Systemic vasculitis involving the kidney: the nephropathologist's point of view.

Kidneys are often targets of systemic vasculitis (SVs), being affected in many different forms and representing a possible sentinel of an underlying multi-organ condition. Renal biopsy still remains the gold standard for the identification, characterization and classification of these diseases, solving complex differential diagnosis thanks to the combined application of light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM). Due to the progressively increasing complexity of renal vasculitis classification systems (e.g. pauci-immune vs immune complex related forms), a clinico-pathological approach is mandatory and adequate technical and interpretative expertise in nephropathology is required to ensure the best standard of care for our patients. In this complex background, the present review aims at summarising the current knowledge and challenges in the world of renal vasculitis, unveiling the potential role of the introduction of digital pathology in this setting, from the creation of hub-spoke networks to the future application of artificial intelligence (AI) tools to aid in the diagnostic and scoring/classification process.

Case Report: Interventional therapy for portal venous stenosis caused by systemic vasculitis.

Systemic vasculitis are multisystem blood vessel disorders. However, Portal venous involvement is extremely rare, which represents a diagnostic and therapeutic challenge due to the heterogeneous nature, a lack of diagnostic criteria and limited effective therapy of vasculitis. We have reported a 48-year-old woman who was previously diagnosed with systemic vasculitis and was treated with prednisone, presented with gastrointestinal (GI) bleeding on admission. Further abdominal contrast-enhanced computed tomography (CT) with three-dimensional reconstruction suggested atrophic left hepatic lobe, enlarged spleen, and severe stenosis of main portal vein. Liver biopsy showed no evidence of fibrosis/cirrhosis. To prevent rebleeding, portal venous angioplasty by balloon dilation with collateral varices embolization was performed, and the GI hemorrhage was resolved completely. However, refractory ascites presented 8 months postoperatively. Abdominal CT angiography confirmed the recurrence of portal venous stenosis. Portal venous angioplasty by stent implantation was then performed to treat the portal hypertension (PHT)-related complications. After the intervention, the patient received anticoagulation therapy and continued immunosuppressive therapy. During the 5-year follow-up, the patient did not experience any onset of GI bleeding or ascites. Therefore, portal venous angioplasty with stent placement could be an effective treatment to prevent PHT-related complications when immunosuppression therapy failed.

Investigating the forensic pathological characteristics of systemic vasculitis: A retrospective study of 20 deaths caused by systemic vasculitis.

Systemic vasculitis (SV) is a condition characterized by vascular inflammatory disease that often involves the medium and small arteries of various organs throughout the body. SV is difficult to diagnose due to the diversity of clinical symptoms and manifestations, and only tissue biopsy is of great significance. Even so, complications or secondary lesions of SV can also lead to death. In forensic medicine, we can often observe multiple vasculitis in histological observations, which is easily overlooked as a primary cause of death in the final diagnosis. Twenty SV cases were registered in our institution from a total of 1088 completed autopsies, which represents 1.83% of the total autopsies. The ages of these 20 SV patients ranged from 16 to 73 years, and the mean age was 41.1 ± 15.9 years. SV usually involves multiple organs, such as the heart, lung, liver, kidney, gastrointestinal system and brain, simultaneously. The intensity of the lesions in the heart and kidney seemed to be more severe than the lesion intensity in other organs in most cases. The causes of death were identified as acute myocarditis (8 cases), acute heart failure (3 cases), cerebral artery rupture (3 cases), cardiovascular artery rupture (2 cases), acute interstitial pneumonia (2 cases), aortic aneurysm rupture (1 case) and acute renal failure (1 case). The typical histopathological changes (smooth muscle degeneration, fibrinoid necrosis, inflammatory cell infiltration and microthrombosis) of arteries observed in this study were of great significance for diagnosing SV. In this article, we try to analyse and summarize the lesion characteristics in cases of death caused by SV in order to provide some help for forensic workers in identifying such cases.

Cutaneous Vasculitis: Review on Diagnosis and Clinicopathologic Correlations.

