Efficacy and short term outcome of intravenous cyclophosphamide therapy in children with lupus nephritis: A tertiary hospital study of Bangladesh

Mohammad Imnul Islam; Asif Ali; Mousumi Ahmed

doi:10.4103/pnjb.pnjb_18_22

ORIGINAL ARTICLE

Year : 2022 | Volume : 7 | Issue : 2 | Page : 53-57

Efficacy and short term outcome of intravenous cyclophosphamide therapy in children with lupus nephritis: A tertiary hospital study of Bangladesh

Mohammad Imnul Islam, Asif Ali, Mousumi Ahmed
Department of Paediatrics, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh

Date of Submission	21-Jul-2022
Date of Acceptance	31-Aug-2022
Date of Web Publication	22-Nov-2022

Correspondence Address:
Dr. Mohammad Imnul Islam
Department of Paediatrics, Bangabandhu Sheikh Mujib Medical University, Dhaka
Bangladesh

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/pnjb.pnjb_18_22

Abstract

Background: Renal involvement is one of the most common and severe manifestations of paediatric systemic lupus erythematosus patients. Intravenous pulse cyclophosphamide (CYC) therapy is effective for lupus nephritis patients observed in different studies. Objective: To evaluate the efficacy and short term outcome of intravenous CYC therapy in renal involvement among paediatric SLE cases. Materials and Methods: This retrospective study was conducted at the department of Paediatrics, Bangabandhu Sheikh Mujib Medical University from January 2018 to December 2021. Sixty-two pSLE patients with renal involvement who met ACR revised classification criteria and completed their follow-up were enrolled in the study. All patients received intravenous CYC monthly for six months along with initially intravenous pulse methylprednisolone followed by oral prednisolone. During the study period, patients were monitored clinically and laboratory evaluations were done at baseline, 3^rd and after 6^th months of follow-up. Results: Among the cases, the female:male ratio was 5.9:1 and mean age was found 12.42 ± 2.13 years. After 3 months of CYC therapy, most patients were clinically improved in haematuria, hypertension, oedema, SLEDAI score and biochemically by ESR, C3, C4, S, Creatinine, Anti-ds-DNA titers, 24-hour urine protein. These initial improvements were further enhanced after 6 months of therapy. Short term outcomes demonstrated that 50%, 38.7% and 11.3% of patients had complete, partial and no responses respectively at the last follow-up. Conclusion: Intravenous CYC therapy effectively treated lupus nephritis patients observed in this study. Around 88% of pSLE patients had complete and partial responses according to EULAR criteria. Hypertension, ant-ds-DNA titers, proteinuria and serum complements were identified as a predictor of remission.

Keywords: Cylophosphamide therapy, lupus nephritis, short term outcome

How to cite this article:
Islam MI, Ali A, Ahmed M. Efficacy and short term outcome of intravenous cyclophosphamide therapy in children with lupus nephritis: A tertiary hospital study of Bangladesh. Paediatr Nephrol J Bangladesh 2022;7:53-7

How to cite this URL:
Islam MI, Ali A, Ahmed M. Efficacy and short term outcome of intravenous cyclophosphamide therapy in children with lupus nephritis: A tertiary hospital study of Bangladesh. Paediatr Nephrol J Bangladesh [serial online] 2022 [cited 2023 Mar 30];7:53-7. Available from: http://www.pnjb-online.org/text.asp?2022/7/2/53/361617

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disorder associated with multiple systems where any organ can be targeted.^[1] About 60–80% of children with SLE has Lupus nephritis (LN) and its increases the chance of renal failure, cardiovascular disease and death.^[2]

According to ACR (American College of Rheumatology) 1997 revised classification criteria for SLE, persistent proteinuria >0.5 gram/24 hour or cellular cast are the presenting features of renal involvement. Besides these patient may present with acute nephritis syndrome (hematuria, hypertension, and variable degree of proteinuria) or nephrotic syndrome (nephritic range protienuria, hyperlipidemia, hypoalbuminemia, and edema) or chronic kidney disease.^[3]

