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. Differential diagnosis This is from other types of vasculitis (especially WG, CSS, PAN), va sculitis mimics (e.g. malignancy, cholesterol embo- lism, atrial myxoma, calciphylaxis) or infection (especially SBE). Other causes of a pulmonary-renal syndrome should be considered such as anti-GBM disease (Goodpasture \200\231s syndrome). \200 \200 \200 Cutaneous Purpuric rash. Neurological Peripheral neuropathy. Blood cultures. Viral serology (HBV, HCV, HIV, CMV). Echocardiography (two-dimensional and/ or transo- esophageal). Key features on examination Cutaneous Purpura are present in 40%. Other lesions include dig ital ischaemia, ulcers, livedo reticularis. CHAPTER 9 Vasculitis 329 Disease assessment \200 Severity of involvement of target organs should be carefully assessed. A \201 ve factor s core has been developed to guide prognosis. Five factor score Proteinuria >1 g/24 h Serum creatinine >140 mol/l Gastrointestinal invo lvement Cardiomyopathy CNS involvement 1 point for each of these items present (from Guille vin et al., 1996). Prognosis \200 Overall mortality with current treatment regimens is 18% at 5 years. There is a risk of rel apse of 50% at 5 years. Poor prognostic factor include age > 65 years at presen- tation, re nal disease, pulmonary hemorrhage. \200 Prognosis based on FFS Figure 9.2 CT thorax from patient with MPA showing extensive pulmonary hemorrhage. FFS 5 year survival (%) relative risk 0 88.1 0.62 Resources Assessment tools The BVAS and VDI should be used to assess disease activity and d amage. 1 74.1* 1.35 \211 2 54.1** 2.40 P < 0.005; **p < 0.0001 compared with FFS = 0 (Gayraud et al., 2001). Patient organizations Vasculitis Foundation: www.vasculitisfoundation.org Stuart Strange Tr ust: www.vasculitis-uk.org Pathology The typical renal biopsy appearance is a focal segmental necrotizing glomerulonep hritis. Extracapillary crescents are present in most renal biopsies and involve 60% of glom - eruli. Glomerular sclerosis is associated with more severe disease. Coding ICD-10 M31.7 Microscopic polyangiitis References Gayraud M, Guillevin L, Le Toumalin P, Cohen P, Lhote F, Cassusus P, et al. Long term follow up of polyarteritis nodosa, microscopic polyangiitis and Churg \200\223Strauss syndrome: analysis of four pro- spective trials including 278 patients. Arthritis Rheum 200 1; 44: 666 \200\22375. Patient advice General \200 Potentially serious multisystem condition, requiring immunosuppressive therapy and lifelong follow-up. Attention to cardiovascular risk. Stop smoking. Healthy balance diet. Regular e xercise. Vaccination (in \202 uenza and pneumococcal). Male and female infertility is a re cognized complication of cyclophosphamide therapy. These patients should be counseled about the possibility of infertility following cyclophosphamide. \200 \200 \200 \200 \200 Guillevin L, Lhote F, Gayraud M, et al. Prognostic factors in polyar- teritis nodosa and Ch urg \200\223Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore) 199 6; 75: 17 \200\22328. Guillevin L, Pagneux C, Teixeira L. Microscopic polyangiitis. In: Ball GV, Bridges L (eds) Vasculitis. Oxford: Oxford University Press, 2008: 2355 \200\223364. Luqmani RA, Bacon PA. Assessment of vasculitis. In: Ball GV, Bridges L (eds) Vasculitis. Ox ford: Oxford University Press, 2008: 297 \200\223 306. See also Wegener \200\231s granulomatosis Microscopic polyangiitis Treatment Intensity of initial immunosuppression depends on extent and severity of organ in volvement (see p. 330). Treatment can be divided into stages: induction, consolidation, and maintenance of remission. p. 324 p. 334 TREATMENT OF ANCA-ASSOCIATED VASCULITIS 330 Treatment of ANCA-associated vasculitis Treatment Intensity of initial immunosuppression for the ANCA- associated vasculitides (WG, CSS, MPA) depends on extent and severity of organ involvement. The principles of treatment are the same for all the AAV. Treatment can be divided into stages: induction, consolidati on and mainte- nance of remission. The EUVAS trials on which the following treatment approa ch were conducted in WG and MPA but the approach is the same for CSS. Refractory