Rheumatic Diseases 2005

Transcription

1 COLLECTED REPORTS ON THE Rheumatic Diseases 2005 SERIES 4 (REVISED) Published by the Arthritis Research Campaign (arc) Editors: Ade O Adebajo FRCP(Glasgow) D John Dickson MBChB FRCP(Glasgow) FRCP(London) MRCGP These reports are produced under the direction of the arc Education Sub-Committee. They were first published individually between 2000 and 2003 and were subsequently reviewed for this volume.

2 PRIMARY SYSTEMIC VASCULITIS Richard A Watts Consultant Rheumatologist, Ipswich Hospital NHS Trust/Senior Lecturer, School of Medicine, Health Policy and Practice, University of East Anglia David GI Scott Consultant Rheumatologist, Norfolk and Norwich University Hospital/Honorary Professor, School of Medicine, Health Policy and Practice, University of East Anglia The primary systemic vasculitides are rare diseases for which classification systems have been developed Modern therapy has converted these from fatal conditions to ones with a relapsing remitting course Cyclophosphamide and corticosteroids are the initial choice of treatment for most patients Cyclophosphamide because of its toxicity should be used for as short a time as possible INTRODUCTION The primary systemic vasculitides (PSV) Wegener s granulomatosis (WG), microscopic polyangiitis (MPA) and Churg Strauss syndrome (CSS) are a group of uncommon diseases characterised by inflammatory cell infiltration and necrosis of blood vessel walls. The severity of vasculitis is related to the size, site and number of vessels affected. The history of these conditions has been well reviewed by Matteson. 1 CLASSIFICATION Classification of PSV remains confusing and controversial because the aetiology is usually unknown and there is considerable overlap in the clinical expression of the different vasculitic syndromes. Classification generally reflects dominant vessel size and antineutrophil cytoplasmic antibody (ANCA) 2 (Figure 1). PSV form a separate group because they (a) often involve small and sometimes medium sized arteries, (b) are most frequently associated with ANCA, (c) are associated with a high risk of glomerulonephritis, and (d) respond well to immunosuppression with cyclophosphamide. The aetiology of these diseases is probably unrelated to immune complex formation in contrast to pure small-vessel vasculitis such as Henoch Schönlein purpura and essential mixed cryoglobulinaemia. In 1990 the American College of Rheumatology (ACR) reported classification criteria of the PSV. 3-5 They considered WG, CSS and polyarteritis nodosa but not MPA. The criteria are specific (87 92%) and sensitive (82 87%) but were never validated against patients without vasculitis. In 1994 the Chapel Hill Consensus Conference (CHCC) presented definitions of PSV including MPA but not diagnostic criteria 6 (Table 1). First published May 2003; reviewed May 2005 EPIDEMIOLOGY Epidemiological studies have been hindered by the relative rarity of PSV. The majority of centres with an interest in these diseases are tertiary referral centres with ill-defined catchment populations. The development of the ACR (1990) criteria and the CHCC definitions has 70

3 Arteriole/capillary venule Small artery Medium artery Large artery Takayasu arteritis Giant cell arteritis Polyarteritis nodosa Kawasaki disease Wegener s granulomatosis Microscopic polyangiitis Churg Strauss syndrome Cryoglobulinaemia Cutaneous leucocytoclastic vasculitis Henoch Schönlein purpura FIGURE 1. Relationship between vessel size and classification. permitted comparative epidemiological studies. Interpretation of the older literature is difficult because of poor and inconsistent classification/diagnosis. The annual incidence of PSV in a community population in Norfolk in was estimated to be 19.8/million. The peak age at diagnosis was years, older than studies from tertiary referral centres would suggest. There was a preponderance of males. 7 The high age at onset has been confirmed from other centres in Europe (Spain and Scandinavia). There are also geographical differences in the incidence of PSV. For example a comparative study in Europe using the same classification criteria in three populations (Lugo, North Western Spain; Norwich, UK; and Tromsø, Northern Norway) reported that WG appeared to be more com-mon in Norway than in Spain, while MPA had the reverse distribution. 8 No difference was found in the incidence of systemic vasculitis between Northern and Southern Germany or between urban and rural populations. 