Healthcost and Clinical Benefits of Rituximab in Steroid Sensitive Nephrotic Syndrome: Perspective From a Middle-Income Country (MyRITUX)

Healthcost and Clinical Benefits of Rituximab in Steroid Sensitive Nephrotic Syndrome: Perspective From a Middle-Income Country (MyRITUX) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Healthcost and Clinical Benefits of Rituximab in Steroid Sensitive Nephrotic Syndrome: Perspective From a Middle-Income Country (MyRITUX) Hai Liang Tan, Yok Chin Yap, Karmila Abu Bakar, Caroline Siew Yin Eng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3811963/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The use of Rituximab for frequently relapsing (FRNS) and steroid dependent nephrotic syndrome (SDNS) is increasingly established. However, the use of Rituximab in resource-limited settings is constrained by its prohibitive cost. Methods This retrospective study included all children aged 1 to 18 years with FRNS and SDNS. The costs incurred when using either Rituximab or cyclosporine were calculated and compared. Clinical data retrieved from medical records. Results Twelve patients received rituximab while 11 patients were treated with cyclosporine. Annualised relapse rate reduced from 5.07 to 1.52 in the Rituximab and 1.01 in the cyclosporine group. Total healthcost was MYR 75,339.81 in the rituximab group and MYR83,098.25 in the cyclosporine group. Cost to reduce one relapse with Rituximab was MYR 1,104.95 /episode compared to Cyclosporine, MYR 1,500.42 /episode. We observed greater reduction in the amount of prednisolone use in the rituximab group (114.33mg/kg versus 99.91mg/kg in the cyclosporine group). Both demonstrated significant reduction in their body mass index z score. There were no infusion related reactions in the rituximab group and cyclosporin was also well tolerated. Conclusion This is the first study to compare the healthcare costs of using rituximab to be carried out in a middle income country. Findings suggest that in such setting, a single infusion of Rituximab as a steroid sparing agent among children with steroid sensitive nephrotic syndrome remains efficacious and feasible. Figures Figure 1 INTRODUCTION Idiopathic childhood nephrotic syndrome (NS) is the most commonly encountered glomerular disease in children. The majority of affected children are steroid sensitive and respond well to glucocorticoid therapy. About 50% of these children would develop frequent relapses and become steroid dependent. [ 1 ]However, the prolonged use of high dose glucocorticoids is associated with an array of adverse effects and toxicities.[ 2 ] These include increased appetite and weight gain, posterior subcapsular cataract, rise in intraocular pressure, hypertension, hyperglycaemia, infection and insulin resistance, Cushing-like syndrome, aggression/neuropsychiatric problems, peptic ulcers and even osteoporosis. It is evident that the need for steroid sparing agents is crucial in the management of these children. Nevertheless, a clinical dilemma exists between maintaining remission and minimizing complications from treatment. Calcineurin inhibitor (CNI) such as cyclosporine, has been established as a first line steroid sparing agent despite the fact that there are known adverse events and up to 5% of patients develop nephrotoxicity.[ 3 ] Thus far, B lymphocyte-depleting therapy has been increasingly used in the developed world, both as a second line steroid sparing agent in children who tried CNI and potentially, even in children who develop dependency for CNI or CNI toxicity. Rituximab has been shown to have excellent efficacy and good safety profile.[ 4 – 8 ] Despite its excellent safety profile and efficacy, many centres tend to reserve Rituximab only for selected cases due to its prohibitive cost. A study done in the Japanese adult population showed that Rituximab has superior cost effectiveness compared to CNI while another involving paediatric population in the US showed similar expenditure in both the Rituximab and CNI groups.[ 9 – 10 ] These cost-analyses studies are mainly conducted in the high-income countries. Due to the varied medicine and healthcare costs in different regions, there is a need for studies that look into locally applicable data in order to guide resource decisions. The main objective of this study is to compare healthcare costs of Rituximab against Cyclosporine when used as steroid sparing agents in steroid sensitive nephrotic syndrome in the setting of a public funded middle-income country. METHODOLOGY Study design This is a retrospective study that included all children aged 1 to 18 years who had steroid dependent nephrotic / frequently relapsing syndrome and were treated with either cyclosporine and/or rituximab from January 2015 to June 2021 at Hospital Tunku Azizah, Kuala Lumpur and Hospital Tuanku Ja’afar, Seremban. Data was retrieved from the hospital electronic database. All patients were followed up for a minimum of 12 months. This study was approved by the Medical Research Ethics Committee and registered with the National Medical Research Registry (NMRR ID: NMRR ID-22-00320-57C) Inclusion and exclusion criteria The inclusion criteria for the study were children aged ≥ 2 to < 18 years with the diagnosis of steroid sensitive idiopathic NS. Children with impaired renal function (estimated glomerular filtration rate, eGFR < 60mls/min1.73m 2 ), steroid resistant nephrotic syndrome, secondary causes of nephrotic syndrome and concomitant use of other immunosuppressive medication such as mycophenolate mofetil (MMF) were excluded. Definitions Nephrotic-range proteinuria Urinary protein creatinine ratio (UPCR) ≥ 200 mg/mmol (2 mg/mg) in a spot urine, or proteinuria ≥ 1000 mg/m2 per day in a 24-h urine sample corresponding to 3 + (300–1000 mg/dL) or 4 + (≥ 1000 mg/dL) by urine dipstick Nephrotic syndrome Nephrotic-range proteinuria and either hypoalbuminemia (serum albumin < 30 g/L) or oedema when serum albumin is not available Complete remission UPCR (based on first morning void or 24 h urine sample) ≤ 20 mg/mmol (0.2 mg/mg) or < 100 mg/m2 per day, respectively, or negative or trace dipstick on three or more consecutive days. Steroid-sensitive nephrotic syndrome (SSNS) Complete remission within 4 weeks of prednisolone at standard dose (60 mg/m2/day or 