Rituximab versus the modified Ponticelli regimen in the treatment of primary membranous nephropathy: a Health Economic Model

Rituximab versus the modified Ponticelli regimen in the treatment of primary membranous... Abstract Background Membranous nephropathy is among the most common causes of nephrotic syndrome worldwide, with a high healthcare burden. Treatment using the modified Ponticelli regimen (mPR) has remained the standard of care for decades, but newer therapies such as rituximab offer promising results with reduced side effects. The cost of this treatment, however, is perceived as a barrier to widespread use, especially in resource limited healthcare systems. Methods We developed a decision-analytic model to estimate the cost-effectiveness of rituximab versus the mPR from the perspective of the National Health Service in the UK over a 1 year, 5 year and lifetime horizon. Primary outcome is the cost-effectiveness of rituximab versus mPR at 5 years post-treatment. Secondary outcomes are cost-effectiveness at 1 and 10 years post-treatment and over a lifetime. Results At 1-year post-treatment, rituximab therapy dominates mPR. At 5 years post-treatment, rituximab therapy is cheaper than the Ponticelli regimen but at a loss of 0.014 quality-adjusted life years (QALYs) with an incremental cost-effectiveness ratio (ICER) of £95 494.13. Over a lifetime, rituximab remains the cheaper option with an incremental cost of −£5251.03 but with a reduced quality of life (incremental QALY of −0.512) giving an ICER of £10 246.09. Conclusions Our analysis indicates that rituximab has the potential to be a cost-effective treatment in the short and medium terms despite the high single-dose cost. This evaluation suggests that further research is warranted and highlights the need for a high-quality clinical trial to confirm the efficacy and cost-effectiveness of rituximab versus the current standard of care. Markov model, membranous nephropathy, nephrotic syndrome INTRODUCTION Membranous nephropathy (MN) is one of the most common causes of adult nephrotic syndrome worldwide with a high healthcare burden in which ∼20% of patients progress to end-stage renal disease (ESRD) [1, 2]. MN has two distinct entities with primary MN (PMN) now considered to be an autoimmune disease since the discovery of the M-type of phospholipase A2 receptor 1 (anti-PLA2R) antibodies [3–7]. In PMN, disease activity and prognosis is still measured by proteinuria level and renal excretory function, with the risk of renal decline falling in the presence of a reduction in proteinuria [6, 8–13]. A key marker of treatment efficacy in PMN is, therefore, control of proteinuria, with or without immunosuppression [14]. Such immunosuppression is generally a combination of alkylating agents and steroids, as used in studies by Ponticelli et al. [15–18]. This regimen of rotating high-dose intravenous steroids and immunosuppression was first described in 1984 and has been the mainstay of treatment ever since [15]. Initially using methylprednisolone and chlorambucil, it was later modified to include methylprednisolone and cyclophosphamide [15–18]. Despite its treatment success, the modified Ponticelli regimen (mPR) bears a significant side-effect profile, including an increased risk of infection, osteoporosis, diabetes mellitus, weight gain, haemorrhagic cystitis, infertility and malignancy [16]. This led many researchers to search for alternative therapies including tacrolimus and mycophenolate mofetil, but with little evidence to show any improvement in outcomes [19–23]. Rituximab has been used extensively in cancer therapy since the late 1990s and more recently for autoimmune diseases. A number of case series and studies have demonstrated potential in PMN but so far randomized controlled trials (RCTs) have been scarce [24–28]. This, combined with the high cost of the medication itself, has restricted its widespread use in resource limited, evidence based, healthcare systems such as the National Health Service (NHS) in the UK. We developed a decision-analytic model to estimate the cost-effectiveness of rituximab therapy versus the standard of care, namely the mPR for the treatment of PMN. MATERIALS AND METHODS A cost-effectiveness analysis was carried out using a stochastic cohort Markov model developed using standard methods [29], conducted from the perspective of current practice in the UK NHS at 2015 prices. The primary outcome was the cost-effectiveness of rituximab versus mPR at 5 years post-treatment. Secondary outcomes were cost-effectiveness at 1 and 10 years post-treatment and over a lifetime. A literature search revealed no studies directly comparing rituximab versus mPR and, therefore, data was taken from the only studies of sufficient size to afford representative outcome assessment as described below. The analysis employed the cost–utility framework where the main measure of benefit is the quality-adjusted life year (QALY) and with analysis outcomes presented in terms of incremental cost-effectiveness ratios (ICERs) of cost per QALY gained. Choice of comparator Here we have used the mPR, which is the standard of treatment as per the Kidney Disease: Improving Global Outcomes guidelines, having established that the majority of UK renal centres use versions of the mPR as described previously [9, 17, 18, 30]. Model structure The model was developed in consultation with an expert panel including physicians, health economists and clinical scientists, and was identical for each treatment arm (Figure 1). FIGURE 1: View largeDownload slide Model structure. FIGURE 1: View largeDownload slide Model structure. For the treatment phase, all patients were assumed to experience active disease and costs were calculated from the papers described below. Following the treatment phase, patients could transition to (persistent) active disease, partial remission or complete remission. Health states then included sustained remission, relapse, ESRD (conservative management, haemo- or peritoneal dialysis and renal transplant) or death. Following the initial treatment phase, patients transitioned between health states on 3-monthly cycles over a lifetime horizon. PMN is generally considered a disease of middle age with the median age of patients with PMN at diagnosis being 53 years; we therefore extended the lifetime over an additional 47 years corresponding to a maximum survival of 100 years [31]. Parameter values Model parameter values and effectiveness of the interventions were based on the most robust data available for each arm; Jha et al. for the mPR arm and Ruggenenti et al. for the rituximab arm [18, 26]. Jha et al. was a prospective RCT comparing the mPR with supportive care, in biopsy proven adults (>16 years) with nephrotic syndrome for >6 months duration and <2 months of treatment with either steroids or immunosuppression. There was a total of 93 patients completing the study, 47 receiving the mPR with oral cyclophosphamide and IV methylprednisolone. Ruggenenti et al. published an observational study describing 100 consecutive patients, considered to be at a high risk of progressing to ESRD or to develop significant cardiovascular complications of their nephrotic syndrome, treated with rituximab and with no control group. It involved two distinct regimens; initially patients received rituximab in 4-weekly doses of 375 mg/m2. However, as many patients on this regimen were found to be B-cell deplete after only the first dose of rituximab, all subsequent patients from 2005 onwards were changed to a titrated regimen. Prior to inclusion in the trial, 32 patients had received treatment with alternative immunosuppression. Twenty of these did achieve partial remission prior to relapsing and necessitating treatment. The remaining 12 never achieved remission prior to starting rituximab. Of the 100 patients described in the study, 71 received a single 375 mg/m2 dose of rituximab and only received a second dose if their serum B cells were >5 cells/mm3. The cost of treatment in the rituximab arm was, therefore, calculated using the same proportion of treatments (with corresponding outcomes) as in this study. This resulted in 29% of the total cost of treatment being taken as the cost of the initial four doses of 375 mg/m2 rituximab regimen and 71% as the cost of the B-cell titration regimen. These papers were also chosen for their similar observational period allowing for a similar evaluation of care; however, partial and complete remission were defined slightly differently (Table 1), Jha et al. having more stringent remission criteria. In practice, there is a cohort of patients that spontaneously remit but the majority will remain nephrotic and, therefore, require treatment. Both these studies, as in clinical practice, have included patients with biopsy-proven MN and significant proteinuria warranting immunosuppression. Both studies have a male predominance reflecting clinical practice and the mean age at presentation was older in the study as described by Ruggenenti et al. Jha et al. was carried out in India and Ruggenenti et al. was carried out in Italy, two differing healthcare systems. However, both studies were carried out using standard methods and are comparable to use in the UK [18, 26] (Table 1). Table 1. Comparison of trials used for model Parameter  Jha et al. [18]  Ruggenenti et al. [26]  Country  India  Italy  Cohort size  47  100  Median follow-up  11 (10.5–11) years  29 (6–121) months  Age (years), mean ± SD  38.0 ± 13.6  51.5 ± 5.9  Gender       Male, n (%)  30 (63.8)  72 (72)   Female, n (%)  17 (36.2)  28 (28)  Disease state definitions      Active disease  Proteinuria ≥3.5 g/day or proteinuria ≥2.5 g/day and serum albumin <2.5 g/dL with oedema and hyperlipidaemia  Proteinuria ≥3.5 g/day  Partial remission  Proteinuria <2.0 g/day or ≥50% reduction from baseline  Proteinuria <3.0 g/day and ≥50% reduction from baseline  Complete remission  Proteinuria <0.2 g/day  Proteinuria <0.3 g/day and ≥50% reduction from baseline  Relapse  Not defined  Proteinuria ≥3.5 g/day after partial or complete remission  Adverse events, n (%)      During infusion       Allergy  0 (0)  8 (8)   Bronchial wheezing  0 (0)  10 (10)   Cutaneous rash  0 (0)  1 (1)   Hypotension  0 (0)  1 (1)   Stroke  0 (0)  3 (3)   TIA  0 (0)  2 (2)   Acute MI  1 (1)  3 (3)   Cancer  0 (0)  3 (3)   Respiratory tract infection  3 (6)  0 (0)   Urinary tract infection  5 (11)  0 (0)   Pyomyositis  1 (2)  0 (0)   Disseminated tuberculosis  1 (2)  0 (0)   Thrombosis  3 (0)  0 (0)   Deaths  1 (1)  4 (4)  Parameter  Jha et al. [18]  Ruggenenti et al. [26]  Country  India  Italy  Cohort size  47  100  Median follow-up  11 (10.5–11) years  29 (6–121) months  Age (years), mean ± SD  38.0 ± 13.6  51.5 ± 5.9  Gender       Male, n (%)  30 (63.8)  72 (72)   Female, n (%)  17 (36.2)  28 (28)  Disease state definitions      Active disease  Proteinuria ≥3.5 g/day or proteinuria ≥2.5 g/day and serum albumin <2.5 g/dL with oedema and hyperlipidaemia  Proteinuria ≥3.5 g/day  Partial remission  Proteinuria <2.0 g/day or ≥50% reduction from baseline  Proteinuria <3.0 g/day and ≥50% reduction from baseline  Complete remission  Proteinuria <0.2 g/day  Proteinuria <0.3 g/day and ≥50% reduction from baseline  Relapse  Not defined  Proteinuria ≥3.5 g/day after partial or complete remission  Adverse events, n (%)      During infusion       Allergy  0 (0)  8 (8)   Bronchial wheezing  0 (0)  10 (10)   Cutaneous rash  0 (0)  1 (1)   Hypotension  0 (0)  1 (1)   Stroke  0 (0)  3 (3)   TIA  0 (0)  2 (2)   Acute MI  1 (1)  3 (3)   Cancer  0 (0)  3 (3)   Respiratory tract infection  3 (6)  0 (0)   Urinary tract infection  5 (11)  0 (0)   Pyomyositis  1 (2)  0 (0)   Disseminated tuberculosis  1 (2)  0 (0)   Thrombosis  3 (0)  0 (0)   Deaths  1 (1)  4 (4)  MI, myocardial infarction Table 1. Comparison of trials used for model Parameter  Jha et al. [18]  Ruggenenti et al. [26]  Country  India  Italy  Cohort size  47  100  Median follow-up  11 (10.5–11) years  29 (6–121) months  Age (years), mean ± SD  38.0 ± 13.6  51.5 ± 5.9  Gender       Male, n (%)  30 (63.8)  72 (72)   Female, n (%)  17 (36.2)  28 (28)  Disease state definitions      Active disease  Proteinuria ≥3.5 g/day or proteinuria ≥2.5 g/day and serum albumin <2.5 g/dL with oedema and hyperlipidaemia  Proteinuria ≥3.5 g/day  Partial remission  Proteinuria <2.0 g/day or ≥50% reduction from baseline  Proteinuria <3.0 g/day and ≥50% reduction from baseline  Complete remission  Proteinuria <0.2 g/day  Proteinuria <0.3 g/day and ≥50% reduction from baseline  Relapse  Not defined  Proteinuria ≥3.5 g/day after partial or complete remission  Adverse events, n (%)      During infusion       Allergy  0 (0)  8 (8)   Bronchial wheezing  0 (0)  10 (10)   Cutaneous rash  0 (0)  1 (1)   Hypotension  0 (0)  1 (1)   Stroke  0 (0)  3 (3)   TIA  0 (0)  2 (2)   Acute MI  1 (1)  3 (3)   Cancer  0 (0)  3 (3)   Respiratory tract infection  3 (6)  0 (0)   Urinary tract infection  5 (11)  0 (0)   Pyomyositis  1 (2)  0 (0)   Disseminated tuberculosis  1 (2)  0 (0)   Thrombosis  3 (0)  0 (0)   Deaths  1 (1)  4 (4)  Parameter  Jha et al. [18]  Ruggenenti et al. [26]  Country  India  Italy  Cohort size  47  100  Median follow-up  11 (10.5–11) years  29 (6–121) months  Age (years), mean ± SD  38.0 ± 13.6  51.5 ± 5.9  Gender       Male, n (%)  30 (63.8)  72 (72)   Female, n (%)  17 (36.2)  28 (28)  Disease state definitions      Active disease  Proteinuria ≥3.5 g/day or proteinuria ≥2.5 g/day and serum albumin <2.5 g/dL with oedema and hyperlipidaemia  Proteinuria ≥3.5 g/day  Partial remission  Proteinuria <2.0 g/day or ≥50% reduction from baseline  Proteinuria <3.0 g/day and ≥50% reduction from baseline  Complete remission  Proteinuria <0.2 g/day  Proteinuria <0.3 g/day and ≥50% reduction from baseline  Relapse  Not defined  Proteinuria ≥3.5 g/day after partial or complete remission  Adverse events, n (%)      During infusion       Allergy  0 (0)  8 (8)   Bronchial wheezing  0 (0)  10 (10)   Cutaneous rash  0 (0)  1 (1)   Hypotension  0 (0)  1 (1)   Stroke  0 (0)  3 (3)   TIA  0 (0)  2 (2)   Acute MI  1 (1)  3 (3)   Cancer  0 (0)  3 (3)   Respiratory tract infection  3 (6)  0 (0)   Urinary tract infection  5 (11)  0 (0)   Pyomyositis  1 (2)  0 (0)   Disseminated tuberculosis  1 (2)  0 (0)   Thrombosis  3 (0)  0 (0)   Deaths  1 (1)  4 (4)  MI, myocardial infarction Probabilities Transition probabilities from the treatment phase to active disease, complete remission, partial remission, relapse and death were taken from the literature as above [18, 26]. Here, there was an assumption of constant hazards based on survival at a single time point. If a patient developed ESRD they transitioned into the renal replacement pathway, which includes conservative management. Transition probabilities after ESRD have been obtained from the UK Renal Registry (2014) [32]. Death rates were taken as those described in the study arms. At the end of the study follow-up, UK Office of National Statistics (ONS) data was used to provide a baseline mortality rate [33]. For patients in active disease, the death rate obtained from the ONS data was added to the transition probability from the studies. Once in partial or complete remission, death rate was taken as that in the ONS only. Death rates once in ESRD were taken from the UK Renal Registry. Costs Healthcare resource use included all healthcare contact, hospital stays, medication and serious adverse event (SAE) episodes described in each publication. The cost of relapse was taken as the cost of treatment but without SAEs. Costs for each hospital/healthcare contact and SAEs were taken from the NHS reference costs 2014–15 [34]. SD was estimated using S = Q3 – Q1/1.35 [35]. The cost of medication was taken from the Drugs and Pharmaceutical electronic market information (eMit) or from the British National Formulary (BNF) 2015 if not available [36, 37]. For medications for which the dose is based on body surface area we used 1.79 m2 [38]. Maintenance therapy was not costed. SD of costs is not provided by the BNF, so these were taken to be half the mean (Tables 2–4). See Supplementary Material for table with disaggregated costs of treatment stage for reference case and regimens used in sensitivity analysis. Table 2. Cost of medication (all medications oral unless otherwise stated; all doses based on weight of 70 kg patient; all prices based on dose and pack size) Medication  Dose  Pack size  Treatment dose  Mean value (£)  SD (£)  Source  IV methylprednisolone  1000 mg  1 pack  1000 mg  11.04  5.90  DFN009 eMIT  Prednisolone tablets  5 mg  100 tablets  35 mg  4.39  0.26  DFC045 eMIT  Oral cyclophosphamide  50 mg  100  140 mg  82.00  41.00  BNF  IV cyclophosphamide  1000 mg  1 vial    9.41  5.56  DHA014 eMIT  Rituximab  10 mg/mL  10 mL vial  375 mg/m2  174.63  87.32  BNF      50 mL vial    873.15  436.58  BNF  Basiliximab  20 mg  1 vial    842.38  421.19  BNF  IV hydrocortisone  100 mg/mL  1 mL amp  100 mg  1.08  0.54  BNF      5 mL amp  500 mg  4.89  2.45  BNF  Paracetamol  500 mg  100 tablets  1000 mg  0.52  0.29  DDM003 eMIT  Ondansetron  8 mg  10 tablets  8 mg  1.06  5.89  DDF029 eMIT  IV chlorphenamine  10 mg/1 mL  5 ampoules  10 mg  22.80  3.52  DCI002 eMIT  Oral mesna  400 mg  10 tablets  400 mg  42.90  21.45  BNF  IV mesna  100 mg/mL  4 mL vial  200 mg  3.95  1.98  BNF  Normal saline  1000 mL  1 bag  1000 mL  0.80  0.40  BNF  Medication  Dose  Pack size  Treatment dose  Mean value (£)  SD (£)  Source  IV methylprednisolone  1000 mg  1 pack  1000 mg  11.04  5.90  DFN009 eMIT  Prednisolone tablets  5 mg  100 tablets  35 mg  4.39  0.26  DFC045 eMIT  Oral cyclophosphamide  50 mg  100  140 mg  82.00  41.00  BNF  IV cyclophosphamide  1000 mg  1 vial    9.41  5.56  DHA014 eMIT  Rituximab  10 mg/mL  10 mL vial  375 mg/m2  174.63  87.32  BNF      50 mL vial    873.15  436.58  BNF  Basiliximab  20 mg  1 vial    842.38  421.19  BNF  IV hydrocortisone  100 mg/mL  1 mL amp  100 mg  1.08  0.54  BNF      5 mL amp  500 mg  4.89  2.45  BNF  Paracetamol  500 mg  100 tablets  1000 mg  0.52  