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 Etiology The etiology is unknown, but like many autoimmune conditions is generally believed to result from an environ- mental trigger interacting with a genetically predisposed host. Infection has long been suspected as a trigger, but not proven. The eye and the ear are bo th capable of mounting a vigorous response to infection, trauma, or toxins. In an experimen tal model of autoimmune keratitis in rats trans- fer of corneal speci \201 c T cells produ ces a severe keratitis. Similarly transfer of activated T cells can induce vestibular in \202 ammation in animal models. Ophthalmic examination Slit lamp examination is necessary to examine the anterior chamber a nd cornea. Fluoroscein angiography is useful to assess retinal vasculitis or retinochoroidi tis. Audiometry \200 95% of patients have hearing loss, with relative sparing of the middle range. Brainstem-evo ked responses are abnormal in patients with cochlear damage. Caloric responses are abnormal with vestibular injury. Clinical features Key points on history The combination of ocular and vestibular symptoms i n a young adult should raise a suspicion of CS. Serological investigations \200 ANCA. ANA, RF, anticardiolipin antibodies are typically negative. Complement. Cryoglobulins . Ocular \200 \200 The predominant complaint is of ocular pain, redness, and photophobia. Blurred vision, tear ing, diplopia, a sensation of foreign body, or visual \201 eld defects occur frequently. Differential diagnosis This is from other types of vasculitis, which may cause scleritis or uveitis (Wegener \200\231s granulomatosis, polyarteritis nodosa, Beh et \200\231s disease ). CS should be considered in any patient presenting with ocular in \202 ammation and evid ence of audiovestibular dysfunction. Vestibular auditory Sudden onset vertigo, nausea, vomiting, tinnitus, and hearing loss. Att acks are similar to Meniere \200\231s disease. Vascular Symptoms of vasculitis depend on the territory and size of vessel involved. Any si ze of vessel may be involved. Large vessel vasculitis akin to Takayasu arteritis is most co mmon. Disease assessment Severity of involvement of target organs should be carefully assessed. Prognosis There is an initial \202 are, which may last several weeks to months, followed by a chronic slowly progressive phase. \200 Neurological Neurological involvement is uncommon in CS, but features include meningitis, e ncephalitis, psychosis, and seizures. Ocular outcomes are good. Blindness occurs in <5% of eyes. Deafness is a frequent and debil itating outcome occur- ring in up to 54% of patients. Corticosteroids may improve the outco me. Vestibular manifestations improve for most patients. Large vessel vasculitis with aorti c incompetence can be associated with a poor prognosis. Musculoskeletal Non-speci \201 c arthralgias and myalgias. Systemic Fever, weight loss, fatigue. \200 Key features on examination Ocular \200 Slit lamp examination is necessary to observe interstitial keratitis, which occurs in 70%. The earliest \201 ndings are faint corneal in \201 ltrates which are 0.5 \200\2231 mm in diameter. Other frequent manifestations are conjunctivitis (35%), iridocyclitis (30%), epi scleritis/scleritis (30%). Less commonly papillitis, posterior uveitis. Pathology \200 Corneal biopsies may show plasma infiltrate and lymphocytes in the deeper layers of the cor nea with scarring and neovascularization. The histology of vessels is similar to that seen in GCA, with an in \202 ammatory in \201 ltrate, intimal proliferation, dis- ruption of t he internal elastic lamina, and multinucleate giant cells. Vestibular auditory Hearing loss occurs in 95%, ataxia (45%), nystagmus (30%), oscillopsia (15%). Cardiovascular Aortitis occurs in 10% with severe aortic regurgitation. Pericarditis, arrhy thmias. CHAPTER 9 Vasculitis 339 Patient advice Rare in \202 ammatory disease of the eye and ear requiring treatment with s teroids and possibly immunosuppressive therapy. Resources Patient organizations Vasculitis Foundation: www.vasculitisfoundation.org References Grasland A, Pouchout J, Hachulla E, Bletry O, Papo T, Vinceneux P, and the Study Group for Cogan \200\231s syndrome. Typical and atypical Cogan \200\231s syndrome: 32 case s and review of the literature. Rheumatology 2004; 43: 1007 \200\22315. Treatment \200 Glucocorticoids are the mainstay of treatment for acute \202 