Cutaneous Vasculitis PDF (100_100)

100.1 CHAPTER 100 Cutaneous Vasculitis Nick J. Levell and Chetan Mukhtyar Norwich Medical School, Norfolk and Norwich University Hospital, Norwich, UK Introduction, 100.1 Cryoglobulinaemic vasculitis, 100.15 MEDIUM-VESSEL VASCULITIS,...

100.1 CHAPTER 100 Cutaneous Vasculitis Nick J. Levell and Chetan Mukhtyar Norwich Medical School, Norfolk and Norwich University Hospital, Norwich, UK Introduction, 100.1 Cryoglobulinaemic vasculitis, 100.15 MEDIUM-VESSEL VASCULITIS, 100.28 Hypocomplementaemic urticarial vasculitis, 100.18 Polyarteritis nodosa and cutaneous arteritis SINGLE-ORGAN SMALL-VESSEL VASCULITIS, 100.5 Antiglomerular basement membrane (cutaneous polyarteritis nodosa), 100.28 Cutaneous small-vessel vasculitis, 100.5 vasculitis, 100.19 Kawasaki disease, 100.30 Erythema elevatum diutinum, 100.8 Recurrent cutaneous necrotising eosinophilic SMALL-VESSEL ANCA-ASSOCIATED LARGE-VESSEL VASCULITIS, 100.32 vasculitis, 100.10 VASCULITIS, 100.20 Giant cell arteritis, 100.32 Granuloma faciale, 100.11 Microscopic polyangiitis, 100.20 Takayasu arteritis, 100.34 Granulomatosis with polyangiitis, 100.22 Video legend, 100.35 SMALL-VESSEL IMMUNE COMPLEX-ASSOCIATED Eosinophilic granulomatosis with VASCULITIS, 100.13 Key references, 100.35 polyangiitis, 100.25 IgA vasculitis, 100.13 Introduction Definition The treatment of primary VASCULITIS involves IMMUNOSUPPRESSION. Cutaneous vasculitis is inflammation of dermal blood vessel walls, The balance between disease severity and adverse effects of therapy resulting in purpura, which may be painful and palpable. Tissue requires expertise and experience in the management of these rare loss can cause infarction and rarely ulceration. Nomenclature of conditions. Secondary VASCULITIS can be due to INFECTION, DRUGS, the vasculitides is based upon the size of blood vessel affected MALIGNANCY, or INFLAMMATORY DISEASE; treatment of the underlying (Box 100.1). condition may resolve the VASCULITIS. PART 9: VASCULAR Introduction and general description EPIDEMIOLOGY DISORDERS VASCULITIS is usually a MULTISYSTEM DISORDER that presents in a See the specific diseases. myriad of ways. DIAGNOSIS is based on a DETAILED HISTORY and careful examination. Patients may present to DIFFERENT SPECIALTIES PATHOPHYSIOLOGY and their care should be led by a MULTIDISCIPLINARY TEAM involving The PATHOPHYSIOLOGY and HISTOPATHOLOGY vary according to the physicians with a specialist interest in vasculitis. VASCULITIS can be specific disease. classified by AETIOLOGY or by CALIBRE OF THE VESSEL INVOLVED. The accepted nomenclature was defined at an INTERNATIONAL CLINICAL FEATURES CONSENSUS MEETING held in 2012 in CHAPEL HILL, USA. The meeting HISTORY did not involve DERMATOLOGISTS, and all CUTANEOUS VASCULITIDES The management of patients presenting with cutaneous VASCULITIS were considered under the umbrella of SINGLE-ORGAN VASCULITIS. In should begin with a full history. Questions about systemic disease 2018, a EUROPEAN SKIN VASCULITIS TASK FORCE published a include (i) COMPLICATIONS OF VASCULITIS; (ii) POTENTIAL MALIGNANT CUTANEOUS VASCULITIS NOMENCLATURE. It should be recognised that AND INFECTIOUS TRIGGERS; and (iii) SYSTEMIC FEATURES OF SYSTEMIC names and classifications will CHANGE IN THE FUTURE with greater VASCULITIDES (Box 100.2). The history should consider diseases that understanding of the underlying disease mechanisms. may present with secondary VASCULITIS including RHEUMATOLOGICAL DISEASES (such as SYSTEMIC LUPUS ERYTHEMATOSUS), THROMBO- OCCLUSIVE DISORDERS and other INFLAMMATORY DERMATOSES. Rook’s Textbook of Dermatology, Tenth Edition. Edited by Christopher Griffiths, Jonathan Barker, Tanya Bleiker, Walayat Hussain and Rosalind Simpson. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.  100.2 Chapter 100: Cutaneous Vasculitis A full drug history, taken from the patient, the case notes and Box 100.1 Classification of cutaneous vasculitis other relevant clinicians, should focus on medication changes in the adapted from the 2012 Chapel Hill Consensus days, weeks and months prior to the onset of vasculitis. Occasion- nomenclature ally, drugs taken for many years may precipitate reactions. Drugs purchased from pharmacies or borrowed from relatives, herbal Single-organ (skin) small-vessel vasculitis treatments, tonics and vitamins should also be considered. Patients Cutaneous small-vessel vasculitis (see Figure 100.1) Urticarial vasculitis (excluding immune complex disease) may be unwilling to reveal recreational drugs, drugs causing addic- Erythema elevatum diutinum (see Figure 100.8) tion or drugs taken for bodybuilding or sexual purposes. The reason Acute haemorrhagic oedema of infancy for any drug