0.29  DDM003 eMIT  Ondansetron  8 mg  10 tablets  8 mg  1.06  5.89  DDF029 eMIT  IV chlorphenamine  10 mg/1 mL  5 ampoules  10 mg  22.80  3.52  DCI002 eMIT  Oral mesna  400 mg  10 tablets  400 mg  42.90  21.45  BNF  IV mesna  100 mg/mL  4 mL vial  200 mg  3.95  1.98  BNF  Normal saline  1000 mL  1 bag  1000 mL  0.80  0.40  BNF  eMIT, Department of Health Electronic Market Information Tool accessed on 30 June 2016 and costs correct to December 2015 [36]. Prices given in eMIT are excluding value added tax, therefore, taken as 20%. BNF accessed on 30 April 2015 [37]. SDs for BNF medicines taken as mean/2 as they are not provided Table 2. Cost of medication (all medications oral unless otherwise stated; all doses based on weight of 70 kg patient; all prices based on dose and pack size) Medication  Dose  Pack size  Treatment dose  Mean value (£)  SD (£)  Source  IV methylprednisolone  1000 mg  1 pack  1000 mg  11.04  5.90  DFN009 eMIT  Prednisolone tablets  5 mg  100 tablets  35 mg  4.39  0.26  DFC045 eMIT  Oral cyclophosphamide  50 mg  100  140 mg  82.00  41.00  BNF  IV cyclophosphamide  1000 mg  1 vial    9.41  5.56  DHA014 eMIT  Rituximab  10 mg/mL  10 mL vial  375 mg/m2  174.63  87.32  BNF      50 mL vial    873.15  436.58  BNF  Basiliximab  20 mg  1 vial    842.38  421.19  BNF  IV hydrocortisone  100 mg/mL  1 mL amp  100 mg  1.08  0.54  BNF      5 mL amp  500 mg  4.89  2.45  BNF  Paracetamol  500 mg  100 tablets  1000 mg  0.52  0.29  DDM003 eMIT  Ondansetron  8 mg  10 tablets  8 mg  1.06  5.89  DDF029 eMIT  IV chlorphenamine  10 mg/1 mL  5 ampoules  10 mg  22.80  3.52  DCI002 eMIT  Oral mesna  400 mg  10 tablets  400 mg  42.90  21.45  BNF  IV mesna  100 mg/mL  4 mL vial  200 mg  3.95  1.98  BNF  Normal saline  1000 mL  1 bag  1000 mL  0.80  0.40  BNF  Medication  Dose  Pack size  Treatment dose  Mean value (£)  SD (£)  Source  IV methylprednisolone  1000 mg  1 pack  1000 mg  11.04  5.90  DFN009 eMIT  Prednisolone tablets  5 mg  100 tablets  35 mg  4.39  0.26  DFC045 eMIT  Oral cyclophosphamide  50 mg  100  140 mg  82.00  41.00  BNF  IV cyclophosphamide  1000 mg  1 vial    9.41  5.56  DHA014 eMIT  Rituximab  10 mg/mL  10 mL vial  375 mg/m2  174.63  87.32  BNF      50 mL vial    873.15  436.58  BNF  Basiliximab  20 mg  1 vial    842.38  421.19  BNF  IV hydrocortisone  100 mg/mL  1 mL amp  100 mg  1.08  0.54  BNF      5 mL amp  500 mg  4.89  2.45  BNF  Paracetamol  500 mg  100 tablets  1000 mg  0.52  0.29  DDM003 eMIT  Ondansetron  8 mg  10 tablets  8 mg  1.06  5.89  DDF029 eMIT  IV chlorphenamine  10 mg/1 mL  5 ampoules  10 mg  22.80  3.52  DCI002 eMIT  Oral mesna  400 mg  10 tablets  400 mg  42.90  21.45  BNF  IV mesna  100 mg/mL  4 mL vial  200 mg  3.95  1.98  BNF  Normal saline  1000 mL  1 bag  1000 mL  0.80  0.40  BNF  eMIT, Department of Health Electronic Market Information Tool accessed on 30 June 2016 and costs correct to December 2015 [36]. Prices given in eMIT are excluding value added tax, therefore, taken as 20%. BNF accessed on 30 April 2015 [37]. SDs for BNF medicines taken as mean/2 as they are not provided Table 3. Cost of healthcare provision (all costs given in British pounds sterling) Health service  Mean value  LQR  UQR  SD  Source  Delivery of chemo (1st)             Simple parenteral  257.00  136.00  311.00  129.63  SB12Z NHS ref costs   Complex and infusional  414.00  250.00  521.00  200.74  SB14Z NHS ref costs  Subsequent chemo  362.00  230.00  413.00  135.56  SB15Z NHS ref costs  AVF, graft or shunt DC  1910.66  1334.41  2342.81  746.96  YQ42Z NHS ref costs  PD-associated procedure DC  1268.00  503.00  1815.00  971.85  LA05Z NHS ref costs  Nephrology clinic  160.00  110.00  185.00  55.56  WF01A 361 NHS ref costs  Transplant clinic  358.00  220.00  493.00  202.22  WF01A 102 NHS ref costs  Haemodialysis             CKD via AVF at base  166.00  143.00  176.00  24.44  RENALCKD LD02A NHS ref costs  PD             Automated PD  71.00  50.00  67.00  12.59  RENALCKD LD12A NHS ref costs  Renal transplant             Cadaver NHB  12 845.93  10 179.00  14 250.00  3015.56  LA01A NHS ref costs   Cadaver HB  12 434.09  12 904.00  14 450.00  1145.19  LA02A NHS ref costs   Live donor  13 828.19  9996.00  17 756.00  5748.15  LA03A NHS ref costs  Pre-transplant workup             Live donor  1205.75  958.00  1559.00  445.19  LA11Z NHS ref costs  B-cell subsets  5.00  2.00  7.00  3.70  DAPS06 NHS ref costs  Health service  Mean value  LQR  UQR  SD  Source  Delivery of chemo (1st)             Simple parenteral  257.00  136.00  311.00  129.63  SB12Z NHS ref costs   Complex and infusional  414.00  250.00  521.00  200.74  SB14Z NHS ref costs  Subsequent chemo  362.00  230.00  413.00  135.56  SB15Z NHS ref costs  AVF, graft or shunt DC  1910.66  1334.41  2342.81  746.96  YQ42Z NHS ref costs  PD-associated procedure DC  1268.00  503.00  1815.00  971.85  LA05Z NHS ref costs  Nephrology clinic  160.00  110.00  185.00  55.56  WF01A 361 NHS ref costs  Transplant clinic  358.00  220.00  493.00  202.22  WF01A 102 NHS ref costs  Haemodialysis             CKD via AVF at base  166.00  143.00  176.00  24.44  RENALCKD LD02A NHS ref costs  PD             Automated PD  71.00  50.00  67.00  12.59  RENALCKD LD12A NHS ref costs  Renal transplant             Cadaver NHB  12 845.93  10 179.00  14 250.00  3015.56  LA01A NHS ref costs   Cadaver HB  12 434.09  12 904.00  14 450.00  1145.19  LA02A NHS ref costs   Live donor  13 828.19  9996.00  17 756.00  5748.15  LA03A NHS ref costs  Pre-transplant workup             Live donor  1205.75  958.00  1559.00  445.19  LA11Z NHS ref costs  B-cell subsets  5.00  2.00  7.00  3.70  DAPS06 NHS ref costs  NHS ref costs, NHS reference costs 2014–2015 [34]. LQR, lower quartile range; UQR, upper quartile range; DC, day case; AVF, arterioventricular fistula; PD, peritoneal dialysis; AKI, acute kidney injury; CKD, chronic kidney disease; NHB, non-heart beating donor; HB, heart beating donor; complex and infusional, complex parenteral and prolonged infusion treatment; SD estimated using S = Q3 – Q1/1.35 from Cochrane Handbook from Systematic Reviews and Interventions 2008 [35] Table 3. Cost of healthcare provision (all costs given in British pounds sterling) Health service  Mean value  LQR  UQR  SD  Source  Delivery of chemo (1st)             Simple parenteral  257.00  136.00  311.00  129.63  SB12Z NHS ref costs   Complex and infusional  414.00  250.00  521.00  200.74  SB14Z NHS ref costs  Subsequent chemo  362.00  230.00  413.00  135.56  SB15Z NHS ref costs  AVF, graft or shunt DC  1910.66  1334.41  2342.81  746.96  YQ42Z NHS ref costs  PD-associated procedure DC  1268.00  503.00  1815.00  971.85  LA05Z NHS ref costs  Nephrology clinic  160.00  110.00  185.00  55.56  WF01A 361 NHS ref costs  Transplant clinic  358.00  220.00  493.00  202.22  WF01A 102 NHS ref costs  Haemodialysis             CKD via AVF at base  166.00  143.00  176.00  24.44  RENALCKD LD02A NHS ref costs  PD             Automated PD  71.00  50.00  67.00  12.59  RENALCKD LD12A NHS ref costs  Renal transplant             Cadaver NHB  12 845.93  10 179.00  14 250.00  3015.56  LA01A NHS ref costs   Cadaver HB  12 434.09  12 904.00  14 450.00  1145.19  LA02A NHS ref costs   Live donor  13 828.19  9996.00  17 756.00  5748.15  LA03A NHS ref costs  Pre-transplant workup             Live donor  1205.75  958.00  1559.00  445.19  LA11Z NHS ref costs  B-cell subsets  5.00  2.00  7.00  3.70  DAPS06 NHS ref costs  Health service  Mean value  LQR  UQR  SD  Source  Delivery of chemo (1st)             Simple parenteral  257.00  136.00  311.00  129.63  SB12Z NHS ref costs   Complex and infusional  414.00  250.00  521.00  200.74  SB14Z NHS ref costs  Subsequent chemo  362.00  230.00  413.00  135.56  SB15Z NHS ref costs  AVF, graft or shunt DC  1910.66  1334.41  2342.81  746.96  YQ42Z NHS ref costs  PD-associated procedure DC  1268.00  503.00  1815.00  971.85  LA05Z NHS ref costs  Nephrology clinic  160.00  110.00  185.00  55.56  WF01A 361 NHS ref costs  Transplant clinic  358.00  220.00  493.00  202.22  WF01A 102 NHS ref costs  Haemodialysis             CKD via AVF at base  166.00  143.00  176.00  24.44  RENALCKD LD02A NHS ref costs  PD             Automated PD  71.00  50.00  67.00  12.59  RENALCKD LD12A NHS ref costs  Renal transplant             Cadaver NHB  12 845.93  10 179.00  14 250.00  3015.56  LA01A NHS ref costs   Cadaver HB  12 434.09  12 904.00  14 450.00  1145.19  LA02A NHS ref costs   Live donor  13 828.19  9996.00  17 756.00  5748.15  LA03A NHS ref costs  Pre-transplant workup             Live donor  1205.75  958.00  1559.00  445.19  LA11Z NHS ref costs  B-cell subsets  5.00  2.00  7.00  3.70  DAPS06 NHS ref costs  NHS ref costs, NHS reference costs 2014–2015 [34]. LQR, lower quartile range; UQR, upper quartile range; DC, day case; AVF, arterioventricular fistula; PD, peritoneal dialysis; AKI, acute kidney injury; CKD, chronic kidney disease; NHB, non-heart beating donor; HB, heart beating donor; complex and infusional, complex parenteral and prolonged infusion treatment; SD estimated using S = Q3 – Q1/1.35 from Cochrane Handbook from Systematic Reviews and Interventions 2008 [35] Table 4. Cost of AEs and SAEs (all costs given in British pounds sterling) Complication  Mean  LQR  UQR  SD  Source  Notes/assumptions  Jha et al. [18]   Respiratory tract infections  1540.00  1255.00  1685.00  318.52  DZ22Q NHS ref costs  Unspecified acute LRTI (0–1)   Urinary tract infections  1503.00  1233.00  1659.00  315.56  LA04S NHS ref costs  Kidney/UTI—no intervention (0–1)   Gluteal abscess  1358.00  960.00  1557.00  442.22  HD26G NHS ref costs  MSK signs or symptoms (0–3)   Bacterial meningitis  2339.00  1561.00  2638.00  797.78  AA22G NHS ref costs  Nervous system infections (0–4)   Pulmonary tuberculosis  2650.00  1702.00  3131.00  1058.52  DZ14J NHS ref costs  Pulmonary, pleural, other Tb   Septicaemia  1993.00  1586.00  2224.00  472.59  WJ06J NHS ref costs  Sepsis (0–1)   Deep-vein thrombosis  1362.00  992.00  1491.00  369.63  YQ51E NHS ref costs  DVT (0–2)  Ruggenenti et al. [26]   Acute MI  1505.00  1205.00  1701.00  367.41  EB10E NHS ref costs  Actual/Suspected MI (0–3)   Stroke  2348.00  1803.00  2597.00  588.15  AA35F NHS ref costs  Stroke (0–3)   TIA  1253.00  978.00  1393.00  307.41  AA29F NHS ref costs  TIA (0–4)   Lung cancer  3047.00  2063.00  3610.00  1145.93  DZ17R NHS ref costs  Resp. neoplasm (0–5)   Breast cancer  3357.00  1504.00  4554.00  2259.26  JA12F NHS ref costs  Malignant—intervention (0–2)   Prostate carcinoma  2268.00  1469.00  2660.00  882.22  LB06M NHS ref costs  Prostate Ca—intervention (0–1)  Complication  Mean  LQR  UQR  SD  Source  Notes/assumptions  Jha et al. [18]   Respiratory tract infections  1540.00  1255.00  1685.00  318.52  DZ22Q NHS ref costs  Unspecified acute LRTI (0–1)   Urinary tract infections  1503.00  1233.00  1659.00  315.56  LA04S NHS ref costs  Kidney/UTI—no intervention (0–1)   Gluteal abscess  1358.00  960.00  1557.00  442.22  HD26G NHS ref costs  MSK signs or symptoms (0–3)   Bacterial meningitis  2339.00  1561.00  2638.00  797.78  AA22G NHS ref costs  Nervous system infections (0–4)   Pulmonary tuberculosis  2650.00  1702.00  3131.00  1058.52  DZ14J NHS ref costs  Pulmonary, pleural, other Tb   Septicaemia  1993.00  1586.00  2224.00  472.59  WJ06J NHS ref costs  Sepsis (0–1)   Deep-vein thrombosis  1362.00  992.00  1491.00  369.63  YQ51E NHS ref costs  DVT (0–2)  Ruggenenti et al. [26]   Acute MI  1505.00  1205.00  1701.00  367.41  EB10E NHS ref costs  Actual/Suspected MI (0–3)   Stroke  2348.00  1803.00  2597.00  588.15  AA35F NHS ref costs  Stroke (0–3)   TIA  1253.00  978.00  1393.00  307.41  AA29F NHS ref costs  TIA (0–4)   Lung cancer  3047.00  2063.00  3610.00  1145.93  DZ17R NHS ref costs  Resp. neoplasm (0–5)   Breast cancer  3357.00  1504.00  4554.00  2259.26  JA12F NHS ref costs  Malignant—intervention (0–2)   Prostate carcinoma  2268.00  1469.00  2660.00  882.22  LB06M NHS ref costs  Prostate Ca—intervention (0–1)  NHS ref costs, NHS reference costs 2014–2015 [34]. LQR, lower quartile range; LRTI, lower respiratory tract infection; MSK, musculoskeletal; UQR, upper quartile range; CC score in parenthesis; TIA, transient ischaemic attack; DVT, deep venous thrombosis; UTI, urinary tract infection. All costs taken as non-elective short stay. SD estimated using SD = Q3 – Q1/1.35 from Cochrane Handbook from Systematic Reviews and Interventions 2008 [35] Table 4. Cost of AEs and SAEs (all costs given in British pounds sterling) Complication  Mean  LQR  UQR  SD  Source  Notes/assumptions  Jha et al. [18]   Respiratory tract infections  1540.00  1255.00  1685.00  318.52  DZ22Q NHS ref costs  Unspecified acute LRTI (0–1)   Urinary tract infections  1503.00  1233.00  1659.00  315.56  LA04S NHS ref costs  Kidney/UTI—no intervention (0–1)   Gluteal abscess  1358.00  960.00  1557.00  442.22  HD26G NHS ref costs  MSK signs or symptoms (0–3)   Bacterial meningitis  2339.00  1561.00  2638.00  797.78  AA22G NHS ref costs  Nervous system infections (0–4)   Pulmonary tuberculosis  2650.00  1702.00  3131.00  1058.52  DZ14J NHS ref costs  Pulmonary, pleural, other Tb   Septicaemia  1993.00  1586.00  2224.00  472.59  WJ06J NHS ref costs  Sepsis (0–1)   Deep-vein thrombosis  1362.00  992.00  1491.00  369.63  YQ51E NHS ref costs  DVT (0–2)  Ruggenenti et al. [26]   Acute MI  1505.00  1205.00  1701.00  367.41  EB10E NHS ref costs  Actual/Suspected MI (0–3)   Stroke  2348.00  1803.00  2597.00  588.15  AA35F NHS ref costs  Stroke (0–3)   TIA  1253.00  978.00  1393.00  307.41  AA29F NHS ref costs  TIA (0–4)   Lung cancer  3047.00  2063.00  3610.00  1145.93  DZ17R NHS ref costs  Resp. neoplasm (0–5)   Breast cancer  3357.00  1504.00  4554.00  2259.26  JA12F NHS ref costs  Malignant—intervention (0–2)   Prostate carcinoma  2268.00  1469.00  2660.00  882.22  LB06M NHS ref costs  Prostate Ca—intervention (0–1)  Complication  Mean  LQR  UQR  SD  Source  Notes/assumptions  Jha et al. [18]   Respiratory tract infections  1540.00  1255.00  1685.00  318.52  DZ22Q NHS ref costs  Unspecified acute LRTI (0–1)   Urinary tract infections  1503.00  1233.00  1659.00  315.56  LA04S NHS ref costs  Kidney/UTI—no intervention (0–1)   Gluteal abscess  1358.00  960.00  1557.00  442.22  HD26G NHS ref costs  MSK signs or symptoms (0–3)   Bacterial meningitis  2339.00  1561.00  2638.00  797.78  AA22G NHS ref costs  Nervous system infections (0–4)   Pulmonary tuberculosis  2650.00  1702.00  3131.00  1058.52  DZ14J NHS ref costs  Pulmonary, pleural, other Tb   Septicaemia  1993.00  1586.00  2224.00  472.59  WJ06J NHS ref costs  Sepsis (0–1)   Deep-vein thrombosis  1362.00  992.00  1491.00  369.63  YQ51E NHS ref costs  DVT (0–2)  Ruggenenti et al. [26]   Acute MI  1505.00  1205.00  1701.00  367.41  EB10E NHS ref costs  Actual/Suspected MI (0–3)   Stroke  2348.00  1803.00  2597.00  588.15  AA35F NHS ref costs  Stroke (0–3)   TIA  1253.00  978.00  1393.00  307.41  AA29F NHS ref costs  TIA (0–4)   Lung cancer  3047.00  2063.00  3610.00  1145.93  DZ17R NHS ref costs  Resp. neoplasm (0–5)   Breast cancer  3357.00  1504.00  4554.00  2259.26  JA12F NHS ref costs  Malignant—intervention (0–2)   Prostate carcinoma  2268.00  1469.00  2660.00  882.22  LB06M NHS ref costs  Prostate Ca—intervention (0–1)  NHS ref costs, NHS reference costs 2014–2015 [34]. LQR, lower quartile range; LRTI, lower respiratory tract infection; MSK, musculoskeletal; UQR, upper quartile range; CC score in parenthesis; TIA, transient ischaemic attack; DVT, deep venous thrombosis; UTI, urinary tract infection. All costs taken as non-elective short stay. SD estimated using SD = Q3 – Q1/1.35 from Cochrane Handbook from Systematic Reviews and Interventions 2008 [35] Utility/quality of life For many patients, the presenting symptoms that bring them to the notice of healthcare professionals, and ultimately to the diagnosis of PMN, is that of the nephrotic syndrome, namely oedema, increasing shortness of breath and fatigue. Currently there are limited data available on the quality of life (or utility) for patients with PMN, therefore, utility values for active disease were taken as that of active nephrotic syndrome, given these are the main symptoms a patient will experience when their disease is active [39]. For patients with partial or complete remission we used age- and sex-matched EQ-5D UK population norms [40]. Once patients reached ESRD, utility values were estimated using SF-36 values from Wyld et al. converted to utility scores [41, 42] (Table 5). Table 5. Quality of life utility values. ESRD. Partial remission and complete remission taken as the same Utility  Mean  LCI  UCI  SD/SE  Source  Notes  Complete remission  0.860  0.630  1.000  0.230  Kind et al. [40]  Age and sex matched  Partial remission  0.860  0.630  1.000  0.230  Kind et al. [40]    Active disease  0.738  0.422  1.000  0.317  Libório et al. [42]  SF-36 converted to EQ-5D  ESRD  0.800  0.650  0.940  0.030  Wyld et al. [39]  CKD (pre-treatment)  Conservative  0.620  0.360  0.890  0.090  Wyld et al. [39]  SF-36 converted to EQ-5D  Haemodialysis  0.680  0.530  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Peritoneal dialysis  0.710  0.590  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Renal transplant  0.820  0.740  0.900  0.040  Wyld et al. [39]  SF-36 converted to EQ-5D  Dead  0.000  0.000  0.000  0.000      Utility  Mean  LCI  UCI  SD/SE  Source  Notes  Complete remission  0.860  0.630  1.000  0.230  Kind et al. [40]  Age and sex matched  Partial remission  0.860  0.630  1.000  0.230  Kind et al. [40]    Active disease  0.738  0.422  1.000  0.317  Libório et al. [42]  SF-36 converted to EQ-5D  ESRD  0.800  0.650  0.940  0.030  Wyld et al. [39]  CKD (pre-treatment)  Conservative  0.620  0.360  0.890  0.090  Wyld et al. [39]  SF-36 converted to EQ-5D  Haemodialysis  0.680  0.530  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Peritoneal dialysis  0.710  0.590  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Renal transplant  0.820  0.740  0.900  0.040  Wyld et al. [39]  SF-36 converted to EQ-5D  Dead  0.000  0.000  0.000  0.000      CKD, chronic kidney disease; LCI, lower 