ares, and recurrences of ocu lar and auditory in \202 ammation. Keratitis and anterior uveitis usually respond to topic al glucocorticoids Posterior scleritis and retinitis require oral glucocorti- coids. Audiov estibular disease requires high dose oral gluco- corticoids (prednisone 1 \200\2232 mg/kg/d ay). Resistant disease requires immunosuppression with methotrexate; ciclosporin, azathiopr ine, tacrolimus, and cyclophosphamide have all been tried. Mazlumzadeh M, Matteson EL. Cogan \200\231s syndrome: an audiovestibular, ocular, and syste mic autoimmune disease. Rheum Dis Clin N Am 2007; 33: 855 \200\22374. BEH \207ET \200\231S DISEASE 340 Beh et \200\231s disease Beh et \200\231s Disease (BD) is a systemic vasculitis of unknown etiology involving veins and arteries of all sizes, character- ized by oro-genital ulceration and ocular involvemen t. Oral ulceration can be minor, major or herpetiform. Minor ulcers are small, shallow, multip le ulcers. They constitute 90% of BD oral ulcers. They heal in 15 days. Major ulcers are la rge 1 \200\2233 cm in diameter and are slow to heal. Diagnostic criteria The International Study Group diagnostic criteria are widely used, but have not been formally validated. Genital ulcers \200 These begin as papules or pustules that ulcerate quickly and tend to become infected. In me n they occur typically on the scrotum and scar on healing. In women vaginal ulcers may go u nnoticed, until they become infected. Formal gynecological examination should be performed in all women suspected of BD. International Study Group diagnostic criteria for Beh et \200\231s disease Recurrent oral ulceration (aphthous or herpetiform) observed by a physician or the patient at least three times over one 12-month period. And two of the following: \200 \200 Skin lesions Skin involvement is common in BD but can be non-speci \201 c. Recurrent genital ulceration. Eye lesions: anterior uveitis, posterior uveitis, cells in th e vitreous by slit lamp examination, or retinal vasculitis. Skin lesions: erythema nodosum, pseudofolliculitis, papulopustular lesions, or acneiform nodules in post- pubescent patien ts not on steroids. Positive pathergy test. Pathergy \200 This is a non-speci \201 c hyper-reactivity in response to minor trauma. It is characteris tic of BD. A history of pathergy is often available with development of papules or pustules at the sites of venepuncture or intravenous cannulation. Pathergy most commonly occurs in patients from the Middle East, Far East, and the Mediterranean littoral. Epidemiology \200 Eye \200 The highest prevalence rates are in Turkey (8 \200\22338/10 000) and Japan (10/10 000). Mor e common around the Mediterranean littoral, the Silk Route, and Japan. BD has been describe d in every ethnic group, but is rare in white Caucasians, and black Africans. Males and fem ales are affected equally, but males tend to have more severe disease. Onset before puberty and after the age of 60 is uncommon. Eye involvement is the most serious manifestation of BD, and is a common cause of blindness and should be sought in all cases. The overall prevalence of eye involvement is 50%. It oc curs frequently within the \201 rst 3 years and rarely after 5 years. Nervous system \200 Headaches are common feature of BD and may represent dural sinus thrombosis. Parenchymal le sions in the brain stem are the most common lesions seen in the CNS. Etiology \200 The etiology is unknown; however, there is likely to be a strong genetic component, as the frequency varies considerably between different ethnic groups. Although often considered to be autoimmune in etiology, there are few features of classic autoimmunity in BD. There is an association with HLA-B51, which is not found in other autoimmune diseases. There is a st ate of immune hyper-reactivity as evidenced by the pathergy reaction. There is overproducti on of pro-in \202 ammatory Th1 type cytokines. No clear infectious cause has yet been iden ti \201 ed. Vascular disease \200 BD can involve both large arteries and veins. Venous involvement is more common (37%). Deep venous thrombosis of the legs is common. Arterial lesions are mainly aneurysmal and can ru pture. Pulmonary artery involvement presents with recurrent haemoptysis, due to rupture int o a bronchus. Musculoskeletal \200 Arthralgias and arthritis occur in 50%. It is usually mono or oligo-articular. Knee, ankle and wrist are the most common sites. It lasts a few weeks and is not destructive. The sacro iliac joints and axial skeleton are spared. 