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

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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 alternatives for intoler- ance or lack of efficacy of AZT or MTX. For patients intolerant of CYC alternative Maintenance therapy should continue Corticosteroids treatments such as MTX, azathioprine for at least 24 months following suc- Steroids in combination with standard (AZT), leflunomide or mycophenolate cessful disease remission. It is advisable immune suppression are useful for the mofetil may be used, but there is little that patients who remain ANCA-positive early control of disease activity in PSV evidence for their use as induction continue immunosuppression for up to but are ineffective as sole therapy for the therapy except for MTX. five years. induction of remission. The optimal ini- tial dosage of steroids and the rate of Maintenance therapy Relapsing disease steroid taper are currently controversial. Steroids are usually given as daily oral CYC should be withdrawn in patients Minor relapse is treated with an increase prednisolone, starting initially at rela- who have achieved successful remission in prednisolone dosage, followed by

Table 4. Categorisation of disease severity and induction therapy.6

Constitutional Typical Threatened vital Serum creatinine Clinical subgroup symptoms ANCA status organ function (µmol/l) Treatment induction*

Localised/early systemic Yes + or – No <150 MTX or CYC Generalised Yes + Yes <500 CYC Severe Yes + Yes >500 CYC/plasma exchange Methylprednisolone

* All induction regimens include oral/intravenous steroids. ANCA = antineutrophil cytoplasmic antibody; CYC = cyclophosphamide; MTX = methotrexate.

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gradually tapering of the dose and opti- PATH-1H (alemtuzumab, anti-CD52), relapse.16 Treatment withdrawal in misation of concurrent immunosuppres- deoxyspergualin and rituximab in refrac- patients with persistently positive ANCA sion. Major relapse is treated with CYC tory disease is still under investigation. It is associated with relapse.17 as for remission induction with an is important to identify potential under- increase in prednisolone; iv methylpred- lying factors influencing persistent or Detection and prevention of nisolone or plasma exchange may also be relapsing disease, including intercurrent potential adverse effects of considered. infection and malignancy as well as non- immunosuppressive therapy Nasal carriage of Staphylococcus aureus compliance. is associated with increased risk of Cyclophosphamide-induced bladder toxicity relapse in patients with WG, although Assessment and monitoring of the causal relation and mechanism disease activity Haemorrhagic cystitis and bladder remain speculative.12 Cyclical application cancer are recognised complications of of mupirocin should be considered in The PSVs are relapsing conditions; therapy. The risk is related to the cumu- patients with WG. relapse may occur any time after diag- lative dose of CYC administered and is nosis and remission induction. Various greatest in patients receiving more than tools may be used to assess disease Refractory disease a cumulative dose of 100 g CYC.18 activity and extent of disease: for Treatment with [sodium-2-] mercap- Disease refractory to full-dose CYC and example the Birmingham Vasculitis toethanesulfonate (MESNA), which pro- prednisolone is rare. More commonly, Activity Score.13,14 The Vasculitis tects against the urothelial toxicity of optimal doses are not tolerated or a pro- Damage Index15 provides a long-term CYC, should be considered in all patients longed relapsing disease course with high outcome of disease and its consequences. receiving CYC therapy. cumulative exposure to CYC and pred- ANCA measurements are not closely nisolone are the indications for alternative associated with disease activity. Treatment agents. should not be escalated solely on the basis Pneumocystis jiroveci infection The use of infliximab, iv immunoglob- of an increase in ANCA but it should be Immunosuppressed patients are at risk ulin, antithymocyte globulin, CAM- taken as a warning of possible impending of Pneumocystis jiroveci. There are no RCT data but observational data support the approach that patients receiving CYC Key Points and corticosteroids should receive trimethoprim/sulfamethoxazole 960 mg Symptoms of systemic vasculitis at presentation are often non-specific and thrice weekly (or aerolised pentami- diagnosis requires a high index of suspicion dine/daily dapsone in patients allergic to trimethoprim/sulfamethoxazole) as A negative antineutrophil cytoplasmic antibody (ANCA) does not exclude primary 19–21 systemic vasculitis prophylaxis against pneumocystis.

Critical organ function is damaged early in disease, so a careful assessment for renal, cardiac and pulmonary involvement, with appropriate tests, is essential Osteoporosis

Studies have included large numbers and have significantly influenced current All patients receiving corticosteroids for management systemic vasculitis should be started on a bisphosphonate with calcium and vit- Treatment regimens are based on early systemic/localised, generalised/organ- threatening or severe/life-threatening disease amin D supplementation.

Localised disease may have local destructive consequences and these patients require cyclophosphamide (CYC) treatment Vaccinations

For both oral and intravenous CYC the aim is a maximum duration of therapy of Immunocompromised patients should six months where successful disease remission has been achieved not receive live vaccines, but should be vaccinated against influenza and Maintenance therapy should continue for at least 24 months or longer in patients pneumococcal infections.22,23 who remain ANCA-positive

ANCA titre does not always correlate with disease activity Conclusions Treatment should not be altered solely according to changes in ANCA titre; the exception is treatment withdrawal which should not be considered in the CYC has transformed the prognosis of presence of a persistently positive ANCA because of a high risk of relapse many of the systemic vasculitides. Early diagnosis and treatment improve the KEY WORDS: cyclophosphamide, diagnosis, treatment, vasculitis outcome. Recently published clinical