disease Disease refractory to full dose cyclophosphamide and pred- nisolone is r are. More commonly, optimal doses are not tolerated or a prolonged relapsing course with hi gh cumula- tive exposure to cyclophosphamide and prednisolone occurs, and is an indication for other agents. Experimental agents include deoxyspergualin, rituximab (anti-CD20). Prevention and detection of toxicity secondary to immunosuppressive therapy. \200 Induction \200 Mesna should be considered in patients receiving IV CYC. The risks of bladder cancer are di rectly related to the cumulative dose of CYC. The risk with modern low dose regimens is unk nown. Pneumocystis jiroveci (formerly carinii) infection. Immunosuppressed patients are at risk of Pneumocystis jiroveci infection. There is no RCT data; observational studies suppor t the use of prophylaxis with trimethoprim/ sulfamethoxazole 960 mg 3 \227 weekly. Osteopor osis see guidelines for prevention of corticos- teroid-induced osteoporosis. Cervical intra epithelial neoplasia. Secondary malignancies are associated with immunosuppressive therapy. Patients receiving treatment with cytotoxic drugs should be considered for an annual cervi cal smear for the \201 rst 3 years after CYC treatment Annual cervical smear yearly for t he \201 rst 3 years after CYC treatment. Mycobacterium infection. Patients receiving ther apy for systemic vasculitis are at an increased risk of reactivation of TB or new infection , therefore, a detailed history, examination, and chest X-ray should be undertaken to asses s the risk of TB. Non-organ/life-threatening: oral corticosteroids com- bined with either methotrexate, mycop henolate mofetil or cyclophosphamide. Oral corticosteroids start at 1 mg/kg (maximum dose 6 0 \200\223 80 mg) and taper quickly aim for 10 mg/day at 6 months. Creatinine <500 mol/l corticosteroids and cyclophos- phamide. CYC can be given either PO (1.5 \200\2232.0 mg/kg/ day) or IV (15 mg/kg, max 1 g). CYC should be continued until 3 months after remission is a chieved and then change to azathioprine. Creatinine >500 mol/l consider use of plasma exc hange in addition to corticosteroids and CYC. Regular monitoring of WBC is necessary. Consi der Septrin prophylaxis against pneumocystis carinii, PPI against gastric ulceration, Mesna against haemorrhagic cystitis, prophylaxis against osteoporosis. Pulmonary hemorrhage cons ider plasma exchange. \200 Maintenance treatment Once remission has been induced and consolidated then maintenance tre atment should be started this is typically after 3 \200\2236 months of therapy. \200 Azathioprine should be used for maintenance in place of cyclophosphamide for a further 18 \200\22324 months. Methotrexate or mycophenolate mofetil are acceptable alternatives in pat ients intolerant of azathioprine. Taper oral prednisolone. Consider Septrin to reduce relap se rate (NB avoid with methotrexate). Follow-up \200 Every 3 \200\2236 months as patients condition dictates. CSS is a relapsing condition and l ifelong follow up is required. 6-monthly urinalysis lifelong is necessary to detect bladder malignancy secondary to CYC ANCA measurements are not closely associated with disease acti vity. Treatment should not be escalated solely on the basis of an increase in ANCA. An incr ease should be taken as a warning of possible impending relapse. Treatment withdrawal in pa tients with persistently positive ANCA is associated with relapse. \200 Relapsing disease Minor relapse can treated with an increase in prednisolone dose, and then gradual taper and optimization of other immunosuppression. Major relapse is treated with c yclo- phosphamide as for induction. Table 9.6 Categorization of treatment according to extent and severity of disease Clinical subgroup Constitutional symptoms Typical ANCA status Threatened vital Serum creatinine ( mol/l) Treatment Induction organ function Localized/early systemic Yes Positive or negative No <150 Methotrexate or cyclophosphamide Generalized Yes Positive Yes <500 Cyclophosphamide Severe Yes Positive Yes >500 Cyclophosphamide/ plasma exchange/methyl prednisolone CHAPTER 9 Vasculitis 331 Diagnosis of ANCA-associated vasculitis Assess extent of disease and