2 mg/kg/day, maximum 60 mg/day) Steroid-resistant nephrotic syndrome (SRNS) Lack of complete remission within 4 weeks of treatment with prednisolone at standard dose [ 11 ] Treatment protocol Steroid At initial diagnosis, all patients were treated with a standard regimen of oral prednisolone at a dose of 60 mg/m 2 daily for an initial 4 weeks followed by alternate day prednisolone of 40mg/m 2 for 4 weeks and then tapered over 4 weeks for total treatment of 12 weeks duration. Relapse was treated with oral prednisolone at a daily dose of 60 mg/m 2 (maximum 60 mg/ day) until remission then the dose of steroid was then reduced to 40 mg/m 2 on alternate days (maximum 40 mg/day) and tapered off. Cyclosporine Patients were given cyclosporine at the time of entering remission as a steroid sparing agent. The cyclosporine dose was 3–5 mg/kg (150 mg/m 2 ) divided in two doses per day. A trough level of 80–100 ng/ml was desirable and the lowest possible dose to maintain remission was preferred. Steroids were tapered as above while patients commenced on cyclosporine.[ 12 – 13 ] Rituximab In both centres, Rituximab was reserved for patients with steroid dependent or frequent relapses who had responded poorly to at least 2 other immunosuppressive therapies. Rituximab was administered after the patient achieved remission. All patients were admitted for the infusion. A single dose of 375 mg/m 2 rituximab was given. Rituximab was diluted in normal saline at a concentration of 1mg/ml and infused over 8–10 hours. Thirty minutes before infusion, patients were premedicated with intravenous hydrocortisone/ methylprednisolone, paracetamol and chlorpheniramine. Pre-infusion screening included serology testing for Hepatitis B, Hepatitis C and chest radiograph to look for evidence of latent tuberculosis. We avoided the use of rituximab in patients who did not receive Bacille-Calmette Guerin (BCG) vaccination in view of the endemic nature of tuberculosis in our country. Primary and secondary endpoints Costs Data for costs referred to readily measurable healthcare related expenditure. In this manuscript, healthcare cost refers to the summation of expenditure incurred for laboratory tests, outpatient consultation (unscheduled emergency department visit inclusive) and inpatient admission. The cost of the study medication (Rituximab and Cyclosporine) were also obtained. This refers to the cost of the drug itself, cost of screening pre-infusion as well as hospital admission for infusion (Rituximab) and cost of routine clinic visits and trough monitoring (Cyclosporine). Ratio of cost of the study medication and number of relapses were calculated to reflect the cost to reduce one relapse in this study. Unit cost was derived from the charges information that would appear in the patient’s hospital bill in a subsidized public health institution. In a fully funded institution, this cost would be totally absorbed by the public healthcare programme. Efficacy Parameters on efficacy of treatment drugs were number of relapses, number of hospital admissions, cumulative amount of corticosteroids prescribed and body mass index z-score (BMI) before and after starting the treatment drug. Adverse effects of medications and occurrence of infection throughout the study period were monitored. In view of the relapsing remitting nature of the disease, annualised relapse rate was calculated as the number of relapses experienced by that patient divided by the number of days the patient participated in the study, and the ratio multiplied by 365.25. Statistical methodology We described continuous data as median (interquartile range, IQR) and categorical variables in percentages. Wherever possible, demographic parameters were expressed as z-scores. Tests for normality were conducted with the Shapiro–Wilk test. Comparison between groups were performed using either the Mann-Whitney U or simple t- test. Level of significance was set at P < 0.05. All statistical analysis was performed using the SPSS software, version 23.0 (SPSS Inc., Chicago, IL, USA). RESULTS Demographics of the study population A total of 23 children were included in the study (Table 1 ). Twelve children were given a single dose of Rituximab as a steroid sparing agent while another 11 children received cyclosporine. Table 1 Clinical characteristics of rituximab and cyclosporine groups RTX (n = 12) CSA (n = 11) Age in years (median, IQR) 12.0 (8.9–14.3) 5.7 (3.9–10.4) Gender, n (%) Male Female 9 (75) 3 (25) 8 (72.7) 3 (27.3) Ethnicity 7 Malay, 3 Indian, 1 Chinese 9 Malay, 2 Chinese Disease duration in years (median, IQR) 6.9 (4.9–10.1) 1.8 (0.6–7.6) Costs Unit cost for rituximab at the time of study was MYR4321.50 (USD 907.52) per vial of 500mg. The cost for 25mg and 100mg of cyclosporine were MYR3.25 (USD 0.68) and MYR13.00 (USD 2.73) respectively. Total cost of the study medication was MYR48,617.98 ( USD 10,209.78 ) in the rituximab group and MYR70,519.85 ( USD 14,809.17 ) in the cyclosporine group. This amount spent reduced the number of relapses by 44 episodes and 47 episodes respectively. Incorporating this cost and its associated healthcare cost, we observe that the figure was lower in the rituximab group compared to the cyclosporine group. (See Fig. 1 and Table 2 ). {At the time of writing, MYR1 equals USD0.21 (11th December 2023)} Table 2 Costing measurements (Values in Malaysian Ringgit, MYR) RTX (n = 12) CSA (n = 11) Median healthcare cost per patient (pre) 3,399.01 (1,712.41-6278.63) USD 713.78 (359.60–1318.51) 2,315.61 (1,357.76-3,556.11) USD 486.28 ( 285.13-746.78) Median healthcare cost per patient (post) 5,315.26 (4,494.94 -7,846.71) USD 1,116.20 (943.93- 1,647.80) 6,192.59 (5,604.62 -11,110.78) USD 1,300.44 (1,176.97-2,333.26) Median Cost of study medication per patient 4,577.27 (3,388.86- 4,577.29) USD 961.23 (711.66-961.23) 5,026.75 (4,926.75–8,821.81) USD 1,055.62 (1,034.62-1,852.58) Total cost of the study medication 48,617.98 USD 10,209.78 70,519.85 USD 14,809.17 Total cost of the study medication + healthcare cost (post) 75,339.81 USD 15,821.36 83,098.25 USD 17,450.63 Cost to reduce one relapse in this study 44 episodes in RTX group; 47 episodes in CSA group 1,104.95 USD 232.04 1,500.42 USD 315.09 We inferred that the cost to reduce one relapse in our cohort was relatively cheaper with