relapse or remission remains to be determined (see Plate 32). Angiography Angiography is not usually required to make the diagnosis. The role of MRA of t he temporal arteries remains to be established. Where extra-cranial large vessel involvemen t is suspected MRA or contrast angiography should be considered. Relapsing disease Minor relapse can be treated with an increase in predniso- lone dose to t he last effective dose. Differential diagnosis Takayasu arteritis (TA) in the younger patient. Other forms of syste mic necrotizing vasculitis may rarely present with vasculitis affecting the temporal arteri es. Refractory disease \200 Use of azathioprine or methotrexate should be consid- ered in patients with relapsing disea se or who are resist- ant to corticosteroids. However, a randomized trial of methotrexate s howed no bene \201 t in either reduction of relapse rate or reduction of steroid dosage. T he role of biologic agents such as in \202 iximab remains to be determined. Disease assessment ESR and CRP are a guide to disease activity, but may be normal in relaps e particularly in patients on corticosteroids. Prognosis Untreated GCA is associated with a signi \201 cant risk of per- manent blindness risk. This is greatly reduced by the early introduction of corticosteroids. The risk of th e second eye being involved in a patient with profound visual loss is 70% within 1 week unl ess treated. The risk of blindness occurring in patients on corticosteroids is very low. Resources Guidelines EULAR recommendations for the management of large vessel vasculitis (M ukhtyar et al., 2008). Patient organizations Vasculitis Foundation. www.vasculitisfoundation.org Pathology Granulomatous necrotizing vasculitis affecting large vessels especially the extra cranial branches of the aorta. There is destruction of the internal elastic lamina with gia nt cells and granuloma formation. The lesions are focal and careful examination of adequate biopsy is required. ICD-10 coding M31.5 Giant cell arteritis with polymyalgia rheumatica M31.6 Other giant cell arteritis References Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatology 1990 criteria for the classi \201 cation of Giant Cell Arteritis. Arthritis Rheum 1990; 33: 11 22 \200\22318. Patient advice General Potentially serious condition, requiring glucocorticoid therapy with a risk of blindness Mazlumzadeh M, et al. Treatment of giant cell arteritis using i nduction therapy with high- dose glucocorticoids: a double-blind, placebo controlled, randomized prospective clinical t rial. Arthritis Rheum 2006; 54: 3310 \200\22318. Treatment Observational studies support the use of high dose gluco- corticoids in GCA. \200 Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large v essel vasculitis. Ann Rheum Dis 2008 (in press). In patients without ocular symptoms oral corticoster- oids starting at 0.7 \200\2231 mg/kg (maximum dose 60 \200\22380 mg). POLYMYALGIA RHEUMATICA 320 Polymyalgia rheumatica Polymyalgia rheumatica (PMR) is an in \202 ammatory condi- tion of the elderly characteriz ed by proximal shoulder and hip girdle pain and morning stiffness. It commonly co-exists wi th giant cell arteritis. Diagnostic criteria Several sets of diagnostic criteria have been proposed, the most useful are given in the Table 9.4. New criteria are being developed by c onsensus, but are still being validated. Key features on history Systemic Fever, weight loss. Musculoskeletal Typically, there is a proximal myalgia affecting the shoulder and hip girdl es. There may be local tenderness, but there should not be muscle tenderness. This may be o f acute onset, and is associated with signi \201 cant morning stiffness. Headache New onset or change in character of headache suggests co-existent giant cell arter itis. Table 9.4 Diagnostic criteria for PMR Bird et al. (1979) Jones & Hazleman (1981) Arthritis A peripheral arthritis may occur, but this is suggestive of elderly onset rheumat oid arthritis. Age (years) >65 Onset <2 weeks Duration >2 months Key features on examination Musculoskeletal \200 Pain location Bilateral shoulder pain and stiffness Shoulder and pelvic girdle There may be muscle tenderness proximally, but this should not be major feature. Weakness i s not a feature of PMR; if present suggests an in \202 ammatory myopathy. The presence of a small joint synovitis suggests elderly onset rheumatoid arthritis. Temporal artery tender ness suggests co-existent GCA. Morning stiffness >1 h Present Tenderness Systemic symptoms Upper arms Depression, weight loss ESR >40 mm/h >30 mm/h, or CRP >6 mg/l General investigations Investigation is directed at establishing the diagnosis and excludin g malignancy. \200 Response to glucocorticoids Prompt and dramatic All criteria Requirements to ful \201 l criteria If any 3 criteria are present, sensitivity is 92% and speci \201 city 80% Acute