Cutaneous vasculitis is an inflammatory disease affecting the dermal blood vessel walls. The skin is a privileged organ in the setting of vasculitis since it is easily accessible for physical examination and safe biopsy, allowing an accurate characterization of inflammatory lesions. The skin is often involved. Also, cutaneous vasculitis can reflect a cutaneous component of a systemic vasculitis, a skin-limited or skin-dominant expression or variant of a systemic vasculitis, or be a single-organ vasculitis per se. Vasculitis lesions are multiple and polymorphic. They may induce a wide spectrum of clinical manifestations depending on the location and the size of the vessels involved. The depth of affected vessels is correlated with the type of cutaneous lesions. Involvement of small superficial vessels results mostly in urticarial, but relatively persistent plaques, papules, and palpable purpura. Involvement of vessels in the dermohypodermic junction or hypodermis results in ulcers, nodules, or livedo. The type of inflammatory infiltrate is also a key finding for the diagnosis of cutaneous vasculitis. Leukocytoclastic vasculitis is not a disease per se but the result of a pathophysiological process common to different causes. A better knowledge of the vascular anatomy of the skin, elementary lesions, and histological characteristics of dermatologic manifestations would allow a more relevant and more efficient diagnostic approach. We also propose a list of additional exams to be performed in front of skin lesions suggestive of vasculitis. The aim of our article is to provide an overview of elementary skin lesions and clinicopathologic correlations in cutaneous and systemic vasculitis.

ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies.

Giant cell arteritis (GCA) is a common form of primary systemic vasculitis in adults, with no reliable indicators of prognosis or treatment responses. We used single cell technologies to comprehensively map immune cell populations in the blood of patients with GCA and identified the CD66b+CD15+CD10lo/-CD64- band neutrophils and CD66bhiCD15+CD10lo/-CD64+/bright myelocytes/metamyelocytes to be unequivocally associated with both the clinical phenotype and response to treatment. Immature neutrophils were resistant to apoptosis, remained in the vasculature for a prolonged period of time, interacted with platelets, and extravasated into the tissue surrounding the temporal arteries of patients with GCA. We discovered that immature neutrophils generated high levels of extracellular reactive oxygen species, leading to enhanced protein oxidation and permeability of endothelial barrier in an in vitro coculture system. The same populations were also detected in other systemic vasculitides. These findings link functions of immature neutrophils to disease pathogenesis, establishing a clinical cellular signature of GCA and suggesting different therapeutic approaches in systemic vascular inflammation.

Role of Neutrophils in Systemic Vasculitides.

Neutrophils and neutrophil extracellular traps (NETs) contribute to the pathogenesis of many autoimmune diseases, including vasculitis. Though neutrophils, and NETs, can break self-tolerance by being a source of autoantigens for autoantibodies in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, playing a key role in driving the autoimmune response, the role of neutrophils and NETs in large vessel vasculitis, including giant cell arteritis (GCA), is not well understood. In this review, we summarize the current insight into molecular mechanisms contributing to neutrophil-mediated pathology in small and medium vessel vasculitis, as well as provide potential translational perspectives on how neutrophils, and NETs, may partake in large vessel vasculitis, a rare disease entity of unclear pathogenesis.

Retiform purpura: Workup and therapeutic considerations in select conditions.

In this article we focus on updates in select etiologies of retiform purpura. These causes of retiform purpura, in addition to bacterial or fungal sepsis, disseminated intravascular coagulation, purpura fulminans, and catastrophic antiphospholipid syndrome, are important diagnoses with potential for morbidity and mortality. Important aspects in the pathophysiology, patient demographics and risk factors, updates in the diagnostic workup, histopathology, and treatment of these specific conditions are discussed.

Systematic literature review informing the 2018 update of the EULAR recommendation for the management of large vessel vasculitis: focus on giant cell arteritis.

Objectives: To analyse the current evidence for the management of large vessel vasculitis (LVV) to inform the 2018 update of the EULAR recommendations. Methods: Two systematic literature reviews (SLRs) dealing with diagnosis/monitoring and treatment strategies for LVV, respectively, were performed. Medline, Embase and Cochrane databases were searched from inception to 31 December 2017. Evidence on imaging was excluded as recently published in dedicated EULAR recommendations. This paper focuses on the data relevant to giant cell arteritis (GCA). Results: We identified 287 eligible articles (122 studies focused on diagnosis/monitoring, 165 on treatment). The implementation of a fast-track approach to diagnosis significantly lowers the risk of permanent visual loss compared with historical cohorts (level of evidence, LoE 2b). Reliable diagnostic or prognostic biomarkers for GCA are still not available (LoE 3b).The SLR confirms the efficacy of prompt initiation of glucocorticoids (GC). There is no high-quality evidence on the most appropriate starting dose, route of administration, tapering and duration of GC (LoE 4). Patients with GCA are at increased risk of dose-dependent GC-related adverse events (LoE 3b). The addition of methotrexate or tocilizumab reduces relapse rates and GC requirements (LoE 1b). There is no consistent evidence that initiating antiplatelet agents at diagnosis would prevent future ischaemic events (LoE 2a). There is little evidence to guide monitoring of patients with GCA. Conclusions: Results from two SLRs identified novel evidence on the management of GCA to guide the 2018 update of the EULAR recommendations on the management of LVV.

