Lup-07086503 281.288

Previous antimalarial therapy in patients diagnosed with lupus nephritis: Influence on outcomes and
A Sisó, M Ramos-Casals, A Bové, P Brito-Zerón, N Soria, S Muñoz, A Testi, J Plaza, J Sentís and A Coca The online version of this article can be found at: can be found at:
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Previous antimalarial therapy in patients diagnosed with lupus nephritis: Influence on outcomes and survival A Sisó1,2, M Ramos-Casals1, A Bové1, P Brito-Zerón1, N Soria1, S Muñoz1, A Testi1, J Plaza1, J Sentís3 and A Coca4 1Department of Autoimmune Diseases, Laboratory of Autoimmune Diseases “Josep Font”, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Statistical Unit, Barcelona, Spain; 2Centre d’Assistència Primària ABS Les Corts, GESCLINIC, Barcelona, Spain; 3Department of Public Health, School of Medicine, University of Barcelona, Barcelona, Spain; and 4Hypertension Unit, Institut Clínic de Medicina i Dermatologia, Hospital The aim of this study was to analyze the effect of exposure to antimalarial drugs at diagnosis oflupus nephritis on the outcome of the disease, especially renal failure, comorbid processes, andsurvival. We analyzed a cohort of 206 consecutive patients with biopsy-proven lupus nephritis.
Renal biopsies were categorized according to the classification proposed by the ISN/RPS in 2003.
Exposure to antimalarial drugs (chloroquine and hydroxychloroquine) was defined as the use ofthese drugs before the diagnosis of lupus nephritis independent of dose and duration. Fifty-six(27%) patients had received antimalarials before the diagnosis of lupus nephritis. During thefollow-up, these patients had a lower frequency of creatinine values >4 mg/dL (2% vs 11%,P = 0.029) and end-stage renal failure (2% vs 11%, P = 0.044) in comparison with those nevertreated with antimalarials. Patients exposed to antimalarials also had a lower frequency of hyper-tension (32% vs 50%, P = 0.027), infections (11% vs 29%, P = 0.006), and thrombotic events (5% vs17%, P = 0.039). Twenty patients (10%) died during the study period. Patients exposed to antima-larials had a lower mortality rate at the end of the follow-up (2% vs 13% for those not exposed toantimalarials, P = 0.029). Multivariate analysis identified thrombosis and infections as statisticallysignificant independent variables. Kaplan–Meier plots showed a lower rate of end-stage renal fail-ure (log rank = 0.04) in patients exposed to antimalarials. In conclusion, exposure to antimalarialsbefore the diagnosis of lupus nephritis was negatively associated with the development of renalfailure, hypertension, thrombosis and infection, and with a better survival rate at the end of thefollow-up. This, together with other published data, suggests that antimalarials should be consid-ered a mandatory therapeutic option in all patients diagnosed with systemic lupus erythemato-sus.
Key words: antimalarials; cardiovascular disease; hydroxychloroquine; lupus nephropathy;mortality; systemic lupus erythematosus; thrombosis bidity and mortality of the overwhelmingly youngfemale population with SLE. Patients with glomerulo- Systemic lupus erythematosus (SLE) is considered the nephritis have a higher mortality rate in comparison most clinically and serologically diverse systemic auto- with those without renal involvement, and nearly 10% immune disease because it may affect any organ with of patients with lupus nephritis (LN) develop end- a broad spectrum of manifestations. The disease mainly involves the skin, joints, kidneys, blood cells, and nervous system,1 and the diversity of clinical and After decades of empirical use, antimalarial drugs analytical features lead to very different forms of pre- (chloroquine and hydroxychloroquine) are currently sentation. Renal disease plays a key role in the prog- considered as a key therapy in SLE. The use of anti-malarials has been associated with a decreased risk of nosis of SLE and contributes significantly to the mor- developing lupus flares and thrombotic events,4–6 less-accrued chronic damage, and a better survival rate in Correspondence to: Dr Manuel Ramos-Casals, Servei de Malalties comparison with patients not treated with these drugs, Autoimmunes, Hospital Clínic, C/Villarroel, 170, 08036-Barcelona, Spain.
even after adjusting for patient characteristics. How- E-mail: mramos@clinic.ub.esReceived 27 August 2007; accepted 25 October 2007 ever, the possible beneficial effects of antimalarial 2008 SAGE Publications Los Angeles, London, New Delhi and Singapore Antimalarials and outcomes of lupus nephritis drugs in patients diagnosed with LN have not yet been Chronic renal failure, defined as raised creatinine levels (>2 mg/dL in two consecutive analytical We analyze the influence of exposure to antimalar- determinations, separated by at least 3 months).
ials at LN diagnosis in the outcome of 206 patients We also recorded creatinine levels higher than followed in a single reference center, especially renal 4 mg/dL. End-stage renal failure was defined as failure, comorbid processes [cardiovascular disease the need for dialysis or renal transplantation.
