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«Clinical Commissioning Policy: Rituximab for the treatment of ANCA-associated vasculitis in adults Reference: NHS England A13/P/a Clinical ...»

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Clinical Commissioning Policy:

Rituximab for the treatment of

ANCA-associated vasculitis in

adults

Reference: NHS England A13/P/a

Clinical Commissioning

Policy:

Rituximab for the

treatment of ANCAassociated vasculitis in

adults

First published: January 2015

Prepared by NHS England Specialised Services Clinical Reference

Group for Specialised Rheumatology

Published by NHS England, in electronic format only.

NHS England INFORMATION READER BOX Directorate Medical Commissioning Operations Patients and Information Nursing Trans. & Corp. Ops. Commissioning Strategy Finance Publications Gateway Reference: 02659 Document Purpose Policy A13/P/a: Clinical Commissioning Policy: Rituximab for the treatment of Document Name ANCA-associated Vasculitis in Adults Author NHS England Publication Date January 2015 Target Audience CCG Clinical Leaders, CCG Accountable Officers, CSU Managing Directors, Foundation Trust CEs, Medical Directors, Directors of PH, Directors of Nursing, NHS England Regional Directors, NHS England Area Directors, Directors of Finance, GPs, NHS Trust CEs Additional Circulation #VALUE!

List Description This policy aims to ensure equitable and cost-effective use of rituximab as a treatment option for people with ANCA-associated vasculitis, both as a remission-induction and a maintenance agent.

Cross Reference A13/S/a Service Specification - Specialised Rheumatology Services (Adult) Superseded Docs A13/P/a: Clinical Commissioning Policy: Rituximab for the treatment of ANCA-associated Vasculitis in Adults - April 2013 (if applicable) Action Required Timing / Deadlines By 00 January 1900 (if applicable) Contact Details for NHS England further information Medical Directorate Specialised Services Skipton House, 80 London Road SE1 6LH www.england.nhs.uk/commissioning/ Document Status This is a controlled document. Whilst this document may be printed, the electronic version posted on the intranet is the controlled copy. Any printed copies of this document are not controlled. As a controlled document, this document should not be saved onto local or network drives but should always be accessed from the intranet Contents Policy Statement

Equality Statement

Plain Language Summary

1. Introduction

2. Definitions

3. Aim and objectives

4. Epidemiology and needs assessment

5. Evidence base

6. Rationale behind the policy statement

7. Criteria for commissioning

8. Patient pathway

9. Governance arrangements

10. Mechanism for funding

11. Audit requirements

12. Documents which have informed this policy

13. Links to other policies

14. Date of review

References

Policy Statement NHS England will commission rituximab for patients with ANCA-associated vasculitis in accordance with the criteria outlined in this document.

In creating this policy NHS England has reviewed this clinical condition and the options for its treatment, including NICE guidance. It has considered the place of this treatment in current clinical practice, whether scientific research has shown the treatment to be of benefit to patients, (including how any benefit is balanced against possible risks) and whether its use represents the best use of NHS resources.

This policy document outlines the arrangements for funding of this treatment for the population in England.

Equality Statement Throughout the production of this document, due regard has been given to eliminate discrimination, harassment and victimization, to advance equality of opportunity, and to foster good relations between people who share a relevant protected characteristic (as cited in under the Equality Act 2010) and those who do not share it.

Plain Language Summary ANCA Associated Vasculitis is a disease in which blood vessels become inflamed, often associated with the presence in the blood stream of ANCA auto-antibodies. Normal antibodies are produced by the immune system to fight infectious agents (such as bacteria). Auto-antibodies are abnormal antibodies that can attack one's own cells and tissues. ANCAs are a type of autoantibody that is associated with inflammation in the walls of small and medium blood vessels in different tissues and organs of the body.

Conventional drug treatments which may involve the use of chemotherapy drugs, such as cyclophosphamide, are usually effective but also have significant potential toxicity. In people whose disease has been unresponsive to conventional treatment or has relapsed despite this, further conventional treatment is likely to produce cumulative toxicity and a poorer response to treatment.

