Review

Cutaneous vasculitis and their differential diagnoses

N. Kluger1, C. Francès2

1Université Montpellier I, Service de ABSTRACT depth and distribution. Even though Dermatologie, Hôpital Saint-Eloi, CHU de Vasculitis is defined as an inflammatory a certain number of syndromes have Montpellier, Montpellier, Paris, France; cell infiltration and destruction of blood been described, a patient may present 2Université Pierre et Marie Curie, Paris 6, vessels identified upon histologic exam- with symptoms that overlap with an- Service de Dermatologie, Hôpital Tenon, Assistance Publique – Hôpitaux de Paris, ination. Cutaneous manifestations are other clinical diagnosis making a diag- Paris, France. frequent during the course of many sys- nosis “at first sight” impossible. Vas- Nicolas Kluger, MD temic vasculitis. Lesions are often not culitis has a histopathologic definition, Camille Francès, MD specific, the most frequent being palpa- therefore its confirmation comes only Please address correspondence to: ble purpura. They may be the first and from the microscopic examination of Camille Francès, only manifestation of the disease or be the lesion. Université Pierre et Marie Curie, a part of a systemic condition. Histolo- The diagnosis of CV is made by mi- Paris 6, Service de Dermatologie, gy is mandatory to confirm the diagno- croscopic examination of hematoxy- Hôpital Tenon, sis of vasculitis to avoid a delayed and lin-eosin stained biopsies (2). A list of Assistance Publique - Hôpitaux de Paris, inappropriate diagnosis that could lead criterias allows a trained pathologist 4, rue de la Chine, to improper management. Cutaneous Paris, France. to diagnose and distinguish an active E-mail: [email protected] histology gave some data that may help vasculitis, from chronic and healed le- Received on May 2, 2009; accepted in to classify the vasculitis without deter- sions of vasculitis and changes that are revised form on June 24, 2009. mining precisely its type. A histological adjacent to vasculitis and may help to Clin Exp Rheumatol 2009: 27 (Suppl. 52): examination of all other skin lesions is define a subtype or the etiology of the S124-S138. necessary. The result of the biopsy has CV (2). Inflammatory infiltrates within © Copyright CLINICAL AND to be correlated to DIF data, medical and around the vessel walls associated EXPERIMENTAL RHEUMATOLOGY 2009. history, physical examination, labora- by intramural and/or intraluminal fibrin tory and radiological findings leading deposition (fibrinoid necrosis) con- Key words: Vasculitis, skin, to the correct diagnosis and effective firm the diagnosis of vasculitis. Some pathology. treatment. changes are suggestive of active vascu- In this review, we discuss the diagnosis litis such as red blood cell extravasation, of cutaneous vasculitis (CV) and the pit- perivascular nuclear dust (leukocyto- falls related to the cutaneous pathology. clasia), eccrine gland necrosis, ulcera- We also describe the essential features of tion, necrosis/infarction. In the absence the major categories of skin vasculitis. of fibrinoid necrosis, the diagnosis of CV becomes more difficult. Lamination Introduction of the adventia, media and/or intima; Vasculitis is defined as an inflamma- perivascular nuclear dust (leukocyto- tory cell infiltration and destruction of clasia) without fibrinoid necrosis; loss blood vessels identified upon histologic of the elastic lamina with acellular scar examination. Cutaneous manifestations tissue; or, subendothelial intramuscular may be the first and only manifestation and/or advential inflammatory cells in of the disease or be a part of a systemic large vessels are all other argues for condition (1). vessel wall damages (2). In this review, we discuss the diagno- A direct immunofluorescence examina- sis of cutaneous vasculitis (CV) and tion (DIF) is also mandatory in case of the pitfalls related to the cutaneous pa- CV. It does not confirm the diagnosis thology. We also describe the essential of CV but allows to orienter for one or features of the major categories of skin another diagnosis. Absence of immune vasculitis. complex is in favor for pauci-immune vasculitis: Wegener’s granulomatosis Diagnosis of cutaneous vasculitis (WG), Churg-Strauss syndrome (CSS), Physical cutaneous signs of vasculitis Microscopic Polyangiitis (MPA). Im- are wide and non-specific. Vasculitis munoglobulin (Ig) G, IgM, IgA and/or Competing interests: none declared. affects the skin with varying intensity, C3 in or around the vessels may be

S-124 Cutaneous vasculitis / N. Kluger & C. Francès REVIEW found in immune mediated vasculitis Table I. Differential diagnoses of vasculitis: lesion must include the epidermis, der- like cryglobulinemia. In all case of CV, cutaneous pseudovasculitis, modified from mis and hypodermis to precise the size immune depositions of Ig and comple- (4). of the affected vessels. Some CV affect ment may be found especially C3 and HEMORRHAGE typically the upper part of the dermis IgM. However, the older the biopsied Thrombopenia like HSP. Therefore, a punch skin bi- lesion is, the less immunoglobulins are Congenital and acquired thrombopathy opsy will permit to show the lesions. In found. After 72h, only C3 is detected. Scurvy the case of polyarteritis nodosa, deep Solar/senile purpura Therefore, a negative DIF does not rule Pigmented purpuric dermatoses muscular vessels of the dermis-hypo- out the diagnosis of CV. Predominance Arthropod dermis and the hypodermis are affected of IgA is highly in favor for Henoch- Viral and drug reactions which imply a deep incisional biopsy. Ehler Danlos syndrome Schönlein purpura (HSP) without be- Gardner-Diamond syndrome Similarly, a livedo should be biopsied ing constant or specifi c (3). IgM depo- on its infliltrated or necrotic areas. sitions are observed, specially in case EMBOLISM In some specific cases, an incidental vas- of circulating rheumatoid factor or cry- Cardiac myxoma culitis may be found on the skin biopsy. Fibrinocruroric emboli oglobulinemia. IgA deposits are absent Cholesterol Emboli This pathologic statement should not in case of cryoglobulinemia. Of note, Other emboli (gazous, fat, neoplastic…) mislead to diagnose a vasculitis. Thus, positive DIF without pathological as- neutrophilic small vessel vasculitis may THROMBOSIS sessment of CV is not relevant. Purpura Fulminans be observed if a biopsy is performed on After confirmation of the diagnosis of Intravascular coagulation an ulcer (2), while the surrounding ves- CV itself, vasculitis may be defined Vitamin K antagonists and heparin induced skin sels are normal. Besides, vessel damage more accurately by vessel size involve- necrosis induced by neutrophils is observed in Antiphospholipid Syndrome ment (small; small and medium vessel Cryoglobulinemia type I lesions related to neutrophilic derma- and medium to large vessel), the extent Thrombocytaemia toses such Sweet’s syndrome (5). of the lesions (superficial perivascular Livedoid vasculopathy/atrophie blanche to dermal and/or subcutaneous) and the Other coagulation disorder (protein C, protein S Clinical pathologic correlation deficiencies…) predominant inflammatory cell infiltra- Calcyphylaxis The cutaneous lesions correlate some- tion. The finding of small-vessel vascu- times with the size of the affected ves- litis with predominance of neutrophilic VASOSPAMS sels. Palpable purpura, infiltrated ery- Drug induced infiltrate and positive DIF is indicative Cocaine thema, urticaria, vesicules, blisters are of cutaneous leukocytoclasic vasculitis, mainly related to small vessel vasculitis HSP, urticarial vasculitis or erythema VASCULAR TRAUMA of the dermis, while subcutaneous nod- elevatum diutinum. More rarely, other ules, ulceration, gangrene are related cells may predominate such as eosino- cin deposition is associated with lupus frequently to medium sized vessel vas- phils or lymphocytes. Presence of both erythematosus and dermatomyositis. culitis located at the dermo-hypoder- small and medium sized vasculitis fa- Intraepidermal or dermal pustules with mal junction or in the subcutaneous fat. vors ANCA associated/pauci immune neutrophils small vessel vasculitis is re- Necrosis and livedo occur when either vasculitis (with negative DIF): CSS, lated to an infectious related vasculitis small and/or larger vessels are involved. MPA, WG or cryoglobulinemia, con- (2). Skin biopsy allows to exclude pseu- nective tissue disease (lupus, rheuma- dovasculitic disorder, a wide group of Clinical manifestation toide arthritis) or hypocomplemental heteregenous diseases that may mimic Cutaneous vasculitis displays a wide vasculitis if DIF is positive. Polyarteri- cutaneous vasculitis (Table I) (4). range of elementary lesions that may tis nodosa is characterized by a neutro- be associated and lead to a pleomor- philic infiltration associated with a me- Pifalls phic appearance of the eruption. CV dium vessel arteries vasculitis. In order to enable the diagnosis of vas- may manifest variously as urticaria, Some extravascular histologic pattern culitis, the choice of the “best” lesion is purpura, infiltrated erythema, hemor- found in the surrounding tissue may be crucial. A lesion of cutaneous vasculi- rhagic vesicles, ulcers, nodules, livedo, helpful to indicate a specific disease. tis should be analyzed withing the first infarcts, digital gangrene (1). Lesions Thus, palisading granulomatous der- 48h after its appearance, otherwise typ- affect primarly the lower limbs. Up- matitis (“Winkelmann granuloma”) is ical signs of vasculitis may be absent. A per extremity, trunk, head and neck in favour for WG, CSS, rheumatoid ar- fresh purpuric lesion displays within the involvement are not usual and may be thritis or systemic lupus erythematosus 24 first hour fibrin deposits in the ves- considered as a sign of severity and/or (2). Presence of eosinophils and flame sel wall, neutrophilic infiltration, sur- of a systemic vasculitis figures associated with such granulo- rounding hemorrhage and intranuclear Palpable purpura is unquestionably the mas are found in CSS while neutrophils debris. After 24 hours, lymphocytes and most frequent manifestation. It is local- and basophilic debris in WG and rheu- macrophages replace neutrophils. After ized on the lower limbs, dependent sites matoid vasculitis. Vacuolar interface 48 hours, lymphocytes predominate. or underlying tight-fitting clothes (Figs. dermatitis with sometimes dermal mu- Moreover, skin biopsy of an infiltrated 1 and 2). Elementary lesion ranges