95% confidence interval; UCI, 95% confidence interval. Table 5. Quality of life utility values. ESRD. Partial remission and complete remission taken as the same Utility  Mean  LCI  UCI  SD/SE  Source  Notes  Complete remission  0.860  0.630  1.000  0.230  Kind et al. [40]  Age and sex matched  Partial remission  0.860  0.630  1.000  0.230  Kind et al. [40]    Active disease  0.738  0.422  1.000  0.317  Libório et al. [42]  SF-36 converted to EQ-5D  ESRD  0.800  0.650  0.940  0.030  Wyld et al. [39]  CKD (pre-treatment)  Conservative  0.620  0.360  0.890  0.090  Wyld et al. [39]  SF-36 converted to EQ-5D  Haemodialysis  0.680  0.530  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Peritoneal dialysis  0.710  0.590  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Renal transplant  0.820  0.740  0.900  0.040  Wyld et al. [39]  SF-36 converted to EQ-5D  Dead  0.000  0.000  0.000  0.000      Utility  Mean  LCI  UCI  SD/SE  Source  Notes  Complete remission  0.860  0.630  1.000  0.230  Kind et al. [40]  Age and sex matched  Partial remission  0.860  0.630  1.000  0.230  Kind et al. [40]    Active disease  0.738  0.422  1.000  0.317  Libório et al. [42]  SF-36 converted to EQ-5D  ESRD  0.800  0.650  0.940  0.030  Wyld et al. [39]  CKD (pre-treatment)  Conservative  0.620  0.360  0.890  0.090  Wyld et al. [39]  SF-36 converted to EQ-5D  Haemodialysis  0.680  0.530  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Peritoneal dialysis  0.710  0.590  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Renal transplant  0.820  0.740  0.900  0.040  Wyld et al. [39]  SF-36 converted to EQ-5D  Dead  0.000  0.000  0.000  0.000      CKD, chronic kidney disease; LCI, lower 95% confidence interval; UCI, 95% confidence interval. Cost-effectiveness analysis All costs are presented as mean cost per patient. Expected costs and QALYs were estimated for each arm and, where appropriate, ICERs calculated (derived from the incremental cost of treating with rituximab and the incremental QALY). ICERs below the £20 000 threshold would indicate that rituximab is considered cost-effective as set by National Institute for Health and Care Excellence (NICE) standards [43]. Following NICE guidelines, half cycle correction was conducted and a discount rate of 3.5% per annum was applied to all outcomes incurred beyond 1 year [43]. Incremental net monetary benefit Incremental net monetary benefit (INMBs) were calculated using the incremental QALY, the incremental cost and the lambda, which in this case is £20 000, as per NICE guidelines [43]. A positive value indicates that rituximab therapy is cost effective and, therefore, the preferred option when compared with the mPR. Deterministic sensitivity analysis We performed one-way sensitivity analysis on a range of parameters to assess the impact of each parameter on the outcome of the model at 5 years post-treatment as described by the INMB. For sensitivity analysis of the costs, these were altered, the quality of life and transition probabilities remaining unchanged. For sensitivity analysis of the transition probabilities, the costs remained unchanged. Exact alterations to costs and probabilities are given below. Rituximab regimens The study described by Ruggenenti et al. used to inform the rituximab arm in our model utilized two different regimens as described in the Materials and methods section. We therefore carried out a sensitivity analysis based on all patients in the rituximab arm receiving the original regimen consisting of 4-weekly infusions of 375 mg/m2 rituximab. We then carried out the analysis based on all patients in the rituximab arm receiving the B-cell titrated regimen, i.e. a single 375 mg/m2 dose of rituximab with a second dose if their serum B cells were subsequently >5 cells/mm3. For both of these, the costs in the Ponticelli arm remained unchanged. Further sensitivity analysis was carried out using the recently reported RCT described by Dahan et al. [27]. Here, patients in the treatment arm were given two doses of 375 mg/m2 rituximab on Days 1 and 8. For this analysis, only the costs in rituximab arm of the model were changed and all outcomes remained the same. Ponticelli regimens The mPR uses low-cost medications but requires multiple hospital admissions to receive steroid infusions. Therefore, to assess the impact that drug delivery has on the overall cost we performed a sensitivity analysis with patients only receiving oral prednisolone and no intravenous (IV) methylprednisolone, with cyclophosphamide remaining unchanged. We also assessed how a change in the cyclophosphamide regimen may affect the overall cost by carrying out a sensitivity analysis using pulsed monthly cyclophosphamide for 6 months with adjunctive oral prednisolone (with no IV methylprednisolone) as described by Kanigicherla et al. [44]. The costs for the rituximab arm remained unchanged for both of these analyses. Other To assess how the cost of drug delivery itself affects the model outcomes we performed a sensitivity analysis with an increase and decrease in the cost of the delivery of an infusion in a day-care setting by 20% and on the cost of the medication itself (rituximab and cyclophosphamide). For the cost of infusion delivery, the cost was altered in both arms. For the cost of medication, the cost was altered in each arm and analysed separately. In order to provide consistency, the cost of cancer in the original analysis was taken as the cost for the least severe form of the disease as per the NHS reference costs [34]. To assess whether the cost of cancer impacts on the results, we used the cost for the most severe form of the various cancers as reported in the NHS reference costs [34] for the sensitivity analysis. Given the known uncertainty in the quality of life measures available, we performed a sensitivity analysis on this by altering the utility value of partial remission to be the same as active disease instead of complete remission. This was changed in both arms simultaneously. Transition probabilities To investigate the impact of the transition probabilities on outcomes, we performed a number of analysis including altering the death rate to be equal in both arms, the chance of developing ESRD and needing renal replacement therapy (RRT) to be equal in both arms and the rate of relapse to be equal in both arms. We analysed the effect of treatment efficacy by altering the transition probabilities of going from the treatment phase to either active disease, partial remission or complete remission by making them equal in both arms. We then altered the chance of transitioning from active disease to remission, so that it was equal in both arms. We altered all transition probabilities to be equal in both arms with no change to costs or utility values. We also increased and decreased the probability, by 20%, of going into remission in the rituximab arm and keeping the Ponticelli arm unchanged. We then performed the same analysis by altering the transition probability in the Ponticelli arm and kept the rituximab arm unchanged. Probabilistic sensitivity analysis A probabilistic sensitivity analysis (PSA) was conducted with 10 000 Monte Carlo simulations based on random draws of all parameter values simultaneously from probability distributions. This provided 10 000 estimates of costs and QALYs, which were used to generate 10 000 ICERs and INMB estimates and allowed us to estimate the level of parameter uncertainty in the analysis. These simulated analyses were plotted on a cost-effectiveness plane and a cost-effectiveness acceptability curve (CEAC) [45]. The CEAC indicates the probability that rituximab is cost-effective versus mPR across a range of willingness to pay per QALY gain thresholds [46]. The higher the probability, the lower the uncertainty is in the model and decision. Validation We employed a number of tests to ensure the model was as valid as possible, although given the nature of the disease and lack of clinical trials, we were unable to perform a full validation. Validation was carried out using recognized techniques [47]. Face validation was carried out with each aspect of the model design, data sources and formulae, and eventual results were reviewed and discussed by a panel of experts including clinicians, clinical scientists and health economists. Internal validation was performed using deterministic sensitivity analysis and testing whether changes in model inputs led to changes in outputs in the expected direction—for example, by increasing the SAE/adverse events (AE) risks for rituximab we expected the cost-effectiveness of that intervention would be reduced. Verification of the code was performed by one clinician and two separate and independent health economists. As there are no other health economic or epidemiological models or RCTs in this area, cross validation, external validation and predictive validation were not possible. RESULTS ICER At 5 years post-treatment, rituximab therapy is cheaper than the Ponticelli regimen but at a loss of 0.014 QALYs. Here the ICER is £95 494.13 (incremental cost −£1355.82 and incremental QALY −0.014). At 1-year post-treatment, rituximab therapy dominates mPR. At 10 years post-treatment, rituximab remains the cheaper option with an incremental cost of −£2201.37. With an incremental QALY of −0.091 the ICER is £24 256.91. Over a lifetime, the ICER was £10 246.09, obtained from the incremental per-patient cost of −£5251.03 and incremental QALY of −0.512. See Supplementary Material for frequency of patients in each disease state at 5 years post-treatment with corresponding costs and QALYs (Table 6). Table 6. Results for both probabilistic and deterministic sensitivity analysis at one, 5 and 10 years post-treatment and over a lifetime (lambda taken as £20 000)   Deterministic sensitivity analysis   Probabilistic sensitivity analysis     Incremental cost  Incremental QALY  ICER  INMB  Incremental cost  Incremental QALY  ICER  INMB  1 year  −£748.20  0.002  Rituximab dominates  £785.44  −£761.19  0.001  Rituximab dominates  £777.54  5 years  −£1355.82  −0.014  £95 494.13  £1071.86  −£1383.61  −0.014  £101 665.93  £1111.42  10 years  −£2201.37  −0.091  £24 256.91  £386.32  −£2217.16  −0.092  £24 222.17  £386.47  Lifetime  −£5251.03  −0.512  £10 246.09  −£4998.79  −£5228.58  −0.612  £2198.07  −£7016.21    Deterministic sensitivity analysis   Probabilistic sensitivity analysis     Incremental cost  Incremental QALY  ICER  INMB  Incremental cost  Incremental QALY  ICER  INMB  1 year  −£748.20  0.002  Rituximab dominates  £785.44  −£761.19  0.001  Rituximab dominates  £777.54  5 years  −£1355.82  −0.014  £95 494.13  £1071.86  −£1383.61  −0.014  £101 665.93  £1111.42  10 years  −£2201.37  −0.091  £24 256.91  £386.32  −£2217.16  −0.092  £24 222.17  £386.47  Lifetime  −£5251.03  −0.512  £10 246.09  −£4998.79  −£5228.58  −0.612  £2198.07  −£7016.21  Table 6. Results for both probabilistic and deterministic sensitivity analysis at one, 5 and 10 years post-treatment and over a lifetime (lambda taken as £20 000)   Deterministic sensitivity analysis   Probabilistic sensitivity analysis     Incremental cost  Incremental QALY  ICER  INMB  Incremental cost  Incremental QALY  ICER  INMB  1 year  −£748.20  0.002  Rituximab dominates  £785.44  −£761.19  0.001  Rituximab dominates  £777.54  5 years  −£1355.82  −0.014  £95 494.13  £1071.86  −£1383.61  −0.014  £101 665.93  £1111.42  10 years  −£2201.37  −0.091  £24 256.91  £386.32  −£2217.16  −0.092  £24 222.17  £386.47  Lifetime  −£5251.03  −0.512  £10 246.09  −£4998.79  −£5228.58  −0.612  £2198.07  −£7016.21    Deterministic sensitivity analysis   Probabilistic sensitivity analysis     Incremental cost  Incremental QALY  ICER  INMB  Incremental cost  Incremental QALY  ICER  INMB  1 year  −£748.20  0.002  Rituximab dominates  £785.44  −£761.19  0.001  Rituximab dominates  £777.54  5 years  −£1355.82  −0.014  £95 494.13  £1071.86  −£1383.61  −0.014  £101 665.93  £1111.42  10 years  −£2201.37  −0.091  £24 256.91  £386.32  −£2217.16  −0.092  £24 222.17  £386.47  Lifetime  −£5251.03  −0.512  £10 246.09  −£4998.79  −£5228.58  −0.612  £2198.07  −£7016.21  Figure 2 presents the cost-effectiveness plane showing incremental costs versus incremental QALY at 1 year, 5 year and over a lifetime. There is a threshold line at £20 000 per QALY for 10 000 PSA simulations. At 1 year and 5 years post-treatment the majority of simulated ICERs are in the right-hand side of the plane, indicating rituximab is more effective. There is a majority of patients in the lower half of the plane indicating that at 5 years post-treatment, rituximab therapy is cheaper. The vast majority are below the £20 000 per QALY threshold set by NICE as the acceptable limit for the cost-effectiveness [43]. Over a lifetime, the majority of patients are in the left lower quadrant showing that rituximab therapy is cheaper but less effective. FIGURE 2: View largeDownload slide Cost-effectiveness plane showing incremental costs versus incremental QALY at 1, 5 and 10 years post-treatment, and over a lifetime. Threshold line at £20 000 per QALY for 10 000 PSA simulations. FIGURE 2: View largeDownload slide Cost-effectiveness plane showing incremental costs versus incremental QALY at 1, 5 and 10 years post-treatment, and over a lifetime. Threshold line at £20 000 per QALY for 10 000 PSA simulations. Cost At 5 years post-treatment the cost for the mPR was −£13 116.65 and the cost for the rituximab regimen was £11 760.83, showing that the mPR is more expensive than rituximab with an incremental cost of −£1355.82. At 1-year post-treatment, the cost of mPR and rituximab was £8676.10 and £7927.90, respectively, giving an incremental cost of −£748.20. At 10 years post-treatment, the cost of mPR was £17 834.30 and for rituximab was £15 632.93, indicating that rituximab continues to be cheaper with an incremental cost of −£2201.37. Over a lifetime the cost of mPR is £29 943.80 compared with £24 692.77 for the mPR; an incremental cost of −£5251.03 (Table 6). QALY The QALY gains for mPR and rituximab were 3.712 and 3.697, respectively at 5 years post-treatment, 0.952 and 0.954, respectively at 1 year, 6.603 and 6.513, respectively at 10 years, and 14.162 and 13.650, respectively over a lifetime. Therefore, at 1-year rituximab confers QALY benefits over mPR but this is reversed by 5 years and continues over a lifetime. INMB At 1 year, 5 years and 10 years post-treatment the INMB of rituximab therapy is £785.44, £1071.86 and £386.32, respectively, indicating rituximab is more cost-effective. Over a lifetime, the INMB is −£4998.79, showing mPR is the more cost-effective option (Table 6). Deterministic sensitivity analysis Constrained to address outcomes with a mixed-protocol rituximab analysis the sensitivity analysis confirms that a major driver of cost for rituximab was the number of infusions required. The original four-dose regimen is too expensive at 5 years post-treatment but for the B-cell titrating regimen and the regimen described by Dahan et al. [27], at 5 years post-treatment, rituximab is the cost-effective option. The other major drivers of cost-effectiveness in the rituximab arm were death rate and the probability of reaching remission. For the mPR arm the main driver of the cost appears to be the frequency of infusions with removal of the cost of IV methylprednisolone resulting in the mPR being more cost-effective at 5 years post-treatment. The use of pulsed monthly IV cyclophosphamide alongside daily oral prednisolone (again without IV methylprednisolone) also resulted in the mPR being the most cost-effective at 5 years post-treatment. See Figure 3 for full tornado plot of sensitivity analysis. FIGURE 3: View largeDownload slide Tornado plot for deterministic sensitivity analysis. FIGURE 3: View largeDownload slide Tornado plot for deterministic sensitivity analysis. CEAC Figure 4 shows the CEAC for the comparison based on the 10 000 PSA simulations. It shows the likelihood that rituximab is cost-effective compared with mPR over a range of willingness-to-pay per QALY gain threshold values (lambda). At a lambda of £20 000 rituximab has a 64% chance of being the cost-effective option at 5 years post-treatment. At a threshold of £30 000 this falls to 61%. This reflects the fact that rituximab is the cheaper option at this time point but with a slightly reduced QALY. FIGURE 4: View largeDownload slide CEAC for the comparison based on the 10 000 PSA simulations. FIGURE 4: View largeDownload slide CEAC for the comparison based on the 10 000 PSA simulations. Threshold analysis In order for rituximab to be the most cost-effective option over a lifetime, threshold analysis shows that the transition probability for treatment to active disease, partial remission and complete remission would have to change from 0.51250 to 0.61706, from 0.28500 to 0.22387 and from 0.20250 to 0.15907, respectively. Alternatively, the transition probability for active disease to death and partial remission to death for rituximab would have to change from 0.00315 to 0.00136 and from 0.00680 to 0.00225, respectively. Threshold analysis to determine the cost at which rituximab represents the cost-effective option over a lifetime showed that due to the disparity in quality of life there is no price at which it is cost-effective over a lifetime. DISCUSSION The NHS, as with healthcare systems around the world, endeavours to provide the best care possible, with limited resources, for its ageing population and increasingly complex patients. This has resulted in NICE, the regulatory body, considering not only the health benefits of therapies but also their economic impact. Rituximab has become increasingly important in the treatment of a range of autoimmune conditions [48–58]. Its attraction lies in its more directed immunoregulation and reduced side-effect profile as compared with other immunosuppressants. Its single-dose cost, however, has limited its use in conditions such as MN, especially where there is a paucity of evidence from RCTs available. With this lack of RCTs but with good