Extracellular vesicles in autoimmune vasculitis - Little dirts light the fire in blood vessels.

Systemic vasculitis is diverse group of autoimmune disorders which are characterized by inflammation of blood vessel walls with deep aching and burning pain. Their underlying etiology and pathophysiology still remain poorly understood. Extracellular vesicles (EVs), including exosomes, microvesicles (MVs), and apoptotic bodies, are membrane vesicular structures that are released either during cell activation, or when cells undergo programmed cell death, including apoptosis, necroptosis, and pyroptosis. Although EVs were thought as cell dusts, but now they have been found to be potently active since they harbor bioactive molecules, such as proteins, lipids, nucleic acids, or multi-molecular complexes. EVs can serve as novel mediators for cell-to-cell communications by delivery bioactive molecules from their parental cells to the recipient cells. Earlier studies mainly focused on MVs budding from membrane surface. Recent studies demonstrated that EVs may also carry molecules from cytoplasm or even from nucleus of their parental cells, and these EVs may carry autoantigens and are important in vasculitis. EVs may play important roles in vasculitis through their potential pathogenic involvements in inflammation, autoimmune responses, procoagulation, endothelial dysfunction/damage, angiogenesis, and intimal hyperplasia. EVs have also been used as specific biomarkers for diagnostic use or disease severity monitoring. In this review, we have focused on the aspects of EV biology most relevant to the pathogenesis of vasculitis, discussed their perspective insights, and summarized the exist literature on EV relevant studies in vasculitis, therefore provides an integration of current knowledge regarding the novel role of EVs in systemic vasculitis.

Pulmonary nodules in a patient with Giant Cell Arteritis.

Giant Cell Arteritis (GCA) is a common systemic vasculitis that involves medium and large arteries, most frequently extracranial branches of the carotid artery. Prompt diagnosis and treatment is essential to prevent devastating complications, such as blindness, stroke and aortic aneurysm or dissection. Typical symptoms include headache, temporal artery tenderness and jaw claudication. On rare occasions patients present with complaints related to pulmonary involvement. These include interstitial infiltration, pulmonary nodules, pleural effusion and pulmonary haemorrhage. The authors report the case of a 74-year-old man who presented with symptoms compatible with GCA confirmed by temporal biopsy, and pulmonary nodules. These lesions were biopsied and histological exam confirmed features compatible with systemic vasculitis. The lesions resolved after two months of steroid treatment. This case shows that we should be aware of atypical GCA manifestations.

Clinical, electrophysiological and laboratory parameters, and outcome in patients with biopsy proven systemic and nonsystemic vasculitic neuropathy.

AIM: To describe the clinical and laboratory findings of patients with biopsy proven vasculitic neuropathy. INTRODUCTION: Peripheral neuropathies form one of the most common disorders of the nervous system. However, more than 50% of them are labelled as 'idiopathic' and, therefore, treatment options become less. In this study, we tried to evaluate the phenotypic as well as laboratory characteristics and outcome of patients with biopsy proven vasculitic neuropathy. PATIENTS AND METHODS: Review of biopsy proven definite or probable vasculitic neuropathy was done. RESULTS: The cohort consisted of 67 subjects. There were 21 patients of systemic vasculitis (SVS) and 46 of non-systemic vasculitic neuropathy (NSVN). The nerve biopsy revealed definite vasculitis in 37 and probable vasculitis in 30 patients. The symptoms at onset were paraesthesia (68.7%), and paraesthesia and weakness (28.4%). Diffuse polyneuropathy occurred in 70.1% patients. The course was chronic in the majority (80.59%) of patients. Electrophysiology revealed mononeuritis multiplex in 32.84%, and polyneuropathy in 67.16% of patients. Pure sensory neuropathy was present in 16.42%. Among the patients who had undergone bilateral nerve conduction studies, the majority (71.05%) of patients had an asymmetric neuropathy. An elevated erythrocyte sedimentation rate (ESR) was observed in 80.59% (mean 71.57 ± 30.81 mm/1hr [in SVS] and 35.24 ± 21.62mm/1 hr in NSVN) of patients. The treatment included steroids, other immunomodulators, and symptomatic medications. The mean follow up was 10.98 ± 9.58 months. The outcome was good in 73.46% (43.8% with SVS and 87.88% with NSVN) patients, with those having a NSVN having a significantly better outcome. CONCLUSION: Vasculitis is a potentially treatable cause of peripheral neuropathy. The clinical features, electrophysiology, laboratory results and nerve biopsy may help in the diagnosis and categorization of patients into non-systemic and systemic vasculitic neuropathies. The long-term outcome is better in patients with NSVN compared to those with systemic vasculitis.