S-125 REVIEW Cutaneous vasculitis / N. Kluger & C. Francès from tiny red macules and pinhead to Fig. 1. Palpable coin-sized petechia, but also sometimes purpura of the lower limbs during leuko- to more extensive plaques and ecchy- cytoclasic vasculitis. moses. Colour range may change from red to purple to brownish yellow as ex- travasated blood is progressively bro- ken. Purpura may disclose a necrotic evolution leading to vesicles, blisters, erosions, ulcerations and ulcer. There is often an association of different lesions in a same patient simultaneously: ery- thematous to purpuric macules, papules and necrotic lesions (Fig. 3). In the case of mixed cryoglobulinemia associated with hepatitis C, purpura may be ab- sent or masked by a residual chronic pigmented brown ocre post-inflamma- tory purpura (“dermite ocre”), sign of Fig. 2. Purpura of former flare-up of the disease without the lower limbs dis- any venous insufficiency. closing cutaneous Papules may present variously. Purpu- vasculitis. Notice the ric papules may be noted but also atyp- respect of the dorsum of the feet related to ical urticaria with distinctive feature the shoe pressure of from common urticaria: duration of the the patient. lesions longer than 24 hours, presence of purpura, postinflammatory pigmen- tation, symptoms of burning rather than itching (6). Papules may display an annular erythema multiformis like erution without any predominance on the lower limbs. Dermal or hypodermal nodules (so- called “subcutaneous nodules”) are always palpable, typically inflamma- tory, tender, red and small-sized. They should be looked after on the vessel Fig. 3. Association territories of the lower limbs, where of different lesions they can be surrounded by livedo re- in a same patient simultaneously: ticularis, but are also observed on other purpuric macules, sites such as the dorsal aspect of upper papules and necrotic limbs or rarely the trunk. Nodules may lesions (known as also gather in groups along the course “trisymptôme de Gougerot”). of superficial arteries and may evolve into necrosis and ulceration. Livedo reticularis is a reddish-blue mottling of the skin in a “fishnet” re- ticular pattern frequently localized on the lower limbs. It may also affect the lower trunk and the upper limbs. Livedo reticularis of CV displays specific find- ings that distinguish it from physiologi- cal cutis marmorata: it is typically ir- regular with broken meshes with some infiltrated areas on careful examina- temperature varies. It may be isolated previous cutaneous lesions, resulting tion. When associated with CV, livedo or associated with other symptoms, es- from the occlusion of dermal vessels. persists indefinitely with some fluctua- pecially nodules and necrosis. Its extension and depth are highly vari- tions in intensity and extensiveness as Necrotic lesions are the final event of able depending on extension and depth

S-126 Cutaneous vasculitis / N. Kluger & C. Francès REVIEW of involved vessels. Localized necrotic times linear) of destroyed tissue are scar is left. The histological features lesions lead to vesicles, then to pus- interspersed with poly-morpho-nuclear consist of a large, sterile abscess in tules due to secondary infection. When leukocytes and leukocytoclastic debris. which thrombosis of small- and me- necrosis is extensive, painful purpura This necrotic area is surrounded by a dium-sized vessels, haemorrhage and is followed by a black necrotic plaque granulomatous mass of histiocytes, necrosis are present. Polymorph neu- with active purpuric border and bul- often in a palisade array. Decrease or trophils are numerous but epithelioid, lous lesions. After removal of necrotic absence of elastic fibers is observed in giant and moonuclear cells are also tissue, ulcerations of various sizes take foci of degenerated collagen. No rela- seen especially in more chronic forms. place. Ulceration/ulcer is the final step tionship is noted between the clinical Leukocytoclastic or lymphocytic vas- of necrosis. appearance of lesions, the histological culitis may be observed, particularly in Non-follicular pustules (pustular vas- features and the associated systemic the active border of the lesion. These culitis) with a purpuric rim may be the disease. However, tissue eosinophilia changes are not pathognomonic and manifestation of small vessel vasculi- is more frequently reported in patients the diagnosis is essentially based on the tis, especially during Behçet’s disease with Churg-Strauss syndrome (2). clinical aspects. or inflammatory diseases of the bowel (Fig. 4) (2). Other frequently observed Panniculitis Granuloma pustules may result from secondary in- Cutaneous eruption consists of recur- Granulomatous lesions with neither fection of necrotic lesions. rent crops of erythematous, oedema- vasculitis nor central necrosis may be Recently, a new entity was described tous and tender subcutaneous nodules. observed in systemic vasculitis, espe- as “macular arteritis” characterized by The nodule size is around 1 or 2 cm but cially WG. Clinical aspect is highly asymptomatic hyperpigmented macules could be much larger. In lobular pan- variable ranging from papules, nod- with a chronic and indolent course. Pa- niculitis, lesions are usually of sym- ules, subcutaneous infiltration, pseu- thology discloses lymphocytic arteritis metrical distribution on the thighs and do-tumour to chronic ulcers. Any site at various stages of evolution ranging the lower legs. They usually regress of the body may be involved: breasts, from fibrinoid necrosis to endarteritis spontaneously with hypo-pigmented scrotum, face, gums, etc. Other granu- obliterans (7-9). and atrophic scar due to fat necrosis. lomatous diseases have to be consid- Occasionally, they may suppurate. In ered in the differential diagnosis like Other skin manifestations septal panniculitis, nodular lesions are sarcoidosis, metastatic Crohn’s disease, associated with systemic vascultis primarily located over the extensor as- mycobacterium infections and foreign Extravascular necrotizing granuloma pects of the lower limbs. They regress bodies granulomas. Initially described by Churg and spontaneously without atrophic scar. Strauss in 1951 as a manifestation of A lobular infiltrate of lymphocytes, Superficial thrombophlebitis allergic angiitis (Churg-Strauss syn- plasma cells and histiocytes with fat Thrombophlebitis of a superficial vein drome), the extravascular granuloma necrosis is common in lobular pannicu- is sometimes clinically evident due to has been further reported in a large va- litis while in septal panniculitis the in- the presence of painful induration of riety of other systemic vasculitis and filtrate surrounds vessels of the septa. the vein with redness and increased connective tissue diseases (Winkel- heat. In other cases, the clinical aspect man). Papular or nodular lesions vary Pyoderma gangrenosum is a non-specific red nodule and diag- in size, from 2 mm to 2 cm or more, Pyoderma gangrenosum lesions usually nosis is only confirmed by histologi- and colour, from red to purple. Central begin as deep-seated, painful nodules cal examination of a deep skin biopsy. crusting and/or ulceration are frequent. or as superficial hemorrhagic pustules, Such lesions are essentially observed Rarely, other aspects are reported like either de novo or after minimal trauma. in thromboangiitis obliterans, Behçet’s vesicles, pustules, arciform plaques or They further break down and ulcerate disease, Crohn’s disease and relapsing firm mass. Sites of involvement are the discharging a purulent and haemor- polychondritis. extensor aspects of the elbows, the fin- rhagic exudate. Ulcers reach 10 cm or gers where they are usually multiple, more, spread, partially regress or re- Gangrene often symmetrical, and less frequently main indolent for a long period. The ir- Gangrene resulting from arterial occlu- the buttocks, the scalp, the knees, the regular edges are raised, red or purplish, sion may be observed in all vasculitis hands, the dorsum of feet, the neck, the undermined, soggy and often perforat- involving medium or large-sized ar- forehead, the ears. ed. The most commonly affected sites teries. It is initially characterized by a Histological features include endothe- are the lower extremities, the buttocks sharply demarcated blue black colour lial necrosis and oedema, fibrinoid and the abdomen but other areas of the of the extremities. The main differen- necrosis of the collagen and granulo- body may be involved. Lesions are usu- tial diagnoses are thrombosis without mas containing eosinophils, histiocytes ally solitary, but may arise in clusters inflammation of the vessel walls and and lymphocytes. The center of the which then coalesce to form polycyclic emboli. Angiography visualizes oc- granuloma consists of basophilic fib- irregular ulcerations. When healing oc- clusion or stenosis of arteries and does rillar necrosis in which bands (some- curs, an atrophic and often cribriform not help distinguishing these different

