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Incidence and predictors of renal disease in Chinese patients with systemic lupus erythematosus
BRIEF OBSERVATION
Incidence and Predictors of Renal Disease in Chinese Patients with Systemic Lupus Erythematosus Chi Chiu Mok, MD, Sandy Shuk Kuen Tang, MB
R
enal involvement in systemic lupus erythematosus (SLE) is a major cause of mortality and morbidity. Although several demographic, ethnic, immunologic, and genetic factors have been associated with nephritis in SLE (1–7), the results are inconsistent, perhaps because these studies were retrospective or because of differences in referral pattern and cohort composition. In this report, we present prospective data on the risk of renal disease in an unselected cohort of Chinese patients with new-onset SLE.
METHODS We studied patients newly diagnosed with SLE, or referred within 6 months of diagnosis, between 1995 and 2002 in the medical departments of Princess Margaret and Tuen Mun Hospital of Hong Kong. All patients were Chinese. All patients fulfilled at least four of the American College of Rheumatology criteria for the classification of SLE (8). They were followed at 6- to 8-week intervals. We screened for renal disease at each clinic visit with urine dipsticks. Those with abnormalities were asked to have quantification of urinary protein excretion and microscopic study of a urine sample. A diagnosis of lupus nephritis was made by at least two rheumatologists/nephrologists, according to standard criteria (8): persistent proteinuria ⱖ0.5 g/d; cellular casts (red cell, hemoglobin, granular, tubular, or mixed); or histologic evidence of lupus glomerulonephritis. Patients who had microscopic hematuria or proteinuria ⬍0.5 g/d, or both, were regarded as having subclinical renal involvement. The time interval between the date of diagnosis of SLE and first appearance of renal disease was recorded. If renal disease did not occur, data were censored at the last visit. Data from patients who died or who were lost to follow-up before the development of nephritis were censored at their last clinic visit.
Statistical Analysis Comparisons between groups were made with the Student t test (continuous data) or the chi-squared test (cat© 2004 by Elsevier Inc. All rights reserved.
egorical data). Logistic regression was used to study the variables associated with the presence of renal disease at diagnosis. Kaplan-Meier survival curves were plotted to estimate the proportion of patients remaining nephritis free at different time intervals. Cox proportional hazards models were used to identify predictors of the development of renal disease. Covariates included age (⬍33 and ⱖ33 years [median]), sex, interval between symptom onset and diagnosis of SLE, extrarenal manifestations, hypocomplementemia, autoantibodies (anti– doublestranded DNA [anti-dsDNA], anti-Ro, anti-La, anti-Sm, antiribonucleoprotein [nRNP]), subclinical renal involvement at diagnosis, and the use of medications (such as hydroxychloroquine and cytotoxic agents). To avoid overfitting, only those variables with the lowest P values in univariate analyses were included in the multivariate models. All statistical analyses were performed using SPSS software, version 12.0 (Chicago, Illinois).
RESULTS We studied 216 patients (88% women), 180 (83%) of whom were diagnosed with SLE in our hospitals (Table 1). The remainder were referred by private practitioners or family physicians; the mean (⫾ SD) interval between SLE diagnosis and first referral to our units was 3.8 ⫾ 2.4 months. Ten patients were lost to follow-up and 9 others died. Sixty-eight patients (31%) had active renal disease at diagnosis (all had daily proteinuria ⱖ0.5 g and 14 had active urinary casts). Another 32 patients (15%) had subclinical renal disease. Renal biopsy specimens, obtained in 54 patients, showed diffuse proliferative nephritis in 37 patients (69%), focal proliferative nephritis in 6 (11%), mesangial nephritis in 3 (6%), and pure membranous nephritis in 8 (15%). (The remaining 14 patients with active renal disease had the diagnosis made by examination of the urinary sediment). In a multivariate model, only a hemoglobin level ⱕ10 g/dL (odds ratio [OR] ⫽ 2.2; 95% confidence interval [CI]: 1.0 to 4.7; P ⫽ 0.04), a positive anti-dsDNA (OR ⫽ 4.1; 95% CI: 1.4 to 12; P ⫽ 0.008), and malar erythema (OR ⫽ 0.4; 95% CI: 0.2 to 0.8; P ⫽ 0.01) were associated with the presence of active renal disease at baseline. The cumulative risk of renal disease since SLE diagnosis was 41% at 12 months, 50% at 24 months, 54% at 36 months, 58% at 48 months, and 60% at 60 months. After 5 years, the chance of developing renal disease for the first time was very low. Among the 148 patients without active renal disease at the onset of SLE, 49 (33%) developed active renal disease, after a median of 14 months. Renal biopsy specimens from 35 of these patients showed diffuse proliferative nephritis in 16 patients (46%), focal proliferative nephritis 0002-9343/04/$–see front matter 791 doi:10.1016/j.amjmed.2004.04.029
