Cutaneous vasculitis in autoinflammatory diseases.

Autoinflammatory diseases (AIDs) characterized by recurrent episodes of localized or systemic inflammation are disorders of the innate immune system. Skin lesions are commonly found in AIDs and cutaneous vasculitis can coexist with AIDs and even present as the most striking feature. This review aims to focus on the frequent cutaneous vasculitis association in three monogenic AIDs including familial Mediterranean fever (FMF), deficiency of adenosine deaminase type 2 (DADA2), and the recently identified adult-onset VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Cutaneous vasculitis in FMF is characterized by: (1) small-vessel vasculitis similar to IgA vasculitis with palpable purpura but increased intussusception complication and less vascular IgA deposit, and (2) cutaneous arteritis-like vasculitis presenting as subcutaneous nodules most often with higher glomerular involvement. DADA2 has a wide spectrum of clinical presentations ranging from fatal systemic vasculitis with multiple strokes, especially in pediatric patients, to limited cutaneous disease in middle-aged patients. DADA2 shares similar clinical and histopathological features with polyarteritis nodosa (PAN). As a result, DADA2 is commonly initially misdiagnosed as childhood PAN. Livedo racemosa reveals the most common cutaneous manifestation of cutaneous vasculitis in patients with DADA2. VEXAS syndrome is a life-threatening disease. A diagnosis of VEXAS syndrome should be strongly considered or could be made in patients with skin lesions characterized by Sweet syndrome-like eruption, livedo racemosa, concomitant relapsing polychondritis, deep venous thrombosis, pulmonary involvement, and progressive hematologic abnormalities such as myelodysplastic syndrome with a unique finding of cytoplasmic vacuoles in myeloid and erythroid precursor cells from bone marrow aspirate smear. As skin involvement is common in AIDs and may present as the most frequent manifestation, especially in DADA2 (70% to 90%) and VEXAS syndrome (83% to 91%), dermatologists play a crucial role in contributing to the early diagnosis of these AIDs with early initiation of the appropriate therapy to avoid progressing fatal outcomes.

Coexistence of Superficial Thrombophlebitis and Cutaneous Venulitis in Behçet's Disease: Report of 5 Cases.

Previous studies have shown that erythema nodosum-like lesions in patients with Behçet's disease show cutaneous vasculitis of either phlebitis or dermal venulitis. To analyse the clinicopathological characteristics of superficial thrombophlebitis as well as cutaneous venulitis in Behçet's disease. We re-evaluated the histopathological features of superficial thrombophlebitis in patients with Behçet's disease. Five patients, one man and four women, developed superficial thrombophlebitis on the lower extremities. Two of the patients had vascular Behçet's disease, both also developed deep vein thrombosis. One patient had intestinal Behçet's disease. In all cases, venulitis in the overlying lower dermis or adjacent subcutis spreading from the main affected subcutaneous thrombophlebitis lesions was observed. Both neutrophilic venulitis (n = 2) and lymphocytic venulitis (n = 3) were observed at the same depth level or upper/lower location of the thrombophlebitis in the same specimens. In addition, concurrent venulitis with fibrin thrombus and fibrinoid necrosis was observed in one case, suggesting that fibrin thrombus affected both venules and muscular veins. By contrast, arteritis or arteriolitis at the same depth level was not observed. Our results showed histopathological features of coexistent thrombophlebitis and venulitis without involvement of either arteries or arterioles in the biopsied specimens of superficial thrombophlebitis. Further studies are necessary to support that those unique histopathological findings are the characteristic features and significant diagnostic indicators of Behçet's disease.

Cutaneous arteriolitis: A novel cutaneous small vessel vasculitis disorder clinicopathologically different from cutaneous polyarteritis nodosa and cutaneous venulitis.

Cutaneous vasculitis can be classified into two types based on the affected vessel size: small vessel vasculitis predominantly affecting dermal venules, and muscular vessel vasculitis as found in cutaneous arteritis predominantly affecting arteries located at the dermal-subcutaneous junction. We describe two cases with a novel small vessel vasculitis disorder, which exclusively affected arterioles in the mid-dermis, and show clinical and pathological difference distinct from cutaneous polyarteritis nodosa and cutaneous venulitis. Both patients were male, and presented with painful infiltrative plaques, involving the palms, soles, and thighs without extracutaneous involvement except for fever and arthralgia. Histopathological examination revealed vasculitis in the mid-dermis characterized by a predominant infiltration of neutrophils with vessel wall fibrinoid necrosis and leukocytoclasia identical to the features of leukocytoclastic vasculitis, except that the affected vessels were arterioles rather than venules. Serological examinations showed normal levels of serum complements, immune complexes, and antineutrophil cytoplasmic antibodies, and vasculitis disorders associated with systemic diseases were excluded in both patients. The patients showed a good response to short-term treatment with prednisolone up to 30 mg. This novel cutaneous arteriolitis clinicopathologically different from both cutaneous venulitis and cutaneous arteritis appears to be a skin-limited disorder.