(CVD), infections, and neoplasia] and survival.
Cardiovascular risk factors, including hyperten-sion >140 mmHg and/or diastolic blood pressure >90 mmHg in two or more consecutive visits), dys-lipidemia (hypercholesterolemia – total cholesterolhigher than 250 mg/dL – and/or hypertriglyceride- mia – triglycerides higher than 150 mg/dL), and/or Patients with SLE consecutively followed in our diabetes mellitus (fasting glycemia higher than department from 1970 until 2006 were evaluated. All 126 mg/dL in at least two determinations).
patients fulfilled the 1997 revised criteria for the clas- Cardiovascular events, including cerebrovascular sification of SLE.7 Of this cohort, patients with accident (confirmed by computed tomography biopsy-proven LN were selected as the study popula- and/or magnetic resonance imaging scans) or ische- tion. Renal biopsies were reviewed by two patholo- mic heart disease (confirmed clinically by elevatedcardiac enzyme levels and/or electrocardiogram).
gists and categorized according to the recent classifi- Thrombotic events, including deep vein thrombo- cation proposed by the ISN/RPS in 20048: class I sis (confirmed by Doppler studies and/or phlebo- (minimal mesangial LN), class II (mesangial prolifer- graphy), pulmonary embolism (diagnosed by ven- ative LN), class III (focal LN), class IV (diffuse LN), tilation/perfusion pulmonary scintigraphy), and/or class V (membranous LN), and class VI (advanced peripheral arterial thrombosis (diagnosed by sclerosing LN). The time of LN diagnosis, defined as the point when the first (diagnostic) renal biopsy was Infections, defined according to a previous report.11 performed, was the starting point for the follow-up in Complications related to the use of corticosteroids, all patients. All patients were prospectively followed including osteopenia, osteoporosis, Cushing dis- with regular visits at 6 to 12-month intervals. The indi- vidual follow-up for each patient was measured from the time of LN diagnosis until the last hospital visit, transfer out or death. Clinical and laboratory datawere collected and computerized according to ourstandard department protocol.9 The design of the study conformed to the ethical standards currently Categorical data were compared using the chi-squared applied in Spain. Because of the anonymous nature and Fisher’s exact tests. Continuous variables were of the study, informed patient consent was not analyzed with the Student’s t-test in large samples of similar variance and with the nonparametric Mann– Exposure to antimalarial drugs (chloroquine and Whitney U-test for small samples, with results indi- hydroxychloroquine) was defined as the use of these cated as mean ± standard error of the mean (SEM). A drugs before the diagnosis of LN independent of dose two-tailed value of P < 0.05 was taken to indicate sta- and duration, according to the definition used by tistical significance. When several independent vari- Alarcón et al.10; exposure was recorded as present if ables appeared to have statistical significance in the documented at the time of the diagnosis of LN or univariate analysis, a multiple logistic regression anal- when antimalarials had been administered at least ysis was performed, taking the dichotomized variable 50% of the period between the diagnosis of SLE and exposure to antimalarial drugs (yes/no) as the depen- the diagnosis of LN. None of our patients had dent variable and those variables that were statistically received more than 400 mg of hydroxychloroquine significant in the univariate analysis as independent variables. The multivariate analysis was adjusted byage at diagnosis of LN, gender, length of follow-up,and the variables that were statistically significant when the baseline characteristics of patients treated The following outcomes were recorded during the with antimalarials or not were compared. A multivar- iate Cox regression analysis using a backward step- Antimalarials and outcomes of lupus nephritisA Sisó, et al.
wise method allowing adjustment for age, gender, diagnosis of 27.73 ± 3.79 months. Renal biopsies length of follow-up and development of cardiovascu- showed class IV in 81 (39%) patients, class III in 49 lar events, and end stage renal failure was used to (24%), class II in 34 (16%), class V in 31 (15%), class I evaluate the effect of antimalarial exposure at LN in eight (4%), and class VI in three (2%) patients.
diagnosis on survival. The hazard ratios (HRs) and Induction therapy included oral prednisone at a dose their 95% confidence intervals (CIs) obtained in the of 1 mg/kg/day in 174 (84%) patients and intravenous adjusted regression analysis were calculated. The results of the analysis of continuous variables are indi-cated as mean ± SEM. Kaplan–Meier survival curves Comparison according to antimalarial exposure for the development of chronic renal failure and deathwere compared using the log-rank and Breslow tests.
