|Ahead of print publication
End of induction treatment outcomes with a novel cyclophosphamide-based regimen for severe lupus nephritis: Single-center experience from South India
V Jayaprakash1, T Dineshkumar2, J Dhanapriya2, D Rajasekar2, R Sakthirajan2, T Balasubramaniyan2, Anila A Kurien3, N Gopalakrishnan2
1 Department of Nephrology, Sri Ramachandra Institute of Higher Education and Research (SRIHER), Chennai, Tamil Nadu, India
2 Institute of Nephrology, Madras Medical College, Chennai, Tamil Nadu, India
3 Pathologist, Renopath, Chennai, Tamil Nadu, India
Department of Nephrology, SRIHER, Porur, Chennai - 600 116, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Cyclophosphamide is commonly used along with pulse steroids for induction immunosuppression treatment of severe forms of lupus nephritis (LN). Renal outcome data for proliferative forms of LN treated with cyclophosphamide from the southern parts of Indian subcontinent are sparse.
Subjects and Methods: It was an observational study done for 2 years. All patients with severe proliferative forms of LN were included. They were treated with fixed monthly single doses of 500 mg intravenous cyclophosphamide-based induction therapy along with pulse and oral steroids, as per protocol. Renal remission rates were assessed at the end of 6 months. Adverse events during the induction therapy were documented.
Results: The study included 41 patients. Of them, 37 (90.24%) patients were female and 4 (9.75%) patients were male. Nephrotic syndrome was the most common renal presentation (53.66%). The most common histological class was Class IV A (75.61%). At the end of induction therapy, complete renal remission occurred in 31.7% of cases and partial remission in 34.14% of cases. Infections were the most common adverse events that occurred in 48.4% of cases.
Conclusions: Renal remission was observed in 65.85% of cases. Fixed low-dose cyclophosphamide-based induction can also be given over a 6-month period. Younger age was a significant risk factor for poor renal outcomes. Failure to achieve renal remission was a risk factor for mortality.
Keywords: Cyclophosphamide, induction treatment, lupus nephritis, remission
|How to cite this URL:|
Jayaprakash V, Dineshkumar T, Dhanapriya J, Rajasekar D, Sakthirajan R, Balasubramaniyan T, Kurien AA, Gopalakrishnan N. End of induction treatment outcomes with a novel cyclophosphamide-based regimen for severe lupus nephritis: Single-center experience from South India. Indian J Rheumatol [Epub ahead of print] [cited 2020 Apr 7]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=278757
| Introduction|| |
Lupus nephritis (LN) is a frequent complication of systemic lupus erythematosus (SLE). The disease is more common in females with female-to-male ratio of about 10:1, but the incidence of LN is almost equal between both genders. The disease onset peaks between the second and fourth decades of age. SLE is more often associated with severe nephritis in children and in males and is milder in older adults.,, SLE and LN are more common with more severe renal involvement in people from African descent, Asian, and Hispanic populations. The incidence of SLE ranges from 1.8 to 7.6 cases/100,000 and prevalence from 40 to 200 cases/100,000. Clinical renal disease at the onset of SLE will be present in 25%–50% of cases, whereas around 60% of adults with SLE will develop renal disease at some time during the disease course.,,
Histological classification of LN was proposed by the World Health Organization and the International Study of Kidney Disease in Children in the past, but the classification now in use was proposed in 2003 by the International Society of Nephrology (ISN) and the Renal Pathology Society (RPS). The ISN/RPS system provides more detailed and more precise pathologic criteria for each class, which facilitates greater reproducibility among pathologists. Patients with a higher activity index or chronicity index in biopsy are more likely to progress to renal failure.
Cyclophosphamide (CYC) is a commonly used induction agent in severe proliferative forms of LN. Adverse effects including fulminant infections can occur depending on the cumulative dose of CYC used for treatment. Not much data from the Indian subcontinent are available assessing the renal remission and adverse event profile in patients treated with IV CYC.