phase response (ESR and CRP): these are both usually raised active PMR. Rarely patien ts may present with a normal ESR or CRP. CK: this should normal. A raised CK suggests an in \202 ammatory myopathy. Renal, liver, bone, and thyroid function: FBC, PSA, Igs, electrop horetic strip, chest X-ray may be needed to exclude malignancy. Epidemiology \200 \200 PMR is more common than GCA. GCA occurs in 4-31% of PMR patients and PMR is present in 1 \200\22366% of GCA patients. The incidence like GCA is highest in Scandinavia 68 \200\22311 2/100 000 persons aged >50 years. Prevalence rates of up to 1:30 in person aged >65 years h ave been reported. There is a female preponderance. The peak age of onset >75 years, very r are < 50 years. Serological investigations \200 RF: a positive RF is suggestive of elderly onset RA, especially if anti-CCP antibodies are also present. ANCA, ANA: anticardiolipin antibodies are all negative. \200 Detection co-existent GCA The optimum method of detecting co-existent GCA is uncertain. Rou tine temporal artery biopsy has a very low detection rate. Biopsy of symptomatic patients i mproves the detection rate. Etiology The etiology is unknown. No clear HLA associations for pure PMR have emerged and i t is likely because of the overlap with GCA that similar HLA associations will be observed. Imaging 18FDG-PET scan 18FDG PET scanning is a useful method of demonstrating associated GC A with large vessel arteritis. The technique is too insensitive to demonstrate the temporal arteries. A PET scan may detect a previously unsuspected malignancy. Polymorphisms in a number of other genes (e.g. ICAM-1, IFN-y, VEGF, IL-1 and endothelial ni tric oxide synthase have been described, suggesting a polygenic etiology. The striking association with age and disease onset suggests that immunosenescence may be i mportant, with possible breakdown in immune tolerance or increased susceptibility to infect ious triggers. Ultrasonography \200 Numerous infections have been implicated in small stud- ies but none so far has emerged fol lowing rigorous case control studies. Ultrasonography of the temporal arteries may demon- strate co-existent GCA. The halo sign i s characteristic. Ultrasonography of the shoulders and hips may reveal evidence of bursitis or synovitis, but similar appearance may occur in elderly onset RA. Clinical features In the early stages, the symptoms can be non-speci \201 c and a high ind ex of suspicion is required to achieve an early diagnosis. CHAPTER 9 Vasculitis 321 MR MR of the shoulders and hips may reveal evidence of bursitis or synovitis, but similar a ppearance may occur in elderly onset RA. Refractory disease \200 Use of azathioprine or methotrexate should be consid- ered in patients with relapsing disea se or resistant to corticosteroids. However, a randomized trial of meth- otrexate showed no benefit in either reduction of relapse rate or steroid dosage. In \202 iximab appears to have no role in the treatment of newly diagnosed PMR. Differential diagnosis The relatively non-speci \201 c presentation of PMR makes the diffe rential wide. There is no diagnostic test. A low thresh- old must be observed for further i nvestigation. The major differential is malignancy, elderly onset RA, polymyositis, myxoede ma, cervical spondylosis, bilateral shoulder capsulitis, and \201 bromyalgia. Follow-up \200 Initially every month until stable and then every 3 \200\2236 months as patient s condition dictates. Follow-up is required. ESR and CRP are a guide to disease activity, but may be n ormal in relapse particularly in patients on corticosteroids. Disease assessment Response criteria and an activity score for PMR have been developed, but as yet are not widely used. Prognosis \200 \200 Resources Assessment tools EULAR response criteria for PMR. PMR generally has a good prognosis. There is an overlap with GCA and, therefore, there is a risk of permanent blindness in untreated patients. This is greatly reduced by the early in troduction of corticoster- oids. The risk of blindness occurring in patients on corti- cost eroids is very low. The majority of patients require corticosteroids for 18 \200\22324 mont hs. Patient organizations Vasculitis Foundation. www.vasculitisfoundation.org Arc lea \202 et. Available at: www.arc.org.uk/ ICD-10 codes M31.5 Giant cell arteritis with polymyalgia rheumatica M35.5 Polymyalgia rheumatica Patient advice General \200 References Bird HA, Esselinckxx W, Dixon A StJ, Mowat AG, Wood PH. An evaluation of criteri a for polymyalgia rheumatica. Ann Rheum Dis 1979; 38: 434 \200\2239. Potentially serious condition, requiring glucocorticoid therapy for 18 \200\22324 months. T here is an association with GCA and, therefore, there is a risk of blindness if associated with GC324A. Jones JG, Hazleman BL. Prognosis and management of polymyalgia rheumatica. Ann Rheum