S-127 REVIEW Cutaneous vasculitis / N. Kluger & C. Francès pathologic processes. The presence of Fig. 4. Pseudo- other skin lesions with histologically folliculitis related to pustular vascu- proven vasculitis is in favour of vas- litis. culitis although thrombosis, vasculitis and emboli may be concomitant as in atheromatous emboli.

Raynaud’s phenomenon Bilateral Raynaud’s phenomenon may occur in 5 to 30% of randomly ques- tioned population. It is classically as- sociated with all types of vasculitis. However, its prevalence is unknown in many vasculitis and its diagnostic value is very low. In contrast, unilateral Ray- naud’s phenomenon suggests an ob- Table II. Approach to the diagnosis of isolated, biopsy-proven, cutaneous vasculitis. structive arterial disease and is mainly observed in Takayasu’s arteritis. ESTABLISH THE SEVERITY : SYSTEMIC INVOLVEMENT ? Complete physical examination • General manifestations : fever, night sweats, weight loss Classification • Joint (arthralgias), muscles (myalgias), lung (hemoptysis, cough, shortness of breath, wheezing), Classification of vasculitis is a real heart (chest pain, murmur) gastrointestinal tract (abdominal pain, gastro-intestinal bleeding), ear, brain-teaser. Existence of overlapping nose, throat (sinusitis, rhinitis) and ocular symtoms (scleritis, sicca syndrome), peripheral (par- clinical features, lack of knowdge re- esthesia, numbness) and central (cephalagia, seizures) nervous system, urologic and genital symp- toms (hematuria, testicular pain) garding precise ethiopathogenic proc- ess of each vasculitis, lack of “pathog- Laboratory studies nomonic” clinical or laboratory or radi- • Kidney function every 3 months : urinalysis, proteinuria, blood urea/creatinine ologic findings make almost impossible • Electrocardiography • Chest x-ray to have a perfect classification. Several classifications have been proposed, IDENTIFY A POTENTIAL CAUSE each of them presenting advantages and Recently introduced drug ? weaknesses. The most commonly used Laboratory studies recommended in the absence of clinical relevant symptoms • Blood cell count, C-reactive protein, erythrocyte sedimentation rate criteria for the classification of vascu- • Serum electrophoresis litis are those of the American College • Liver tests: transaminases, hepatitis B and C virus serologies of Rheumatology (ACR) criteria es- • Cryoglobulins • Antinuclear antibodies, anti-dsDNA, anti-extractable nuclear antigens (Ro/Ssa, La/SSb, RNP, tablished in 1990 (10) and the Chapel Sm…), rheumatoid factors Hill Consensus Conference (CHCC) in • Antineutrophils cytoplasmic antibodies (ANCA) 1992 (11). A “classical” exemple taken • Complement levels (CH50, C3, C4) by authors to show the weakness of the • Anti-streptolysin O titers ACR criteria and the CHCC is the PAN Complementary exams according to medical history and clinical findings / MPA distinction. Indeed, the ACR • HIV test classification recognizes only polyar- • Blood culture teritis nodosa as a medium-sized vessel • Lumbar puncture • Echocardiography vasculitis that could affect also small • Viral serologies (parvovirus B19, Epstein Barr virus, CMV…) proposed in case of pregnancy or in vessel too. Conversely, the CHCC defi- immunocompromised hosts nitions – based on pathological con- • Sinus CT scan and teeth examination siderations – exclude small vessel in- volvement in PAN. Consequently, any Approach to the diagnosis prompt to initiate immunosuppressive patient with PAN and purpura will be of cutaneous vasculitis treatment and 2) to identify a potential considered as having MPA or another The first step being completed - having curable cause (Table II). The precise small vessel vasculitis (6). Classifica- proved by a skin biopsy the presence of diagnosis is made by the combination tion criteria should be restricted to their cutaneous vasculitis and analyzed his of clinical history, clinical, laboratory primary use, i.e. stratify uniform popu- precise subtype (cell infiltration, size and radiologic findings. Therefore, pa- lations who carry a diagnosis. In clini- of the involved vessel, DIF) - the phy- tients precise past medical data, history cal practice, a final diagnosis should sician collect all the relevant data that of the disease including newly intro- rely on the interpretation of clinical, will help him 1) to establish the severity duced drugs or episode evocative for laboratory, radiologic and pathological of the CV by the absence or the pres- acute infection, are mandatory. Indeed, findings. ence of systemic involvement that will any cutaneous vasculitis occuring in a