Rituximab, MYR 1,104.95 (USD 232.04) /episode compared to Cyclosporine, MYR 1,500.42 (USD 315.09) /episode. Efficacy of treatment The total number of relapses reduced significantly in both groups. The median annualised relapse rate was 5.07 (4.06–6.85) and 5.07 (5.07–6.09) before treatment for the Rituximab and Cyclosporine group respectively. Post treatment (at the end of 12 months), the median annualised relapse rate reduced to 1.52 (0.00–2.79) and 1.01 (0.00–1.01) respectively. (See Table 3 ). Table 3 Efficacy parameters RTX (n = 12) p* CSA (n = 11) p* Number of relapses (pre) 64 p < 0.001 60 p < 0.001 Number of relapses (post) 20 13 Number of reduction in relapses 44 47 Annualised relapse rate (median(IQR); pre) 5.07(4.06–6.85) 5.07(5.07–6.09) Annualised relapse rate (median(IQR); post) 1.52 (0.00–2.79) 1.01(0.00-1.01) Number of admissions (pre) 25 p = 0.089 16 p = 0.016 Number of admissions (post) 13 1 Cumulative prednisolone dose mg/kg (median; pre) 189.28 (160.15- 248.72) p = 0.097 164.10 (133.69–249.34) p = 0.008 Cumulative prednisolone dose mg/kg (median; post) 74.95 (25.89–138.23) 64.19 (36.67–79.78) BMI z-score kgm − 2 (median; pre) 1.12 (-0.15 to 2.09) p = 0.007 1.78 (0.53 to 2.42) p = 0.039 BMI z-score kgm − 2 (median; post) 0.63 (-0.825 to 1.72) 1.55 (-0.41 to 2.11) * comparison of p is performed within the group (pre- and post- treatment) There were no infusion related reactions in the rituximab group and cyclosporine was also well tolerated. One patient reported to have community acquired pneumonia in the RTX group but recovered well soon after discharge; this may be an unrelated adverse effect. DISCUSSION Cyclosporine is used commonly in our country as a steroid sparing agent among steroid sensitive nephrotic syndrome children who continue to relapse after given a trial of either levamisole, cyclophosphamide or both. Rituximab is reserved for children who continue to relapse despite multiple immunosuppressive medications including cyclosporine. Analysing real-world data, the cohort of patients in the Rituximab group were older and had a longer disease vintage compared to the cyclosporine group. The rituximab group also had more relapses, hospital admissions as well as more exposure to steroids at baseline. The total healthcare cost (pre) for patients was higher in the Rituximab group as expected due to the more complicated course of disease. In both groups, overall cost of treatment incurred (cost of the study medication and associated healthcare cost) was higher after introduction of the studied steroid sparing agents due to the high cost of the respective drugs. Nevertheless, it is evident that the increment in this cost was lower in the Rituximab group compared to the Cyclosporine group. The recurring dosing of Cyclosporine over a period of 1 year and the need for regular monitoring of trough levels potentially contributed to this observation. Iorember et al[ 10 ] reported a comparable expenditure of Rituximab and calcineurin inhibitors (either Cyclosporine or Tacrolimus) in a retrospective analysis of their practice at Louisiana. In another population study in Far East Asia, Takura et al[ 9 ] demonstrated evidence of effectiveness, shown by reduced number of relapses and reduced total medical costs, which collectively supported cost-effectiveness of Rituximab in clinical practice. Our data showed that the cost to reduce one relapse was lower in Rituximab. This is potentially an important piece of information to consider when determining distribution of resources. In Malaysia, provision of healthcare at public health facilities is heavily subsidized by the government. Although a parallel private healthcare pathway is available, the burden on the public funding remains steep.[ 14 ] To our knowledge, this is the first study looking at cost parameters for Rituximab use in children with nephrotic syndrome in our country. The secondary outcome of this study was to evaluate the practice of using a single dose of Rituximab to maintain remission in this group of children by comparing it with the existing standard therapy in our setting which is Cyclosporine. Single dose of Rituximab has been reported to be effective literature. In this study, performance of Rituximab is comparable to that of Cyclosporine as illustrated by the significant reduction of number of relapses, the annual relapse rate and improvement in body mass index z-score. Disease burden that affects the psychosocial development of the patients and the dynamics of the affected families is an important entity. Incorporating health-related quality of life and patient-reported outcomes is the key to any successful health programme. It is evident from literature that children with idiopathic nephrotic syndrome have lower health-related quality life scores. Those with prolonged disease vintage and difficult to treat phenotypes have poorer quality.[ 15 – 18 ] In our study, reduction in hospital admission, relapses and improvement in BMI z-scores are indirect markers to suggest possible improvement in quality of life. The limitations of our study include its retrospective nature and the small sample size. In real-world practice, the utility of Rituximab is prohibited by its seemingly high cost. In addition, many aspects of quality-adjusted life year (QALY) in children are not fully developed yet and this limits analysis of the pharmacoeconomic aspects of Rituximab in our study.[ 19 – 22 ] Nevertheless, the findings from our study suggest data to support its use even in a middle-income country. In conclusion, a single dose infusion of Rituximab as a steroid sparing agent among children with steroid sensitive nephrotic syndrome is efficacious and feasible, even in a middle-income country. Clinicians should consider the benefits of maintaining remission in these children from medical as well as psychosocial perspectives and not be hindered by the seemingly high cost of treatment. 