severity Limited/early Creatinine > 150 mol/l Organ-threatening Creatinine <500 mol/l Life/organ-threatening Creatinine >500 mol/l Prednisolone + CYC Prednisolone + methotrexate or CYC Prednisolone + CYC + plasma exchange Remission Switch to AZA or MTX taper prednisolone Taper AZA or MTX Figure 9.3 Algorithm for the management of ANCA-associated systemic vasculitis (from Laprai k et al., 2007). Resources Guidelines \200 Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of main- tenance therapy for va sculitis associated with antineutrophil cytoplasmic auto antibodies. N Engl J Med 2003; 349 : 36 \200\22344. BSR and BHPR guidelines on treatment systemic vasculitis for the management of adults with ANCA associated vasculitis. EULAR recommendations for the management of small and medium si zed vessel vasculitis. Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange and high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol 200 7; 18: 2180 \200\2238. Lapraik C, Watts RA, Scott DG. BSR & BHPR guidelines for the management of adults with ANCA associated vasculitis. Rheumatology 2007; 46: 1615 \200\22316 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. Mukhtyar C, Guillevin L, Cid M, et al. EULAR recommendations for the management of small an d medium sized vessel vasculitis. Ann Rheum Dis 2008 (in press). De Groot K, Rasmussen N, Bacon P, et al. Randomized trial of cyclo- phosphamide versus meth otrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody a ssociated vasculitis. Arthritis Rheum 2005; 52: 2462 \200\2238. POLYARTERITIS NODOSA 332 Polyarteritis nodosa 12 months infection and hepatitis is mild before develop- ment of PAN. Familial cases are r are and there are no clear HLA associations. Polyarteritis nodosa (PAN) is a rare medium vessel vasculitis that is often associated with HBV infection. De \201 nition The Chapel Hill Consensus Conference defined polyarteritis nodosa as: Key features on history In the early stages, the symptoms can be non-speci \201 c and a hi gh index of suspicion is required to achieve an early diagnosis Necrotizing in \202 ammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Systemic Fever, weight loss, myalgia, arthralgia. Classi \201 cation criteria The ACR in 1990 developed classi \201 cation criteria that ar e widely used in clinical trials. There are no validated diagnostic criteria. Cutaneous Rash. Neurological Peripheral neuropathy \200\223 motor or sensory neuropathy. ACR (1990) classi \201 cation criteria for PAN 1. Weight loss: loss of 4 kg or more of bod y weight since the illness began, not due to dieting or other factors. Testicular pain Key features on examination Features of HBV pain are similar to those observed in non- HBV PAN apart from more frequent GIT involvement, extra-glomerular renovascular disease with ma lignant hypertension and orchitis in HBV-PAN. 2. Livedo reticularis: mottled reticular pattern over the skin of portions of the extremiti es or torso. 3 Testicular pain or tenderness: pain or tenderness of the testicles, not due to infection, trauma, or other causes. Testicular tenderness (orchitis) occurs in: Hypertension Which may be malignant, occurs in 31%. 4. Myalgias, weakness, or leg tenderness: diffuse myalgias (excluding shoulder or hip girdl e) or weakness of muscles or tenderness of leg muscles. 5. Mononeuropathy or polyneuropathy : develop- ment of mononeuropathy, multiple mononeuropa- thies, or polyneuropathy. Cutaneous Livedo reticularis, a mottled reticular pattern over the ex- tremities. Neurological Mononeuritis multiplex is the most common pattern of neurological involvement (83.5%). 6. Diastolic BP >90 mmHg: development of hyper- tension with diastolic BP >90 mmHg. 7. Elevated blood urea or creatinine: elevated BUN >40 mg/dl or creatinine 1.5 mg/dl, not d ue to dehydration or obstruction. General investigations Investigation is directed at establishing the diagnosis and assessin g the extent and severity of organ involvement. \200 8. Hepatitis B virus: presence of hepatitis B surface antigen or antibody in serum. FBC anemia, leucocytosis, eosinophils (eosinophilia suggestive CSS). Acute phase response ( ESR and CRP). 