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VAS RECOMMMENTDATION BR

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VAS RECOMMMENTDATION BR Guidelines BSR and BHPR guidelines for the management of adults with ANCA associated vasculitis C. Lapraik1, R. Watts2,3, P. Bacon4, D. Carruthers5, K. Chakravarty6, D. D’Cruz7, L. Guillevin8, L. Harper9, D. Jayne10, R. Luqmani11, J. Mooney12, D. Scott1,2 on beha...
VAS RECOMMMENTDATION BR
Guidelines BSR and BHPR guidelines for the management of adults with ANCA associated vasculitis C. Lapraik1, R. Watts2,3, P. Bacon4, D. Carruthers5, K. Chakravarty6, D. D’Cruz7, L. Guillevin8, L. Harper9, D. Jayne10, R. Luqmani11, J. Mooney12, D. Scott1,2 on behalf of the BSR and BHPR Standards, Guidelines and Audit Working Group KEY WORDS: Vasculitis, Guideline, Management, Cyclophosphamide. Section 1: Scope and purpose 1.1 Background to disease The primary systemic vasculitides (PSV) are heterogeneous, multi- system disorders characterized by inflammation and necrosis of small and medium blood vessels. Their aetiology is unknown. Three distinct clinico-pathological syndromes, often associated with anti-neutrophil cytoplasmic antibodies (ANCA) [sometimes called ANCA associated vasculitis (AAV)], have been identified and collectively comprise the most common subgroup: Wegener’s granulomatosis (WG), Churg–Strauss syndrome (CSS) and microscopic polyangiitis (MPA). Other forms of systemic vascu- litis (listed in Table 1) are usually ANCA negative, and are defined by their clinico-pathological features. There are no validated diagnostic criteria for primary systemic vasculitis. However, the American College of Rheumatology (ACR) devised classification criteria for different vasculitides including WG, CSS and polyarteritis nodosa (PAN) but not MPA, and the Chapel Hill consensus conference (CHCC) recommended definitions for WG, CSS, PAN and MPA [1–4]. The CHCC definitions were not intended for classification or diagnosis but provide a useful description of disease and include some features that have been used for classification purposes. Lanham et al. [5] reviewed CSS in 1984 and provided a slightly different and mainly clinical orientated set of classification criteria when compared with the ACR for CSS. The ACR also provided classification criteria for giant cell arteritis, Takayasu’s arteritis, classical polyarteritis nodosa and Henoch–Scho¨nlein purpura. The treatment for these conditions is outside the scope of this review which concentrates on the ANCA associated vasculitides. However, there are patients with primary and secondary vasculitis that are treated with cyclophosphamide, and these guidelines can be used for such conditions although the references to clinical studies for these conditions have not been included in this document. The classification of systemic vasculitis seen in Table 1 is the most widely accepted classification system [6]. There are several measures of disease activity, severity and damage such as the Birmingham Vasculitis Activity Score (BVAS), Vasculitis Damage Index (VDI), the damage extent index (DEI) and the five factor score. BVAS and VDI are validated clinical tools that are most widely used as measures of disease severity, activity and damage [7, 8]. It should be noted that these do not incorporate ANCA as part of the assessment of disease activity. The use of cyclophosphamide and other immunosuppressive agents has transformed the prognosis of many of the systemic vasculitides. The natural history of untreated WG and MPA is of a rapidly progressive, usually fatal disease. Walton observed a mean survival of 5 months, with 82% of patients dying within 1 yr and more than 90% dying within 2 yrs in patients with WG [9]. The introduction of cyclophosphamide combined with prednisolone resulted in a significant improvement in mortality of WG with a 5-yr survival rate of 82%, although there remains considerable morbidity associated with both disease and treatment [10, 11]. The prognosis is worse for elderly patients, those with renal disease (especially high creatinine at presentation), pulmonary involvement, high ESR and those with a high disease activity and damage scores [12–17]. Diagnosis. In the early phases of the disease, the symptoms can be non-specific and a high index of suspicion is required to 1Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich, 2School of Medicine Health Policy and Practice, University of East Anglia, Norwich, 3Department of Rheumatology, Ipswich Hospital NHS Trust, Ipswich, 4Department of Rheumatology, University of Birmingham, 5Department of Rheumatology, City Hospital Birmingham, 6Department of Rheumatology, Harrold Wood Hospital, London, 7Department of Rheumatology, St Thomas’s Hospital, London, 8Department of Internal Medicine, University of Paris-Nord, Paris, 9Department of Nephrology, Queen Elizabeth Hospital, Birmingham, 10Department of Nephrology, Addenbrooke’s Hospital, Cambridge, 11Department of Rheumatology, Nuffield Orthopaedic Centre and