Goal of immunosuppressive therapy in LN children is to induce and sustain remission with minimize the adverse effect of drug therapy. A Recent study recommended that mycophenolate mofetil (MMF), calcineurin inhibitors, or their combination were most effective compared to intravenous cyclophosphamide (CYC) for inducing remission in pSLE with nephritis.^[4] From the end of 1980, Intravenous cyclophosphamide (CYC) pulse therapy has been used to treat lupus nephritis patients.^[5] The European League Against Rheumatism and ACR guidelines recommended CYC and mycophenolate mofetil for the initial management of lupus nephritis.^[6],[7] CYC therapy in combination with steroid was effective for moderate to severe proliferative LN observed in long term studies.^[8] This drug was reported as an essential and frequent regimen for successfully treating paediatric LN patients.^[9] The initial regimen recommended for the proliferative LN by the National Institute of Health (NIH) protocol included monthly pulse intravenous CYC for six months for remission induction followed by MMF or azathioprine as maintenance therapy.^[10]

However, in a resource constraint country like Bangladesh, CYC therapy is the most cost-effective option compare to MMF and others. In addition, very few patients are may be able to continue these drugs e.g. MMF for a long period of time. To the best of our knowledge, no such study was conducted in our country related to the effectiveness of CYC therapy in pSLE with renal involvement. So this study aimed to evaluate the efficacy and short term outcome of intravenous CYC therapy in children with lupus nephritis.

Materials and Methods

This was a retrospective study conducted at department of paediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU) from January 2018 to December 2021. Sixty two pSLE patients with renal involvement who met ACR revised classification criteria^[3] including proteinuria ≥ 500 mg in 24 h and/or urine routine examination showed active cellular casts/sediments [>5 RBC/high power field (HPF) and >5 WBC/HPF] and completed their follow-up were enrolled in the study. Informed consent has been taken before enrollment. All of them had biopsy proven class II, III, IV and V according to International Society of Nephrology/ Renal Pathology Society criteria^[11] except few cases who were severally ill at presentation. Patients who had treated previously with any other immunosuppressive drugs (such as cyclophosphamide, MMF, cyclosporine) and steroid 2 mg/kg/day for last 1 months were excluded from the study. Other exclusion criteria were severe infection, cerebral lupus, liver disease and anti phospholipid syndrome or with positive antiphospholipid antibodies.

Data were collected in a pre-designed structured questionnaire from web based data pool of paediatric rheumatology wing of this department. Relevant clinical examination and necessary laboratory investigations for SLE diagnosis were done at initial visit. Demographic details including age, sex and disease duration, clinical presentations and disease activity status- SLE disease activity index (SLEDAI)^[12] were recorded in the questionnaire. Baseline laboratory investigations including Hb%, total white cell count, differentials, platelet count, ESR, serum creatinine, serum ALT, lipid profiles, chest x-ray, urine routine analysis, 24-hour urine total protein (UTP), serum complement (C3,C4), anti-nuclear antibody(ANA), anti- double stranded DNA (anti ds-DNA) were done.

All patients received Intravenous CP (0.75 gm/m²) monthly for six months along with initially intravenous pulse methylprednisolone for 3 days followed by 1.5 mg/kg/day oral prednisolone for 4 weeks. Gradually steroid was tapered by 5 mg every 2 week interval until 30 mg/day and then 2.5 mg every 2 weeks interval until a maintenance dose of 5 mg/day was reached. Every patient administered hydroxychloroquine (5 mg/kg/day) after eye evaluation. Hypertension was treated with angiotensin-converting enzyme inhibitors and other appropriate drugs (Ca channel blockers etc).

During the study period, patients were monitored both clinically and laboratory evaluation at baseline, 3 months and 6 months of follow-up. We also compared treatment responses of CYC at 3 months and at the end of 6 months. European League Against Rheumatism (EULAR) recommended criteria for partial response, complete response and remission^[13] were used in this cohort to see the treatment response of CYC therapy. EULAR definition of partial response, complete response and remission are given below.