Dis 1981; 40: 1 \200\2235. Treatment Prednisolone is the mainstay of treatment. Leeb BF, Bird HA, Nesher G, Andel I, Hueber W, Logar D, et al. EULAR response criteria for polymyalgia rheumatica: results of an initiative of the European collaborating polymyalgia group. Ann Rheum Dis 2003; 62: 1189 \200\22394. Newly diagnosed patients \200 In patients without symptoms of GCA oral glucocorti- coid starting at 15 mg/day. There shou ld be a very rapid (< 48 h) response. If there is not a rapid response the diagnosis should be ques- tioned. Oral corticosteroids should be tapered quickly aiming for 7.5 mg/day at 6 months. Adjunctive low dose weekly methotrexate reduces the risk of relapse and reduces ex posure to corticosteroids. Mahr AD, Jover JA, Spiera RF, Hernandez-Garcia C, Fernandez- Gutierrez B, LaValley MP, et a l. Adjunctive methotrexate for treat- ment of giant cell arteritis. Arthritis Rheum 2007; 5 6: 2789 \200\22397. Salvarani C, Macchioni P, Manzini C, Paolazzi G, Trotta A, Manganelli P , et al. In \202 iximab plus prednisone or placebo plus prednisone for the initial treatme nt of polymyalgia rheumatica: a randomized trial. Ann Intern Med 2007; 146: 631 \200\2239. See also Giant cell arteritis Relapsing disease Minor relapse be can treated with an increase in prednisolone dose to the last effective dose. TAKAYASU ARTERITIS 322 Takayasu arteritis Takayasu arteritis (TA) is a rare systemic vasculitis of un- known etiology, characterized by a large vessel vasculitis. De \201 nition The Chapel Hill Consensus Conference de \201 ned TA as: Granulomatous in \202 ammation of the aorta and its major branches. Usually oc curs in patients younger than 50. Cardiovascular \200 The most common symptoms at presentation are absence or asymmetry of peripheral pulses. Cla udication of arm or legs (occurs in 50%). Transient visual disturbance (scotoma, blurring, or diplopia; 12%). Transient ischaemic attacks and stroke are uncommon at presentation. Classi \201 cation criteria The ACR in 1990 developed classi \201 cation criteria, which are widely used in clinical trials. Key features on examination Cardiovascular \200 Blood pressure inequality between arms and legs. This should be done in all 4 limbs. Brachi al/subclavian artery involvement may make measurement of blood pressure in the arms dif \201 cult or impossible. In severe cases, intra- arterial measurement may be necessary. Hyp ertension new onset (28%) cases and 58% have evidence of renal artery stenosis. Vascular br uits most often heard over the carotid arteries. Carotidynia (tenderness over carotids) is rare, but characteristic. ACR classi \201 cation criteria for Takayasu arteritis 1. Age < 40 years old: development of symptoms or signs related to Takayasu arteritis at age < 40 years. 2. Claudication of ex tremities: development and worsening of fatigue and discomfort in muscles of one or more ex tremity while in use, especially the upper extremities. \200 3. Decreased brachial arterial pulse: decreased Neurological Evidence of previous stroke. General investigations \200 FBC anemia is commo n. \200 ESR and CRP are elevated. pulsation of one or both brachial arteries. 4. BP difference >10 mmHg: difference of >10 mmHg in systolic blood pressure between arms. 5. Bruit over subclavian arteries or aorta: Bruit audible on auscultation over one or both subclavian arteries or abdominal aorta. 6. Arteriogram abnormality: arteriographic nar- rowing or occlusion of the entire aorta, it s proximal branches, or large arteries in the proximal upper or lower extremities, not due to atherosclerosis, \201 bro- muscular dysplasia, or similar causes; changes usually foca l or segmental. Imaging Angiography Percutaneous intravascular contrast angiography has been the gold stand ard investigation for the diagnosis of TA. Lo- calized narrowing or irregularity of the lum en is the earli- est lesion detectable, and may develop into stenosis and occlusion. The ch aracterisitic \201 nding is the presence of skip lesions, where stenosis or aneurysms alt ernate with nor- mal vessels. The angiographic appearances have been clas- si \201 ed into \201 ve types. Angiography is invasive and provides information on luminal anatomy, and cannot study changes in the vessel wall (Table 9.5). Note: for purposes of classi \201 cation a patient shall be said to have Takaya- sus arter itis if at least 3 of these 6 criteria are present. The presence of any 3 or more criteria yields a sensitivity of 90.5% and speci \201 city of 97.8%. From Arend et al. (1994). Epidemiology \200 \200 Incidence 1 \200\2232/million/year in most populations studied. The prevalence in a Japanes e autopsy series was 1 in 3000 cases. Most series report a female preponderance (80 \200 \22390%). Occurs aged <50 years with a median age of onset of 25 \200\22330 years. Table 9.5 Angiographic classi \201 cation of TA