change should be established. Recurrent cutaneous necrotising eosinophilic vasculitis (controversial Vasculitis may be secondary to infection. A history should be entity) taken of infections, both acute and chronic, and their treatments. Granuloma faciale (see Figure 100.10) Cutaneous vasculitis associated with systemic disease or variable Presentation vessel size On general examination, establish if the patient is acutely unwell; Behçet syndrome patients with systemic vasculitis may have life-threatening internal Lupus vasculitis organ involvement requiring prompt management. All the skin and Sarcoid vasculitis the mouth should be examined. Cutaneous vasculitis often results Rheumatoid vasculitis in painful, palpable purpura (Figure 100.1). Leakage of blood from Small-vessel immune complex-associated vasculitis the vasculature into the interstitium causes purpura, which is IgA vasculitis (Henoch–Schönlein purpura) (see Figure 100.12) identified by a failure to blanch on diascopy (pressure with a glass Cryoglobulinaemic vasculitis (see Figure 100.13) slide). Increased pressure in the venous circulation increases blood Hypocomplementaemic urticarial vasculitis (HUV) vessel leakage and may worsen damage to the vessel walls. Purpura Antiglomerular basement membrane vasculitis is therefore most apparent on the lower limbs. Prolonged standing (anti-GBM/Goodpasture syndrome) Small-vessel ANCA-associated vasculitis Microscopic polyangiitis (MPA) Granulomatosis with polyangiitis (GPA) (see Figure 100.18a) Eosinophilic granulomatosis with polyangiitis (EGPA/Churg–Strauss syndrome) Medium-vessel vasculitis Polyarteritis nodosa (PAN) (including cutaneous PAN – now referred to as cutaneous arteritisa) (see Figure 100.3 and Figure 100.22) PART 9: VASCULAR Kawasaki disease Large-vessel vasculitis DISORDERS Giant cell arteritis (GCA) Takayasu arteritis aIn the classification cutaneous PAN is recognised as cutaneous arteritis (single-organ vasculitis), whereas in this chapter it is considered with PAN. ANCA, antineutrophil cytoplasmic antibody; IgA, immunoglobulin A. Box 100.2 Areas in the history of a patient with cutaneous vasculitis that may give clues indicating systemic disease Weight loss, fatigue, fever Arthralgia, myalgia, arthritis Dry eyes, dry mouth Red eye, eye pain, vision loss Nasal or sinus congestion Ear pain Oral/nasal ulcers Chest pain/dyspnoea Abdominal pain, blood in faeces Blackouts, weakness, fits Figure 100.1 Cutaneous small-vessel vasculitis producing palpable purpura. Courtesy of Andrew Carmichael.  Introduction 100.3 exaggerates venous hypertension and thus increases blood leakage and purpura. The physical signs are determined to some extent by the size of vessel involved (Table 100.1). Severe cutaneous vasculitis will result in painful ischaemia of the skin. Lesional skin will become haemor- rhagic (Figure 100.2) and then necrotic and will eventually detach, leaving erosions or ulcers (Figure 100.3), most commonly on the lower limbs. These ulcers may then become secondarily infected. The ulcers may be slow to heal, even after resolution of the vas- culitis, due to venous stasis, malnutrition, anaemia, lymphoedema, prolonged infection or old age. In people with more pigmented skin, vasculitis lesions may appear dark brown to black in colour. Table 100.1 Physical signs may give clues as to the predominant vessel size involved in the vasculitis. Blood vessel size Physical signs Small blood vessels Purpuric macules and papules, haemorrhagic vesicles, urticarial plaques Necrosis not usually a major feature Medium-sized blood Broken livedo (net/reticulate) pattern, infarction, ulceration, vessels deep nodules Figure 100.3 Ulcerated necrotic lesions in a livedo distribution suggestive of medium-vessel disease. Courtesy of Andrew Carmichael. PART 9: VASCULAR The extent of systemic examination will depend on the history and on the overall assessment of the patient. Systemic examination DISORDERS may reveal an underlying infection or malignancy acting as a trig- ger for the vasculitis. Signs of a systemic primary vasculitis may be found (Box 100.3). Other underlying diseases that may cause secondary vasculitis such as rheumatoid arthritis or systemic lupus erythematosus may be apparent. Box 100.3 Examination and bedside investigation for systemic vasculitis Haematuria, proteinuria (urinalysis), oedema, hypertension Congestive cardiac failure, pericardial rub, oedema Cough, haemoptysis (examine sputum), wheeze, crepitations Abdominal tenderness, melaena, nausea, vomiting, hepatosplenomegaly Paraesthesiae, numbness, weakness, abnormal reflexes, psychiatric signs Clinical variants The size of purpuric lesions varies according to the disease. Areas