9 AETIOLOGY AND PATHOGENESIS The PSV are generally considered to be autoimmune diseases, but of unknown aetiology, because of the strong association between these diseases and ANCA. Environmental and genetic factors are also reported to be of increasing importance, as outlined below. While human leucocyte antigen (HLA) associations are important in many autoimmune diseases, no clear associations have been found between HLA and PSV. Alpha-1 antitrypsin the main inhibitor of proteinase 3 (PR3) PiZ allele has been associated with more severe WG, but is not sufficient on its own to induce disease. 10 ANCA, first described by Davies et al in 1982, 11 were associated with WG in They are antibodies directed against neutrophil granule constituents. Two main pat- TABLE 1. Chapel Hill Consensus definitions for primary systemic vasculitis. Classical polyarteritis nodosa Wegener s granulomatosis Churg Strauss syndrome Microscopic polyangiitis Necrotising inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries or venules Granulomatous inflammation involving the respiratory tract and necrotising vasculitis affecting small to medium sized vessels (capillaries, venules, arterioles and arteries) Eosinophil rich and granulomatous inflammation involving the respiratory tract and necrotising vasculitis affecting small to medium sized vessels associated with asthma and blood eosinophilia Necrotising vasculitis with few or no immune deposits affecting small vessels (capillaries, venules, arterioles) Adapted from Jennette et al

4 terns of staining are recognised using indirect immunofluorescence: cytoplasmic (canca), a coarse granular staining of the cytoplasm, and perinuclear (panca), with staining chiefly around the nucleus, leaving the cytoplasm unstained. The main target antigen for canca is serine PR3 located in azurophilic granules, and for panca myeloperoxidase (MPO), an enzyme from azurophilic granules that catalyses peroxidation of chloride to hypochlorite. Anti-PR3 antibodies are highly specific (>90%) for generalised WG. 13 panca associated with myeloperoxidase antibodies are more typically found in MPA and CSS but are much less specific. ANCA often correlate with disease activity, and there is increasing evidence to support their role in pathogenesis. In vitro, ANCA can activate cytokine-primed neutrophils by binding to antigens expressed on the cell surface, generating a respiratory burst and releasing proteolytic granules and pro-inflammatory cytokines. ANCA also interfere with apoptosis by preventing removal of apoptotic cells, which can result in secondary necrosis and further inflammation. The inflammatory process also results in increased endothelial cell activation, such that these cells express adhesion molecules which in turn attach leucocytes, releasing cytokines, attracting more leucocytes and releasing prothrombotic factors, all of which contribute to the inflammatory cascade. Endothelial cell and neutrophil activation may also be important in the initial phase of vasculitis where persistence and progression of the inflammatory process may lead to the migration of monocytes and T-cells into areas of active disease, leading to an uncontrolled inflammatory response with tissue damage and scarring (reviewed in Sezkanecz and Koch). 14 Trigger factors The predominance of respiratory involvement, especially in WG, led Duna et al to investigate inhaled agents. They observed no increase in inhaled particulates and fumes in WG in general, but a significant increase in those with respiratory disease. 15 A number of other trigger factors have also been reported in association with systemic vasculitis, including silica, solvents, allergy and vaccination. A recent case-control study showed an association between occupations with high exposure to silica and PSV. In particular panca/mpo-positive patients showed an association rather than canca/pr3. This supports data from three case-control studies which also showed an association between silica and ANCA-positive glomerulonephritis, MPA and WG. One of these casecontrol studies found a significant association between occupational exposure to organic solvents and WG and canca-positive vasculitis. In addition this study noted for the first time an association between farming and PSV, in particular livestock farming as opposed to crops. 16 A number of drugs have been implicated in the development of PSV. Patients with high-titre MPO antibodies are more likely to have used hydrallazine, propylthiouracil or allopurinol. 17 Leucotriene antagonists have been associated with development of CSS. 18 CLINICAL FEATURES Wegener s granulomatosis WG is characterised by necrotising granulomata of the upper and lower respiratory tract, necrotising vasculitis and focal glomerulonephritis. A more limited form, with lesions limited to the upper and lower respiratory tract, can occur. Upper-airways disease is the most common presenting feature, occurring in more than 70% of patients at presentation, and develops in >90% of patients. Nasal disease presents with obstruction, nasal ulcers and septal perforation, serosanguinous discharge or epistaxis. Destruction of the nasal septum results in the typical saddle-nose deformity. Sinusitis is present in 85% at some time during the disease. Laryngotracheal disease may be asymptomatic, but can present with hoarseness or stridor and upper-airways obstruction. Renal disease is a feature of WG, occurring in 18% of patients at presentation and in 77% subsequently. 