Historically, the study center treated proliferative forms of LN with high doses of intravenous (IV) cyclophosphamide as per the National Institutes of Health (NIH) protocol. The observation for several years was that the patients did not tolerate such high doses and mortality due to infectious diseases occurred rather than due to lupus activity. Hence, it was decided to go down on monthly cyclophosphamide dose to 500 mg without modifying the steroid dosing. Furthermore, monthly dosing could allow clinicians to detect infectious complications much earlier.
| Subjects and Methods|| |
It was an observational study done at the Institute of Nephrology, Madras Medical College, Chennai, over a period of 2 years. All patients with severe proliferative forms of LN (Class III A, Class III A + V, Class IV A, and Class IV A + V), who were treated with low-dose CYC-based induction treatment regimen, were included in the study. Patients who were treated with mycophenolate mofetil (MMF) as induction therapy, patients who had received CYC in the past, and patients who were initially treated with MMF and subsequently changed to CYC-based treatment regimen, were excluded.
In patients with clinical features suggestive of LN, renal biopsy was performed after necessary biochemical and serological investigations. For severe LN, CYC-based induction therapy which included monthly pulses of 500 mg IV CYC as infusion was given for 6 months. Before starting the first dose of IV CYC, all the patients received 1000 mg of pulse methylprednisolone (MP) for 3 consecutive days, followed by 1 mg/kg body weight of oral prednisolone for 1 month, followed by tapering at 5 mg/week to achieve a maintenance dose of 7.5 mg/day. Hydroxychloroquine sulfate, Angiotensin converting enzyme inhibitors/Angiotensin receptor blockers, and statins were prescribed as indicated.
Patients were reviewed fortnightly. Adverse effects during CYC therapy were identified and treated and the events were documented. Complete renal remission (CR) was defined as return to normal serum creatinine, along with inactive urine sediment and urine protein/creatinine ratio (PCR) <0.5. Partial remission (PR) was defined as a decrease in urine PCR to <3 in patients who had nephrotic-range proteinuria or a decrease in urine PCR by 50% in those who had baseline urine PCR <3, along with improvement or stabilization of serum creatinine. Renal remission rates of the illness were assessed at the end of 6 months. Adverse events during CYC therapy from individual patients were consolidated at the end of 6-month period. The institutional ethics committee clearance was obtained for the study (No. 14102015). Results were analyzed using Statistical Package for the Social Sciences (SPSS) version 16.0 software (SPSS Inc., Chicago, IL, USA). Descriptive analysis was done for the baseline characteristics and adverse event profile. The study population was divided into remission and 'no remission' groups, and baseline characteristics were compared to find the predictors for renal remission using Independent t-test. Fisher's exact test was used to find any association between renal remission and mortality. P < 0.05 was considered statistically significant.
| Results|| |
The study included 41 patients. Of them, 37 (90.24%) patients were female and 4 (9.75%) were male. The age group in the study population ranged from 11 to 52 years, with a mean age of 27.1 ± 9.24 years. The duration between the diagnosis of SLE and the onset of LN ranged from 0 month to 142 months, with the mean duration being 13.34 ± 27.19 months. Extrarenal features were present in 37 (90.24%) cases. Alopecia was the most common extrarenal feature present in 73.17% of cases, followed by joint pain (63.4%), fever (41.46%), oral ulcers (34.14%), malar rash (24.4%), seizures (4.88%), and serositis (2.45%).
The mean hemoglobin of the study population was 8.8 ± 1.62 g/dl. The mean total count and platelet count at presentation were 7185 ± 3001 cells/cumm and 1.76 ± 0.58 lakh cells/mm 3, respectively. The mean blood urea and serum creatinine were 53.15 ± 24.4 mg/dl and 2.25 ± 1.45 mg/dl, respectively. The baseline mean urine PCR was 8.8. Nephrotic syndrome was the most common renal presentation. The most common histological class was Class IV A [Table 1]. Crescentic glomerulonephritis was present in 6 (14.65%) cases and findings suggestive of vasculitis and TMA were present in one case each.
At the end of 6 months, systemic hypertension was persistent in 3 (8.33%) cases. The mean urine PCR was 1.96 ± 1.86 in all the surviving patients. The mean blood urea and serum creatinine at 6 months of follow-up were 28.64 ± 4.7 mg/dl and 0.96 ± 0.2 mg/dl, respectively. Five (12.2%) patients had worsening of GFR and all of them died.