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. BD is multisystem and not all fe atures will occur at presentation; therefore, a detailed past history is required, particul arly with regard to genital ulceration, skin and eye involvement. Gastrointestinal \200 Lesions of BD occur throughout the GI tract and are histologically indistinguishable from i n \202 ammatory bowel disease. They are chronic, multiple deep ulcers associated with chro nic in \202 ammation and occasionally granulomata. Key features on history Oral ulcers \200 These occur in 97 \200\22399% of patients and are frequently the \201 rst manifestation. They may occur many years before development of other manifestations. Key features on examination X-ray Chest radiography may show pulmonary artery aneurysms. CHAPTER 9 Vasculitis 341 Differential diagnosis \200 Genital ulcers are often painful and a local analgesic gel may be required. Topical cortico steroids are usually nec- essary and may be applied using a gel. An asthma inhaler may be a convenient way of delivering topical steroids to relatively inaccessible regions. Colchici ne and thalidomide are effective in controlling ulceration. This is from other types of vasculitis. The key feature is the occurrence of oro-genital ul cers as there are very few other conditions in which this is a predominant feature. Oral ul cers must be differentiated from other causes of oral ulceration such as benign aphthous ul cers, viral infection, and in \202 ammatory bowel disease. The oral ulcers of BD tend to b e more frequent and multiple. Genital ulcers especially in the absence of oral ulcers need to be distinguished from herpetic ulcers or other viral ulcers, in \202 ammatory bowel dis ease. MAGIC syndrome is an overlap between relapsing poly- chondritis and Beh et \200\231s disease. Mouth and genital ulcers with in \202 amed cartilage (MAGIC). Ophthalmic \200 Oral corticosteroids are used, but there are no control- led trials. Azathioprine in an RCT is effective at controlling ocular disease compared with placebo. Other drugs that are use d include ciclosporin, interferon alpha, and tacrolimus. Prognosis \200 \200 \200 Resources Guidelines EULAR recommendations for the management of Beh et \200\231s disease: report of a task force of the European Standing Committee for International Clinical Studi es Including Therapeutics (ESCISIT). Young males have an increased mortality. Ocular involvement can lead to blindness in 5 \200 \22310%. Major vessel involvement (arterial or venous) is associated with mortality in 1 \200\2233% of patients. Pathology Histological examination of oral ulcers shows a lympho- cytic and monocytic in \201 ltrate in the basal layer and dermis with erosion of the epidermis. Patient organizations Beh et \200\231s Syndrome Society: www.behcets.org.uk American Beh et \200\231s Disease Association: www.behcets. com Patient advice General Potentially serious multisystem condition, requiring immunosuppressi ve therapy and lifelong follow-up. References Hatemi G, Silman A, Bang D, Bodaghi B, Chamberlain M, Gul A, et al. EULAR recomm endations for the management of Beh et \200\231s dis- ease: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCI SIT). Ann Rheum Dis 2008 (in press). Treatment Oro-genital ulceration \200 International Study Group for Beh et \200\231s Disease. Criteria for Patients with minor aphthous like lesions may respond well to topical corticosteroids. Majo r and persistent lesions may require oral corticosteroids. Secondary infection should be tr eated with appropriate antibacterial or antifungal agents. diagnosis of Beh et \200\231s disease. Lancet 1990; 335: 1078 \200\22380. HENOCH \200\223SCH \226NLEIN PURPURA 342 Henoch \200\223Sch nlein purpura A number of HLA associations have been reported including HLA B35 and DRB1*01 with nephriti s. HSP nephritis and IgA nephropathy have been associated with de \201 ciencies in C2 and C4, and with deletion of C4 genes. Henoch \200\223Sch nlein purpura (HSP) is an acute small vessel vasculitis occurring predo minately in childhood. The classi- cal triad is arthritis, palpable purpura, and abnormal r enal sediment. Classi \201 cation The CHCC de \201 ned HSP as: Clinical features Key features on history Cutaneous A rash is present in all cases, but is not always the