CRITICAL REVIEW Cutaneous Vasculitis Update: Diagnostic Criteria, Classification, Epidemiology, Etiology, Pathogenesis, Evaluation and Prognosis J. Andrew Carlson, MD, FRPC,* Bernard T. Ng, MD,‡ and Ko-Ron Chen, MD, PhD† CLA: cutaneous leukocytoclastic angiitis (a.k.a. cutaneous leuko- Abstract: Vasculitis, inflammation of the vessel wall, can result in cytoclastic vasculitis) mural destruction with hemorrhage, aneurysm formation, and CSS: Churg-Strauss syndrome infarction, or intimal-medial hyperplasia and subsequent stenosis CTD: connective tissue disease (collagen vascular disease) leading to tissue ischemia. The skin, in part due to its large vascular CTDV: CTD associated vasculitis bed, exposure to cold temperatures, and frequent presence of stasis, is CV: cryoglobulinemic vasculitis DIF: direct immunofluorescent studies involved in many distinct as well as un-named vasculitic syndromes GCA: giant cell (temporal) arteritis that vary from localized and self-limited to generalized and life- HE: hematoxylan and eosin stained tissue sections threatening with multi-organ disease. To exclude mimics of vas- HSP: Henoch-Scho¨nlein purpura culitis, diagnosis of cutaneous vasculitis requires biopsy confirmation IC: immune complexes where its acute signs (fibrinoid necrosis), chronic signs (endarteritis LCV: leukocytoclastic vasculitis (a.k.a. hypersensitivity angiitis/ obliterans), or past signs (acellular scar of healed arteritis) must be cutaneous leukocytoclastic vasculitis) recognized and presence of extravascular findings such as patterned MPA: microscopic polyangiitis fibrosis or collagenolytic granulomas noted. Although vasculitis can MPO: myeloperoxidase be classified by etiology, many cases have no identifiable cause, and PAN: polyarteritis nodosa a single etiologic agent can elicit several distinct clinicopathologic PR3: proteinase 3 PSV: primary systemic vasculitis expressions of vasculitis. Therefore, the classification of cutaneous RA: rheumatoid arthritis vasculitis is best approached morphologically by determining vessel SLE: systemic lupus erythematosus size and principal inflammatory response. These histologic patterns UV: urticarial vasculitis roughly correlate with pathogenic mechanisms that, when coupled WG: Wegener granulomatosis with direct immunofluorescent examination, anti-neutrophil cyto- plasmic antibody (ANCA) status, and findings from work-up for (Am J Dermatopathol 2005;27:504–528) systemic disease, allow for specific diagnosis, and ultimately, more effective therapy. Herein, we review cutaneous vasculitis focusing on diagnostic criteria, classification, epidemiology, etiology, pathogen- ew diseases in clinical medicine cause as much diagnostic esis, and evaluation of the cutaneous vasculitis patient. Fand therapeutic consternation as vasculitis.1–6 Vasculitis is Key Words: classification, etiology, epidemiology, pathogenesis, simply inflammation directed at blood vessels identified by direct immunofluorescence, ANCA, systemic vasculitis, localized histologic examination. When blood vessel inflammation occurs, vasculitis, endarteritis obliterans vessel wall destruction with hemorrhage and aneurysm for- mation or stenosis due to intimal hyperplasia can occur, both of which may lead to tissue ischemia and infarction. Vasculitis Abbreviations can be a primary process (no known cause or association), or a phenomenon secondary to drug ingestion, infection, or the ACR: American College of Rheumatology presence of a systemic disease (eg, rheumatoid arthritis) or to AECA: antiendothelial antibodies local factor such as trauma. Systemic and localized vasculitis ANCA: antineutrophil cytoplasmic antibodies often affects the skin and subcutis, likely due in part to their APS: antiphospholipid antibody syndrome large vascular bed, hemodynamic factors (eg, stasis in lower CHCC: Chapel Hill Consensus Conference extremities), and environmental influences (eg, cold exposure). Frequent skin involvement by vasculitic syndromes, seen as From the *Divisions of Dermatology and Dermatopathology, Albany Medical diverse and dynamic patterns of discoloration, swelling, hem- College, Albany, New York; †Department of Dermatology, Saiseikai orrhage, and/or necrosis, may be their initial and/or most Central Hospital, Tokyo, Japan; and ‡Department of Pathology, Albany accessible manifestations. Thus, dermatopathologists and Medical College, Albany, New York. dermatologists often become involved in the diagnosis and Reprints: J. Andrew Carlson, Divisions of Dermatology and Dermatopathology, 2,5,7 Albany Medical College MC-81, Albany, NY 12208 (e-mail: carlsoa@mail. management of vasculitis. amc.edu). Cutaneous vasculitis presents as a mosaic of clinical Copyright Ó 2005 by Lippincott Williams & Wilkins and histologic findings due to varied pathogenic mechanisms. 