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Oxford university press Hawthorne G, Richardson J, Osborne R (1999) The Assessment of Quality of Life (AQoL) instrument: a psychometric measure of Health-Related Quality of Life. Qual Life Res 8:209–224. https://doi.org/10.1023/A:1008815005736 Petrou S (2022) Methodological challenges surrounding QALY estimation for paediatric economic evaluation. Cost Eff Resour Alloc 20:10. https://doi.org/10.1186/s12962-022-00345-4 Thorrington D, Eames K (2015) Measuring Health Utilities in Children and Adolescents: A Systematic Review of the Literature. PLoS ONE 10(8):e0135672. https://doi.org/10.1371/journal.pone.0135672 Supplementary Files MyRITUXvisualabstract.png Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3811963","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":264168682,"identity":"59d10cb9-715e-41c5-ad8b-5e5f8546c53b","order_by":0,"name":"Hai Liang Tan","email":"","orcid":"","institution":"Hospital Tuanku Ja'afar Seremban","correspondingAuthor":false,"prefix":"","firstName":"Hai","middleName":"Liang","lastName":"Tan","suffix":""},{"id":264168683,"identity":"fa2a8e73-0e4c-4ac4-9394-a099a51964d4","order_by":1,"name":"Yok Chin Yap","email":"","orcid":"","institution":"Hospital Kuala Lumpur","correspondingAuthor":false,"prefix":"","firstName":"Yok","middleName":"Chin","lastName":"Yap","suffix":""},{"id":264168684,"identity":"46700dae-3c0a-4e58-9455-e6b8fe40e2ec","order_by":2,"name":"Karmila Abu Bakar","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYBACCRCRUMAgB+bxEK/FgMGYRC0MBgyJDURrkWw/+3TDAwO79A3XDjA+eNvGEG1wgIAWaZ50sxsJBsm5G24nMBvObWPI3UBIixxDGhtQCzNIC5s0L1Fa+J+BtNSnG9xOYP9NlBZpCbAthxOAWtiYidIiOQNsy3HDmbcTmyXnnJPInUlIi8T5NLabPyqq5fluJx/88KbMJrePkBYkwNgAMoJBgQQtUCDfQLKWUTAKRsEoGOYAAPkwQnDLpZpaAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-6272-4969","institution":"Universiti Malaya Fakulti Perubatan: University of Malaya Faculty of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Karmila","middleName":"Abu","lastName":"Bakar","suffix":""},{"id":264168685,"identity":"8291b96a-071a-4937-912e-0ba5db92d002","order_by":3,"name":"Caroline Siew Yin Eng","email":"","orcid":"https://orcid.org/0000-0001-9805-3730","institution":"Hospital Tuanku Ja'afar Seremban","correspondingAuthor":false,"prefix":"","firstName":"Caroline","middleName":"Siew Yin","lastName":"Eng","suffix":""}],"badges":[],"createdAt":"2023-12-27 11:21:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3811963/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3811963/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49133936,"identity":"ee728cef-f64b-4657-a86e-eb3e65c43c18","added_by":"auto","created_at":"2024-01-03 16:48:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":265753,"visible":true,"origin":"","legend":"\u003cp\u003eMedian healthcare cost per patient per year (cost of study medication inclusive)\u003c/p\u003e","description":"","filename":"figure1myrtx.png","url":"https://assets-eu.researchsquare.com/files/rs-3811963/v1/3ff2c2516a19d3b4c8a8ebb9.png"},{"id":50274124,"identity":"54a7d2c8-fa08-4c9c-a94b-809767557c20","added_by":"auto","created_at":"2024-01-28 22:16:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":467431,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3811963/v1/eaec9d84-4b51-4ec3-b95b-4897e91e1b32.pdf"},{"id":49133935,"identity":"6c6280fa-e892-4488-aba6-09489fb85b6e","added_by":"auto","created_at":"2024-01-03 16:48:51","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":969544,"visible":true,"origin":"","legend":"","description":"","filename":"MyRITUXvisualabstract.png","url":"https://assets-eu.researchsquare.com/files/rs-3811963/v1/aff0903040022601a3917042.png"}],"financialInterests":"","formattedTitle":"\u003cp\u003eHealthcost and Clinical Benefits of Rituximab in Steroid Sensitive Nephrotic Syndrome: Perspective From a Middle-Income Country (MyRITUX)\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eIdiopathic childhood nephrotic syndrome (NS) is the most commonly encountered glomerular disease in children. The majority of affected children are steroid sensitive and respond well to glucocorticoid therapy. About 50% of these children would develop frequent relapses and become steroid dependent. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]However, the prolonged use of high dose glucocorticoids is associated with an array of adverse effects and toxicities.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] These include increased appetite and weight gain, posterior subcapsular cataract, rise in intraocular pressure, hypertension, hyperglycaemia, infection and insulin resistance, Cushing-like syndrome, aggression/neuropsychiatric problems, peptic ulcers and even osteoporosis. It is evident that the need for steroid sparing agents is crucial in the management of these children. Nevertheless, a clinical dilemma exists between maintaining remission and minimizing complications from treatment.\u003c/p\u003e \u003cp\u003eCalcineurin inhibitor (CNI) such as cyclosporine, has been established as a first line steroid sparing agent despite the fact that there are known adverse events and up to 5% of patients develop nephrotoxicity.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Thus far, B lymphocyte-depleting therapy has been increasingly used in the developed world, both as a second line steroid sparing agent in children who tried CNI and potentially, even in children who develop dependency for CNI or CNI toxicity. Rituximab has been shown to have excellent efficacy and good safety profile.[\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eDespite its excellent safety profile and efficacy, many centres tend to reserve Rituximab only for selected cases due to its prohibitive cost. A study done in the Japanese adult population showed that Rituximab has superior cost effectiveness compared to CNI while another involving paediatric population in the US showed similar expenditure in both the Rituximab and CNI groups.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] These cost-analyses studies are mainly conducted in the high-income countries. Due to the varied medicine and healthcare costs in different regions, there is a need for studies that look into locally applicable data in order to guide resource decisions. The main objective of this study is to compare healthcare costs of Rituximab against Cyclosporine when used as steroid sparing agents in steroid sensitive nephrotic syndrome in the setting of a public funded middle-income country.