9. Arteriographic abnormality: arteriogram show- ing aneurysms or occlusion of the visceral arteries, not due to arteriosclerosis, \201 bromuscular dyspla- sia, or other non-in \202 ammatory causes. 10. Biopsy of small or medium vessel: histological changes showing the presence of sized ar tery containing PMN granulocytes or granulocytes and mononuclear leucocytes in the artery w all. Note for purposes of classi \201 cation a patient shall be said to have PAN if at least 3 of these 10 criteria are present. The presence of any 3 or more criteria yields a sensitivi ty of 82.2% and speci \201 city of 86.6% (from Lightfoot et al., 1990). Epidemiology \200 Classical polyarteritis nodosa as de \201 ned by the CHCC is very rare with an annual inci dence of <1/million HBV PAN occurs with an incidence of 77/million in HBV endemic areas The incidence of HBV PAN is falling due to increased vaccination against HBV and screening of blood prod- ucts for HBV infection. The commonest cause is now drug abuse. Etiology In areas endemic for HBV up to 95% of cases are associ- ated with HBV infection. P AN usually develops within Figure. 9.4 Angiogram showing microaneurysms and segmental cortical infarction. CHAPTER 9 Vasculitis 333 Pathology \200 Liver function. Abnormalities suggest presence of HBV or HCV infection. Necrotizing vasculitis affecting medium and small arteries, the lesions are focal. The in \202 ammation is characterized by \201 brinoid necrosis and a pleomorphic cellular in \201 l- trate. With predominant macrophages and lymphocytes. 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 excre- tion or u rine protein/creatinine ratio). Liver function (including markers of viral infection such a s HBV and HCV). Nervous system (nerve conduction studies in all four limbs, biopsy). Cardia c function (ECG, echocardiography). Angiography should be performed if PAN is suspected. An giography will show the typical microaneurysms and/ or stenosis in the celiac axis and rena l vasculature. Skin (biopsy). Patient advice \200 Potentially serious multisystem condition, requiring immunosuppressive therapy and lifelong follow-up. Association with HBV infection. Treatment \200 Treatment of non-HBV PAN: the principles, as for other types of vasculitis, are based on im munosuppression. Treatment can be divided into stages: induction, consoli- dation and maint enance of remission. For details see p. 334. HBV associated PAN should be treated with anti viral therapy: there are no controlled trials as the condition is rare. The current preferr ed protocol is Lamivudine (100 mg/day) combined with plasma exchange to remove immune compl exes. This is accompanied by a short course of corticosteroids. Seroconversion from HBeAG t o HBeAB is usually achieved. And is associated with a decreased risk of relapse. \200 Biopsy of an affected organ should be obtained where possible to con \201 rm diagnosis pri or to treatment Serological investigations \200 ANCA. PAN with or without HBV infection is not asso- ciated with ANCA. ANA, RF, anticardiol ipin antibodies, complement. Cryoglobulins are negative or normal. Resources Assessment tools The BVAS and VDI should be used to assess disease activity and damage. Differential diagnosis This is from other types of vasculitis (especially MPA, CSS), vascul itis mimics (e.g. malignancy, cholesterol embolism, atrial myxoma, calciphylaxis), or infec tion (especially SBE). \200 \200 \200 Guidelines EULAR recommendations for the management of small and medium-sized vessel vasculitis. Blood cultures. Viral serology (HIV, CMV). Echocardiogr aphy transoesophageal). Patient organizations Vasculitis Foundation: www.vasculitisfoundation.org Stuart Strange Tr ust: www.vasculitis-uk.org (two-dimensional and/or ICD-10 coding M30.0 Disease assessment \200 Polyarteritis nodosa 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 Vascu litis Damage Index (VDI). General health function can be assessed using the SF-36 or HAQ. References Guillevin L, Mahr A, Callard P, Godemer P, Pagnoux C, Leray E, et al. Hepatitis B virus associated polyarteritis nodosa: clinical charac- teristics, outcome and impact of treatment in 115 patients. Medicine 2005; 84: 313 \200\22322. 