cohort of patients with SLE. Systemic Lupus International Collaborating Clinics Damage Index (SDI) at 3 years was considered as our primary outcome. Patients with SDI > 0 at 3 years were considered cases and patients with SDI = 0 were controls. Cases and controls were first compared by univariate analysis. Then conditional logistic regression models adjusting for potential confounders were done to study the effect of HCQ on damage accrual.

Results. Included in the analysis were 481 patients who had 3 or more years of followup. Out of this cohort, we could match 151 cases with 151 controls. Univariate analysis identified age, the use of any immunosuppressive drugs, HCQ, and cumulative dose of steroids as significant covariates associated with damage accrual. In multivariate analysis, the use of HCQ remained significantly associated with less damage (OR 0.34, 95% CI 0.132–0.867), while age (OR 1.05, 95% CI 1.027–1.078) and a variable combining SLE activity and steroid dose (OR 1.73, 95% CI 1.306–2.295) were associated with damage at 3 years.

Conclusion. We demonstrated that HCQ use was associated with less damage at 3 years after diagnosis of SLE when attention was given and adjustment done for disease activity and steroid dose, duration of disease, and calendar year of diagnosis.

Key Indexing Terms:

Systemic lupus erythematosus (SLE) is an autoimmune systemic illness characterized by acute and chronic inflammation of multiple organs. Antimalarial (AM) drugs, mainly hydroxychloroquine (HCQ), have been commonly prescribed in SLE to treat constitutional symptoms, rashes, and arthritis, and to prevent flares1. The immune-modulatory effect of AM is mediated by several mechanisms including antagonizing Toll-like receptor (TLR) activation, possibly by altering pH or through competitive inhibition. This can result in inhibition of interferon-α (IFN-α) expression and activation of multiple IFN-α-mediated pathways2. Although processing of low-affinity antigens (e.g., self-antigens) is blocked, the immune response against high-affinity antigens (e.g., bacterial peptides) is not impaired, which results in an effective immunomodulation without immunosuppression3.

Despite the extensive use of AM in the treatment of SLE for decades, their numerous beneficial effects have only been demonstrated in recent years2. Ruiz-Irastorza, et al performed a systematic review of literature on clinical efficacy and side effects of AM in SLE, and given their wide-spectrum benefits and overall safety, suggested that these agents should be used in all patients with SLE1. In that review, 11 studies were identified supporting the beneficial effects of AM on SLE disease activity4,5,6,7,8,9,10,11,12,12a,12b, 6 on thrombosis13,14,15,16,17,18, 2 on organ damage19,20, 2 on survival16,21, 9 on lipid profile22,23,24,25,26,27,28,29,30, and 4 on bone metabolism. That review showed that large series have consistently demonstrated the absence of serious adverse events even after prolonged use1. This emerging evidence supporting the use of AM in SLE has changed the practice pattern toward more frequent use of HCQ in patients with SLE31.

Survival of patients with SLE has improved significantly over time32. As patients with SLE live longer, cumulative damage has become an important outcome33. Current evidence indicates that damage accrual occurs within the first few years after disease onset (mean of 3.8 yrs)34.

Organ damage profoundly affects patients’ functional and psychosocial state and health-related quality of life. Therefore, it is extremely important to identify predictors of damage and protective factors to prevent this irreversible sequel, aiming to improve survival, function, and health-related quality of life in these patients32.

In 2005, Fessler, et al demonstrated a protective role for HCQ against damage accrual in patients with SLE enrolled in a prospective cohort (LUMINA), with baseline disease duration of up to 5 years19. In that study, damage accrual over time was compared in patients who were taking HCQ at baseline with patients who were not taking this medication, and demonstrated a protective effect19. More recently, Lopez, et al35 analyzed data from another prospective SLE cohort (University College Hospital, London, Lupus Clinic) to assess the association between disease activity and damage accrual. They evaluated potential predictors of damage, and HCQ was protective in the univariate analysis, but this effect was not observed when the analysis was adjusted for other confounders35.

Antimalarial drugs have traditionally been used for the treatment of mild to moderate SLE, particularly prior to the widespread use of these agents in recent years. This may lead to confounding by indication when studying the benefits of AM drugs in a longitudinal observational study in which treatments are not randomized. Indeed, patients with milder disease who were typically treated with AM drugs would naturally accrue less damage compared to those with severe multiorgan involvement. Fessler, et al19 used a statistical matching technique that attempts to estimate the effect of AM drugs by accounting for the covariates that predict receiving it in the first place. This technique, called propensity score analysis, attempts to address the problem of confounding by indication. The study by Lopez, et al on the other hand used multivariate analysis to adjust for potential confounders35,36.

Evidence for the beneficial effects of AM continues to grow. To collect and review the existing data, we updated the systematic review performed by Ruiz-Irastorza, et al1. It was found that the effect of HCQ on damage accrual during the initial years after diagnosis of SLE has not been evaluated. To capture the treatment effect in the early stage of disease, we conducted a nested case-control study in a large inception cohort where patients were enrolled at the time of diagnosis and we assessed the outcome, i.e., damage at 3 years. We matched case-control pairs by calendar year of diagnosis and severity of disease for the possibility of confounding by practice patterns or by treatment indication.

MATERIALS AND METHODS

Literature review

A comprehensive systematic review performed by Ruiz-Irastorza, et al1 published in 2010 included English literature between 1982 and 2007, from Medline and Embase databases. We used the same search strategy and reviewed the literature between January 2007 and October 2012 from the same databases (Appendix 1 and 2). We selected clinical trials and observational studies, including adult patients, in which the clinical effects and/or toxicity of AM were analyzed. Case reports were excluded except for toxicity reports.

Study population

An inception cohort of patients with a diagnosis of SLE made within 1 year of enrollment between 1970 and 2009 was identified from the University of Toronto Lupus Clinic database. Ethical review and approval from the University Health Network Research Ethics Board were implemented in creating this database and participants’ informed consent was collected at enrollment. In this cohort, diagnosis was based on fulfilling 4 or more of the 1971 or 1982 American College of Rheumatology (ACR) classification criteria37, or 3 ACR criteria plus having a diagnostic histological lesion of SLE (on renal or skin biopsy). Patients with at least 2 visits who had been followed for at least 3 years were included in the current study.

Clinical variables

Demographic information included ethnicity, sex, and age at baseline, education status (finished high school), and calendar year of diagnosis. Disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K)38 and damage was measured by the Systemic Lupus International Collaborating Clinics Damage Index (SDI)39,40,41. Other clinical variables included the adjusted mean SLEDAI (AMS), which is a valid measure of the average SLEDAI over the period of observation42, and the maximum SLEDAI in the first 3 years. We limited our measure of AM exposure to that of HCQ because that is by far the most commonly used AM drug in our center. Treatment variables included dichotomous variable (whether used during the first 3 years) for HCQ, use of immunosuppressive drugs (any of azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil, cyclosporine), and steroids. Because azathioprine is the most often used immunosuppressive drug in our cohort, we also studied azathioprine use alone. Duration of HCQ exposure (in months) during the first 3 years was also addressed as one of our independent variables.

Outcome variable and matching procedure

Our outcome of interest was damage (SDI) at 3 years. SDI was recorded in the database annually for all patients and was zero by definition at baseline. A case-control study was performed to control for the known confounders, especially disease activity and severity. We defined as cases all patients with SDI > 0 at 3 years. Controls were defined as patients with an SDI of zero at 3 years. Patients who missed the Year 3 visit but their subsequent SDI scores were zero were also considered controls. We performed an in-depth chart review to document the SDI at Year 3 for patients who missed the Year 3 followup but had a subsequent SDI > 0 to determine the time at which damage had developed. For each case, 1 control was matched based on disease severity as defined by the highest SLEDAI score over the study period and the calendar year of diagnosis. This practice would minimize the confounding effect of practice pattern change over time toward more frequent use of AM agent in patients with SLE.