evidence that rituximab can provide a benefit for patients in a number of trials and case series [24–28], we constructed a Markov model to assess its cost-effectiveness when compared with the standard of care, i.e. the mPR. Using costs from the UK NHS we found that at every time point analysed rituximab was the cheapest option and this was especially true if using the B-cell titration regimen. At 1 year post-treatment, the QALY was better using rituximab than the mPR, but over a lifetime this reduced with the mPR providing an increment of approximately half a QALY. However, rituximab may still represent value for money given that the cost savings are so high for every QALY lost. It appears that the main driver of cost for the mPR is the frequency of infusions, adding cost to an inexpensive medication such as methylprednisolone. This is also true for rituximab, with the original regimen, in which patients have four doses, proving less cost-effective [25]. In the B-cell titration regimen [24], patients continue to have a good response to treatment but with fewer infusions, making it consistently more cost-effective. The reduction in quality of life for rituximab over time is in part associated with the slightly increased risk of death and to a lesser extent the higher risk of relapse after rituximab. Our model, however, is a conservative estimate for the quality of life benefits from rituximab, as we do not take into account late complications associated with the therapies. It is well documented that there is an increased risk of malignancy many years after treatment with cyclophosphamide [59]. Rituximab in contrast, appears to have fewer complications and no indication of an increased risk of malignancy. Our model does not capture the quality of life associated with the provision of treatment, such as early onset side effects, notably nausea in cyclophosphamide or with the number of visits. With the reduced side-effect profile and reduced hospital visits needed for rituximab therapy one could deduce that this would contribute to an improved quality of life although this is not possible to prove in this model. This is the most comprehensive estimate of the cost-effectiveness of treatment for PMN to date but it does come with limitations. The spread of results on the scatterplot for the PSA at the lifetime horizon indicates significant uncertainty in the results with the robustness of data available degenerating over time. This highlights the need for further good quality long-term prospective research comparing these therapies. Another limitation is that this evaluation was based on a naīve comparison; if other single arm or cohort study data becomes available it may be that an indirect comparison would then be feasible. Due to the paucity of RCTs investigating the efficacy of rituximab in PMN we opted to base the rituximab arm on the largest data series available for its use in this condition. This is a prospective observational study with all the limitations this confers on the data such as patient selection and centre bias, but it remains the most robust data available. This and the Jha study used to inform the model are international studies (Italy and India), but for precision our model is costed to the UK health system. At present, there are no large-scale clinical trials published using rituximab in a UK population, and there have been no large clinical trials in the UK using cyclophosphamide for the treatment of PMN. Another limitation has been the assignment of utility values to the disease. There are good validated data for population norms but renal-specific quality of life data are scarce. This meant that for active disease and RRT we had to convert SF-36 scores to utility values using standard methods [39–42]. PMN can be a slowly progressing disease with many patients following a relapsing and remitting pattern over a number of years. Here, we used only the rates for transition to ESRD and RRT as described in the two papers. This is likely to have underestimated the degree to which patients progressed to ESRD over a lifetime due to the relatively short follow-up time of the studies. Given the uncertainty already apparent in the model over a lifetime, it adds further evidence for the need for long-term RCTs in PMN. This model has only included the cost of therapy at a tertiary level. It was beyond the scope of the study to assess the overall societal cost and there is likely to be significant cost to patients, families and carers in the form of lost days of work, travel costs and equipment costs. The cost of primary healthcare contact has also not been included in this model. CONCLUSION Rituximab has shown promise as a therapy for PMN in a number of studies but the high cost of the medication has proven to be a barrier to its widespread acceptance. Here, we have constructed the most detailed economic model yet for the treatment of PMN and show that rituximab is not more expensive than the gold standard treatment and is cheaper over a lifetime. This work highlights the uncertainty surrounding PMN treatment with the small number of RCTs available to guide practitioners and commissioning bodies. Based on the evidence available, the longer term effectiveness of rituximab in PMN needs further evaluation, and importantly, long-term trials comparing rituximab with cyclophosphamide-based therapy should be undertaken to help establish the most cost-effective management of the condition. SUPPLEMENTARY DATA Supplementary data are available at ndt online. ACKNOWLEDGEMENTS Special thanks go to Dr Ian Jacob, Manchester Centre for Health Economics, University of Manchester, UK for discussions on the model. An abstract of this research was presented at the American Society of Nephrology in Chicago, November 2016. FUNDING This research was supported financially by Kidneys for Life Charity (charity no. 505256). P.B. acknowledges support from Medical Research Council Project grant MR/J010847/1, and EU Framework 7 Programme Grant 305608, ‘EURenOmics’. We also acknowledge support from the Manchester Academic Healthcare Science Centre (MAHSC) (186/200). CONFLICT OF INTEREST STATEMENT M.V. received consultancy fees from Chemocentryx for work in vasculitis. REFERENCES 1 McGrogan A, Franssen CFM, de Vries CS. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transplant  2011; 26: 414– 430 Google Scholar CrossRef Search ADS PubMed  2 Schieppati A, Mosconi L, Perna A et al.   Prognosis of untreated patients with idiopathic membranous nephropathy. N Engl J Med  1993; 329: 85– 89 Google Scholar CrossRef Search ADS PubMed  3 Beck LHJr, Bonegio RGB, Lambeau G et al.   M-type phospholipase a 2Receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med  2009; 361: 11– 21 Google Scholar CrossRef Search ADS PubMed  4 Stanescu HC, Arcos-Burgos M, Medlar A et al.   Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med  2011; 364: 616– 626 Google Scholar CrossRef Search ADS PubMed  5 Coenen MJH, Hofstra JM, Debiec H et al.   Phospholipase A2 Receptor (PLA2R1) sequence variants in idiopathic membranous nephropathy. J Am Soc Nephrol  2013; 24: 677– 683 Google Scholar CrossRef Search ADS PubMed  6 Kanigicherla D, Gummadova J, McKenzie EA et al.   Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy. Kidney Int  2013; 83: 940– 948 Google Scholar CrossRef Search ADS PubMed  7 Hofstra JM, Debiec H, Short CD et al.   Antiphospholipase A2 Receptor antibody titer and subclass in idiopathic membranous nephropathy. J Am Soc Nephrol  2012; 23: 1735– 1743 Google Scholar CrossRef Search ADS PubMed  8 Hofstra JM, Wetzels JFM. Management of patients with membranous nephropathy. Nephrol Dial Transplant  2012; 27: 6– 9 Google Scholar CrossRef Search ADS PubMed  9 Hofstra JM, Beck LH, Beck DM et al.   Anti-phospholipase A2 Receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clin J Am Soc Nephrol  2011; 6: 1286– 1291 Google Scholar CrossRef Search ADS PubMed  10 Bech AP, Hofstra JM, Brenchley PE et al.   Association of Anti-PLA2R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy. Clin J Am Soc Nephrol  2014; 9: 1386– 1392 Google Scholar CrossRef Search ADS PubMed  11 Ruggenenti P, Debiec H, Ruggiero B et al.   Anti-phospholipase A2 Receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. J Am Soc Nephrol  2015; 26: 2545– 2558 Google Scholar CrossRef Search ADS PubMed  12 Beck LH, Fervenza FC, Beck DM et al.   Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol  2011; 22: 1543– 1550 Google Scholar CrossRef Search ADS PubMed  13 Hoxha E, Thiele I, Zahner G et al.   Phospholipase A2 Receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy. J Am Soc Nephrol  2014; 25: 1357– 1366 Google Scholar CrossRef Search ADS PubMed  14 Eknoyan G, Eckardt KU, Kasiske BL. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int  2012; 2: 186– 197 Google Scholar CrossRef Search ADS   15 Ponticelli C, Zucchelli P, Imbasciati E et al.   Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med  1984; 310: 946– 950 Google Scholar CrossRef Search ADS PubMed  16 Ponticelli C, Zucchelli P, Passerini P et al.   A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int  1995; 48: 1600– 1604 Google Scholar CrossRef Search ADS PubMed  17 Ponticelli C, Altieri P, Scolari F et al.   A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol  1998; 9: 444– 450 Google Scholar PubMed  18 Jha V, Ganguli A, Saha TK et al.   A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. J Am Soc Nephrol  2007; 18: 1899– 1904 Google Scholar CrossRef Search ADS PubMed  19 Dussol B, Morange S, Burtey S et al.   Mycophenolate mofetil monotherapy in membranous nephropathy: a 1-year randomized controlled trial. Am J Kidney Dis  2008; 52: 699– 705 Google Scholar CrossRef Search ADS PubMed  20 Chan TM, Lin AW, Tang SC et al.   Prospective controlled study on mycophenolate mofetil and prednisolone in the treatment of membranous nephropathy with nephrotic syndrome. Nephrology (Carlton)  2007; 12: 576– 581 Google Scholar CrossRef Search ADS PubMed  21 Praga M, Barrio V, Juárez GF et al.   Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial. Kidney Int  2007; 71: 924– 930 Google Scholar CrossRef Search ADS PubMed  22 Wetzels JFM. Tacrolimus in membranous nephropathy. Kidney Int  2008; 73: 238 Google Scholar CrossRef Search ADS PubMed  23 Yuan H, Liu N, Sun G-D et al.   Effect of prolonged tacrolimus treatment in idiopathic membranous nephropathy with nephrotic syndrome. Pharmacology  2013; 91: 259– 266 Google Scholar CrossRef Search ADS PubMed  24 Cravedi P, Ruggenenti P, Sghirlanzoni MC et al.   Titrating rituximab to circulating B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy. Clin J Am Soc Nephrol  2007; 2: 932– 937 Google Scholar CrossRef Search ADS PubMed  25 Remuzzi G, Chiurchiu C, Abbate M et al.   Rituximab for idiopathic membranous nephropathy. Lancet  2002; 360: 923– 924 Google Scholar CrossRef Search ADS PubMed  26 Ruggenenti P, Cravedi P, Chianca A et al.   Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol  2012; 23: 1416– 1425 Google Scholar CrossRef Search ADS PubMed  27 Dahan K, Debiec H, Plaisier E et al.   Rituximab for severe membranous nephropathy: a 6-month trial with extended follow-up. J Am Soc Nephrol  2017; 28: 348– 358 Google Scholar CrossRef Search ADS PubMed  28 Dahan K, Debiec H, Plaisier E et al.   GEMRITUX study group. Rituximab for severe membranous nephropathy: a 6-month trial with extended follow-up. J Am Soc Nephrol  2017; 28: 348– 358 Google Scholar CrossRef Search ADS PubMed  29 Sonnenberg FA, Beck JR. Markov models in medical decision making a practical guide. medical decision making. Med Decis Making  1993; 13: 322– 338 Google Scholar CrossRef Search ADS PubMed  30 Kanigicherla DAK, Hamilton P, Venning MC et al.   Results of survey on management of membranous nephropathy in the United Kingdom *on behalf of the UK MN RADAR steering group. Nephrol Dial Transplant  2015; 30: iii108– iii108 Google Scholar CrossRef Search ADS   31 Kanigicherla DAK, Short CD, Roberts SA et al.   Long-term outcomes of persistent disease and relapse in primary membranous nephropathy. Nephrol Dialysis Transplant  2016; 31: 2108– 2114 Google Scholar CrossRef Search ADS   32 Gilg J, Pruthi R, Fogarty D. UK Renal Registry 17th Annual Report: Chapter 1 UK renal replacement therapy incidence in 2013: National and Centre-specific Analyses. Nephron  2015; 129: 1– 29 Google Scholar CrossRef Search ADS PubMed  33 Office of National Statistics. Historic and Projected Mortality Rates (qx) from the 2010-based UK Life Tables: Principal Projection, 1951-2060. https://www.ons.gov.uk/ons/rel/lifetables/historic-and-projected-mortality-data-from-the-uk-life-tables/2010-based/rft-qx-principal.xls (15 December 2017, date last accessed) 34 NHS Reference Costs 2014 to 2015. https://www.gov.uk/government/publications/nhs-reference-costs-2014-to-2015 (14 December 2017, date last accessed) 35 Higgins JP, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions . Chichester, UK: John Wiley & Sons, Ltd, 2008 Google Scholar CrossRef Search ADS   36 Drugs and pharmaceutical electronic market information (eMit). https://www.gov.uk/government/publications/drugs-and-pharmaceutical-electronic-market-information-emit (25 January 2016, date last accessed) 37 Joint Formulary Committee. British National Formulary . 69th edn. London: BMJ Group and Pharmaceutical Press, 2015 38 Sacco JJ, Botten J, Macbeth F et al.   The average body surface area of adult cancer patients in the UK: a multicentre retrospective study. PLoS ONE  2010; 5: e8933 Google Scholar CrossRef Search ADS PubMed  39 Wyld M, Morton RL, Hayen A et al.   A systematic review and meta-analysis of utility-based quality of life in chronic kidney disease treatments. PLoS Med  2012; 9: e1001307 Google Scholar CrossRef Search ADS PubMed  40 Kind P, Hardman G, Macran S. UK population norms for EQ-5D. York, UK: Centre for Health Economics, University of York, Working Papers, 1999 41 Ara R, Brazier J. Deriving an algorithm to convert the eight mean SF-36 dimension scores into a mean EQ-5D preference-based score from published studies (where patient level data are not available). Value Health  2008; 11: 1131– 1143 Google Scholar CrossRef Search ADS PubMed  42 Libório AB, Santos JPL, Minete NFA et al.   Proteinuria is associated with quality of life and depression in adults with primary glomerulopathy and preserved renal function. PLoS ONE  2012; 7: e37763 Google Scholar CrossRef Search ADS PubMed  43 NICE. Process and methods guides: guide to the methods of technology appraisal 2013. https://www.nice.org.uk/process/pmg9/chapter/foreward (3 March 2016, date last accessed) 44 Kanigicherla DA, Hamilton P, Czapla K et al.   Intravenous pulse cyclophosphamide and steroids induce immunological and clinical remission in new-incident and relapsing primary membranous nephropathy. Nephrology (Carlton)  2018; 23: 60– 68 Google Scholar CrossRef Search ADS PubMed  45 Briggs A, Fenn P. Confidence intervals or surfaces? Uncertainty on the cost‐effectiveness plane. Health Econ  1998; 7: 723– 740 Google Scholar CrossRef Search ADS PubMed  46 Fenwick E, O’Brien BJ, Briggs A. Cost-effectiveness acceptability curves–facts, fallacies and frequently asked questions. Health Econ  2004; 13: 405– 415 Google Scholar CrossRef Search ADS PubMed  47 Eddy DM, Hollingworth W, Caro JJ; ISPOR-SMDM Modeling Good Research Practices Task Force. Model transparency and validation: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force-7. Med Decis Making  2012; 32: 733– 743 Google Scholar CrossRef Search ADS PubMed  48 Stone JH, Merkel PA, Spiera R et al.   Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med  2010; 363: 221– 232 Google Scholar CrossRef Search ADS PubMed  49 Jones RB, Tervaert JWC, Hauser T et al.   Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med  2010; 363: 211– 220 Google Scholar CrossRef Search ADS PubMed  50 Buch MH, Smolen JS, Betteridge N et al.   Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. BMJ Publishing Group Ltd and European League against Rheumatism  2011; 70: 909– 920 51 Walsh M, Jayne D. Rituximab in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis and systemic lupus erythematosus: past, present and future. Kidney Int  2007; 72: 676– 682 Google Scholar CrossRef Search ADS PubMed  52 Keogh KA, Ytterberg SR, Fervenza FC et al.   Rituximab for refractory Wegener’s granulomatosis. Am J Respir Crit Care Med  2006; 173: 180– 187 Google Scholar CrossRef Search ADS PubMed  53 Pillebout E, Rocha F, Fardet L et al.   Successful outcome using rituximab as the only immunomodulation in Henoch-Schonlein purpura: case report. Nephrol Dial Transplant  2011; 26: 2044– 2046 Google Scholar CrossRef Search ADS PubMed  54 Gürcan HM, Keskin DB, Stern JNH et al.   A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacology  2009; 9: 10– 25 Google Scholar CrossRef Search ADS   55 Jones RB, Ferraro AJ, Chaudhry AN et al.   A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum  2009; 60: 2156– 2168 Google Scholar CrossRef Search ADS PubMed  56 Pindi ST, Michot J-M, Snanoudj R et al.   Successful outcome of a corticodependent Henoch-Schönlein purpura adult with rituximab. Case Reports in Medicine, vol. 2014, Article ID 619218, 4 pages, 2014. doi:10.1155/2014/619218 57 Smith KGC, Jones RB, Burns SM et al.   Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: remission, relapse, and re-treatment. Arthritis Rheum  2006; 54: 2970– 2982 Google Scholar CrossRef Search ADS PubMed  58 Stasi R, Stipa E, Del Poeta G et al.   Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab. Rheumatology  2006; 45: 1432– 1436 Google Scholar CrossRef Search ADS PubMed  59 van den Brand JAJG, van Dijk PR, Hofstra JM et al.   Cancer risk after cyclophosphamide treatment in idiopathic membranous nephropathy. Clin J Am Soc Nephrol  2014; 9: 1066– 1073 Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Rituximab versus the modified Ponticelli regimen in the treatment of primary membranous nephropathy: a Health Economic Model

Loading next page...