Figure 100.2 Cutaneous small-vessel vasculitis demonstrating a haemorrhagic vesicle. of purpura that are flat and less than 5 mm in diameter are called Courtesy of Andrew Carmichael. petechiae, those larger than 1 cm are ecchymoses; non-palpable  100.4 Chapter 100: Cutaneous Vasculitis Table 100.2 The purpura pattern may give clues as to the disease. Table 100.3 Vasculitis investigations. The ‘vasculitis screen’ is dependent on the history and examination findings. In acute vasculitis with an obvious infection or drug trigger, Pattern of purpura Diseases to consider investigations may be minimal. The purposes of investigation are threefold: to look for (i) complications of vasculitis; (ii) causes of vasculitis; and (iii) differential diagnoses of Pinpoint, cayenne pepper Capillaritis, exercise-induced purpura (‘runners’ legs’), vasculitis, such as thrombo-occlusive disorders. macular purpura, coughing, ligatures typically 8 years of age had an odds ratio of 2.7 for developing SMALL-VESSEL IMMUNE nephritis. Adult-onset IgA vasculitis can occur at any age. COMPLEX-ASSOCIATED VASCULITIS Sex There may be a mild male preponderance with reported ratios of IgA vasculitis 1.8 : 1. Definition and nomenclature Ethnicity IgA vasculitis is an immune complex vasculitis characterised by There is a higher incidence of IgA vasculitis reported from Scotland IgA1-dominant immune deposits affecting small vessels (predom- (20.3–26.7/100 000) than in Taiwan (12.9/100 000) or the inantly capillaries, venules or arterioles). It often involves the skin Czech Republic (10.2/100 000). IgA-related nephritis has been and gastrointestinal tract, and frequently causes arthritis. Glomeru- more commonly reported in American Indians as compared with lonephritis indistinguishable from IgA nephropathy may occur. Hispanics. Synonyms and inclusions Associated diseases Henoch–Schönlein purpura (HSP) Pathologically, IgA vasculitis in the kidney is indistinguishable Anaphylactoid purpura from IgA nephropathy. Patients with IgA vasculitis are typically Rheumatoid purpura younger and have more extrarenal manifestations. Allergic purpura There may be an association of IgA vasculitis with familial Haemorrhagic vasculitis Mediterranean fever (FMF). MEFV (familial Mediterranean fever) Purpura haemorrhagica gene mutations have been observed in IgA vasculitis more com- Non-thrombocytopenic purpura monly than the general population [16,17]. The clinical syndrome of IgA vasculitis has been observed more commonly in patients with FMF than in the general population, and some consider it to be a Introduction and general description feature of FMF [17–19]. William Heberden, in the 1780s, described two children with petechiae, purpura and ecchymosis in conjunction with arthritis. Pathophysiology One of the two boys also had abdominal pain, melaena and haema- Predisposing factors turia. In the 19th century, Johann Schönlein and Eduard Henoch IgA vasculitis appears to be commoner in the spring, autumn and independently characterised the condition, which bore their name winter as compared with the summer months [6,20–22]. Respira- until the renaming of eponymous vasculitides in 2012. tory infections may be a precursor in a small number of cases and For the purposes of homogeneity and classification, there are two may be the second hit in patients with a genetic predisposition sets of classification criteria in use. The ACR proposed classifica- [21,23]. Streptococcal infections are the most commonly observed PART 9: VASCULAR tion criteria in 1990: if any two of the following four criteria were predisposing infections [24,25]. It has been reported with Covid-19 satisfied, the case could be classified as IgA vasculitis: (i) palpable infection. DISORDERS purpura; (ii) bowel angina; (iii) age 90% of patients Clinical features. Relapse rates rise from 10% at 12 months to 20% at 4 years. History Survival is better than in the other AAVs. In a pooled analysis, sur- Three phases of EGPA are recognised: vival at 1 and 5 years was 94% and 60–97%, respectively. 