A Case of Cutaneous Arteritis Presenting as Infiltrated Erythema in Eosinophilic Granulomatosis With Polyangiitis: Features of the Unique Morphological Evolution of Arteritis as a Diagnostic Clue.

Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome) is a rare systemic vasculitis affecting small- and medium-sized vasculature, associated with asthma and eosinophilia. Different levels of vasculitis in cutaneous lesions have been observed, including dermal small vessel vasculitis and subcutaneous muscular vessel vasculitis. Although the EGPA-associated small vessel vasculitis described as leukocytoclastic vasculitis can be often found in the documented literature, the features of subcutaneous muscular vessel vasculitis in EGPA-associated cutaneous lesions have been rarely demonstrated clinically and histopathologically in English literature. Herein, we report a case of EGPA involving infiltrated erythema on the extremities, with different stages of cutaneous arteritis characterized by eosinophilic arteritis and granulomatous arteritis in the same affected artery. We present this as a unique diagnostic clue for EGPA.

Systemic lupus erythematosus with refractory ulcerated livedoid vasculopathy: Successful treatment with intravenous immunoglobulin and warfarin.

We reported a patient with systemic lupus erythematosus complicated by livedoid vasculopathy (LV), who responded well to intravenous immunoglobulin and warfarin. Cutaneous lesions of LV resemble those of cutaneous vasculitis. LV should be included in the differential diagnosis of leg ulcerations even in the presence of autoimmune disorders.

Outline of guidelines for the management of vasculitis and vascular disorders in Japan, 2016 revised edition.

The proposal by the 1994 International Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitides (CHCC1994) and by the CHCC2012 markedly influenced the classification and way of considering cutaneous vasculitis. In the proposal by the CHCC1994, hypersensitivity angiitis was defined as an equivalent pathological condition to microscopic polyangiitis or cutaneous leukocytoclastic angiitis (CLA), and it was not adopted as a disease name. However, CLA which was positioned as a type of small-vessel vasculitis is only a pathological name. In the proposal by the CHCC2012, a new category of single-organ vasculitis included CLA and cutaneous arteritis. Vasculitis allergica cutis (Ruiter) corresponded to CLA and cutaneous polyarteritis nodosa corresponded to cutaneous arteritis. The Japanese Dermatological Association (JDA) prepared guidelines for the management of vasculitis and vascular disorders in 2008 based on the proposal by the CHCC1994 and their original viewpoint of dermatology. The JDA subsequently revised the 2008 edition guidelines in 2016 following publication of the proposal of the CHCC2012 in Japanese. We presented the outline of the 2016 edition guidelines and propose a treatment algorithm for primary vasculitides based on the evaluation of the cutaneous symptoms for cases suspected as primary cutaneous vasculitides, which integrates the 2008 JDA guideline and CHCC2012 classification. This is the secondary English version of the original Japanese manuscript for the guideline for management of vasculitis and vascular disorders published in the Japanese Journal of Dermatology 127(3); 299-415, 2017.

Nomenclature of Cutaneous Vasculitis: Dermatologic Addendum to the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.

OBJECTIVE: To prepare a dermatologic addendum to the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012) to address vasculitides affecting the skin (D-CHCC). The goal was to standardize the names and definitions for cutaneous vasculitis. METHODS: A nominal group technique with a facilitator was used to reach consensus on the D-CHCC nomenclature, using multiple face-to-face meetings, e-mail discussions, and teleconferences. RESULTS: Standardized names, definitions, and descriptions were adopted for cutaneous components of systemic vasculitides (e.g., cutaneous IgA vasculitis as a component of systemic IgA vasculitis), skin-limited variants of systemic vasculitides (e.g., skin-limited IgA vasculitis, drug-induced skin-limited antineutrophil cytoplasmic antibody-associated vasculitis), and cutaneous single-organ vasculitides that have no systemic counterparts (e.g., nodular vasculitis). Cutaneous vasculitides that were not included in the CHCC2012 nomenclature were introduced. CONCLUSION: Standardized names and definitions are a prerequisite for developing validated classification and diagnostic criteria for cutaneous vasculitis. Accurate identification of specifically defined variants of systemic and skin-limited vasculitides requires knowledgeable integration of data from clinical, laboratory, and pathologic studies. This proposed nomenclature of vasculitides affecting the skin, the D-CHCC, provides a standard framework both for clinicians and for investigators.