46 Clinical Medicine Vol 7 No 1 January/February 2007 CME Rheumatology trials and smaller case series provide evi- Randomized trial of cyclophosphamide 17 Birck R, Schmitt W, Kaelsch IA, van der dence for new treatment options and versus methotrexate for induction of Woude FJ. Serial ANCA determinations for treatment stratification, but there is a remission in early systemic antineutrophil monitoring disease activity in patients with cytoplasmic antibody-associated vasculitis. ANCA-associated vasculitis: systematic continued need for better and less toxic Arthritis Rheum 2005;52:2461–9. review. Am J Kidney Dis 2006;47:15–23. treatment regimens. 9 De Groot K, Muhler M, Reinhold-Keller E 18 Talar-Williams C, Hijazi YM, Walther MM et al. Randomised controlled trial of daily et al. Cyclophosphamide-induced cystitis oral versus pulsed cyclophosphamide for and bladder cancer in patients with References induction of remission in ANCA associated Wegener granulomatosis. Ann Intern Med systemic vasculitis. Kidney Blood Press Res 1996;124:477–84. 1 Watts RA, Scott DG. Overview of the 2005;28:195 (abstract). 19 Guillevin L, Cordier JF, Lhote F et al. inflammatory vascular disease. In: 10 Gaskin G, Jayne D. Adjunctive plasma A prospective, multicenter, randomized Hochberg MC, Silman AJ, Smolen JE, exchange is superior to methylprednisolone trial comparing steroids and pulse Weinblatt ME, Weisman MH (eds). in acute renal failure due to ANCA cyclophosphamide versus steroids and oral Rheumatology, 3rd edn. Edinburgh: Mosby, associated glomerulonephritis. J Am Soc cyclophosphamide in the treatment of 2003:1583–91. Nephrol 2002;13:F-FC010. generalized Wegener’s granulomatosis. 2 Watts RA, Scott DG. Epidemiology of 11 Jayne D, Rasmussen N, Andrassy K et al. Arthritis Rheum 1997;40:2187–98. vasculitis. In: Ball GV, Bridges L (eds). A randomized trial of maintenance therapy 20 Reinhold-Keller E, Beuge N, Latza U et al. Vasculitis. Oxford: Oxford University Press, for vasculitis associated with antineutrophil An interdisciplinary approach to the care 2002:211–26. cytoplasmic autoantibodies. N Engl J Med of patients with Wegener’s granulomatosis: 3 Gardner-Medwin JM, Dolezalova P, 2003;349:36–44. long-term outcome in 155 patients. Cummins C, Southwood TR. Incidence of 12 Stegeman CA, Tervaert JW, Sluiter WJ et al. Arthritis Rheum 2000;43:1021–32. Henoch-Schonlein purpura, Kawasaki Association of chronic nasal carriage of 21 Chung JB, Armstrong K, Schwartz SJ, disease, and rare vasculitides in children of Staphylococcus aureus and higher release Albert D. Cost-effectiveness of prophylaxis different ethnic origins. Lancet 2002;360: rates in Wegener granulomatosis. Ann against Pneumocystis carinii in patients 1197–202. Intern Med 1994;120:12–7. with Wegener’s granulomatosis undergoing 4 McLaren JS, Stimson RH, McRorie ER, 13 Bacon PA, Luqmani RA. Assessment of immunosuppressive therapy. Arthritis Coia JE, Luqmani RA. The diagnostic value vasculitis. In: Ball GV, Bridges L (eds). Rheum 2000;43:1841–8. of anti-neutrophil cytoplasmic antibody Vasculitis. Oxford: Oxford University Press, 22 British Society for Rheumatology (2002) testing in a routine clinical setting. QJM 2002:246–54. vaccinations in the immunocompromised 2001;94:615–21. 14 Luqmani RA, Bacon PA, Moots RJ et al. person. Guidelines for the patient taking 5 Lane SE, Watts RA, Shepstone L, Scott DG. Birmingham Vasculitis Activity Score immunosuppressant, steroids and the new Primary systemic vasculitis: clinical (BVAS) in systemic necrotizing vasculitis. biologic therapies. www.rheumatology.org.uk features and mortality. QJM QJM 1994;87:671–8. 23 Gluck T. Vaccinate your 2005;98:97–111. 15 Exley AR, Bacon PA, Luqmani RA et al. immunocompromised patients! 6 Rasmussen N, Jayne DR, Abramowicz D Development and initial validation of the Rheumatology (Oxford) 2006;45:9–10. et al. European therapeutic trials in ANCA Vasculitis Damage Index for the associated systemic vasculitis: disease standardized clinical assessment of damage scoring, consensus, regimens and proposed in the systemic vasculitides. Arthritis clinical trials. Clin Exp Immunol 1995; Rheum 1997;40:371–80. 101(Supp 1):29–34. 16 Sanders JS, Huitma MG, Kallenberg CS, 7 Lapraik C, Watts RA, Scott DG. BSR and Stegeman CA. Prediction of relapses in BHPR guidelines for the management of PR3-ANCA-associated vasculitis by adults with ANCA associated vasculitis. assessing responses of ANCA titres to Rheumatology (in press). treatment. Rheumatology (Oxford) 2006;45: 8 De Groot K, Rasmussen N, Bacon P et al. 724–9.

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