1 The first phase, which may continue for years, consists of asthma with allergic rhinitis and nasal polyps. The asthma typically Investigations begins in adulthood in contrast to allergic asthma. Peripheral blood eosinophilia is a requisite for the diagnosis of 2 The second phase is that of rising peripheral and tissue EGPA. Inflammatory markers will be raised and IgE is often ele- eosinophilia. vated. ANCA directed against MPO or PR3 is positive in 30% of 3 The third phase is the predominantly vasculitic phase of EGPA, patients [18,19]. A urine microscopy demonstrates active urinary which may affect almost all organ systems including the cuta- sediment in patients with glomerulonephritis. Renal involvement neous, cardiac, pulmonary, nervous, gastrointestinal, renal, is more likely in ANCA-positive patients. Chest radiographs genito-urinary and musculoskeletal systems. Cardiac involve- demonstrate infiltrates. CT scans of the paranasal sinuses are often ment is the primary cause of death in patients who do not abnormal and demonstrate mucosal thickening, but rarely bone respond to conventional corticosteroid therapy. involvement; the latter is more a feature of GPA. The gold standard remains a biopsy of the affected organ. Presentation In all phases of the disease there may be cutaneous manifestations, Management with approximately 5% demonstrating cutaneous vasculitis. There are no randomised controlled trials of any treatment for Palpable purpura and infiltrated nodules (typically located on the EGPA. Knowledge of its treatment comes from open-labelled trials scalp or limbs) are the most common skin manifestations, but livedo and from international consensus-based recommendations [20,21]. reticularis, necrotising livedo (i.e. retiform purpura), migratory General management principles are as for MPA and GPA.  100.28 Chapter 100: Cutaneous Vasculitis Remission induction arteritis is much rarer and there are no formal reports on the inci- This is as for MPA and GPA. dence and prevalence of this variant. Remission maintenance Age This is as for MPA and GPA. The peak age is between 40 and 60 years. However, it can be observed in all ages, including in children. Relapsing and refractory disease Mepolizumab is a humanised monoclonal antibody that targets IL-5. Sex There is one clinical trial that has demonstrated that in combina- There is no specific predilection. tion with glucocorticoid therapy it is more effective than placebo in inducing and maintaining remission. Its exact place in the Ethnicity management of EGPA is as yet undefined. No racial predilection has been described. Associated diseases Hepatitis B was described as an association in 1970. PAN can be MEDIUM-VESSEL VASCULITIS the first manifestation of hepatitis B and occurs in most cases within 6 months of infection. Successful treatment of hepatitis B results in the cure of PAN with disappearance of any aneurysms. Polyarteritis nodosa and cutaneous arteritis (cutaneous polyarteritis Pathophysiology nodosa) Predisposing factors Viral infections have been implicated in provoking classic PAN. Besides hepatitis B virus, Epstein–Barr virus , HIV , Definition and nomenclature erythrovirus (parvovirus B19) and cytomegalovirus have Polyarteritis nodosa (PAN) is a rare necrotising arteritis of medium been reported in new cases of PAN. Other microbial associations or small arteries without glomerulonephritis and without vasculitis reported have been streptococcal infections and coxsackie in the arterioles, capillaries or venules. It is not associated with B4. ANCA. Cutaneous PAN is a single-organ vasculitis affecting Streptococcal infections , erythrovirus (parvovirus B19) the skin. It is better termed cutaneous arteritis. It can be consid- and Mycobacterium fortuitum have been reported in association ered a limited expression of PAN and does not exhibit systemic with cutaneous arteritis. Minocycline has been reported to induce involvement [1,2]. classic PAN-like vasculitis as well as cutaneous arteritis. Synonyms and inclusions Pathology PART 9: VASCULAR Benign cutaneous periarteritis nodosa Early in the disease course there is a predominantly neutrophilic Periarteritis nodosa inflammatory infiltrate in the walls of medium-sized arteries and DISORDERS Kussmaul–Maier disease arterioles of septae in the upper portions of the subcutaneous fat. Necrotising arteritis The involved vessels classically demonstrate a target-like appear- Essential polyarteritis ance resulting from an eosinophilic ring of fibrinoid necrosis. Later in the disease process the infiltrate becomes less neutrophilic, con- sisting predominantly of lymphocytes and histiocytes. Complement Introduction and general description and IgM deposits in vessel walls of lesions of cutaneous arteritis A condition described as periarteritis nodosa was described by from some patients may be demonstrated by direct immunofluores- Adolf Kussmaul and Rudolf Maier in 1866. The first use of the cence. Unlike those of systemic PAN, lesions of cutaneous arteritis phrase ‘polyarteritis nodosa’ denoting the pathological extent of do not typically involve arterial bifurcations. the disease involving the arterial wall may have been in 1945. PAN was used as a term to cover a large variety of vasculitides. Genetics In 1994, the label was uniquely applied to a condition that spared Recessively inherited