Type Site of involvement \200 I Branches of aortic arch IIa Ascending aorta, aortic arch and its branches Etiology The etiology is unknown. TA has been linked to infection, but no clear organism as yet been identi \201 ed. Autoimmunity is suggested by the presence of anti-endothelial an tibodies. TA has been associated with HLA B52 and DR4, but no consistent overall associatio n has emerged. Clinical features The occurrence of stroke in a young person especially when associated with a high ESR or CRP should heighten suspicion of TA. IIb Ascending aorta, aortic arch and its branches and thoracic descending aorta III Thoracic descending aorta, abdominal aorta and/or renal arteries IV Abdominal aorta and/or renal arteries V Combination of Types IIb and IV From Moriwaki et al. (1997). Magnetic resonance angiography MRA can provide high resolution imaging of anatomical featur es, including mural thickening, luminal changes, and aneurysm formation. 18FDG-PET 18F-FDG is taken up by metabolically active cells, including sites of in \202 ammation. Uptake can be visualized in the walls of in \202 amed large vessels (>4 mm). Small studies suggest Key features on history Systemic Fever, weight loss. Musculoskeletal Myalgia, arthralgia are common at presentation. CHAPTER 9 Vasculitis 323 18FDG-PET is useful in the assessment of active disease and response to treatment, but the exact role remains to be determined. Relapsing disease Relapse is treated with increased in prednisolone dose and optimization o f immunosuppression. High resolution Doppler ultrasound High resolution Doppler ultrasound provides a non-invasi ve method of assessing disease especially in the carotid and subclavian arteries. The role remains to be evaluated. Refractory disease Consideration should be given to the use of other immu- nosuppressive ag ents, such as mycophenolate mofetil and biological agents, such as in \202 iximab. There i s limited data for the latter, but open studies are encouraging. Serological investigations ANCA, ANA, RF, and anticardiolipin antibodies are all typically negative in TA. Surgery Stenotic lesions may be treated surgically, either with bypass procedures or stenti ng. Stenting should be consid- ered for renovascular hypertension. Revascularization should only be considered if stenotic or occlusive lesions are leading to haemodynamic compromise , or aneurismal lesions, which may rupture. There is a high restenosis rate of 20 \200\2233 0%. Differential diagnosis This is from other types of vasculitis especially in giant cell arte ritis in the older patient. Disease assessment Severity of involvement of target organs sho uld be care- fully assessed. ESR and CRP may be helpful in assessing disease activity and r esponse to treatment, but are unreli- able in some patients. May be normal in patients with progressive disease. Resources Assessment tools The BVAS and VDI can be used to assess activity and damage. Prognosis \200 Guidelines EULAR recommendations for the management of large vessel vasculitis. Mortality: the overall mortality rate is low at around 3% in the USA. Remission can be achi eved in the majority of patients using corticosteroids, but 73% of patients in a recent US series required additional immunosuppressants to achieve or maintain remission. Relapse occ urred in 96% of patients in a recent US series. Restenosis is common after initially succes sful angioplasty. Patient organizations Vasculitis Foundation. www.vasculitisfoundation.org Stuart Strange Tr ust. www.vasculitis-uk.org ICD-10 code M31.4 Aortic arch Syndrome (Takayasu arteritis) Pathology Granulomatous necrotizing vasculitis affecting large vessels. There is adventitia l thickening, cellular infiltration of the tunica media, with local destruction of the vasc ular smooth muscle. The intima becomes \201 brosed, which leads to stenosis. Patient advi ce Potentially serious multisystem condition, requiring immunosuppressive therapy and life- long follow-up. References Arend WA, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classi \201 cation of Takayasu arteritis. Arthritis Rheum 1990; 33: 1101 \200\2237. Maksimowicz-McKinnon K, Clark TM, Hoffman GC. Limitations of therapy and a guarded prognosi s in an American cohort of Takayasu arteritis patients. Arthritis Rheum 2007; 56: 1000 \200 \2239. Andrews J, Mason JC. Takayasu \200\231s arteritis-recent advances in imaging offer promise. Rheumatology 2007; 46: 6 \200\22315. Liang P, Tan-Ong M, Hoffman GS. Takayasu arteritis: vascular interventions and outcomes. J Rheumatol 2004; 31: 102 \200\2236. Treatment There are no randomized controlled trials of treatment in TA. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large v essel vasculitis. Ann Rheum Dis 2008 (in press). Moriwaki R, Noda M, Yajima M, Sharma BK, Numano F. Clinical manifestations of Takayasu arte ritis in India and Japan-new classi- \201 cation of angiographic \201 ndings. Angiology 1997; 48: 369 \200\22379. Initial therapy \200 Oral corticosteroids start at 1 mg/kg (maximum dose 60 \200\22380 mg) and taper quickly; ai m for 10 mg/day at 6 months. Immunosuppression with methotrexate or azathioprine should be started at the same time as oral corticosteroids. Control hypertension. WEGENER \200\231S GRANULOMATOSIS 324 Wegener \200\231s granulomatosis Wegener \200\231s granulomatosis is a rare systemic vasculitis of unknown etiology, charact erized by involvement of the upper airways with granuloma formation. De \201 nition The Chapel Hill Consensus Conference de \201 ned Wegener \200\231s granulo matosis as: Granulomatous in \202 ammation involving the respira- tory tract and necrotizing vasculiti s affecting small to medium sized vessels (e.g. capillaries, venules, arteri- oles and arte ries). Necrotizing glomerulonephritis is common. The ACR in 1990 developed classi \201 cation criteria, which are widely used in clinical t rials. There are no validated diagnostic criteria. ACR criteria for classi \201 cation of Wegener \200\231s granulomatosis 1. Nasal or oral i n \202 ammation: development of pain- ful or painless oral ulcers or purulent or bloody na sal discharge. 2. Abnormal chest radiograph : chest radiograph showing the presence of nodules, \201 xed in \201 ltrates or cavities . Figure 9.1 CT thorax from patient with WG showing extensive pulmonary cavitation This \201 nally results in intravascular lysis of neutrophils and necrotizing vasculitis. 3. Urinary sediment: microhaematuria (>5 red cells per high power \201 eld) or red cell c asts in urinary sediment. Clinical features Key points on history In the early stages, the symptoms can be non-speci \201 c and a high index of suspicion is required to achieve an early diagnosis. 4. Granulomatous inflammation: histological changes showing granulomatous on biopsy in \202 am- mation within the wall of an artery or in the perivas- cular or extravascular area (artery or arteriole). For purposes of classi \201 cation, a person shall be said to have Wegener \200\231s granu lomatosis if at least 2 of these 4 criteria are present. The presence of any 2 or more crit eria yields a sensitivity of 88.2% and speci \201 city of 92.0%. (Leavitt et al., 1990). Symptoms suggestive of WG include: Systemic: Fever, weight loss, myalgia, arthralgia. ENT Epistaxis, nasal crusting, deafness, sinusitis. Epidemiology \200 \200 \200 \200 \200 The incidence in Europe is 10/million/year. The prevalence in Europe is 190/million. In mos t studies there is a male preponderance (Figure 9.1). The peak age of onset 65 \200\22374 y ears. In Europe WG is more common at higher latitudes than MPA. Occurs most frequently in w hite Caucasians and is much rarer in other ethnic groups. Pulmonary Cough, haemoptysis, dyspnoea. Cutaneous Purpuric rash, ulcers (see Plate 16). Peripheral neuropathy Key features on examination Skin Purpura, ulcers. Etiology The etiology is unknown, but like many autoimmune con- ditions is generally believ ed to result from an environmental trigger interacting with a genetically predisposed host. Arthritis Eye Scleritis, proptosis is suggestive of a retro-orbital mass. Genetic factors Familial cases are rare and there are no clear HLA associa- tions. HLA-DPB* 0401 has been associated in some studies. Numerous cytokine and signal transducer gene poly mor- phisms have been studied, but again no clear associations have emerged. No infectious triggers have been identi \201 ed. In vitro and animal studies support the idea that PR3- ANCA is has a pathogenic role in the induction of vasculitis. PR3-ANCA interaction with neu trophils primed with TNFA or IL-1 results in their degranulation, generation of oxygen radi cals, endothelial damage, and leucocyte recruitment. ENT: Nasal collapse, suggestive of destructive sino-nasal disease (see Plate 15). General investigations Investigation is directed at establishing the diagnosis and assessin g the extent and severity of organ involvement. \200 FBC anemia, leucocytosis, eosinophils (an eosinophilia is suggestive of CSS). Acute phase r esponse (ESR and CRP). Liver function. \200 CHAPTER 9 Vasculitis 325 Mortality with current treatment regimens is 18% at 5 years. Poor prognostic factor include age >65 years at presen- tation, renal disease, pulmonary hemorrhage. 