S-128 Cutaneous vasculitis / N. Kluger & C. Francès REVIEW patient with a known systemic vasculi- venules) without any systemic involve- ESR may be elevated and antinuclear tis should prompt to look after intercur- ment. Diagnosis of CLA is therefore a antibodies may be positive (6, 19). rent triggering factor like infection or a diagnosis of exclusion. Patients usu- Histology of UV usually shows a newly introduced drug before diagnosis ally present with a crop of lesions (in- sparse neutrophilic infiltrate with focal of flare-up the disease. Full physical ex- filtrated purpura, papules, vesicules, small vessel neutrophilic vasculitis or amination will include search for: fever, urticaria) affecting the declive areas, perivascular nuclear debris, fibrin de- weight loss, night sweat, arthralgias, tight-fitting clothes and trauma sites. posits, with or without red blood cells myalgias, hemoptysis, cough, shortness Arthralgias may be present and should in the superficial dermis. HUV display of breath, wheezing, murmur, chest not rule out the diagnosis. Biopsy will sparse interstitial and perivascular neu- pain, sicca syndrome, photosensitivity, show a neutrophilic infiltrate affecting trophilic infiltrate while eosinophils eye or ear symptoms, sinusitis, numb- small vessels with fibrinoid necrosis. are more common during NUV. C3 de- ness, paresthesia, abdominal pain, gas- Lesions resolve spontaneously within posits with or without immunoglobulin tro-intestinal bleeding, hematuria and weeks or months and episode remain IgM are seen on DIF. DIF and a lupus testicular pain (1, 6). A certain number isolated. In most cases, no cause is de- band test (basement membrane depos- of complementary examinations are tected. Approximately 10% of the pa- its of C3 and/or immunoglobulins) are compulsory like urinalysis, proteinu- tient will experience chronic evolution more frequently seen during HUV (2). ria, blood urea/creatinine, chest x-ray (6). However, systemic disease (HSP, and electrocardiography. Urinalysis WG, MPA) may disclose initially CLA Henoch-Schönlein purpura and proteinuria should be performed presentation before renal vasculitis oc- Henoch-Schönlein purpura (HSP, also from a weekly to a monthly basis dur- curs (13). This confirms the outmost known as anaphylactoid purpura, aller- ing at least 3 months. In the absence of importance of proteinuria and urinalysis gic purpura and haemorrhagic capillary clinical relevant symptoms that allow several months after the disease. toxicosis) is a small vessel vasculitis to suspect a precise diagnosis, authors Of note, a specific condition was re- associated with IgA-immune deposits recommend the following laboratory cently described under various names representing approximately 10% of all studies: blood cell count, C-reactive (Golfer’s vasculitis and exercice in- cases of cutaneous vasculitis (2). HSP protein, ESR, liver tests, cryoglobulins, duced vasculitis) in healthy individu- mainly affects young boys aged from antinuclear antibodies, anti-dsDNA, als, mostly women, who developped 4 to 8 years old with a seasonal win- anti-extractable nuclear antigens (Ro/ cutaneous vasculitis after prolonged ter predominance following an acute Ssa, La/SSb, RNP, Sm), rheumatoid exercise during hot weather without upper respiratory tract infection in factors, antineutrophils cytoplasmic any systemic involvement (14-18). half of the cases. Initially described as antibodies (ANCA), complement lev- the combination of palpable purpura, els (CH50, C3, C4), anti-streptolysin Urticarial vasculitis (UV) arthritis, gastro-intestinal involvement O titers. According to clinical findings, UV is a rare, chronic, and unpredictible and glomerulonephritis, HSP was then HIV test, blood culture, echocardiog- condition, that affect 5 to 10% of the defined by CHCC according to IgA raphy and/or lumbar puncture will be patients with chronic urticaria. In most vascular deposits (11). However, the performed. For some authors, viral se- cases, UV remains idiopathic. Nonethe- latter are neither sensitive nor specific rologies like parvovirus B19, Epstein less, it may be associated with connec- of HSP. They may be found in other Barr virus, CMV should be systematic tive tissue diseases (mainly Sjögren’s various conditions such as cryoglob- but we do not recommend this attitude syndrome, systemic lupus erythemato- ulinemia, livedoid vasculitis and other as no therapy will be proposed except sus), mixed cryoglobulinemia, hepati- vasculitis. The skin is always affected. in case of pregnancy or in immuno- tis C infection, drugs, viral infection, Its presentation and histology are un- compromised hosts. Sinus CT scan and monoclonal gammapathy (Schnitzler’s distinguishable from CLA (Fig. 6) (2). teeth examination can be suggested in syndrome) and malignancies (Fig. 5). Lesions occur in successive waves then the absence of any found cause. Physi- Distinguishing the hypocomplemen- resolve spontaneously. cans should not loose from sight and temic form of UV (HUV), noted in 20- The biopsy of an early lesion shows a warn the patients that in 50% of all cas- 30% of the cases, from normocomple- small vessel neutrophilic vasculitis of es of cutaneous vasculitis, no specific mentemic UV (NUV) is useful. NUV the superficial and mid dermis. In the cause is found (12). (70-80% of the UV) is idiopathic, re- later stages, mononuclear cells may stricted to the skin and self resolving. predominate. In fresh lesions, DIF may Small vassel vasculitis HUV is more often associated with show IgA and C3 deposits. Join involve- Cutaneous leukocytoclasic connective tissue diseases. HUV syn- ment with arthritis, abdominal pain, angiitis (CLA) drome is characterized by lupus - like gastro-intestinal bleeding and mesangi- CLA, as defined by CCHC in 1992 in manifestations (arthralgias, arthritis, al glomerulonephritis are other features replacement of the former hypersensi- uveitis, scleritis, glomerulonephritis that increase the likelihood of such di- tivity vasculitis, is characterized by an and obstructive lung disease) and cir- agnosis. A long-term follow-up for chil- isolated cutaneous vasculitis affecting culating anti-C1q antibodies. Serum dren and adult is mandatory as they may the small vessels (mainly post-capillary levels of C1q, C3 and C4 are variable. develop later on a chronic renal failure

S-129 REVIEW Cutaneous vasculitis / N. Kluger & C. Francès especially in case of preexisting neph- Fig. 5. Urticarial rotic syndrome, hypertension, renal fail- vasculitis. ure in children, fever, purpura affecting the trunk and elevated ESR (20). Infantile acute haemorrhagic oedema is characterized by the following features: febrile onset in children younger than 2 years of age; oedema of the scalp, hands, feet and peri-orbital tissue pre- ceding purpura; lack of renal and gas- trointestinal involvement. Recovery is expected within 3 weeks. Oedema probably results from an increased cap- illary permeability due to an underlying vasculitis. This entity is considered by some as a distinct clinical entity, espe- cially for its better prognosis, and be- lieved by others to be a variant of HSP.

Essential cryoglobulinemic vasculitis (21-26) Cryoglobulins are immunogloblulins that persist in the serum, precipitate with cold temperature, and resolubi- lize when rewarmed.Only mixed type II and III cryoglobulinemia are respon- sible for vasculitis. Type I cryoglob- ulinemia is responsible for thrombosis rather than vasculitis. Skin manifestations occur in 60% to 100% of patients with symptomatic cryoglobulinemia. They are a frequent presenting complaint and often come along with arthralgia and weakness. The disease has a tendency to wax and Fig. 6. Purpu- wane. Women outnumber men with a ric lesions of the sex ratio W/M of 1.3/1. The average buttocks during age of onset is 50 years. The interval Henoch-Schölein between the first skin manifestation purpura. and diagnosis of cryoglobulinemia varies from 0 to 10 years. Palpable purpura of the lower extremities is the main manifestation, present from 30 to 100% of the patients. The lesions may extend progressively to the abdomen. Purpura often displays seasonal trig- gering (winter time, cold exposure) or related to prolonged standing, physical exertion, or trauma. Purpuric lesions can first start by a preceding burning sensation and leave a brown residual pigmentation (“dermite ocre”) within and can retrospectively evoke the diag- enon and cold induced acrocyanosis 10 days. Lesions are more commonly nosis. Infarction, haemorrhagic crusts are relatively more common in type observed on the head and mucosal ar- and ulcers are present in 10 to 25% of I cryoglobulinemia. Mixed cryglob- eas (ears, nose, mouth) in type I cry- patients. Widespread necrotic areas, ulinemia is more often responsible for oglobulinemia. Post-inflammatory pig- head and mucosal involvement, live- urticaria or purpura (25). On histology, mentation is noted in 40% of patients doid vasculitis, Raynaud’s phenom- purpura corresponds to a leukocyto-