\u003c/p\u003e"},{"header":"METHODOLOGY","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis is a retrospective study that included all children aged 1 to 18 years who had steroid dependent nephrotic / frequently relapsing syndrome and were treated with either cyclosporine and/or rituximab from January 2015 to June 2021 at Hospital Tunku Azizah, Kuala Lumpur and Hospital Tuanku Ja\u0026rsquo;afar, Seremban. Data was retrieved from the hospital electronic database. All patients were followed up for a minimum of 12 months. This study was approved by the Medical Research Ethics Committee and registered with the National Medical Research Registry (NMRR ID: NMRR ID-22-00320-57C)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eInclusion and exclusion criteria\u003c/h2\u003e \u003cp\u003eThe inclusion criteria for the study were children aged\u0026thinsp;\u0026ge;\u0026thinsp;2 to \u0026lt;\u0026thinsp;18 years with the diagnosis of steroid sensitive idiopathic NS. Children with impaired renal function (estimated glomerular filtration rate, eGFR\u0026thinsp;\u0026lt;\u0026thinsp;60mls/min1.73m\u003csup\u003e2\u003c/sup\u003e), steroid resistant nephrotic syndrome, secondary causes of nephrotic syndrome and concomitant use of other immunosuppressive medication such as mycophenolate mofetil (MMF) were excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDefinitions\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eNephrotic-range proteinuria\u003c/h2\u003e \u003cp\u003eUrinary protein creatinine ratio (UPCR)\u0026thinsp;\u0026ge;\u0026thinsp;200 mg/mmol (2 mg/mg) in a spot urine, or proteinuria\u0026thinsp;\u0026ge;\u0026thinsp;1000 mg/m2 per day in a 24-h urine sample corresponding to 3 + (300\u0026ndash;1000 mg/dL) or 4 + (\u0026ge;\u0026thinsp;1000 mg/dL) by urine dipstick\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eNephrotic syndrome\u003c/h2\u003e \u003cp\u003eNephrotic-range proteinuria and either hypoalbuminemia (serum albumin\u0026thinsp;\u0026lt;\u0026thinsp;30 g/L) or oedema when serum albumin is not available\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eComplete remission\u003c/h2\u003e \u003cp\u003eUPCR (based on first morning void or 24 h urine sample)\u0026thinsp;\u0026le;\u0026thinsp;20 mg/mmol (0.2 mg/mg) or \u0026lt;\u0026thinsp;100 mg/m2 per day, respectively, or negative or trace dipstick on three or more consecutive days.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSteroid-sensitive nephrotic syndrome (SSNS)\u003c/h2\u003e \u003cp\u003eComplete remission within 4 weeks of prednisolone at standard dose (60 mg/m2/day or 2 mg/kg/day, maximum 60 mg/day)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSteroid-resistant nephrotic syndrome (SRNS)\u003c/h2\u003e \u003cp\u003eLack of complete remission within 4 weeks of treatment with prednisolone at standard dose [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eTreatment protocol\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003eSteroid\u003c/h2\u003e \u003cp\u003eAt initial diagnosis, all patients were treated with a standard regimen of oral prednisolone at a dose of 60 mg/m\u003csup\u003e2\u003c/sup\u003e daily for an initial 4 weeks followed by alternate day prednisolone of 40mg/m\u003csup\u003e2\u003c/sup\u003e for 4 weeks and then tapered over 4 weeks for total treatment of 12 weeks duration. Relapse was treated with oral prednisolone at a daily dose of 60 mg/m\u003csup\u003e2\u003c/sup\u003e (maximum 60 mg/ day) until remission then the dose of steroid was then reduced to 40 mg/m\u003csup\u003e2\u003c/sup\u003e on alternate days (maximum 40 mg/day) and tapered off.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eCyclosporine\u003c/h2\u003e \u003cp\u003ePatients were given cyclosporine at the time of entering remission as a steroid sparing agent. The cyclosporine dose was 3\u0026ndash;5 mg/kg (150 mg/m\u003csup\u003e2\u003c/sup\u003e) divided in two doses per day. A trough level of 80\u0026ndash;100 ng/ml was desirable and the lowest possible dose to maintain remission was preferred. Steroids were tapered as above while patients commenced on cyclosporine.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eRituximab\u003c/h2\u003e \u003cp\u003eIn both centres, Rituximab was reserved for patients with steroid dependent or frequent relapses who had responded poorly to at least 2 other immunosuppressive therapies.\u003c/p\u003e \u003cp\u003eRituximab was administered after the patient achieved remission. All patients were admitted for the infusion. A single dose of 375 mg/m\u003csup\u003e2\u003c/sup\u003e rituximab was given. Rituximab was diluted in normal saline at a concentration of 1mg/ml and infused over 8\u0026ndash;10 hours. Thirty minutes before infusion, patients were premedicated with intravenous hydrocortisone/ methylprednisolone, paracetamol and chlorpheniramine.\u003c/p\u003e \u003cp\u003ePre-infusion screening included serology testing for Hepatitis B, Hepatitis C and chest radiograph to look for evidence of latent tuberculosis. We avoided the use of rituximab in patients who did not receive Bacille-Calmette Guerin (BCG) vaccination in view of the endemic nature of tuberculosis in our country.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003ePrimary and secondary endpoints\u003c/h2\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003eCosts\u003c/h2\u003e \u003cp\u003eData for costs referred to readily measurable healthcare related expenditure. In this manuscript, healthcare cost refers to the summation of expenditure incurred for laboratory tests, outpatient consultation (unscheduled emergency department visit inclusive) and inpatient admission. The cost of the study medication (Rituximab and Cyclosporine) were also obtained. This refers to the cost of the drug itself, cost of screening pre-infusion as well as hospital admission for infusion (Rituximab) and cost of routine clinic visits and trough monitoring (Cyclosporine). Ratio of cost of the study medication and number of relapses were calculated to reflect the cost to reduce one relapse in this study. Unit cost was derived from the charges information that would appear in the patient\u0026rsquo;s hospital bill in a subsidized public health institution. In a fully funded institution, this cost would be totally absorbed by the public healthcare programme.