AHEI acute hemorrhagic edema of infancy ANCA anti-neutrophil cytoplasmic antibodies BCGB acillus Calmette-Guerin CHCC Chapel Hill Consensus conference CSVV cutaneous small vessel vasculitis CV cutaneous vasculitis C3, C4, C1 qserum complement factors 3, 4, 1 qHA Hepatitis AHB Hepatitis BHPV human papilloma virus HSP Henoch-Schoenlein purpura HUV hypocomplementemic urticarial vasculitis HV hypersensitivity vasculitis IC immune complexes MMR measles, mumps, rubellaPANpolyarteritis nodosaSLEsystemic lupus erythematosusSOCVsingle organ cutaneous vasculitisUVurticarial vasculitis
Keywords
Single organ cutaneous vasculitis, Small vessel vasculitis of the skin, Adverse event, Immunization Guidelines, Case definition
1. Preamble
1.1. Need for developing case definitions and guidelines for data collection, analysis, and presentation for single organ cutaneous vasculitis as an adverse event following immunization
Vasculitides are a group of heterogeneous conditions characterized by inflammation of blood vessel wall, which can occur in any organ system. Cutaneous involvement occurs almost exclusively with vasculitis of small and medium-sized vessels [1]. Cutaneous vasculitis (CV) may be: (a) a single organ disease limited to the skin, (b) primary CV with secondary systemic involvement, or (c) a cutaneous manifestation of systemic vasculitis [1].
Several classifications and definitions have been proposed for vasculitides, for example those published by the American College of Rheumatology and the Chapel Hill Consensus Conference (CHCC), but they all have various limitations [2], [3], [4]. The proliferation of names for CV is principally due to the fact that various disorders can be associated with small-vessel vasculitis of the skin: sometimes it is only cutaneous and in other cases there can be other organ involvement [5].
In 1952, upon the first classification, the term “hypersensitivity vasculitis” (HV) was coined to distinguish forms of necrotizing arteritis of small vessels from polyarteritis nodosa (PAN), which involved larger vessels. HV derives its name from animal models of vasculitis induced by horse serum or drug administration to cause hypersensitivity reactions [5]. Subsequently, the term has been refined to denote small vessel vasculitis confined mainly to the skin and not associated with any other primary vasculitis (i.e. Henoch-Schoenlein purpura, granulomatosis with polyangiitis or cryoglobulinemia). The 1994 CHCC proposed an alternative term for HV – “cutaneous leukocytoclastic angiitis” because of the frequent failure to identify a precipitant factor for hypersensitivity reaction. This term was also problematic because histological features were not always consistent with this clinical phenotype [5]. The more comprehensive definition of cutaneous small vessel vasculitis (CSVV), which includes clinical and histological features of HV and leukocytoclastic vasculitis irrespective of a possible triggering factor is also used. More recently, the 2012 revised CHCC nomenclature recommended that for single organ vasculitis, which is applied to vasculitis in arteries or veins of any size in a single organ that has no features that indicate that it is a limited expression of a systemic vasculitis, the involved organ and vessel type should be included in the name (e.g. cutaneous small vessel vasculitis) [4]. Therefore, for this case definition we adopted the term single organ cutaneous vasculitis (SOCV), which refers to small vessel vasculitis of the skin where systemic involvement has been excluded.
1.1.1. Subtypes of single organ cutaneous vasculitis
CSVV is the most common type of vasculitis, and primarily affects cutaneous post-capillary venules of the dermis [6]. In most cases, it is histologically characterized by leukocytoclastic vasculitis, but lymphocytic vasculitis has been described too. The term CSVV is generally reserved for small vessel vasculitis of the skin without medium-sized vessel involvement, regardless of the clinical severity of the skin disease or the underlying etiology. CSVV is often idiopathic in nature, but may be secondary to an underlying cause such as an infection or medication. Extracutaneous involvement may occur but it is uncommon and usually mild [1].
In the group of CSVV a well-characterized form is urticarial vasculitis (UV), a small vessel vasculitis with predominant skin involvement manifesting with urticarial lesions [7], [8]. UV consists of persistent urticarial lesions (beyond 24–36 h) showing the histopathological features of leukocytoclastic vasculitis [1]. Lesions consist of erythematous, indurated wheals, with or without angioedema, particularly on the trunk and lower extremities. Lesions are associated with burning and pain rather than pruritus and leave post-inflammatory hyperpigmentation and bruising. Although UV is most often idiopathic, it can be associated with autoimmune connective tissue diseases, infections, medications and haematologic malignancies [8]. The most important prognostic feature is the presence or absence of hypocomplementemia. More severely affected patients often are those exhibiting hypocomplementemia. The typical age group involves young to middle-aged women [9]. Seventy to eighty percent of cases of UV have normal complement levels in blood samples [1]. These patients tend to have a skin-limited disease, whereas those with decreased complement levels are more likely to have systemic manifestations [1]. About 80–90% of patients with hypocomplementemic urticarial vasculitis (HUV) may meet the criteria for diagnosis of systemic lupus erythematosus (SLE), or Sjogren syndrome or cryoglobulinemia [5].
Another manifestation of CSVV is acute haemorrhagic edema of infancy (AHEI), also known as Finkelstein’s disease, a benign cutaneous leukocytoclastic vasculitis affecting children aged 4 months to 2 years. It was considered to be a cutaneous variant of Henoch-Schöenlein Purpura (HSP); however, unlike HSP, clinical manifestations, lesion location and histology of skin lesions differ [10].
In this document other subtypes of CSVV associated with systemic involvement (i.e. anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, cryoglobulinemia) are not discussed. Polyarteritis nodosa (PAN) can rarely manifest as SOCV. However, as it is characterized by specific clinical and histological features due to the involvement of medium-size vessels, it is envisioned to be defined separately.