S-130 Cutaneous vasculitis / N. Kluger & C. Francès REVIEW clastic vasculitis of the small dermal In septic vasculitis, dermatologic le- vasculitis, especially with PAN (37). vessels. DIF studies have shown IgM, sions occur abruptly in a context of Concurrent malignancy during giant IgG, and C3 deposits in some patients septicaemia secondary to bacterial in- cell arteritis (GCA) is not a rare as ob- with acute vasculitis. In type I cry- fection such as Neisseria meningitidis, served in up to 7.4% of the cases, with oglobulinemia, thrombosis is the main Neisseria gonorrheae, Haemophilus solid malignancies and hematological histological feature, sometimes associ- and Candida. They are characterized disorders, especially myelodysplastic ated with vasculitis. Globally, the clini- by pustular purpura, vesicles, blisters syndromes. Clinical features are not cal and histological aspects of purpura and erythematous macules with small specific (38). are not different wether HCV infection pustules of the extremities. Histology is present or not. displays occlusive luminal thrombi of Connective tissue disease platelets, blood cells, fibrins and neu- associated vasculitis Drug-induced vasculitis (27-30) trophils, less nuclear debris, deep der- Vasculitis is an uncommon but impor- Approximately 15 to 20% of the cu- mal and arteriolar involvement, hemor- tant manifestation that may complicate taneous vasculitis may be induced rahge, subepidermal and intraepidermal CTD, mainly systemic lupus erythema- by drug intake (2). Time schedule is pustules with necrosis. Micro-organisms tosus (SLE), rheumatoid arthritis and highly variable after drug intake, rang- are rarely seen with Gram staining. Sjögren’s syndrome (SS), but also der- ing from hours to years. Drugs from matomyositis, scleroderma and poly- almost every class may be implicated Malignancy-induced vasculitis (33-38) chondritis. in sporadic cases of vasculitis (27), but Cutaneous vasculitis is rarely associ- some pharmaceutical classes are more ated with malignancies (less than 5% Systemic lupus erythematosus frequent: propylthiouracil, hydralazine, of the cases). Four percent of all the cutaneous vas- colony-stimulating factors, allopurinol, Blanco et al. found only 4 patients with culitis are related to systemic lupus ery- cefaclor, minocycline, D-penicillamine, an underlying malignancy in a study thematosus (SLE). phenytoin, isotretinoin, and methotrex- including 303 unselected patients with Cutaneous vasculitis is the most fre- ate (27). Moreover, chemicals, food, cutaneous vasculitis. Moreover, these quent manifestation with purpura, urti- vitamins, nutritionnal supplements may patients displayed clinical and labora- carial vasculitis and livedo reticularis. also cause vasculitis. There is no spe- tory data suggestive of the associated According to a recent series (39), pa- cific clinical or laboratory pattern. Of disorder (33). In most of the cases, tients with SLE related vasculitis have note, a specific subset of cases of CV vasculitis is often the consequences a higher prevalence of livedo reticula- associated with ANCA was separated of circulating monoclonal antibodies ris. A caracteristic feature of cutaneous (28) and recently used anti-tumor necro- during lymphoproliferatives disorders vasculitis during SLE is the palmar and sis factor alpha may also be reponsible i.e. cryoglobulins. Thus, recently, Fain digital pulp infarcts as small tender for cutaneous vasculitis (29). Vasculitis et al. reviewed 60 cases of vasculitis purpuric macules or depressed punc- usually occurs after drug dosage in- associated with malignancy with cuta- tated scares of the palmar surfaces and creases and after rechallenge with the neous involvement in 78% of the cases. fingertips. Histology will show a small culprit drug. Drug-induced vasculitis Cutaneous leukocytoclastic was found vessel neutrophilic vasculitis. Vascular may be restricted to the skin or at worse in 45% of the cases, polyarteritis nodo- deposits of IgG and/or IgM deposits be life threatning in case of multiple sa in 36.7%, WG in 6.7%, MPA in 5%, with complement are seen often with organ systems involvement. Death rate and HSP in 5%. Malignancies were he- basement membrane depositis on DIF of drug induced vasculitis is estimated mopathies (63%) with myelodysplas- in half of the patients (2, 6). to 10% (30). Drug-induced vasculitis is tic syndrome in 32% and lymphoma considered as an exclusion diagnosis. 30%. Solid tumors represented 37% of Rheumatoid vasculitis (RV) (40, 41) However, we suggest that a newly in- the cases. Synchronous diagnosis oc- RV is a rare inflammatory condition of troduced drug should be always looked curred in almost 40% of the cases (34). the small- and medium-sized vessels after any flare up of CV, even if the According to a small series of 15 pa- that affects a subset of approximately 1 patient has already an identified cause tients with vasculitis and solid tumor, to 5% of the patients with established (primary vasculitis, CTD). the commonest malignancies were car- rheumatoid arthritis (RA) (40). It is cinomas of urinary organs, lung, and defined as an exclusion diagnosis after Infection-induced vasculitis (31, 32) gastrointestinal tract (35). having ruled out all other causes of vas- All microorganisms (virus, bacteria, Some rare associations deserve to be culitis during RA (infection, drug hyper- fungi, parasites) may be responsible known. Vasculitis with leukaemic cell sensitivity, malignancy, or other vascu- for cutnaeous vasculitis, especially in infiltration (‘leukaemia vasculitis’) oc- litides: WG, cryoglobulinemia, PAN). case of a subacute or chronic infection. curs while neoplastic cells mediate ves- The skin is the most commonly affected Twenty percent of cutaneous vasculitis sel injury. Patients with such lesions do in 90% of the cases with focal digital are related to an infection. Hepatitis have an aggressive clinical course and a infarcts with nailfold involvement ap- B and C are known cause of PAN and poor prognosis (36). Hairy-cell leukae- pearing as dark perinungual macules cryoglobulinemia. mia may be associated with cutaneous (Bywaters lesions), maculopapular ery-

S-131 REVIEW Cutaneous vasculitis / N. Kluger & C. Francès thema, palpable purpura, haemorrhagic munologic features of SS. Severity of On histology, there is an amicrobial neu- blisters, ulcers, and gangrene. Petechiae the vasculitis is directly correlated with trophilic infiltration with a lymphocytic and purpura occur mostly in the lower circulating cryoglobulins. CV during infiltrate and an inconstant leukocyto- extremities and have no specific charac- primary Sjögren’s syndrome may be clastic vasculitis. Non-bacterial follicu- teristics. Ulcers are usually deep, pain- associated with lymphoma. litis can be histologically undistinguish- ful, with a punched-out aspect and tend able from a bacterial folliculitis. to be found in the lower extremities in Behçet’s disease (40-42) Cutaneous aphthae are less frequent, unusual locations, such as the dorsum In 1937, a Turkish dermatologist, Hul- mainly observed in folds. of the foot or the tibia. Moreover, sub- usi Behçet, described an entity associat- Nodules are present in 30 to 50% of cutaneous nodules, livedo reticularis, ing oral aphthosis, genital aphthosis and cases, sometimes resembling erythema atrophie blanche, pyoderma gangreno- ocular inflammation. Since then, vari- nodosum, on the anterior aspects of sum and erythema elevatum diutinum ous other manifestations have been re- lower limbs. Histology shows a septal or have been also reported. Chen et al. lated to this disease, known as Behçet’s lobular infiltration of hypodermis con- described three different pathological disease (BD). Skin lesions are frequent sisting of lymphocytes, histiocytes and patterns upon histology of cutaneous le- and helpful for the diagnosis. This enti- neutrophils. Rarely a lymphocytic or a sions of RV: i) dermal necrotizing venu- ty is unique as it may involve any blood leukocytoclastic vasculitis is described. litis with predominance of neutrophilic vessel from aorta to capillary veins. These nodules correspond sometimes infiltrates (leucocytoclastic vasculitis) Complex aphthosis is the mucosal hall- to a superficial thrombophlebitis. characterised clinically by purpura, mark of this disease. Oral aphthae occur In a few patients, tender erythematous haemorrhagic bullae, maculopapular as the first manifestation in 25 to 75% papules and plaques resembling those erythema and erythema elevatum di- of cases. They are usually undistinguish- of Sweet’s disease may be present on utinum; ii) acute or healed arteritis at able from ordinary aphthae. They form a the face and neck. Pyoderma gangreno- the junction of dermis and subcutis, 1 to 3 cm, painful ulceration of variable sum-like lesions have also been report- histologically resembling cutaneous depth with a yellow fibrinous base sur- ed in some cases. The association with polyarteritis nodosa, in nodules, livedo rounded by erythema. Patients may have gastrointestinal involvement raises the reticularis and ulcerations and iii) co- single or multiples ulcers spontaneously difficult problem of the differential existence of arteritis and dermal venu- healing in 1 to 4 weeks without scarring. diagnosis with inflammatory entero- litis in subcutaneous nodules, atrophie Ulcers may also be herpetiform with colitis. Other manifestations have been blanche and purpura. DIF disclosed pinpoint lesions occurring in coalescing occasionally described: livedo reticula- dermal small vessel wall depositions clusters. The usual affected sites are lips, ris, purpuric lesions, erythema multi- of immunoglobulin (IgM) and/or C3 gums, cheeks and tongue and less fre- forme-like lesions. (41). Cutaneous RV overlaps both the quently pharynx and palate. Frequency The pathergy test is an induced cuta- characteristics of cutaneous necrotizing of recurrences is highly variable. In the neous reaction resembling pseudo-fol- venulitis and cutaneous polyarteritis diagnostic criteria of the International liculitis. When the skin is pricked by a nodosa. Leucocytoclastic vasculitis in Study Group on Behçet’s disease, at least needle or injected with saline, an ery- RA patients does not necessarily indi- three recurrences per year are required. thematous papule or pustule develops cate a favourable prognosis (41). Pathologic features are usually non-spe- within 24 to 48 hours. Pathergy is a cific with rarely a lymphocytic or leuko- characteristic response in Turkish, Is- Primary Sjögren’s syndrome (SS) (42) cytoklastic vasculitis. Genital aphthae raeli, French and Japanese patients but Cutaneous vasculitis represents almost are present in 60 to 80% of cases. They is uncommon in North American and 60% of the cutaneous manifestations are similar to oral aphthae but do not British patients. The use of needles of during SS. usually recur as often. In men, they are large diameter with a blunt point seems Vasculitis occurs mostly in female pa- mainly localized on the scrotum with a to increase the sensitivity of this test. tients at a mean age of 50 years. Symp- permanent residual scar, more rarely on On histology, a lymphocytic and neu- toms are non-specific (palpable pur- the sheath or the meatus. In women, vul- trophilic dermal infiltration has been pura, urticarial lesions, erythematosus va is predominantly involved; aphthae observed in the first 24 hours. Vasculi- maculopapules). Vasculitis is often, resolve without scar. Ocular or perineal tis is rare. Immunoglobulin and/or com- but not always, related to circulating aphthae are rarely reported. plement deposits in vessels wall may be cryoglobulin. Small-sized vessels (leu- Pseudo-folliculitis is the most frequent obvious using DIF techniques. Of note, kocytoclastic vasculitis) are mainly af- skin lesion, observed in 39 to 60% of positive pathergy is not pathognomonic fected, while medium-sized vessel vas- cases (Fig. 4). It presents as non-follic- of BD, as 8% of the patients with in- culitis are uncommon. Compared with ular erythematous papules that become flammatory bowel disease may present SS patients without vasculitis, patients pustular, then secondly resolve or ul- such positive reaction (46). On a phys- with cutaneous vasculitis had a higher cerate. They are mainly located on the io-pathological point of view, BAFF prevalence of articular involvement, trunk, the lower limbs, the buttocks and and its signalling in B cells were shown peripheral neuropathy, Raynaud’s phe- the genitalia but may occur on other to be implicated in the development of nomenon, renal involvement, and im- parts of the body like palms and soles. skin disease in patients with BD (46).