Rituximab has been shown to be an effective alternative treatment and is likely to offer particular benefit in specific situations when conventional treatment has either failed or cannot be safely used.or where future fertility may be an issue. Rituximab is therefore available as a treatment option for patients with ANCA Associated Vasculitis according to the criteria outlined in this document. Information on the outcome of rituximab use will be collected and will inform future treatments.

1. Introduction ANCA-associated vasculitis comprises three conditions which share overlapping clinical and serological features and are characterised by necrotising inflammation of small vessel walls; Granulomatosis with Polyangiitis (GPA, Wegener’s), Microscopic Polyangiitis (MPA) and Eosinophilic Granulomatosis with Polyangiitis (EGPA, Churg Strauss Syndrome). Although the cause is unknown, ANCA antibodies, cytokineprimed neutrophils, and B-lymphocytes are recognised to have an important role in disease pathogenesis.





These are rare conditions, with incidence estimated at 20 per million and peak age of onset 60-70 years. Without treatment they are usually fatal, and not everyone responds to treatment; on average, 80% of those treated will be alive at two years, and 20% of these survivors will have significant renal disease. Increasing age and renal involvement at diagnosis are poor prognostic factors.

These diseases frequently involve multiple organ systems: most commonly the kidneys, ENT/respiratory tract, skin and nervous system are affected.

Management of all three conditions is identical and involves three phases;

remission induction, remission maintenance, and treatment of relapse. At regular intervals it is essential to formally assess and define disease activity and damage status using a formal instrument (e.g. BVAS, VDI), so that accurate ascertainment of remission, refractory disease or relapse can be documented in every patient.

The likelihood of relapse varies according to disease, but is highest in GPA;

up to 50% of patients will relapse within 5 years, even with maintenance immunosuppression. Each relapse carries a risk that additional critical organ damage will occur, leading to an irreversible deterioration in health. Relapse is often associated with significantly increased NHS costs e.g. hospitalisation, and both the costs (drug and day case activity) and infection risk from steroids and immunosuppression of remission re-induction. Significant costs also accrue at relapse from the accumulation of further organ damage, particularly if this leads to further renal damage and risk of renal replacement therapy.

Thus prevention of relapse is a key priority, as this improves long-term outcomes for people living with vasculitis and directly reduces NHS activity and costs.

Cyclophosphamide is the standard remission induction agent, and is usually given for 3-6 months, adjusted for age, body weight, and renal function. The majority of people treated with Cyclophosphamide will attain remission.

However, 15% will not, and will continue to have active or progressive disease that is refractory to conventional treatment. Cyclophosphamide has significant side effects including gonadal toxicity inducing premature ovarian failure, bone marrow depression and infection, haemorrhagic cystitis, and an increased risk of future uroepithelial (bladder) cancer.

Thus new treatments that can potentially avoid the chemotherapy side effects

of Cyclophosphamide are needed.

Two randomised clinical trials of rituximab (RAVE and RITUXVAS), and many positive case series, provide a supporting evidence base to vasculitis clinicians (predominantly nephrologists and rheumatologists) who have needed to use rituximab as an alternative to Cyclophosphamide over the last 10 years (1, 2).

NICE has published guidance on the use of rituximab for the treatment of ANCA-associated vasculitis, as an option for inducing remission in adults with severe active Granulomatosis with Polyangiitis (Wegener’s) and Microscopic Polyangiitis, if specific criteria are met.

• The disease has remained active or progressed despite a course of cyclophosphamide lasting 3–6 months; OR

• Cyclophosphamide is contraindicated (as defined in the summary of product characteristics) or not tolerated; OR

• The person has not completed their family and treatment with cyclophosphamide may materially affect their fertility; OR

• Further cyclophosphamide treatment would exceed the maximum cumulative cyclophosphamide dose; OR

• The person has had uroepithelial malignancy.

