CME: CLINICAL PRACTICE AND ITS BASIS The aetiology is unknown but, like most autoimmune diseases, involves a complex interaction between environmental Rheumatology factors and a genetically predisposed host. Edited by Richard Watts DM FRCP, Investigation and diagnosis of Consultant Rheumatologist, Ipswich Hospital NHS Trust; Senior Lecturer, primary systemic vasculitis School of Medicine, Health Policy, University of East Anglia (Table 2) Symptoms can be non-specific in the early phases of the disease and a high Background index of suspicion is required. Symptoms Modern management that should prompt consideration of a The systemic vasculitides are a group of diagnosis of vasculitis are unexplained of primary systemic heterogeneous, relatively uncommon systemic disturbance, arthritis or conditions characterised by inflamma- arthralgia, polymyalgia, episcleritis, vasculitis tion and necrosis of blood vessel walls. neuropathy, microscopic haematuria, They are classified according to vessel pulmonary infiltrates or nodules and size (Table 1).1 Primary systemic vas- maturity-onset asthma. Chloe Lapraik MB MRCP, Specialist Registrar culitis (PSV) (comprising Wegener’s Acute-phase reactants such as in Rheumatology, Luton and Dunstable granulomatosis (WG), Churg-Strauss C-reactive protein and erythrocyte sedi- Hospital syndrome (CSS) and microscopic mentation rate are typically elevated in Richard Watts DM FRCP, Consultant polyangiitis (MPA)) typically involves the acute phase. Urinalysis should be Rheumatologist, Ipswich Hospital NHS Trust; medium and small vessels and is associ- performed as soon as the diagnosis of Senior Lecturer, School of Medicine, Health Policy and Practice, University of East Anglia ated with the presence of antineutrophil vasculitis is suspected because renal cytoplasmic antibodies (ANCA). This involvement may progress silently and it David GI Scott MD FRCP, Consultant group is sometimes described as ANCA- is associated with a worse prognosis. Full Rheumatologist, Norfolk and Norwich University Hospital NHS Trust; Honorary associated vasculitis (AAV). blood count should be measured, Professor, School of Medicine, Health Policy Most data on the incidence and preva- looking particularly for eosinophilia. It and Practice, University of East Anglia lence of PSV have come from Europe. is essential to investigate critical organ The consensus is that: function for renal, cardiac and pul- Clin Med 2007;7:43–7 • the overall annual incidence is monary involvement, with appropriate approximately 10–20 per million organ-specific tests (Fig 1). the peak age of onset is 65–74 years Autoantibodies including ANCA are • useful in the appropriate clinical setting. It it is slightly more common in men • is important to recognise that a negative 2,3 • it is very rare in childhood. ANCA does not exclude vasculitis and a positive ANCA does not necessarily prove 4 Table 1. Classification of systemic vasculitis. Reprinted with permission from Elsevier.1 vasculitis. Infection should be excluded by blood Vasculitis culture and appropriate serology because Dominant vessel Primary Secondary treatment for PSV involves intense immunosuppression. Large arteries Giant cell arteritis Aortitis associated with RA, The choice of biopsy site depends on Takayasu’s arteritis infection (eg syphilis, TB) the clinical features, but skin and renal Medium arteries Classical PAN Hepatitis B-associated PAN biopsies are often helpful for diagnosis. Kawasaki disease Treatment should not be delayed for a Small vessels and Wegener’s granulomatosis Vasculitis secondary to RA, biopsy if there are strong clinical grounds medium arteries Churg-Strauss syndrome SLE, Sjögren’s syndrome, for a diagnosis of vasculitis. Microscopic polyangiitis drugs, infection (eg HIV) Imaging investigations including Small vessels Henoch-Schonlein purpura Drugs Cryoglobulinaemia Hepatitis C-associated angiography should be carefully consid- Cutaneous leucocytoclastic infection ered in appropriate cases. Coeliac axis angiitis angiography has an important role in the diagnosis of polyarteritis nodosa. PAN = polyarteritis nodosa; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; TB = tuberculosis. There are a number of conditions that may mimic systemic vasculitis and these Clinical Medicine Vol 7 No 1 January/February 2007 43 CME Rheumatology Table 2. Investigation of vasculitis. must be considered in the differential diagnosis (Table 3). Assessment of inflammation Blood count and differential cell count (total white cell count, eosinophils) Acute-phase response (ESR, CRP) Treatment Liver function Assessment of organ involvement Urinalysis (proteinuria, haematuria, casts) The natural history of untreated PSV is Renal function (creatinine clearance, 24-hour