Statistical analysis

Descriptive statistics were generated for cases and controls at baseline. Univariate conditional logistic regression was performed on each potential predictor of the outcome SDI. We then constructed multivariable conditional logistic regression models to study the effect of HCQ use on the development of damage while adjusting for age, sex, ethnicity, AMS, azathioprine use, and cumulative steroid dose. AMS and cumulative steroid dose were found to be statistically correlated (r = 0.36). To capture the overall contribution of these variables as a proxy for severity of disease during the followup period, we performed 2 sets of models: one using each variable AMS and steroid dose separately and another using a variable that combined the doses. For that second model, we created a new variable combining categories of AMS scores and steroid dose. First we verified the normal distribution of AMS in cases and controls. Then we categorized AMS and cumulative steroid dose into quartiles. For AMS (throughout the first 3 years of followup), we defined our 4 categories as AMS of < 3, ≥ 3 and < 6, ≥ 6 and < 9, and ≥ 9, and assigned scores of 1, 2, 3, and 4 to each, respectively. Similarly for cumulative steroid dose (gram), we categorized patients based on this variable’s quartiles into 4 groups of 0, > 0 and < 9, ≥ 9 and < 18, and ≥ 18 g, with scores of 1, 2, 3, and 4 assigned to each, respectively. The summation of each pair of these subscores for an individual patient comprised the composite variable for that person, e.g., for a patient whose AMS in 3 years was 4 and the cumulative dose of steroid was 8 g, the index variable would be 4 (2 + 2).

Similar models were built to assess the effect of HCQ treatment duration on SDI adjusted for the above confounders. The statistical software SAS (version 9) was used for all statistical analyses and the significance level was set at 5%.

RESULTS

Literature review

Our search identified 1550 papers. After reviewing titles and abstracts, 58 papers were selected for full review. Forty-seven papers were included in the final review. Adverse events were assessed in 14 studies including 11 case reports43,44,45,46,47,48,49,50,51,52,53,54,55,56 (Appendix 3). We found further evidence supporting the findings of the systematic review by Ruiz-Irastorza, et al1 for thrombosis57,58,59,60,61, survival21,33,62,63, disease activity47,64,65, lipid profile17,28,51,66,67,68,69,70, and damage35,36,71,72,73,74,75,76, while we found evidence for delayed SLE onset77, reduced major infection rate78, and possible protective effect on malignancy79, with the use of AM. We updated the reports on toxicity and did not find new alarming signals. Overall, our literature review reinforces the conclusions of Ruiz-Irastorza, et al1.

Main analysis

Our study population consisted of an inception cohort of 685 patients. Of those 685, 481 patients had 3 or more years of followup and were included in further analysis. Of this cohort, 174 were potential cases and 307 were identified as potential controls. We were able to match 151 cases with 1 control each (151 pairs) based on the calendar year of diagnosis (± 3 yrs) and maximum SLEDAI (< 2 points of that of the matched case). Baseline characteristics of cases and controls and the results of the univariate analyses are shown in Table 1. The distribution of patients in each AMS and cumulative steroid dose category is shown in Table 2.

View this table:
Table 1.

Characteristics of cases and controls and univariate analysis for risk factors associated with damage accrual in patients with systemic lupus erythematosus (SLE).

View this table:
Table 2.

Distribution of patients in 4 categories of cumulative steroid dose and AMS [adjusted mean SLEDAI (Systemic Lupus Erythematosus Disease Activity Index)].

As expected by design, AMS and maximum SLEDAI in the 2 groups were not significantly different. Mean age was higher among cases. Univariate analyses identified the use of any immunosuppressive drugs including azathioprine (OR 2.71, 95% CI 1.55–4.72, p = 0.0005) and azathioprine alone (OR 2.75, 95% CI 1.55–4.87, p = 0.0005) significantly associated with an increased risk of damage at Year 3, while the use of HCQ (OR 0.33, 95% CI 0.15–0.74, p = 0.0071) was associated with a reduced risk. The longer duration of HCQ therapy seemed to be protective; however, the OR was almost 1 (OR 0.977, 95% CI 0.958–0.997, p = 0.0254). Interestingly, the majority of cases and controls had not received HCQ during the first 3 years.

Table 3 shows the results of our multivariate model that includes AMS and cumulative steroid dose as separate variables. Table 4 demonstrates the additional model we created based on the composite variable SLE activity and steroid dose. In the multivariate analyses, HCQ use was associated with less damage at 3 years (OR 0.34, 95% CI 0.132–0.838) and the effect of azathioprine use was no longer significant. The beneficial effect of HCQ on damage at 3 years remained significant in the additional model (OR 0.34, 95% CI 0.132–0.867; Table 4). The “Lupus activity and steroid dose” variable was independently associated with an increased risk of damage (OR 1.73, 95% CI 1.306–2.295), and age remained significant (OR 1.05, 95% CI 1.027–1.078) in this model.

View this table:
Table 3.

Multivariate analysis for risk factors associated with damage accrual in patients with SLE.

View this table:
Table 4.

Multivariate analysis for risk factors associated with damage accrual in patients with SLE (including the lupus activity steroid dose variable).

When the variable “HCQ use” was replaced with the variable “Duration of HCQ therapy” as a predictor, this variable was not significant in the multivariate models that included AMS and cumulative steroid dose (OR 0.98, 95% CI 0.96–1.003) or the composite SLE activity and steroid dose variable (OR 0.98, 95% CI 0.96–1.005; data not shown).

DISCUSSION

In this nested case-control study, we demonstrated that HCQ was associated with less damage as early as 3 years after disease onset. With improved management, patients with SLE live longer33 but at the cost of an increased chance of developing premature comorbidities or damage. Any protective measures against damage accrual can potentially affect patients’ quality of life and longterm outcomes.

The clinical efficacy and adverse events of AM were demonstrated in an extensive review that supported beneficial effects of these agents on SLE disease activity, survival, damage, thromboembolic events, lipid profile, and bone metabolism1. Our updated search identified supporting evidence for clinical efficacy of HCQ in SLE published over the past 5 years in favor of improvements in survival21,33,62,63, disease activity64,65, lipid profile, glucose control, metabolic syndrome17,28,66,67,68,69,70, and prevention of thromboembolic events31,57,58,59,60,61. Eight studies evaluated the effect of AM on damage. Three74,75,76 of 4 studies72,74,75,76 assessing renal damage and outcome of lupus nephritis showed beneficial effects. One found longer time to integument damage36 and 1 showed longer time to neuropsychiatric damage71. Two studies focused on the effect of HCQ on the fetus (Appendix 4). Two studies assessed overall damage (SDI) as the main outcome35,73. Petri, et al considered the last available visit SDI as the main outcome when they analyzed data on 2054 patients. About a third of those patients were enrolled within 1 year of disease onset and 27% had disease > 5 years at enrollment. The use of AM was associated with less damage but when adjusted for confounders in multivariate analysis, only age and steroid use remained significant (HCQ HR: 0.9, 95% CI 0.7–1.0, p = 0.06)73. The primary objective of the Lopez, et al study was to assess the association between disease activity and new damage (SDI change ≥ 1) in 350 patients with SLE, i.e., a number of these patients already had damage at the beginning of the followup. Disease duration varied from 0 to 34 years (median 6 yrs). The use of HCQ was not significant in multivariate analysis using Cox proportional hazards models35.

