Advice
Key points from the evidence
Key points from the evidence
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The content of this evidence summary was up-to-date in November 2016. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information. |
Summary
Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are types of glomerulonephritis. MCD is an immune-mediated condition affecting the kidneys, FSGS is not a specific disease entity but a histological lesion, often of unknown aetiology, which is characterised by segmental areas of glomerular sclerosis. Most of the evidence for using rituximab in adults with MCD and FSGS comes from uncontrolled and non‑randomised observational studies performed outside the UK with small sample sizes. The populations in the included studies varied, as did the dose of rituximab used, adjuvant treatment, and follow-up time. The studies in people with MCD and FSGS in their native kidneys reported that treatment with rituximab reduced disease relapse rates, or achieved complete or partial remission. The study in renal transplant recipients with MCD and FSGS did not report any significant difference in treatment outcomes for those treated with rituximab compared to those receiving other immunosuppressants. However, the limitations outlined above make it difficult to draw firm conclusions on the efficacy and safety of rituximab for treating adults with MCD or FSGS.
Regulatory status: off-label. This topic was prioritised because there was a high volume of requests from the NHS.
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Effectiveness
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Safety
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Patient factors
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Resource implications
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Introduction and current guidance
Minimal change disease (MCD) is an immune-mediated condition affecting the kidneys. It is usually of unknown cause, but can sometimes be associated with Hodgkin's disease or the use of nonsteroidal anti-inflammatory drugs (Oxford Textbook of Medicine, 5th Edition). Focal segmental glomerulosclerosis (FSGS) is not a specific disease entity but a histological lesion, often of unknown aetiology, which is characterised by segmental areas of glomerular sclerosis (Oxford Textbook of Medicine, 5th Edition).
The general management of MCD and FSGS in adults includes controlling the condition, and preventing end-stage renal disease and associated complications. Evidence‑based recommendations on the management of the various types of glomerulonephritis, including MCD and FSGS, were published by the International Society of Nephrology in 2012 in the KDIGO clinical practice guideline for glomerulonephritis. Treatment with a corticosteroid such as prednisolone is recommended for the initial episode of MCD or FSGS. For adults with MCD, a calcineurin inhibitor (such as ciclosporin or tacrolimius) or oral cyclophosphamide are alternatives for those with relative contraindications or intolerance to corticosteroids. A calcineurin inhibitor, cyclophosphamide or mycophenolate mofetil are recommended for frequently relapsing MCD. For adults with FSGS, calcineurin inhibitors can be considered as alternatives for those with relative contraindications or intolerance to corticosteroids. Relapses of FSGS are managed using the same treatment as in MCD. Ciclosporin is recommended for steroid-resistant FSGS. Combination treatment with mycophenolate mofetil and high-dose dexamethasone is recommended for people with steroid-resistant FSGS who are intolerant to ciclosporin (KDIGO clinical practice guideline for glomerulonephritis). However, specialists involved in the production of this evidence summary commented that prednisolone is usually used in the UK, rather than dexamethasone.
Not all of these drugs are licensed specifically for use in people with MCD or FSGS and use of some of these drugs would be off‑label (see the summaries of product characteristics for the individual drugs for specific prescribing information).
Product overview
Rituximab concentrate for solution for intravenous infusion (MabThera, Roche Products Limited) is licensed in adults for treating non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, rheumatoid arthritis, and granulomatosis with polyangiitis and microscopic polyangiitis. It is administered as an intravenous infusion, which can take several hours, depending on the dose and rate of infusion.
Rituximab is not licensed for treating MCD or FSGS and so use for this indication is off-label.
In line with the guidance from the General Medical Council (GMC), it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using rituximab outside its authorised indications.
Rituximab 10 mg/ml concentrate for solution for intravenous infusion (MabThera, Roche Products Limited) costs (excluding VAT; MIMS September 2016):
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2×10 ml=£349.25
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1×50 ml=£873.15
Evidence review
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A systematic review of 14 observational studies (Kronbichler et al. 2014) assessed the efficacy of rituximab treatment in adults with frequently relapsing or steroid-dependent nephrotic syndrome caused by MCD (n=77) or FSGS (n=9). Commonly used rituximab dosing regimens were single dose ranging from 375 mg/m2 to a fixed administration of 500–1000 mg or 4 consecutive infusions of 375 mg/m2. Follow-up time varied amongst the included studies from 5.1 to 82 months. The authors report that the median follow-up was 12 months.
