Cutaneous vasculitis: insights into pathogenesis and histopathological features.

The mechanisms underlying the onset and progression of vasculitis remain poorly understood. This condition is characterized by damage to the vascular wall, recruitment of inflammatory cells, and subsequent structural remodeling, which are hallmarks of vasculitis. The histopathological classification of vasculitis relies on the size of the affected vessel and the predominant type of inflammatory cell involved - neutrophils in acute cases, lymphocytes in chronic conditions, and histiocytes in granulomatous forms. Pathological changes progress in every context, and a single vasculitic pattern can be associated with various systemic conditions. Conversely, a single causative agent may lead to multiple distinct clinical and pathological manifestations of vasculitis. Moreover, many cases of vasculitis have no identifiable cause. A foundational understanding of the normal structure of the cutaneous vascular network is crucial. Similarly, identifying the cellular and molecular participants and their roles in forming the "dermal microvascular unit" is propedeutical.This review aims to elucidate the complex mechanisms involved in the initiation and progression of vasculitis, offering a comprehensive overview of its histopathological classification, underlying causes, and the significant role of the cutaneous vascular network and cellular dynamics. By integrating the latest insights from studies on NETosis and the implications of lymphocytic infiltration in autoimmune diseases, we seek to bridge gaps in current knowledge and highlight areas for future research. Our discussion extends to the clinical implications of vasculitis, emphasizing the importance of identifying etiological agents and understanding the diverse histopathological manifestations to improve diagnostic accuracy and treatment outcomes.

Leucocytoclastic vasculitis due to acute bacterial endocarditis resolves with antibiotics.

Infective endocarditis is associated with a variety of clinical signs, but its association with multisystem vasculitis is rarely reported. A high index of suspicion is necessary to differentiate a primary autoimmune vasculitis from an infectious cause as the wrong treatment can lead to significant morbidity and mortality. We present a 71-year-old female patient with negative blood cultures, on antibiotics for recent bacteraemia, who presented with cutaneous and renal leucocytoclastic vasculitis. Workup revealed a vegetation adjacent to her right atrial pacemaker lead consistent with infective endocarditis and her vasculitis completely resolved with appropriate antibiotics.

Regulating the Polarization of Macrophages: A Promising Approach to Vascular Dermatosis.

Macrophages, a kind of innate immune cells, derive from monocytes in circulation and play a crucial role in the innate and adaptive immunity. Under the stimulation of the signals from local microenvironment, macrophages generally tend to differentiate into two main functional phenotypes depending on their high plasticity and heterogeneity, namely, classically activated macrophage (M1) and alternatively activated macrophage (M2). This phenomenon is often called macrophage polarization. In pathological conditions, chronic persistent inflammation could induce an aberrant response of macrophage and cause a shift in their phenotypes. Moreover, this shift would result in the alteration of macrophage polarization in some vascular dermatoses; e.g., an increase in proinflammatory M1 emerges from Behcet's disease (BD), psoriasis, and systemic lupus erythematosus (SLE), whereas an enhancement in anti-inflammatory M2 appears in infantile hemangioma (IH). Individual polarized phenotypes and their complicated cytokine networks may crucially mediate in the pathological processes of some vascular diseases (vascular dermatosis in particular) by activation of T cell subsets (such as Th1, Th2, Th17, and Treg cells), deterioration of oxidative stress damage, and induction of angiogenesis, but the specific mechanism remains ambiguous. Therefore, in this review, we discuss the possible role of macrophage polarization in the pathological processes of vascular skin diseases. In addition, it is proposed that regulation of macrophage polarization may become a potential strategy for controlling these disorders.

Successful Treatment of Painful Cutaneous Vasculopathy With Rivaroxaban in a Patient With Systemic Lupus Erythematosus.

Novel oral anticoagulant (NOAC) medications have revolutionized hematology and cardiology. Recently, NOACs have demonstrated additional promise in dermatology. Specifically, rivaroxaban, a direct factor Xa inhibitor NOAC, has been shown to be successful in the treatment of livedoid vasculopathy. Herein, we describe a patient with systemic lupus erythematosus who presented with painful cutaneous vasculopathy, demonstrated on biopsy with occlusive microvascular fibrin thrombi without evidence of concurrent vasculitis. Interestingly, imaging and laboratory studies did not show evidence of hypercoagulability, arterial disease, or embolic disease. The patient’s vasculopathy and pain progressed despite antiplatelet therapy, often considered first-line in cases of microvascular occlusive disease. However, with rivaroxaban therapy, the patient experienced complete regression of her painful lesions, thereby supporting a further role for NOACs in cutaneous vasculopathy treatment. J Drugs Dermatol. 2020;19(5) doi:10.36849/JDD.2020.4684.