present- ing feature. Vasculitis, with IgA-dominant immune deposits, affecting small vessels i.e. capillaries, ve nules, or arteri- oles). Typically involves skin, gut, and glomeruli, and is associated wit h arthralgia or arthritis. Gastrointestinal \200 Abdominal pain, related to meals and suggestive of mesenteric ischaemia. Bloody diarrhea. N ausea and vomiting. Criteria The ACR in 1990 developed classi \201 cation criteria, which are widely used in c linical trials. There are no validated diagnostic criteria. Criteria for childhood HSP have recently been developed. \200 Musculoskeletal \200 Arthralgias with or without joint swelling may precede the rash by several days in up to 25 % of cases, and occurs in 83% of children. The typical pattern is oligoarticular involving the legs. ACR classi \201 cation criteria for Henoch \200\223 Sch nlein purpura 1. Palpable purpura : slightly elevated purpuric rash over one or more areas of the skin not related to thrombo cytopaenia. Renal \200 Nephropathy may present with gross haematuria lasting for a few days. In children renal inv olvement is usually only detected on urinalysis. Renal involvement occurs in up to 80% of a dults and one third of children. 2. Bowel angina: diffuse abdominal pain worse after meals, or bowel ischaemia, usually bloo dy diarrhea. 3. Age at onset <20 years: development of \201 rst symptoms at age 20 years or less. Other Rarer manifestations include orchitis (9%), seizures 2% and (1%) duodenal obstruction (1%), intussusception (2%). 4. Wall granulocytes on biopsy: histological changes showing granulocytes in the walls of a rteries or venules. Note: for purposes of classi \201 cation a patient shall be said to have Henoch \200\223Sc h nlein purpura if at least 2 of these 4 criteria are present. The presence of any 2 or mo re criteria yields a sensitivity of 87.1% and speci \201 city of 87.7% (from Mills et al., 1990). Key features on examination Cutaneous \200 Palpable purpura, most common over the posterior aspects of the legs and buttocks. The arms and trunk are less commonly involved. The rash is usually petechial or purpuric with macul ar and papular elements. Urticarial or vesicular lesions may be occasionally seen. Adults m ay develop skin necrosis particularly in dependent areas. Classi \201 cation criteria for childhood HSP Palpable purpura in the presence of at least one of: \200 \200 \200 \200 Diffuse abdominal pain Any biopsy showing predominant IgA deposition Arthralgia or arthriti s Any haematuria and/or proteinuria. Musculoskeletal In \202 ammatory synovitis most commonly affecting the lower limb joints, in an oligoarticular pattern. From Ozen et al. (2006). Epidemiology \200 \200 Gastrointestinal Diffuse abdominal tenderness, which may be suf \201 ciently severe to mim ic an acute abdomen. HSP can be compli- cated by intussusception in children and this must be con- sidered with referral to pediatric surgery if suspected (palpable mass, bloody stoo l, signs of obstruction). The peak age of onset is 5 \200\2237 years. The annual incidence is 135 \200\223180/million children aged 0 \200\22314 years. HSP is rare in adults (>16 years) with an incidence of 1 3/million. HSP is commoner in children of Asian and Caucasian ori- gin than Afro-Caribbeans . Slightly more common in boys (1.2:1.0). Renal Rare. Features of nephrotic syndrome with peripheral oedema. General investigations The majority of children with a classical presentation do not need i nvestigation to establish the diagnosis. It is imperative to perform a urinalysis for blood and check the blood pressure with an appropriately sized cuff. If there is any doubt of th e diagnosis then further investigations Etiology The etiology is unknown. Report of associations with streptococci, mycoplasma, Bar tonella, and viruses suggest an infectious etiology, but no clear association has emerged. Seasonal peaks in incidence have been reported, but no consistent pattern has emerged in th e various population studied. CHAPTER 9 Vasculitis 343 Chronic renal failure develops in <5% of children and is associated with hypertension, neph ritis or nephrotic syndrome at presentation. Renal failure is more common in adults. are required. In adults, the following investigations should be performed since the conditi on is much less common and usually more severe \200 FBC and \201 lm. Anemia (only if severe GI or renal haem- orrhage), leucocytosis. Exclude