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Relapse was defined as proteinuria greater than 3.0–3.5 g of protein per day as measured by a 24-hour urine collection or 300–350 mg/mmol if spot urine was used for analysis. The median relapse rate before treatment with rituximab was 1.3 (range 0 to 9) per year; this was reduced to 0 (range 0 to 2) relapses per year after treatment with rituximab (p<0.001). The results were combined for MCD and FSGS.
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Response to treatment was categorised by the authors of the systematic review as complete or partial remission. Complete remission was considered as a proteinuria value of 300 mg/day or less. Partial remission was considered as a decrease of the initial urinary protein loss by at least 50% and a proteinuria value of 3.5 g/day or less. Of the participants with MCD treated with rituximab, 72 out of 73 had a response to treatment. Out of the 7 participants with FSGS, 6 achieved complete or partial remission. The authors were unable to obtain information on the response rate for 6 of the participants with MCD (n=4) and FSGS (n=2).
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The intensity of concomitant immunosuppressive therapy (measured using a semi-quantitative scoring system) was statistically significantly reduced (p<0.001) following treatment with rituximab. The number of participants receiving concomitant immunosuppressants other than steroids was reduced from 60 at the time of first treatment with rituximab to 12 at the time of last follow-up (p<0.001). The number of participants receiving steroids was also reduced from 84 at the time of first treatment with rituximab to 27 at the time of last follow-up. The results were combined for MCD and FSGS.
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A prospective observational study (Sugiura et al. 2011) examined the efficacy and safety of single-dose rituximab for adults (n=24) with primary glomerular disease including MCD (10 people), FSGS (4 people), membranous nephropathy (4 people), membranoproliferative glomerulonephritis (1 person) and immunuoglobulin A nephropathy (5 people). Four participants (all with MCD) had steroid-dependent nephrotic syndrome. Ten participants had steroid-resistant nephrotic syndrome and included people with MCD, FSGS, membranous nephropathy and membranoproliferative glomerulonephritis. Rituximab was administered by intravenous infusion as a single dose of 375 mg/m2 body surface area (maximum 500 mg). Follow‑up times were at 1, 3 and 6 months after rituximab infusion.
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There was a statistically significant decrease in mean (± standard deviation) observed urinary protein at 6 months after rituximab administration compared with baseline. For participants with MCD the levels decreased from 3.8±4.1 g/day at baseline to 0.42±1.2 g/day at 6 months (p<0.05). For participants with FSGS the levels decreased from 5.2±2.4 g/day at baseline to 2.3±2.8 g/day at 6 months to (p<0.05).
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In the participants with MCD and FSGS, the mean (± standard deviation) corticosteroid dose (prednisolone or methylprednisolone) was reduced from 21.0±12.7 to 11.5±11.8 mg/day (p<0.05) and from 23.8±12.5 to 10.0±9.1 mg/day (not statistically significant), respectively at 6 months after administration with rituximab.
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Two out of 10 participants with MCD and 1 out of 4 participants with FSGS were able to discontinue their corticosteroids 6 months after administration with rituximab.
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A retrospective cohort study (Spinner et al. 2015) compared single-dose rituximab treatment (median 200 [range 100 to 1000] mg) for recurrent glomerulonephritis post‑renal transplant with a control group who did not receive rituximab. The forms of glomerulonephritis included FSGS, MCD, membranoproliferative glomerulonephritis, membranous nephropathy, lupus nephritis, Wegener's granulomatosis and immunoglobulin A nephropathy. Of the 48 included adults, 25 (n=0 with MCD and n=7 with FSGS) received treatment with rituximab and 23 (n=1 with MCD and n=6 with FSGS) did not receive rituximab. Both groups received other treatments for recurrent glomerulonephritis and anti-rejection therapy. The median follow-up time in the intervention group was 769 (range 363 to 1301) days compared with 1358 (range 236 to 2710) days for the control group (p=0.18). Only 20 participants in the control group (6 with FSGS and 0 with MCD) and 13 people (4 with FSGS and 1 with MCD) in the intervention were assessed for treatment response outcomes because of various exclusions.
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The authors included an analysis which assessed the response to treatment based on the type of glomerulonephritis. Out of 6 participants with FSGS treated with rituximab, 2 achieved complete response, 1 achieved partial response and 3 did not respond to treatment. In 4 participants with FSGS who were not treated with rituximab, 2 achieved complete response, 1 achieved partial response and 1 participant did not respond to treatment. The participant with MCD in the control group achieved partial response; however, there were no participant(s) in the intervention group with MCD. The authors reported no significant difference between the intervention and control groups in complete and partial response rates in adults with FSGS or MCD (p=1.00 for both comparisons).