Complete response (CR)

Proteinuria < 0.2 g/day with normal GFR (>90 mL/min) or, if previously abnormal, improved to a stable level within 10% of normal GFR (≥81 mL/min) and inactive urinary sediment (<5 RBC/hpf or WBC/hpf [or <10/ mm³] and no cellular casts).

Partial response (PR)

Proteinuria ≤0.5 g/day with normal GFR (>90 mL/min) or, if previously abnormal, improved to a stable level within 10% of normal GFR (≥81 mL/min) and inactive urinary sediment.

Remission

A sustained response of at least 3–6 months, but it cannot be concluded to be a complete remission in the absence of a biopsy.

The Joint European League Against Rheumatism (EULAR) and the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) proposed repeat kidney biopsy 6-months after induction therapy for LN in children, but this has not been universally adopted.^[6] There are different school of thought for the repeat kidney biopsy among paediatric rheumatologists and also paediatric nephrologists in the different centers.^[14] In this cohort we were unable to do repeat biopsy in these patients due to some limitations.

Data were checked, verified, and analyzed by SPSS (statistical program for social science) software 20. Chi-square test was used to see the association between categorical data. A p-value of less than 0.05 was considered significant.

Result

A total 62 children were enrolled in this study. Among the cases, the female:male ratio was 5.9:1 and mean age was found 12.42 ± 2.13 years. Most of the patients were above 10 years of age (66.12%) and female predominant (85.5%) and 50% of patients had disease duration between 6–12 months. [Table 1] Baseline clinical and laboratory evaluations showed proteinuria (96.8%)was the most common clinical feature (77.4%) followed by oedema, hypertension and haematuria. ANA was positive in most (98.3%) of the patients and mean SLEDAI was 20.89 ± 4.45. [Table 2] Renal biopsy results showed class 4 (58.4%) were the most common types followed by class 2 and class 3 found in this cohort.[Table 3] After six months of intravenous CYC therapy, 50% of pSLE patients went into complete response, 38.7% of patients into partial response and 11.3% patient had no response according to EULAR criteria [Table 4].

Table 1: Demographic characteristics of Lupus nephritis patients (n = 62)

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Table 2: Clinical features and baseline investigations of Lupus nephritis patients (n = 62)

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Table 3: Class distribution of lupus nephritis among cases (n = 53)

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Table 4: Outcomes of lupus nephritis after IV CYC (n = 62)

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[Table 5] showing the comparison of clinical parameters at baseline, 3^rd and 6^th months of CYC therapy. Oedema, hypertension and SLEDAI were improved significantly after 3^rd and 6^th months of CYC therapy. Among the laboratory parameters including ESR, Anti ds-DNA and 24 hour UTP reduced significantly after 3^rd months and 6^th of IV CYC therapy. Comparison of renal predictor between response and non response group shown hypertension, serum complements, anti ds-DNA titers and 24 hour UTP reduced significantly in remission group [Table 6].

Table 5: Comparison of clinical and laboratory parameters at diagnosis with 3^rd and 6^th months after IV CYC (n = 62)

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Table 6: Comparison of renal predictors between response and non response group

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Discussion

It is difficult to determine the disease activity status and associated renal damage of LN patients because of the diversity and complexity of the clinical manifestations. Predicting the response to CYC for lupus nephritis is clinically important because the degree of response cannot be determined until several months after initiation of therapy^[6] and failure in response to therapy might result in outcomes that significantly worsen a patient’s quality of life and even threaten the life.^[7]

In the current study, the mean age of the patient was 12.42 ± 2.13 years and highest number of cases (66.12%) were found in the more than 10 years of age group. Hagelberg et al. in a Canadian study observed similar findings in their study where mean age of the patient’s was 13.2 year.^[15] Girls were found to be predominant with a female to male ratio 5.9:1 was found in this cohort. A Chinese study by Yuan F et al. observed a female to male ratio 6.8: 1 which was similar to our study.^[16]