19 It may not be clinically apparent and must be constantly sought. Patients may present with life-threatening renal failure due to rapidly progressive glomerulonephritis requiring urgent dialysis and immunosuppression. At the other end of the spectrum are patients with proteinuria or haematuria with no impairment of renal function. Any renal involvement is associated with a significantly worse outcome and in particular serum creatinine of >500 µmol/l at presentation may be difficult to reverse. Pulmonary involvement is one of the main features of WG, occurring in 45% at presentation and 87% during the course of the disease. 19 Cough, haemoptysis and pleuritis are most common. The most frequent radiological features are pulmonary infiltrates, haemorrhage and hilar lymphadenopathy. Cutaneous manifestations occur in around 50% of patients, and include ulcers, palpable purpura, papules and nodules. Neurological involvement with peripheral neuropathy or mononeuritis multiplex is less common at presentation but can be detected (often subclinically) in up to half of patients with time. 72

5 Ocular disease occurs in 50%, with any compartment of eye potentially being affected keratitis, conjunctivitis, scleritis, episcleritis, uveitis, retro-orbital pseudotumour, retinal vessel occlusion and optic neuritis. Visual loss is reported in up to 8% of patients. Musculoskeletal symptoms are common in WG patients, with most patients experiencing arthralgias and/or myalgias. A true synovitis can be seen in 25% of patients. Microscopic polyangiitis Kussmaul and Maier 20 described a patient with periarteritis nodosa characterised by inflammation and necrosis of medium-sized arteries, resulting in aneurysm formation and organ infarction. Wainwright and Davson 21 described patients with segmental glomerulonephritis who also had features of polyarteritis nodosa (PAN) with extra-renal involvement. They used the term microscopic polyarteritis nodosa for such patients, whose dominant feature was rapidly progressive renal failure. Such patients are now termed as having microscopic polyangiitis (MPA). Patients with MPA share some features with WG patients 22 and in early disease distinction may be difficult. Renal disease is characteristic and the typical histological appearance is a focal segmental necrotising glomerulonephritis. Pulmonary haemorrhage is also common (up to 29%). Mononeuritis multiplex as in WG is uncommon, and ocular and nasopharyngeal symptoms are less common than in WG. Polyarteritis nodosa Polyarteritis nodosa is now usually called classical PAN to distinguish it from MPA. Organ infarction (i.e. gut, nerve, bowel) is typical as a consequence of medium artery involvement. Orchitis is a characteristic but uncommon feature. Mononeuritis multiplex is common (70% at presentation). Classical PAN is also ANCA negative by this definition and appears to be quite rare, at least in the UK. Churg Strauss syndrome The characteristic features of CSS are asthma (typically late onset), peripheral blood and tissue eosinophilia, fever, and systemic vasculitis. Asthma especially distinguishes CSS from WG, MPA and PAN. Histologically there is a granulomatous necrotising vasculitis. Renal involvement is relatively uncommon. Asthma is the cardinal feature and precedes systemic features in virtually all cases; onset is late in life and becomes more severe until the onset of vasculitis. Chest radiography shows infiltrates in up to 77%. 23 Cardiac disease is common and is an important cause of mortality, due to congestive heart failure, pericardial effusion and restrictive cardiomyopathy. Mononeuritis multiplex is a common (70%) feature of both PAN and CSS, where it is much more frequent than in WG and MPA. INVESTIGATION AND DIAGNOSIS Investigation is directed towards (a) establishing and confirming the diagnosis, (b) assessing the extent of organ involvement, and (c) assessing disease activity. The first stage is to consider that systemic vasculitis might be present in any patient with multisystem disease. It is important to differentiate between PSV and syndromes that may mimic PSV, particularly infection, malignancy and connective tissue disease (Table 2). It is especially important to exclude infection as PSV is treated with highdose corticosteroids and immunosuppressive agents. Urinalysis is the single most important investigation. The extent of renal impairment and rate of deterioration in renal function is a major determinant of prognosis. The detection of proteinuria and/or haematuria in a patient with a systemic illness mandates immediate further investigation and is a medical emergency. ASSESSMENT OF ORGAN INVOLVEMENT Urinalysis is a sensitive means of detecting renal involvement, and an active urinary sediment with red blood cells (RBC) and casts indicates glomerular disease. Serum TABLE 2. Mimics of systemic vasculitis. 