 
/lp/ou_press/rituximab-versus-the-modified-ponticelli-regimen-in-the-treatment-of-NiTS0H5AH9
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
ISSN
0931-0509
eISSN
1460-2385
D.O.I.
10.1093/ndt/gfy049
Publisher site
See Article on Publisher Site

Abstract

Abstract Background Membranous nephropathy is among the most common causes of nephrotic syndrome worldwide, with a high healthcare burden. Treatment using the modified Ponticelli regimen (mPR) has remained the standard of care for decades, but newer therapies such as rituximab offer promising results with reduced side effects. The cost of this treatment, however, is perceived as a barrier to widespread use, especially in resource limited healthcare systems. Methods We developed a decision-analytic model to estimate the cost-effectiveness of rituximab versus the mPR from the perspective of the National Health Service in the UK over a 1 year, 5 year and lifetime horizon. Primary outcome is the cost-effectiveness of rituximab versus mPR at 5 years post-treatment. Secondary outcomes are cost-effectiveness at 1 and 10 years post-treatment and over a lifetime. Results At 1-year post-treatment, rituximab therapy dominates mPR. At 5 years post-treatment, rituximab therapy is cheaper than the Ponticelli regimen but at a loss of 0.014 quality-adjusted life years (QALYs) with an incremental cost-effectiveness ratio (ICER) of £95 494.13. Over a lifetime, rituximab remains the cheaper option with an incremental cost of −£5251.03 but with a reduced quality of life (incremental QALY of −0.512) giving an ICER of £10 246.09. Conclusions Our analysis indicates that rituximab has the potential to be a cost-effective treatment in the short and medium terms despite the high single-dose cost. This evaluation suggests that further research is warranted and highlights the need for a high-quality clinical trial to confirm the efficacy and cost-effectiveness of rituximab versus the current standard of care. Markov model, membranous nephropathy, nephrotic syndrome INTRODUCTION Membranous nephropathy (MN) is one of the most common causes of adult nephrotic syndrome worldwide with a high healthcare burden in which ∼20% of patients progress to end-stage renal disease (ESRD) [1, 2]. MN has two distinct entities with primary MN (PMN) now considered to be an autoimmune disease since the discovery of the M-type of phospholipase A2 receptor 1 (anti-PLA2R) antibodies [3–7]. In PMN, disease activity and prognosis is still measured by proteinuria level and renal excretory function, with the risk of renal decline falling in the presence of a reduction in proteinuria [6, 8–13]. A key marker of treatment efficacy in PMN is, therefore, control of proteinuria, with or without immunosuppression [14]. Such immunosuppression is generally a combination of alkylating agents and steroids, as used in studies by Ponticelli et al. [15–18]. This regimen of rotating high-dose intravenous steroids and immunosuppression was first described in 1984 and has been the mainstay of treatment ever since [15]. Initially using methylprednisolone and chlorambucil, it was later modified to include methylprednisolone and cyclophosphamide [15–18]. Despite its treatment success, the modified Ponticelli regimen (mPR) bears a significant side-effect profile, including an increased risk of infection, osteoporosis, diabetes mellitus, weight gain, haemorrhagic cystitis, infertility and malignancy [16]. This led many researchers to search for alternative therapies including tacrolimus and mycophenolate mofetil, but with little evidence to show any improvement in outcomes [19–23]. Rituximab has been used extensively in cancer therapy since the late 1990s and more recently for autoimmune diseases. A number of case series and studies have demonstrated potential in PMN but so far randomized controlled trials (RCTs) have been scarce [24–28]. This, combined with the high cost of the medication itself, has restricted its widespread use in resource limited, evidence based, healthcare systems such as the National Health Service (NHS) in the UK. We developed a decision-analytic model to estimate the cost-effectiveness of rituximab therapy versus the standard of care, namely the mPR for the treatment of PMN. MATERIALS AND METHODS A cost-effectiveness analysis was carried out using a stochastic cohort Markov model developed using standard methods [29], conducted from the perspective of current practice in the UK NHS at 2015 prices. The primary outcome was the cost-effectiveness of rituximab versus mPR at 5 years post-treatment. Secondary outcomes were cost-effectiveness at 1 and 10 years post-treatment and over a lifetime. A literature search revealed no studies directly comparing rituximab versus mPR and, therefore, data was taken from the only studies of sufficient size to afford representative outcome assessment as described below. The analysis employed the cost–utility framework where the main measure of benefit is the quality-adjusted life year (QALY) and with analysis outcomes presented in terms of incremental cost-effectiveness ratios (ICERs) of cost per QALY gained. Choice of comparator Here we have used the mPR, which is the standard of treatment as per the Kidney Disease: Improving Global Outcomes guidelines, having established that the majority of UK renal centres use versions of the mPR as described previously [9, 17, 18, 30]. Model structure The model was developed in consultation with an expert panel including physicians, health economists and clinical scientists, and was identical for each treatment arm (Figure 1). FIGURE 1: View largeDownload slide Model structure. FIGURE 1: View largeDownload slide Model structure. For the treatment phase, all patients were assumed to experience active disease and costs were calculated from the papers described below. Following the treatment phase, patients could transition to (persistent) active disease, partial remission or complete remission. Health states then included sustained remission, relapse, ESRD (conservative management, haemo- or peritoneal dialysis and renal transplant) or death. Following the initial treatment phase, patients transitioned between health states on 3-monthly cycles over a lifetime horizon. PMN is generally considered a disease of middle age with the median age of patients with PMN at diagnosis being 53 years; we therefore extended the lifetime over an additional 47 years corresponding to a maximum survival of 100 years [31]. Parameter values Model parameter values and effectiveness of the interventions were based on the most robust data available for each arm; Jha et al. for the mPR arm and Ruggenenti et al. for the rituximab arm [18, 26]. Jha et al. was a prospective RCT comparing the mPR with supportive care, in biopsy proven adults (>16 years) with nephrotic syndrome for >6 months duration and <2 months of treatment with either steroids or immunosuppression. There was a total of 93 patients completing the study, 47 receiving the mPR with oral cyclophosphamide and IV methylprednisolone. Ruggenenti et al. published an observational study describing 100 consecutive patients, considered to be at a high risk of progressing to ESRD or to develop significant cardiovascular complications of their nephrotic syndrome, treated with rituximab and with no control group. It involved two distinct regimens; initially patients received rituximab in 4-weekly doses of 375 mg/m2. However, as many patients on this regimen were found to be B-cell deplete after only the first dose of rituximab, all subsequent patients from 2005 onwards were changed to a titrated regimen. Prior to inclusion in the trial, 32 patients had received treatment with alternative immunosuppression. Twenty of these did achieve partial remission prior to relapsing and necessitating treatment. The remaining 12 never achieved remission prior to starting rituximab. Of the 100 patients described in the study, 71 received a single 375 mg/m2 dose of rituximab and only received a second dose if their serum B cells were >5 cells/mm3. The cost of treatment in the rituximab arm was, therefore, calculated using the same proportion of treatments (with corresponding outcomes) as in this study. This resulted in 29% of the total cost of treatment being taken as the cost of the initial four doses of 375 mg/m2 rituximab regimen and 71% as the cost of the B-cell titration regimen. These papers were also chosen for their similar observational period allowing for a similar evaluation of care; however, partial and complete remission were defined slightly differently (Table 1), Jha et al. having more stringent remission criteria. In practice, there is a cohort of patients that spontaneously remit but the majority will remain nephrotic and, therefore, require treatment. Both these studies, as in clinical practice, have included patients with biopsy-proven MN and significant proteinuria warranting immunosuppression. Both studies have a male predominance reflecting clinical practice and the mean age at presentation was older in the study as described by Ruggenenti et al. Jha et al. was carried out in India and Ruggenenti et al. was carried out in Italy, two differing healthcare systems. However, both studies were carried out using standard methods and are comparable to use in the UK [18, 26] (Table 1). Table 1. Comparison of trials used for model Parameter  Jha et al. [18]  Ruggenenti et al. [26]  Country  India  Italy  Cohort size  47  100  Median follow-up  11 (10.5–11) years  29 (6–121) months  Age (years), mean ± SD  38.0 ± 13.6  51.5 ± 5.9  Gender       Male, n (%)  30 (63.8)  72 (72)   Female, n (%)  17 (36.2)  28 (28)  Disease state definitions      Active disease  Proteinuria ≥3.5 g/day or proteinuria ≥2.5 g/day and serum albumin <2.5 g/dL with oedema and hyperlipidaemia  Proteinuria ≥3.5 g/day  Partial remission  Proteinuria <2.0 g/day or ≥50% reduction from baseline  Proteinuria <3.0 g/day and ≥50% reduction from baseline  Complete remission  Proteinuria <0.2 g/day  Proteinuria <0.3 g/day and ≥50% reduction from baseline  Relapse  Not defined  Proteinuria ≥3.5 g/day after partial or complete remission  Adverse events, n (%)      During infusion       Allergy  0 (0)  8 (8)   Bronchial wheezing  0 (0)  10 (10)   Cutaneous rash  0 (0)  1 (1)   Hypotension  0 (0)  1 (1)   Stroke  0 (0)  3 (3)   TIA  0 (0)  2 (2)   Acute MI  1 (1)  3 (3)   Cancer  0 (0)  3 (3)   Respiratory tract infection  3 (6)  0 (0)   Urinary tract infection  5 (11)  0 (0)   Pyomyositis  1 (2)  0 (0)   Disseminated tuberculosis  1 (2)  0 (0)   Thrombosis  3 (0)  0 (0)   Deaths  1 (1)  4 (4)  Parameter  Jha et al. [18]  Ruggenenti et al. [26]  Country  India  Italy  Cohort size  47  100  Median follow-up  11 (10.5–11) years  29 (6–121) months  Age (years), mean ± SD  38.0 ± 13.6  51.5 ± 5.9  Gender       Male, n (%)  30 (63.8)  72 (72)   Female, n (%)  17 (36.2)  28 (28)  Disease state definitions      Active disease  Proteinuria ≥3.5 g/day or proteinuria ≥2.5 g/day and serum albumin <2.5 g/dL with oedema and hyperlipidaemia  Proteinuria ≥3.5 g/day  Partial remission  Proteinuria <2.0 g/day or ≥50% reduction from baseline  Proteinuria <3.0 g/day and ≥50% reduction from baseline  Complete remission  Proteinuria <0.2 g/day  Proteinuria <0.3 g/day and ≥50% reduction from baseline  Relapse  Not defined  Proteinuria ≥3.5 g/day after partial or complete remission  Adverse events, n (%)      During infusion       Allergy  0 (0)  8 (8)   Bronchial wheezing  0 (0)  10 (10)   Cutaneous rash  0 (0)  1 (1)   Hypotension  0 (0)  1 (1)   Stroke  0 (0)  3 (3)   TIA  0 (0)  2 (2)   Acute MI  1 (1)  3 (3)   Cancer  0 (0)  3 (3)   Respiratory tract infection  3 (6)  0 (0)   Urinary tract infection  5 (11)  0 (0)   Pyomyositis  1 (2)  0 (0)   Disseminated tuberculosis  1 (2)  0 (0)   Thrombosis  3 (0)  0 (0)   Deaths  1 (1)  4 (4)  MI, myocardial infarction Table 1. Comparison of trials used for model Parameter  Jha et al. [18]  Ruggenenti et al. [26]  Country  India  Italy  Cohort size  47  100  Median follow-up  11 (10.5–11) years  29 (6–121) months  Age (years), mean ± SD  38.0 ± 13.6  51.5 ± 5.9  Gender       Male, n (%)  30 (63.8)  72 (72)   Female, n (%)  17 (36.2)  28 (28)  Disease state definitions      Active disease  Proteinuria ≥3.5 g/day or proteinuria ≥2.5 g/day and serum albumin <2.5 g/dL with oedema and hyperlipidaemia  Proteinuria ≥3.5 g/day  Partial remission  Proteinuria <2.0 g/day or ≥50% reduction from baseline  Proteinuria <3.0 g/day and ≥50% reduction from baseline  Complete remission  Proteinuria <0.2 g/day  Proteinuria <0.3 g/day and ≥50% reduction from baseline  Relapse  Not defined  Proteinuria ≥3.5 g/day after partial or complete remission  Adverse events, n (%)      During infusion       Allergy  0 (0)  8 (8)   Bronchial wheezing  0 (0)  10 (10)   Cutaneous rash  0 (0)  1 (1)   Hypotension  0 (0)  1 (1)   Stroke  0 (0)  3 (3)   TIA  0 (0)  2 (2)   Acute MI  1 (1)  3 (3)   Cancer  0 (0)  3 (3)   Respiratory tract infection  3 (6)  0 (0)   Urinary tract infection  5 (11)  0 (0)   Pyomyositis  1 (2)  0 (0)   Disseminated tuberculosis  1 (2)  0 (0)   Thrombosis  3 (0)  0 (0)   Deaths  1 (1)  4 (4)  Parameter  Jha et al. [18]  Ruggenenti et al. [26]  Country  India  Italy  Cohort size  47  100  Median follow-up  11 (10.5–11) years  29 (6–121) months  Age (years), mean ± SD  38.0 ± 13.6  51.5 ± 5.9  Gender       Male, n (%)  30 (63.8)  72 (72)   Female, n (%)  17 (36.2)  28 (28)  Disease state definitions      Active disease  Proteinuria ≥3.5 g/day or proteinuria ≥2.5 g/day and serum albumin <2.5 g/dL with oedema and hyperlipidaemia  Proteinuria ≥3.5 g/day  Partial remission  Proteinuria <2.0 g/day or ≥50% reduction from baseline  Proteinuria <3.0 g/day and ≥50% reduction from baseline  Complete remission  Proteinuria <0.2 g/day  Proteinuria <0.3 g/day and ≥50% reduction from baseline  Relapse  Not defined  Proteinuria ≥3.5 g/day after partial or complete remission  Adverse events, n (%)      During infusion       Allergy  0 (0)  8 (8)   Bronchial wheezing  0 (0)  10 (10)   Cutaneous rash  0 (0)  1 (1)   Hypotension  0 (0)  1 (1)   Stroke  0 (0)  3 (3)   TIA  0 (0)  2 (2)   Acute MI  1 (1)  3 (3)   Cancer  0 (0)  3 (3)   Respiratory tract infection  3 (6)  0 (0)   Urinary tract infection  5 (11)  0 (0)   Pyomyositis  1 (2)  0 (0)   Disseminated tuberculosis  1 (2)  0 (0)   Thrombosis  3 (0)  0 (0)   Deaths  1 (1)  4 (4)  MI, myocardial infarction Probabilities Transition probabilities from the treatment phase to active disease, complete remission, partial remission, relapse and death were taken from the literature as above [18, 26]. Here, there was an assumption of constant hazards based on survival at a single time point. If a patient developed ESRD they transitioned into the renal replacement pathway, which includes conservative management. Transition probabilities after ESRD have been obtained from the UK Renal Registry (2014) [32]. Death rates were taken as those described in the study arms. At the end of the study follow-up, UK Office of National Statistics (ONS) data was used to provide a baseline mortality rate [33]. For patients in active disease, the death rate obtained from the ONS data was added to the transition probability from the studies. Once in partial or complete remission, death rate was taken as that in the ONS only. Death rates once in ESRD were taken from the UK Renal Registry. Costs Healthcare resource use included all healthcare contact, hospital stays, medication and serious adverse event (SAE) episodes described in each publication. The cost of relapse was taken as the cost of treatment but without SAEs. Costs for each hospital/healthcare contact and SAEs were taken from the NHS reference costs 2014–15 [34]. SD was estimated using S = Q3 – Q1/1.35 [35]. The cost of medication was taken from the Drugs and Pharmaceutical electronic market information (eMit) or from the British National Formulary (BNF) 2015 if not available [36, 37]. For medications for which the dose is based on body surface area we used 1.79 m2 [38]. Maintenance therapy was not costed. SD of costs is not provided by the BNF, so these were taken to be half the mean (Tables 2–4). See Supplementary Material for table with disaggregated costs of treatment stage for reference case and regimens used in sensitivity analysis. Table 2. Cost of medication (all medications oral unless otherwise stated; all doses based on weight of 70 kg patient; all prices based on dose and pack size) Medication  Dose  Pack size  Treatment dose  Mean value (£)  SD (£)  Source  IV methylprednisolone  1000 mg  1 pack  1000 mg  11.04  5.90  DFN009 eMIT  Prednisolone tablets  5 mg  100 tablets  35 mg  4.39  0.26  DFC045 eMIT  Oral cyclophosphamide  50 mg  100  140 mg  82.00  41.00  BNF  IV cyclophosphamide  1000 mg  1 vial    9.41  5.56  DHA014 eMIT  Rituximab  10 mg/mL  10 mL vial  375 mg/m2  174.63  87.32  BNF      50 mL vial    873.15  436.58  BNF  Basiliximab  20 mg  1 vial    842.38  421.19  BNF  IV hydrocortisone  100 mg/mL  1 mL amp  100 mg  1.08  0.54  BNF      5 mL amp  500 mg  4.89  2.45  BNF  Paracetamol  500 mg  100 tablets  1000 mg  0.52  0.29  DDM003 eMIT  Ondansetron  8 mg  10 tablets  8 mg  1.06  5.89  DDF029 eMIT  IV chlorphenamine  10 mg/1 mL  5 ampoules  10 mg  22.80  3.52  DCI002 eMIT  Oral mesna  400 mg  10 tablets  400 mg  42.90  21.45  BNF  IV mesna  100 mg/mL  4 mL vial  200 mg  3.95  1.98  BNF  Normal saline  1000 mL  1 bag  1000 mL  0.80  0.40  BNF  Medication  Dose  Pack size  Treatment dose  Mean value (£)  SD (£)  Source  IV methylprednisolone  1000 mg  1 pack  1000 mg  11.04  5.90  DFN009 eMIT  Prednisolone tablets  5 mg  100 tablets  35 mg  4.39  0.26  DFC045 eMIT  Oral cyclophosphamide  50 mg  100  140 mg  82.00  41.00  BNF  IV cyclophosphamide  1000 mg  1 vial    9.41  5.56  DHA014 eMIT  Rituximab  10 mg/mL  10 mL vial  375 mg/m2  174.63  87.32  BNF      50 mL vial    873.15  436.58  BNF  Basiliximab  20 mg  1 vial    842.38  421.19  BNF  IV hydrocortisone  100 mg/mL  1 mL amp  100 mg  1.08  0.54  BNF      5 mL amp  500 mg  4.89  2.45  BNF  Paracetamol  500 