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Table 1. Clinical Characteristics of Patients by the Presence or Absence of Active Renal Disease at the Onset of Systemic Lupus Erythematosus Active Renal Disease Characteristic
Yes (n ⫽ 68)
No (n ⫽ 148)
P Value
Number (%) or Mean ⫾ SD Age at SLE diagnosis (years) Female sex Time between symptom onset and SLE diagnosis (weeks) Clinical features at diagnosis Fever Alopecia Raynaud phenomenon Arthritis/arthralgia Malar erythema Photosensitivity Discoid rash Oral ulcers Hemoglobin ⱕ10 g/dL Hemolytic anemia Leukopenia Lymphopenia Thrombocytopenia Lymphadenopathy Psychosis Seizure Serositis Cutaneous vasculitis ANA Anti-dsDNA Low serum C3 level Anti-Sm Anti-Ro Anti-La Anti-nRNP
35.8 ⫾ 13.1 57 (84) 5.2 ⫾ 17
33.8 ⫾ 13.4 134 (91) 5.7 ⫾ 9.9
0.29 0.15 0.85
25 (37) 17 (25) 7 (10) 42 (62) 18 (26) 11 (16) 1 (1) 5 (7) 37 (54) 12 (18) 25 (37) 42 (62) 18 (26) 11 (16) 1 (1) 3 (4) 11 (16) 6 (9) 68 (100) 63 (93) 60 (88) 5 (7) 39 (57) 7 (10) 12 (18)
51 (34) 37 (25) 38 (26) 111 (75) 77 (52) 50 (34) 11 (7) 14 (9) 38 (26) 14 (9) 50 (34) 74 (50) 26 (18) 14 (9) 8 (5) 6 (4) 18 (12) 26 (18) 146 (99) 107 (72) 110 (74) 22 (15) 90 (61) 22 (15) 36 (24)
0.74 1.00 0.01 0.05 ⬍0.001 0.008 0.15 0.80 ⬍0.01 0.09 0.67 0.11 0.13 0.15 0.33 1.00 0.42 0.09 0.84 0.001 0.02 0.18 0.63 0.36 0.27
ANA ⫽ antinuclear antibody; dsDNA ⫽ double-stranded DNA; nRNP ⫽ ribonucleoprotein; SLE ⫽ systemic lupus erythematosus.
in 12 (34%), mesangial nephritis in 1 (3%), and pure membranous nephritis in 6 (17%). The cumulative risk of active renal disease was 14% at 12 months, 28% at 24 months, 33% at 36 months, 38% at 48 months, and 41% at 60 months (Figure 1). Of the eight variables associated with the development of active renal disease in univariate models (Table 2), only subclinical renal disease and a hemoglobin level ⱕ10 g/dL were significant multivariate predictors of the development of active renal disease (Figures 1 and 2). A separate analysis showed that men were more likely than women to have subclinical renal disease at baseline (36% [5/14] vs. 19% [26/134], P ⫽ 0.15), antidsDNA (86% [12/14] vs. 71% [95/134], P ⫽ 0.24), and hypocomplementemia (100% [14/14] vs. 72% [96/134], P ⫽ 0.02), but less likely to have arthritis (43% [6/14] vs. 78% [105/134], P ⫽ 0.004). 792
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DISCUSSION This prospective study shows that renal disease is common in Chinese patients with SLE, occurring in 60% of patients within the first 5 years of diagnosis. We previously reported that 45% of SLE patients seen at an academic rheumatology unit had renal involvement after a mean of 45 months after disease onset (9). To obtain a valid estimate of the risk of renal disease, only patients with new-onset SLE were included. Bias in referral was reduced by including patients under the care of all specialists, not just rheumatologists. Our data are therefore representative of Chinese patients with SLE in Hong Kong. Several previous studies have reported that men with SLE have earlier onset and more severe nephritis than do
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Probability of not developing renal disease
01.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3
P = 0.001 (log-rank test)
0.2 0
12
24
36
48
60
Time (months) Number at risk No renal disease
116
100
69
48
33
24
Subclinical renal disease
32
16
13
10
7
1
Figure 1. Risk of renal disease by the presence of absence of subclinical renal involvement at the onset of systemic lupus erythematosus.
women (10 –12), and a study of multiethnic SLE patients in the United States found that renal disease was especially frequent in Asian men (1). In our cohort of Chinese patients, men were more likely to develop lupus nephritis than were women, but male sex was not associated with renal disease in the multivariate model. This could be related to the higher frequency of subclinical renal disease, anti-dsDNA, and hypocomplementemia, but lower
frequency of arthritis in men; all of these were also associated with the development of nephritis. Anti-dsDNA can be isolated from glomerular eluates of patients with active nephritis. DNA-anti-DNA immune complexes, formed in circulation or in situ, induce complement activation and inflammation after renal deposition. Renal flares in SLE are often preceded by rising anti-dsDNA titers and falling complement levels (13).