protein, of a rapidly progressive, usually fatal dis- excretion, biopsy) ease. With modern treatment regimens Chest radiograph Liver function the five-year survival rates are 45% for 5 Nervous system (nerve conduction studies, biopsy) MPA, 76% for WG and 68% for CSS. Muscle (EMG, creatinine kinase, biopsy) The European Vasculitis Study Group Cardiac function (ECG, echocardiography) (EUVAS) has recently completed a series Gut (angiography) of multicentre randomised controlled Skin (biopsy) trials (RCTs).6 Detailed guidelines for the Serological tests ANCA (including proteinase 3, myeloperoxidase) management of the PSV have recently Antinuclear antibodies Rheumatoid factor been developed by the British Society for Anticardiolipin antibodies Rheumatology.7 Complement Current treatment is based on Cryoglobulins assessing severity and extent of disease, Differential diagnosis Blood cultures subdividing the disease into three groups Viral serology (HBV, HCV, HIV, CMV) as adopted by EUVAS (Table 4). Echocardiography (2-dimensional, transoesophageal or both) Treatment can be divided into three stages: induction, consolidation and ANCA = antineutrophil cytoplasmic antibody; CMV = cytomegalovirus; CRP = C-reactive protein; EMG = maintenance of remission. electromyography; ESR = erythrocyte sedimentation rate; HBV = hepatitis B virus; HCV = hepatitis C virus. Treatment for remission induction Localised/early systemic disease Cyclophosphamide (CYC) (maximum dose oral 200 mg/day or intravenous pulse 15 mg/kg) and methotrexate (MTX) (maximum 20–25 mg/week) are the most established treatments for this category. MTX is effective but may be associated with a higher relapse rate; any evidence of progression or relapse should be treated with CYC.8 Localised disease can have significant local destructive consequences and these patients require CYC treatment. Generalised/threatened organ involvement Initial treatment of patients with gener- alised/organ-threatening disease should include CYC and steroids. CYC may be given as continuous low-dose oral treat- ment (2 mg/kg/day, maximum 200 mg/day) or by intravenous (iv) pulse (15 mg/kg, maximum 1,500 mg per Fig 1. Algorithm for the management of primary systemic vasculitis (PSV).7 pulse), initially at two-weekly intervals AZA = azathioprine; creat = creatinine; CYC = cyclophosphamide; MTX = methotrexate; and then three-weekly. Dose reduc- Pred = prednisolone. tions should be made for age and renal 44 Clinical Medicine Vol 7 No 1 January/February 2007 CME Rheumatology function. The recently completed EUVAS Table 3. Differentiation to be made from conditions that may mimic primary systemic 1 trial of pulse versus continuous low-dose vasculitis. Reprinted with permission from Elsevier. oral CYC showed no difference in remis- Multisystem disease Infection Subacute bacterial endocarditis sion rates and no increased risk of relapse Neisseria in the iv treated patients.9 Continuous Rickettsiae low-dose oral CYC was associated with a Malignancy Metastatic carcinoma Paraneoplastic higher total CYC dosage and a significant Other Sweet’s syndrome increase in infection risk. The cumulative Occlusive vasculopathy Embolic Cholesterol crystals dose of CYC was lower for the iv pulse Atrial myoma regimen than for the continuous oral Infection regimen when administered for the same Calciphylaxis period of time. Thrombotic Antiphospholipid syndrome Procoagulant states Current clinical practice considers Cryofibrinogenaemia transfer to maintenance therapy after Others Ergot 3–6 months of CYC therapy if successful Radiation disease remission has been achieved. The Degos syndrome aim should be for a maximum duration Severe Raynaud’s Acute digital loss of therapy of six months where successful Buerger’s disease disease remission has been achieved. Angiographic Aneurysmal Fibromuscular dysplasia Neurofibromatosis Severe/life-threatening disease Occlusion Coarctation Patients with PSV presenting with severe renal failure (creatinine >500 µmol/l) tively high doses (1 mg/kg up to about and either AZT or MTX substituted. A should be treated with CYC (either 60 mg) and tapered to about 10 mg/day recent trial comparing CYC and AZT pulsed iv or continuous low-dose oral) at six months.10 Steroids (250–500 mg iv found them equally effective at main- and steroids, with adjuvant plasma methylprednisolone) are sometimes taining remission, with similar relapse exchange.10 Plasma exchange should also given with the first two pulses of iv CYC. rates but increased toxicity in the CYC be considered in those with other life- group.11 MTX may be used in patients threatening manifestations of disease Patients intolerant of intolerant of AZT, with mycophenolate such as pulmonary haemorrhage. cyclophosphamide or leflunomide as