mg  100 tablets  1000 mg  0.52  0.29  DDM003 eMIT  Ondansetron  8 mg  10 tablets  8 mg  1.06  5.89  DDF029 eMIT  IV chlorphenamine  10 mg/1 mL  5 ampoules  10 mg  22.80  3.52  DCI002 eMIT  Oral mesna  400 mg  10 tablets  400 mg  42.90  21.45  BNF  IV mesna  100 mg/mL  4 mL vial  200 mg  3.95  1.98  BNF  Normal saline  1000 mL  1 bag  1000 mL  0.80  0.40  BNF  eMIT, Department of Health Electronic Market Information Tool accessed on 30 June 2016 and costs correct to December 2015 [36]. Prices given in eMIT are excluding value added tax, therefore, taken as 20%. BNF accessed on 30 April 2015 [37]. SDs for BNF medicines taken as mean/2 as they are not provided Table 2. Cost of medication (all medications oral unless otherwise stated; all doses based on weight of 70 kg patient; all prices based on dose and pack size) Medication  Dose  Pack size  Treatment dose  Mean value (£)  SD (£)  Source  IV methylprednisolone  1000 mg  1 pack  1000 mg  11.04  5.90  DFN009 eMIT  Prednisolone tablets  5 mg  100 tablets  35 mg  4.39  0.26  DFC045 eMIT  Oral cyclophosphamide  50 mg  100  140 mg  82.00  41.00  BNF  IV cyclophosphamide  1000 mg  1 vial    9.41  5.56  DHA014 eMIT  Rituximab  10 mg/mL  10 mL vial  375 mg/m2  174.63  87.32  BNF      50 mL vial    873.15  436.58  BNF  Basiliximab  20 mg  1 vial    842.38  421.19  BNF  IV hydrocortisone  100 mg/mL  1 mL amp  100 mg  1.08  0.54  BNF      5 mL amp  500 mg  4.89  2.45  BNF  Paracetamol  500 mg  100 tablets  1000 mg  0.52  0.29  DDM003 eMIT  Ondansetron  8 mg  10 tablets  8 mg  1.06  5.89  DDF029 eMIT  IV chlorphenamine  10 mg/1 mL  5 ampoules  10 mg  22.80  3.52  DCI002 eMIT  Oral mesna  400 mg  10 tablets  400 mg  42.90  21.45  BNF  IV mesna  100 mg/mL  4 mL vial  200 mg  3.95  1.98  BNF  Normal saline  1000 mL  1 bag  1000 mL  0.80  0.40  BNF  Medication  Dose  Pack size  Treatment dose  Mean value (£)  SD (£)  Source  IV methylprednisolone  1000 mg  1 pack  1000 mg  11.04  5.90  DFN009 eMIT  Prednisolone tablets  5 mg  100 tablets  35 mg  4.39  0.26  DFC045 eMIT  Oral cyclophosphamide  50 mg  100  140 mg  82.00  41.00  BNF  IV cyclophosphamide  1000 mg  1 vial    9.41  5.56  DHA014 eMIT  Rituximab  10 mg/mL  10 mL vial  375 mg/m2  174.63  87.32  BNF      50 mL vial    873.15  436.58  BNF  Basiliximab  20 mg  1 vial    842.38  421.19  BNF  IV hydrocortisone  100 mg/mL  1 mL amp  100 mg  1.08  0.54  BNF      5 mL amp  500 mg  4.89  2.45  BNF  Paracetamol  500 mg  100 tablets  1000 mg  0.52  0.29  DDM003 eMIT  Ondansetron  8 mg  10 tablets  8 mg  1.06  5.89  DDF029 eMIT  IV chlorphenamine  10 mg/1 mL  5 ampoules  10 mg  22.80  3.52  DCI002 eMIT  Oral mesna  400 mg  10 tablets  400 mg  42.90  21.45  BNF  IV mesna  100 mg/mL  4 mL vial  200 mg  3.95  1.98  BNF  Normal saline  1000 mL  1 bag  1000 mL  0.80  0.40  BNF  eMIT, Department of Health Electronic Market Information Tool accessed on 30 June 2016 and costs correct to December 2015 [36]. Prices given in eMIT are excluding value added tax, therefore, taken as 20%. BNF accessed on 30 April 2015 [37]. SDs for BNF medicines taken as mean/2 as they are not provided Table 3. Cost of healthcare provision (all costs given in British pounds sterling) Health service  Mean value  LQR  UQR  SD  Source  Delivery of chemo (1st)             Simple parenteral  257.00  136.00  311.00  129.63  SB12Z NHS ref costs   Complex and infusional  414.00  250.00  521.00  200.74  SB14Z NHS ref costs  Subsequent chemo  362.00  230.00  413.00  135.56  SB15Z NHS ref costs  AVF, graft or shunt DC  1910.66  1334.41  2342.81  746.96  YQ42Z NHS ref costs  PD-associated procedure DC  1268.00  503.00  1815.00  971.85  LA05Z NHS ref costs  Nephrology clinic  160.00  110.00  185.00  55.56  WF01A 361 NHS ref costs  Transplant clinic  358.00  220.00  493.00  202.22  WF01A 102 NHS ref costs  Haemodialysis             CKD via AVF at base  166.00  143.00  176.00  24.44  RENALCKD LD02A NHS ref costs  PD             Automated PD  71.00  50.00  67.00  12.59  RENALCKD LD12A NHS ref costs  Renal transplant             Cadaver NHB  12 845.93  10 179.00  14 250.00  3015.56  LA01A NHS ref costs   Cadaver HB  12 434.09  12 904.00  14 450.00  1145.19  LA02A NHS ref costs   Live donor  13 828.19  9996.00  17 756.00  5748.15  LA03A NHS ref costs  Pre-transplant workup             Live donor  1205.75  958.00  1559.00  445.19  LA11Z NHS ref costs  B-cell subsets  5.00  2.00  7.00  3.70  DAPS06 NHS ref costs  Health service  Mean value  LQR  UQR  SD  Source  Delivery of chemo (1st)             Simple parenteral  257.00  136.00  311.00  129.63  SB12Z NHS ref costs   Complex and infusional  414.00  250.00  521.00  200.74  SB14Z NHS ref costs  Subsequent chemo  362.00  230.00  413.00  135.56  SB15Z NHS ref costs  AVF, graft or shunt DC  1910.66  1334.41  2342.81  746.96  YQ42Z NHS ref costs  PD-associated procedure DC  1268.00  503.00  1815.00  971.85  LA05Z NHS ref costs  Nephrology clinic  160.00  110.00  185.00  55.56  WF01A 361 NHS ref costs  Transplant clinic  358.00  220.00  493.00  202.22  WF01A 102 NHS ref costs  Haemodialysis             CKD via AVF at base  166.00  143.00  176.00  24.44  RENALCKD LD02A NHS ref costs  PD             Automated PD  71.00  50.00  67.00  12.59  RENALCKD LD12A NHS ref costs  Renal transplant             Cadaver NHB  12 845.93  10 179.00  14 250.00  3015.56  LA01A NHS ref costs   Cadaver HB  12 434.09  12 904.00  14 450.00  1145.19  LA02A NHS ref costs   Live donor  13 828.19  9996.00  17 756.00  5748.15  LA03A NHS ref costs  Pre-transplant workup             Live donor  1205.75  958.00  1559.00  445.19  LA11Z NHS ref costs  B-cell subsets  5.00  2.00  7.00  3.70  DAPS06 NHS ref costs  NHS ref costs, NHS reference costs 2014–2015 [34]. LQR, lower quartile range; UQR, upper quartile range; DC, day case; AVF, arterioventricular fistula; PD, peritoneal dialysis; AKI, acute kidney injury; CKD, chronic kidney disease; NHB, non-heart beating donor; HB, heart beating donor; complex and infusional, complex parenteral and prolonged infusion treatment; SD estimated using S = Q3 – Q1/1.35 from Cochrane Handbook from Systematic Reviews and Interventions 2008 [35] Table 3. Cost of healthcare provision (all costs given in British pounds sterling) Health service  Mean value  LQR  UQR  SD  Source  Delivery of chemo (1st)             Simple parenteral  257.00  136.00  311.00  129.63  SB12Z NHS ref costs   Complex and infusional  414.00  250.00  521.00  200.74  SB14Z NHS ref costs  Subsequent chemo  362.00  230.00  413.00  135.56  SB15Z NHS ref costs  AVF, graft or shunt DC  1910.66  1334.41  2342.81  746.96  YQ42Z NHS ref costs  PD-associated procedure DC  1268.00  503.00  1815.00  971.85  LA05Z NHS ref costs  Nephrology clinic  160.00  110.00  185.00  55.56  WF01A 361 NHS ref costs  Transplant clinic  358.00  220.00  493.00  202.22  WF01A 102 NHS ref costs  Haemodialysis             CKD via AVF at base  166.00  143.00  176.00  24.44  RENALCKD LD02A NHS ref costs  PD             Automated PD  71.00  50.00  67.00  12.59  RENALCKD LD12A NHS ref costs  Renal transplant             Cadaver NHB  12 845.93  10 179.00  14 250.00  3015.56  LA01A NHS ref costs   Cadaver HB  12 434.09  12 904.00  14 450.00  1145.19  LA02A NHS ref costs   Live donor  13 828.19  9996.00  17 756.00  5748.15  LA03A NHS ref costs  Pre-transplant workup             Live donor  1205.75  958.00  1559.00  445.19  LA11Z NHS ref costs  B-cell subsets  5.00  2.00  7.00  3.70  DAPS06 NHS ref costs  Health service  Mean value  LQR  UQR  SD  Source  Delivery of chemo (1st)             Simple parenteral  257.00  136.00  311.00  129.63  SB12Z NHS ref costs   Complex and infusional  414.00  250.00  521.00  200.74  SB14Z NHS ref costs  Subsequent chemo  362.00  230.00  413.00  135.56  SB15Z NHS ref costs  AVF, graft or shunt DC  1910.66  1334.41  2342.81  746.96  YQ42Z NHS ref costs  PD-associated procedure DC  1268.00  503.00  1815.00  971.85  LA05Z NHS ref costs  Nephrology clinic  160.00  110.00  185.00  55.56  WF01A 361 NHS ref costs  Transplant clinic  358.00  220.00  493.00  202.22  WF01A 102 NHS ref costs  Haemodialysis             CKD via AVF at base  166.00  143.00  176.00  24.44  RENALCKD LD02A NHS ref costs  PD             Automated PD  71.00  50.00  67.00  12.59  RENALCKD LD12A NHS ref costs  Renal transplant             Cadaver NHB  12 845.93  10 179.00  14 250.00  3015.56  LA01A NHS ref costs   Cadaver HB  12 434.09  12 904.00  14 450.00  1145.19  LA02A NHS ref costs   Live donor  13 828.19  9996.00  17 756.00  5748.15  LA03A NHS ref costs  Pre-transplant workup             Live donor  1205.75  958.00  1559.00  445.19  LA11Z NHS ref costs  B-cell subsets  5.00  2.00  7.00  3.70  DAPS06 NHS ref costs  NHS ref costs, NHS reference costs 2014–2015 [34]. LQR, lower quartile range; UQR, upper quartile range; DC, day case; AVF, arterioventricular fistula; PD, peritoneal dialysis; AKI, acute kidney injury; CKD, chronic kidney disease; NHB, non-heart beating donor; HB, heart beating donor; complex and infusional, complex parenteral and prolonged infusion treatment; SD estimated using S = Q3 – Q1/1.35 from Cochrane Handbook from Systematic Reviews and Interventions 2008 [35] Table 4. Cost of AEs and SAEs (all costs given in British pounds sterling) Complication  Mean  LQR  UQR  SD  Source  Notes/assumptions  Jha et al. [18]   Respiratory tract infections  1540.00  1255.00  1685.00  318.52  DZ22Q NHS ref costs  Unspecified acute LRTI (0–1)   Urinary tract infections  1503.00  1233.00  1659.00  315.56  LA04S NHS ref costs  Kidney/UTI—no intervention (0–1)   Gluteal abscess  1358.00  960.00  1557.00  442.22  HD26G NHS ref costs  MSK signs or symptoms (0–3)   Bacterial meningitis  2339.00  1561.00  2638.00  797.78  AA22G NHS ref costs  Nervous system infections (0–4)   Pulmonary tuberculosis  2650.00  1702.00  3131.00  1058.52  DZ14J NHS ref costs  Pulmonary, pleural, other Tb   Septicaemia  1993.00  1586.00  2224.00  472.59  WJ06J NHS ref costs  Sepsis (0–1)   Deep-vein thrombosis  1362.00  992.00  1491.00  369.63  YQ51E NHS ref costs  DVT (0–2)  Ruggenenti et al. [26]   Acute MI  1505.00  1205.00  1701.00  367.41  EB10E NHS ref costs  Actual/Suspected MI (0–3)   Stroke  2348.00  1803.00  2597.00  588.15  AA35F NHS ref costs  Stroke (0–3)   TIA  1253.00  978.00  1393.00  307.41  AA29F NHS ref costs  TIA (0–4)   Lung cancer  3047.00  2063.00  3610.00  1145.93  DZ17R NHS ref costs  Resp. neoplasm (0–5)   Breast cancer  3357.00  1504.00  4554.00  2259.26  JA12F NHS ref costs  Malignant—intervention (0–2)   Prostate carcinoma  2268.00  1469.00  2660.00  882.22  LB06M NHS ref costs  Prostate Ca—intervention (0–1)  Complication  Mean  LQR  UQR  SD  Source  Notes/assumptions  Jha et al. [18]   Respiratory tract infections  1540.00  1255.00  1685.00  318.52  DZ22Q NHS ref costs  Unspecified acute LRTI (0–1)   Urinary tract infections  1503.00  1233.00  1659.00  315.56  LA04S NHS ref costs  Kidney/UTI—no intervention (0–1)   Gluteal abscess  1358.00  960.00  1557.00  442.22  HD26G NHS ref costs  MSK signs or symptoms (0–3)   Bacterial meningitis  2339.00  1561.00  2638.00  797.78  AA22G NHS ref costs  Nervous system infections (0–4)   Pulmonary tuberculosis  2650.00  1702.00  3131.00  1058.52  DZ14J NHS ref costs  Pulmonary, pleural, other Tb   Septicaemia  1993.00  1586.00  2224.00  472.59  WJ06J NHS ref costs  Sepsis (0–1)   Deep-vein thrombosis  1362.00  992.00  1491.00  369.63  YQ51E NHS ref costs  DVT (0–2)  Ruggenenti et al. [26]   Acute MI  1505.00  1205.00  1701.00  367.41  EB10E NHS ref costs  Actual/Suspected MI (0–3)   Stroke  2348.00  1803.00  2597.00  588.15  AA35F NHS ref costs  Stroke (0–3)   TIA  1253.00  978.00  1393.00  307.41  AA29F NHS ref costs  TIA (0–4)   Lung cancer  3047.00  2063.00  3610.00  1145.93  DZ17R NHS ref costs  Resp. neoplasm (0–5)   Breast cancer  3357.00  1504.00  4554.00  2259.26  JA12F NHS ref costs  Malignant—intervention (0–2)   Prostate carcinoma  2268.00  1469.00  2660.00  882.22  LB06M NHS ref costs  Prostate Ca—intervention (0–1)  NHS ref costs, NHS reference costs 2014–2015 [34]. LQR, lower quartile range; LRTI, lower respiratory tract infection; MSK, musculoskeletal; UQR, upper quartile range; CC score in parenthesis; TIA, transient ischaemic attack; DVT, deep venous thrombosis; UTI, urinary tract infection. All costs taken as non-elective short stay. SD estimated using SD = Q3 – Q1/1.35 from Cochrane Handbook from Systematic Reviews and Interventions 2008 [35] Table 4. Cost of AEs and SAEs (all costs given in British pounds sterling) Complication  Mean  LQR  UQR  SD  Source  Notes/assumptions  Jha et al. [18]   Respiratory tract infections  1540.00  1255.00  1685.00  318.52  DZ22Q NHS ref costs  Unspecified acute LRTI (0–1)   Urinary tract infections  1503.00  1233.00  1659.00  315.56  LA04S NHS ref costs  Kidney/UTI—no intervention (0–1)   Gluteal abscess  1358.00  960.00  1557.00  442.22  HD26G NHS ref costs  MSK signs or symptoms (0–3)   Bacterial meningitis  2339.00  1561.00  2638.00  797.78  AA22G NHS ref costs  Nervous system infections (0–4)   Pulmonary tuberculosis  2650.00  1702.00  3131.00  1058.52  DZ14J NHS ref costs  Pulmonary, pleural, other Tb   Septicaemia  1993.00  1586.00  2224.00  472.59  WJ06J NHS ref costs  Sepsis (0–1)   Deep-vein thrombosis  1362.00  992.00  1491.00  369.63  YQ51E NHS ref costs  DVT (0–2)  Ruggenenti et al. [26]   Acute MI  1505.00  1205.00  1701.00  367.41  EB10E NHS ref costs  Actual/Suspected MI (0–3)   Stroke  2348.00  1803.00  2597.00  588.15  AA35F NHS ref costs  Stroke (0–3)   TIA  1253.00  978.00  1393.00  307.41  AA29F NHS ref costs  TIA (0–4)   Lung cancer  3047.00  2063.00  3610.00  1145.93  DZ17R NHS ref costs  Resp. neoplasm (0–5)   Breast cancer  3357.00  1504.00  4554.00  2259.26  JA12F NHS ref costs  Malignant—intervention (0–2)   Prostate carcinoma  2268.00  1469.00  2660.00  882.22  LB06M NHS ref costs  Prostate Ca—intervention (0–1)  Complication  Mean  LQR  UQR  SD  Source  Notes/assumptions  Jha et al. [18]   Respiratory tract infections  1540.00  1255.00  1685.00  318.52  DZ22Q NHS ref costs  Unspecified acute LRTI (0–1)   Urinary tract infections  1503.00  1233.00  1659.00  315.56  LA04S NHS ref costs  Kidney/UTI—no intervention (0–1)   Gluteal abscess  1358.00  960.00  1557.00  442.22  HD26G NHS ref costs  MSK signs or symptoms (0–3)   Bacterial meningitis  2339.00  1561.00  2638.00  797.78  AA22G NHS ref costs  Nervous system infections (0–4)   Pulmonary tuberculosis  2650.00  1702.00  3131.00  1058.52  DZ14J NHS ref costs  Pulmonary, pleural, other Tb   Septicaemia  1993.00  1586.00  2224.00  472.59  WJ06J NHS ref costs  Sepsis (0–1)   Deep-vein thrombosis  1362.00  992.00  1491.00  369.63  YQ51E NHS ref costs  DVT (0–2)  Ruggenenti et al. [26]   Acute MI  1505.00  1205.00  1701.00  367.41  EB10E NHS ref costs  Actual/Suspected MI (0–3)   Stroke  2348.00  1803.00  2597.00  588.15  AA35F NHS ref costs  Stroke (0–3)   TIA  1253.00  978.00  1393.00  307.41  AA29F NHS ref costs  TIA (0–4)   Lung cancer  3047.00  2063.00  3610.00  1145.93  DZ17R NHS ref costs  Resp. neoplasm (0–5)   Breast cancer  3357.00  1504.00  4554.00  2259.26  JA12F NHS ref costs  Malignant—intervention (0–2)   Prostate carcinoma  2268.00  1469.00  2660.00  882.22  LB06M NHS ref costs  Prostate Ca—intervention (0–1)  NHS ref costs, NHS reference costs 2014–2015 [34]. LQR, lower quartile range; LRTI, lower respiratory tract infection; MSK, musculoskeletal; UQR, upper quartile range; CC score in parenthesis; TIA, transient ischaemic attack; DVT, deep venous thrombosis; UTI, urinary tract infection. All costs taken as non-elective short stay. SD estimated using SD = Q3 – Q1/1.35 from Cochrane Handbook from Systematic Reviews and Interventions 2008 [35] Utility/quality of life For many patients, the presenting symptoms that bring them to the notice of healthcare professionals, and ultimately to the diagnosis of PMN, is that of the nephrotic syndrome, namely oedema, increasing shortness of breath and fatigue. Currently there are limited data available on the quality of life (or utility) for patients with PMN, therefore, utility values for active disease were taken as that of active nephrotic syndrome, given these are the main symptoms a patient will experience when their disease is active [39]. For patients with partial or complete remission we used age- and sex-matched EQ-5D UK population norms [40]. Once patients reached ESRD, utility values were estimated using SF-36 values from Wyld et al. converted to utility scores [41, 42] (Table 5). Table 5. Quality of life utility values. ESRD. Partial remission and complete remission taken as the same Utility  Mean  LCI  UCI  SD/SE  Source  Notes  Complete remission  0.860  0.630  1.000  0.230  Kind et al. [40]  Age and sex matched  Partial remission  0.860  0.630  1.000  0.230  Kind et al. [40]    Active disease  0.738  0.422  1.000  0.317  Libório et al. [42]  SF-36 converted to EQ-5D  ESRD  0.800  0.650  0.940  0.030  Wyld et al. [39]  CKD (pre-treatment)  Conservative  0.620  0.360  0.890  0.090  Wyld et al. [39]  SF-36 converted to EQ-5D  Haemodialysis  0.680  0.530  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Peritoneal dialysis  0.710  0.590  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Renal transplant  0.820  0.740  0.900  0.040  Wyld et al. [39]  SF-36 converted to EQ-5D  Dead  0.000  0.000  0.000  0.000      Utility  Mean  LCI  UCI  SD/SE  Source  Notes  Complete remission  0.860  0.630  1.000  0.230  Kind et al. [40]  Age and sex matched  Partial remission  0.860  0.630  1.000  0.230  Kind et al. [40]    Active disease  0.738  0.422  1.000  0.317  Libório et al. [42]  SF-36 converted to EQ-5D  ESRD  0.800  0.650  0.940  0.030  Wyld et al. [39]  CKD (pre-treatment)  Conservative  0.620  0.360  0.890  0.090  Wyld et al. [39]  SF-36 converted to EQ-5D  Haemodialysis  0.680  0.530  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Peritoneal dialysis  0.710  0.590  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Renal transplant  0.820  0.740  0.900  0.040  Wyld et al. [39]  SF-36 converted to EQ-5D  Dead  0.000  0.000  0.000  0.000      CKD, chronic kidney