The beneficial effect of HCQ on cumulative damage was previously shown in 2 other studies19,20. One had a small sample size, and the possibility of confounding by indication was not considered in the analysis20. In the more recent study, Fessler, et al showed that HCQ use at baseline was associated with a reduced risk of developing new damage (HR 0.73, 95% CI 0.52–1.00, p = 0.05) in 518 patients with SLE for ≤ 5 years who did not have damage at baseline19. The disease duration at baseline in this study was up to 5 years. In patients who had no damage at study entry, HCQ use decreased the risk of damage accrual (HR 0.55, 95% CI 0.34–0.8, p = 0.0111). This was not observed in those receiving HCQ who had damage. Propensity score was used to adjust for potential confounders19. Propensity score analyses improve the risk of confounding by indication but will not be optimal if all relevant variables are not included in the propensity score model, and remaining unmeasured confounding may still be present and cause bias80.

Among existing studies, our analysis is, to our knowledge, the only one assessing early damage accrual in an inception SLE cohort. Our study supports the results from Fessler, et al19,20 using different analysis, which allowed us to adjust for disease severity, duration of disease, and calendar year of diagnosis.

Considering the study design and the nature of observational studies in general, our work has certain limitations. Despite our best efforts to minimize confounding, by matching cases and controls based on the main confounders and adjusting our final models for other possible confounders, it is still possible that our results are affected by residual (hidden) confounding. This could explain the association observed between the use of azathioprine and damage accrual in the univariate analysis that is no longer significant in the multivariate analysis. Residual confounding is one of the major limitations researchers face with the analysis of observational data. A controlled clinical trial would be ideal to prove the effect of HCQ use but such a trial is unlikely to be conducted considering ethical restrictions on the use of placebo when several benefits have been proven for HCQ in SLE.

We were interested in evaluating the effect of the treatment duration (HCQ exposure) on this important outcome. We found an association in univariate analysis but not in multivariate analysis. This could be due to the small numbers of treated patients among both cases and controls. We also tried to determine whether there was any specific organ damage that was prevented in HCQ users by comparing SDI items in users with nonusers. This analysis was again limited, owing to the small number of HCQ users among cases, and was only significant for pulmonary fibrosis (data not shown).

Compared to other conventionally used immunomodulators, HCQ is inexpensive, widely available, well tolerated, and has low toxicity. Our findings are in support of the wide and early use of this medication in patients with SLE in the absence of contraindications.

APPENDIX 1

Figure

The search strategy1. [References for all appendices follow Appendix 4.]

APPENDIX 2

View this table:

Overview of included studies - Clinical effects

APPENDIX 3

View this table:

Overview of included studies- Adverse events

APPENDIX 4

View this table:

Overview of included studies- Effects on fetus

APPENDIX 5

References for Appendices 1–4

  1. 1.
    1. Ruiz-Irastorza G.,
    2. Ramos-Casals M.,
    3. Brito-Zeron P.,
    4. Khamashta M.A.
    , Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis, 2010. 69(1): p. 20–8.
    OpenUrlAbstract/FREE Full Text
  2. 2.
    1. Willis R.,
    2. Seif A.M.,
    3. McGwin G. Jr..,
    4. Martinez-Martinez L.A.,
    5. Gonzalez E.B.,
    6. Dang N.,
    7. Papalardo E.,
    8. Liu J.,
    9. Vila L.M.,
    10. Reveille J.D.,
    11. Alarcon G.S.,
    12. Pierangeli S.S.
    , Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort. Lupus, 2012. 21(8): p. 830–5.
    OpenUrlAbstract/FREE Full Text
  3. 3.
    1. Shinjo S.K.
    , Systemic lupus erythematosus in the elderly: antimalarials in disease remission. Rheumatol Int, 2009. 29(9): p. 1087–90.
    OpenUrlCrossRefPubMed
  4. 4.
    1. Broder A.,
    2. Putterman C.
    , Hydroxychloroquine Use Is Associated with Lower Odds of Persistently Positive Antiphospholipid Antibodies and/or Lupus Anticoagulant in Systemic Lupus Erythematosus. J Rheumatol, 2012.
  5. 5.
    1. Jung H.,
    2. Bobba R.,
    3. Su J,
    4. Shariati-Sarabi Z.,
    5. Gladman D.D.,
    6. Urowitz M.,
    7. Lou W.,
    8. Fortin P.R.
    , The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum, 2010. 62(3): p. 863–8.
    OpenUrlCrossRefPubMed
  6. 6.
    1. Becker-Merok A.,
    2. Nossent J.
    , Prevalence, predictors and outcome of vascular damage in systemic lupus erythematosus. Lupus, 2009. 18(6): p. 508–15.
    OpenUrlAbstract/FREE Full Text
  7. 7.
    1. Kaiser R.,
    2. Cleveland C.M.,
    3. Criswell L.A.
    , Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort. Ann Rheum Dis, 2009. 68(2): p. 238–41.
    OpenUrlAbstract/FREE Full Text
  8. 8.
    1. Tektonidou M.G.,
    2. Laskari K.,
    3. Panagiotakos D.B.,
    4. Moutsopoulos H.M.
    , Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Rheum, 2009. 61(1): p. 29–36.
    OpenUrlCrossRefPubMed
  9. 9.
    1. Choojitarom K.,
    2. Verasertniyom O.,
    3. Totemchokchyakarn K.,
    4. Nantiruj K.,
    5. Sumethkul V,
    6. Janwityanujit S.
    , Lupus nephritis and Raynaud’s phenomenon are significant risk factors for vascular thrombosis in SLE patients with positive antiphospholipid antibodies. Clin Rheumatol, 2008. 27(3): p. 345–51.
    OpenUrlCrossRefPubMed
  10. 10.
    1. Feng X.,
    2. Zou Y.,
    3. Pan W.,
    4. Wang X.,
    5. Wu M.,
    6. Zhang M,
    7. Tao J.,
    8. Zhang Y.,
    9. Tan K.,
    10. Li J.,
    11. Chen Z.,
    12. Ding X.,
    13. Qian X.,
    14. Da Z.,
    15. Wang M.,
    16. Sun L.
    , Prognostic indicators of hospitalized patients with systemic lupus erythematosus: a large retrospective multicenter study in China. J Rheumatol, 2011. 38(7): p. 1289–95.
    OpenUrlAbstract/FREE Full Text
  11. 11.
    1. Shinjo S.K.,
    2. Bonfa E.,
    3. Wojdyla D.,
    4. Borba E.F.,
    5. Ramirez L.A.,
    6. Scherbarth H.R.,
    7. Brenol J.C.,
    8. Chacon-Diaz R.,
    9. Neira O.J.,
    10. Berbotto G.A.,
    11. De La Torre I.G.,
    12. Acevedo-Vazquez E.M.,
    13. Massardo L.,
    14. Barile-Fabris L.A.,
    15. Caeiro F.,
    16. Silveira L.H.,
    17. Sato E.I.,
    18. Buliubasich S.,
    19. Alarcon G.S.,
    20. Pons-Estel B.A.
    , Antimalarial treatment may have a time-dependent effect on lupus survival: data from a multinational Latin American inception cohort. Arthritis Rheum, 2010. 62(3): p. 855–62.
    OpenUrlCrossRefPubMed
  12. 12.
    1. Urowitz M.B.,
    2. Gladman D.D.,
    3. Tom B.D.,
    4. Ibanez D,
    5. Farewell V.T.
    , Changing patterns in mortality and disease outcomes for patients with systemic lupus erythematosus. J Rheumatol, 2008. 35(11): p. 2152–8.
    OpenUrlAbstract/FREE Full Text
  13. 13.
    1. Alarcon G.S.,
    2. McGwin G.,
    3. Bertoli A.M.,
    4. Fessler B.J.,
    5. Calvo-Alen J.,
    6. Bastian H.M.,
    7. Vila L.M.,
    8. Reveille J.D.
    , Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis, 2007. 66(9): p. 1168–72.
    OpenUrlAbstract/FREE Full Text
  14. 14.
    1. Lopez R.,
    2. Davidson J.E.,
    3. Beeby M.D.,
    4. Egger P.J.,
    5. Isenberg D.A.
    , Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort. Rheumatology (Oxford), 2012. 51(3): p. 491–8.
    OpenUrlAbstract/FREE Full Text
  15. 15.
    1. Okpechi I.G.,
    2. Ayodele O.E.,
    3. Jones E.S.,
    4. Duffield M.,
    5. Swanepoel C.R.
    , Outcome of patients with membranous lupus nephritis in Cape Town South Africa. Nephrol Dial Transplant, 2012. 27(9): p. 3509–15.
    OpenUrlAbstract/FREE Full Text
  16. 16.
    1. Petri M.,
    2. Purvey S.,
    3. Fang H.,
    4. Magder L.S.
    , Predictors of organ damage in systemic lupus erythematosus: The hopkins’ lupus cohort. Arthritis Rheum, 2012.
  17. 17.
    1. Pons-Estel G.J.,
    2. Alarcon G.S.,
    3. Hachuel L.,
    4. Boggio G.,
    5. Wojdyla D.,
    6. Pascual-Ramos V.,
    7. Soriano E.R.,
    8. Saurit V.,
    9. Cavalcanti F.S.,
    10. Guzman R.A.,
    11. Guibert-Toledano M.,
    12. Sauza Del Pozo M.J.,
    13. Amigo M.C.,
    14. Alva M.,
    15. Esteva-Spinetti M.H.,
    16. Pons-Estel B.A.
    , Anti-malarials exert a protective effect while Mestizo patients are at increased risk of developing SLE renal disease: data from a Latin-American cohort. Rheumatology (Oxford), 2012. 51(7): p. 1293–8.
    OpenUrlAbstract/FREE Full Text
  18. 18.
    1. Pons-Estel G.J.,
    2. Alarcon G.S.,
    3. Gonzalez L.A.,
    4. Zhang J.,
    5. Vila L.M.,
    6. Reveille J.D.,
    7. McGwin G. Jr..
    , Possible protective effect of hydroxychloroquine on delaying the occurrence of integument damage in lupus: LXXI, data from a multiethnic cohort. Arthritis Care Res (Hoboken), 2010. 62(3): p. 393–400.
    OpenUrlCrossRefPubMed
  19. 19.
    1. Gonzalez L.A.,
    2. Pons-Estel G.J.,
    3. Zhang J.,
    4. Vila L.M.,
    5. Reveille J.D.,
    6. Alarcon G.S.
    , Time to neuropsychiatric damage occurrence in LUMINA (LXVI): a multi-ethnic lupus cohort. Lupus, 2009. 18(9): p. 822–30.
    OpenUrlAbstract/FREE Full Text
  20. 20.
    1. Pons-Estel G.J.,
    2. Alarcon G.S.,
    3. McGwin G. Jr..,
    4. Danila M.I.,
    5. Zhang J.,
    6. Bastian H.M.,
    7. Reveille J.D.,
    8. Vila L.M.
    , Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum, 2009. 61(6): p. 830–9.
    OpenUrlCrossRefPubMed
  21. 21.
    1. Siso A.,
    2. Ramos-Casals M.,
    3. Bove A.,
    4. Brito-Zeron P.,
    5. Soria N.,
    6. Munoz S.,
    7. Testi A.,
    8. Plaza J.,
    9. Sentis J.,
    10. Coca A.
    , Previous antimalarial therapy in patients diagnosed with lupus nephritis: influence on outcomes and survival. Lupus, 2008. 17(4): p. 281–8.
    OpenUrlAbstract/FREE Full Text
  22. 22.
    1. James J.A.,
    2. Kim-Howard X.R.,