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Adverse events reported in the systematic review (Kronbichler et al. 2014) included infusion-related reactions that consisted of transient hypotension (3 people), itchy red eyes (1 person), cough (2 people), hiccough (1 person) and exanthema (1 person). Bronchopneumonia was observed in 1 person 2 months after treatment with rituximab. A long-term complication of mild leukopenia in 1 person with MCD had also been observed. In the study by Sugiura et al. (2011), 1 participant experienced an adverse event; a cutaneous eruption which did not require discontinuation of rituximab infusion (type of primary glomerular disease not reported).
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The SPC for rituximab describes that infusion-related reactions are very common in people treated with intravenous rituximab for any licensed indication. Severe infusion-related reactions with a fatal outcome have been reported in post-marketing use. Serious infections, including fatalities, can occur during rituximab therapy, and rituximab is contraindicated in people with an active, severe infection (for example, tuberculosis, sepsis and opportunistic infections), and in people who are severely immunocompromised. Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in people receiving rituximab. Hepatitis B virus screening should be performed in all people before starting treatment with rituximab and people with active hepatitis B infection should not be treated with the drug. Very rare cases of fatal progressive multifocal leukoencephalopathy have been reported after use of rituximab and people should be monitored at regular intervals for any new or worsening neurological symptoms or signs suggestive of this condition. See the SPC for rituximab for full details of warnings, contraindications and adverse events.
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Most of the evidence for using rituximab in adults with MCD and FSGS comes from uncontrolled observational studies outside of the UK, with no randomisation and no comparator arm (the exception being Spinner et al. 2015, who used a non-randomised control group as a comparator in their retrospective study). The studies, Kronbichler et al. (2014), Spinner et al. (2015) and Sugiura et al. (2011) all had small sample sizes. Kronbichler et al. (2014) included a total of 86 people, 77 with MCD and 9 with FSGS from 14 studies. However the individual included studies only contained between 1 and 25 people with MCD, and 1 and 3 people with FSGS. Spinner et al. (2015) and Sugiura et al. (2011) included a total of 14 (MCD=1, FSGS=13; and MCD=10, FSGS=4 respectively) people with MCD or FSGS. The populations in the included studies varied in terms of cause of glomerulonephritis and disease characteristics (such as albumin levels, duration and treatment of disease). The dose of rituximab used, treatment with concomitant steroids and immunosuppressants (some of which are not available in the UK) and follow‑up time also varied. Clinical outcome measures also varied across studies. For some outcomes, the studies reported pooled data for MCD, FSGS and other forms of glomerulonephritis; it may not be appropriate to pool data from people with different disease processes. There were limited data on the effect of rituximab on kidney function. All of these factors make it difficult to draw firm conclusions about the effect of rituximab in people with MCD or FSGS from the evidence reviewed.
Context and estimated impact for the NHS
People with MCD or FSGS undergoing treatment with corticosteroids may exhibit steroid resistance, steroid dependence or complications of steroid therapy such as cataracts, diabetes and osteoporosis. Immunosuppressants such as ciclosporin also have significant adverse effects, which limit their long-term use in people presenting with nephrotic syndrome. Low quality evidence suggests that rituximab could be considered for use in people who experience these complications.
Comparing the cost of rituximab with other therapies for MCD or FSGS is difficult because there is a lack of evidence to establish an optimal dose and drug regimen (including using either a fixed or multiple dosage, and combination with other treatments).
Most of the studies in this evidence summary used rituximab as a single dose or multiple doses ranging from 375 mg/m2 to a fixed administration of 100–1000 mg or consecutive infusions (no more than 4) of 375 mg/m2. Costs would vary depending on the height and weight of a person.
As an approximate guide, the cost for 1, 2, 3 or 4 doses of intravenous rituximab 375 mg/m2 based on an adult with a body surface area of 1.86 m2 is estimated to be £1222.40, £2444.80, £3667.20 and £4889.60, respectively (assuming wastage and excluding VAT; MIMS September 2016).
Information for the public
A plain English summary is available on the NICE website. This sets out the main points from the evidence summary in non-technical language and may be especially helpful for people with minimal change disease or focal segmental glomerulosclerosis who are thinking about trying rituximab.
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About this evidence summary 'Evidence summaries: unlicensed or off-label medicines' summarise the published evidence for selected unlicensed or off-label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision-making and support the construction and updating of local formularies. The summaries support decision-making on the use of an unlicensed or off-label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance. |