disease; LCI, lower 95% confidence interval; UCI, 95% confidence interval. Table 5. Quality of life utility values. ESRD. Partial remission and complete remission taken as the same Utility  Mean  LCI  UCI  SD/SE  Source  Notes  Complete remission  0.860  0.630  1.000  0.230  Kind et al. [40]  Age and sex matched  Partial remission  0.860  0.630  1.000  0.230  Kind et al. [40]    Active disease  0.738  0.422  1.000  0.317  Libório et al. [42]  SF-36 converted to EQ-5D  ESRD  0.800  0.650  0.940  0.030  Wyld et al. [39]  CKD (pre-treatment)  Conservative  0.620  0.360  0.890  0.090  Wyld et al. [39]  SF-36 converted to EQ-5D  Haemodialysis  0.680  0.530  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Peritoneal dialysis  0.710  0.590  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Renal transplant  0.820  0.740  0.900  0.040  Wyld et al. [39]  SF-36 converted to EQ-5D  Dead  0.000  0.000  0.000  0.000      Utility  Mean  LCI  UCI  SD/SE  Source  Notes  Complete remission  0.860  0.630  1.000  0.230  Kind et al. [40]  Age and sex matched  Partial remission  0.860  0.630  1.000  0.230  Kind et al. [40]    Active disease  0.738  0.422  1.000  0.317  Libório et al. [42]  SF-36 converted to EQ-5D  ESRD  0.800  0.650  0.940  0.030  Wyld et al. [39]  CKD (pre-treatment)  Conservative  0.620  0.360  0.890  0.090  Wyld et al. [39]  SF-36 converted to EQ-5D  Haemodialysis  0.680  0.530  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Peritoneal dialysis  0.710  0.590  0.820  0.020  Wyld et al. [39]  SF-36 converted to EQ-5D  Renal transplant  0.820  0.740  0.900  0.040  Wyld et al. [39]  SF-36 converted to EQ-5D  Dead  0.000  0.000  0.000  0.000      CKD, chronic kidney disease; LCI, lower 95% confidence interval; UCI, 95% confidence interval. Cost-effectiveness analysis All costs are presented as mean cost per patient. Expected costs and QALYs were estimated for each arm and, where appropriate, ICERs calculated (derived from the incremental cost of treating with rituximab and the incremental QALY). ICERs below the £20 000 threshold would indicate that rituximab is considered cost-effective as set by National Institute for Health and Care Excellence (NICE) standards [43]. Following NICE guidelines, half cycle correction was conducted and a discount rate of 3.5% per annum was applied to all outcomes incurred beyond 1 year [43]. Incremental net monetary benefit Incremental net monetary benefit (INMBs) were calculated using the incremental QALY, the incremental cost and the lambda, which in this case is £20 000, as per NICE guidelines [43]. A positive value indicates that rituximab therapy is cost effective and, therefore, the preferred option when compared with the mPR. Deterministic sensitivity analysis We performed one-way sensitivity analysis on a range of parameters to assess the impact of each parameter on the outcome of the model at 5 years post-treatment as described by the INMB. For sensitivity analysis of the costs, these were altered, the quality of life and transition probabilities remaining unchanged. For sensitivity analysis of the transition probabilities, the costs remained unchanged. Exact alterations to costs and probabilities are given below. Rituximab regimens The study described by Ruggenenti et al. used to inform the rituximab arm in our model utilized two different regimens as described in the Materials and methods section. We therefore carried out a sensitivity analysis based on all patients in the rituximab arm receiving the original regimen consisting of 4-weekly infusions of 375 mg/m2 rituximab. We then carried out the analysis based on all patients in the rituximab arm receiving the B-cell titrated regimen, i.e. a single 375 mg/m2 dose of rituximab with a second dose if their serum B cells were subsequently >5 cells/mm3. For both of these, the costs in the Ponticelli arm remained unchanged. Further sensitivity analysis was carried out using the recently reported RCT described by Dahan et al. [27]. Here, patients in the treatment arm were given two doses of 375 mg/m2 rituximab on Days 1 and 8. For this analysis, only the costs in rituximab arm of the model were changed and all outcomes remained the same. Ponticelli regimens The mPR uses low-cost medications but requires multiple hospital admissions to receive steroid infusions. Therefore, to assess the impact that drug delivery has on the overall cost we performed a sensitivity analysis with patients only receiving oral prednisolone and no intravenous (IV) methylprednisolone, with cyclophosphamide remaining unchanged. We also assessed how a change in the cyclophosphamide regimen may affect the overall cost by carrying out a sensitivity analysis using pulsed monthly cyclophosphamide for 6 months with adjunctive oral prednisolone (with no IV methylprednisolone) as described by Kanigicherla et al. [44]. The costs for the rituximab arm remained unchanged for both of these analyses. Other To assess how the cost of drug delivery itself affects the model outcomes we performed a sensitivity analysis with an increase and decrease in the cost of the delivery of an infusion in a day-care setting by 20% and on the cost of the medication itself (rituximab and cyclophosphamide). For the cost of infusion delivery, the cost was altered in both arms. For the cost of medication, the cost was altered in each arm and analysed separately. In order to provide consistency, the cost of cancer in the original analysis was taken as the cost for the least severe form of the disease as per the NHS reference costs [34]. To assess whether the cost of cancer impacts on the results, we used the cost for the most severe form of the various cancers as reported in the NHS reference costs [34] for the sensitivity analysis. Given the known uncertainty in the quality of life measures available, we performed a sensitivity analysis on this by altering the utility value of partial remission to be the same as active disease instead of complete remission. This was changed in both arms simultaneously. Transition probabilities To investigate the impact of the transition probabilities on outcomes, we performed a number of analysis including altering the death rate to be equal in both arms, the chance of developing ESRD and needing renal replacement therapy (RRT) to be equal in both arms and the rate of relapse to be equal in both arms. We analysed the effect of treatment efficacy by altering the transition probabilities of going from the treatment phase to either active disease, partial remission or complete remission by making them equal in both arms. We then altered the chance of transitioning from active disease to remission, so that it was equal in both arms. We altered all transition probabilities to be equal in both arms with no change to costs or utility values. We also increased and decreased the probability, by 20%, of going into remission in the rituximab arm and keeping the Ponticelli arm unchanged. We then performed the same analysis by altering the transition probability in the Ponticelli arm and kept the rituximab arm unchanged. Probabilistic sensitivity analysis A probabilistic sensitivity analysis (PSA) was conducted with 10 000 Monte Carlo simulations based on random draws of all parameter values simultaneously from probability distributions. This provided 10 000 estimates of costs and QALYs, which were used to generate 10 000 ICERs and INMB estimates and allowed us to estimate the level of parameter uncertainty in the analysis. These simulated analyses were plotted on a cost-effectiveness plane and a cost-effectiveness acceptability curve (CEAC) [45]. The CEAC indicates the probability that rituximab is cost-effective versus mPR across a range of willingness to pay per QALY gain thresholds [46]. The higher the probability, the lower the uncertainty is in the model and decision. Validation We employed a number of tests to ensure the model was as valid as possible, although given the nature of the disease and lack of clinical trials, we were unable to perform a full validation. Validation was carried out using recognized techniques [47]. Face validation was carried out with each aspect of the model design, data sources and formulae, and eventual results were reviewed and discussed by a panel of experts including clinicians, clinical scientists and health economists. Internal validation was performed using deterministic sensitivity analysis and testing whether changes in model inputs led to changes in outputs in the expected direction—for example, by increasing the SAE/adverse events (AE) risks for rituximab we expected the cost-effectiveness of that intervention would be reduced. Verification of the code was performed by one clinician and two separate and independent health economists. As there are no other health economic or epidemiological models or RCTs in this area, cross validation, external validation and predictive validation were not possible. RESULTS ICER At 5 years post-treatment, rituximab therapy is cheaper than the Ponticelli regimen but at a loss of 0.014 QALYs. Here the ICER is £95 494.13 (incremental cost −£1355.82 and incremental QALY −0.014). At 1-year post-treatment, rituximab therapy dominates mPR. At 10 years post-treatment, rituximab remains the cheaper option with an incremental cost of −£2201.37. With an incremental QALY of −0.091 the ICER is £24 256.91. Over a lifetime, the ICER was £10 246.09, obtained from the incremental per-patient cost of −£5251.03 and incremental QALY of −0.512. See Supplementary Material for frequency of patients in each disease state at 5 years post-treatment with corresponding costs and QALYs (Table 6). Table 6. Results for both probabilistic and deterministic sensitivity analysis at one, 5 and 10 years post-treatment and over a lifetime (lambda taken as £20 000)   Deterministic sensitivity analysis   Probabilistic sensitivity analysis     Incremental cost  Incremental QALY  ICER  INMB  Incremental cost  Incremental QALY  ICER  INMB  1 year  −£748.20  0.002  Rituximab dominates  £785.44  −£761.19  0.001  Rituximab dominates  £777.54  5 years  −£1355.82  −0.014  £95 494.13  £1071.86  −£1383.61  −0.014  £101 665.93  £1111.42  10 years  −£2201.37  −0.091  £24 256.91  £386.32  −£2217.16  −0.092  £24 222.17  £386.47  Lifetime  −£5251.03  −0.512  £10 246.09  −£4998.79  −£5228.58  −0.612  £2198.07  −£7016.21    Deterministic sensitivity analysis   Probabilistic sensitivity analysis     Incremental cost  Incremental QALY  ICER  INMB  Incremental cost  Incremental QALY  ICER  INMB  1 year  −£748.20  0.002  Rituximab dominates  £785.44  −£761.19  0.001  Rituximab dominates  £777.54  5 years  −£1355.82  −0.014  £95 494.13  £1071.86  −£1383.61  −0.014  £101 665.93  £1111.42  10 years  −£2201.37  −0.091  £24 256.91  £386.32  −£2217.16  −0.092  £24 222.17  £386.47  Lifetime  −£5251.03  −0.512  £10 246.09  −£4998.79  −£5228.58  −0.612  £2198.07  −£7016.21  Table 6. Results for both probabilistic and deterministic sensitivity analysis at one, 5 and 10 years post-treatment and over a lifetime (lambda taken as £20 000)   Deterministic sensitivity analysis   Probabilistic sensitivity analysis     Incremental cost  Incremental QALY  ICER  INMB  Incremental cost  Incremental QALY  ICER  INMB  1 year  −£748.20  0.002  Rituximab dominates  £785.44  −£761.19  0.001  Rituximab dominates  £777.54  5 years  −£1355.82  −0.014  £95 494.13  £1071.86  −£1383.61  −0.014  £101 665.93  £1111.42  10 years  −£2201.37  −0.091  £24 256.91  £386.32  −£2217.16  −0.092  £24 222.17  £386.47  Lifetime  −£5251.03  −0.512  £10 246.09  −£4998.79  −£5228.58  −0.612  £2198.07  −£7016.21    Deterministic sensitivity analysis   Probabilistic sensitivity analysis     Incremental cost  Incremental QALY  ICER  INMB  Incremental cost  Incremental QALY  ICER  INMB  1 year  −£748.20  0.002  Rituximab dominates  £785.44  −£761.19  0.001  Rituximab dominates  £777.54  5 years  −£1355.82  −0.014  £95 494.13  £1071.86  −£1383.61  −0.014  £101 665.93  £1111.42  10 years  −£2201.37  −0.091  £24 256.91  £386.32  −£2217.16  −0.092  £24 222.17  £386.47  Lifetime  −£5251.03  −0.512  £10 246.09  −£4998.79  −£5228.58  −0.612  £2198.07  −£7016.21  Figure 2 presents the cost-effectiveness plane showing incremental costs versus incremental QALY at 1 year, 5 year and over a lifetime. There is a threshold line at £20 000 per QALY for 10 000 PSA simulations. At 1 year and 5 years post-treatment the majority of simulated ICERs are in the right-hand side of the plane, indicating rituximab is more effective. There is a majority of patients in the lower half of the plane indicating that at 5 years post-treatment, rituximab therapy is cheaper. The vast majority are below the £20 000 per QALY threshold set by NICE as the acceptable limit for the cost-effectiveness [43]. Over a lifetime, the majority of patients are in the left lower quadrant showing that rituximab therapy is cheaper but less effective. FIGURE 2: View largeDownload slide Cost-effectiveness plane showing incremental costs versus incremental QALY at 1, 5 and 10 years post-treatment, and over a lifetime. Threshold line at £20 000 per QALY for 10 000 PSA simulations. FIGURE 2: View largeDownload slide Cost-effectiveness plane showing incremental costs versus incremental QALY at 1, 5 and 10 years post-treatment, and over a lifetime. Threshold line at £20 000 per QALY for 10 000 PSA simulations. Cost At 5 years post-treatment the cost for the mPR was −£13 116.65 and the cost for the rituximab regimen was £11 760.83, showing that the mPR is more expensive than rituximab with an incremental cost of −£1355.82. At 1-year post-treatment, the cost of mPR and rituximab was £8676.10 and £7927.90, respectively, giving an incremental cost of −£748.20. At 10 years post-treatment, the cost of mPR was £17 834.30 and for rituximab was £15 632.93, indicating that rituximab continues to be cheaper with an incremental cost of −£2201.37. Over a lifetime the cost of mPR is £29 943.80 compared with £24 692.77 for the mPR; an incremental cost of −£5251.03 (Table 6). QALY The QALY gains for mPR and rituximab were 3.712 and 3.697, respectively at 5 years post-treatment, 0.952 and 0.954, respectively at 1 year, 6.603 and 6.513, respectively at 10 years, and 14.162 and 13.650, respectively over a lifetime. Therefore, at 1-year rituximab confers QALY benefits over mPR but this is reversed by 5 years and continues over a lifetime. INMB At 1 year, 5 years and 10 years post-treatment the INMB of rituximab therapy is £785.44, £1071.86 and £386.32, respectively, indicating rituximab is more cost-effective. Over a lifetime, the INMB is −£4998.79, showing mPR is the more cost-effective option (Table 6). Deterministic sensitivity analysis Constrained to address outcomes with a mixed-protocol rituximab analysis the sensitivity analysis confirms that a major driver of cost for rituximab was the number of infusions required. The original four-dose regimen is too expensive at 5 years post-treatment but for the B-cell titrating regimen and the regimen described by Dahan et al. [27], at 5 years post-treatment, rituximab is the cost-effective option. The other major drivers of cost-effectiveness in the rituximab arm were death rate and the probability of reaching remission. For the mPR arm the main driver of the cost appears to be the frequency of infusions with removal of the cost of IV methylprednisolone resulting in the mPR being more cost-effective at 5 years post-treatment. The use of pulsed monthly IV cyclophosphamide alongside daily oral prednisolone (again without IV methylprednisolone) also resulted in the mPR being the most cost-effective at 5 years post-treatment. See Figure 3 for full tornado plot of sensitivity analysis. FIGURE 3: View largeDownload slide Tornado plot for deterministic sensitivity analysis. FIGURE 3: View largeDownload slide Tornado plot for deterministic sensitivity analysis. CEAC Figure 4 shows the CEAC for the comparison based on the 10 000 PSA simulations. It shows the likelihood that rituximab is cost-effective compared with mPR over a range of willingness-to-pay per QALY gain threshold values (lambda). At a lambda of £20 000 rituximab has a 64% chance of being the cost-effective option at 5 years post-treatment. At a threshold of £30 000 this falls to 61%. This reflects the fact that rituximab is the cheaper option at this time point but with a slightly reduced QALY. FIGURE 4: View largeDownload slide CEAC for the comparison based on the 10 000 PSA simulations. FIGURE 4: View largeDownload slide CEAC for the comparison based on the 10 000 PSA simulations. Threshold analysis In order for rituximab to be the most cost-effective option over a lifetime, threshold analysis shows that the transition probability for treatment to active disease, partial remission and complete remission would have to change from 0.51250 to 0.61706, from 0.28500 to 0.22387 and from 0.20250 to 0.15907, respectively. Alternatively, the transition probability for active disease to death and partial remission to death for rituximab would have to change from 0.00315 to 0.00136 and from 0.00680 to 0.00225, respectively. Threshold analysis to determine the cost at which rituximab represents the cost-effective option over a lifetime showed that due to the disparity in quality of life there is no price at which it is cost-effective over a lifetime. DISCUSSION The NHS, as with healthcare systems around the world, endeavours to provide the best care possible, with limited resources, for its ageing population and increasingly complex patients. This has resulted in NICE, the regulatory body, considering not only the health benefits of therapies but also their economic impact. Rituximab has become increasingly important in the treatment of a range of autoimmune conditions [48–58]. Its attraction lies in its more directed immunoregulation and reduced side-effect profile as compared with other immunosuppressants. Its single-dose cost, however, has limited its use in conditions such as MN, especially where there is a paucity of evidence from RCTs available. With this lack