We classified patients with LN into two groups: The statistical analysis was performed using the SPSS patients who never received antimalarial therapy (n = 150) and those who had received antimalarials(n = 56) before the diagnosis of LN. We comparedthe main baseline epidemiological, clinical, and immu- nological features at LN diagnosis (Table 1). Patientsnever treated with antimalarials had a shorter meantime of SLE evolution (28.98 vs 31.29 months, P = 0.001), a higher prevalence of previous corticoste- A total of 206 patients (185 women and 21 men, 95% roid treatment (58% vs 32%, P < 0.001), and a higher Caucasian) with LN were included. The mean age at frequency of raised levels of creatinine at LN diagno- SLE diagnosis was 30.0 years (SEM 0.88, range 8–67) sis (23% vs 11%, P = 0.05) in comparison with and 31.3 years (SEM 0.32, range 8–67) at diagnosis of patients treated with antimalarials, although only pre- LN, with a mean time of evolution of SLE until LN Baseline characteristics at diagnosis of lupus nephritis of patients treated or not with antimalarials Antimalarial exposure before the diagnosis of LN Previous treatment with immunosuppressant Abbreviations: LN: lupus nephritis; SLE: systemic lupus erythematosus; dsDNA: double stranded DNA.
*Statistically significant in multivariate analysis.
Antimalarials and outcomes of lupus nephritis independent variable in the multivariate analysis. No treated with antimalarials. Thus, patients exposed to significant differences were found in the comparison antimalarials had a lower mortality rate at the end of of the main epidemiological features, LN classes, the follow-up (2% vs 13% for those not exposed to immunological markers at LN diagnosis or induction antimalarials, P = 0.029). The causes of death are shown in Table 3. Overall, infections were the mostfrequent causes of death in patients not exposed to antimalarials, followed by renal failure, CVD, andneoplasia. In the patient treated with antimalarials At the end of follow-up (mean follow-up 148 months), who died, death was due to primary pulmonary patients treated with antimalarials had a lower fre- quency of creatinine values >4 mg/dL (2% vs 11%, Multivariate analysis adjusted by age, gender, P = 0.044) and end-stage renal failure (end-stage length of follow-up, and the significant variables renal disease, ESRD) (2% vs 11%, P = 0.029) in com- from Table 1 identified thrombosis (P = 0.014) and parison with those never treated with antimalarials infections (P = 0.03) as statistically significant inde- (Table 2). With respect to CVD, patients exposed to pendent variables associated with antimalarial expo- antimalarials had a lower frequency in the develop-ment of cardiovascular risk factors, especially arterialhypertension (32% vs 50%, P = 0.027), and a lower Cardiovascular events and causes of death in patients frequency of cardiovascular events in comparison treated or not with antimalarials before the diagnosis of LN with those never treated with antimalarials, although the difference was not statistically significant (9% vs 15%, P = 0.264). Patients exposed to antimalarials before LN diagnosis also had a lower frequency ofcomorbid complications, especially infections (11% vs 29%, P = 0.006) and thrombotic events (5% vs Twenty patients (10%) died during the study period. Mean age at the time of death was 46.5 ± 4.13 years, with a mean follow-up to death of 154.60 ± 23.66 months. Nineteen of the 20 deaths (95%) occurred in patients who had never received antimalarials, compared with only one (5%) patient Abbreviation: LN: lupus nephropathy; APS: antiphospholipid syndrome.
Outcomes of patients with lupus nephropathy treated or not with antimalarials before the diagnosis of LN Antimalarial exposure before the diagnosis of LN Abbreviation: LN: lupus nephritis.
aPatients with creatinine >2 mg/dL at diagnosis of LN were not included.
bPatients with creatinine >4 mg/dL at diagnosis of LN were not included.
*Significant independent variables in the adjusted multivariate analysis.
Antimalarials and outcomes of lupus nephritisA Sisó, et al.
antimalarial exposure (P = 0.042, HR 0.233, CI 95%0.051–0.981) and gender (P = 0.016, HR 0.225, CI95% 0.072–0.706) for survival.