idiopathic thrombocyto- penic purpura and leukemia. Coagulation screen normal. Acute phase response (ESR and CRP). Blood culture to rule out meningococcal septicaemia. Patient advice \200 \200 \200 Self-limiting acute vasculitis, prognosis is generally good, with a low risk of recurrence. Risk of signi \201 cant renal involvement is low but urine samples should be tested and b lood pressure checked (by GP) initially weekly and then monthly for a year. Return if prote inuria occurs or haematuria does not resolve Assessment of organ involvement In all patients \200 Urinalysis (proteinuria, haematuria, red cell casts), should be performed urgently in all p atients in whom HSP is suspected. Renal function (creatinine clearance, quantification of p rotein leak if present using either 24-h protein excretion or urine protein/creatinine rati o). Blood pressure. Treatment Most patients do not need speci \201 c therapy, as the condi- tion is self-limit ing. NSAIDs help arthralgia, but should be avoided in those with signi \201 cant renal inv olvement. The role of corticosteroids is controversial. Several RCTS have shown that in children the routine use of corticosteroids early in the disease process does not alter the progression to severe nephritis or GI com- plications (Huber et al., 2004; Ronkainen et al., 2006). In these studies oral prednisolone was used at a dose of 1 \200\2232 mg/kg/day tapering rapidl y over 2 \200\2234 weeks. Prednisolone is, however, effective in reducing the sever- ity of abdominal pain and arthralgias. Patients with severe abdominal should therefore probably r eceive corticos- teroids. Rule out intussusception prior to treatment There are no RCTs to guide therapy in patients with rapidly progressive or established glomerulonephritis and th ese patients should receive immunosuppressive therapy with prednisolone combined with cyclo phos- phamide initially with maintenance azathioprine. For details see p. 562. Treatment of adults has been less well studied, but follows the same principles as childhood disease. Serological investigations \200 ANA, ANCA, RF should all be negative. A positive ANA or ANCA suggests the presence of a con nective tissue disease or other vasculitis. Complement levels are normal. Biopsy A renal biopsy should be considered in both children and adults if there is signi \201 cant proteinuria or haematuria that persists (in children > 1 year). Pathology \200 IgA-dominant immune deposits are observed in the walls of small vessels and in the renal gl omeruli. The cutaneous lesions of HSP show a small vessel vascu- litis with involvement of the capillaries, post capillary venules and non-muscular arteries. There is often leuco- cy toclasis. The appearances are dif \201 cult to distinguish from leucocytoclastic (hypersen sitivity) vasculitis or other small vessel vasculitis. IgA deposits are present in the skin lesions of HSP and may be a distinguishing feature. In the kidney the earliest lesion is f ocal or diffuse prolif- erative glomerulonephritis. The appearances may be IgA nephropathy. Immunofluorescence reveals diffuse mesangial IgA deposition. Resources Internet resources www.vasculitisfoundation.org ICD-10 code D69.0 Allergic purpura indistinguishable from References Huber Am, King J, McKaine P, Klassen T, Pothos M. A randomized placebo controlle d trial of prednisolone in early Henoch- Sch nlein purpura. Bio Med Central 2004; 2: 7. Differential diagnosis The classical triad of palpable purpura, arthritis, and gastro- inte stinal involvement makes the diagnosis relatively easy in children. In adults, other types of vasculitis should be considered, especially in those who are ANCA or ANA positive. Mills JA, Michel BA, Bloch DA, Calabrese LH, Hunder GG, Arend WP. et al. The ACR 1990 class i \201 cation criteria for the classi \201 ca- tion of Henoch \200\223Sch nlein purpura. Arthritis Rheum 1990; 33: 1114 \200\22321. Ozen S, Ruperto N, Dillon MJ, et al. EULAR/PReS endorsed consensus criteria for the classi \201 cation of childhood vasculitides. Ann Rheum Dis 2006; 65: 936 \200\22341. Prognosis \200 Ronkainen J, Koskimies O, Ala-Houhala M, et al. Early prednisone therapy in Henoch-Sch nle in purpura: a randomized, double- blind, placebo-controlled trial. J Pediatr 2006; 149: 241 \200\2237. Overall, prognosis is determined by the extent of renal involvement. Most patients have a g ood prognosis and the illness is