|Year : 2016 | Volume
| Issue : 3 | Page : 136-143
Treatment outcomes from a multiethnic lupus cohort with proliferative nephritis
Angela Pakozdi1, Ravindra Rajakariar2, Michael Sheaff3, Debasish Pyne1
1 Department of Rheumatology, Mile End Hospital, London E1 4DG, United Kingdom
2 Department of Nephrology, Royal London Hospital, London E1 1BB, United Kingdom
3 Department of Histopathology, Royal London Hospital, London E1 1BB, United Kingdom
|Date of Web Publication||11-Aug-2016|
Dr. Debasish Pyne
Department of Rheumatology, Mile End Hospital, Bancroft Road, London E1 4DG
Source of Support: None, Conflict of Interest: None
Objective: To assess treatment responses and long-term outcomes in a multiethnic lupus cohort with proliferative lupus nephritis (LN) from a single United Kingdom (UK) center.
Methods: 86 lupus patients were diagnosed with active proliferative LN between 1995 and 2015 at Barts Health, a large inner city hospital in London, UK. They were grouped by ethnicity into South Asians (Bangladeshi, Indian, Pakistani, and Sri Lankan), blacks (African Blacks and Afro-Caribbeans), and Caucasians. Remission rates were analyzed at 6 and 24 months after induction treatment with cyclophosphamide (CYC) or mycophenolate mofetil (MMF). Prognostic factors for the treatment response were identified by regression analysis. Kaplan-Meier method was applied to assess long-term renal survival and Cox proportional hazards model for risk factors for developing end-stage renal disease.
Results: MMF achieved a higher remission rate in blacks compared to CYC (70% vs. 16.7%, P = 0.005) at 6 months, showed a trend in Asians (77.8% vs. 38.9%, P = 0.057), and comparable response in Caucasians (42.9% vs. 55.6%, P = 0.614). Low baseline serum creatinine was the strongest predictor for favorable treatment response (odds ratio 0.98, 95% confidence interval [95% CI]: 0.97-0.99, P = 0.045). Renal survival glomerular filtration rate (GFR >15 ml/min/1.73 m 2 ) was 79.8% and 75.6% at 5 and 10 years, lowest in blacks (60.5%) followed by Asians (86.7%) then Caucasians (88.9%) (P = 0.030). Low GFR (GFR <30 ml/min/1.73 m 2 ) on presentation was an independent risk factor for poor 10 years renal survival (hazard ratio 32.55, 95% CI: 3.70-286.64, P = 0.002).
Conclusions: MMF appears to be at least as effective as CYC as an induction agent in this multiethnic cohort but there were important differences in long-term renal outcomes based on ethnic group and baseline GFR and creatinine.
Keywords: Ethnicity, immunosuppression, lupus nephritis, systemic lupus erythematosus
|How to cite this article:|
Pakozdi A, Rajakariar R, Sheaff M, Pyne D. Treatment outcomes from a multiethnic lupus cohort with proliferative nephritis. Indian J Rheumatol 2016;11:136-43
| Introduction|| |
Renal disease is a major predictor of poor outcome in systemic lupus erythematosus (SLE). The overall prevalence of lupus nephritis (LN) is estimated to be around 50-60%  and ethnicity is known to be an important determinant. African-American blacks, American Hispanics, South Asians, and Chinese have higher incidence and prevalence rates of LN compared to European whites and their renal disease tends to be more severe. ,,,,
Standard therapies in LN include high dose cyclophosphamide (CYC) (the National Institute of Health regime [NIH]);  low dose CYC (the EuroLupus regime),  mycophenolate mofetil (MMF), , azathioprine,  and more recently rituximab.  Subgroup analysis from the Aspreva Lupus Management Study (ALMS) showed that Hispanics and blacks tend to respond better to MMF than intravenous (IV) CYC.  In contrast, IV CYC seemed to be more efficacious in Koreans,  and equivalent efficacy has been shown between MMF and CYC in Chinese, ,, Malaysians,  and Indians  with proliferative LN. For European Caucasians, the Euro-Lupus study  showed that a low dose CYC regime was as effective as the higher dose NIH regime in LN patients with preserved renal function.
To date, no firm conclusions have been drawn for preferential induction regimes for the South Asians with LN. Most of the published literature on Asian patients with LN is based on Chinese data, with South Asians (Bangladeshi, Pakistani, Indians, and Sri Lankans) being under-represented. The comparative efficacy of high dose and low dose CYC has not been evaluated in this patient group, and although MMF at 2 g/day has been shown to be effective in Oriental Asians. ,, There are little data on the optimal dosage in other Asian populations.