1. Systemic multisystem disease Infection Malignancy Other 2. Vessel occlusion Embolic Thrombotic Other 3. Angiographic appearances Aneurysmal Occlusion Subacute bacterial endocarditis Neisseria meningitidis Rickettsiae Metastatic carcinoma Paraneoplastic Sweet syndrome Connective tissue disorders Cholesterol crystals Atrial myxoma Mycotic (infection) Antiphospholipid syndrome Procoagulant states Calciphylaxis Ergotism Radiation Degos syndrome Severe Raynaud s phenomenon Acute digital loss (atheromatous) Fibromuscular dysplasia Neurofibromatosis Coarctation of the aorta 73

6 urea and creatinine may be normal despite active renal disease. Renal biopsy will serve to confirm the diagnosis and document the extent of renal inflammation or scarring. Leucocytosis suggests either a primary vasculitis or infection. Leucopaenia is a rare presenting feature of vasculitis and if present suggests vasculitis secondary to systemic lupus erythematosus or the effects of previous immunosuppressive therapy. A significant peripheral blood eosinophilia (1.5 x 109/l) suggests CSS or a drug reaction. A hypochromic microcytic anaemia may be indicative of gastrointestinal bleeding, pulmonary haemorrhage or active persistent inflammation. The degree of inflammation may be assessed by measurement of the acute phase response (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)). Neither is specific and each may be elevated in any inflammatory condition, including vasculitis. A disproportionate increase in CRP compared with ESR should raise the suspicion of infection. Chest radiography should be performed in all patients with suspected systemic vasculitis to assess the presence of infiltrates, haemorrhage or granulomata and to exclude infection. High-resolution computerised tomography (CT) improves the detection of pulmonary lesions of WG and pulmonary fibrosis, and can be useful in assessing response to treatment. Infection (especially tuberculosis), sarcoidosis and malignancy can mimic the CT appearance of WG. Suspicious lesions should be biopsied to exclude malignancy or infection. Plain sinus films or CT should be obtained to assess the extent of sinus involvement; however there is difficulty in distinguishing scarring from active disease. Patients with active ear, nose and throat (ENT) symptoms should have formal endoscopy by an otolaryngologist and biopsies obtained from areas of inflammation. Histology in active disease is often non-specific and is difficult to distinguish from chronic infection. Echocardiography is essential as part of the investigation to exclude bacterial endocarditis and atrial myxoma. Myocarditis is especially frequent in CSS and poor ventricular function can be demonstrated by echocardiography. Neurological signs may be subtle with evidence only of minor sensory impairment. Nerve conduction studies performed on four limbs will demonstrate evidence of mononeuritis multiplex (especially PAN and CSS). CONFIRMATION OF DIAGNOSIS Tissue biopsy is vitally important to confirm the diagnosis prior to treatment with potentially toxic immunosuppressive drugs. The choice of tissue to biopsy is crucial. Biopsy of uninvolved tissue is less likely to yield a positive result. In the acutely sick patient in whom the evidence for vasculitis is strong and infection has been ruled out treatment should not be delayed solely to obtain the biopsy. Biopsy on occasion may reveal clinically unexpected findings such as cholesterol crystals or myxomatous emboli. It is not usually necessary to biopsy more than one organ to confirm the diagnosis; however, multiple biopsies of clinically affected organs may be required to assess the extent of organ involvement and to exclude alternative diagnoses. OTHER INVESTIGATIONS Blood cultures, clotting screen, viral serology and echocardiography are important to exclude infection and other conditions that may present as systemic multisystem disease and hence mimic vasculitis. ASSESSMENT OF DISEASE ACTIVITY Modern therapy of the systemic vasculitides has dramatically altered the prognosis of PSV from acute fulminating life-threatening conditions to chronic diseases with considerable morbidity arising from either disease activity or therapy. Several systems have been developed to assess disease activity and damage (as reviewed by Carruthers and Bacon). 