    3. Bruner B.F.,
    4. Jonsson M.K.,
    5. McClain M.T.,
    6. Arbuckle M.R.,
    7. Walker C.,
    8. Dennis G.J.,
    9. Merrill J.T.,
    10. Harley J.B.
    , Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus, 2007. 16(6): p. 401–9.
    OpenUrlAbstract/FREE Full Text
  23. 23.
    1. Chong Y.B.,
    2. Yap D.Y.,
    3. Tang C.S.,
    4. Chan T.M.
    , Dyslipidaemia in patients with lupus nephritis. Nephrology (Carlton), 2011. 16(5): p. 511–7.
    OpenUrlCrossRefPubMed
  24. 24.
    1. Rossoni C.,
    2. Bisi M.C.,
    3. Keiserman M.W.,
    4. Staub H.L.
    , Antimalarials and cholesterol profile of patients with systemic lupus erythematosus. Rev Bras Reumatol, 2011. 51(4): p. 383–4, 386–7.
    OpenUrlPubMed
  25. 25.
    1. Nikpour M.,
    2. Gladman D.D.,
    3. Ibanez D.,
    4. Harvey P.J.,
    5. Urowitz M.B.
    , Variability over time and correlates of cholesterol and blood pressure in systemic lupus erythematosus: a longitudinal cohort study. Arthritis Res Ther, 2010. 12(3): p. R125.
    OpenUrlCrossRefPubMed
  26. 26.
    1. Penn S.K.,
    2. Kao A.H.,
    3. Schott L.L.,
    4. Elliott J.R.,
    5. Toledo F.G.,
    6. Kuller L.,
    7. Manzi S.,
    8. Wasko M.C.
    , Hydroxychloroquine and glycemia in women with rheumatoid arthritis and systemic lupus erythematosus. J Rheumatol, 2010. 37(6): p. 1136–42.
    OpenUrlAbstract/FREE Full Text
  27. 27.
    1. Cardoso C.R.,
    2. Signorelli F.V.,
    3. Papi J.A.,
    4. Salles G.F.
    , Prevalence and factors associated with dyslipoproteinemias in Brazilian systemic lupus erythematosus patients. Rheumatol Int, 2008. 28(4): p. 323–7.
    OpenUrlCrossRefPubMed
  28. 28.
    1. Sabio J.M.,
    2. Zamora-Pasadas M.,
    3. Jimenez-Jaimez J.,
    4. Albadalejo F.,
    5. Vargas-Hitos J.,
    6. Rodriguez del Aguila M.D.,
    7. Hidalgo-Tenorio C.,
    8. Gonzalez-Gay M.A.,
    9. Jimenez-Alonso J.
    , Metabolic syndrome in patients with systemic lupus erythematosus from Southern Spain. Lupus, 2008. 17(9): p. 849–59.
    OpenUrlAbstract/FREE Full Text
  29. 29.
    1. Sachet J.C.,
    2. Borba E.F.,
    3. Bonfa E.,
    4. Vinagre C.G.,
    5. Silva V.M.,
    6. Maranhao R.C.
    , Chloroquine increases low-density lipoprotein removal from plasma in systemic lupus patients. Lupus, 2007. 16(4): p. 273–8.
    OpenUrlAbstract/FREE Full Text
  30. 30.
    1. Ruiz-Irastorza G.,
    2. Olivares N.,
    3. Ruiz-Arruza I.,
    4. Martinez-Berriotxoa A.,
    5. Egurbide M.V.,
    6. Aguirre C.
    , Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther, 2009. 11(4): p. R109.
    OpenUrlCrossRefPubMed
  31. 31.
    1. Ruiz-Irastorza G.,
    2. Ugarte A.,
    3. Egurbide M.V.,
    4. Garmendia M.,
    5. Pijoan J.I.,
    6. Martinez-Berriotxoa A.,
    7. Aguirre C.
    , Antimalarials may influence the risk of malignancy in systemic lupus erythematosus. Ann Rheum Dis, 2007. 66(6): p. 815–7.
    OpenUrlAbstract/FREE Full Text
  32. 32.
    1. Lee W.J.,
    2. Ko M.K.,
    3. Lee B.R.
    , Hydroxychloroquine retinopathy combined with retinal pigment epithelium detachment. Cutan Ocul Toxicol, 2012. 31(2): p. 144–7.
    OpenUrlCrossRefPubMed
  33. 33.
    1. Hsu W.,
    2. Chiu N.,
    3. Huang S.
    Hydroxychloroquine-induced acute psychosis in a systemic lupus erythematosus female. Acta Neuropsychiatrica 2011: 23: 318–319
    OpenUrlCrossRef
  34. 34.
    1. Muthukrishnan P.,
    2. Roukoz H.,
    3. Grafton G.,
    4. Jessurun J.,
    5. Colvin-Adams M.
    , Hydroxychloroquine-induced cardiomyopathy: a case report. Circ Heart Fail, 2011. 4(2): p. e7–8.
    OpenUrlFREE Full Text
  35. 35.
    1. Skare T.,
    2. Ribeiro C.F.,
    3. Souza F.H.,
    4. Haendchen L.,
    5. Jordao J.M.
    , Antimalarial cutaneous side effects: a study in 209 users. Cutan Ocul Toxicol, 2011. 30(1): p. 45–9.
    OpenUrlCrossRefPubMed
  36. 36.
    1. Wolfe F.,
    2. Marmor M.F.
    , Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res (Hoboken), 2010. 62(6): p. 775–84.
    OpenUrlCrossRefPubMed
  37. 37.
    1. Fleury O.,
    2. Droitcourt C.,
    3. Polard E.,
    4. Chevrant-Breton J.
    , Reversible ageusia as an adverse effect of hydroxychloroquine treatment. J Eur Acad Dermatol Venereol, 2009. 23(5): p. 604–5.
    OpenUrlCrossRefPubMed
  38. 38.
    1. Lateef A.,
    2. Tan K.B.,
    3. Lau T.C.
    , Acute generalized exanthematous pustulosis and toxic epidermal necrolysis induced by hydroxychloroquine. Clin Rheumatol, 2009. 28(12): p. 1449–52.
    OpenUrlCrossRefPubMed
  39. 39.
    1. Manohar V.A.,
    2. Moder K.G.,
    3. Edwards W.D.,
    4. Klarich K.
    , Restrictive cardiomyopathy secondary to hydroxychloroquine therapy. J Rheumatol, 2009. 36(2): p. 440–1.
    OpenUrlFREE Full Text
  40. 40.
    1. Collins G.B.,
    2. McAllister M.S.
    , Chloroquine psychosis masquerading as PCP: a case report. J Psychoactive Drugs, 2008. 40(2): p. 211–4.
    OpenUrlCrossRefPubMed
  41. 41.
    1. Puri P.K.,
    2. Lountzis N.I.,
    3. Tyler W.,
    4. Ferringer T.
    , Hydroxychloroquine-induced hyperpigmentation: the staining pattern. J Cutan Pathol, 2008. 35(12): p. 1134–7.
    OpenUrlCrossRefPubMed
  42. 42.
    1. Costedoat-Chalumeau N.,
    2. Hulot J.S.,
    3. Amoura Z.,
    4. Leroux G.,
    5. Lechat P.,
    6. Funck-Brentano C.,
    7. Piette J.C.
    , Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases. Rheumatology (Oxford), 2007. 46(5): p. 808–10.
    OpenUrlAbstract/FREE Full Text
  43. 43.
    1. Ferreras A.,
    2. Pinilla I.,
    3. Abecia E.,
    4. Pajarin A.B.,
    5. Honrubia F.M.
    , [Retinal toxicity following chloroquine therapy]. Arch Soc Esp Oftalmol, 2007. 82(2): p. 103–8.
    OpenUrlPubMed
  44. 44.
    1. Muslimani A.A.,
    2. Spiro T.P.,
    3. Chaudhry A.A.,
    4. Daw H.A.
    , Secondary myelodysplastic syndrome after hydroxychloroquine therapy. Ann Hematol, 2007. 86(7): p. 531–4.
    OpenUrlCrossRefPubMed
  45. 45.
    1. Stas P.,
    2. Faes D.,
    3. Noyens P.
    , Conduction disorder and QT prolongation secondary to long-term treatment with chloroquine. Int J Cardiol, 2008. 127(2): p. e80–2.
    OpenUrlCrossRefPubMed
  46. 46.
    1. Izmirly P.M.,
    2. Costedoat-Chalumeau N.,
    3. Pisoni C.N.,
    4. Khamashta M.A.,
    5. Kim M.Y.,
    6. Saxena A.,
    7. Friedman D.,
    8. Llanos C.,
    9. Piette J.C.,
    10. Buyon J.P.
    , Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation, 2012. 126(1): p. 76–82.
    OpenUrlAbstract/FREE Full Text
  47. 47.
    1. Renault F.,
    2. Flores-Guevara R.,
    3. Renaud C.,
    4. Richard P.,
    5. Vermersch A.I.,
    6. Gold F.
    Visual neurophysiological dysfunction in infants exposed to hydroxychloroquine in utero. Acta Paediatr. 2009 Sep;98(9):p.1500–3 2009.
    OpenUrlCrossRefPubMed
  • Accepted for publication February 4, 2013.