Here, we report on the treatment and long-term renal outcomes for a multiethnic lupus cohort with proliferative LN from a large tertiary lupus center in the United Kingdom (UK).
| Methods|| |
Patients and study design
This retrospective study was undertaken at a tertiary lupus center within a large university hospital, Barts Health NHS Trust, UK. Patients with biopsy-proven proliferative LN diagnosed between 1995 and 2013 who had a follow-up of at least 6 months were included. LN classes based on glomerular pathology were defined according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification. , All patients fulfilled at least four of the American College of Rheumatology (ACR) revised classification criteria for SLE.  Patients were divided into three ethnic groups: Asians from the South Asian Subcontinent (Bangladesh, India, Pakistan, or Sri Lanka), blacks (African Blacks or Afro-Caribbeans), and white Caucasians.
In our center, the main induction regimes were CYC or MMF. CYC was either given orally (1.5-2 mg/kg/day for 3-6 months)  or IV as per the NIH regimen (6 pulses of monthly CYC 0.75 g/m 2 of body surface).  The low dose Euro-Lupus regimen (six infusions of fortnightly CYC 500 mg) has been used for the past decade as comparable efficacy and lower harm rates have been shown in trials.  Because of the variation in the route of administration, the cumulative dose of CYC was calculated for all patients for the first 6 months. Prednisolone was given to all patients at a dosage of 1 mg/kg/day for 4-6 weeks and then tapered to 7.5-10 mg by 6-9 months. IV methylprednisolone was given to 28 patients who presented with renal impairment. MMF was given orally in divided doses with a target dose of 2-3 g/day. , For maintenance treatment, either azathioprine (2 mg/kg/day) or MMF was used.
Definition of treatment response and relapse
Complete remission (CR) was defined as proteinuria <0.5 g/day (or urine protein/creatinine ratio <50 mg/mmol)  and improved or stable creatinine (<10% rise in serum creatinine). End-stage renal disease (ESRD) was defined as a decreased estimated glomerular filtration rate (GFR) <15 ml/min/1.73 m 2 .  Proteinuric flares were defined as proteinuria >1 g/day (or urine protein/creatinine ratio >100 mg/mmol)  in case of previously achieved CR.
Descriptive analyses were performed on the clinical and histological data. Continuous variables are given as means (standard deviation) or medians with interquartile range (IQR). One way ANOVA, Mann-Whitney U-test, or Kruskal-Wallis tests were used to analyze data, comparing two or three groups. For categorical variables, Pearson's Chi test was used, and data are shown as percentages. Multiple logistic regression analysis was conducted to evaluate potential predictors of remission. Odds ratios (ORs) and 95% confidence intervals (CIs) for renal response were calculated for each predictor. Collinearity diagnostics were run to rule out the potential presence of multicollinearity. Times to event analyses were performed according to the Kaplan-Meier method. Cox proportional hazards model was used to evaluate the effect of demographic and baseline biochemical variables on renal prognosis. All statistical analyses were performed using SPSS software version 22 for Mac (SPSS Inc., Chicago, IL, USA); P < 0.05 were considered statistically significant.
| Results|| |
A total of 86 patients were diagnosed with biopsy-proven proliferative LN (ISN/RPS Class III or IV). The baseline characteristics of our patient cohort are shown in [Table 1]. About 38 LN patients were African blacks or Afro-Caribbeans (44.2%), 30 were South Asians (34.9%), and 18 were Caucasians (20.9%). Asians presenting with LN (and SLE) were on average 6 years younger than Caucasians although this did not reach statistical significance (P = 0.105). 70.6% (n = 12) of Caucasians, 57.9% (n = 22) of blacks and 38.5% (n = 10) of South Asians presented with LN at time of SLE diagnosis or within 6 months (P = 0.098). Extractable nuclear antigen antibodies were less frequent in Caucasians compared to Asians or blacks (P < 0.001). The discrepancy between ethnic groups was attributable to more RNP (P < 0.001) and Sm antibodies in blacks (P = 0.002).
|Table 1: Baseline demographics and characteristics of lupus nephritis patients |
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Renal biopsy showed Class III glomerulonephritis in 31 (36%) and Class IV in 55 patients (64%); however, 18 patients (20.9%) had additional membranous lesions (Class V), nine with Class III and nine with Class IV LN.