Platelets in Skin Autoimmune Diseases.

Systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and small vessel vasculitis are three autoimmune diseases frequently manifested in the skin. They share common pathogenic features, including production of autoantibodies, loss of tolerance to self-antigens, tissue necrosis and fibrosis, vasculopathy and activation of the coagulation system. Platelets occupy a central part within the coagulation cascade and are well-recognized for their hemostatic role. However, recent cumulative evidence implicates their additional and multifaceted immunoregulatory functions. Platelets express immune receptors and they store growth factors, cytokines, and chemokines in their granules enabling a significant contribution to inflammation. A plethora of activating triggers such as damage associated molecular patterns (DAMPs) released from damaged endothelial cells, immune complexes, or complement effector molecules can mediate platelet activation. Activated platelets further foster an inflammatory environment and the crosstalk with the endothelium and leukocytes by the release of immunoactive molecules and microparticles. Further insight into the pathogenic implications of platelet activation will pave the way for new therapeutic strategies targeting autoimmune diseases. In this review, we discuss the inflammatory functions of platelets and their mechanistic contribution to the pathophysiology of SSc, ANCA associated small vessel vasculitis and other autoimmune diseases affecting the skin.

Are the cutaneous manifestations in patients with primary antiphospholipid syndrome a marker for predicting lung manifestations?

OBJECTIVES: The aim of this study was to investigate association between pulmonary and skin manifestations in a large group of patients with primary antiphospholipid syndrome (PAPS) as well as their connection with antiphospholipid antibodies. METHODS: Our prospective study comprises of 390 patients with primary APS. Antiphospholipid antibody (aPL) analysis included detection of aCL (IgG/IgM), ß2GPI (IgG/IgM) and LA. Distinct pulmonary and skin associations were determined, as well as their associations with aPL. RESULTS: In PAPS patients the presence of LA was more common in PTE (p=0.005) and in pulmonary microthrombosis (p=0.003). We revealed statistical significance considering the presence of aCL IgM and pulmonary microthrombosis (p=0.05). Skin ulcerations correlated with positive titres aCL IgM and ß2 GPI IgM (p=0.03 and 0.04, respectively), while pseudovasculitis correlated with positive titres ß2 GPI IgM (p=0.02). PAPS patients were more more likely to develop pulmonary thromboembolisam if they had livedo reticularis (p=0.005), skin ulcerations (p=0.007), pseudovasculitic lesions (p=0.01), superficial cutaneous necrosis (p=0.005), and digital gangrene (p=0.02). Patients were also more prone to pulmonary microthrombosis if they already had livedo reticularis (p=0.03), skin ulcerations (p=0.007), pseudovasculitic lesions (p=0.05), superficial cutaneous necrosis (p=0.006), and digital gangrene (p=0.02). CONCLUSIONS: There is strong link between some pulmonary and skin manifestations in PAPS patients, suggesting complexity and evolutionary nature of APS. The presence of skin manifestations may be a high risk factor for several types of serious pulmonary manifestations in PAPS. Certain aPL types are associated with distinct pulmonary and skin manifestation, suggesting their predictive role.

Approach to cutaneous vasculitides with special emphasis on small vessel vasculitis: histopathology and direct immunofluorescence.

PURPOSE OF REVIEW: The present review will focus on recent publications in cutaneous vasculitides. RECENT FINDINGS: Some histopathological and clinical features, such as papillary dermal edema, perivascular C3 deposition, clinically evident edema, and lesions above the waist, may point out renal or gastrointestinal involvement in Henoch-Schönlein purpura (HSP). HSP associated with familial Mediterranean fever differs from typical isolated HSP by showing no deposits of IgA, much younger age, and location of the lesions on the face or the trunk. Single-organ cutaneous small vessel vasculitis is a more restricted entity than hypersensitivity vasculitis and HSP. Because cutaneous polyarteritis nodosa and macular lymphocytic arteritis share some clinicopathologic features, the question is raised whether they are not two different entities. Several histopathological features defining IgG4-related disease are found in granuloma faciale and erythema elevatum diutinum, two localized chronic cutaneous vasculitis; however, in a recent series no diagnostic criteria for IgG4-related disease was detected in them. SUMMARY: When a patient presents with skin lesions, in which necrotizing or leukocytoclastic vascuitis is confirmed histologically, irrespective of the size of the affected vessel, the possibility of systemic vasculitis, an infection, medication, or a systemic disease such as systemic lupus erythematosus must be searched before reaching definitive diagnosis.