REFERENCES

  1. 1.↵
    1. Ruiz-Irastorza G,
    2. Ramos-Casals M,
    3. Brito-Zeron P,
    4. Khamashta MA
    . Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: A systematic review. Ann Rheum Dis 2010;69:20–8.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Wallace DJ,
    2. Gudsoorkar VS,
    3. Weisman MH,
    4. Venuturupalli SR
    . New insights into mechanisms of therapeutic effects of antimalarial agents in SLE. Nat Rev Rheumatol 2012;8:522–33.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Fox R
    . Anti-malarial drugs: Possible mechanisms of action in autoimmune disease and prospects for drug development. Lupus 1996;5 Suppl 1:S4–10.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. N Engl J Med 1991;324:150–4.
    OpenUrlPubMed
  5. 5.↵
    1. Barber CE,
    2. Geldenhuys L,
    3. Hanly JG
    . Sustained remission of lupus nephritis. Lupus 2006;15:94–101.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Clowse ME,
    2. Magder L,
    3. Witter F,
    4. Petri M
    . Hydroxychloroquine in lupus pregnancy. Arthritis Rheum 2006;54:3640–7.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Cortes-Hernandez J,
    2. Ordi-Ros J,
    3. Paredes F,
    4. Casellas M,
    5. Castillo F,
    6. Vilardell-Tarres M
    . Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: A prospective study of 103 pregnancies. Rheumatology 2002;41:643–50.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Kasitanon N,
    2. Fine DM,
    3. Haas M,
    4. Magder LS,
    5. Petri M
    . Hydroxychloroquine use predicts complete renal remission within 12 months among patients treated with mycophenolate mofetil therapy for membranous lupus nephritis. Lupus 2006;15:366–70.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Meinao IM,
    2. Sato EI,
    3. Andrade LE,
    4. Ferraz MB,
    5. Atra E
    . Controlled trial with chloroquine diphosphate in systemic lupus erythematosus. Lupus 1996;5:237–41.
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    1. Tsakonas E,
    2. Joseph L,
    3. Esdaile JM,
    4. Choquette D,
    5. Senecal JL,
    6. Cividino A,
    7. et al.
    A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. Lupus 1998;7:80–5.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Williams HJ,
    2. Egger MJ,
    3. Singer JZ,
    4. Willkens RF,
    5. Kalunian KC,
    6. Clegg DO,
    7. et al.
    Comparison of hydroxychloroquine and placebo in the treatment of the arthropathy of mild systemic lupus erythematosus. J Rheumatol 1994;21:1457–62.
    OpenUrlPubMed
  12. 12.↵
    1. Wozniacka A,
    2. Lesiak A,
    3. Narbutt J,
    4. McCauliffe DP,
    5. Sysa-Jedrzejowska A
    . Chloroquine treatment influences proinflammatory cytokine levels in systemic lupus erythematosus patients. Lupus 2006;15:268–75.
    OpenUrlAbstract/FREE Full Text
  13. 12a.↵
    1. Levy R,
    2. Vilela V,
    3. Cataldo M,
    4. Ramos RC,
    5. Duarte JL,
    6. Tura BR,
    7. et al.
    Hydroxychloroquine (HCQ) in lupus pregnancy: A double-blind and placebo-controlled study. Lupus 2001;10:401–4.
    OpenUrlAbstract/FREE Full Text
  14. 12b.↵
    1. Costedoat-Chalumeau N,
    2. Amoura Z,
    3. Hulot J,
    4. Hammoud HA,
    5. Aymard G,
    6. Cacoub P,
    7. et al.
    Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum 2006;54:3284–90.
    OpenUrlCrossRefPubMed
  15. 13.↵
    1. Erkan D,
    2. Yazici Y,
    3. Peterson MG,
    4. Sammaritano L,
    5. Lockshin MD
    . A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology 2002;41:924–9.
    OpenUrlAbstract/FREE Full Text
  16. 14.↵
    1. Mok CC,
    2. Tang SS,
    3. To CH,
    4. Petri M
    . Incidence and risk factors of thromboembolism in systemic lupus erythematosus: A comparison of three ethnic groups. Arthritis Rheum 2005;52:2774–82.
    OpenUrlCrossRefPubMed
  17. 15.↵
    1. Mok CC,
    2. Tong KH,
    3. To CH,
    4. Siu YP,
    5. Ho LY,
    6. Au TC
    . Risk and predictors of arterial thrombosis in lupus and non-lupus primary glomerulonephritis: A comparative study. Medicine 2007;86:203–9.
    OpenUrlCrossRefPubMed
  18. 16.↵
    1. Ruiz-Irastorza G,
    2. Egurbide MV,
    3. Pijoan JI,
    4. Garmendia M,
    5. Villar I,
    6. Martinez-Berriotxoa A,
    7. et al.
    Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus 2006;15:577–83.
    OpenUrlAbstract/FREE Full Text
  19. 17.↵
    1. Sabio JM,
    2. Zamora-Pasadas M,
    3. Jimenez-Jaimez J,
    4. Albadalejo F,
    5. Vargas-Hitos J,
    6. Rodriguez del Aguila MD,
    7. et al.
    Metabolic syndrome in patients with systemic lupus erythematosus from Southern Spain. Lupus 2008;17:849–59.
    OpenUrlAbstract/FREE Full Text
  20. 18.↵
    1. Wallace DJ
    . Does hydroxychloroquine sulfate prevent clot formation in systemic lupus erythematosus? Arthritis Rheum 1987;30:1435–6.
    OpenUrlPubMed
  21. 19.↵
    1. Fessler BJ,
    2. Alarcon GS,
    3. McGwin G Jr.,
    4. Roseman J,
    5. Bastian HM,
    6. Friedman AW,
    7. et al.
    Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual. Arthritis Rheum 2005;52:1473–80.
    OpenUrlCrossRefPubMed
  22. 20.↵
    1. Molad Y,
    2. Gorshtein A,
    3. Wysenbeek AJ,
    4. Guedj D,
    5. Majadla R,
    6. Weinberger A,
    7. et al.
    Protective effect of hydroxychloroquine in systemic lupus erythematosus. Prospective long-term study of an Israeli cohort. Lupus 2002;11:356–61.
    OpenUrlAbstract/FREE Full Text
  23. 21.↵
    1. Alarcon GS,
    2. McGwin G,
    3. Bertoli AM,
    4. Fessler BJ,
    5. Calvo-Alen J,
    6. Bastian HM,
    7. et al.
    Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: Data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis 2007;66:1168–72.
    OpenUrlAbstract/FREE Full Text
  24. 22.↵
    1. Borba EF,
    2. Bonfa E
    . Longterm beneficial effect of chloroquine diphosphate on lipoprotein profile in lupus patients with and without steroid therapy. J Rheumatol 2001;28:780–5.
    OpenUrlAbstract/FREE Full Text
  25. 23.↵
    1. Chung CP,
    2. Avalos I,
    3. Oeser A,
    4. Gebretsadik T,
    5. Shintani A,
    6. Raggi P,
    7. et al.
    High prevalence of the metabolic syndrome in patients with systemic lupus erythematosus: Association with disease characteristics and cardiovascular risk factors. Ann Rheum Dis 2007;66:208–14.
    OpenUrlAbstract/FREE Full Text
  26. 24.↵
    1. Hodis HN,
    2. Quismorio FP Jr.,
    3. Wickham E,
    4. Blankenhorn DH
    . The lipid, lipoprotein, and apolipoprotein effects of hydroxychloroquine in patients with systemic lupus erythematosus. J Rheumatol 1993;20:661–5.
    OpenUrlPubMed
  27. 25.↵
    1. Munoz-Valle JF,
    2. Vazquez-Del Mercado M,
    3. Ruiz-Quezada S,
    4. Oregon-Romero E,
    5. Navarro-Hernandez RE,
    6. Ramirez-Barragan J,
    7. et al.
    Polymorphism of the beta3-adrenergic receptor and lipid profile in patients with rheumatoid arthritis and systemic lupus erythematosus treated with chloroquine. Rheumatol Int 2003;23:99–103.