Table 2. Univariate and Multivariate Predictors of the Development of Active Renal Disease in Patients without Active Renal Disease at Onset (n ⫽ 148) Univariate
Variables Subclinical renal disease* Hemoglobin ⱕ10 g/dL Male sex Positive anti-dsDNA Arthritis Lymphadenopathy Low serum C3 Use of hydroxychloroquine for ⱖ6 months
Multivariate
Hazard Ratio (95% Confidence Interval)
P Value
Hazard Ratio (95% Confidence Interval)
P Value
2.7 (1.5–4.9) 2.5 (1.4–4.4) 2.2 (1.0–4.9) 2.4 (1.1–5.3) 0.6 (0.3–1.0) 2.1 (1.0–4.5) 2.1 (1.0–4.5) 0.5 (0.3–1.0)
0.001 0.002 0.05 0.03 0.05 0.05 0.05 0.03
2.2 (1.2–4.3) 1.9 (1.0–3.6) — — — — — —
0.02 0.05 — — — — — —
* Microscopic hematuria, proteinuria ⬍0.5 g/d, or both. dsDNA ⫽ double-stranded DNA. November 15, 2004
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Figure 2. Risk of renal disease by hemoglobin level at the onset of systemic lupus erythematosus.
Reducing anti-dsDNA titers by making B cells more tolerant is effective in reducing and delaying lupus nephritis flares (14). Anti-dsDNA also predicts the development of proliferative lupus glomerulonephritis (15). Although we found that anti-dsDNA was associated with prevalent nephritis at the onset of SLE, we were unable to demonstrate that anti-dsDNA was an independent predictor of the development of renal disease in our multivariate model. As seroconversion of anti-dsDNA may occur just before the onset of nephritis, anti-dsDNA status at the time of the diagnosis of SLE may not be a good predictor. Moreover, we included all forms of renal disease, including those without histologic data. Some subtypes of lupus nephritis, such as membranous nephropathy, have not been linked to anti-dsDNA. The anti-Ro antibody has been associated with nephritis in patients with SLE, but the presence of both anti-Ro and anti-La appeared to be protective in one study (6). Anti-Sm and antiribosomal P antibodies have also been linked to lupus nephritis, although the data are inconsistent (5,7,16). More recently, antihistone antibodies were reported to predict the onset of proliferative lupus nephritis in patients without overt renal disease (15). Although anti-Ro appears to be more common in Chinese 794
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patients with SLE (17–19), we did not observe a relation between anti-Ro and renal disease in our study. We did find that a low hemoglobin level (ⱕ10 g/dL) was an independent predictor of renal disease at onset and during the course of SLE. Most of our patients had normochromic normocytic anemia without an obvious cause, other than SLE. Although some patients had elevated serum creatinine levels, the degree and duration of renal impairment was insufficient to explain the anemia. Autoantibodies or cytokines that suppress erythropoiesis may be responsible. Subclinical renal disease has been well described in SLE. Renal biopsy specimens in patients without clinical renal disease often reveal histologic evidence of lupus nephritis, usually of the milder types (20,21). In our study, subclinical renal involvement at the onset of SLE, as evidenced by microscopic hematuria and trace proteinuria, predicted the subsequent development of overt renal disease. The risk was independent of demographic characteristics, autoantibodies, and treatment for extrarenal manifestations. Thus, patients with SLE who have subtle renal disease at presentation should be followed closely. There are considerable interethnic differences in the incidence and prognosis of renal disease in SLE. In the
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United States, blacks and Hispanics have more frequent and more severe lupus nephritis than do whites (1,3,22,23). Although the prognosis of Chinese patients with lupus nephritis is similar to that of whites (24), the incidence of nephritis in our Chinese patients appears to be higher (18,19). Genetic factors may affect susceptibility to lupus nephritis. Both HLA and non-HLA alleles have been implicated (25–28). Because about one third of our SLE patients have not yet developed any evidence of overt renal disease, studies to identify genetic differences between these patients and those with more severe forms of SLE may be useful.