CR was observed in 13 (31.7%) cases and PR in 14 (34.14%) cases. 34.14% (n = 14) of cases did not achieve renal remission [Table 2].
|Table 2: Comparison of clinical and lab parameters between remission and “no remission” groups|
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Subgroup analysis was done for juvenile age group and male gender. Both the groups had worse renal outcomes and mortality. Ten (24.39%) patients belonged to the adolescent age group (age <20 years). CR occurred in 3 cases, PR occurred in 1 case, and 4 cases did not attain remission. Two patients died during induction treatment period.
Two out of four male patients had crescentic glomerulonephritis. Three males died during the induction treatment period. The one who survived did not attain renal remission.
Major infective episode was defined as illness requiring inpatient antibiotic therapy. One major infective episode happened in 14 (34.14%) cases, 2 major infective episodes occurred in 2 (4.87%) patients, and 3 (7.31%) patients had 3 major infective episodes. Four (9.75%) patients had 1 episode of urinary tract infection (UTI), 1 had UTI twice, and 1 person had 3 episodes of UTI in the 6-month treatment period. Herpes zoster occurred in 5 (12.19%) cases, bacterial pneumonia in 4 (9.75%) cases, pulmonary tuberculosis and esophageal candidiasis in 2 cases (4.87%) each, and otitis media and acute gastroenteritis occurred in a case each. Twenty-one (51.2%) cases did not have any major infective episodes. Leukopenia was documented once in 2 (4.87%) patients during the 6-month treatment period. Steroid-induced diabetes mellitus occurred in one patient and one individual had steroid-induced cataract. Neurological adverse events occurred in 7 (17.07%) patients. Three patients had severe headache and four had generalized tonic–clonic seizures (GTCS), and among them, one had GTCS due to posterior reversible encephalopathy syndrome. Amenorrhea occurred in 12 (31.56%) females during induction therapy with CYC. Alopecia was present in 19 (46.34%) cases. Barring alopecia, 27 (65.85%) cases had at least one adverse event during the 6-month treatment period.
Younger age predicted worse renal outcomes (P = 0.024) (independent t-test) [Table 2]. Failure to attain renal remission was associated with mortality (P = 0.003) (Fisher's exact test). None of the other parameters predicted renal remission or mortality.
| Discussion|| |
Age, gender, and African race were important prognostic variables for patient and renal survival in SLE in some studies.,,, In a study including 65 patients with severe LN from NIH, clinical features at study entry associated with poor outcomes included age, patients from African descent, hematocrit < 26%, serum creatinine >2.4 mg/dl, activity index (>7), chronicity index (>3), presence of cellular crescents, and interstitial fibrosis in renal biopsy. In another study of 89 patients with diffuse proliferative LN, age, sex, duration of SLE duration, uncontrolled hypertension, or any individual histologic variable were not associated with poor outcomes. Entry serum creatinine >3.0 mg/dl, combined activity and chronicity indices on biopsy, and African American race predicted a poor outcome. Five-year renal survival rate was 95% for the Caucasian population, but only 58% for African American population. More rapid renal remission and CRs are associated with improved long-term prognosis., Renal flares during the course of SLE may predict poor renal outcome.,, Elevated dsDNA antibody titer and low serum complement levels do not correlate with long-term renal outcomes. Anemia has been a poor prognostic finding regardless of the underlying cause., Severe hypertension has been related to poor renal outcomes in some studies. Baseline heavy proteinuria and renal dysfunction are indicative of a poor renal prognosis in the vast majority of series. The duration of nephritis and rate of GFR decline may also predict prognosis.
CYC is a widely used induction agent for therapy in proliferative forms of LN. In trials conducted by NIH, the dose of CYC used was 0.5–1 g/m 2 per month in both induction and maintenance phases.,,,,, In the high-dose arm of Euro-Lupus Nephritis Trial (ELNT), the mean IV CYC dose was 8.5 ± 1.9 g totally, and in the low-dose arm, the dose was 3 g. ELNT study suggested that low dose CYC given in a shorter duration and followed by AZA maintenance, is an effective induction regimen with better side effect profile.
CYC dose should be reduced by 20%–30% in patients with moderate-to-severe renal insufficiency, and dose should be adjusted to keep the neutrophil count around 3000 cells/mm 3. Adverse events such as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), leukemia, cystitis, and gonadal toxicity occur with increasing cumulative doses of CYC.