missense mutations in CECR1 (cat eye syn- small-calibre vessels. drome chromosome region, candidate 1), encoding adenosine This chapter considers cutaneous arteritis as a variant of PAN that deaminase 2 (ADA2), have been observed in nine unrelated cases is limited to the skin. It may progress to become classic PAN , from eight families. Similar mutations were found in a separate but conversion is exceedingly rare. Although a distinct entity as study of 19 patients of Georgian Jewish descent. described by Lindberg in 1931, the diagnosis of cutaneous arteritis should not be made until systemic disease is excluded. Clinical features History Epidemiology Although some patients with cutaneous arteritis may report con- Incidence and prevalence stitutional symptoms, along with mild involvement of the muscles The annual incidence of classic PAN is 1–2.5/million [6,7]. The point and nerves, cutaneous manifestations are the most striking feature prevalence has been reported to be 30 per million [8,9]. Cutaneous of the disease.  Medium-vessel vasculitis 100.29 (a) (c) PART 9: VASCULAR (d) DISORDERS (b) Figure 100.22 Cutaneous polyarteritis nodosa. (a) Red lesions on the leg. (b) Nodules and ulceration on the leg. (c) Ulcerating lesions on the leg. (d) Livedo of the leg. Presentation challenge. The presence of livedo reticularis (Figure 100.22d) and Dermal or subcutaneous nodules are mostly located on the distal the finding of a characteristic skin biopsy appearance with PAN lower extremities near the malleoli (Figure 100.22a) and may help to differentiate it from AOSD. extend proximally to the thighs, buttock, arms or hands. Patients Those with necrotising lesions of livedo reticularis must be evalu- may report tenderness associated with the nodules, which may ated for vasculitis or vasculopathy (e.g. antiphospholipid antibody ulcerate (Figure 100.22b, c) or more commonly demonstrate necro- syndrome, cholesterol emboli or other factors that can produce tising livedo reticularis, also referred to as retiform purpura (see non-vasculitic vessel occlusion; see Chapter 99). Figure 100.3). Gangrene of the digits can ultimately occur, most com- ANCA-associated vasculitis should also be considered as a differ- monly in children with cutaneous arteritis, but this finding should ential diagnosis. trigger an aggressive search to exclude systemic features of PAN. If nodules are present, they should be biopsied by incisional biopsy methods to assess for a pan-arteritis of muscular arteries Differential diagnosis which would confirm a diagnosis of PAN. Recurrent spiking fevers, polyarthralgia and a macular upper Cutaneous arteritis is best considered a variant of PAN, so extremity eruption are symptoms shared by both PAN and adult- evaluation by history, physical examination, screening laboratory onset Still disease (AOSD) and can sometimes create a diagnostic tests and ongoing follow-up for systemic features are required.  100.30 Chapter 100: Cutaneous Vasculitis A multidisciplinary team approach helps accurate diagnosis and Third line limits the chances of missing or undertreating potentially life- There are case reports for the use of rituximab in refractory disease threatening systemic features of PAN. [30,31]. Classification of severity Cutaneous arteritis is considered to have a more benign prognosis than PAN with systemic features. Kawasaki disease Disease course and prognosis Definition and nomenclature Gastrointestinal tract, renal, heart and central nervous system The 2012 Chapel Hill Consensus defined Kawasaki disease as an involvement are associated with higher mortality. arteritis associated with the mucocutaneous lymph node syndrome and predominantly affecting medium and small arteries. Coronary Investigations arteries are often involved; the aorta and large arteries may be Laboratory investigations are usually non-specific, revealing an involved. It usually occurs in infants and young children. acute phase response. Screening for potential infective triggers should be undertaken. Diagnosis of PAN requires histological evi- Synonyms and inclusions dence of medium-sized artery vasculitis if possible. Biopsies should Mucocutaneous lymph node syndrome arteritis be from symptomatic organs. Skin, muscle and nerve histology Mucocutaneous lymph node syndrome offer higher diagnostic yield and may be safer. If biopsies are Kawasaki syndrome unsupportive, visceral angiography may identify multiple micro- Infantile polyarteritis aneurysms suggesting PAN. Management Introduction and general description There should be screening for infection (see the section on pre- Kawasaki disease occurs typically in infants and children less than disposing factors) and consideration