Severe infections in systemic necrotizing vasculitis.

Infections in patients with systemic vasculitis represent one of the main causes of mortality. Corticosteroid use, immunosuppressive therapy, age, associated organic involvement and dialysis dependence are risk factors of infection. OBJECTIVES: To determine the prevalence of severe infection and associated factors in patients diagnosed with ANCA-associated vasculitis (AAV) and Polyarteritis Nodosa (PAN). METHODS: retrospective study was conduced in a single rheumatology center (2000-2018). We included patients diagnosed with AAV (Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA) and Microscopic Polyangiitis (PAM) and Polyarteritis nodosa (PAN). Serious infectious events requiring hospitalisation or prolonged antibiotic/antiviral treatment, recurrent infection of Herpes Zoster Virus or opportunistic infections were evaluated. Sites of infection, isolated microorganisms and mortality related were analyzed. RESULTS: 105 patients were analyzed, follow-up time median 18 m, 58.7% were women and median age was 52 years. Types of vasculitis: 41.9% PAM, 16.2% EPGA, 40% GPA, 1.9% PAN. Constitutional, pulmonary, renal and otorhinolaryngology manifestations were the most frequent. PREVALENCE OF INFECTION: 34.2%, with a median of 3 months from diagnosis of vasculitis to the infectious event. Low respiratory tract (42.8%), sepsis (31.4%), and urinary tract (14.3%) were the most common sites of infections. Bacterial aetiology was the most prevalent (67.7%). Mortality at the first event was 14.3% and a 72.2% of patients were in the induction phase of treatment. Infectious events were significantly associated with age > 65 years (p = 0.030), presence of lung (p = 0.016) and renal involvement (p = 0.001), BVASv3 > 15, mortality (p = 0.0002). CONCLUSIONS: The prevalence of infection was 34.2%. Lower airway infections, septicemia and urinary tract infections were the most prevalent. Infections were associated with renal and pulmonary involvement, age older than 65 years and score BVAS > 15. Severe infections were associated with mortality, especially in elderly patients.

First reported case in an Irish flock of MCF- like systemic necrotizing vasculitis in sheep associated with ovine herpesvirus 2.

BACKGROUND: Ovine gammaherpesvirus 2 (OvHV-2) is the causative agent of sheep associated malignant catarrhal fever (MCF). As sheep are the adapted host for OvHV-2, it is generally presumed that infection is not associated with disease in this species. However, a recent case review combined in-situ hybridisation, PCR and histopathology and correlated the viral distribution with systemic necrotizing vasculitis and concluded OvHV-2 was the likely agent responsible for sporadic, MCF-like vascular disease in sheep. CASE PRESENTATION: Using similar methods this case study reports on the findings of the first reported cases in an Irish Flock of MCF- like systemic necrotizing vasculitis in sheep associated with OvHV-2. Sheep A, a 16-month-old Texel-cross hogget displayed signs of ill- thrift, Sheep B, a nine-month-old Belclare-cross lamb, was found dead having displayed no obvious symptoms. Both cases occurred on the same farm, however the animals were not related. Lymphohistiocytic vasculitis of various tissues was the predominant histopathological finding in both animals. CONCLUSION: By combining histopathology, PCR and in-situ hybridisation results, MCF- like systemic necrotizing vasculitis associated with OvHV-2 has been diagnosed for the first time in an Irish flock.

Neuro-Behçet With a Thalamic Lesion: A Case Report.

Behçet's disease (BD) is an autoimmune disease characterized by multisystemic variable-vessel vasculitis and oral, genital, and intestinal ulcers. Neurological involvement or "Neuro-Behçet" (NB) manifests due to parenchymal inflammation. We present the case of a 21-year-old male with a five-year-old history of intermittent chronic oral and genital ulcers who presented with headache, right hemiparesis, progressive loss of visual acuity, and a thalamic tumor-like lesion on magnetic resonance imaging (MRI). A brain biopsy showed multiple perivascular infarcts associated with vasculitis affecting arterioles, venules, and capillaries.