On presentation, baseline median proteinuria was 3.9 g/day (IQR: 1.8-7.7 g/day), being in the nephrotic range in 61.8% of patients, with no statistical difference between ethnic groups. Blacks presented with the worst renal function (median serum creatinine 131 μmol/L, equivalent to 1.48 mg/dl; IQR: 92-269 μmol/L, P = 0.036), and 6 (15.8%) required renal replacement therapy on presentation (compared to two Asian and one Caucasian patient).
Of the nine patients (10.8%) requiring renal replacement therapy on presentation, six patients had an irreversible renal loss. As at the time of presentation they had advanced tubulointerstitial scarring they were unlikely to recover independent renal function and therefore were excluded from the outcome analysis.
CYC was the induction regimen in 58.8% of LN patients (n = 47) with a median cumulative dose of 5.6 g (IQR: 3-9 g) calculated for the first 6 months, while 33.8% received MMF (n = 27) with median dose of 2 g/day (IQR: 2-2 g), six patients (7.5%) received different induction treatment (azathioprine or rituximab). Black patients presenting with worse renal function were more likely to receive CYC than MMF (median creatinine 133 μmol/L vs. 90 μmol/L, equivalent to 1.5 mg/dL vs. 1.02 mg/dL, respectively, P = 0.027). No difference in baseline biochemical parameters was observed between treatment arms in the other two ethnic groups including the level of proteinuria, serum albumin, or creatinine concentrations.
CR rates by 6 and 24 months were analyzed [Figure 1]. At 6 months, MMF achieved a higher remission rate in blacks than CYC (70% vs. 16.7%, respectively; P = 0.005). In this ethnic group, we noted a mutual imbalance toward treating patients with higher baseline creatinine with CYC; therefore, we analyzed treatment response in those with relatively preserved renal function (estimated GFR >60 ml/min/1.73 m 2 , n = 14). Of those, only 14.3% of MMF-treated patients were not in CR in contrast to 83.3% of patients treated with CYC (P = 0.013). Although there was a trend to have a better response to MMF, there was no statistically significant difference in remission rates in South Asians (77.8% vs. 38.9%, MMF vs. CYC, respectively; P = 0.057). In contrast, in Caucasians, there was no difference observed with both MMF and CYC showing similar remission rates (42.9% vs. 55.6%, MMF vs. CYC, P = 0.614). Among those with abnormal baseline lupus activity markers, normalization of dsDNA, C3, and C4 happened in 42.9% (n = 24), 90% (n = 45), and 70% (n = 35) by 6 months, respectively, with no differences among the ethnic groups. By 24 months, there was trend for greater response to MMF than CYC in both Asians (88.9% vs. 62.5%, respectively, P = 0.158) and blacks (70% vs. 47.7%, respectively, P = 0.244), but not in Caucasians (83.3% vs. 88.9%, respectively, P = 0.756).
|Figure 1: Complete remission rates by 6 and 24 months by ethnicity and treatment group. At 6 months, the overall complete remission rate was higher in patients treated with mycophenolate mofetil compared to cyclophosphamide. Remission rates at 6 months indicated that South Asian and black patients tended to respond better to mycophenolate mofetil. By 24 months, there was a tendency for higher remission rates in patients treated with mycophenolate mofetil induction; however, the difference was not statistically significant|
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We determined predictive risk factors for failure to achieve CR by 24 months [Table 2]. By univariate logistic regression analysis, we found that black race, diffuse proliferative LN (Class IV), and higher serum creatinine at onset were associated with lack of remission by 24 months. However, multivariate logistic regression model indicated that the only independent prognostic factor for remission failure was baseline serum creatinine level (OR: 0.98, per increase of 1 μmol/L, equivalent to 0.01 mg/dL, 95% CI: 0.97-0.999, P = 0.045).
|Table 2: Factors predicting 24 months proliferative lupus nephritis remission by univariate and multivariate logistic regression analysis |
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Long-term outcome of proliferative lupus nephritis
During long-term follow-up, with a median time of 73 months (IQR: 31-110), 62.8% achieved CR (n = 54), Asians (6 months, IQR: 4-8 months) and Caucasians (8 months, IQR: 6-14 months) tended to respond earlier than blacks (11 months, IQR: 6-21 months) (P = 0.106). Among the responders, 15 (34.7%) had a relapse during long-term follow-up. Around 42.1% of blacks, 23.5% of Asians, and 23.1% of Caucasians had flares (P = 0.381). The median time from remission to flare was 47 months (IQR: 18.5-96.3); 25 months in South Asians (IQR: 9-103), 45 months in blacks (IQR: 21.5-95.5), and 48 months in Caucasians (IQR: 38.5-88) (P = 0.393). More patients relapsed in the CYC induction group than in the MMF group (n = 12, 44.4% vs. n = 3, 13.6%, respectively, P = 0.02).
