Chapter 7 Vasculitis 7 As already mentioned, the dermis normally contains are affected. The inflammatory cell infiltrate con- only a sparse amount of lymphocytes, mainly located sists mainly of neutrophils. The presence of nuclear around postcapillary venules. There are no neutrophils fragments from disintegrating neutrophils (leuko- or eosinophils (Bos et al. 1987). In response to inflam- cytoclasis) is a conspicuous phenomenon. matory stimuli, a variable number of one or several • II. Lymphocytic venular vasculitis: venules in the kinds of inflammatory cells migrate through the walls dermis and the dermal–subcutaneous interface are of venules and accumulate in the tissue. Even though affected. The perivascular cell infiltrates consist of these vessels take part in an inflammatory process, lymphocytes. we do not talk about vasculitis if there are no signs • III. Granulomatous venular vasculitis: venules in the of vascular damage. To call it vasculitis there should dermis and the dermal–subcutaneous interface are be, in addition to perivascular cell infiltrates, injury to affected and surrounded by small areas of necrotic the vessels visible under the light microscope and ex- tissue, in turn encircled by epithelioid cell granulo- pressed as thrombi and/or fibrinoid (i.e., eosinophilic mas and a sparse number of lymphocytes. and glossy) necrosis of the wall. The lesions (whether • IV. Neutrophilic arterial vasculitis: arterioles in the few or numerous) are always segmental (i.e., focal), deep dermis and arterioles and small arteries in the and engage only a very small part of the length of subcutis are affected. The inflammatory cell infil- the vessel. In the engaged segment the whole or only trate is strictly perivascular and mainly composed a part of the vessel‘s circumference may be involved. of neutrophils. Leukocytoclasis is prominent. Fibrin thrombi and wall necrosis are fresh lesions that • V. Lymphocytic/monocytic arterial vasculitis: arte- indicate an acute vascular injury or acute vasculitis. rioles in the deep dermis and arterioles and small There is also deposition in the tissue outside the ves- arteries in the subcutis are affected and surrounded sel of eosinophilic fibrinous (protein-rich) exudate by a well-demarcated mononuclear inflammatory and extravasation of erythrocytes. This is the result cell infiltrate. of necrosis of the vessel wall including the basement • VI. Granulomatous neutrophilic arterial vasculitis: membrane. However, extravasation of erythrocytes is small arteries in the subcutis and ascending arte- not per se a sign of acute vasculitis. It may occur with- rioles show neutrophilic leukocytoclastic vasculitis. out visible signs of damage to the wall, as is the case in In the surrounding tissue there are large necrotic scurvy, where the production of the collagen, support- areas surrounded by epithelioid cell granulomas ing the vessel wall is impaired, in senile, atrophic skin, and sometimes abscesses. and in the tissue around newly formed vessels, which • VII. Mixed group: venules in the dermis and at the are leaky (Fig. 22.5). dermal–subcutaneous interface are affected. In a While scrutinizing material comprising vascu- dense inflammatory cell infiltrate of mixed type lar skin lesions collected since the 1960s, the author there are dilated venules with protruding endothe- found that with respect to the histopathologic pattern, lial cells and/or conspicuously thick-walled venules, it is possible to discriminate six distinct categories of and in some cases simultaneously venules showing vasculitis, which the author has tried to anchor in the fibrinoid necrosis and/or thrombosis. literature. In a further category (category VII), a group of vasculitis is discussed, which includes entities and cases, which clinically are widely different, but histo- 7.1 pathologically show some similarities (Fig. 7.1): Category I: Neutrophilic Venular Vasculitis • I. Neutrophilic venular vasculitis: venules in the This kind of vasculitis is generally calledleukocytoclas- dermis and the dermal–subcutaneous interface tic vasculitis (synonyms are, among others: necrotiz- 36 7 Vasculitis I. Neutrophilic venular II. Lymphocytic venular III. Granulomatous venular vasculitis vasculitis vasculitis IV. Neutrophilic arterial V. Lymphocytic/monocytic VI. Granulomatous neutrophilic vasculitis arterial vasculitis arterial vasculitis VII. Mixed group vasculitis Abnormalities in Arteriolosclerosis blood components Arteriole-capillary Necrotic tissue Neutrophil Lymphocyte Venule Arteriolosclerosis Monocyte Plasma cell Thick-walled venule Nuclear dust Epithelioid cell Fig. 7.1 Diagram of vascular lesions 7.1 Category I: Neutrophilic Venular Vasculitis 37 ing vasculitis, hypersensitivity vasculitis, hypersen- typical