50% chance relapse a t 5 years. Assessment of organ involvement In all patients \200 Urinalysis (proteinuria, haematuria, red cell casts), should be performed urgently in all p atients in whom systemic vasculitis is suspected. Renal function (creatinine clearance, qua nti \201 cation of protein leak if present using either 24-h protein excretion or urine pr otein/creatinine ratio). CXR may show in \201 ltrates, hemorrhage, granuloma. Liver functi on. Pathology Biopsies of affected organs show a granulomatous necro- tizing vasculitis affecti ng medium and small vessels. In the kidney the typical appearance is a focal segmental necr otizing vasculitis. \200 Where appropriate \200 Patient advice Potentially serious multisystem condition, requiring immu- nosuppressive the rapy and life-long follow-up. Nervous system (nerve conduction studies in all four limbs, biopsy). Cardiac function (ECG, echocardiography). Gut (celiac axis angiography). Skin (biopsy). Biopsy of an affected org an should be obtained where \200 \200 Treatment For the general approach to treatment for Wegener \200\231s granulomatosis and AN CA-associated vasculitis, see p. 330. possible to con \201 rm diagnosis prior to treatment Resources Assessment tools The BVAS and VDI should be used to assess disease activity and d amage. Serological investigations \200 ANCA. A cANCA pattern on indirect immuno \202 uores- cence and PR3 by ELISA are together s trongly associated with WG (>90%). Preferably both indirect immuno \202 uo- rescence and E LISA for PR3/MPO should be performed in all patients. ANA, RF, anticardiolipin antibodies, complement will be negative. Cryoglobulins to differentiate from cryoglobulinaemic vasculit is. Patient organizations Vasculitis Foundation. www.vasculitisfoundation.org Stuart Strange Tr ust. www.vasculitis-uk.org Coding ICD-10 M31.3 Wegener \200\231s granulomatosis References Birck R, Schmitt W, Kaelsch IA, van Der Woude FJ. Serial ANCA determinations for monitoring disease activity in patients with ANCA-associated vasculitis: systematic review . Am J Kidney Dis 2006; 47: 15 \200\22323. Differential diagnosis This is from other types of vasculitis (especially MPA, CSS, PAN), v asculitis mimics (e.g. malignancy, cholesterol embolism, atrial myxoma, calciphylaxis) or i nfection (especially SBE). \200 \200 \200 Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37: 187 \200\22392. Blood cultures. Viral serology (HBV, HCV, HIV, CMV). Echocardiography (two dimensional and/ or transo- esophageal). Lamprecht P, Holl-Ulrich K, Gross W. Wegener \200\231s granulomatosis: pathogenesis. In: Ba ll GV, Bridges L (eds) Vasculitis, 2nd edn. Oxford: Oxford University Press 2008: 391 \200 \223402. Disease assessment \200 Leavitt, RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classi \201 cation of Wegener \200\231s granulomatosis. Arthritis Rheum 1990; 33: 1101 \200\2237. Severity of involvement of target organs should be carefully assessed. Where appropriate sc oring systems should be used. Active uncontrolled disease is associated with cumula- tive o rgan damage which should be assessed using the Birmingham Vasculitis Damage Index (VDI). Ge neral health function can be assessed using the SF-36 or HAQ. Luqmani RA, Bacon PA. Assessment of vasculitis. In: Ball GV, Bridges L (eds) Vasculitis, 2n d edn. Oxford: Oxford University Press 2008: 297 \200\223306. \200 See also Churg \200\223Strauss syndrome Microscopic polyangiitis p.326 p.328 Prognosis \200 Untreated WG has very high mortality (82% at 1 year). This has been substantially improved following the intro- duction of prednisolone and cyclophosphamide. CHURG \200\223STRAUSS SYNDROME 326 Churg \200\223Strauss Syndrome Churg \200\223Strauss Syndrome (CSS) is a rare systemic vasculitis of unknown etiology, cha racterized by late onset asthma with peripheral and tissue eosinophilia. HLA-DRB4 has recently been reported to be associated with CSS. Churg \200\223Strauss Syndrome has been associated with the use of leukotriene inhibitors. The association is now be- lieved to be an unmasking of previously undiagnosed Churg \200 \223Strauss syndrome, rather than precipitation of de novo vasculitis. De \201 nition The Chapel Hill Consensus Conference de \201 ned Churg \200\223 Strauss Sy ndrome as Eosinophil-rich and granulomatous in \202 ammation involving the respiratory tra ct and necrotizing vasculitis affecting small to medium-sized vessels associated with asthm a and eosinophilia. Clinical features Key points on history In the early stages, the symptoms can be non-speci \201 c and a high index of suspicion is required to achieve an early diagnosis. There is t ypically a history of adult onset asthma that has become more dif \201 cult to control, re quiring oral corticosteroids. Cardiac involvement is more common than in WG or MPA. Classi \201 cation criteria The ACR in 1990 developed classi \201 cation criteria, which are widely used in clinical trials. They have a speci \201 city of 99.7% and sensitivity o f 85.0%. There are no validated diag- nostic criteria. Lanham in 1984 produced criteria tha t have not been validated. Symptoms suggestive of CSS include: Systemic: Fever, weight loss, myalgia, arthralgia. ACR criteria for classi \201 cation CSS 1. Asthma: history of wheezing or diffuse high pit ch Pulmonary Cough, wheeze, dyspnoea. Upper respiratory tract symp- toms occur in 50 \200\2236 0%. Asthma is virtually universal. rales on expiration. 