should be given to a trial of 5 years of age. It was first recognised in 1967 and thought to be discontinuing medication that predates disease. If associated with a benign, febrile illness associated with mucocutaneous inflamma- hepatitis B infection, antiviral therapies form the focus of treatment tion and lymphadenopathy, until the demonstration of associated in combination with immunosuppressive treatment. coronary arteritis in 1975. It is thought to be the commonest cause of acquired heart disease in children. Prompt diagnosis with treat- First line ment with aspirin and IVIg reduces heart complications [3,4]. Non-steroidal anti-inflammatory drugs and salicylates can be an effective treatment for symptoms of cutaneous arteritis. High-dose Epidemiology corticosteroids followed by tapering of the dosage over 3–6 months PART 9: VASCULAR Incidence and prevalence may occasionally be necessary for some patients. Also, without The annual incidence per 100 000 children aged under 5 years evidence from controlled trials, but based on a strong association DISORDERS was 8.4 in England in the period 1998–2003. In a series of with streptococcal infection, penicillin is often used for treatment epidemiological surveys, Nakamura et al. have established that and prophylaxis in children with cutaneous arteritis. Screening for the incidence was rising in Japan every year and had peaked at recent streptococcal infection with anti-DNAse B or other tests may 240/100 000 in 2010. guide this decision. Other treatments documented in anecdotal reports include the Age use of dipyridamole, sulfapyridine, pentoxifylline and dapsone. The disease almost always occurs in children. Low-dose weekly methotrexate (7.5–20 mg/week) has been successful in some patients with skin lesions unresponsive to cor- ticosteroids given topically, intralesionally and orally. Chronic Sex leg ulcers resistant to treatment with high-dose corticosteroids have There is a mild male predilection. been successfully treated with granulocyte–macrophage colony- stimulating factor (GM-CSF). Ethnicity The disease is much more common in Asia, particularly in Japan. Second line There is international consensus that PAN requires treatment with Associated diseases a combination of cyclophosphamide and corticosteroids which Associated diseases include coronary vessel aneurysms and achieves sustained remission but probably does not alter survival myocardial infarction.. For patients with hepatitis B-associated PAN, the recom- mendation is to start with high-dose corticosteroids for 2 weeks Pathophysiology followed by antiviral treatment and plasma exchange. This Kawasaki disease is thought to be due to an intense inflammatory treatment should be supervised at a specialist centre in conjunction response to an unidentified infectious agent in genetically suscepti- with a hepatologist. ble hosts.  Medium-vessel vasculitis 100.31 Pathology Differential diagnosis The angiitis of Kawasaki disease affects nearly all organs, with a Scarlet fever, systemic-onset juvenile idiopathic arthritis and ery- very high frequency of cardiac involvement. It is predominantly a thema multiforme can mimic Kawasaki disease, as can other vasculitis of medium-sized arteries but can involve any smaller and localised and systemic infections. The diagnosis should be sus- larger calibre blood vessels. Initially, there is medial oedema asso- pected in a child with prolonged fever. ciated with neutrophilic infiltration. The inflammatory processes lead to the breakdown of internal and external elastic laminae, Classification of severity resulting in aneurysms and thrombosis. The inflammatory pro- The Harada score has been used in some countries as an indica- cesses heal with scarring and resultant stenosis of the affected blood tion for IVIg therapy. Four of the following seven criteria are vessel. needed: (i) white blood count >12 000/mm3 ; (ii) platelet count 3; (iv) haematocrit 50 years) annual incidence per 100 000 popu- DISORDERS lation was 18.8 in Olmsted county, Minnesota, USA and 22.0 in the UK. Age This affects people over the age of 50 years. The age-specific inci- (a) dence per 100 000 population rises from 2.2 in the sixth decade to 51.9 in the ninth decade. Sex The disease is 2–3 times more common in women than men. Ethnicity Giant cell arteritis is considered a disease that particularly targets people who have northern European ancestry. Associated diseases Symptoms of polymyalgia rheumatica are commonly seen in GCA and it is hypothesised that the two conditions may have a similar (b) aetiology or lie on a disease spectrum. It is equally possible that Figure 100.23 Giant cell arteritis at (a) lower and (b) higher magnification showing the shoulder girdle involvement because of the subclavian artery involvement of the vessel wall by a granulomatous reaction. Dystyrophic calcification is and its branches may be mistaken for polymyalgia rheumatica. also seen. Courtesy of Dr Eduardo Calonje.  