Despite the use of CYC in the treatment of severe proliferative forms of LN for more than four decades, the dose and duration of therapy remain undefined. This can be related to the lack of well-designed randomized controlled trials (RCTs) comparing different CYC-based treatment regimens, enrolling patients from different ethnicities. This may be difficult in the future too, considering the technical difficulties in conducting clinical trials in LN. In multicentric and multinational trials, it may be difficult to ensure that a treatment and monitoring protocol is strictly and uniformly followed. A very long duration of observation may be necessary to reveal a difference in outcomes between different treatment arms and investigators have to be perseverant in their efforts for such a long period.
The present study population was compared with similar cohorts from landmark studies which had received same cumulative doses of IV CYC therapy , [Table 3]. Mean age, gender distribution, mean hemoglobin, and the incidence of hypertension were comparable across study cohorts. Baseline proteinuria, renal function, and biopsy features were worse in this study cohort.
|Table 3: Comparison of baseline characteristics, induction treatment regimen, and renal outcomes|
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In this study, all patients received the same dose of IV CYC, irrespective of baseline urine PCR, serum creatinine, or clinical presentation including RPRF/crescentic glomerulonephritis. Class IV A/IV A + 5 lesions constituted 82.93% of our study cohort. Isolated class V lesions were not included in our study population. Rathi et al. excluded patients with baseline serum creatinine ≥3 mg/dl, crescentic glomerulonephritis, and patients with neurological and pulmonary lupus. Class V lesions accounted for 28% of cases in CYC arm in his study. In low-dose IV CYC of ELNT, class V constituted 4.5% of the study population.
Renal remission rates at the end of 6 months were comparable with other similar cohorts [Table 3]. In another retrospective study from Sri Lanka which included 72 proliferative LN patients treated with ELNT regimen, CR was noted in 28% of cases and PR in 47% of cases.
All the three study groups received the same cumulative dose of CYC (3 grams) at the end of induction treatment period. Even though patients with higher mean proteinuria, baseline impaired renal function, presence of more aggressive renal biopsy lesions (when compared with the other 2 cohorts) were included in the study population, the rates of renal remission attained were comparable with the other similar cohorts.,,, Racial factors, subtle differences in steroid dosing, and timeline of assessing renal remission after CYC cumulative dose could have contributed to minor differences in the renal outcomes in the study cohorts.
Five (13.89%) patients, 2 males and 3 females, died during induction treatment. All the patients who succumbed to the illness had at least one major infective episode. Severe baseline disease characteristics in our study population could have contributed to increased mortality. Six patients (4 females and 2 males) had crescentic glomerulonephritis. Both males died due to infectious complications (bronchopneumonia and sepsis). Four females survived the induction treatment period. None had attained CR. Three attained PR and 1 did not attain renal remission. All patients (n = 36; 87.80%) who survived the induction phase in this study had either normal renal function or at least stabilization of baseline serum creatinine at the end of 6 months.
Adverse events during the induction therapy were documented and analyzed at the end of induction treatment period and compared with similar study cohorts [Table 4].
This study cohort had higher number of patients with alopecia (n = 19; 46.34%). Furthermore, it had increased number of female patients with transient amenorrhea (n = 12; 29.26%). There were no uniform definitions to define alopecia and amenorrhea and there could have been both subjective and objective variations in assessing them.
Outcomes of low-dose IV CYC for LN were comparable with those of MMF-based induction therapy in the Indian population, and day care therapy with IV CYC is advantageous in financially constraint public hospitals. To the best of our knowledge, this is the first study which has used low-dose IV CYC over a 6-month period (NIH protocol induction duration). The outcomes suggest that the low-dose IV CYC dose could also be given monthly, especially in centers which use NIH protocols for the treatment of proliferative LN and have experienced high infection rates.
The inherent drawbacks of any observational study apply to this study. Whether high doses of CYC would have led to far better renal outcomes and without increased adverse event profile could be ascertained only by properly designed multicentric RCTs with good sample size and long-term follow-up.
| Conclusions|| |
Renal remission was observed in 65.85% of cases and is comparable with published global data. The study suggests that fixed low-dose IV CYC could also be given over a 6-month period. Younger age was a significant risk factor for poor renal outcomes. Failure to achieve renal remission was a risk factor for mortality. Infections were the most common adverse events that occurred in 48.4% of patients during the induction treatment period.
We thank Dr. M. M. Kavitha, Associate Professor of Rheumatology, Saveetha Medical College, Chennai for reviewing this manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]