The course of LN is difficult to predict for variousreasons, including the heterogeneity of its clinical pre-sentation, the different classification criteria, the inci-dence of histological transformation, and the differenttherapeutic schedules used.12 No single factor seems tobe determinant in estimating the prognosis of LN, anda range of demographic, clinical, laboratory, and his-topathological parameters are usually used to analyzethe prognosis and response to therapy.13 Antimalarials are a long-standing safe, inexpensive therapy for SLE. Reports have shown that antimalar-ials are effective in controlling mild/moderate SLE.13,14 Kaplan–Meier plots showing end-stage renal failure in Recent studies from the Hopkins Lupus15 and patients with lupus nephritis (LN) treated (dotted line) or not LUMINA cohorts5 suggest that hydroxychloroquine (continuous line) with antimalarials before the diagnosis of LN(log rank = 0.04).
may have a long-term protective effect on SLE-relatedorgan damage. In addition, Costedoat-Chalumeauet al.16 have recently reported that low whole-bloodhydroxychloroquine concentrations are a strong pre-dictor of SLE exacerbation, whereas the randomizeddiscontinuation trial by the Canadian Hydroxychloro-quine Study Group17 found that the relative risk ofsevere SLE exacerbation in patients who discontinuedhydroxychloroquine was six times greater than thatobserved in those who continued hydroxychloroquine.
A possible etiopathogenic explanation could be basedin the capacity of antimalarials to inhibit the activationof intracellular toll-like receptors.18 Few studies have supported a role for antimalarial therapy in severe SLE involvement such as vasculitis,central nervous system involvement, or nephritis. Ourresults show that patients treated with antimalarialsbefore the diagnosis of LN had a fivefold lower prev-alence of end-stage renal failure at the end of thefollow-up in comparison with patients never treatedwith antimalarials. This suggests that the use of anti- Kaplan–Meier plots showing survival rates of patients malarials before the diagnosis of LN may be a protec- with lupus nephritis (LN) treated (dotted line) or not (continuousline) with antimalarials before the diagnosis of LN (log tive factor for the development of further renal failure.
Some recent studies have suggested beneficial effectsfor antimalarials in patients with LN. Kasitanonet al.19 found that the concurrent use of hydroxychlor- sure. Figures 1 and 2 show Kaplan–Meier plots for oquine has a statistically significant positive effect on end-stage renal failure (log rank = 0.04) and the sur- renal remission in patients with membranous LN trea- vival rate (log rank = 0.07) of patients treated or not ted with mycophenolate. In a follow-up study by the with antimalarials at the time of the diagnosis of LN, Canadian Hydroxychloroquine Study Group,20 the respectively. Multivariate Cox regression analysis rate of nephritis flares was reduced by 74% in patients identified antimalarial exposure as statistically signifi- who continued on hydroxychloroquine, although the cant independent variable (P = 0.05, HR 0.294, CI difference was not statistically significant in compari- 95% 0.026–1.009) for the development of ESRD and son with those who discontinued the drug. Barber Antimalarials and outcomes of lupus nephritis et al.21 found that patients with LN with sustained the addition of chloroquine to conventional treatment remission were more likely to have been treated with hydroxychloroquine than those who did not attain improved survival in patients with glioblastoma multi- forme. A recent data has also suggested a possible Antimalarials not only have anti-inflammatory protective effect for antimalarials in the development of neoplasia in patients with SLE. Ruiz-Irastorza et al.30 found a prevalence of neoplasia of 13% in hyperglycemic effects.4,22,23 We found a lower fre- patients never treated with antimalarials in compari- quency of CVD in patients exposed to antimalarials, son with 1.3% in those who had received antimalar- including both risk factors and events. Similar results ials, with an adjusted hazard ratio for cancer of 0.15.
were found by Bessant et al.,24 who reported that SLE Interestingly, none of our patients with LN exposed to patients with CVD were less likely to have received antimalarials developed neoplasia during the follow- treatment with hydroxychloroquine than those with- up, in comparison with five (3%) of those not exposed.