2. Eosinophilia >10% on white cell differential count. 3. Mononeuropathy or polyneuropathy: develop- ment of mononeuropathy, multiple mononeuropathies, or polyneuropathy (i.e. glove/ stocking distribution) attributable to systemic vasculitis. Cutaneous Purpuric rash or cutaneous granulomata occur in up to 50%. 4. Pulmonary in \201 ltrates, non- \201 xed: migratory or transient pulmonary radiographs (not including \201 xed in \201 ltrates), attributable to a systemic vasculitis. Neurological Peripheral neuropathy or mononeuritis multiplex occurs in up to 76%. 5. Paranasal sinus abnormality: history of acute or chronic paranasalor tenderness or radio graphic opaci \201 cation of the paranasal sinuses. Cardiac Dyspnoea, cardiac failure, arrthymia, due to endomyocar- dial disease occurs in 47% . 6. Extravascular eosinophils: biopsy including artery, arteriole, or venule showing accumul ations of eosinophils in extravascular areas Renal involvement Occurs in 50%. For purposes of classi \201 cation, a person shall be said to have Churg \200\223Strauss S yndrome if at least 4 of these 6 criteria are present. Masi et al., 1990. Key features on examination Cutaneous Purpuric vasculitic rash or palpable granulomata. Lanham criteria for Churg \200\223Strauss syndrome 1. Asthma. 2. Peripheral blood eosinophi lia >1 \227 109l. 3. Systemic vasculitis involving two or more extra Musculoskeletal Arthritis. Ophthalmic: Scleritis (uncommon <5%). pulmonary organs. ENT Nasal polyps. Note: biopsy evidence of granuloma is not required (Lanham et al., 1984). Neurological Mononeuritis multiplex; sensory or motor neuropathy. Epidemiology \200 \200 \200 \200 The incidence in Europe is 2/million/year. In most studies there is a male preponderance. T he peak age onset is 65 \200\22374 years. Occurs most frequently in white Caucasians, is mu ch rarer in other ethnic groups. General investigations Investigation is directed at establishing the diagnosis and assessin g the extent and severity of organ involvement. \200 FBC anemia, leucocytosis, eosinophil count >1.5 x 109 is particularly suggestive of CSS. Ac ute phase response (ESR and CRP). Liver function. \200 Etiology The etiology is unknown. Allergy is a common feature to all patients. Tissue injur y is due to toxic eosinophil and neutrophil degranulation products. Eosinophils are acti- v ated and markers of eosinophil activation mirror disease activity. CHAPTER 9 Vasculitis 327 Prognosis \200 \200 Assessment of organ involvement In all patients \200 1-year survival rate is 83.2% and 5-year survival is 68.1%. Poor prognostic factor include age > 65 years at presen- tation, renal disease, pulmonary hemorrhage. Urinalysis (proteinuria, haematuria, red cell casts). This should be performed urgently in all patients in whom systemic vasculitis is suspected. Renal function (creatinine clearance , quanti \201 cation of protein leak if present using either 24-h protein excretion or uri ne protein/creatinine ratio). CXR may show in \201 ltrates, hemorrhage, granuloma. Liver f unction. Pathology Granulomatous necrotizing vasculitis affecting medium and small vessels typically with an eosinophilic in \201 ltrate. Patient advice \200 General Potentially serious multisystem condition, requiring immu- nosuppressive therapy an d lifelong follow-up Where appropriate \200 Nervous system (nerve conduction studies in all four limbs, biopsy). Cardiac function (ECG, echocardiography). Gut (celiac axis angiography). Skin (biopsy). Treatment Intensity of initial immunosuppression depends on extent and severity of organ in volvement. Treatment can be di- vided into stages: induction, consolidation and maintenance of remission. The EUVAS trials on which the treatment approach is based were conducted in WG and MPA, but the treatment approach is similar. \200 \200 Biopsy of an affected organ should be obtained where possible to con \201 rm diagnosis prior to treatment Serological investigations \200 Resources Assessment tools The BVAS and VDI should be used to assess disease activity and d amage. ANCA. About 50% of patients are ANCA positive typically MPO-ANCA. ANA, RF, anticardiolipin antibodies, complement, cryoglobulins are normal or negative. Patient organizations Vasculitis Foundation: www.vasculitisfoundation.org Stuart Strange Tr ust: www.vasculitis-uk.org Differential diagnosis This is from other types of vasculitis (especially WG, MPA, PAN), va sculitis mimics (e.g. malignancy, cholesterol embo- lism, atrial myxoma, calciphylaxis) or infection (especially SBE). Infection should be excluded. ICD-10 coding M30.1 Polyarteritis with lung involvement (Churg \200\223 Strauss). Allergic granulomatous angiit is. Differentiation needs to be made from other causes of hypereosinophilia such as