24 These include the Birmingham Vasculitis Activity Score (BVAS), Groningen index and the Vasculitis Activity Index (VAI). The BVAS is the most widely applicable to different types of necrotising vasculitis and has been systematically validated. 25 The BVAS was devised by a group of interested clinicians and pathologists. It is a comprehensive scoring system, which includes nine organ systems. Clinical features that are attributable to active vasculitis and that have occurred anew and been present within the previous 4 weeks are recorded. Organ involvement associated with a worse prognosis is given a greater weighting. BVAS has also been used to develop definitions of remission and relapse, which are now being used in multicentre trials. Vasculitis results in organ damage due either to the disease itself or to therapy. Damage is defined as an irreversible process that is the result of scars and is not due to acute inflammation or grumbling disease activity. The Vasculitis Damage Index (VDI) is also an organbased system and is scored after 3 months. The VDI is comprehensive, permits accumulation of damage with time and has been validated. 26 The final component of patient assessment is function. The SF-36 has been validated for use in patients with vasculitis and is included in the Vasculitis Integrated Assessment Log (VITAL) for disease assessment

7 PROGNOSIS The natural history of untreated PSV is of a rapidly progressive, usually fatal disease. Prior to the introduction of corticosteroids in WG, Walton observed a mean survival of 5 months, with 82% of patients dying within 1 year and more than 90% dying within 2 years. 28 The introduction of corticosteroids resulted in an improvement in survival in PAN to 50% at 5 years. 29 The median survival in WG was only 12.5 months using corticosteroids alone, with most patients dying of sepsis or uncontrolled disease. 30 In the 1970s, at the National Institutes of Health (NIH), USA, the introduction of cyclophosphamide (CYC) combined with prednisolone resulted in a significant improvement in the mortality of WG with a 5-year survival of 82%, 31,32 and most modern series report 5-year survival figures of 80 90%. Overall however the extent and number of organs determine the prognosis involved. The five factor score (FFS) was developed in a retrospective study of PAN and CSS by Guillevin et al. 33 A poor prognosis was associated with age >50 years and the presence of cardiomyopathy, nephropathy (proteinuria >1 g/l; creatinine >1.58 mg/dl), gastrointestinal tract involvement (bleeding, perforation, infarction or pancreatitis) and central nervous system (CNS) involvement. An FFS of 2 is associated with 53% mortality at 6 years, compared with 14% in patients with an FFS of 0. The BVAS at presentation is also indicative of prognosis. In a cross-sectional study patients with a subsequent fatal outcome had a median initial BVAS of 20.5, those with active untreated disease 7.5, and those with inactive disease TREATMENT The gold standard for the initial treatment of PSV is corticosteroids and CYC. The original NIH regimen combines low dose oral CYC (2.0 mg/kg/day) with prednisolone initially at a dose of 1.0 mg/kg/day. CYC was continued for at least 1 year after the patient achieved complete remission and was then tapered. Prednisolone was continued daily for at least 4 weeks and changed to alternateday dosing prior to tapering. Patients were then maintained solely on CYC. In a prospective open study of 133 patients who received this regimen 75% achieved a complete remission and an 80% survival rate was observed over a mean follow-up of 8 years. Relapse was observed in 50% of patients and drug toxicity was observed in 42%. 18 Corticosteroids were withdrawn at median interval of 12 months. This regimen was designed to minimise exposure to corticosteroids and avoid neutropaenia. CYC-associated side-effects were frequent cystitis (43%), bladder cancer (2.8%) and myelodysplasia (2%). In this study the bladder cancer rate was increased 33-fold, compared to non-exposed individuals. Serious infections (those requiring hospitalisation and intravenous antibiotics) occurred in 46% of patients (0.11 infections per patient year). To try and further minimise toxicity CYC has been given by intermittent bolus infusion. Whether this approach is as efficacious as conventional daily oral CYC has been fiercely controversial. A recent meta-analysis of patients with ANCA-associated vasculitis reported that pulse CYC was more effective than oral CYC at induction of remission; it was slightly less effective in preventing relapse but had fewer side-effects. 