University of Oxford, Oxford and 12School of Nursing and Midwifery, University of East Anglia, Norwich. Submitted 3 November 2006; revised version accepted 24 April 2007. Correspondence to: Dr Richard Watts, Consultant Rheumatologist, Ipswich Hospital NHS Trust, Heath Road, Ipswich IP4 5PD, UK. E-mail: Richard.watts@ipswichhospital.nhs.uk Rheumatology 2007;46:1–11 doi:10.1093/rheumatology/kem146b 1 � The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org achieve an early diagnosis. Symptoms that should prompt consideration of a diagnosis of vasculitis are unexplained systemic disturbance, arthritis or arthralgia, polymyalgia, episcleritis, neuropathy, microscopic haematuria, pulmonary infiltrates or nodules and maturity onset asthma. Once major organ involvement occurs the diagnosis usually becomes clear. Unfortunately, the presence of more advanced disease at diagnosis limits the potential benefit of therapy. Detailed clinical and laboratory assessments are very important to provide a full picture of the disease and assist in identifying the specific type of vasculitis in the majority of cases. Laboratory and imaging studies are essential in helping to confirm a clinical diagnosis but are of limited value in the absence of clinical signs when considering a diagnosis of systemic vasculitis and its differential diagnosis [18]. Differential diagnosis. Vasculitic syndromes are considered in the differential diagnosis of patients with multi system illness or pyrexia of unknown origin. However, there are a number of specific conditions that can mimic vasculitis, including infections, non-infectious inflammatory diseases, malignancy, drugs and factitious illnesses. Disorders such as atrial myxoma, cholesterol emboli and catastrophic anti-phospholipid syndrome may also mimic vasculitic disorders. Vasculitis occurs commonly in the context of other autoimmune connective tissue diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [19, 20]. Investigations. Investigations are aimed at confirming the diagnosis, excluding secondary causes of vasculitis, assessing organ involvement and disease severity. Acute phase reactants such as CRP and ESR are typically elevated in the acute phases of most vasculitides. Urinalysis should be performed as soon as a diagnosis of vasculitis is suspected because renal involvement in particular may progress silently. Full blood count (FBC) should be measured, looking particularly for eosinophilia. It is essential to investigate critical organ function including renal, cardiac and pulmonary assessments, with appropriate organ-specific tests (creatinine clearance, echo-cardiography, pulmonary function tests, etc). Autoantibodies including ANCA are useful in the appropriate clinical setting. It is important to recognize that a negative ANCA does not exclude vasculitis and a positive ANCA does not necessarily prove vasculitis [18]. ANCA specificity is also important, with the presence of PR3 ANCA being strongly suggestive of a diagnosis of WG [21]. MPO ANCA is less specific, but also is most frequently associated with MPA and CSS. Thirty percentage of cases with CSS or localized WG may be ANCA negative. Other useful tests include ANA (to exclude SLE, although it can be difficult to interpret the presence of pANCA in the presence of ANA), rheumatoid factor, complement levels (may be raised as part of an acute phase response but lowered in immune complex mediated essential mixed cryoglobulinaemia, bacterial infections and SLE), cardiolipin antibodies and lupus anti- coagulant for anti-phospholipid syndrome and cryoglobulins. Cryoglobulinaemia may occur in isolation or in association with other connective tissue diseases. In essential mixed cryoglobulin- aemia associated with small vessel vasculitis, the cryoglobulins may be associated with internal organ damage and may require aggressive therapy. Infection should be excluded by blood culture and appropriate serology (including parvovirus, Hepatitis B, Hepatitis C and HIV) because the treatment for PSV involves intense immunosuppres- sion. A tissue diagnosis should be obtained wherever possible. The choice of biopsy site is dependant on the clinical features, but skin and renal are often helpful for diagnosis. It is important to recognize that very early in the disease process, the classical histological features of vasculitis may be absent. For example, in one series of patients with WG with classical disease only 50% had classical granuloma on histology. Upper airway biopsy frequently shows changes compatible with the diagnosis but rarely classical granulomatous vasculitis. The treatment should not be delayed solely to get a biopsy if there are strong clinical grounds to make a diagnosis of vasculitis. Imaging investigations including angiography should be care- fully considered in appropriate cases. The role of MRA/MRI and PET are particularly valuable in assessing large vessel vasculitis such as giant cell arteritis, but they have limited availability. Coeliac axis angiography should be considered in situations where PAN is strongly suspected, such as patients with severe abdominal pain, frank haematuria and HBV infection. 