self-limiting, resolving within 2 \200\2233 weeks. Up to 5 0% of children have recurrences typically purpura and abdomi- nal pain. Haematuria and prot einuria may persist for up to 1 year in 50% of children. Saulsbury FT. Henoch-Sch nlein purpura in children. Report of 100 patients and review of t he literature. Medicine (Baltimore) 1999; 78: 395 \200\223409. KAWASAKI DISEASE 344 Kawasaki disease vascular occlusion. In \202 ammatory cell in \201 ltration continues for 3 \200\2234 week s and then resolves, leaving scarring. Kawasaki disease (KD) is an acute small and medium vessel vasculitis occurring in childhood with a predilection for the coronary arteries. Previously known as \200\230mucocutaneous lymph node syndrome \200\231. Clinical features Key features on history Systemic \200 Diagnostic criteria Criteria have been developed by the Japanese Kawasaki Research committe e. Acute febrile illness lasting at least 5 days, unresponsive to NSAIDS/paracetamol. Cervical lymphadenopathy, may be unilateral. Diagnostic criteria for Kawasaki disease 1. Fever persisting for 5 days 2. Bilateral conjun ctival congestion 3. Oromucosal \200 \200 \200 Mucocutaneous \200 \200 Swelling of hands and feet, red palms and soles. Truncal rash. Musculoskeletal Acute polyarthralgia. Reddening of lips. Strawberry tongue. Diffuse injection of oral and pharyngeal mucosa. Cardiac Angina, dyspnoea. 4. Polymorphous exanthem 5. Peripheral extremities \200 Key features on examination The child is miserable. Initial stage: \200 \200 Convalescent stage: membranous desquamation from \201 ngerti ps reddening of palms and soles; indurative oedema. Mucosal \200 Bilateral conjunctival congestion, suffused without exudates. Erythema and \201 ssuring o f lips and oropharynx. Strawberry tongue. Non-purulent cervical lymphadenopathy. \200 \200 6. Acute non-purulent cervical lymphadenopathy At least \201 ve items are required for a diagnosis of KD. If coronary aneu- rysms are no ted on 2D echocardiography or coronary angiography then 4 items are suf \201 cient (from K amiya, 1984). Cutaneous \200 Indurative oedema of hands and feet, erythema palms and soles. Polymorphous exanthema, peri neal accentuation. Desquamation \201 ngers and toes in convalescent period only. \200 Epidemiology \200 In Japan the annual incidence is 150/100 000 children aged <4 years. 50% are aged <2 years. Onset age >10 years is rare. KD occurs worldwide, but is most prevalent in Japan and East Asia. In the UK the incidence is 14.6/100 000 in Indian Subcontinent Asians and 4.6/100 000 in White Caucasians. \200 \200 Musculoskeletal \200 \200 Polyarthritis (less common). Irritability and aseptic meningitis are frequent, abdominal pa in and diarrhea, hydrops of gall bladder, and hepa- tomegaly rarer. Cardiovascular \200 Heart murmurs mitral regurgitation most common. Valvular heart disease occurs in 1% patient s. Gallop rhythm. Faint heart sounds, suggestive of pericardial effusion. Pericarditis occu rs in 13% patients. Peripheral artery aneurysms (1%). Aetiopathogenesis The aetiopathogenesis is unknown. An infectious etiology has long been su spected. Cyclical epidemics have been observed especially in Japan supporting the notion th at there is an infectious cause. So far no speci \201 c organism has been identi \201 ed. \200 General investigations Investigation is directed at establishing the diagnosis, and assessi ng the extent and severity of organ involvement. \200 KD is similar to scarlet fever and toxic shock syndrome, and it has been suggested that KD is caused by toxin producing bacteria with superantigen activity. The acute phase of KD is associated with production of in \202 ammatory cytokines, including TNF-alpha, IL-1B, and y-IFN with induction of endothelial injury via ELAM-1 and ICAM-1. FBC mild anemia, leucocytosis with a left shift, throm- bocytosis in the second week of ill ness. Acute phase response (signi \201 cantly raised ESR and CRP). Elevated liver enzymes, hypoalbuminaemia. Urinalysis sterile pyuria, proteinuria. \200 \200 Pathology Coronary arteritis begins with oedema in the media with a lymphocytic and macroph age in \201 ltration. This spreads to cause a panarteritis involving all layers of the ves sel wall. Around the twelfth day the artery begins to dilate, abnormal blood \202 ow lead s to thrombus formation and Assessment of organ involvement Cardiac \200 Electrocardiography: prolonged PR/QT