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy\u003c/h2\u003e \u003cp\u003eParameters on efficacy of treatment drugs were number of relapses, number of hospital admissions, cumulative amount of corticosteroids prescribed and body mass index z-score (BMI) before and after starting the treatment drug. Adverse effects of medications and occurrence of infection throughout the study period were monitored. In view of the relapsing remitting nature of the disease, annualised relapse rate was calculated as the number of relapses experienced by that patient divided by the number of days the patient participated in the study, and the ratio multiplied by 365.25.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methodology\u003c/h2\u003e \u003cp\u003eWe described continuous data as median (interquartile range, IQR) and categorical variables in percentages. Wherever possible, demographic parameters were expressed as z-scores. Tests for normality were conducted with the Shapiro\u0026ndash;Wilk test. Comparison between groups were performed using either the Mann-Whitney U or simple t- test. Level of significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All statistical analysis was performed using the SPSS software, version 23.0 (SPSS Inc., Chicago, IL, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eDemographics of the study population\u003c/h2\u003e \u003cp\u003eA total of 23 children were included in the study (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Twelve children were given a single dose of Rituximab as a steroid sparing agent while another 11 children received cyclosporine.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical characteristics of rituximab and cyclosporine groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRTX (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCSA (n\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge in years (median, IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.0 (8.9\u0026ndash;14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.7 (3.9\u0026ndash;10.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, n (%)\u003c/p\u003e \u003cp\u003eMale\u003c/p\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (75)\u003c/p\u003e \u003cp\u003e3 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (72.7)\u003c/p\u003e \u003cp\u003e3 (27.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEthnicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 Malay, 3 Indian, 1 Chinese\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 Malay, 2 Chinese\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease duration in years (median, IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.9 (4.9\u0026ndash;10.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.8 (0.6\u0026ndash;7.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eCosts\u003c/h2\u003e \u003cp\u003eUnit cost for rituximab at the time of study was MYR4321.50 (USD 907.52) per vial of 500mg. The cost for 25mg and 100mg of cyclosporine were MYR3.25 (USD 0.68) and MYR13.00 (USD 2.73) respectively. Total cost of the study medication was MYR48,617.98 (\u003cem\u003eUSD 10,209.78\u003c/em\u003e) in the rituximab group and MYR70,519.85 (\u003cem\u003eUSD 14,809.17\u003c/em\u003e ) in the cyclosporine group. This amount spent reduced the number of relapses by 44 episodes and 47 episodes respectively. Incorporating this cost and its associated healthcare cost, we observe that the figure was lower in the rituximab group compared to the cyclosporine group. (See Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003e{At the time of writing, MYR1 equals USD0.21 (11th December 2023)}\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCosting measurements (Values in Malaysian Ringgit, MYR)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRTX (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCSA (n\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian healthcare cost per patient (pre)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3,399.01\u003c/p\u003e \u003cp\u003e(1,712.41-6278.63)\u003c/p\u003e \u003cp\u003e\u003cem\u003eUSD 713.78\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003e(359.60\u0026ndash;1318.51)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2,315.61\u003c/p\u003e \u003cp\u003e(1,357.76-3,556.11)\u003c/p\u003e \u003cp\u003e\u003cem\u003eUSD 486.28\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003e( 285.13-746.78)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian\u0026nbsp; healthcare cost per patient (post)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5,315.26\u003c/p\u003e \u003cp\u003e(4,494.94 -7,846.71)\u003c/p\u003e \u003cp\u003e\u003cem\u003eUSD 1,116.20\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003e(943.93- 1,647.80)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6,192.59\u003c/p\u003e \u003cp\u003e(5,604.62 -11,110.78)\u003c/p\u003e \u003cp\u003e\u003cem\u003eUSD 1,300.44\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003e(1,176.97-2,333.26)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Cost of study medication per patient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4,577.27\u003c/p\u003e \u003cp\u003e(3,388.86- 4,577.29)\u003c/p\u003e \u003cp\u003e\u003cem\u003eUSD 961.23\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003e(711.66-961.23)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5,026.75\u003c/p\u003e \u003cp\u003e(4,926.75\u0026ndash;8,821.81)\u003c/p\u003e \u003cp\u003e\u003cem\u003eUSD 1,055.62\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003e(1,034.62-1,852.58)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cost of the study medication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48,617.98\u003c/p\u003e \u003cp\u003e\u003cem\u003eUSD 10,209.78\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70,519.85\u003c/p\u003e \u003cp\u003e\u003cem\u003eUSD 14,809.17\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cost of the study medication\u0026thinsp;+\u0026thinsp;healthcare cost (post)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75,339.81\u003c/p\u003e \u003cp\u003e\u003cem\u003eUSD 15,821.36\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83,098.25\u003c/p\u003e \u003cp\u003e\u003cem\u003eUSD 17,450.63\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCost to reduce one relapse in this study\u003c/p\u003e \u003cp\u003e\u003cem\u003e44 episodes in RTX group; 47 episodes in CSA group\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,104.95\u003c/p\u003e \u003cp\u003e\u003cem\u003eUSD 232.04\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,500.42\u003c/p\u003e \u003cp\u003e\u003cem\u003eUSD 315.09\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe inferred that the cost to reduce one relapse in our cohort was relatively cheaper with Rituximab, MYR 1,104.95 (USD 232.04) /episode compared to Cyclosporine, MYR 1,500.42 (USD 315.09) /episode.