REFERENCES 1. Seligman VA, Lum RF, Olson JL, et al. Demographic differences in the development of lupus nephritis: a retrospective analysis. Am J Med. 2002;112:726 –729. 2. Hopkinson ND, Jenkinson C, Muir KR, et al. Racial group, socioeconomic status, and the development of persistent proteinuria in systemic lupus erythematosus. Ann Rheum Dis. 2000;59:116 –119. 3. Bastian HM, Roseman JM, McGwin G Jr, et al. LUMINA Study Group. LUpus in MInority populations: NAture vs nurture. Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis. Lupus. 2002;11:152–160. 4. Alba P, Bento L, Cuadrado MJ, et al. Anti-dsDNA, anti-Sm antibodies, and the lupus anticoagulant: significant factors associated with lupus nephritis. Ann Rheum Dis. 2003;62:556 –560. 5. Chindalore V, Neas B, Reichlin M. The association between antiribosomal P antibodies and active nephritis in systemic lupus erythematosus. Clin Immunol Immunopathol. 1998;87:292–296. 6. Wasicek CA, Reichlin M. Clinical and serological differences between systemic lupus erythematosus patients with antibodies to Ro versus patients with antibodies to Ro and La. J Clin Invest. 1982;69: 835– 843. 7. Homma M, Mimori T, Takeda Y, et al. Autoantibodies to the Sm antigen: immunological approach to clinical aspects of systemic lupus erythematosus. J Rheumatol. 1987;14(suppl 13):188 –193. 8. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271–1277. 9. Mok CC, Lee KW, Ho CTK, et al. A prospective study of survival and prognostic indicators of systemic lupus erythematosus in a southern Chinese population. Rheumatology (Oxf). 2000;39:399 – 406. 10. Ward MM, Studenski S. Systemic lupus erythematosus in men: a multivariate analysis of gender differences in clinical manifestations. J Rheumatol. 1990;17:220 –224. 11. Mok CC, Lau CS, Chan TM, Wong RWS. Clinical characteristics and outcome of southern Chinese males with systemic lupus erythematosus. Lupus. 1999;8:188 –196. 12. Molina JF, Drenkard C, Molina J, et al. Systemic lupus erythematosus in males. A study of 107 Latin American patients. Medicine. 1996;75:124 –130. 13. Bootsma H, Spronk P, Derksen R, et al. Prevention of relapses in systemic lupus erythematosus. Lancet. 1995;345:1595–1599.
14. Alarcon-Segovia D, Tumlin JA, Furie RA, et al. LJP 394 for the prevention of renal flare in patients with systemic lupus erythematosus: results from a randomized, double-blind, placebocontrolled study. Arthritis Rheum. 2003;48:442– 454. 15. Cortes-Hernandez J, Ordi-Ros J, Labrador M, et al. Antihistone and anti-double-stranded deoxyribonucleic acid antibodies are associated with renal disease in systemic lupus erythematosus. Am J Med. 2004;116:165–173. 16. Massardo L, Burgos P, Martinez ME, et al. Antiribosomal P protein antibodies in Chilean SLE patients: no association with renal disease. Lupus. 2002;11:379 –383. 17. Mok CC, Lau CS. Lupus in Hong Kong Chinese. Lupus. 2003;12: 717–722. 18. Cervera R, Khamashta MA, Font J, et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. The European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore). 1993;72: 113–124. 19. Pistiner M, Wallace DJ, Nessim S, et al. Lupus erythematosus in the 1980’s: a survey of 570 patients. Semin Arthritis Rheum. 1991;21:55– 64. 20. Zabaleta-Lanz M, Vargas-Arenas RE, Tapanes F, et al. Silent nephritis in systemic lupus erythematosus. Lupus. 2003;12:26 –30. 21. Gonzalez-Crespo MR, Lopez-Fernandez JI, Usera G, et al. Outcome of silent lupus nephritis. Semin Arthritis Rheum. 1996;26:468 – 476. 22. Dooley MA, Hogan S, Jennette C, Falk R. Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Glomerular Disease Collaborative Network. Kidney Int. 1997;51: 1188 –1195. 23. Huong DL, Papo T, Beaufils H, et al. Renal involvement in systemic lupus erythematosus. A study of 180 patients from a single center. Medicine (Baltimore). 1999;78:148 –166. 24. Mok CC, Wong RWS, Lau CS. Lupus nephritis in Southern Chinese patients: clinicopathologic findings and long-term outcome. Am J Kidney Dis. 1999;34:315–323. 25. Zuniga R, Ng S, Peterson MG, et al. Low-binding alleles of Fcgamma receptor types IIA and IIIA are inherited independently and are associated with systemic lupus erythematosus in Hispanic patients. Arthritis Rheum. 2001;44:361–367. 26. Seligman VA, Suarez C, Lum R, et al. The Fcgamma receptor IIIA158F allele is a major risk factor for the development of lupus nephritis among Caucasians but not non-Caucasians. Arthritis Rheum. 2001;44:618 – 625. 27. Mok CC, Lanchbury JS, Chan DW, Lau CS. Interleukin-10 promoter polymorphisms in Southern Chinese patients with systemic lupus erythematosus. Arthritis Rheum. 1998;41:1090 –1095. 28. Parsa A, Peden E, Lum RF, et al. Association of angiotensinconverting enzyme polymorphisms with systemic lupus erythematosus and nephritis: analysis of 644 SLE families. Genes Immun. 2002;3(suppl 1):S42–S46. From the Department of Medicine, Tuen Mun Hospital (CCM), and the Department of Medicine, Princess Margaret Hospital (SSKT), Hong Kong, Special Administrative Region, China. Requests for reprints should be addressed to Chi Chiu Mok, MD, Department of Medicine, Tuen Mun Hospital, Tsing Chung Koon Road, New Territories, Hong Kong, Special Administrative Region, China, or [email protected]. Manuscript submitted October 17, 2003, and accepted in revised form April 15, 2004.