Prognosis and future developments in vasculitis.

The prognosis of ANCA-associated vasculitis has been transformed in recent years. Once it was a set of invariably acute and fatal conditions, but these disorders are currently considered to be chronic diseases. This change is largely attributable to earlier diagnosis and the careful application of immunotherapeutics. However, patients still experience premature mortality, relapse, comorbid ill health and poor quality of life. Mortality rates in large-vessel vasculitis are not comparable; however, morbidity and poor patient outcomes prevail. Toxicity secondary to glucocorticoids represents a common driver of poor outcomes across systemic vasculitis. The main thrust of future treatment strategies is to reduce if not eliminate exposure to these agents.

Investigations in systemic vasculitis - The role of imaging.

Imaging plays an increasing role for confirming a suspected diagnosis of giant cell arteritis (GCA) or Takayasu arteritis (TAK). Ultrasound, magnetic resonance imaging (MRI), and computed tomography demonstrate a homogeneous, most commonly concentric, arterial wall thickening. 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) displays increased FDG uptake of inflamed artery walls delineating increased metabolism. Ultrasound and MRI are recommended to be the initial imaging modalities in cranial GCA and TAK, respectively. Extracranial disease can be confirmed by all four modalities, particularly by PET in case of inflammation of unknown origin. If the diagnosis remains uncertain, additional investigations including biopsy and/or additional imaging are recommended. Imaging should be performed by a trained specialist using appropriate operational procedures and settings with appropriate equipment. Further research is necessary on the role of imaging for disease monitoring. This review will discuss advantages and disadvantages of imaging modalities in the diagnosis of vasculitis.

Immune-Mediated Systemic Vasculitis as the Proposed Cause of Sudden-Onset Sensorineural Hearing Loss following Lassa Virus Exposure in Cynomolgus Macaques.

Lassa virus (LASV) causes a severe, often fatal hemorrhagic disease in regions in Africa where the disease is endemic, and approximately 30% of patients develop sudden-onset sensorineural hearing loss after recovering from acute disease. The causal mechanism of hearing loss in LASV-infected patients remains elusive. Here, we report findings after closely examining the chronic disease experienced by surviving macaques assigned to LASV exposure control groups in two different studies. All nonhuman primates (NHPs) developed typical signs and symptoms of Lassa fever, and seven succumbed during the acute phase of disease. Three NHPs survived beyond the acute phase and became chronically ill but survived to the study endpoint, 45 days postexposure. All three of these survivors displayed continuous disease symptoms, and apparent hearing loss was observed using daily subjective measurements, including response to auditory stimulation and tuning fork tests. Objective measurements of profound unilateral or bilateral sensorineural hearing loss were confirmed for two of the survivors by brainstem auditory evoked response (BAER) analysis. Histologic examination of inner ear structures and other tissues revealed the presence of severe vascular lesions consistent with systemic vasculitides. These systemic immune-mediated vascular disorders have been associated with sudden hearing loss. Other vascular-specific damage was also observed to be present in many of the sampled tissues, and we were able to identify persistent virus in the perivascular tissues in the brain tissue of survivors. Serological analyses of two of the three survivors revealed the presence of autoimmune disease markers. Our findings point toward an immune-mediated etiology for Lassa fever-associated sudden-onset hearing loss and lay the foundation for developing potential therapies to prevent and/or cure Lassa fever-associated sudden-onset hearing loss.IMPORTANCE Lassa virus is one of the most common causes of viral hemorrhagic fever. A frequent, but as yet unexplained, consequence of infection with Lassa virus is acute, sudden-onset sensorineural hearing loss in one or both ears. Deafness is observed in approximately 30% of surviving Lassa fever patients, an attack rate that is approximately 300% higher than mumps virus infection, which was previously thought to be the most common cause of virus-induced deafness. Here, we provide evidence from Lassa virus-infected cynomolgus macaques implicating an immune-mediated vasculitis syndrome underlying the pathology of Lassa fever-associated deafness. These findings could change the way human Lassa fever patients are medically managed in order to prevent deafness by including diagnostic monitoring of human survivors for onset of vasculitides via available imaging methods and/or other diagnostic markers of immune-mediated vascular disease.