phenomenon and often striking. Serious injury sitivity angiitis, allergic vasculitis, and anaphylactoid to vessels in the subepidermal region gives rise to ar- purpura). Spells of leukocytoclastic vasculitis may be eas of spongiosis and vesicles/bullae in the epidermis, triggered by bacterial and viral infections and drugs. and sometimes to ulceration. When the acute phase Sometimes an eruption appears shortly after an inci- declines the histopathologic pattern becomes nonspe- dent of sore throat due to streptococcal infection or cific and neutrophils are replaced by macrophages and after a spell of gastrointestinal malaise. It may appear lymphocytes. without any other symptoms, but can be accompanied by fever and increased erythrocyte sedimentation rate (ESR), or hematuria indicating renal involvement. 7.1.3 Also leukocytoclastic vasculitis may be an expres- Pathogenesis sion of systemic diseases such as classic systemic poly- Investigations have shown that leukocytoclastic vas- arteritis nodosa, systemic lupus erythematosus and culitis, which is not caused by direct invasion of bac- rheumatoid arthritis (Weedon 1997). teria or virus, is an expression of the hypersensitivity reaction type III. In the blood, soluble antigens from bacteria, virus or drugs bind to antibodies and form 7.1.1 antigen–antibody complexes (immune complexes). Clinical Appearance The size of the immune complexes, which is critical, The patient exhibits one or several spells of a polymor- depends on the concentration of the two components phic, widespread, or localized rash. This includes dif- antigen and antibody. A high excess of antibody gives ferent-sized reddish papules (sometimes coalescing to rise to large complexes. These are rapidly trapped and plaques), petechiae and ecchymoses. Some papules are phagocytosed by macrophages lining the sinusoids of markedly edematous and have a central vesicle/bulla the liver, spleen and bone marrow, and consequently or are ulcerated/crusted. If the outbreak is localized, are put out of action. A high excess of antigen gives the most common areas affected are the lower legs. rise to small and harmless complexes. However, a The rash is called “palpable purpura”, a term often used moderately high excess of antibody forms medium- by dermatologists as synonymous with leukocytoclas- sized complexes which are small enough to circulate tic vasculitis. However, sometimes purpura is the only for a long time but large enough to be caught in small manifestation of leukocytoclastic vasculitis. In pa- vessels and cause damage. Antibody in the immune tients with palpable lesions, petechiae are common in complexes is mainly IgG and IgM. areas exposed to pressure and may be found under the It has been shown by means of electron microscopy elastic bands of underwear, or arise in normal-appear- and immunofluorescence that these complexes are ing skin after a blood pressure check. The rash usually taken up focally by the endothelial cells and are stored vanishes spontaneously in a few weeks with hyperpig- in the wall of the venules and in the perivascular tissue mentation or atrophic scars, or without any residue. before any damage appears in the vessel. The inflam- Ulcerations on the lower legs may remain and enlarge, matory process leading to tissue destruction is trig- and thus imitate varicose ulcers. gered when complement binds to IgG or IgM antibod- ies in the complexes and becomes activated. The three activated components of complement C3a, C4a and 7.1.2 C5a (also called anaphylatoxins) cause direct injury to Histopathologic Appearance tissue cells. Like histamine and serotonin they induce Different-sized venules at all levels of the dermis are venular leakage, and attract neutrophils (Sect. 5.2.1). affected, but the most conspicuous changes are of- Neutrophils phagocytose the immune complexes. ten seen in the upper half. If the only clinical sign is When the neutrophils die and disintegrate they release purpura, the vasculitis is discreet and confined to the hydrolytic enzymes which contribute to the tissue subepidermal area. The pattern is variegated. There damage. The consumption of complement gives rise are fibrinoid necrosis of vessel walls with or without to hypocomplementemia (Braverman and Yen 1975; thrombosis, and a fibrinous exudate and red blood cells Lawley and Kubota 1990). in the perivascular tissue. In fresh lesions the inflam- matory cell infiltrates consist mainly of neutrophils, but there also are some lymphocytes, and sometimes a substantial number of eosinophils. The presence of nuclear dust due to disintegration of neutrophils is a 38 7 Vasculitis Fig. 7.2 Neutrophilic venular vasculitis. a Lower leg with rest of them are more or less obscured by nuclear fragments and densely set different-sized