[Cutaneous symptoms of various vasculitides]. / Kutane Symptome der Vaskulitiden.

The skin is one of the organs most frequently involved in vasculitides. Cutaneous vasculitis may present (1) part of a systemic vasculitis (e.g., IgA vasculitis), (2) a skin-restricted or skin-dominant variant of the corresponding systemic vasculitis without clinically apparent visceral involvement (e.g., cutaneous IgA vasculitis), or (3) a vasculitis occurring exclusively in the skin (e.g., erythema elevatun diutinum). The clinical symptoms of vasculitides are markedly determined by the size of the predominantly affected blood vessels. Systemic polyarteritis nodosa is regarded as a medium vessel vasculitis and is associated with multiple skin symptoms: (1) vasculitis of digital arteries with ensuing digital infarction, (2) livedo racemosa and subcutaneous nodules, and (3) in some patients even purpura and hemorrhagic macules due to additional small vessel vasculitis. In contrast, in its skin-restricted entity (i.e., cutaneous polyarteritis nodosa), the predominant symptoms are subcutaneous nodules surrounded by livedo racemosa, often on the lower legs. Among small-vessel vasculitides palpable purpura with predilection for the legs is a nearly pathognomonic feature of immune complex vasculitis. Variations in clinical symptoms indicate additional pathophysiological mechanisms or different vascultides: (1) ANCA-associated vasculitides often also entail nodules or sometimes livedo, (2) cryoglobulinemic vasculitis additionally may present with necrosis at cold exposed areas and involvement of vessels of various size, (3) small vessel vasculitis associated with systemic lupus erythematosus or rheumatoid arthritis shows predilection for additional sites (e.g., nailfolds) and also involvement of vessels beyond postcapillary venules, (4) recurrent macular vasculitis in hypergammaglobulinemia also occurs on dependent parts, but shows numerous small hemorrhagic macules instead of palpable purpura, (5) erythema elevatum diutinum begins with brightly red to violaceous plaques at extensor sites, followed by fibrotic nodules. Consequently, cutaneous symptoms provide pivotal clues for further diagnosis and ensuing management of vasculitides.

The role of KIR2DL3/HLA-C*0802 in Brazilian patients with rheumatoid vasculitis.

OBJECTIVES: Rheumatoid arthritis is a polygenically controlled systemic autoimmune disease. Rheumatoid vasculitis is an important extra-articular phenotype of rheumatoid arthritis that can result in deep cutaneous ulcers. The objective of this study was to establish a correlation between the frequency of major histocompatibility complex class I/II alleles and killer immunoglobulin-like receptor genotypes in patients with cutaneous rheumatoid vasculitis. METHODS: Using the Scott & Bacon 1984 criteria to diagnose rheumatoid vasculitis and after excluding any other causes such as diabetes, atherosclerosis, adverse drug reactions, infection, and smoking, patients who met the criteria were selected. All of the selected rheumatoid vasculitis patients presented deep cutaneous ulcers. Identification of the major histocompatibility complex class I/II and killer immunoglobulin-like receptor genotypes was performed by polymerase chain reaction assays of samples collected from the 23 rheumatoid vasculitis patients as well as from 80 controls (40 non-rheumatoid vasculitis RA control patients and 40 healthy volunteers). RESULTS: An association between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and cutaneous lesions in rheumatoid vasculitis patients and a correlation between the inhibitor KIR2DL3 and the HLA-C*0802 ligand in rheumatoid vasculitis patients were found. CONCLUSION: An association was found between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and the development of cutaneous lesions in rheumatoid vasculitis patients. Additionally, the HLA-C*0802 ligand protects these individuals from developing cutaneous lesions.