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Volume 117 795
Incidence and Predictors of Renal Disease in Chinese Patients with Systemic Lupus Erythematosus Chi Chiu Mok, MD, Sandy Shuk Kuen Tang, MB
R
enal involvement in systemic lupus erythematosus (SLE) is a major cause of mortality and morbidity. Although several demographic, ethnic, immunologic, and genetic factors have been associated with nephritis in SLE (1–7), the results are inconsistent, perhaps because these studies were retrospective or because of differences in referral pattern and cohort composition. In this report, we present prospective data on the risk of renal disease in an unselected cohort of Chinese patients with new-onset SLE.
METHODS We studied patients newly diagnosed with SLE, or referred within 6 months of diagnosis, between 1995 and 2002 in the medical departments of Princess Margaret and Tuen Mun Hospital of Hong Kong. All patients were Chinese. All patients fulfilled at least four of the American College of Rheumatology criteria for the classification of SLE (8). They were followed at 6- to 8-week intervals. We screened for renal disease at each clinic visit with urine dipsticks. Those with abnormalities were asked to have quantification of urinary protein excretion and microscopic study of a urine sample. A diagnosis of lupus nephritis was made by at least two rheumatologists/nephrologists, according to standard criteria (8): persistent proteinuria ⱖ0.5 g/d; cellular casts (red cell, hemoglobin, granular, tubular, or mixed); or histologic evidence of lupus glomerulonephritis. Patients who had microscopic hematuria or proteinuria ⬍0.5 g/d, or both, were regarded as having subclinical renal involvement. The time interval between the date of diagnosis of SLE and first appearance of renal disease was recorded. If renal disease did not occur, data were censored at the last visit. Data from patients who died or who were lost to follow-up before the development of nephritis were censored at their last clinic visit.
Statistical Analysis Comparisons between groups were made with the Student t test (continuous data) or the chi-squared test (cat© 2004 by Elsevier Inc. All rights reserved.
egorical data). Logistic regression was used to study the variables associated with the presence of renal disease at diagnosis. Kaplan-Meier survival curves were plotted to estimate the proportion of patients remaining nephritis free at different time intervals. Cox proportional hazards models were used to identify predictors of the development of renal disease. Covariates included age (⬍33 and ⱖ33 years [median]), sex, interval between symptom onset and diagnosis of SLE, extrarenal manifestations, hypocomplementemia, autoantibodies (anti– doublestranded DNA [anti-dsDNA], anti-Ro, anti-La, anti-Sm, antiribonucleoprotein [nRNP]), subclinical renal involvement at diagnosis, and the use of medications (such as hydroxychloroquine and cytotoxic agents). To avoid overfitting, only those variables with the lowest P values in univariate analyses were included in the multivariate models. All statistical analyses were performed using SPSS software, version 12.0 (Chicago, Illinois).
RESULTS We studied 216 patients (88% women), 180 (83%) of whom were diagnosed with SLE in our hospitals (Table 1). The remainder were referred by private practitioners or family physicians; the mean (⫾ SD) interval between SLE diagnosis and first referral to our units was 3.8 ⫾ 2.4 months. Ten patients were lost to follow-up and 9 others died. Sixty-eight patients (31%) had active renal disease at diagnosis (all had daily proteinuria ⱖ0.5 g and 14 had active urinary casts). Another 32 patients (15%) had subclinical renal disease. Renal biopsy specimens, obtained in 54 patients, showed diffuse proliferative nephritis in 37 patients (69%), focal proliferative nephritis in 6 (11%), mesangial nephritis in 3 (6%), and pure membranous nephritis in 8 (15%). (The remaining 14 patients with active renal disease had the diagnosis made by examination of the urinary sediment). In a multivariate model, only a hemoglobin level ⱕ10 g/dL (odds ratio [OR] ⫽ 2.2; 95% confidence interval [CI]: 1.0 to 4.7; P ⫽ 0.04), a positive anti-dsDNA (OR ⫽ 4.1; 95% CI: 1.4 to 12; P ⫽ 0.008), and malar erythema (OR ⫽ 0.4; 95% CI: 0.2 to 0.8; P ⫽ 0.01) were associated with the presence of active renal disease at baseline. The cumulative risk of renal disease since SLE diagnosis was 41% at 12 months, 50% at 24 months, 54% at 36 months, 58% at 48 months, and 60% at 60 months. After 5 years, the chance of developing renal disease for the first time was very low. Among the 148 patients without active renal disease at the onset of SLE, 49 (33%) developed active renal disease, after a median of 14 months. Renal biopsy specimens from 35 of these patients showed diffuse proliferative nephritis in 16 patients (46%), focal proliferative nephritis 0002-9343/04/$–see front matter 791 doi:10.1016/j.amjmed.2004.04.029