S-132 Cutaneous vasculitis / N. Kluger & C. Francès REVIEW

Churg-Strauss syndrome more than half of patients. Skin lesions gestive of WG than other vasculitides In 1951, Churg and Strauss defined al- rapidly respond to systemic corticoster- (55). Skin features are exceptionally lergic granulomatosis as a distinct en- oids and eosinophilia may be absent. similar to erythema elevatum diuti- tity occurring in asthmatic adults and DIF is negative. num with IgA paraproteinemia (56). associated with fever, eosinophilia, Nodules are quite frequent, mainly systemic vasculitis and extra-vascular Microscopic polyangiitis (50, 51) localized on the limbs. Extensive and granulomas. The microscopic form of PAN, now painful cutaneous ulcerations may Skin lesions have been observed in 40 called microscopic polyangiitis (MPA), precede by weeks to years other sys- to 75% of cases depending on series. is defined as a systemic vasculitis of temic manifestations. These ulcers are They are rarely the presenting symp- small-sized vessels (i.e. capillaries, sometimes described as “pyoderma tom (6%) (48, 49). Palpable purpura, venules or arterioles) without extravac- gangrenosum-like lesions”, especially petechia, ecchymoses, hemorrhagic ular granuloma. MPA is associated with when they follow a localized trauma- bullae on lower extremities is the segmental necrotizing glomerulonephri- tism or the breakdown of painful nod- most frequent cutaneous manifestation tis and anti-neutrophil cytoplasm anti- ules or pustules. However, they usually (50%). Cutaneous nodules (30%) or bodies of the myeloperoxidase type. lack the typical raised, tender, under- papules are also very frequent, some- Dermatologic manifestations occur in mined border of pyoderma gangreno- times with an urticarial appearance, lo- 25 to 60% of patients (50). Purpuric le- sum. Sometimes numerous, they are cated on the lower limbs or on the ex- sions of the lower limbs are the most located on the limbs, the trunk, the face tensor side of the elbows, fingers, scalp frequent. Other lesions have been re- (pre-auricular area), the breasts (mim- and/or breast (Fig. 7). Lesions of the ported such as erythematous macules, icking adeno-carcinoma with possible fingers are usually multiple, often sym- vesicles, bullae, splinter haemorrhages, nipple retraction and galactorrhea) and metrical, and most commonly localized annular purpura, nodules, palmar ery- the perineum. Digital gangrene are at both lateral sides of the distal inter- thema, erythema elevatum diutinum, occasionally reported. Florid xanthe- phalangeal joint. These nodules or pa- oral ulcers, facial oedema and pyoder- lasma is associated with longstanding pules of the upper limbs have frequent- ma gangrenosum-like lesion. Leuko- granulomatous orbital and periorbital ly central crusting or ulceration. Their cytoclastic vasculitis of the small ves- infiltration. In contrast to PAN, livedo consistence is usually firm. A pustular sels of the dermis is usually observed. reticularis is unusual in WG. or vesicular component is rarely noted. Sometimes, arterioles or smaller ves- Frequency of oral manifestations is Various other dermatologic lesions sels of the deep dermis and subcutane- difficult to estimate from literature have been reported: maculo-papules ous fat are also involved, explaining the series since they are often included resembling erythema multiforme, ul- nodular appearance of skin lesions. DIF in ear-nose-throat symptoms and not cerations, livedo reticularis, patchy is usually negative but the presence of described separately. Oral ulcers are and migratory urticarial rash, nail fold vascular deposits of immunoglobulins sometimes reported independently of infarction with splinter haemorrhages, and complement does not exclude the other oral manifestations. They are and facial oedema (49). diagnosis. Of note, neither the cutane- undoubtedly frequent, present in 10% Histologically, three distinct patterns ous manifestations, or the skin histolog- to 50% of cases depending on series. that can be associated on a biospy are ical studies contribute to the distinction Unlike aphthae, they are persistent and noted during CSS: i) a small vessel between PAN and MPA (51). not recurrent. Their number and locali- eosinophil rich neutrophilic vasculitis zation are highly variable. Hyperplas- of the superficial and mid dermis and Wegener’s granulomatosis (52-58) tic gingivitis is usually not mentioned eosinophiic rich neutrophilic muscu- Wegener’s granulomatosis (WG) is in the largest series. However well- lar vessel vasculitis, ii), dermal eosi- characterized by granulomatous necro- documented case-reports have been nophilia and iii) palisading neutrophilic tizing inflammatory lesions of the up- published. Gingival changes include a and granulomatous inflammation with per and lower respiratory tractus, usu- granular aspect and red to purple colour degenerated collagen bundels (so called ally accompanied by rapidly progress- with many petechiae (Fig. 8). The en- “red” granulomas). Nodules correspond ing glomerulonephritis. tire peri-odontium and gingival mucosa to granulomatous vasculitis, or necro- Skin lesions occur in 14 to 77% of cases may be involved resulting in tooth mo- tizing vasculitis of arterioles of the deep depending on series (52, 53). They are bility and loss of teeth or palate ulcera- dermis or hypodermis (similar to those inaugural in about 10% of cases and are tion (Fig. 9). Significant but incomplete observed in PAN) or to extra-vascular exceptionally isolated as the presenting improvement is observed with empiric granuloma. In fact extra-vascular gran- symptom (54). Palpable purpura of the antimicrobial therapy. Genital ulcers uloma correlates, in the majority of pa- lower extremities is undoubtedly the are uncommon although penile necro- tients, with papules and nodules on the most frequently observed. Necrotic sis has previously been described. extensor aspects of the elbows. Finally, papules of the extensor aspects of the As usual, purpuric papules correspond histological findings of skin lesions can limbs are less frequent but more sug- to leukocytoclastic vasculitis of small be disappointing, typical granuloma gestive of WG. Facial involvement has vessels; necrotic and purpuric lesions and eosinophilia not being detected in been reported and would be more sug- could result from necrotizing vasculitis

