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A 33-year-old female was admitted to our department complaining of multifocal paresthesia and weakness of the upper and lower extremities that had developed over the previous three months. She had also been undergoing treatment for atopic dermatitis with dupilumab, an anti-interleukin 4/13 receptor antibody. A nerve conduction study revealed multifocal axonal sensorimotor neuropathy of bilateral limbs. On admission, a small erythema appeared on her right forearm, but it was atypical for vasculitic skin lesions due to its location and time course. Nonetheless, a biopsy revealed medium-sized vessel vasculitis. The patient was therefore diagnosed with vasculitic neuropathy caused by cutaneous arteritis. Methylprednisolone pulse therapy with prednisolone and azathioprine markedly improved her symptoms. A skin biopsy is useful when mononeuropathy multiplex is suspected, even if the skin findings are atypical for vasculitic rash.

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Polyarteritis nodosa (PAN) is a systemic necrotising vasculitis with a poor prognosis, characterised by inflammation and necrosis of medium-sized arteries. PAN patients can present with a wide range of systemic manifestations, whereas cutaneous arteritis (CA) is a restricted manifestation to skin of the disease with a more favourable prognosis. Thus, differentiation between PAN and CA is crucial. Here, we present two cases that were initially diagnosed as CA due to the limited presence of systemic symptoms, but were finally diagnosed as PAN through catheter-based angiography. Although contrast-enhanced computed tomography and computed tomographic angiography are increasingly used to diagnose PAN, neither case had any abnormal findings on these examinations. Our cases therefore underscore that catheter-based angiography is critical for differentiation between PAN and CA, even in cases with limited systemic symptoms.

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The ongoing debate on whether lymphocytic thrombophilic arteritis (LTA) is a separate disease or a type of polyarteritis nodosa (PAN) has yet to be settled. In this study, we analyzed the nature of infiltrating cells in LTA to resolve this controversy. Skin biopsies from five female patients (mean age 29.4 years, age range 16-45 years) diagnosed with LTA were immunostained for CD3, CD20, CD68, lysozyme, myeloid cell nuclear differentiation antigen, myeloperoxidase, and PU.1. Immunohistochemistry revealed that the majority of mononuclear cells in all five cases were not lymphocytes but myelomonocytic cells. Given that the infiltrating cells are of the myelomonocyte lineage including immature myeloid cells, PAN was deemed the more appropriate diagnosis for the five cases rather than LTA. Whether PAN with immature myeloid cells (histiocytoid PAN) is the same disease as conventional PAN with mature neutrophils requires further investigation.

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Cutaneous arteritis (CA) is a single-organ vasculitis that exclusively affects the small to medium-sized arteries of the skin. Diagnosis depends on a histological investigation with skin biopsy, which could be burdensome for both patients and clinicians. Moreover, the pathogenesis of CA remains unstudied, and treatment has not yet been established. Herein, we applied our proteome-wide autoantibody screening method to explore autoantibodies in the serum of CA patients. As a result, anti-transcobalamin receptor (TCblR) antibodies (Abs) were specifically detected in 24% of CA patients. Patients with positive anti-TCblR Abs were spared from peripheral neuropathy compared to those with negative anti-TCblR Abs, showing characteristics as CA confined to the skin. In addition, we revealed that anti-TCblR Abs trigger the autocrine loop of interleukin-6 mediated by tripartite motif-containing protein 21 in human endothelial cells and induce periarterial inflammation in murine skin. Furthermore, we demonstrated that methylcobalamin, a ligand of TCblR, ameliorates inflammation caused by anti-TCblR Abs both in vitro and in vivo. Collectively, our investigation unveils the pathologic significance of anti-TCblR Abs in CA and their potential as a diagnostic marker and a pathophysiology-oriented therapeutic target.