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Table 1. Clinical Characteristics of Patients by the Presence or Absence of Active Renal Disease at the Onset of Systemic Lupus Erythematosus Active Renal Disease Characteristic
Yes (n ⫽ 68)
No (n ⫽ 148)
P Value
Number (%) or Mean ⫾ SD Age at SLE diagnosis (years) Female sex Time between symptom onset and SLE diagnosis (weeks) Clinical features at diagnosis Fever Alopecia Raynaud phenomenon Arthritis/arthralgia Malar erythema Photosensitivity Discoid rash Oral ulcers Hemoglobin ⱕ10 g/dL Hemolytic anemia Leukopenia Lymphopenia Thrombocytopenia Lymphadenopathy Psychosis Seizure Serositis Cutaneous vasculitis ANA Anti-dsDNA Low serum C3 level Anti-Sm Anti-Ro Anti-La Anti-nRNP
35.8 ⫾ 13.1 57 (84) 5.2 ⫾ 17
33.8 ⫾ 13.4 134 (91) 5.7 ⫾ 9.9
0.29 0.15 0.85
25 (37) 17 (25) 7 (10) 42 (62) 18 (26) 11 (16) 1 (1) 5 (7) 37 (54) 12 (18) 25 (37) 42 (62) 18 (26) 11 (16) 1 (1) 3 (4) 11 (16) 6 (9) 68 (100) 63 (93) 60 (88) 5 (7) 39 (57) 7 (10) 12 (18)
51 (34) 37 (25) 38 (26) 111 (75) 77 (52) 50 (34) 11 (7) 14 (9) 38 (26) 14 (9) 50 (34) 74 (50) 26 (18) 14 (9) 8 (5) 6 (4) 18 (12) 26 (18) 146 (99) 107 (72) 110 (74) 22 (15) 90 (61) 22 (15) 36 (24)
0.74 1.00 0.01 0.05 ⬍0.001 0.008 0.15 0.80 ⬍0.01 0.09 0.67 0.11 0.13 0.15 0.33 1.00 0.42 0.09 0.84 0.001 0.02 0.18 0.63 0.36 0.27
ANA ⫽ antinuclear antibody; dsDNA ⫽ double-stranded DNA; nRNP ⫽ ribonucleoprotein; SLE ⫽ systemic lupus erythematosus.
in 12 (34%), mesangial nephritis in 1 (3%), and pure membranous nephritis in 6 (17%). The cumulative risk of active renal disease was 14% at 12 months, 28% at 24 months, 33% at 36 months, 38% at 48 months, and 41% at 60 months (Figure 1). Of the eight variables associated with the development of active renal disease in univariate models (Table 2), only subclinical renal disease and a hemoglobin level ⱕ10 g/dL were significant multivariate predictors of the development of active renal disease (Figures 1 and 2). A separate analysis showed that men were more likely than women to have subclinical renal disease at baseline (36% [5/14] vs. 19% [26/134], P ⫽ 0.15), antidsDNA (86% [12/14] vs. 71% [95/134], P ⫽ 0.24), and hypocomplementemia (100% [14/14] vs. 72% [96/134], P ⫽ 0.02), but less likely to have arthritis (43% [6/14] vs. 78% [105/134], P ⫽ 0.004). 792
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DISCUSSION This prospective study shows that renal disease is common in Chinese patients with SLE, occurring in 60% of patients within the first 5 years of diagnosis. We previously reported that 45% of SLE patients seen at an academic rheumatology unit had renal involvement after a mean of 45 months after disease onset (9). To obtain a valid estimate of the risk of renal disease, only patients with new-onset SLE were included. Bias in referral was reduced by including patients under the care of all specialists, not just rheumatologists. Our data are therefore representative of Chinese patients with SLE in Hong Kong. Several previous studies have reported that men with SLE have earlier onset and more severe nephritis than do
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Probability of not developing renal disease
01.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3
P = 0.001 (log-rank test)
0.2 0
12
24
36
48
60
Time (months) Number at risk No renal disease
116
100
69
48
33
24
Subclinical renal disease
32
16
13
10
7
1
Figure 1. Risk of renal disease by the presence of absence of subclinical renal involvement at the onset of systemic lupus erythematosus.
women (10 –12), and a study of multiethnic SLE patients in the United States found that renal disease was especially frequent in Asian men (1). In our cohort of Chinese patients, men were more likely to develop lupus nephritis than were women, but male sex was not associated with renal disease in the multivariate model. This could be related to the higher frequency of subclinical renal disease, anti-dsDNA, and hypocomplementemia, but lower
frequency of arthritis in men; all of these were also associated with the development of nephritis. Anti-dsDNA can be isolated from glomerular eluates of patients with active nephritis. DNA-anti-DNA immune complexes, formed in circulation or in situ, induce complement activation and inflammation after renal deposition. Renal flares in SLE are often preceded by rising anti-dsDNA titers and falling complement levels (13).