Large-vessel vasculitis 100.33 Genetics Complications and co-morbidities There is no known genetic association. Permanent visual loss can be a presenting feature. There is a risk of aortic aneurysms developing as a late complication. Clinical features History Disease course and prognosis Fever and weight loss may occur, and GCA is associated with Following a diagnosis of GCA there is a slight excess mortality shoulder girdle stiffness in about 50% of patients. Headache may over 2 years (standard mortality rate 1.52; 95% confidence interval be localised to the area of the affected artery that is temporal with 1.20–1.85), but not with longer follow-up. The excess mortality temporal arteritis and occipital with occipital arteritis. The headache was greater in women and in those aged ≤70 years. may start abruptly. Facial pain may occur on chewing due to clau- dication of the jaw muscles because of maxillary arteritis. Sudden, Investigations permanent visual loss is related to involvement of the branches International recommendations advocate an imaging modality like of the ophthalmic artery causing either anterior ischaemic optic ultrasonography as the first line of investigation. In those where this neuropathy or central retinal artery occlusion. Transient monocu- is negative, but there is a high suspicion, a temporal artery biopsy lar loss of vision (amaurosis fugax) may precede permanent loss. may be offered. The ESR or CRP is almost always elevated. A nor- Vertebrobasilar artery involvement may cause posterior cerebral mochromic, normocytic anaemia, thrombocytosis and raised alka- circulation or a cerebellar stroke. line phosphatase may all be present. Colour Doppler ultrasound of the temporal and axillary arteries (Video 100.1) in steroid-naïve patients commonly reveals intramural inflammatory change – the Presentation halo sign (Figure 100.24). Positron emission tomography with Patients may present with a new headache on the background of 18-fluorodeoxyglucose is of value in demonstrating aortitis. feeling generally unwell or with painless loss of vision. Very rarely, GCA may present with skin infarction. The temporal arteries may be tender, thickened and pulseless. A bruit may be heard over affected Management arteries (e.g. the axillary artery). Treatment should be started as soon as the diagnosis is suspected in order to avoid complications; if the diagnosis turns out to be incorrect, the corticosteroids can be withdrawn. Intravenous Clinical variants methylprednisolone 500–1000 mg daily for 3 days, followed by oral Isolated involvement of the extracranial arteries is well recognised prednisolone, could be considered in individuals with threatened with a phenotype that is not unlike Takayasu arteritis. visual loss in the absence of any contraindications. Differential diagnosis First line The temporal artery can be involved in other vasculitides, such Corticosteroids, for example prednisolone 40–60 mg daily, are used PART 9: VASCULAR as ANCA-associated vasculitides [7,8]. Cancer should always for GCA. The dose can usually be reduced slowly in small be looked for when the diagnosis of GCA cannot be established steps every month, providing that the CRP and ESR levels remain DISORDERS beyond doubt. controlled. Treatment is usually for about 2 years. Figure 100.24 Ultrasonographic image of the superficial temporal artery demonstrating (on the left) concentric hypoechoic thickening of the intima–media complex and (on the right) the compression sign, where it is possible to eradicate the lumen on pressure, but not the hypoechoic thickening. The image was taken with a GE Logiq™ e ultrasound machine with a 10–22 MHz linear probe. Courtesy of Georgina Ducker.  100.34 Chapter 100: Cutaneous Vasculitis Second line lumen may be narrowed secondary to the fibrosing stenotic lesions Methotrexate 20 mg/week subcutaneously can be used in addi- and/or by intraluminal thrombosis. In older patients there may tion to prednisolone for individuals with relapsing disease. be superimposed atherosclerosis, and calcification in the wall may Toclizumab 162 mg/week subcutaneously has been shown to be occur as a late feature. highly effective in reducing the need for prednisolone in individuals with GCA. The authors usually reserve this as a third line treatment Genetics or as second line in those where methotrexate is contraindicated or IL-12B on chromosome 5, MLX on chromosome 17, FCGR2A/ not tolerated. FCGR3A