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. Lightfoot R, Michel B, Bloch D, et al. The American College of Rheumatology 1990 criteria f or the classi \201 cation of polyarteritis nodosa. Arthritis Rheum 1990; 33: 1088 \200\223 93. Prognosis \200 Pagnoux C, Cohen P, Guillevin L. Vasculitis secondary to infections. Clin Exp Rheumatol 2006; 24 (Suppl. 2): S71 \200\22381. HBV-PAN has a good prognosis with 60% survival at 10 years. HBV-PAN treated with anti-viral therapy has a 6% relapse rate. PAN tends not to be a relapsing remitting disease. Poor pro gnostic factor include age >65 years at presen- tation, gastrointestinal involvement. Watts RA, Scott DGI. Overview of the in \202 ammatory vascular disease. In: Hochberg MC, S ilman AJ, Smolen JE, Weinblatt ME, Weisman MH (eds) Rheumatology. 1583 \200\22391. See also Microscopic polyangiitis \200 CRYOGLOBULINAEMIA 334 Cryoglobulinaemia FBC anemia, leucocytosis, eosinophils (eosinophilia suggestive CSS). Acute phase response ( ESR and CRP). Liver function. Cryoglobulinaemic vasculitis is a rare medium/small vessel vasculitis that is often associa ted with hepatitis C virus (HCV) infection. \200 De \201 nition The Chapel Hill Consensus Conference de \201 ned cryoglob- ulinaemic vascu litis as: 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 excre- tion or u rine protein/creatinine ratio). Vasculitis, with cryoglobulin immune deposits, af- fecting small vessels (i.e. capillaries, venules, or arte- rioles), and associated with cryoglobulins in serum. Skin and glomeruli are often involved. Etiology There is a strong association between HCV infection and essential mixed cryoglobul inaemia, with 80 \200\22390% of such patients positive for anti-HCV antibodies. Type II cry oglobulins with a monoclonal IgM-kappa is most typically associated with cryoglobulinaemic vasculitis. Circulating HCV RNA has been found in the peripheral blood of patients with cry oglobulinaemia. HCV has been identi \201 ed within cutaneous vasculitis lesions and has be en selectively concentrated together with speci \201 c antibody in cryoprecipitates. Cryoglobulin detection Cryoglobulins are proteins that precipitate in the cold. Samples for cryoglobulin detection must be kept warm during transportation to the laboratory. Where appropriate \200 Nervous system (nerve conduction studies in all four limbs, biopsy) electrophysiological va riables may be altered in up to 80% of patients. Cardiac function (ECG, echocardiography). The exact mechanism of formation of cryoprecipitates is unknown. However, HCV virions and n on-envelope core proteins form cold insoluble immune complexes. There is strong evidence of a clonal B cell expansion. Biopsy Biopsy of an affected organ should be obtained where possible to con \201 rm diagno sis prior to treatment. Cryo- globulins may be detected tissue biopsies especially renal bi opsy specimens. 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. Renal disease is common. Viral serology HCV, HBC, HIV, and CMV serology. Meltzer \200\231s triad (purpura, arthralgia, weakness) is present Serological investigations \200 \200 \200 in < 40%. ANCA, ANA, anticardiolipin antibodies are negative. RF is present in 70%. Complement. Hypoc omplementaemia is present in 90% and is a useful distinguishing feature from ANCA associ- a ted vasculitis in which complement levels are normal. Key features on history Systemic Fever, weight loss, myalgia, arthralgia. Cutaneous Rash, purpura, Raynaud \200\231s phenomenon. Differential diagnosis This is from other types of vasculitis (especially WG, MPA, CSS), va sculitis mimics (e.g. malignancy, cholesterol embolism, atrial myxoma, calciphylaxis), or i nfection (espe- cially SBE). Disease assessment \200 Neurological Subacute, gradual onset may be either symmetric or asymmetric peripheral neuro pathy, acute mononeuritis multiplex. Musculoskeletal Arthralgias or arthritis. 