S-133 REVIEW Cutaneous vasculitis / N. Kluger & C. Francès of superficial and/or deep dermal and Fig. 7. Granulo- subcutaneous vessels. Others lesions matous lesions dur- ing Churg-Strauss are more frequently associated with vasculitis. granulomatous inflammation. Papules or papulonecrotic lesions correspond to leukocytoclastic or granulomatous vasculitis of small vessels or extra-vas- cular granuloma. Nodules correspond to necrotizing or granulomatous vasculitis of medium-sized arterioles or extra- vascular granuloma. All these lesions may lead to ulceration with a secondary mixed inflammatory pattern. Pathologic findings of oral ulcerations are often non-specific showing acute and chronic inflammation. In other cases, a granulo- matous infiltration is present. Gingival hyperplasia corresponds to a chronic Fig. 8. Gingival histiocytic inflammation with inconstant hyperplasia during vasculitis, necrosis and giant cells infil- Wegener’s granulo- trate. Pseudo-epitheliomatous hyperpla- matosis. sia and micro-abscesses with polymor- pho-nuclear leukocytes and eosinophils are occasionally encountered. Except xanthelasma, all clinical or his- tological types of skin lesions are as- sociated with active systemic disease. They disappear in few weeks or months after treatment onset and are reported in about 50% of relapses. Cutaneous WG vasculitis is associated with an active, rapidly progressive disases compared to patients without cutaneous vasculitis and with granulomatous lesions (57). Fig. 9. Palate ul- Since 1966, limited and sub-acute ceration during forms of WG have been individualized Wegener’s granulo- matosis. without kidney involvement. In our ex- perience, the most frequently observed skin lesions in these forms are nod- ules with granulomatous infiltration or granulomatous vasculitis on histology (58). DIF of skin lesions may reveal IgM and complement deposits. Polyarteritis nodosa (PAN) According to the names and definitions of vasculitis adopted by the Chapel Hill consensus conference on the nomen- clature of systemic vasculitis, classic polyarteritis nodosa (PAN) is charac- terized by a necrotizing inflammation The skin hallmarks of cutaneous PAN and on the feet. Arms, trunk, head, of medium-sized or small arteries with- are nodules. These cutaneous or sub- and buttocks also can be involved. out glomerulonephritis or vasculitis in cutaneous nodules are the first sign of The number of nodules is highly vari- arterioles, capillaries or venules. the disease and appear in groups along able according to each flare and dis- Systemic PAN is actually very rare; its the course of superficial arteries. They play a course ranging from a few days evolution is acute with skin manifesta- measure between 5 and 25 mm in di- to more than 2 months. Nodules may tions different of those observed in cuta- ameter and are mainly located on the leave a violaceous livedoid colour or neous PAN which is a chronic disease. lower legs, especially around the knees pigmentation that persist for months to

S-134 Cutaneous vasculitis / N. Kluger & C. Francès REVIEW

Fig. 10. Cutaneous ported with variable prevalence in the nodules during poly- large series of the literature. This prev- arteritis nodosa. alence has ranged from 28% to 60% for PAN series (51). In the series of Agard et al. (61), skin involvement (purpura, nodules) was the first presenting sign in 11% of their patients with PAN. They are less frequently observed in patients older than 65 years. We found in our recent series of patients with systemic PAN that the most frequent skin lesions observed were palpable purpura (19%), livedo (17%) and nodules (15%) (51). Although this systemic disease mainly affects the medium-sized arteries of Fig. 11. Chronic the kidney, liver, heart and gastrointes- painful fibrinous ul- tinal tract, the most common cutaneous cerations during cu- taneous polyarteritis finding is palpable purpura correspond- nodosa. (Notice the ing to a small vessel vasculitis. Other “atrophie blanche” manifestations have been reported such lesions around the as urticaria, transient erythema, super- ulcerations). ficial phlebitis, Raynaud’s phenome- non, splinter haemorrhages. Localized oedema is usually associated with un- derlying muscular involvement.

Granulomatous vasculitis Granulomatous vasculitis (Fig. 13) is associated with heterogeneous diseases and/or conditions, mostly represented by Takayasu’s arteritis (TA) and giant cell arteritis (GCA). Other rare causes of granulomatous vasculitis include years (Fig. 10). Livedo reticularis may surrounding the involved artery is char- sarcoidosis, metastatic Crohn’s disease, precede come along or follow the onset acteristic, in contrast with the more dif- ulcerative colitis, CTD (SLE, RA), lym- of nodules. In PAN, livedo reticularis fuse panniculitis usually found in other phoproliferative processes, hepatitis C, is typically suspended, located on the nodular diseases. Presence of eosi- herpes and zoster-related vasculitis (4, lower limbs, the dorsal aspects of upper nophil among the infiltrate should not 62). Their clinical aspect vary greatly limbs and rarely the trunk. The fishnet rule out the diagnosis. Evolved nodules ranging from papules, nodules, subcu- reticular pattern is irregular with bro- may only show reparative signs in the taneous infiltration or pseudo-tumor to ken meshes. On careful examination, panniculus and mild chronic inflam- chronic ulcer developing at any site of infiltrated areas of the fishnet pattern mation and fibrosis of the artery wall. the body. are found. Painful ulcerations are fre- Therefore, old lesions should not be quently associated with tender and biopsied. DIF may show non-specific Takayasu’s arteritis (63-66) firm plaques resulting from coalescent immunoglobulins IgM and comple- TA is a rare chronic inflammatory ar- nodules (Fig. 11). Lastly, some patients ment deposits (60). For some authors, teriopathy of unknown origin that pre- may present atrophic, ivory-coloured, the recently described “macular arteri- dominantly affects the aorta and its stellate-shaped scars (atrophie blanche) tis” may be a form of latent cutaneous main branches. Two, eventually over- (59). These clinical features are char- PAN (7, 8). lapping, stages of this disease have acteristic of cutaneous PAN which, by These chronic, benign limited cutane- been distinguished: a first systemic definition, only affects small arteries ous forms of periarteritis nodosa are in non-specific inflammatory stage fol- of the skin. A full-thickness excison fact frequently associated with arthral- lowed by an occlusive stage character- of an active inflammatory nodule will gia and pure sensitive neuropathy. Sys- ized by inflammation of the media and show a necrotizing arteritis with vari- temic acute disease rarely occurs in the adventitial layers of the large vessels able amounts of fibrinoid necrosis and course of cutaneous PAN. wall resulting in vascular stenosis and/ leukocytoclasia, edema, and inflamma- Cutaneous manifestations occurring or aneurysm formation. tory cells (Fig. 12). Focal panniculitis during systemic PAN have been re- Skin manifestations have been reported

S-135 REVIEW Cutaneous vasculitis / N. Kluger & C. Francès in 2.8 to 28% of patients. Some are di- Fig. 12. Micro- rectly related to large vessels occlusion scopic examina- tion of a cutaneous such as unilateral Raynaud’s phenome- nodule during PAN: non, digital gangrene or unilateral dig- necrotizing arteritis ital clubbing. Other skin manifestations with fibrinoid necro- were frequently thought to be related to sis and leukocyto- clasia, edema, and this vasculitis i.e. ulcerated or non-ul- inflammatory cells. cerated nodules of the lower limbs, py- oderma gangrenosum, livedo reticula- ris, papular or papulo-necrotic lesions, superficial phlebitis, Sweet’s lesions. Other manifestations are occasionally related without evident relationship with TA: urticaria, angioedema, ery- thema multiforme, erythematous erup- tions and “dermatitis“. The prevalence of these different skin lesions greatly varies from Asian to European coun- tries. In northern America and Europe, acute or sub-acute inflammatory nod- ules are the most commonly observed skin lesions. Erythema induratum cor- responds to ulcerated sub-acute nodu- lar lesions. The histological features of these nodules are variable. They may correspond to granulomatous or necro- tizing vasculitis of small-sized or me- dium-sized arterioles of the dermis or hypodermis, extra-vascular granuloma, septal or lobular panniculitis. Usually, there is no correlation between the lo- calization of the nodules and alterations of large vessels revealed by angiogra- phy. Furthermore, these nodules can oc- cur at any stage of the disease. Tuber- culoid infiltration has been reported in Fig. 13. Micro- biopsies from papular or papulo-necrot- scopic examination of granulomatous ic lesions raising the problem of an in- vasculitis. fectious origin of the disease. These lesions mainly occur at the occlusive stage of the disease. In Japan, pyoderma gangrenosum-like lesions are frequent, especially at the occlusive stage; this type of lesions has also been reported in patients from northern Africa. The re- lationship between skin manifestations and TA is based on the absence of other aetiology and on the parallel course of skin lesions and vasculitis. Whatever is the stage of the disease, recurrence of skin lesions is strongly suggestive of arteritis reactivation. represents less than 1% of all cutaneous patients, cutaneous symptoms represent vasculitis. Skin manifestations are often only 2% of the inaugural symptoms and Giant cell arteritis (GCA) (67-71) observed in the late stages of the dis- they dont occur isolated (69). Classical- GCA is a systemic vasculitis with a pre- ease. Therefore, they are actually rare ly, scalp and temples are tender and red. dilection for small- to medium-sized due to an early diagnosis. According Tender cordlike nodules are palpable cranial arteries in elderly patients. It to a french retrospective study of 260 over the course of temporal, occipital