on chromosome 1 and HLA-B*52:01 are known associ- ations [7,8]. Two independent susceptibility loci have been identified in the HLA region (HLA-DQB1/HLA-DRB1 and HLA-B/MICA). Takayasu arteritis Clinical features History Definition and nomenclature Headache, malaise and fever are common presenting symptoms Takayasu arteritis is often granulomatous and predominantly affects in children. Cutaneous lesions are present in around one-third of the aorta and/or its major branches. The onset is usually in those patients. younger than 50 years. Presentation Synonyms and inclusions Hypertension, pyrexia and pulseless disease are common findings Takayasu disease in children. Skin lesions have been reported in up to a third of cases Takayasu syndrome and may comprise erythema nodosum, erythema induratum and Pulseless disease pyoderma gangrenosum, as well as ulcerated subacute nodular Aortic arch syndrome lesions, papulonecrotic eruptions, red papular lesions of the hands Aortitis syndrome and fingers, facial lupus-like rashes and panniculitis. Cuta- Occlusive thromboarteriopathy neous necrotising vasculitis has been described resembling nodular vasculitis/erythema induratum. The skin lesions do not appear to relate to the distribution of vascular involvement in any way. Introduction and general description Mikito Takayasu, a Japanese ophthalmologist, is credited with the eponym, but the earliest convincing clinical and pathological Complications and co-morbidities description in literature of this disease was provided by William Renal artery stenosis, increased arterial stiffness and increased sen- Savory’s account of a 22-year-old woman’s 13-month hospital stay sitivity of the carotid sinus reflex all contribute to the hypertension. and postmortem examination that demonstrated widespread large Involvement of the renal arteries can also cause renal dysfunction, PART 9: VASCULAR arterial inflammation. and abdominal pain, bleeding or perforation may result from ischaemia or infarction of a viscus. Involvement of the aortic arch DISORDERS Epidemiology and its branches can lead to the ‘aortic arch syndrome’ with arm Incidence and prevalence claudication, absent radial or brachial pulses (hence ‘pulseless The annual incidence of Takayasu arteritis in Europe and the USA is disease’) or subclavian artery bruits. Aortic regurgitation, coronary 0.5–2.5/million [3,4,5]. The incidence in Japan is believed to be much artery ischaemia with angina or myocardial infarction, pulmonary higher. hypertension, stroke, syncope and visual disturbances can occur. Age Disease course and prognosis The disease is seen in younger people, typically below the age of Most patients with Takayasu arteritis will need vascular surgery 50 years, and is found also in children. , although restenosis is common. The disease and its treat- ment both lead to an impairment in quality of life even for patients Sex believed to be in remission. The disease is commoner in females than males. Investigations Ethnicity Positron emission tomography using 18-fluorodeoxyglucose has It is found in all populations but is commoner in Asians. replaced conventional angiography as the gold standard for the diagnosis of Takayasu arteritis. However, due to the high radiation Pathophysiology dose, magnetic resonance angiography could be used for follow-up Pathology monitoring. The ESR and CRP are usually elevated but this may be The aorta and its branches are targeted and skip lesions can occur. modest. During the acute phase, a pan-arteritis is present. The inflammatory infiltrate may be predominantly around the vasa vasorum, and Management fibrosis gradually replaces the inflammatory infiltrates. The vessel There are no proven treatments in Takayasu arteritis.  Key references 100.35 First line 23 Ayoub N, Charuel J-L, Diemerte M-C et al. Antineutrophil cytoplasmic antibod- ies of IgA class in neutrophilic dermatoses with emphasis on erythema elevatum Prednisolone 1 mg/kg/day is the usual favoured first line treat- diutinum. Arch Dermatol 2004;140:931–6. ment. 24 Chow RKP, Benny WB, Coupe RL et al. Erythema elevatum diutinum associ- ated with IgA paraproteinaemia successfully controlled with intermittent plasma Second line exchange. Arch Dermatol 1996;132:1360–4. Tocilizumab 162 mg/week subcutaneously is added to the pred- 25 Kohler IK, Lorincz AL. Erythema elevatum diutinum treated with niacinamide nisolone in individuals with relapsing or refractory disease. and tetracycline. Arch Dermatol 1980;116:693–5. 26 Frieling GW, Williams NL, Sim SJ. Novel use of topical 5% dapsone gel in ery- thema elevatum diutinum: safer and effective. J Drugs Dermatol 2013;12:381–4. 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