These NICE criteria also align with the recommendations in the BSR and BHPR guideline for the management of all adults with ANCA-associated vasculitis, but with one important exception (3). This relates to the definition of when “further cyclophosphamide treatment would exceed the maximum cumulative cyclophosphamide dose.” NICE has defined this dose as 25g, which is equivalent to two induction courses of IV cyclophosphamide. The current NICE guidance therefore positions the routine use of Rituximab at the time of third remission induction i.e. at second relapse. However, the evidence in the RAVE trial is that, in relapsing patients, rituximab is more effective than cyclophosphamide.

Relapsing patients are also those are greatest risk of cumulative CYC toxicity, which is likely to increase even before a threshold of 25g is reached. There is therefore clinical and cost-effective justification for using rituximab at first relapse, before a threshold of 25g cyclophosphamide is reached.

NICE were restricted in their appraisal to only being able to assess the dose of rituximab that is licensed for this indication. This is the “lymphoma” regimen of four infusions at weekly intervals of 375mg/m2. However, in England currently, the majority of existing centres managing patients with ANCA associated vasculitis use rituximab in routine clinical practice at the lower dose of two 1g infusions two weeks apart. This is also the dose schedule used in all other autoimmune rheumatic diseases e.g. Rheumatoid Arthritis (licensed dose) and SLE (off label use). This regimen results in a lower total dose of rituximab, delivered over a shorter period of time, and is therefore more convenient for patients. The clinical consensus, as indicated in the BSR and BHPR guideline, is that both protocols appear equally effective. In a retrospective review of 65 patients, the two regimens were compared and were found to be of equal efficacy, with no difference in the duration of B cell depletion or the therapeutic effect.

If the lower dose schedule is employed, there is a significant NHS cost saving in terms of reduced NHS activity (50%) and reduced drug costs (40%) compared to the higher licensed dose.

Utilising the rituximab Ig x2 regimen also results in a cost saving compared to a course of IV cyclophosphamide for relapsing patients. This means that it is both clinically effective and cost effective to use rituximab at time of first relapse after initial cyclophosphamide induction, rather than re-treating relapsing patients with cyclophosphamide again until they had reached their maximum dose of 25g. This specific requirement has therefore been amended in this commissioning policy.

NICE also only appraised the use of Rituximab for the two most common types of ANCA associated vasculitis, namely Granulomatosis with Polyangiitis (Wegener’s) and microscopic polyangiitis. These two subtypes comprise 90% of all cases of ANCA associated vasculitis. The third subtype of ANCA associated vasculitis, Eosinophilic Granulomatosis with Polyangiitis (EGPA, Churg Strauss Syndrome), is much rarer (10% of all cases), but shares similiar clinical features and identical treatment strategies to the other two conditions. Although there have been no large trials of Rituximab for EGPA because of it’s rarity, and use in this condition is off-label, case series data report similar efficacy to that seen in the other two subtypes.

Maintenance treatment with rituximab was also outside the scope of the NICE appraisal, as this was restricted to the marketing authorisation of remission induction. However, because of the pivotal importance of preventing relapse, there is a subgroup of patients for whom maintenance rituximab is required, and this is currently commissioned by NHS England as per Commissioning Policy. This revised policy therefore continues to include specific situations where maintenance treatment is clinically and cost effective but provides greater clarity and incorporates additional criteria that must be met.

2. Definitions Rituximab is a monoclonal antibody that targets CD-20, a cell surface marker that is widely expressed on B-cells, leading to B cell depletion. Rituximab has a license for the treatment of lymphomas, rheumatoid arthritis, and ANCAassociated vasculitis. Rituximab is also commissioned by NHS England (offlabel) in other autoimmune diseases according to specific criteria (e.g.

Systemic Lupus Erythematosus Policy A13/PS/a).

3. Aim and objectives This policy aims to ensure equitable and cost-effective use of rituximab as a treatment option for people with ANCA-associated vasculitis, both as a remission-induction and a maintenance agent.



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