BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis

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The ANCA-associated vasculitides (AAVs) are heterogeneous, multisystem disorders characterized by inflammation and necrosis of small and medium blood vessels with unknown aetiology. Three distinct clinico-pathological syndromes have been identified: granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis and microscopic polyangiitis. The Chapel Hill Consensus Conference (CHCC) in 2012 updated the definitions, however, there are still no validated diagnostic criteria. The aim of this document is to provide guidelines for the management of adults with AAV. The target audience is rheumatologists, nephrologists, general physicians, specialists, trainees and nurse practitioners. The guideline does not cover the management of other systemic vasculitides or the treatment of children. This is a short summary of the guideline. The full guideline is available as supplementary material, available at Rheumatology Online. For definitions of levels of evidence and recommendation strength see Tables 1 and 2. Level of evidence Determination of recommendation strength We have produced evidence-based recommendations for treatment, giving a grade of recommendation (from A to D) and an algorithm to illustrate the approach to the management of a patient with newly diagnosed AAV. Patients with disease consistent with the definitions of ANCA vasculitis as defined by the CHCC in 2012 are eligible for treatment and use of this guideline. For a diagnosis of ANCA vasculitis, it is important to exclude other causes of systemic illness such as malignancy, systemic infection, drugs, secondary vasculitides or mimics. Remission: well-controlled disease. On drug remission: prednisolone dose ≤10 mg/day and a BVAS ≤1 for ≥6 months. Drug-free remission: ≥6 months off all treatment for vasculitis. Relapsing: disease that has been previously well controlled with or without drugs and has become active. Minor relapse: increase of one or more new or worse minor items and no major BVAS items. Major relapse: increase of one or more major BVAS item. Refractory: progressive disease that is unresponsive to current therapy, i.e. remission is not achieved. All patients with AAV should be considered to have severe, potentially life- or organ-threatening disease. Treatment regimens are divided into induction, maintenance and long-term follow-up. Patients who relapse may require a further course of induction therapy (secondary). The essential principles of management are Rapid diagnosis Rapid initiation of treatment Early induction of remission to prevent organ damage Maintenance of remission with the aim of eventual drug withdrawal Prevention of drug toxicity All patients with newly diagnosed AAV should be assessed for treatment with glucocorticoids (GCs) and i.v. pulse cyclophosphamide (CYC) or rituximab (RTX) (A) (Fig. 1). Algorithm of the treatment guideline for AAV CYC should be given by i.v. pulses initially at 2-week intervals and then at 3-week intervals following the CYCLOPS trial regimen (A). The standard dose is 15 mg/kg, reduced for age and renal function. Because of the lower toxicity, the i.v. regimen is preferred (B). Each individual course of CYC should be ≥3 months and ≤6 months (B). Lifetime exposure to CYC should be ≤25 g since the long-term toxicity of CYC is determined by cumulative dose (C). Patients on CYC should be monitored regularly and the dose should be reduced if there is CYC-induced leucopenia/neutropenia (B). Patients intolerant to CYC can be effectively treated with RTX (B). RTX is as effective as CYC for remission induction of previously untreated patients and is preferable when CYC avoidance is desirable, such as in young people at risk of infertility and those at high risk of infection (B). The licensed RTX dosing protocol is 375 mg/m2/week for 4 weeks (B), however, 1 g repeated after 2 weeks is equally effective (C). MTX (up to 25–30 mg/week) and MMF (up to 3 g/day) are alternative remission induction agents for patients with evidence of low disease activity and not at risk of suffering organ damage as assessed by the BVAS (A). MTX should not be used in patients with moderate or severe renal impairment (B). MMF may be an alternative to MTX (B). Patients with AAV presenting with severe renal failure (creatinine >500 μmol/l) should be treated with pulsed CYC and GCs, with adjuvant plasma exchange in a centre experienced in its use (B). Treatment with plasma exchange should also be considered in those with other life-threatening manifestations of disease, such as pulmonary haemorrhage (C). Induction therapy for AAV includes treatment with high-dose GCs in combination with another immunosuppressive agent (CYC, RTX) (A). GCs are usually given as daily oral prednisolone, initially at relatively high doses (1 mg/kg up to 60 mg) (B) with the dose rapidly reduced to 15 mg prednisolone at 12 weeks (C). Longer courses of GCs may cause increased risk of infection, but may be associated with fewer relapses (A). GC i.v. infusions (250–500 mg methyl-prednisolone) are sometimes given just prior to or with the first