out CVD. Our results showed a modest effect of anti- After a mean follow-up of more than 12 years, only malarials in reducing diabetes or dyslipidemia in our one of our 56 patients with LN exposed to antimalar- LN patients compared with the effect found in ials died, in comparison with 19 of the 150 patients not patients with rheumatoid arthritis25 or other SLE exposed, a sevenfold difference. A recent study by populations.26,27 This may be due to the lower preva- Alarcón et al.10 showed that hydroxychloroquine lence of diabetes and dyslipidemia found in our exerts a clear protective effect in terms of survival patients. In contrast, we found a significant reduction regardless of whether clinical and socio-demographic in the development of hypertension during the follow- characteristics are taken into consideration. Ruiz- up of our patients with LN, suggesting that the pre- Irastorza et al.30 also found that the majority of deaths diagnostic use of antimalarials in patients with LN in their SLE cohort occurred in patients who were may play a protective role against the development never treated with antimalarials. This protective role of one of the main cardiovascular complications of antimalarials in the survival of patients with SLE is probably due to their effect in preventing flares and Ruiz-Irastorza et al.6 have recently suggested that limiting accrued chronic damage, both factors closely antimalarials may have a protective effect against related to mortality.5,15,31,32 We also found that our thrombosis in patients with SLE, results which we patients exposed to antimalarials had a lower fre- confirmed. During the follow-up, our patients with quency of the main adverse outcomes associated LN exposed to antimalarials had three-times less with LN (renal failure, CVD, infections, and neopla- thrombotic events than those never exposed to anti- sia). Logically, this is reflected by the increased sur- malarials. These results suggest the possible use of vival in these patients, none of whom died of causes antimalarials as a safe, effective option in both pri- related to renal or CVD, infections, or neoplasia.
mary and secondary prophylaxis of thrombosis in This uncontrolled, retrospective study has some patients with antiphospholipid syndrome, either pri- limitations. As it was an observational cohort study, treatment allocation was based only on the clinical We also found that patients exposed to antimalar- judgement of the treating physician. As a result, the ials had nearly two-third less infections during the observed effects attributed to antimalarials may be follow-up than those not exposed, a difference that biased by confounding variables that could influence was statistically significant in the adjusted multivari- the treatments administered. In addition, the possible ate analysis. In addition, exposure to antimalarials influence of exposure to antimalarials subsequent to was associated with a lower frequency of complica- the diagnosis of LN was not analyzed, although more tions related to the corticosteroid use, although the than 95% of patients were taking antimalarials at the difference was not statistically significant. Thus, the last study visit. A statistical approach using a time- pre-diagnostic use of antimalarials in patients with dependent analysis would have being more convincing LN might prevent the side effects associated with the and the results more solid. In spite of these limitations, prolonged use of corticosteroids, such as metabolic the importance of performing observational studies alterations or osteonecrosis (as recently suggested by analyzing large cohorts of ‘real-world’ patients with Calvo-Alén et al.28) and the high susceptibility to In conclusion, this study shows that exposure to Recent data point to a potential influence for anti- antimalarials before the diagnosis of LN is negatively malarials in the development of malignancies. In a associated with the development of the main adverse randomized clinical trial, Sotelo et al.29 showed that outcomes during the follow-up of patients with SLE.
Antimalarials and outcomes of lupus nephritisA Sisó, et al.
Protective effects of antimalarials in patients with SLE: studies published in the last 5 years Protection against thrombosisIncreased survival Increased clearance of low-density lipoprotein Protection against end-stage renal failureLower risk of developing HTAProtection against thrombosisProtection against infectionsIncreased survival Abbreviations: SLE: systemic lupus erythematosus; LN: lupus nephropathy; MLN: membranous LN; HTA: hypertension.
The protective effect was especially significant for end- 8 Weening, JJ, D’Agati, VD, Schwartz, MM, et al. International stage renal failure, hypertension, thrombosis, and Society of Nephrology Working Group on the Classification ofLupus Nephritis, Renal Pathology Society Working Group on the infection and was associated with a better survival Classification of Lupus Nephritis. The classification of glomerulone- rate at the end of the follow-up. This, together with phritis in systemic lupus erythematosus revisited. Kidney Int 2004; 65: other published data (Table 4), suggests that antima- 9 Font, J, Cervera, R, Ramos-Casals, M, et al. Clusters of clinical and larials should be considered a mandatory therapeutic immunologic features in systemic lupus erythematosus: analysis of 600 option in all patients diagnosed with SLE.
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10 Alarcon, GS, McGwin, G, Bertoli, AM, et al. for the LUMINA Study Group. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, amultiethnic US cohort (LUMINA L). Ann Rheum Dis 2007; 66: This work is dedicated to the memory of Dr Josep Font (1953–2006), who was principally responsible 11 Bosch, X, Guilabert, A, Pallares, L, et al. Infections in systemic lupus erythematosus: a prospective and controlled study of 110 patients.
for the creation and follow-up of one of the largest European cohorts of patients with SLE for more 12 Font, J, Ramos-Casals, M, Cervera, R, et al. Cardiovascular risk fac- than 30 years. We thank David Buss for his editorial tors and the long-term outcome of lupus nephritis. QJM 2001; 94: 19–26.
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