the hypereo sinophilic syndrome, eosinophilic leukemia and chronic parasitic infection. References Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eo sinophilia: a clinical approach to the Churg \200\223 Strauss syndrome. Medicine (Baltimore ) 1984; 63: 65 \200\22381. Disease assessment \200 Severity of involvement of target organs should be carefully assessed. Where appropriate sc oring systems should be used. A number of scoring systems are available. The Birmingham Vas culitis Activity Score is widely used in clinical trials. Active uncontrolled disease is as sociated with cumula- tive organ damage which should be assessed using the Birmingham VDI. General health function can be assessed using the SF-36 or HAQ. Luqmani RA, Bacon PA. Assessment of vasculitis. In: Ball GV, Bridges L (eds) Vasculitis. Ox ford: Oxford University Press, 2008: 297 \200\223306. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for t he classi \201 cation of Churg \200\223 Strauss Syndrome. Arthritis Rheum 1990; 33: 1094 \200\223100. Specks U. Churg \200\223Strauss Syndrome. In: Ball GV, Bridges L (eds) Vasculitis. Oxford: Oxford University Press, 2008: 429 \200\22338. MICROSCOPIC POLYANGIITIS 328 Microscopic polyangiitis De \201 nition The Chapel Hill Consensus Conference de \201 ned micro- scopic polyangiiti s as a: Neurological Mononeuritis multiplex, sensorimotor neuropathy are present in up to 60%. Necrotizing vasculitis, with few or no immune deposits, affecting small vessels (i.e. capil laries, venules, or arte- rioles). Necrotizing arteritis involving small and medium sized a rteries may be present. Necrotizing glo- merulonephritis is very common. Pulmonary capillar itis often occurs. Pulmonary Interstitial lung disease occurs as a consequence of recur- rent hemorrhage. General investigations Investigation is directed at establishing the diagnosis and assessin g the extent and severity of organ involvement. \200 Classi \201 cation criteria The ACR 1990 classi \201 cation criteria did not include micr o- scopic polyangiitis. There are no validated diagnostic criteria FBC anemia, leucocytosis, eosinophils (eosinophilia is suggestive of CSS). Acute phase resp onse (ESR and CRP). Liver function. \200 Epidemiology \200 \200 \200 \200 The incidence in Europe is 3 \200\2238/million/year. Peak age onset 65 \200\22374 years. Mo re common at lower latitudes in Europe. Occurs most frequently in white Caucasians, is much rarer in other ethnic groups. Assessment of organ involvement In all patients \200 Urinalysis (proteinuria, haematuria, red cell casts). This should be performed urgently in all patients in whom systemic vasculitis is suspected. Renal function (creatinine clearance , quanti \201 cation of protein leak if present using either 24-h protein excretion or uri ne protein/creatinine ratio). CXR may show in \201 ltrates, hemorrhage. Etiology MPO is a 140 KDa protein composed of two heterodimers. The gene is located at 17q2 1.3. Myeloperoxidase (MPO) comprises 5% of neutrophil proteins and is present in the cytopl asmic granules. The precise function of MPO is un- certain, the enzyme may catalyze the H2O 2 dependent oxidation of halides that can kill microbes. Alternatively MPO may protect dige stive enzymes from oxidative dena- turation by removing H2O2 from the phagocytic granule. Where appropriate \200 Nervous system (nerve conduction studies in all four limbs, biopsy). Cardiac function (ECG, echocardiography). Gut (celiac axis angiography). Skin (biopsy). Pulmonary function tests may show increased gas transfer indicative of alveolar hemorrhage. \200 \200 \200 The mechanisms involved in ANCA-induced neutrophil activation are not clearly understood. I n a rat model MPO- ANCA are pathogenic. Immunization with a human MPO led to development of anti-MPO antibodies and a systemic vasculitis. Tissue biopsy Biopsy of an affected organ should be obtained where possible to con \201 rm diagnosis prior to treatment. Clinical features In the early stages, the symptoms can be non-speci \201 c and a high ind ex of suspicion is required to achieve an early diagnosis. There may be an indolent course for several months before diagnosis. Serological investigations \200 ANCA: A pANCA pattern on indirect immuno \202 uores- cence and MPO by ELISA are together a ssociated with MPA (75%). Anti-GBM: negative in MPA, their presence indicates the occurrenc e of anti-GBM disease (Goodpasture \200\231s syndrome). ANA, RF: anticardiolipin antibodies are typically negative. Complement. Cryoglobulins. Key features on history Systemic Fever, weight loss, myalgia, arthralgia are present in 56 \200\22376% of patients. Pulmonary Cough, haemoptysis, dyspnoea. Haemoptysis especially in a patient with renal fail ure suggests MPA or anti-GBM disease. \200 Renal Renal involvement is often asymptomatic, but is present in virtually all patients.