34 This is probably due to the lower cumulative doses of CYC used in the pulse regimens. A multicentre European trial (CYCLOPS) is currently under way to answer the question whether pulsed therapy is as effective as and safer than continuous oral CYC in terms of induction and maintenance of remission and adverse effects. 35 Over the years the duration of CYC treatment has gradually been reduced. The CYCAZAREM trial compared short duration (3 6 months) with longer duration CYC (1 year), using azathioprine (AZA) as maintenance therapy patients with ANCA-associated vasculitis were studied; oral cyclophosphamide and corticosteroids resulted in remission in 144 patients. 7 patients died in the induction phase. There was no difference in relapse rates up to the end of the study at 18 months after treatment outset, suggesting that CYC can safely be withdrawn following induction of remission. Methotrexate (MTX) has been advocated as an alternative to AZA for maintenance of remission and to CYC for induction of remission. Data from the NORAM trial comparing MTX with CYC in patients with limited or non-renal PSV indicate that MTX can be as effective as CYC at inducing remission in these patients at 6 months. The relapse rate after 1 year (when the trial medications were stopped) was unacceptably high in both groups, suggesting that even in non-renal ANCA-associated vasculitis (AAV) therapy should be gently tapered. 37 Langford et al 38 at the NIH performed an open-label prospective study; 31 patients with active WG were included. Following induction of remission with CYC, MTX was substituted. The initial dose of MTX was given within 1 2 days of the last CYC dose if the white blood cell count (WBC) was acceptable. Methotrexate was started at a dose of 0.3 mg/kg and gradually escalated to a maximum of mg/week. Comparison with historical controls treated with the standard NIH regimen of daily oral CYC for >1 year suggests that the relapse rate was no greater in the MTX treated patients. Toxicity was low, but two patients developed MTX pneumonitis. 75

8 In patients with severe renal disease (creatinine >500 µmol/l), plasma exchange has long been advocated. The MEPEX trial comparing methylprednisolone and plasma exchange has recently been reported. 39 Plasma exchange improves renal survival and quality of life in this group of patients compared with methylprednisolone as adjunctive therapy. Recently there have been encouraging reports using biologic therapies in PSV. Anti-tumour necrosis factor alpha (TNFα) therapy with infliximab has been reported to be successful in a small number of patients. 40 Etanercept has been shown not to be effective at maintenance of disease remission when used in addition to conventional therapy (glucocorticoids plus CYC or MTX). 41 Rituximab, a chimeric monoclonal antibody, induces selective depletion of B lymphocytes by targeting the CD20 surface antigen. In a small open study of 11 patients with refractory ANCA-associated vasculitis, all patients achieved remission and treatment was well tolerated. However, only one of the patients had MPA. 42 Despite the developments outlined above, treatment is still associated with significant potential morbidity. Patients receiving CYC should receive co-trimoxazole as prophylaxis against Pneumocystis carinii infection and mesna to reduce the potential risk of haemorrhagic cystitis and bladder cancer. Prophylaxis against osteoporosis should be provided in line with current guidelines. In summary, modern therapy for PSV involves a staged approach: induction with cyclophosphamide followed by a switch to azathioprine or methotrexate once remission has been achieved. CONCLUSION The primary systemic vasculitides are rare diseases, still of unknown aetiology, although since the discovery of ANCA there has been considerable progress towards understanding their pathogenesis. The introduction of immunosuppressant therapy with cyclophosphamide and corticosteroids has dramatically improved the prognosis from conditions with high mortality to chronic diseases with a relapsing and remitting course. These treatment regimen are associated with substantial toxicity and one of the main thrusts of current research is to devise therapies which are substantially less toxic. Biologic agents have recently been trialled in limited numbers of patients and may prove to be an effective form of therapy in the future as an alternative to conventional immunosuppression. Other future developments will include a clearer understanding of the role of ANCA in the pathogenesis and causation of endothelial damage. FURTHER READING Ball GV, Bridges SL Jr (ed). Vasculitis. Oxford: Oxford University Press, REFERENCES 1. Matteson EL. 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