Renal survival (GFR >15 ml/min/1.73 m 2 ) was calculated for all 86 patients and was found to be 79.8% (n = 67) and 75.6% (n = 65) at 5 and 10 years. Kaplan-Meier estimates of ESRD rate indicated blacks having the highest rate of ESRD (n = 15, 39.5%, P = 0.032, using log-rank test), followed by Asians (n = 4, 13.3%) and Caucasians (n = 2, 11.1%) [Figure 2]. Diffuse proliferative LN was the underlying histological diagnosis in 95.2% (n = 19). Among patients reaching ESRD, 16 patients have required renal replacement therapy and 12 received a renal transplant. There was no difference in long-term patient survival rates among the ethnic groups (P = 0.981, using log-rank test). Four patients died more than 5 years after LN onset (one heart failure, one subarachnoidal hemorrhage due to cerebral vasculitis and two from unknown causes).
|Figure 2: Kaplan-Meier estimate of 10 years renal survival by race. Renal survival (glomerular filtration rate >15 ml/min/1.73 m2) was 75.6% at 10 years, lowest in blacks (60.5%) followed by Asians (86.7%) then Caucasians (88.9%)|
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Cox proportional hazards modeling was used to identify potential baseline predictors of developing ESRD by 10 years [Table 3]. Excluding those presented with irreversible renal damage, multivariate analysis indicated that low GFR (<30 ml/min/1.73 2 ) was the only independent predictor of ESRD among the baseline variables (hazard ratio [HR]: 32.55, 95% CI: 3.70-286.64, P = 0.002). Although the lack of CR at 6 months seemed to predict poor renal survival at 10 years, the result was not statistically significant (HR: 60.38, 95% CI: 0.57-6365.78, P = 0.084).
|Table 3: Cox proportional hazards model for baseline predictors of developing end-stage renal disease by 10 years |
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Severe infections during induction phase tended to be more common in patients treated with CYC than MMF (n = 7, 15% vs. n = 2, 8%; P = 0.642). Four patients (4.9%) developed six malignancies in the follow-up period (four cervical cancers, one papillary carcinoma of the thyroid, and one meningioma); induction treatment was CYC in two and MMF in two patients. While CYC caused gonadal toxicity in seven patients (14.3%), none occurred in the MMF-treated group.
| Discussion|| |
The current study reports the renal outcome of LN in a multiethnic cohort from a tertiary inner city Lupus Centre in the UK. Ethnicity has been shown to influence renal outcomes, affecting not only the incidence and prevalence of the disease but also the disease activity and its prognosis.  Unlike in black, Caucasian, Hispanic, and Oriental ethnic groups, much less is known about the outcome of LN in South Asians (Indians, Pakistanis, Sri Lankans, and Bangladeshi).  We observed differences between the ethnic groups with more than half of our black lupus population presenting with active proliferative LN at the time of SLE diagnosis or within 6 months, while South Asians presented more commonly after this time point. A similar observation has been made in Chinese Asians where less than a third of lupus patients had active LN as the initial presentation of SLE.  We observed that South Asian and black patients were younger at the time of SLE and LN diagnosis when compared to Caucasians by a mean age of 6 years. Previous studies have shown similar differences between blacks and Caucasians. 
Very few studies have compared disease severity and outcomes in South Asians to other ethnic groups. We found that blacks presented with significantly higher serum creatinine levels, including six patients with severe renal insufficiency (15.5%) requiring immediate renal replacement therapy. Although the frequency of nephrotic range proteinuria at onset was virtually equal in all three ethnic groups (61.8%), Asians tended to have more severe proteinuria and lower serum albumin concentrations.
The treatment of LN is guided by histological diagnosis and clinical presentation. For proliferative LN, the most common agents for induction treatment are CYC or MMF. We found higher remission rates with MMF compared to CYC in the black subgroup at 6 months; however, the difference was not statistically significant at 24 months. In white Caucasians, no difference was observed in remission rates between patients treated with either drug. In South Asian patients, although we found no statistical difference between treatment groups, there was a definite trend to respond better to MMF than CYC at both 6 and 24 months.