1.2 Need for guideline The primary systemic vasculitides are more common than was previously realized with an incidence of 20/million and peak age of onset 60–70 yrs [22]. Treatment has evolved over the last 20–30 yrs and a number of new treatments are now available. Therefore, it seems appropriate to review the current treatments and to highlight where there is an evidence base for treatment protocols and where treatment is based on individual preference. 1.3 Objective of guideline The aim of this document is to provide guidelines for the management of adults with primary systemic vasculitis/ANCA associated vasculitis, especially the induction and maintenance of remission. The guidelines concentrate particularly on the indica- tions for using cyclophosphamide and the different therapeutic regimens available. 1.4 Target audience The target audience includes rheumatologists, general physicians and specialists who may come across vasculitis in the course of their work. We are also aiming guidance towards specialist registrars in training, nurse practitioners dealing with vasculitis and the information will also be of value to primary care physicians to increase their understanding of these unusual conditions. It is important, however, to recognize that these diseases are relatively rare and it is recommended that a referral to a consultant with a specialist interest in vasculitis is made in most cases. Centres without consultants with a specialist interest in vasculitis should contact expert centres and be in close liaison for detailed advice. TABLE 1. Classification of systemic vasculitis Dominant vessel Primary Secondary Large arteries Giant cell arteritis Aortitis associated Takayasu’s arteritis with RA, infection (e.g. syphilis,TB) Medium arteries Classical PAN Hepatitis B Kawasaki disease associated PAN Small vessels and medium arteries Wegener’s granulomatosisa Vasculitis secondary to rheumatoid arthritis, systemic lupus erythematosus, Churg–Strauss syndromea Microscopic polyangiitisa Sjo¨grens syndrome, drugs, infection (e.g. HIV) Small vessels Henoch–Scho¨nlein purpura Drugs, hepatitis C-associated infectionCryoglobulinaemia cutaneous leucocytoclastic angiitis aDiseases most commonly associated with ANCA and a significant risk of renal involvement, and most responsive to immunosuppression with cyclophosphamide. 2 C. Lapraik et al. 1.5 The areas the guideline does not cover The guidelines do not cover the management of other systemic vasculitides, for example giant cell arteritis, Takayasu’s arteritis, cutaneous vasculitis, classical PAN, cryoglobulinaemic vasculitis, Henoch–Scho¨nlein purpura. Section 2: Stakeholder involvement 2.1 Names and roles of members of multidisciplinary team Coordination team Chair. Professor David GI Scott, Consultant Rheumatologist, Norfolk and Norwich University Hospital; Honorary Professor, University of East Anglia School of Medicine, Health Policy and Practice. Members. Dr Richard Watts, Consultant Rheumatologist, Ipswich Hospital, Senior Lecturer University of East Anglia School of Medicine, Health Policy and Practice. Dr Chloe Lapraik, Rheumatology Research Fellow, Norfolk and Norwich University Hospital. Working group members/advisors. Professor Paul Bacon, Emeritus Professor, Birmingham. Dr David Carruthers, Consultant Rheumatologist, City Hospital Birmingham. Professor Kuntal Chakravarty, Consultant Rheumatologist, Harrold Wood Hospital. Dr David D’Cruz, Consultant Rheumatologist, St Thomas’s Hospital. Professor Loic Guillevin, Professor of Medicine, Hospital Avicenne, University of Paris-Nord. Dr Lorraine Harper, Senior Lecturer in Nephrology, Birmingham. Dr David Jayne, Consultant Nephrologist, Addenbrooke’s Hospital, Cambridge. Dr Raashid Luqmani, Consultant Rheumatologist, Nuffield Orthopaedic Centre, Oxford. Allied health care professional representative. Mrs. Janice Mooney, Nurse Lecturer, School of Nursing and Midwifery, University of East Anglia. 2.2 Names and affiliations of users on the working party The draft guidelines were reviewed by Mrs Judy Bilner (patient). 2.3 Involvement and affiliations of other people or organizations including user representative organization and pharmaceutical companies in the development of the guideline The Stuart Strange Trust is a registered charity that offers support to family friends and sufferers of vasculitis. The guidelines have been reviewed by Paul Pegg, the general secretary for the Trust, who has given his approval and support on behalf of the Stuart Strange Trust. Section 3: Rigour of development 3.1 Statement of scope of literature search and strategy employed The general search strategy was to look for all evidence synthesis in the Cochrane library and Medline (Ovid). The MEDLINE database was also searched for randomized controlled trials and non-randomized trials. The reference lists of identified papers and previous reviews were also searched. 