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 Vasc ulitis Damage Index (VDI). General health function can be assessed using the SF-36 or HAQ. Key features on examination Cutaneous Purpura (less often: urticaria, livedo, exanthem, acr al necrosis, leg ulcers). Neurological Polyneuropathy is present in 40-70% (distal, symmetrical or asymmetrical, moto r and/or sensory polyneuropathy, acute mononeuritis multiplex). Muscle weakness Proximal muscle weakness. Prognosis Relapsing remitting disease requiring maintenance anti-viral therapy. General investigations Investigation is directed at establishing the diagnosis and assessin g the extent and severity of organ involvement. CHAPTER 9 Vasculitis 335 Pathology The characteristic lesion on renal biopsy is a membranop- roliferative glomerulon ephritis with intracapillary thrombi, which contain cryoglobulin precipitates. This disting uishes it from ANCA-associated vasculitis. Guidelines EULAR recommendations for the management of small- and medium-sized vessel vasculitis. Patient organizations Vasculitis Foundation: www.vasculitisfoundation.org Stuart Strange Tr ust: www.vasculitis-uk.org Patient advice \200 \200 Systemic vasculitis associated with HCV infection. Relapsing remitting disease requiring lo ng-term treatment with anti-viral therapy. ICD-10 coding D89.1 Cryoglobulinaemia References Galli, M, Invernizzi F, Monti G. Cryoglobulinaemic vasculitis. In: Ball GV, Brid ges L (eds) Vasculitis. Oxford: Oxford University Press, 2008: 529 \200\22344. Treatment \200 Severe or life-threatening disease should be treated with steroids, cyclophosphamide +/ \210\222 plasma exchange. Less severe disease (arthralgia, purpura, neuropathy) with IFN-al pha, ribivirin +/ \210\222 plasma exchange. Interferon and ribivirin is effective. Ribiviri n alone is ineffective. The role of anti-CD20 therapy remains to be determined. Because of the relapsing nature of disease maintenance anti-viral therapy is necessary. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of medium and small vessel vasculitis. Ann Rheum Dis 2008 (in press). Pagnoux C, Cohen P, Guillevin L. Vasculitis secondary to infections. Clin Exp Rheumatol 2006; 24 (Suppl. 2): S71 \200\22381. \200 Resources Assessment tools The BVAS and VDI should be used to assess disease activity and damage. PRIMARY CENTRAL NERVOUS SYSTEM VASCULITIS 336 Primary central nervous system vasculitis Imaging Cerebral angiography \200 Primary central nervous system vasculitis (PCNSV) is a rare vasculitis of unknown etiology affecting the brain and spinal cord. Angiographic changes are found in multiple vessels usually bilateral (90%). Involvement of small vessels is more common than large vessels. Large vessel involvement alone is uncommon . Conventional angiography is probably more sensitive for detecting intracranial vasculitis than MRA. Epidemiology \200 \200 \200 The annual incidence is 2.4/million in Olmsted County (USA). The mean age at diagnosis was 47 years. The condition is more common in females (3:2). Diagnostic criteria (i) Recent history or presence of an acquired neurological Magnetic resonance angiography Involvement of both large and small vessels is typically see n, with multiple vessel abnormalities. de \201 cit unexplained by other causes. (ii) Evidence of vasculitis in a CNS biopsy specimen. (iii) Cerebral angiogram with changes characteristic of Magnetic resonance imaging \200 \200 Cerebral MRI is abnormal in 97% of patients. The most common lesion is cerebral infarction seen in half of patients, the majority of patients have multiple infarctions often bilatera l and involving the cortex and subcortex. Intracranial hemorrhage is unusual (<10%). Gadoli nium-enhancing lesions can be seen in one-third of patients. vasculitis. Diagnosis requires i) and ii) or iii) (Calabrese & Mallek, 1988). These criteria have not b een validated. Etiology The etiology is unknown. \200 Clinical features Key feature on history Neurological \200 \200 \200 Brain biopsy \200 Headache: present in 63% at presentation. Altered cognition: occurs in 50%. Stroke: persist ent de \201 cit occurs in 40% with 28% having a transient ischaemic attack. Visual symptom s occur in 42%, with \201 eld defects in 21%, diplopia in 16%, loss visual acuity in 11%. Nausea and vomiting occur in 25%. CNS biopsy is necessary to make a de \201 nitive diagnosis and is positive in two-thirds o f patients. Histology may show a granulomatous vasculitis, with or