Table 2. Univariate and Multivariate Predictors of the Development of Active Renal Disease in Patients without Active Renal Disease at Onset (n ⫽ 148) Univariate
Variables Subclinical renal disease* Hemoglobin ⱕ10 g/dL Male sex Positive anti-dsDNA Arthritis Lymphadenopathy Low serum C3 Use of hydroxychloroquine for ⱖ6 months
Multivariate
Hazard Ratio (95% Confidence Interval)
P Value
Hazard Ratio (95% Confidence Interval)
P Value
2.7 (1.5–4.9) 2.5 (1.4–4.4) 2.2 (1.0–4.9) 2.4 (1.1–5.3) 0.6 (0.3–1.0) 2.1 (1.0–4.5) 2.1 (1.0–4.5) 0.5 (0.3–1.0)
0.001 0.002 0.05 0.03 0.05 0.05 0.05 0.03
2.2 (1.2–4.3) 1.9 (1.0–3.6) — — — — — —
0.02 0.05 — — — — — —
* Microscopic hematuria, proteinuria ⬍0.5 g/d, or both. dsDNA ⫽ double-stranded DNA. November 15, 2004
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Figure 2. Risk of renal disease by hemoglobin level at the onset of systemic lupus erythematosus.
Reducing anti-dsDNA titers by making B cells more tolerant is effective in reducing and delaying lupus nephritis flares (14). Anti-dsDNA also predicts the development of proliferative lupus glomerulonephritis (15). Although we found that anti-dsDNA was associated with prevalent nephritis at the onset of SLE, we were unable to demonstrate that anti-dsDNA was an independent predictor of the development of renal disease in our multivariate model. As seroconversion of anti-dsDNA may occur just before the onset of nephritis, anti-dsDNA status at the time of the diagnosis of SLE may not be a good predictor. Moreover, we included all forms of renal disease, including those without histologic data. Some subtypes of lupus nephritis, such as membranous nephropathy, have not been linked to anti-dsDNA. The anti-Ro antibody has been associated with nephritis in patients with SLE, but the presence of both anti-Ro and anti-La appeared to be protective in one study (6). Anti-Sm and antiribosomal P antibodies have also been linked to lupus nephritis, although the data are inconsistent (5,7,16). More recently, antihistone antibodies were reported to predict the onset of proliferative lupus nephritis in patients without overt renal disease (15). Although anti-Ro appears to be more common in Chinese 794
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patients with SLE (17–19), we did not observe a relation between anti-Ro and renal disease in our study. We did find that a low hemoglobin level (ⱕ10 g/dL) was an independent predictor of renal disease at onset and during the course of SLE. Most of our patients had normochromic normocytic anemia without an obvious cause, other than SLE. Although some patients had elevated serum creatinine levels, the degree and duration of renal impairment was insufficient to explain the anemia. Autoantibodies or cytokines that suppress erythropoiesis may be responsible. Subclinical renal disease has been well described in SLE. Renal biopsy specimens in patients without clinical renal disease often reveal histologic evidence of lupus nephritis, usually of the milder types (20,21). In our study, subclinical renal involvement at the onset of SLE, as evidenced by microscopic hematuria and trace proteinuria, predicted the subsequent development of overt renal disease. The risk was independent of demographic characteristics, autoantibodies, and treatment for extrarenal manifestations. Thus, patients with SLE who have subtle renal disease at presentation should be followed closely. There are considerable interethnic differences in the incidence and prognosis of renal disease in SLE. In the
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United States, blacks and Hispanics have more frequent and more severe lupus nephritis than do whites (1,3,22,23). Although the prognosis of Chinese patients with lupus nephritis is similar to that of whites (24), the incidence of nephritis in our Chinese patients appears to be higher (18,19). Genetic factors may affect susceptibility to lupus nephritis. Both HLA and non-HLA alleles have been implicated (25–28). Because about one third of our SLE patients have not yet developed any evidence of overt renal disease, studies to identify genetic differences between these patients and those with more severe forms of SLE may be useful.