    OpenUrlPubMed
  28. 26.↵
    1. Petri M,
    2. Lakatta C,
    3. Magder L,
    4. 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;96:254–9.
    OpenUrlCrossRefPubMed
  29. 27.↵
    1. Rahman P,
    2. Gladman DD,
    3. Urowitz MB,
    4. Yuen K,
    5. Hallett D,
    6. Bruce IN
    . The cholesterol lowering effect of antimalarial drugs is enhanced in patients with lupus taking corticosteroid drugs. J Rheumatol 1999;26:325–30.
    OpenUrlPubMed
  30. 28.↵
    1. Sachet JC,
    2. Borba EF,
    3. Bonfa E,
    4. Vinagre CG,
    5. Silva VM,
    6. Maranhao RC
    . Chloroquine increases low-density lipoprotein removal from plasma in systemic lupus patients. Lupus 2007;16:273–8.
    OpenUrlAbstract/FREE Full Text
  31. 29.↵
    1. Tam LS,
    2. Gladman DD,
    3. Hallett DC,
    4. Rahman P,
    5. Urowitz MB
    . Effect of antimalarial agents on the fasting lipid profile in systemic lupus erythematosus. J Rheumatol 2000;27:2142–5.
    OpenUrlPubMed
  32. 30.↵
    1. Tam LS,
    2. Li EK,
    3. Lam CW,
    4. Tomlinson B
    . Hydroxychloroquine has no significant effect on lipids and apolipoproteins in Chinese systemic lupus erythematosus patients with mild or inactive disease. Lupus 2000;9:413–6.
    OpenUrlAbstract/FREE Full Text
  33. 31.↵
    1. Jung H,
    2. Bobba R,
    3. Su J,
    4. Shariati-Sarabi Z,
    5. Gladman D,
    6. Urowitz MB,
    7. et al.
    The protective effect of antimalarial drug on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum 2010;62:863–8.
    OpenUrlCrossRefPubMed
  34. 32.↵
    1. Mak A,
    2. Isenberg DA,
    3. Lau CS
    . Global trends, potential mechanisms and early detection of organ damage in SLE. Nat Rev Rheumatol 2012 [E-pub ahead of print].
  35. 33.↵
    1. Urowitz MB,
    2. Gladman DD,
    3. Tom BD,
    4. Ibanez D,
    5. Farewell VT
    . Changing patterns in mortality and disease outcomes for patients with systemic lupus erythematosus. J Rheumatol 2008;35:2152–8.
    OpenUrlAbstract/FREE Full Text
  36. 34.↵
    1. Rivest C,
    2. Lew RA,
    3. Welsing PM,
    4. Sangha O,
    5. Wright EA,
    6. Roberts WN,
    7. et al.
    Association between clinical factors, socioeconomic status, and organ damage in recent onset systemic lupus erythematosus. J Rheumatol 2000;27:680–4.
    OpenUrlPubMed
  37. 35.↵
    1. Lopez R,
    2. Davidson JE,
    3. Beeby MD,
    4. Egger PJ,
    5. Isenberg DA
    . Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort. Rheumatology 2012;51:491–8.
    OpenUrlAbstract/FREE Full Text
  38. 36.↵
    1. Pons-Estel GJ,
    2. Alarcon GS,
    3. Gonzalez LA,
    4. Zhang J,
    5. Vila LM,
    6. Reveille JD,
    7. et al.
    Possible protective effect of hydroxychloroquine on delaying the occurrence of integument damage in lupus: LXXI, data from a multiethnic cohort. Arthritis Care Res 2010;62:393–400.
    OpenUrlCrossRef
  39. 37.↵
    1. Tan EM,
    2. Cohen AS,
    3. Fries JF,
    4. Masi AT,
    5. McShane DJ,
    6. Rothfield NF,
    7. et al.
    The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7.
    OpenUrlCrossRefPubMed
  40. 38.↵
    1. Gladman DD,
    2. Ibanez D,
    3. Urowitz MB
    . Systemic Lupus Erythematosus Disease Activity Index 2000. J Rheumatol 2002;29:288–91.
    OpenUrlAbstract/FREE Full Text
  41. 39.↵
    1. Gladman DD,
    2. Urowitz M,
    3. Goldsmith C,
    4. Fortin PR,
    5. Ginzler E,
    6. Gordon C,
    7. 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;40:809–13.
    OpenUrlCrossRefPubMed
  42. 40.↵
    1. Gladman DD,
    2. Goldsmith CH,
    3. Urowitz MB,
    4. Bacon P,
    5. Fortin P,
    6. Ginzler E,
    7. et al.
    The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for systemic lupus erythematosus international comparison. J Rheumatol 2000;27:373–6.
    OpenUrlPubMed
  43. 41.↵
    1. Gladman DD,
    2. Ginzler E,
    3. Goldsmith C,
    4. Fortin PR,
    5. Liang MH,
    6. Urowitz M,
    7. et al.
    The development and initial validation of the SLICC/ACR Damage Index for SLE. Arthritis Rheum 1996;39:363–9.
    OpenUrlCrossRefPubMed
  44. 42.↵
    1. Ibanez D,
    2. Urowitz MB,
    3. Gladman DD
    . Summarizing disease features over time: I. Adjusted mean SLEDAI derivation and application to an index of disease activity in lupus. J Rheumatol 2003;30:1977–82.
    OpenUrlAbstract/FREE Full Text
  45. 43.↵
    1. Collins GB,
    2. McAllister MS
    . Chloroquine psychosis masquerading as PCP: A case report. J Psychoactive Drugs 2008;40:211–4.
    OpenUrlCrossRefPubMed
  46. 44.↵
    1. Costedoat-Chalumeau N,
    2. Hulot JS,
    3. Amoura Z,
    4. Leroux G,
    5. Lechat P,
    6. Funck-Brentano C,
    7. et al.
    Heart conduction disorders related to antimalarials toxicity: An analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases. Rheumatology 2007;46:808–10.
    OpenUrlAbstract/FREE Full Text
  47. 45.↵
    1. Ferreras A,
    2. Pinilla I,
    3. Abecia E,
    4. Pajarin AB,
    5. Honrubia FM
    . [Retinal toxicity following chloroquine therapy – in Spanish]. Arch Soc Esp Oftalmol 2007;82:103–8.
    OpenUrlPubMed
  48. 46.↵
    1. Fleury O,
    2. Droitcourt C,
    3. Polard E,
    4. Chevrant-Breton J
    . Reversible ageusia as an adverse effect of hydroxychloroquine treatment. J Eur Acad Dermatol Venereol 2009;23:604–5.
    OpenUrlCrossRefPubMed
  49. 47.↵
    1. Hsu WY,
    2. Chiu NY,
    3. Huang SS
    . Hydroxychloroquine-induced acute psychosis in a systemic lupus erythematosus female. Acta Neuropsychiatr 2011;23:318–9.
    OpenUrlCrossRef
  50. 48.↵
    1. Lateef A,
    2. Tan KB,
    3. Lau TC
    . Acute generalized exanthematous pustulosis and toxic epidermal necrolysis induced by hydroxychloroquine. Clin Rheumatol 2009;28:1449–52.
    OpenUrlCrossRefPubMed
  51. 49.↵
    1. Lee WJ,
    2. Ko MK,
    3. Lee BR
    . Hydroxychloroquine retinopathy combined with retinal pigment epithelium detachment. Cutan Ocul Toxicol 2012;31:144–7.
    OpenUrlCrossRefPubMed
  52. 50.↵
    1. Manohar VA,
    2. Moder KG,
    3. Edwards WD,
    4. Klarich K
    . Restrictive cardiomyopathy secondary to hydroxychloroquine therapy. J Rheumatol 2009;36:440–1.
    OpenUrlFREE Full Text
  53. 51.↵
    1. Muslimani AA,
    2. Spiro TP,
    3. Chaudhry AA,
    4. Daw HA
    . Secondary myelodysplastic syndrome after hydroxychloroquine therapy. Ann Hematol 2007;86:531–4.
    OpenUrlCrossRefPubMed
  54. 52.↵
    1. Muthukrishnan P,
    2. Roukoz H,
    3. Grafton G,
    4. Jessurun J,
    5. Colvin-Adams M
    . Hydroxychloroquine-induced cardiomyopathy: A case report. Circ Heart Fail 2011;4:e7–8.
    OpenUrlFREE Full Text
  55. 53.↵
    1. Puri PK,
    2. Lountzis NI,
    3. Tyler W,
    4. Ferringer T
    . Hydroxychloroquine-induced hyperpigmentation: the staining pattern. J Cutan Pathol 2008;35:1134–7.
    OpenUrlCrossRefPubMed
  56. 54.↵
    1. Skare T,
    2. Ribeiro CF,
    3. Souza FH,
    4. Haendchen L,
    5. Jordao JM