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eEfficacy of treatment\u003c/h2\u003e \u003cp\u003eThe total number of relapses reduced significantly in both groups. The median annualised relapse rate was 5.07 (4.06\u0026ndash;6.85) and 5.07 (5.07\u0026ndash;6.09) before treatment for the Rituximab and Cyclosporine group respectively. Post treatment (at the end of 12 months), the median annualised relapse rate reduced to 1.52 (0.00\u0026ndash;2.79) and 1.01 (0.00\u0026ndash;1.01) respectively. (See Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEfficacy parameters\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRTX (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCSA (n\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of relapses (pre)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of relapses (post)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of reduction in relapses\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnnualised relapse rate (median(IQR); pre)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.07(4.06\u0026ndash;6.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.07(5.07\u0026ndash;6.09)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnnualised relapse rate (median(IQR); post)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.52 (0.00\u0026ndash;2.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.01(0.00-1.01)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of admissions (pre)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.089\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of admissions (post)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCumulative prednisolone dose mg/kg (median; pre)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e189.28\u003c/p\u003e \u003cp\u003e(160.15- 248.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.097\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e164.10\u003c/p\u003e \u003cp\u003e(133.69\u0026ndash;249.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCumulative prednisolone dose mg/kg (median; post)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74.95\u003c/p\u003e \u003cp\u003e(25.89\u0026ndash;138.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64.19\u003c/p\u003e \u003cp\u003e(36.67\u0026ndash;79.78)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI z-score kgm\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e (median; pre)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.12 (-0.15 to 2.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.78\u003c/p\u003e \u003cp\u003e(0.53 to 2.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.039\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI z-score kgm\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e (median; post)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003cp\u003e(-0.825 to 1.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.55\u003c/p\u003e \u003cp\u003e(-0.41 to 2.11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003cp\u003e* comparison of p is performed within the group (pre- and post- treatment)\u003c/p\u003e \u003cp\u003eThere were no infusion related reactions in the rituximab group and cyclosporine was also well tolerated. One patient reported to have community acquired pneumonia in the RTX group but recovered well soon after discharge; this may be an unrelated adverse effect.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eCyclosporine is used commonly in our country as a steroid sparing agent among steroid sensitive nephrotic syndrome children who continue to relapse after given a trial of either levamisole, cyclophosphamide or both. Rituximab is reserved for children who continue to relapse despite multiple immunosuppressive medications including cyclosporine. Analysing real-world data, the cohort of patients in the Rituximab group were older and had a longer disease vintage compared to the cyclosporine group. The rituximab group also had more relapses, hospital admissions as well as more exposure to steroids at baseline.\u003c/p\u003e \u003cp\u003eThe total healthcare cost (pre) for patients was higher in the Rituximab group as expected due to the more complicated course of disease. In both groups, overall cost of treatment incurred (cost of the study medication and associated healthcare cost) was higher after introduction of the studied steroid sparing agents due to the high cost of the respective drugs. Nevertheless, it is evident that the increment in this cost was lower in the Rituximab group compared to the Cyclosporine group. The recurring dosing of Cyclosporine over a period of 1 year and the need for regular monitoring of trough levels potentially contributed to this observation.\u003c/p\u003e \u003cp\u003eIorember et al[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] reported a comparable expenditure of Rituximab and calcineurin inhibitors (either Cyclosporine or Tacrolimus) in a retrospective analysis of their practice at Louisiana. In another population study in Far East Asia, Takura et al[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] demonstrated evidence of effectiveness, shown by reduced number of relapses and reduced total medical costs, which collectively supported cost-effectiveness of Rituximab in clinical practice. Our data showed that the cost to reduce one relapse was lower in Rituximab. This is potentially an important piece of information to consider when determining distribution of resources. In Malaysia, provision of healthcare at public health facilities is heavily subsidized by the government. Although a parallel private healthcare pathway is available, the burden on the public funding remains steep.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] To our knowledge, this is the first study looking at cost parameters for Rituximab use in children with nephrotic syndrome in our country.