The role of KIR2DL3/HLA-C*0802 in Brazilian patients with rheumatoid vasculitis

OBJECTIVES: Rheumatoid arthritis is a polygenically controlled systemic autoimmune disease. Rheumatoid vasculitis is an important extra-articular phenotype of rheumatoid arthritis that can result in deep cutaneous ulcers. The objective of this study was to establish a correlation between the frequency of major histocompatibility complex class I/II alleles and killer immunoglobulin-like receptor genotypes in patients with cutaneous rheumatoid vasculitis. METHODS: Using the Scott & Bacon 1984 criteria to diagnose rheumatoid vasculitis and after excluding any other causes such as diabetes, atherosclerosis, adverse drug reactions, infection, and smoking, patients who met the criteria were selected. All of the selected rheumatoid vasculitis patients presented deep cutaneous ulcers. Identification of the major histocompatibility complex class I/II and killer immunoglobulin-like receptor genotypes was performed by polymerase chain reaction assays of samples collected from the 23 rheumatoid vasculitis patients as well as from 80 controls (40 non-rheumatoid vasculitis RA control patients and 40 healthy volunteers). RESULTS: An association between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and cutaneous lesions in rheumatoid vasculitis patients and a correlation between the inhibitor KIR2DL3 and the HLA-C*0802 ligand in rheumatoid vasculitis patients were found. CONCLUSION: An association was found between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and the development of cutaneous lesions in rheumatoid vasculitis patients. Additionally, the HLA-C*0802 ligand protects these individuals from developing cutaneous lesions. .

Small vessel vasculitis of the skin.

Small vessel vasculitis in the skin manifests with palpable purpura on the lower extremities. This clinical presentation prompts a complete physical examination, history, and review of systems, as well as biopsies for routine processing and direct immunofluorescence to confirm the diagnosis. The presence of vasculitis in other organs, associated underlying conditions, and the severity of cutaneous manifestations dictate management. The majority of cases are self-limited, and overall the prognosis is favorable. Still, a subset of patients can have serious complications and chronic or recurrent disease.

Early excision and grafting, an alternative approach to the surgical management of large body surface area levamisole-adulterated cocaine induced skin necrosis.

Levamisole-adulterated cocaine as a cause of retiform purpura progressing to full-thickness skin necrosis was first documented in 2003 and currently comprises over 200 reported cases. Whereas, its presentation, pathophysiology, and diagnostic workup have been reasonably well-defined, only one publication has significantly detailed its surgical management. For this reason there exists a relative absence of data in comparison to its reported incidence to suggest a preferred treatment strategy. In the case mentioned, treatment emphasized delayed surgical intervention while awaiting lesion demarcation and the monitoring of autoantibodies. At our institution we offer an alternative approach and present the case of a 34 year old female who presented with 49% TBSA, levamisole-induced skin necrosis managed with early surgical excision and skin grafting. The patient presented three days following cocaine exposure with painful, purpura involving the ears, nose, buttocks, and bilateral lower extremities which quickly progressed to areas of full-thickness necrosis. Lab analysis demonstrated elevated p-ANCA and c-ANCA, as well as leukopenia, decreased C4 complement, and urinalysis positive for levamisole, corroborating the diagnosis. Contrasting the most thoroughly documented case in which the patient underwent first surgical excision on hospital day 36 and underwent 18 total excisions, our patient underwent first excision on hospital day 10 and received only one primary excision prior to definitive autografting. To our knowledge, this is the largest surface area surgically treated that did not result in surgical amputation or autoamputation of limbs or appendages, respectively. We contend that early excision and grafting provides optimal surgical management of this syndrome while avoiding the morbidity seen with delayed intervention.

Vasculitis: determinants of disease patterns.

The vasculitides are a large group of heterogeneous diseases for which it has been assumed that pathogenesis is largely autoimmune. As clinicians, we distinguish one form of vasculitis from another on the basis of observed patterns of organ injury, the size of the vessels affected and histopathological findings. The terms 'small-vessel', 'medium-vessel' and 'large-vessel' vasculitis are useful clinical descriptors, but fail to inform us about why vessels of a certain calibre are favoured by one disease and not another. Classification based on vessel size also fails to consider that vessels of a specific calibre are not equally prone to injury. Distinct vulnerabilities undoubtedly relate to the fact that same-size vessels in different tissues may not be identical conduits. In fact, vessels become specialized, from the earliest stages of embryonic development, to suit the needs of different anatomical locations. Vessels of the same calibre in different locations and organs are as different as the organ parenchymal cells through which they travel. The dialogue between developing vessels and the tissues they perfuse is designed to meet special local needs. Added to the story of vascular diversity and vulnerability are changes that occur during growth, development and ageing. An improved understanding of the unique territorial vulnerabilities of vessels could form the basis of new hypotheses for the aetiopathogenesis of the vasculitides. This Review considers how certain antigens, including infectious agents, might become disease-relevant and how vascular diversity could influence disease phenotypes and the spectrum of vascular inflammatory diseases.