without acute necrosis. A lymphocytic pattern may be seen. Electroencephalography There are no speci \201 c features. Findings include dysrhythmias, epileptogenic changes, and delta waves. Systemic These are relatively uncommon with fever occurring in 9%. Differential diagnosis This is from other types of vasculitis (e.g. PAN or SLE). Infection needs to be excluded especially Varicella zoster, CMV, etc. Hypercoagulable states may mimi c PCNSV. Key features on examination Neurological \200 \200 \200 \200 \200 Focal neurological de \201 cit. Paraparesis or quadriparesis in 7%. Visual \201 eld defe cts occur in 21% Decreased visual acuity in 11%. Papilloedema in 5%. Prognosis \200 PCNSV is associated with increased mortality compared with the general population. Poor pro gnosis is associ- ated with the following at presentation neurological de \201 cit, cerebr al infarction, cerebral infarction, and large vessel involvement. Cerebral infarction is fr equent cause of death. Relapse in a fourth of patients followed for a mean of 13 months. General investigations Investigation is directed at establishing the diagnosis and assessin g the extent and severity of organ involvement. \200 \200 \200 FBC is typically normal. Acute phase response (ESR and CRP) are infrequently elevated. Live r function. Pathology There is evidence of transmural vessel in \202 ammation with involvement of the leptomeningeal and parenchymal vessels. Fibrinoid necrosis may be present. Serological investigations ANCA, ANA, RF, anticardiolipin antibodies, complement, cryoglobu lins are normal or negative. Patient advice General Potentially serious neurological condition, requiring immunosuppress ive therapy and lifelong follow-up. Cerebral spinal \202 uid Abnormalities in the CSF are found in 88% of patients. The white cell count is typically mildly elevated with an increase in total protein. RBCs are found in 79%. Treatment There are no controlled trials to guide therapy. CHAPTER 9 Vasculitis 337 Refractory disease Refractory disease may require treatment with novel agents such as mycop henolate mofetil or biological agents, but there is at the present time little evidence to support their use. Induction High dose corticosteroids are necessary \200 Oral corticosteroids start at 1 mg/kg (maximum dose 60 \200\22380 mg) and taper quickly aim for 10 mg/day at 6 months. Consider pulse IV steroids in severe cases. In patients with a poor prognostic outcome consider use of cyclophosphamide. Cyclophosphamide may be given eit her orally or intrave- nously (see p. 562 for details). \200 Follow-up As dictated by clinical condition. Resources Patient organizations Vasculitis Foundation: www.vasculitisfoundation.org Maintenance Maintenance therapy is with oral corticosteroids with a tapering dose of predni solone. The majority of patients require treatment for less than 18 months. References Calabrese H, Mallek JA. Primary angiitis of the central nervous system: report o f 8 new cases, review of the literature, and pro- posal for diagnostic criteria. Medicine ( Baltimore) 1988; 67: 20 \200\22339. Salvarani C, Brown RD, Calamia KT, et al. Primary centr al nervous system vasculitis: analysis of 101 patients. Annl Neurol 2007, epubl. Relapsing disease Relapse is treated with an increase in prednisolone dosage and the introd uction of other immunosuppressive agents, such as cyclophosphamide or azathioprine. COGAN \200\231S SYNDROME 338 Cogan \200\231s syndrome General investigations Investigation is directed at establishing the diagnosis, and assessi ng the extent and severity of organ involvement. \200 \200 Cogan \200\231s syndrome (CS) is a rare in \202 ammatory disease of unknown etiology, char acterized by involvement of the eye and inner ear. FBC anemia, leucocytosis, with relative lymphopaenia. Acute phase response (ESR and CRP). Epidemiology \200 CS occur mainly in young adults with peak incidence in the 20s. The incidence and prevalenc e is unknown. There is no gender predominance. Assessment of organ involvement In all patients Urinalysis (proteinuria, haematuria, red ce ll casts), should be performed urgently in all patients in whom systemic vasculitis is susp ected. \200 