of RCTs but with good evidence that rituximab can provide a benefit for patients in a number of trials and case series [24–28], we constructed a Markov model to assess its cost-effectiveness when compared with the standard of care, i.e. the mPR. Using costs from the UK NHS we found that at every time point analysed rituximab was the cheapest option and this was especially true if using the B-cell titration regimen. At 1 year post-treatment, the QALY was better using rituximab than the mPR, but over a lifetime this reduced with the mPR providing an increment of approximately half a QALY. However, rituximab may still represent value for money given that the cost savings are so high for every QALY lost. It appears that the main driver of cost for the mPR is the frequency of infusions, adding cost to an inexpensive medication such as methylprednisolone. This is also true for rituximab, with the original regimen, in which patients have four doses, proving less cost-effective [25]. In the B-cell titration regimen [24], patients continue to have a good response to treatment but with fewer infusions, making it consistently more cost-effective. The reduction in quality of life for rituximab over time is in part associated with the slightly increased risk of death and to a lesser extent the higher risk of relapse after rituximab. Our model, however, is a conservative estimate for the quality of life benefits from rituximab, as we do not take into account late complications associated with the therapies. It is well documented that there is an increased risk of malignancy many years after treatment with cyclophosphamide [59]. Rituximab in contrast, appears to have fewer complications and no indication of an increased risk of malignancy. Our model does not capture the quality of life associated with the provision of treatment, such as early onset side effects, notably nausea in cyclophosphamide or with the number of visits. With the reduced side-effect profile and reduced hospital visits needed for rituximab therapy one could deduce that this would contribute to an improved quality of life although this is not possible to prove in this model. This is the most comprehensive estimate of the cost-effectiveness of treatment for PMN to date but it does come with limitations. The spread of results on the scatterplot for the PSA at the lifetime horizon indicates significant uncertainty in the results with the robustness of data available degenerating over time. This highlights the need for further good quality long-term prospective research comparing these therapies. Another limitation is that this evaluation was based on a naīve comparison; if other single arm or cohort study data becomes available it may be that an indirect comparison would then be feasible. Due to the paucity of RCTs investigating the efficacy of rituximab in PMN we opted to base the rituximab arm on the largest data series available for its use in this condition. This is a prospective observational study with all the limitations this confers on the data such as patient selection and centre bias, but it remains the most robust data available. This and the Jha study used to inform the model are international studies (Italy and India), but for precision our model is costed to the UK health system. At present, there are no large-scale clinical trials published using rituximab in a UK population, and there have been no large clinical trials in the UK using cyclophosphamide for the treatment of PMN. Another limitation has been the assignment of utility values to the disease. There are good validated data for population norms but renal-specific quality of life data are scarce. This meant that for active disease and RRT we had to convert SF-36 scores to utility values using standard methods [39–42]. PMN can be a slowly progressing disease with many patients following a relapsing and remitting pattern over a number of years. Here, we used only the rates for transition to ESRD and RRT as described in the two papers. This is likely to have underestimated the degree to which patients progressed to ESRD over a lifetime due to the relatively short follow-up time of the studies. Given the uncertainty already apparent in the model over a lifetime, it adds further evidence for the need for long-term RCTs in PMN. This model has only included the cost of therapy at a tertiary level. It was beyond the scope of the study to assess the overall societal cost and there is likely to be significant cost to patients, families and carers in the form of lost days of work, travel costs and equipment costs. The cost of primary healthcare contact has also not been included in this model. CONCLUSION Rituximab has shown promise as a therapy for PMN in a number of studies but the high cost of the medication has proven to be a barrier to its widespread acceptance. Here, we have constructed the most detailed economic model yet for the treatment of PMN and show that rituximab is not more expensive than the gold standard treatment and is cheaper over a lifetime. This work highlights the uncertainty surrounding PMN treatment with the small number of RCTs available to guide practitioners and commissioning bodies. Based on the evidence available, the longer term effectiveness of rituximab in PMN needs further evaluation, and importantly, long-term trials comparing rituximab with cyclophosphamide-based therapy should be undertaken to help establish the most cost-effective management of the condition. SUPPLEMENTARY DATA Supplementary data are available at ndt online. ACKNOWLEDGEMENTS Special thanks go to Dr Ian Jacob, Manchester Centre for Health Economics, University of Manchester, UK for discussions on the model. An abstract of this research was presented at the American Society of Nephrology in Chicago, November 2016. FUNDING This research was supported financially by Kidneys for Life Charity (charity no. 505256). P.B. acknowledges support from Medical Research Council Project grant MR/J010847/1, and EU Framework 7 Programme Grant 305608, ‘EURenOmics’. We also acknowledge support from the Manchester Academic Healthcare Science Centre (MAHSC) (186/200). CONFLICT OF INTEREST STATEMENT M.V. received consultancy fees from Chemocentryx for work in vasculitis. REFERENCES 1 McGrogan A, Franssen CFM, de Vries CS. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transplant  2011; 26: 414– 430 Google Scholar CrossRef Search ADS PubMed  2 Schieppati A, Mosconi L, Perna A et al.   Prognosis of untreated patients with idiopathic membranous nephropathy. N Engl J Med  1993; 329: 85– 89 Google Scholar CrossRef Search ADS PubMed  3 Beck LHJr, Bonegio RGB, Lambeau G et al.   M-type phospholipase a 2Receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med  2009; 361: 11– 21 Google Scholar CrossRef Search ADS PubMed  4 Stanescu HC, Arcos-Burgos M, Medlar A et al.   Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med  2011; 364: 616– 626 Google Scholar CrossRef Search ADS PubMed  5 Coenen MJH, Hofstra JM, Debiec H et al.   Phospholipase A2 Receptor (PLA2R1) sequence variants in idiopathic membranous nephropathy. J Am Soc Nephrol  2013; 24: 677– 683 Google Scholar CrossRef Search ADS PubMed  6 Kanigicherla D, Gummadova J, McKenzie EA et al.   Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy. Kidney Int  2013; 83: 940– 948 Google Scholar CrossRef Search ADS PubMed  7 Hofstra JM, Debiec H, Short CD et al.   Antiphospholipase A2 Receptor antibody titer and subclass in idiopathic membranous nephropathy. J Am Soc Nephrol  2012; 23: 1735– 1743 Google Scholar CrossRef Search ADS PubMed  8 Hofstra JM, Wetzels JFM. Management of patients with membranous nephropathy. Nephrol Dial Transplant  2012; 27: 6– 9 Google Scholar CrossRef Search ADS PubMed  9 Hofstra JM, Beck LH, Beck DM et al.   Anti-phospholipase A2 Receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clin J Am Soc Nephrol  2011; 6: 1286– 1291 Google Scholar CrossRef Search ADS PubMed  10 Bech AP, Hofstra JM, Brenchley PE et al.   Association of Anti-PLA2R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy. Clin J Am Soc Nephrol  2014; 9: 1386– 1392 Google Scholar CrossRef Search ADS PubMed  11 Ruggenenti P, Debiec H, Ruggiero B et al.   Anti-phospholipase A2 Receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. J Am Soc Nephrol  2015; 26: 2545– 2558 Google Scholar CrossRef Search ADS PubMed  12 Beck LH, Fervenza FC, Beck DM et al.   Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol  2011; 22: 1543– 1550 Google Scholar CrossRef Search ADS PubMed  13 Hoxha E, Thiele I, Zahner G et al.   Phospholipase A2 Receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy. J Am Soc Nephrol  2014; 25: 1357– 1366 Google Scholar CrossRef Search ADS PubMed  14 Eknoyan G, Eckardt KU, Kasiske BL. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int  2012; 2: 186– 197 Google Scholar CrossRef Search ADS   15 Ponticelli C, Zucchelli P, Imbasciati E et al.   Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med  1984; 310: 946– 950 Google Scholar CrossRef Search ADS PubMed  16 Ponticelli C, Zucchelli P, Passerini P et al.   A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int  1995; 48: 1600– 1604 Google Scholar CrossRef Search ADS PubMed  17 Ponticelli C, Altieri P, Scolari F et al.   A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol  1998; 9: 444– 450 Google Scholar PubMed  18 Jha V, Ganguli A, Saha TK et al.   A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. J Am Soc Nephrol  2007; 18: 1899– 1904 Google Scholar CrossRef Search ADS PubMed  19 Dussol B, Morange S, Burtey S et al.   Mycophenolate mofetil monotherapy in membranous nephropathy: a 1-year randomized controlled trial. Am J Kidney Dis  2008; 52: 699– 705 Google Scholar CrossRef Search ADS PubMed  20 Chan TM, Lin AW, Tang SC et al.   Prospective controlled study on mycophenolate mofetil and prednisolone in the treatment of membranous nephropathy with nephrotic syndrome. Nephrology (Carlton)  2007; 12: 576– 581 Google Scholar CrossRef Search ADS PubMed  21 Praga M, Barrio V, Juárez GF et al.   Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial. Kidney Int  2007; 71: 924– 930 Google Scholar CrossRef Search ADS PubMed  22 Wetzels JFM. Tacrolimus in membranous nephropathy. Kidney Int  2008; 73: 238 Google Scholar CrossRef Search ADS PubMed  23 Yuan H, Liu N, Sun G-D et al.   Effect of prolonged tacrolimus treatment in idiopathic membranous nephropathy with nephrotic syndrome. Pharmacology  2013; 91: 259– 266 Google Scholar CrossRef Search ADS PubMed  24 Cravedi P, Ruggenenti P, Sghirlanzoni MC et al.   Titrating rituximab to circulating B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy. Clin J Am Soc Nephrol  2007; 2: 932– 937 Google Scholar CrossRef Search ADS PubMed  25 Remuzzi G, Chiurchiu C, Abbate M et al.   Rituximab for idiopathic membranous nephropathy. Lancet  2002; 360: 923– 924 Google Scholar CrossRef Search ADS PubMed  26 Ruggenenti P, Cravedi P, Chianca A et al.   Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol  2012; 23: 1416– 1425 Google Scholar CrossRef Search ADS PubMed  27 Dahan K, Debiec H, Plaisier E et al.   Rituximab for severe membranous nephropathy: a 6-month trial with extended follow-up. J Am Soc Nephrol  2017; 28: 348– 358 Google Scholar CrossRef Search ADS PubMed  28 Dahan K, Debiec H, Plaisier E et al.   GEMRITUX study group. Rituximab for severe membranous nephropathy: a 6-month trial with extended follow-up. J Am Soc Nephrol  2017; 28: 348– 358 Google Scholar CrossRef Search ADS PubMed  29 Sonnenberg FA, Beck JR. Markov models in medical decision making a practical guide. medical decision making. Med Decis Making  1993; 13: 322– 338 Google Scholar CrossRef Search ADS PubMed  30 Kanigicherla DAK, Hamilton P, Venning MC et al.   Results of survey on management of membranous nephropathy in the United Kingdom *on behalf of the UK MN RADAR steering group. Nephrol Dial Transplant  2015; 30: iii108– iii108 Google Scholar CrossRef Search ADS   31 Kanigicherla DAK, Short CD, Roberts SA et al.   Long-term outcomes of persistent disease and relapse in primary membranous nephropathy. Nephrol Dialysis Transplant  2016; 31: 2108– 2114 Google Scholar CrossRef Search ADS   32 Gilg J, Pruthi R, Fogarty D. UK Renal Registry 17th Annual Report: Chapter 1 UK renal replacement therapy incidence in 2013: National and Centre-specific Analyses. Nephron  2015; 129: 1– 29 Google Scholar CrossRef Search ADS PubMed  33 Office of National Statistics. Historic and Projected Mortality Rates (qx) from the 2010-based UK Life Tables: Principal Projection, 1951-2060. https://www.ons.gov.uk/ons/rel/lifetables/historic-and-projected-mortality-data-from-the-uk-life-tables/2010-based/rft-qx-principal.xls (15 December 2017, date last accessed) 34 NHS Reference Costs 2014 to 2015. https://www.gov.uk/government/publications/nhs-reference-costs-2014-to-2015 (14 December 2017, date last accessed) 35 Higgins JP, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions . Chichester, UK: John Wiley & Sons, Ltd, 2008 Google Scholar CrossRef Search ADS   36 Drugs and pharmaceutical electronic market information (eMit). https://www.gov.uk/government/publications/drugs-and-pharmaceutical-electronic-market-information-emit (25 January 2016, date last accessed) 37 Joint Formulary Committee. British National Formulary . 69th edn. London: BMJ Group and Pharmaceutical Press, 2015 38 Sacco JJ, Botten J, Macbeth F et al.   The average body surface area of adult cancer patients in the UK: a multicentre retrospective study. PLoS ONE  2010; 5: e8933 Google Scholar CrossRef Search ADS PubMed  39 Wyld M, Morton RL, Hayen A et al.   A systematic review and meta-analysis of utility-based quality of life in chronic kidney disease treatments. PLoS Med  2012; 9: e1001307 Google Scholar CrossRef Search ADS PubMed  40 Kind P, Hardman G, Macran S. UK population norms for EQ-5D. York, UK: Centre for Health Economics, University of York, Working Papers, 1999 41 Ara R, Brazier J. Deriving an algorithm to convert the eight mean SF-36 dimension scores into a mean EQ-5D preference-based score from published studies (where patient level data are not available). Value Health  2008; 11: 1131– 1143 Google Scholar CrossRef Search ADS PubMed  42 Libório AB, Santos JPL, Minete NFA et al.   Proteinuria is associated with quality of life and depression in adults with primary glomerulopathy and preserved renal function. PLoS ONE  2012; 7: e37763 Google Scholar CrossRef Search ADS PubMed  43 NICE. Process and methods guides: guide to the methods of technology appraisal 2013. https://www.nice.org.uk/process/pmg9/chapter/foreward (3 March 2016, date last accessed) 44 Kanigicherla DA, Hamilton P, Czapla K et al.   Intravenous pulse cyclophosphamide and steroids induce immunological and clinical remission in new-incident and relapsing primary membranous nephropathy. Nephrology (Carlton)  2018; 23: 60– 68 Google Scholar CrossRef Search ADS PubMed  45 Briggs A, Fenn P. Confidence intervals or surfaces? Uncertainty on the cost‐effectiveness plane. Health Econ  1998; 7: 723– 740 Google Scholar CrossRef Search ADS PubMed  46 Fenwick E, O’Brien BJ, Briggs A. Cost-effectiveness acceptability curves–facts, fallacies and frequently asked questions. Health Econ  2004; 13: 405– 415 Google Scholar CrossRef Search ADS PubMed  47 Eddy DM, Hollingworth W, Caro JJ; ISPOR-SMDM Modeling Good Research Practices Task Force. Model transparency and validation: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force-7. Med Decis Making  2012; 32: 733– 743 Google Scholar CrossRef Search ADS PubMed  48 Stone JH, Merkel PA, Spiera R et al.   Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med  2010; 363: 221– 232 Google Scholar CrossRef Search ADS PubMed  49 Jones RB, Tervaert JWC, Hauser T et al.   Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med  2010; 363: 211– 220 Google Scholar CrossRef Search ADS PubMed  50 Buch MH, Smolen JS, Betteridge N et al.   Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. BMJ Publishing Group Ltd and European League against Rheumatism  2011; 70: 909– 920 51 Walsh M, Jayne D. Rituximab in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis and systemic lupus erythematosus: past, present and future. Kidney Int  2007; 72: 676– 682 Google Scholar CrossRef Search ADS PubMed  52 Keogh KA, Ytterberg SR, Fervenza FC et al.   Rituximab for refractory Wegener’s granulomatosis. Am J Respir Crit Care Med  2006; 173: 180– 187 Google Scholar CrossRef Search ADS PubMed  53 Pillebout E, Rocha F, Fardet L et al.   Successful outcome using rituximab as the only immunomodulation in Henoch-Schonlein purpura: case report. Nephrol Dial Transplant  2011; 26: 2044– 2046 Google Scholar CrossRef Search ADS PubMed  54 Gürcan HM, Keskin DB, Stern JNH et al.   A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacology  2009; 9: 10– 25 Google Scholar CrossRef Search ADS   55 Jones RB, Ferraro AJ, Chaudhry AN et al.   A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum  2009; 60: 2156– 2168 Google Scholar CrossRef Search ADS PubMed  56 Pindi ST, Michot J-M, Snanoudj R et al.   Successful outcome of a corticodependent Henoch-Schönlein purpura adult with rituximab. Case Reports in Medicine, vol. 2014, Article ID 619218, 4 pages, 2014. doi:10.1155/2014/619218 57 Smith KGC, Jones RB, Burns SM et al.   Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: remission, relapse, and re-treatment. Arthritis Rheum  2006; 54: 2970– 2982 Google Scholar CrossRef Search ADS PubMed  58 Stasi R, Stipa E, Del Poeta G et al.   Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab. Rheumatology  2006; 45: 1432– 1436 Google Scholar CrossRef Search ADS PubMed  59 van den Brand JAJG, van Dijk PR, Hofstra JM et al.   Cancer risk after cyclophosphamide treatment in idiopathic membranous nephropathy. Clin J Am Soc Nephrol  2014; 9: 1066– 1073 Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Nephrology Dialysis TransplantationOxford University Press

Published: Mar 29, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off