An important consideration in our LN cohort was that in all the ethnic subgroups, the achieved median daily dose of MMF was 2 g (IQR: 2-2). This is lower than used in the ALMS trial, which investigated the efficacy of MMF in proliferative and membranous LN, and targeted higher doses of 2.5-3 g/day. While the Kidney Disease: Improving Global Outcomes and the European League Against Rheumatism guidelines recommend using MMF with a target dose of 3 g/day, , the ACR guideline suggests aiming for 3 g/day in non-Asians and a lower dose of 2 g/day in Asians, in part due to the higher incidence of severe infections observed in the Chinese cohort of the ALMS trial.  Our study suggests that the lower dose of 2 g MMF is an effective induction dose although it is possible that a higher dosage would have led to greater response rates in our cohort.
There has been growing evidence that MMF offers equivalent ,,, or in some studies higher , remission rates than IV CYC for LN induction treatment. Post hoc subgroup analysis of the racial groups in the ALMS trial found that more Hispanic patients responded to MMF than CYC, and there was a trend to achieve higher remission rates in blacks, while similar response rates were observed in Asians (mainly oriental Asians from China) and in Caucasians.  Based on this, the ACR guideline recommends stratifying induction by race using MMF rather than CYC in African-Americans and Hispanics. As none of these trials involved a sufficient number of South Asian patients, no such recommendation on optimal induction regimen could be offered to them.
The remission rates we found in South Asians were generally higher compared with those published from South Asian countries. In this cohort, 51.9% of Asians achieved CR within 6 months and 72% within 24 months. In comparison, a recent study from the Eastern India found a remission rate of only 44% at 6 months (CR in 21% and partial remission in 23%); however, these patients presented with more chronic disease, characterized by lower GFR and high chronicity indices on renal biopsy, with a considerable delay of 14 months on average from presentation to initiation of induction treatment.  Another study from South India showed higher (51.3%) CR rates with the average time to remission of 15 months in South Asians with proliferative LN treated with IV CYC.  Results of a randomized open-label trial carried out in India, comparing efficacy of oral MMF (1.5-3 g/day) with low dose IV CYC (EuroLupus regimen) for induction treatment of less severe proliferative and membranous LN (Class III, IV, and V) have revealed nearly equal remission rates in both study arms by 24 weeks, 52% of the CYC-treated, and 54% of the MMF-treated Indians. 
The 10 years renal survival rate was lowest in blacks (60.5%), compared to South Asians (86.7%) and Caucasians (88.9%). Determining prognostic factors in LN is important in order to identify those at increased risk of irreversible end organ damage. Our study has shown that baseline creatinine level is the most important risk factor to predict poor treatment response and the development of ESRD within 10 years. Previous studies found several other prognostic risk factors for renal failures, such as the level of proteinuria, anemia, younger age, or treatment response by 6 months. ,,
Racial differences in outcome may be due to both genetic and environmental factors. HLA-DRB1*1501 and HLA-DQA1*0101 alleles,  interferon regulatory factor 5,  tyrosine kinase,  and signal transducer and activator of transcription 4 genes  have been shown to associate with LN. Geographic and socioeconomic factors also contribute to the observed racial differences in LN severity and treatment response. A large multicenter study, stratifying SLE patients according to the method of payment for medical care, showed disappearing discrepancies between survival rates of different ethnic groups.
There are a number of limitations to our study. First, it is retrospective in design. We cannot exclude the possibility that there was bias introduced toward treating more severe disease with CYC rather than MMF. This was evident in the black ethnic group where patients treated with CYC had higher serum creatinine levels at presentation. However, there were no significant differences in baseline characteristics between treatment groups for Asians and Caucasians. The study included a relatively small number of patients after dividing them into ethnic groups; therefore, larger studies covering wider geographical areas would be needed to confirm the findings.
Our study reports on presentation and treatment responses in multiethnic cohort with proliferative LN. Black patients were more likely to present with advanced and irreversible renal disease. Compared to blacks, both South Asian and Caucasian groups less commonly had anti-RNP and anti-Sm antibodies took less time for their disease to remit and had significantly better long-term renal survival. MMF seemed to be at least as effective as CYC in achieving remission in blacks, Caucasians, and South Asians although firm conclusions cannot be made for those with the most severe renal pathology presenting with raised creatinine.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]