Reappraisal of histopathology of cutaneous polyarteritis nodosa.

BACKGROUND: There is controversy on whether lymphocytic thrombophilic arteritis (LTA) and macular arteritis (MA) are a different entity from cutaneous polyarteritis nodosa (C-PAN). OBJECTIVE: To evaluate the controversy on LTA/MA by examining the morphologic changes during the dynamic inflammatory process. MATERIALS AND METHODS: A clinical and histopathological investigation of 46 biopsy specimens from 21 histopathologically proven C-PAN patients at our hospital was performed. RESULTS: Most of the biopsy findings revealed arteritis in the subacute and reparative stages. Coexistence of different stages was found in over half of the specimens. Two biopsy specimens consistent with LTA/MA showed coexisting histologically proven (subacute stage) C-PAN in other lesions. Analyses of the longitudinal sections showed focal and segmental arteritis. Patients overall improved well with compression stockings, anti-inflammatory agents, a prostaglandin analog and antiplatelet agents. Currently, three patients are medication free and only require compression stockings. CONCLUSION: LTA/MA seems to be part of the spectrum of C-PAN. The vasculitic lesions of C-PAN are segmental and focal, and coexist in different stages. As the chronic stage of C-PAN can be mistaken as LTA/MA, it is necessary to perform multiple biopsies, serial sections and analyses of longitudinal sections to confirm the main finding of vasculitis.

Molecular analysis of Dirofilaria repens removed from a subcutaneous nodule in a Japanese woman after a tour to Europe.

A premature female Dirofilaria species, subsequently identified as Dirofilaria repens by its morphological features and mitochondrial 12S ribosomal RNA (12S rRNA) gene sequence, was removed from a subcutaneous nodule of the right temporal region of the head in a Japanese woman 2 years after she noticed swelling of her left calf following an insect sting during a tour to Europe; headache symptoms were noticed a few months later. The sequences of the mitochondrial 12S rRNA and cytochrome c oxidase subunit I genes from the organism were almost identical to those of sequences AM779772 (100% homology, 337/337) and AM749233 (99.8% homology, 536/537) of D. repens isolated from humans in Italy. However, the phylogenetic position of the 18S rRNA-internal transcribed spacer 1-5.8S rRNA region was in the same cluster as that of sequence JX290195 of Dirofilaria sp. "hongkongensis" (96.7% homology, 348/360), which was recently reported from Hong Kong as a novel Dirofilaria species. Information on regional genetic variation in D. repens isolated from animals and humans remains scarce. We report the detailed genetic features of this filaria as a reference isolate from a specific endemic area, to enrich the genetic database of D. repens.

Spectrum of cutaneous vasculitis in eosinophilic granulomatosis with polyangiitis (Churg-Strauss): a case series.

BACKGROUND: The diverse histopathologic spectrum of cutaneous vasculitis in eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome) has not been well described. METHODS: Fifteen skin biopsy specimens from 9 EGPA patients with histopathologically proven necrotizing vasculitis were reviewed clinicopathologically. RESULTS: Among 8 patients with dermal small vessel vasculitis, neutrophilic vasculitis was observed in 2 myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA)-positive patients, whereas the remaining 6 MPO-ANCA-negative patients showed eosinophilic vasculitis in 3 and a mixed infiltrate of neutrophils and eosinophils in another 3 patients. Five patients with muscular vessel vasculitis showed vasculitis at different inflammatory stages in separate or coexisting at the same biopsied skin lesions: acute stage (eosinophilic vasculitis), granulomatous stage (granulomatous vasculitis), and healed stage. Coexistent small vessel and muscular vessel vasculitis was found in 4 patients. CONCLUSIONS: The histopathologic spectrum of dermal small vessel vasculitis in EGPA ranges from eosinophilic vasculitis with negative MPO-ANCA at one end to neutrophilic vasculitis with positive MPO-ANCA at the other end. The affected vessels ranging from dermal small vessels to subcutaneous muscular vessels in addition to the MPO-ANCA phenotype may account for the many facets of vasculitis in EGPA.