\u003c/p\u003e \u003cp\u003eThe secondary outcome of this study was to evaluate the practice of using a single dose of Rituximab to maintain remission in this group of children by comparing it with the existing standard therapy in our setting which is Cyclosporine. Single dose of Rituximab has been reported to be effective literature. In this study, performance of Rituximab is comparable to that of Cyclosporine as illustrated by the significant reduction of number of relapses, the annual relapse rate and improvement in body mass index z-score. Disease burden that affects the psychosocial development of the patients and the dynamics of the affected families is an important entity. Incorporating health-related quality of life and patient-reported outcomes is the key to any successful health programme. It is evident from literature that children with idiopathic nephrotic syndrome have lower health-related quality life scores. Those with prolonged disease vintage and difficult to treat phenotypes have poorer quality.[\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] In our study, reduction in hospital admission, relapses and improvement in BMI z-scores are indirect markers to suggest possible improvement in quality of life.\u003c/p\u003e \u003cp\u003eThe limitations of our study include its retrospective nature and the small sample size. In real-world practice, the utility of Rituximab is prohibited by its seemingly high cost. In addition, many aspects of quality-adjusted life year (QALY) in children are not fully developed yet and this limits analysis of the pharmacoeconomic aspects of Rituximab in our study.[\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] Nevertheless, the findings from our study suggest data to support its use even in a middle-income country.\u003c/p\u003e \u003cp\u003eIn conclusion, a single dose infusion of Rituximab as a steroid sparing agent among children with steroid sensitive nephrotic syndrome is efficacious and feasible, even in a middle-income country. Clinicians should consider the benefits of maintaining remission in these children from medical as well as psychosocial perspectives and not be hindered by the seemingly high cost of treatment.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTeeninga N, Kist-van Holthe JE, van Rijswijk N, de Mos NI, Hop WC, Wetzels JF, van der Heijden AJ, Nauta J (2013) Extending prednisolone treatment does not reduce relapses in childhood nephrotic syndrome. J Am Soc Nephrology: JASN 24(1):149\u0026ndash;159. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1681/ASN.2012070646\u003c/span\u003e\u003cspan address=\"10.1681/ASN.2012070646\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOray M, Abu Samra K, Ebrahimiadib N, Meese H, Foster CS (2016) Long-term side effects of glucocorticoids. 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Retrieved from \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://thejmch.com/index.php/thejmch/article/view/579\u003c/span\u003e\u003cspan address=\"https://thejmch.com/index.php/thejmch/article/view/579\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDrummond MF, Sculpher MJ, Claxton K, Stoddart GL, Torrance GW (2015) Methods for the economic evaluation of health care programmes. Oxford university press\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHawthorne G, Richardson J, Osborne R (1999) The Assessment of Quality of Life (AQoL) instrument: a psychometric measure of Health-Related Quality of Life. 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PLoS ONE 10(8):e0135672. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1371/journal.pone.0135672\u003c/span\u003e\u003cspan address=\"10.1371/journal.pone.0135672\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3811963/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3811963/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe use of Rituximab for frequently relapsing (FRNS) and steroid dependent nephrotic syndrome (SDNS) is increasingly established. However, the use of Rituximab in resource-limited settings is constrained by its prohibitive cost.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study included all children aged 1 to 18 years with FRNS and SDNS. The costs incurred when using either Rituximab or cyclosporine were calculated and compared. Clinical data retrieved from medical records.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eTwelve patients received rituximab while 11 patients were treated with cyclosporine. Annualised relapse rate reduced from 5.07 to 1.52 in the Rituximab and 1.01 in the cyclosporine group. Total healthcost was MYR 75,339.81 in the rituximab group and MYR83,098.25 in the cyclosporine group. Cost to reduce one relapse with Rituximab was MYR 1,104.95 /episode compared to Cyclosporine, MYR 1,500.42 /episode. We observed greater reduction in the amount of prednisolone use in the rituximab group (114.33mg/kg versus 99.91mg/kg in the cyclosporine group). Both demonstrated significant reduction in their body mass index z score. There were no infusion related reactions in the rituximab group and cyclosporin was also well tolerated.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis is the first study to compare the healthcare costs of using rituximab to be carried out in a middle income country. Findings suggest that in such setting, a single infusion of Rituximab as a steroid sparing agent among children with steroid sensitive nephrotic syndrome remains efficacious and feasible.\u003c/p\u003e","manuscriptTitle":"Healthcost and Clinical Benefits of Rituximab in Steroid Sensitive Nephrotic Syndrome: Perspective From a Middle-Income Country (MyRITUX)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-03 16:48:47","doi":"10.21203/rs.3.rs-3811963/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c06c77e0-8935-4b3d-a6f3-7e1e8ea66ba5","owner":[],"postedDate":"January 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-01-28T22:08:41+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-03 16:48:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3811963","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3811963","identity":"rs-3811963","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}