3.2 Statement of extent of Cochrane, Nice, RCP, SIGN guidelines To date, no Cochrane reviews have been published and there are few formal meta-analyses. There are no NICE, RCP, SIGN guidelines for the treatment of primary systemic vasculitis. 3.3 Statement of any limits of search The search was conducted in November 2005. No time or language limits were placed on the search. 3.4 Statement of when guideline will be updated The guideline will be updated every 3 yrs following publication. Section 4: The guideline itself There are no clear cut diagnostic criteria for systemic vasculitis. It is common to apply classification criteria as surrogates for diagnosis, but we recognize the limitations of this approach. For the purpose of these guidelines, we have proposed the following statements to allow us to identify patients who have a diagnosis of vasculitis for the purpose of eligibility for treatment. 4.1 Eligibility criteria Eligibility for treatment depends on the assumption that a definite diagnosis of vasculitis has already been made. The following criteria must be fulfilled prior to a diagnosis of vasculitis: A. Symptoms and signs characteristic of systemic vasculitis. B. At least one of the following: 1. Histological evidence of vasculitis and/or granuloma formation, 2. Positive serology for ANCA (either cANCA/PR3 or pANCA/MPO), 3. Specific indirect evidence of vasculitis (from angiography, MRI, CT imaging, neurophysiologyy). yNeurophysiology must show mononeuritis multiplex or mononeuropathy C. No other diagnosis to account for symptoms or signs. 4.2 Exclusion criteria For a diagnosis of primary systemic vasculitis, it is important to consider other causes of systemic illness as outlined below, which must be excluded as far as possible: 1. Malignancy, 2. Systemic infection—especially bacterial endocarditis, 3. Drugs—known to be associated with vasculitis (e.g. propylthiouracil, allopurinol, hydralazine and cocaine), 4. Secondary forms of vasculitis associated with primary connective tissue disease such as rheumatoid arthritis or systemic lupus erythematosus. 5. Other vasculitides including Behc¸et’s disease, Takayasu’s arteritis, giant cell arteritis, Kawasaki’s disease, Cryoglobulinaemia, Henoch Scho¨nlein Purpura (must have a biopsy demonstrating IgA deposits). 6. Vasculitis mimics, for example anti-phospholipid syndrome, cholesterol embolism, calciphylaxis and atrial myxoma. 4.3 Remission induction treatment Treatment for vasculitis requires induction of remission followed by maintenance. Treatment regimens for each phase of disease are different and are outlined subsequently. The categor- ization used here follows that adopted by the European Vasculitis Study Group (EUVAS) for clinical trials. Guidelines for the management of adults with AAV 3 Treatment is tailored according to severity and extent of disease. The level of immunosuppression should reflect the severity of vasculitis. Table 2 shows categorization of disease severity. Limited WG as used in the US literature most closely overlaps with the early systemic/localized group. 4.3a Recommendation for patients with generalized disease/threatened organ involvement. Initial treatment of patients with primary systemic vasculitis with generalized/threa- tened vital organ loss should include cyclophosphamide. Cyclophosphamide may be given orally or intravenously (daily oral 2mg/kg or IV pulses at 2- or 3- week intervals at a dose of 15mg/kg) (Table 3) (A). Cyclophosphamide dose should be tapered to maintain total white cell count above 4� 109/l and neutrophils >2.0� 109 to reduce risk of infection (B). Cyclophosphamide dosage should be reduced for age (B) and renal function (C). Current clinical practice with these protocols for remission induction are associated with an expected remission rate of �80% at 3 months and 90% at 6 months [24]. Dose reductions Dose reductions for continuous low dose oral cyclophosphamide: For oral administration, if age >60 years the dose of cyclophosphamide should be reduced by 25%. If the age is >75 years the dose should be reduced by 50% to avoid neutropenia [25] (B). Reductions for pulsed cyclophosphamide, see Table 3. Remission induction Continuous low dose oral cyclophosphamide regimen: Continuous low dose cyclophosphamide 2mg/kg/day should be given for 3 months. The maximum dosage of continuous low dose oral cyclophosphamide is 200mg/day. If remission is not achieved by 3 months, continue 2mg/kg/day, until remission is achieved then reduce cyclophosphamide to 1.5mg/kg/day. The total duration of treatment with cyclopho- sphamide should not usually exceed 6 months [24]. Current clinical practice considers a transfer to maintenance therapy at 3 months or within 3 and 6 months if remission is delayed (A). Continuous low dose oral cyclophosphamide monitoring: Check full blood count (FBC), weekly for the first month, 2 weekly for the second and third month and then monthly thereafter. If w
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