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Cutaneous polyarteritis nodosa (cPAN) was first reported by Lindberg in 1931. It has been recognized as a skin-limited vasculitis whose cutaneous histopathological features are indistinguishable from those of PAN. Cutaneous arteritis (CA) was defined as a form of single-organ vasculitis in the revised Chapel Hill Classification and was recognized as the same disease as cPAN. It became known that deficiency of adenosine deaminase 2 (DADA2) cases were included in cases that had been diagnosed with CA. Because of their similarity and differences in the treatment methods, DADA2 should be considered in CA cases, especially if they are diagnosed or developed in early childhood. Cutaneous arteritis may be classified as an immune complex-mediated vasculitis. It was reported that the pathogenesis of anti-lysosomal-associated membrane protein-2 (LAMP-2) antibodies and anti-phosphatidylserine-prothrombin complex (PS/PT) antibodies as good parameters in CA. The main skin manifestations include livedo racemosa, subcutaneous nodules, and ulcers. Although CA is recognized to have a benign clinical course, it has become known that it is easy to relapse. The existence of skin ulcers upon diagnosis or sensory neuropathies was suggested to be a predictor of poor prognosis. Cutaneous arteritis with them may need to be treated with more intensive therapies.

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We previously reported that IgA vasculitis and cutaneous arteritis could be dependently associated with the presence of the antiphosphatidylserine/prothrombin complex (anti-PS/PT) antibody and lysosomal-associated membrane protein-2 (LAMP-2). The copy number of LAMP-2 mRNA in skin tissue samples from rats with cutaneous vasculitis induced by intravenous administration of anti-PS/PT antibody after subcutaneous histone injection was significantly higher than in those without cutaneous vasculitis. We found LAMP-2 protein overexpression in neutrophils and vascular endothelial cells of the affected blood vessels in rats with cutaneous vasculitis induced by intravenous administration of anti-PS/PT antibody after cutaneous priming by histones. We found typical cutaneous small-vessel vasculitis in the skin of rats given intravenous injection of both anti-PS/PT antibody and anti-LAMP-2 antibody after cutaneous priming by histones. We suggested that the introduction of skin local histones and anti-PS/PT antibody in serum could move LAMP-2 to the cell surface of neutrophils and vascular endothelial cells, and that anti-LAMP-2 antibody could bridge these cells through antigen-specific binding in typical cutaneous small-vessel vasculitis.

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PURPOSE OF REVIEW: To provide an updated review on epidemiology, clinical manifestations, diagnostic assessment, treatment, and prognosis of localized vasculitis, following the 2012 Revised International Chapel Hill Consensus Conference Nomenclature on single-organ vasculitis. RECENT FINDINGS: Localized, single-organ vasculitides encompass a group of rare conditions in which there is no evidence of concomitant systemic vasculitis. Most data on this topic derives from case reports and small case series. Although some aspects of these diseases, such as clinical manifestations and histologic findings, have already been extensively investigated, there is still a lack of robust data concerning the pathogenesis, epidemiology, and treatment. Localized vasculitides may have a wide range of clinical features depending on the organ affected. The inflammatory process may have a multifocal/diffuse or unifocal distribution. Diagnosis is usually based on histopathology findings and exclusion of systemic vasculitis, which may frequently pose a challenge. Further research on treatment is warranted.

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OBJECTIVE: Cutaneous polyarteritis nodosa (CPAN) is a necrotizing vasculitis of the middle-size vessels, confined to the skin. We conducted a systematic review in order to identify studies evaluating the different treatment modalities used in CPAN. METHODS: This systematic review was conducted according to PRISMA guidelines, registered in PROSPERO: CRD42020222195. PubMed/Medline databases were searched from inception to December of 2020 using the terms: (Polyarteritis nodosa[Title/Abstract]) AND ((therapy[Title/Abstract]) OR (management[Title/Abstract]) OR (treatment[Title/Abstract]))' and 'Cutaneous arteritis [Title/Abstract]'. Articles evaluating pertaining to the management of CPAN in adults were eligible for inclusion. RESULTS: A total of seven eligible case series with 325 unique patients were included. No study included a control population. In general, systemic corticosteroids were widely used as induction treatment. Immunosuppressive agents combined with corticosteroids were AZA, hydroxychloroquine, sulfasalazine, sulphapyridine, CYC, MTX, mycophenolate, tacrolimus, rituxima and thalidomide. Other agents utilized in the studies were dapsone, colchicine, non-steroid anti-inflammatory drugs, salicylates, warfarin and clopidogrel. In some studies, the presence of ulcerations was associated with an increased risk of relapse. CONCLUSION: The evidence available regarding the management of patients with CPAN is limited at best. Further studies are needed in order to evaluate the effect of treatment on disease remission, relapses and mortality.