REFERENCES 1. Seligman VA, Lum RF, Olson JL, et al. Demographic differences in the development of lupus nephritis: a retrospective analysis. Am J Med. 2002;112:726 –729. 2. Hopkinson ND, Jenkinson C, Muir KR, et al. Racial group, socioeconomic status, and the development of persistent proteinuria in systemic lupus erythematosus. Ann Rheum Dis. 2000;59:116 –119. 3. Bastian HM, Roseman JM, McGwin G Jr, et al. LUMINA Study Group. LUpus in MInority populations: NAture vs nurture. Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis. Lupus. 2002;11:152–160. 4. Alba P, Bento L, Cuadrado MJ, et al. Anti-dsDNA, anti-Sm antibodies, and the lupus anticoagulant: significant factors associated with lupus nephritis. Ann Rheum Dis. 2003;62:556 –560. 5. Chindalore V, Neas B, Reichlin M. The association between antiribosomal P antibodies and active nephritis in systemic lupus erythematosus. Clin Immunol Immunopathol. 1998;87:292–296. 6. Wasicek CA, Reichlin M. Clinical and serological differences between systemic lupus erythematosus patients with antibodies to Ro versus patients with antibodies to Ro and La. J Clin Invest. 1982;69: 835– 843. 7. Homma M, Mimori T, Takeda Y, et al. Autoantibodies to the Sm antigen: immunological approach to clinical aspects of systemic lupus erythematosus. J Rheumatol. 1987;14(suppl 13):188 –193. 8. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271–1277. 9. Mok CC, Lee KW, Ho CTK, et al. A prospective study of survival and prognostic indicators of systemic lupus erythematosus in a southern Chinese population. Rheumatology (Oxf). 2000;39:399 – 406. 10. Ward MM, Studenski S. Systemic lupus erythematosus in men: a multivariate analysis of gender differences in clinical manifestations. J Rheumatol. 1990;17:220 –224. 11. Mok CC, Lau CS, Chan TM, Wong RWS. Clinical characteristics and outcome of southern Chinese males with systemic lupus erythematosus. Lupus. 1999;8:188 –196. 12. Molina JF, Drenkard C, Molina J, et al. Systemic lupus erythematosus in males. A study of 107 Latin American patients. Medicine. 1996;75:124 –130. 13. Bootsma H, Spronk P, Derksen R, et al. Prevention of relapses in systemic lupus erythematosus. Lancet. 1995;345:1595–1599.
14. Alarcon-Segovia D, Tumlin JA, Furie RA, et al. LJP 394 for the prevention of renal flare in patients with systemic lupus erythematosus: results from a randomized, double-blind, placebocontrolled study. Arthritis Rheum. 2003;48:442– 454. 15. Cortes-Hernandez J, Ordi-Ros J, Labrador M, et al. Antihistone and anti-double-stranded deoxyribonucleic acid antibodies are associated with renal disease in systemic lupus erythematosus. Am J Med. 2004;116:165–173. 16. Massardo L, Burgos P, Martinez ME, et al. Antiribosomal P protein antibodies in Chilean SLE patients: no association with renal disease. Lupus. 2002;11:379 –383. 17. Mok CC, Lau CS. Lupus in Hong Kong Chinese. Lupus. 2003;12: 717–722. 18. Cervera R, Khamashta MA, Font J, et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. The European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore). 1993;72: 113–124. 19. Pistiner M, Wallace DJ, Nessim S, et al. Lupus erythematosus in the 1980’s: a survey of 570 patients. Semin Arthritis Rheum. 1991;21:55– 64. 20. Zabaleta-Lanz M, Vargas-Arenas RE, Tapanes F, et al. Silent nephritis in systemic lupus erythematosus. Lupus. 2003;12:26 –30. 21. Gonzalez-Crespo MR, Lopez-Fernandez JI, Usera G, et al. Outcome of silent lupus nephritis. Semin Arthritis Rheum. 1996;26:468 – 476. 22. Dooley MA, Hogan S, Jennette C, Falk R. Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Glomerular Disease Collaborative Network. Kidney Int. 1997;51: 1188 –1195. 23. Huong DL, Papo T, Beaufils H, et al. Renal involvement in systemic lupus erythematosus. A study of 180 patients from a single center. Medicine (Baltimore). 1999;78:148 –166. 24. Mok CC, Wong RWS, Lau CS. Lupus nephritis in Southern Chinese patients: clinicopathologic findings and long-term outcome. Am J Kidney Dis. 1999;34:315–323. 25. Zuniga R, Ng S, Peterson MG, et al. Low-binding alleles of Fcgamma receptor types IIA and IIIA are inherited independently and are associated with systemic lupus erythematosus in Hispanic patients. Arthritis Rheum. 2001;44:361–367. 26. Seligman VA, Suarez C, Lum R, et al. The Fcgamma receptor IIIA158F allele is a major risk factor for the development of lupus nephritis among Caucasians but not non-Caucasians. Arthritis Rheum. 2001;44:618 – 625. 27. Mok CC, Lanchbury JS, Chan DW, Lau CS. Interleukin-10 promoter polymorphisms in Southern Chinese patients with systemic lupus erythematosus. Arthritis Rheum. 1998;41:1090 –1095. 28. Parsa A, Peden E, Lum RF, et al. Association of angiotensinconverting enzyme polymorphisms with systemic lupus erythematosus and nephritis: analysis of 644 SLE families. Genes Immun. 2002;3(suppl 1):S42–S46. From the Department of Medicine, Tuen Mun Hospital (CCM), and the Department of Medicine, Princess Margaret Hospital (SSKT), Hong Kong, Special Administrative Region, China. Requests for reprints should be addressed to Chi Chiu Mok, MD, Department of Medicine, Tuen Mun Hospital, Tsing Chung Koon Road, New Territories, Hong Kong, Special Administrative Region, China, or [email protected]. Manuscript submitted October 17, 2003, and accepted in revised form April 15, 2004.
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