two pulses of CYC (C). Following successful remission, CYC should be withdrawn and substituted with either AZA or MTX (A). MMF (C) or LEF (B) may be used as alternatives for intolerance to or lack of efficacy of AZA or MTX. Patients should continue maintenance therapy for at least 24 months following successful disease remission (B). Patients with GPA or patients who remain PR3-ANCA positive should continue immunosuppression for up to 5 years (C). RTX may also be used as maintenance therapy, and re-treatment can be decided based on fixed-interval regimens or evidence of relapse (C). The recommended RTX regimen uses 1 g every 4–6 months for 2 years (B). Patients in continual remission for at least 1 year on maintenance therapy should be considered for tapering of GC treatment (D). Following GC withdrawal, other immunosuppressive therapy may be withdrawn after 6 months (D). Relapsing disease should be treated with an increase in immunosuppression. A minor relapse may be treated with an increase in prednisolone dosage and optimization of concurrent immunosuppression (C). A major relapse may be treated with RTX (A) or CYC with an increase in prednisolone (B). The addition of i.v. methylprednisolone or plasma exchange may also be considered (C). Drivers for relapse need to be identified and addressed and may include infection, malignancy and change of drug therapy (D). Refractory disease should only be treated in close collaboration with expert/tertiary centres via a hub-and-spoke model (D). RTX is more effective than CYC in refractory AAV (A). If the patient has not had previous treatment with RTX, then the first choice is RTX (A). Drivers for refractory disease should be sought and clinicians should consider revision of the clinical diagnosis (D). Validated tools [such as the BVAS, Vasculitis Damage Index (VDI) and 36-item Short Form (SF-36)] should be used by trained staff to assess disease activity, extent of damage and quality of life (D). ANCA should be detected using IIF with ELISA to confirm PR3 or MPO specificity (C) and checked at diagnosis, relapse, change of therapy, every 6 months while on treatment and annually while off treatment (B). Results should be available within 1 working day (D). Treatment should not be escalated solely on the basis of an increase in ANCA (B). The following recommendations should be considered for patients with AAV on immunosuppressive therapy: Routine blood test monitoring [full blood count (FBC), urea and electrolytes (U&Es), liver function tests (LFTs)] (C) Regular urinalysis and mesna for protection against CYC-induced urothelial toxicity (C) Serum immunoglobulin measurement before each cycle of RTX therapy (C) Trimethoprim/sulfamethoxazole as prophylaxis against Pneumocystis jiroveci (B) Antifungal prophylaxis (C) Staphylococcal aureus treatment with long-term nasal mupirocin (C) Screening for cervical intraepithelial neoplasia (CIN) (female patients) (C) Counselling about the possibility of infertility following CYC treatment (C) Prophylaxis against osteoporosis where appropriate (A) Tuberculosis screening (C) Vaccination against pneumococcal infection, influenza and hepatitis B (C) Cardiovascular and thromboembolic risk assessment (C) Patients should receive ongoing, tailored education and information about AAV and be encouraged to engage in self-monitoring to improve treatment compliance and long-term outcomes (D). They should have access to information about alternative and complementary therapies that might provide symptomatic relief (D). Patients with AAV should be managed by a nominated clinician within clinical networks linked with centres of expertise and other specialities within the local organization (D). People with a suspected diagnosis of systemic vasculitis should be rapidly assessed by a specialist physician with an expertise in vasculitis (D). Self-referral mechanisms should be in place for patients, enabling rapid access to a specialist when flaring occurs (D). Patients with AAV require long-term follow-up and should be encouraged to take part in studies and registries (D). Their annual review should follow a structured format. Audits may need to be conducted on a collaborative basis and may be focused on service delivery and patient-specific areas. Rapid access to specialist physicians. Access to multidisciplinary team. Provision of personalized education about the disease and its effects. Access to a full range of therapies. Opportunity to participate in registries and research projects. Disclosure statement: R.A.W. has acted as a consultant for Roche and Euro Nippon Kayaku and has received unit support in the form of sponsorships for departmental meetings from multiple providers. D.J. has acted as a consultant for Roche/Genentech, Genzyme, GSK, UCB and Vijorpharma and has received research grants from Roche/Genentech and Genzyme. D.D.C has acted as a consultant and has participated on advisory boards for GSK, Roche, TEVA and Bristol-Myers Squibb and has received fees for speakers’ bureaus from GSK. M.V. received unit and/or research support from Roche UK, Chemocentryx and GSK. All other authors have declared no conflicts of interest.