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We assessed the IgG and IgM prevalence of anti-phosphatidylserine/prothrombin complex (aPS/PT) antibodies (Abs) in patients with vasculitis using a novel commercial ELISA kit. To examine whether aPS/PT Abs were involved in the pathogenesis of cutaneous vasculitis, inbred wild-type rats were intravenously administered with a rat IgM class aPS/PT monoclonal Ab established previously or with rat immunoglobulins as controls. To express PS on the surface of vascular endothelium, these rats were given a subcutaneous injection of cell-free histones in advance. Serum IgM aPS/PT Ab levels were elevated in patients with systemic vasculitis with skin involvement and cutaneous arteritis compared to those in patients with systemic vasculitis without skin involvement and healthy controls. There was no significant difference in the serum levels of IgG aPS/PT Abs between the patients and healthy controls. Correspondingly, inbred wild-type rats intravenously administered with the aPS/PT monoclonal IgM Ab after appropriate priming-subcutaneous histone injection developed cutaneous vasculitis. Some rats given rat IgM instead of the aPS/PT monoclonal Ab also developed cutaneous vasculitis, whereas vasculitis did not occur in rats given IgG or only priming by histones. We suggested that IgM aPS/PT Abs could be involved in the pathogenesis of cutaneous vasculitis based on these findings.

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The etiology of polyarteritis nodosa (PAN) and localized PAN, including cutaneous arteritis (CA), remains unknown; however, initial endothelial damage has been implicated. The intima of the vasculitis lesions is predominantly infiltrated by innate-like bystander-activated CD8 T cells, in addition to the macrophages. Macrophages are among the major inflammatory cells involved in innate immunity and are classified into M1 and M2 subtypes. M1-type macrophages kill pathogens and cause inflammation, while M2-type macrophages promote the repair of tissues. Macrophage subtypes infiltrating in PAN and localized PAN vasculitis lesions have not yet been investigated. Innate immune response to a triggering factor on the endothelial cell surface may initiate CA pathogenesis. Thus, many M1-type macrophages may infiltrate in the intima during early CA. We assessed this hypothesis by immunohistochemical observation of macrophage phenotypes and polarization. Twenty-seven skin biopsy specimens from patients with CA were retrieved. Based on histology, we classified CA into four phases. The phenotypes of infiltrating macrophages in CA were evaluated by immunohistochemistry using antibodies against Iba-1, a pan-macrophage marker, and CD163, an M2-type macrophage marker. Our results showed that the ratio of CD163-positive M2-type macrophages to Iba1-positive macrophages was lower in the intima in the early stage of CA than in the later stage. In the media to adventitia, there was no significant difference in the ratios between these stages. These findings indicate that innate immunity is involved in the intima in the early stage of CA, suggesting that a trigger for CA might exist in endothelial cells.