S-136 Cutaneous vasculitis / N. Kluger & C. Francès REVIEW or facial arteries. Pulsations in these ar- look for the presence of systemic in- References teries are diminished or absent. Excep- volvement (heart, lung, kidney) and ii) 1. CARLSON JA, CAVALIERE LF, GRANT-KELS JM: Cutaneous vasculitis: diagnosis and man- tionally, multiple scalp aneurysms have to identify a potential curable cause. agement. Clin Dermatol 2006; 24: 414-29. been reported. However, complementary explorations. 2. CARLSON JA, CHEN KR: Cutaneous vasculi- The majority of other skin lesions are should be orientered by clinical context tis update: small vessel neutrophilic vascu- the consequence of ischemia related to (Table II). Moreover, any patient with litis syndromes. Am J Dermatopathol 2006; 28: 486-506. cranial arteries occlusion and localized a known underlying disease that may 3. CROWSON AN, MIHM MC JR, MAGRO CM: on the tongue and the scalp. Glossitis be responsible for CV should be asked Cutaneous vasculitis: a review. J Cutan occurs in 10% of patients, and may about any new drug intake, infectious Pathol 2003; 30: 161-73. 4. CARLSON JA, CHEN KR: Cutaneous pseu- sometimes be revealing. The tongue like episode and carefully examined dovasculitis. Am J Dermatopathol 2007; 29: has a red, raw-beef colour and may be- to rule out an other potential cause of 44-55. come blistered, scaling or gangrenous. vasculitis. 5. MALONE JC, SLONE SP, WILLS-FRANK LA et al.: Vascular inflammation (vasculitis) in Necrosis usually occurs in the anterior In most of the cases, CV remains res- Sweet syndrome: a clinicopathologic study two-thirds. Lesions may start as crusts triced to a single, self-limited and short- of 28 biopsy specimens from 21 patients. of the scalp that misdiagnosed for her- lived episode of purpura of the lower Arch Dermatol 2002; 138: 345-9. pes zoster lesions. Bullae, ulcers or limbs without any visceral involvement 6. FIORENTINO DF: Cutaneous vasculitis. J Am Acad Dermatol 2003; 48: 311-40. massive necrosis may then affect the and relapse. In this frequent situation, 7. SADAHIRA C, YOSHIDA T, MATSUOKA Y, scalp. Patients with scalp necrosis rep- treatment is not compulsory. However, TAKAI I, NODA M, KUBOTA Y: Macular ar- resent a subgroup of severe GCA with support stockings or panty hose are teritis in Japanese patients. J Am Acad Der- matol 2005; 52: 364-6. older age of onset and frequent seri- recommended. Aspirin or anti-inflam- 8. AL-DARAJI W, GREGORY AN, CARLSON JA: ous complications such as visual loss, matory agents can be given for symp- “Macular arteritis”: a latent form of cuta- gangrene of the tongue or nasal septum tomatic relief. If the disease persists, neous polyarteritis nodosa? Am J Dermat- necrosis. The mean interval between worsen or is symptomatic (burning opathol 2008; 30: 145-9. 9. BUCKTHAL-MCCUIN J, MUTASIM DF: onset of symptoms of GCA and scalp sensation, pain) with a restriction to the Macular arteritis mimicking pigmented pur- necrosis is 3.0 months. Under treat- skin, various drugs can be given, usu- puric dermatosis in a 6-year-old caucasian ment, scalp healing is complete or sat- ally colchicine at the dose of 1 to 2 mg/ girl. Pediatr Dermatol 2009; 26: 93-5. 10. HUNDER GG, AREND WP, BLOCH DA et al.: isfactory in 75% of cases. In other cas- day for one month. Alternatives include The American College of Rheumatology 1990 es, skin grafts are possible. Less severe dapsone titrate (25-50 mg/day) or pen- criteria for the classification of vasculitis. In- chronic ischemia of the scalp leads to toxyphililine (400 mg, 3 times a day). troduction. Arthritis Rheum 1990; 33: 1065-7. thinning or loss of hair. Ischemic skin Extensive, recurrent skin disease with 11. JENNETTE JC, FALK RJ, ANDRASSY K et al.: Nomenclature of systemic vasculitides. Pro- lesions of the neck or the cheeks are persistant lesions, vesicles, ulcers, nod- posal of an international consensus confer- occasionally reported. Rarely, vessels ules; intractable symptoms or systemic ence. Arthritis Rheum 1994; 37: 187-92. of the lower limbs are involved lead- vasculitis with other organ involvment 12. BONNEFOY M, CLAUDY AL: Prospective study of factors associated with leukocyto- ing to ischemic ulcerations or distal may prompt initiation of immunosup- clastic vasculitis. Ann Dermatol Venereol gangrene. Skin biopsy of the border of pressive therapies such as corticoster- 1988; 115: 27-32. ulceration or necrotic tissue is rarely oids, methotrexate, azathioprine, cy- 13. IOANNIDOU DJ, KRASAGAKIS K, DAPHNIS contributive since granulomatous vas- closporine or cyclophosphamide (1). EK, PERAKIS KE, SOTSIOU F, TOSCA AD: Cutaneous small vessel vasculitis: an entity culitis has been shown in only 2 of with frequent renal involvement. Arch Der- 24 biopsies from patients with scalp Conclusion matol 2002; 138: 412-4. necrosis. Other skin manifestations Cutaneous lesions are frequent during 14. PRINS M, VERAART JC, VERMEULEN AH, HULSMANS RF, NEUMANN HA: Leucocyto- have been published as case-reports: the course of many systemic vasculi- clastic vasculitis induced by prolonged exer- nodules of the lower limbs with granu- tis. Lesions are often not specific, the cise. Br J Dermatol 1996; 134: 915-8. lomatous vasculitis in the hypodermis most frequent being palpable purpura. 15. RAMELET AA: Exercise-induced purpura. or septal panniculitis, butterfly rash Histology is mandatory to confirm the Dermatology. 2004; 208: 293-6. 16. RAMELET AA: Exercise-induced vasculitis. J with transient oedema. Senile purpura diagnosis of vasculitis to avoid delayed Eur Acad Dermatol Venereol 2006; 20: 423-7. is frequent on sun-exposed skin ar- and inappropriate diagnosis that could 17. KELLY RI, OPIE J, NIXON R: Golfer’s vasculi- eas in elderly patients, especially when lead to improper management. Cutane- tis. Australas J Dermatol 2005; 46: 11-4. 18. RAMELET AA: Golfer’s vasculitis. Australas treated with corticosteroids. However, ous histology gave some data that may J Dermatol 2006; 47: 211. palpable purpura of the lower limbs help to classify the vasculitis without 19. WISNIESKI JJ, BAER AN, CHRISTENSEN J et due to vasculitis is exceptional. determining precisely its type. An his- al.: Hypocomplementemic urticarial vasculi- tis syndrome. Clinical and serologic findings tological examination of all other skin in 18 patients. Medicine (Baltimore) 1995; Management of cutaneous lesions is necessary. The result of the 74: 24-41. vasculitis biopsy has to be correlated to DIF data, 20. TANCREDE-BOHIN E, OCHONISKY S, VIGN- Management of isolated, biopsy-prov- medical history, physical examination, ON-PENNAMEN MD, FLAGEUL B, MOREL P, RYBOJAD M: Schönlein-Henoch purpura en, CV without clinical manifestation laboratory and radiological findings in adult patients. Predictive factors for IgA in favor for systemic involvement leading to the correct diagnosis and ef- glomerulonephritis in a retrospective study of or for a specific cause, include : i) to fective treatment. 57 cases. Arch Dermatol 1997; 133: 438-42.

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