Diagnostic and prognostic role of renal histopathology in rheumatic diseases.

The objective was to evaluate renal involvement in several rheumatic diseases (i.e. rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, systemic sclerosis, systemic vasculitides). The method chosen was to define histopathological profiles reported in renal biopsies performed on patients with renal involvement due to different rheumatic diseases. Renal involvement observed in patients with rheumatic disease can be the direct result of the disease per se and/or a complication of drugs used in the disease treatment. The clinical-pathological correlations derived from the study of renal tissues can be useful for differential diagnosis, prognosis assessment and therapeutic decisions. Renal biopsy should be considered as an important tool for the management of nephropathies in patients with systemic rheumatic diseases.

Histopathology of the skin in rheumatic diseases.

Rheumatological systemic autoimmune diseases, such as connective tissue diseases, rheumatoid arthritis or spondyloarthritis, are characterized by the presence of joint involvement associated with extra-articular manifestations. Among them, cutaneous diseases are often the most relevant and representative clinical manifestation, as in psoriatic arthritis, scleroderma or systemic lupus erythematosus. In this context, it is useful for rheumatologists to understand better skin diseases and their histopathological features. Evaluation of skin biopsy specimens can be helpful not only to confirm the diagnosis in both classic and clinically atypical variants, but also to improve further our knowledge of the pathogenetic mechanisms and the close link between skin and articular diseases. In this review, we discuss the clinical features, diagnostic evaluation and the histopathological features of skin manifestation of the most relevant rheumatological autoimmune diseases.

Mast cells and primary systemic vasculitides.

Vasculitides are characterized by inflammation and necrosis of blood vessels leading to vessel occlusion and ischemic damages of tissues. Among the inflammatory cells involved in vasculitides, neutrophils, T cells, and macrophages have been identified as the predominant cell type. This review article is focused on the role of mast cells in these chronic inflammatory processes. Mast cells are characterized by their complex plasticity. Increasing evidences document that mast cells exert both pro- and anti-inflammatory functions depending on the cell types and the microenvironment they reside in. In this context, mast cell mediators able to modulate progression of vasculitides at different levels and the anatomic localization of mast cells in different vasculitides will be described. Finally, therapeutic approach including inhibition of recruitment of mast cells to the inflammatory infiltrate and blockade of their proinflammatory effects and proangiogenic functions as potential new targets for the treatment of these diseases will be discussed.

New use for an old treatment: Hydroxychloroquine as a potential treatment for systemic vasculitis.

Antimalarials have been an effective and safe treatment for autoimmune rheumatic diseases such as systemic lupus erythematosus for more than a hundred years. There are surprisingly few reports of hydroxychloroquine use in the systemic vasculitides. Hydroxychloroquine has antithrombotic, cardiovascular, antimicrobial and antineoplastic effects, making it a potentially valuable treatment for patients with systemic vasculitis who are at risk of infections, malignancy and thrombotic events. We report the successful use of hydroxychloroquine in patients with ANCA vasculitis, Henoch Schonlein purpura/IgA vasculitis, Takayasu's arteritis and polyarteritis nodosa. We review the immunomodulatory mechanisms of action of hydroxychloroquine and the existing evidence for its use in the treatment of vasculitis, with a particular focus on ANCA subtypes.

An Autopsy Case of Myeloperoxidase-anti-neutrophil Cytoplasmic Antibody (MPO-ANCA)-associated Vasculitis Accompanied by Cryoglobulinemic Vasculitis Affecting the Kidneys, Skin, and Gastrointestinal Tract.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and cryoglobulinemic vasculitis (CV) rarely coexist. An 83-year-old woman was admitted with rapidly progressive renal failure, gastrointestinal hemorrhage and purpura with myeloperoxidase (MPO)-ANCA positivity and cryoglobulinemia. Despite intensive immunosuppressive treatment, she died of aspergillus pneumonia. Autopsy revealed necrotizing crescentic glomerulitis in the majority of the glomeruli, accompanied by partially membranoproliferative-like glomerular changes. Immunofluorescence staining revealed the presence of neutrophil extracellular trap (NET) formation in the glomeruli and cutaneous arteries. These pathological findings suggested that MPO-AAV and/or CV caused NET formation, leading to lethal systemic vasculitis.