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We developed a questionnaire to examine the findings of cutaneous arteritis among dermatological specialists experienced in vasculitis as certified by the Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. We sent a questionnaire to 12 dermatological facilities identified through the revised Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. Retrospective data obtained from 84 patients at the 12 dermatological facilities between 2012 January 2016 December were evaluated. The 84 patients were categorized into two groups, a systemic steroid treatment group (group 1, n = 52) and a no systemic steroid treatment group (group 2, n = 32). C-reactive protein in group 1 patients was significantly higher than that in group 2 patients. Frequency of fever, arthritis, myalgia- and peripheral neuropathy in group 1 was significantly higher than that in group 2. We propose that these symptoms could serve as early markers for the transfer from cutaneous arteritis to systemic polyarteritis nodosa. We further suggest that patients who are subsequently associated with cerebral hemorrhage and infarction, who are originally diagnosed as having cutaneous arteritis, could progress to systemic polyarteritis nodosa. The study demonstrated that it is important for dermatologists to detect these findings early in order to establish an accurate diagnosis and a timely treatment.

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Some patients originally diagnosed with cutaneous arteritis (CA) could develop additional disease manifestations, including peripheral neurological involvement. We evaluated the biological neurological parameters among CA patients who underwent nerve conduction studies for neurological involvement in the lower extremities. We reviewed 164 patients who were originally diagnosed with CA at our dermatology department between 2004 and 2015. Seventeen (10.4%) of the CA patients underwent further nerve conduction studies to determine their peripheral neurological manifestations, primarily in the lower extremities, in our neurology division. The frequency of low compound muscle action potential (CMAP) was significantly higher compared with that of delayed latency in both the peroneal nerve and sural nerve based on nerve conduction studies. The frequency of low CMAP was significantly higher compared with that of prolonged distal latency in both the peroneal and sural nerves. We suggest that impairment of the nerve axon pathways in the peroneal and sural nerves could result in the peripheral neurological manifestations in the lower extremities in CA patients.

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A 55-year-old man was admitted with paralysis of the left lower leg. He had purpura in the left lower extremity for three years, left calf pain for two years, and dysesthesia in the left plantar region and first toe for one year. A physical examination revealed livedo reticularis on the left leg and mononeuritis multiplex was diagnosed in the bilateral tibial and left peroneal nerve area. Anti-neutrophil cytoplasmic antibody was negative. A nerve conduction study showed decreased amplitude of compound muscle-action potential in the bilateral tibial and the left peroneal nerve, sensory nerve action potential in the bilateral sural nerve. A skin biopsy revealed inflammatory cells on blood vessel walls and cutaneous arteritis was diagnosed. Cyclophosphamide pulse therapy with steroid and anti-coagulation improved the neurological symptoms. A skin biopsy should be considered when patients present with mononeuritis multiplex in the lower extremities and cutaneous findings such as livedo reticularis in the symptomatic area.

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Cutaneous arteritis (cutaneous polyarteritis nodosa, CA) is a necrotizing vasculitis of arteries within the skin. CA is a new classification under single-organ vasculitis, as adopted by the 2012 Chapel Hill consensus conference (CHCC 2012). Some patients originally diagnosed as having CA could develop additional disease manifestations that warrant reclassifying as systemic polyarteritis nodosa (PAN) according to the CHCC 2012. We retrospectively investigated 101 patients with CA seen at our department between 2003 and 2012. There was a significantly higher frequency of inflammatory plaques and leg edema in CA patients with elevated C-reactive protein (CRP) compared to CA patients with normal CRP. Similarly, there were significant differences in the incidence of arthralgia and mononeuritis multiplex between the two patient groups. We found significantly positive correlations between CRP and creatinine titers in serum in all 101 CA patients. Prednisolone was administrated in a significantly greater percentage of patients with elevated CRP compared to patients with normal CRP. Repeated i.v. cyclophosphamide pulse therapy (IV-CY) with prednisolone therapy at an early stage resulted in complete resolution without adverse effects or severe complications. We regard inflammatory plaques and leg edema with elevated serum CRP as an indication of a more severe condition, and treated them effectively with prednisolone. Assuming mononeuritis multiplex and/or arthritis exist with elevated CRP, we propose that earlier treatment by IV-CY with prednisolone should be indicated for CA patients who demonstrate these more severe manifestations to prevent progression to PAN.

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