504 Am J Dermatopathol Volume 27, Number 6, December 2005 Am J Dermatopathol Volume 27, Number 6, December 2005 Cutaneous Vasculitis Update Physical signs of vasculitis include urticaria, purpura, purpuric associated diseases or triggering factors, and monitoring by papules, infiltrated erythema, ulcer, infarct, livedo reticularis, histology and/or laboratory tests, may be decisive for optimal and nodules that affect the skin with varying intensity, depth, therapy of vasculitis. and distribution creating a number of named syndromes, for In this first part of this 2-part review, diagnostic criteria, example, erythema induratum (nodular vasculitis), Henoch- classification, etiology, epidemiology, pathogenesis, and eval- Schonlein purpura (HSP), or Wegener granulomatosis (WG). uation of patients presenting with cutaneous vasculitis will be However, in many cases, specific clinical entities do not always discussed. In the second part, specific vasculitic entities, pri- correlate exactly with mechanisms and any one patient may mary and secondary, that can affect the skin will be presented have a constellation of morphologic signs that overlaps in the context of morphologic and pathophysiologic classifi- with another clinical entity thus preventing confident clinical cation scheme. A primarily morphologic-based scheme is used diagnosis.8,9 A definitive diagnosis of vasculitis requires his- rather than the etiologic-based one, as it is the most practical tologic confirmation in almost all cases because few vasculitic method to generate a relevant differential diagnosis when in- syndromes have pathognomonic clinical, radiographic, and/or terpreting a skin biopsy showing vasculitis (Fig. 1). laboratory findings.6,10 However, a biopsy diagnosis of vas- culitis cannot stand by itself, as it must be correlated with clinical history, physical and laboratory findings, and/or an- DIAGNOSIS AND CLASSIFICATION giographic features. For instance, a diagnosis of vasculitis OF VASCULITIS restricted to the skin (aka, hypersensitivity vasculitis, cuta- The diagnosis of vasculitis is a medical challenge due to neous leukocytoclastic angiitis) requires that the systemic the unknown or incompletely understood etiology and patho- manifestations of vasculitis be sought and found absent.5 If genesis of most vasculitides as well as their protean and systemic vasculitis is present, imaging studies can provide a overlapping clinicopathologic features.14,15 For instance, hepa- useful means to determine disease extension and activity10 and titis C infection can be found in association with several dif- serology, such as C-reactive protein and anti-neutrophilic ferent types of vasculitis such as polyarteritis nodosa (PAN), cytoplasmic antibodies (ANCA) levels and type can be used to cryoglobulinemic vasculitis (CV), and hypersensitivity/cuta- monitor disease activity and predict mortality risk, respec- neous leukocytoclastic angiitis (CLA).16 (Henceforth, leuko- tively.11,12 In addition, clinical features such as the presence of cytoclastic vasculitis (LCV) will be used to describe patients arthralgias and cryoglobulinemia, and absence of fever can with the histologic reaction pattern of small vessel neutrophilic predict a chronic course.13 Lastly, the histopathologic in- vasculitis with or without systemic disease; the Chapel Hill terpretation for vasculitis is dependent on the type of biopsy, Consensus Conference (CHCC) term ‘‘cutaneous leukocyto- age of the cutaneous lesion sampled, effects of prior treatment clastic angiitis (CLA)’’ will be used to describe patients with and experience of the pathologist. Not only the diagnosis of cutaneous LCV without systemic disease.) To efficaciously vasculitis, but also the recognition of the specific type, manage vasculitis, a precise and accurate diagnostic FIGURE 1. The size of vessel in- volvement is one histologic feature in conjunction with the dominant inflammatory cell that allow for classification of most common forms of cutaneous vasculitis. In general, Henoch-Scho¨nlein purpura (HSP) and cutaneous leukocytoclastic an- giitis (CLA) (aka, leukocytoclastic or hypersensitivity vasculitis) affect the superficial vessels of the skin whereas polyarteritis nodosa (PAN), nodular vasculitis (Nod Vas), and giant cell arteritis (GCA) affect deep muscular vessels found at the dermal-subcutis interface and within the subcutis. Most other forms of vasculitis such as cryoglobulinemic vasculitis (CV), connective tissue disease (CTDV) vasculitis, and anti-neutrophilic anti- body associated vasculitides (ANCA+ vasculitis: Wegener vasculitis, Churg-Strauss syndrome, and microscopic polyangiitis) can affect both small and muscular vessels (although not necessarily in the same biopsy). The diagnostic yield