    . Antimalarial cutaneous side effects: A study in 209 users. Cutan Ocul Toxicol 2011;30:45–9.
    OpenUrlCrossRefPubMed
  57. 55.↵
    1. Stas P,
    2. Faes D,
    3. Noyens P
    . Conduction disorder and QT prolongation secondary to long-term treatment with chloroquine. Int J Cardiol 2008;127:e80–2.
    OpenUrlCrossRefPubMed
  58. 56.↵
    1. Wolfe F,
    2. Marmor MF
    . Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res 2010;62:775–84.
    OpenUrlCrossRef
  59. 57.↵
    1. Becker-Merok A,
    2. Nossent J
    . Prevalence, predictors and outcome of vascular damage in systemic lupus erythematosus. Lupus 2009;18:508–15.
    OpenUrlAbstract/FREE Full Text
  60. 58.↵
    1. Broder A,
    2. Putterman C
    . Hydroxychloroquine use is associated with lower odds of persistently positive antiphospholipid antibodies and/or lupus anticoagulant in systemic lupus erythematosus. J Rheumatol 2013;40:30–3.
    OpenUrlAbstract/FREE Full Text
  61. 59.↵
    1. Choojitarom K,
    2. Verasertniyom O,
    3. Totemchokchyakarn K,
    4. Nantiruj K,
    5. Sumethkul V,
    6. Janwityanujit S
    . Lupus nephritis and Raynaud’s phenomenon are significant risk factors for vascular thrombosis in SLE patients with positive antiphospholipid antibodies. Clin Rheumatol 2008;27:345–51.
    OpenUrlCrossRefPubMed
  62. 60.↵
    1. Kaiser R,
    2. Cleveland CM,
    3. Criswell LA
    . Risk and protective factors for thrombosis in systemic lupus erythematosus: Results from a large, multi-ethnic cohort. Ann Rheum Dis 2009;68:238–41.
    OpenUrlAbstract/FREE Full Text
  63. 61.↵
    1. Tektonidou MG,
    2. Laskari K,
    3. Panagiotakos DB,
    4. Moutsopoulos HM
    . Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Rheum 2009;61:29–36.
    OpenUrlCrossRefPubMed
  64. 62.↵
    1. Feng X,
    2. Zou Y,
    3. Pan W,
    4. Wang X,
    5. Wu M,
    6. Zhang M,
    7. et al.
    Prognostic indicators of hospitalized patients with systemic lupus erythematosus: A large retrospective multicenter study in China. J Rheumatol 2011;38:1289–95.
    OpenUrlAbstract/FREE Full Text
  65. 63.↵
    1. Shinjo SK,
    2. Bonfa E,
    3. Wojdyla D,
    4. Borba EF,
    5. Ramirez LA,
    6. Scherbarth HR,
    7. et al.
    Antimalarial treatment may have a time-dependent effect on lupus survival: Data from a multinational Latin American inception cohort. Arthritis Rheum 2010;62:855–62.
    OpenUrlCrossRefPubMed
  66. 64.↵
    1. Shinjo SK
    . Systemic lupus erythematosus in the elderly: Antimalarials in disease remission. Rheumatol Int 2009;29:1087–90.
    OpenUrlCrossRefPubMed
  67. 65.↵
    1. Willis R,
    2. Seif AM,
    3. McGwin G Jr.,
    4. Martinez-Martinez LA,
    5. González EB,
    6. Dang N,
    7. et al.
    Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: Data from LUMINA (LXXV), a multiethnic US cohort. Lupus 2012;21:830–5.
    OpenUrlAbstract/FREE Full Text
  68. 66.↵
    1. Cardoso CR,
    2. Signorelli FV,
    3. Papi JA,
    4. Salles GF
    . Prevalence and factors associated with dyslipoproteinemias in Brazilian systemic lupus erythematosus patients. Rheumatol Int 2008;28:323–7.
    OpenUrlCrossRefPubMed
  69. 67.↵
    1. Chong YB,
    2. Yap DY,
    3. Tang CS,
    4. Chan TM
    . Dyslipidaemia in patients with lupus nephritis. Nephrology 2011;16:511–7.
    OpenUrlCrossRefPubMed
  70. 68.↵
    1. Nikpour M,
    2. Gladman DD,
    3. Ibanez D,
    4. Harvey PJ,
    5. Urowitz MB
    . Variability over time and correlates of cholesterol and blood pressure in systemic lupus erythematosus: A longitudinal cohort study. Arthritis Res Ther 2010;12:R125.
    OpenUrlCrossRefPubMed
  71. 69.↵
    1. Penn SK,
    2. Kao AH,
    3. Schott LL,
    4. Elliott JR,
    5. Toledo FG,
    6. Kuller L,
    7. et al.
    Hydroxychloroquine and glycemia in women with rheumatoid arthritis and systemic lupus erythematosus. J Rheumatol 2010;37:1136–42.
    OpenUrlAbstract/FREE Full Text
  72. 70.↵
    1. Rossoni C,
    2. Bisi MC,
    3. Keiserman MW,
    4. Staub HL
    . Antimalarials and cholesterol profile of patients with systemic lupus erythematosus. Rev Bras Reumatol 2011;51:383–4, 386–7.
    OpenUrlPubMed
  73. 71.↵
    1. Gonzalez LA,
    2. Pons-Estel GJ,
    3. Zhang J,
    4. Vila LM,
    5. Reveille JD,
    6. Alarcon GS
    . Time to neuropsychiatric damage occurrence in LUMINA (LXVI): A multi-ethnic lupus cohort. Lupus 2009;18:822–30.
    OpenUrlAbstract/FREE Full Text
  74. 72.↵
    1. Okpechi IG,
    2. Ayodele OE,
    3. Jones ES,
    4. Duffield M,
    5. Swanepoel CR
    . Outcome of patients with membranous lupus nephritis in Cape Town South Africa. Nephrol Dial Transplant 2012;27:3509–15.
    OpenUrlAbstract/FREE Full Text
  75. 73.↵
    1. Petri M,
    2. Purvey S,
    3. Fang H,
    4. Magder LS
    . Predictors of organ damage in systemic lupus erythematosus: The Hopkins Lupus Cohort. Arthritis Rheum 2012;64:4021–8.
    OpenUrlCrossRefPubMed
  76. 74.↵
    1. Pons-Estel GJ,
    2. Alarcon GS,
    3. Hachuel L,
    4. Boggio G,
    5. Wojdyla D,
    6. Pascual-Ramos V,
    7. et al.
    Anti-malarials exert a protective effect while Mestizo patients are at increased risk of developing SLE renal disease: Data from a Latin-American cohort. Rheumatology 2012;51:1293–8.
    OpenUrlAbstract/FREE Full Text
  77. 75.↵
    1. Pons-Estel GJ,
    2. Alarcon GS,
    3. McGwin G Jr.,
    4. Danila MI,
    5. Zhang J,
    6. Bastian HM,
    7. et al.
    Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum 2009;61:830–9.
    OpenUrlCrossRefPubMed
  78. 76.↵
    1. Siso A,
    2. Ramos-Casals M,
    3. Bove A,
    4. Brito-Zeron P,
    5. Soria N,
    6. Munoz S,
    7. et al.
    Previous antimalarial therapy in patients diagnosed with lupus nephritis: Influence on outcomes and survival. Lupus 2008;17:281–8.
    OpenUrlAbstract/FREE Full Text
  79. 77.↵
    1. James JA,
    2. Kim-Howard XR,
    3. Bruner BF,
    4. Jonsson MK,
    5. McClain MT,
    6. Arbuckle MR,
    7. et al.
    Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus 2007;16:401–9.
    OpenUrlAbstract/FREE Full Text
  80. 78.↵
    1. Ruiz-Irastorza G,
    2. Olivares N,
    3. Ruiz-Arruza I,
    4. Martinez-Berriotxoa A,
    5. Egurbide MV,
    6. Aguirre C
    . Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther 2009;11:R109.
    OpenUrlCrossRefPubMed
  81. 79.↵
    1. Ruiz-Irastorza G,
    2. Ugarte A,
    3. Egurbide MV,
    4. Garmendia M,
    5. Pijoan JI,
    6. Martinez-Berriotxoa A,
    7. et al.
    Antimalarials may influence the risk of malignancy in systemic lupus erythematosus. Ann Rheum Dis 2007;66:815–7.
    OpenUrlAbstract/FREE Full Text
  82. 80.↵
    1. Winkelmayer WC,
    2. Kurth T
    . Propensity scores: Help or hype? Nephrol Dial Transplant 2004;19:1671–3.
    OpenUrlFREE Full Text
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools

 Request Permissions

Bookmark this article

Jump to section

Keywords

SYSTEMIC LUPUS ERYTHEMATOSUS
OUTCOMES RESEARCH
DISEASE ACTIVITY
HYDROXYCHLOROQUINE
DAMAGE

Keywords