intervals, abnormal Q waves, low voltage, ST-T changes , dysrhythmias CHAPTER 9 Vasculitis 345 The optimal dose and timing of IVIg remains controver- sial and single doses of IVIg 2 g/kg has been show to be effective. Intravenous corticosteroids have been show in a recent RCT to confer no additional benefit when used in conjunction with IVIg. Echocardiography: \200 \200 dilatation of coronary arteries; coronary artery aneurysms are shown in 10 \200\22320% of p atients; pericardial effusion. Angiography: \200 Convalescent phase \200 coronary angiography enables accurate de \201 nition of coronary artery abnormalities and the severity of valvular lesions; angiography should be performed in patients with cardiova scular involvement because there is a risk of progression to ischaemic heart disease especi ally in patients with giant aneurysms. Aspirin 3 \200\2235 mg/kg for 6 \200\2238 weeks in those without coronary abnormalities. As pirin should be continued in patients with coronary abnormalities until they have resolved. Anti-coagulation with warfarin should be considered in those with giant aneurysms. Other t herapies. \200 Serological investigations \200 ANA, ANCA, RF all negative. \200 Complement levels are normal. Plasma exchange, TNF-alpha blockade with in \202 iximab and cytotoxic therapy have all bee n used successfully but there is not controlled trial data to support their use. Differential diagnosis Conditions to be considered/excluded: Erythema multi- forme/Steven \200\231s Johnson, scarlet fever, toxic shock syndrome, systemic JIA, measles, reactive art hritis. Follow-up \200 All children should have a repeat 2D echocardiography in the convalescent phase (4 \200\223 6 weeks) regardless of ini- tial echocardiography in accute phase. Regular 2D echocardiogra phy is required in patients with coronary aneurysms to document regression. Management shou ld be in conjunction with a pediatric cardiologist. Prognosis \200 \200 \200 Generally good. The recurrence rate is 3.3%. Mortality is very low 0.1 \200\2230.2% and is due to acute myocardial infarction. 50% of coronary aneurysms regress at 2 years. KD is now the commonest cause of acquired cardiac disease, and may cause premature adult atheroscler osis. \200 Resources Patient organizations Kawasaki disease foundation: www.kdfoundation.org Patient advice \200 ICD 10 code M30.3 Mucocutaneous lymph node syndrome (Kawasaki). Potentially serious acute vasculitis, prognosis is generally good, with a low risk of recur rence. Risk of development of coronary aneurysms. References Kamiya T. Research committee on Kawasaki disease. Tkio: Ministry of Health and Welfare, 1984. Treatment Acute phase \200 Newburger JW, Sleeper LW, McCridle BW, et al. Randomized trial of pulse corticosteroid ther apy for primary treatment of Kawasaki disease. N Engl J Med 2000; 356: 663 \200\22375. Aspirin high dose 80 \200\223100 mg/kg per day in divided doses for 14 days. Intravenous im munoglobulin (IVIg) 400 mg/kg for 4 days. When given within the \201 rst ten days the rat e of aneu- rysm formation is reduced to 5% overall, and 15% for giant aneurysms. The combin ation of high dose aspirin and IVIg has been shown in an RCT to prevent coronary artery ane urysm formation (Neuberger et al., 1986, 1991, 2000). Newburger JW, Takahashi M, Beiser AS, et al. A single infusion of gamma globulin as compare d with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med 1991; 324: 1633 \200\2239. Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndr ome with intravenous gamma globulin. N Engl J Med 1986; 315: 341 \200\2237. RELAPSING POLYCHONDRITIS 346 Relapsing polychondritis Respiratory Dyspnoea with stridor is suggestive of tracheal involvement. Respiratory involv ement is the most serious complication of RP. Up to 50% of patients have respiratory involv ement. Relapsing polychondritis (RP) is a rare condition character- ized by in \202 ammation and destruction of cartilage. De \201 nition Relapsing polychondritis is a rare condition characterized by recurrent epi sodes of in \202 ammation and destruction of cartilage. Ophthalmic Painful red eyes with blurred vision suggest scleritis or episcleritis. Diagnostic criteria The following diagnostic criteria have been proposed. Cutaneous Skin involvement is common with purpura. Key features on examination Cartilage in \202 ammation \200 Diagnostic criteria for relapsing polychondritis \200 \200 \200 \200 