A Turkish study by Odaman Al found macroscopic haematuria, hypertension, oedema and bedside urine albumin were 14.3%, 53.5%, 73.2% and 96.5% of lupus patients, respectively, at the time of diagnosis.^[17] These observations were similar to the present study results except for renal failure which was not found in the present study. In the present study mean SLEDAI score was 20.89 ± 4.45 which was consistent with the findings of a Japanese study by Igarashi 2013^[5] where their mean score was 18.8 ± 4.6 at baseline. Baskin et al. in a another Turkish study observed baseline laboratory results were relevant to the present study.^[18] They had ANA positivity in 90%, Anti-ds DNA in 85% and low complements in 85% of pSLE cases in their study.^[7] In this cohort, ANA positivity (98.3%), raised Anti-ds DNA titers, increased 24- hour urinary total protein and decreased serum complement (C3,C4) were documented. Chiu et al. in their Tawanian study also observed similar findings to our study.^[9]

The most frequent histopathological finding of lupus nephritis in our case was class IV nephritis (58.4%), followed by class II, class III and class V respectively. Odaman Al et al. also found almost similar histopathological findings. Majority of cases had Class IV lupus nephritis (53.5%), followed by class II, class III and class V nephritis respectively found in their study.^[16]

In this study, we have observed complete response, partial response and no response in 50%, 38.7% and 11.3% of pSLE patients respectively after 6^th months of CYC therapy. Radovan Bogdanovic et al. in their follow up study over a period of 18 year found that, remission achieved in 80% of patients, either complete (50%) or partial (30%) which is similar to our results.^[19] In another Indian study observed 84.6% of pSLE patients achieved remission (complete or partial) and 15.4% did not respond to therapy in one year follow- up study.^[20] Tangnararatchakit et al. found that 38.7% of pSLE had complete remission and 58% of them still had significant proteinuria and raised serum creatinine in their study.^[21] Sample size, outcome criteria and follow-up period of the above studies were not similar to the current study but outcome results were found to be more or less relevant to our study.

In the present study, after 3^rd and 6^th months of IV CYC therapy, haematuria, hypertension, oedema, mean SLEDAI score were significantly improved in comparison to baseline. Similarly, haemoglobin, ESR, complement levels (C3,C4), anti ds DNA titre, serum creatinine, 24 hour UTP all were significantly improved after 3^rd and 6^th months of initial therapy. A Thailand based study showed most of the LN patients were clinically improved after 3 months of treatment IV CYC therapy evidenced by significant improvements in 24-hour urinary total protein, serum creatinine, serum albumin and C3 level.^[21] On the other hand Lehman et al. in a one year follow-up study conducted at USA on childhood lupus nephritis^[22] and Chiu SJ et al. study conducted at Taiwan on adult lupus nephritis observed similar finding to our study after 6 months of initial IV CYC therapy.^[9]

Sidgel et al. in a Nepalese study reported that massive proteinuria, severe hypoalbuminemia and serum albumin were the significant parameters to attainment of remission.^[23] In this study, we observed hypertension, serum complements, anti ds DNA titer, 24 hour UTP were found significant predictors for remission after 6 months of IV CYC therapy. Emre S et al. in a study done at Turkey also found similar parameters which were significant in predicting remission.^[24] Hypertension, impaired renal function, anemia and nephrotic syndrome were the important predictors of remission observed in their study.

This center is the largest paediatric tertiary center where paediatric rheumatology services are accessible for the last 17 years. SLE diagnosis was validated for every patient, and the same group of paeditric rheumatologists made the validation, diminishing inclusion bias. Follow-up evaluations including clinical and laboratory results were well documented in the online data base except few cases. And retrospective nature is the limitation of the study.

Conclusion

From this study it may be concluded that IV CYC therapy was effective to treat lupus nephritis patients. Around 88% of pSLE patients had both complete and partial response according to EULAR criteria. This study identified hypertension, raising titres of ant-ds-DNA, proteinuria and low serum complements as predictors of remission.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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