Renal involvement in eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis, which typically affects small-to medium-sized blood vessels. It is characterized by the presence of tissue infiltrates rich in eosinophils, along with the formation of granulomatous lesions. About 40% of cases have positive anti-neutrophil cytoplasm antibodies (ANCA), with predominant perinuclear staining, and anti-myeloperoxidase (anti-MPO) specificity in about 65% of cases. Typical manifestations of EGPA include the late onset of asthma, nasal and sinus-related symptoms, peripheral neuropathy, and significant eosinophilia observed in the peripheral blood. In contrast to granulomatosis with polyangiitis and microscopic polyangiitis, renal involvement in EGPA is less frequent (about 25%) and poorly studied. Necrotizing pauci-immune crescentic glomerulonephritis is the most common renal presentation in patients with ANCA-positive EGPA. Although rarely, other forms of renal involvement may also be observed, such as eosinophilic interstitial nephritis, mesangial glomerulonephritis, membranous nephropathy, or focal sclerosis. A standardized treatment for EGPA with renal involvement has not been defined, however the survival and the renal outcomes are usually better than in the other ANCA-associated vasculitides. Nonetheless, kidney disease is an adverse prognostic factor for EGPA patients. Larger studies are required to better describe the renal involvement, in particular for patterns different from crescentic glomerulonephritis, and to favor the development of a consensual therapeutic approach. In this article, in addition to personal data, we will review recent findings on patient clinical phenotypes based on ANCA, genetics and the impact of biological drugs on disease management.

A Case of Anti-neutrophil Cytoplasmic Antibody-Associated Vasculitis Presenting With Diffuse Alveolar Hemorrhage and Renal Sparing.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a necrotizing vasculitis disease that traditionally includes three variants classified based on their clinical and pathological appearance: microscopic polyangiitis (MPA), granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis (alternatively, Churg-Strauss syndrome). The mainstay of AAV treatment is immunosuppressive treatments, which improve survival and lower rates of end-stage kidney disease. Here we describe a patient with MPA ANCA who presented with diffuse alveolar hemorrhage and, six months later, recurrent pulmonary hemorrhage with renal sparing while off therapy.

Clinical features and long-term outcomes of patients with systemic polyarteritis nodosa diagnosed since 2005: Data from 196 patients.

BACKGROUND: The landscape of polyarteritis nodosa (PAN) has substantially changed during the last decades. Recent data regarding causes, characteristics, and prognosis of systemic PAN in the modern era are lacking. METHODS: This retrospective study included patients with systemic PAN referred to the French Vasculitis Study Group between 2005 and 2019. Characteristics, associated conditions and outcomes were collected, and predictors of relapse and death were analyzed. RESULTS: 196 patients were included. Main clinical symptoms were constitutional (84%), neurological (59%), skin (58%) and musculoskeletal (58%) manifestations. Secondary PAN accounted for 55 (28%) patients, including myelodysplastic syndrome (9%), solid cancer (7%), lymphoma (4%) and autoinflammatory diseases (4%). No patient had active HBV infection. All treated patients (98.5%) received glucocorticoids (GCs), alone (41%) or in combination with immunosuppressants (59%), with remission achieved in 90%. Relapses were independently associated with age >65 years (HR 1.85; 95% CI1.12-3.08), gastrointestinal involvement (1.95; 95% CI1.09-3.52) and skin necrotic lesions (HR 1.95; 95%CI 1.24-3.05). One-, 5- and 10-year overall survival rates were 93%, 87% and 81%, respectively. In multivariate analyses, age >65 years (HR 2.80; 95%CI 1.23-6.37), necrotic purpura (HR 4.16; 95%CI 1.62-10.70), acute kidney injury (HR 4.89; 95% 1.71-13.99) and secondary PAN (HR 2.98; 95%CI 1.29-6.85) were independently associated with mortality. CONCLUSION: Landscape of PAN has changed during the last decades, with the disappearance of HBV-PAN and the emergence of secondary PAN. Relapse rate remains high, especially in aged patients with gastrointestinal and cutaneous necrosis, as well as mortality.

Expert perspectives on pathological findings in vasculitis.

Pathological findings are important in the diagnosis of vasculitis. However, due to the rarity of the disease, standard textbooks usually devote only a few pages to this topic, and this makes it difficult for clinicians not specializing in vasculitis to fully understand the pathological findings in vasculitis. To address the paucity of information, we present representative pathological findings in vasculitis classified in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012). The CHCC2012 classifies 26 vasculitides into seven categories: (1) large-vessel vasculitis, (2) medium-vessel vasculitis, (3) small-vessel vasculitis, including antineutrophil cytoplasmic antibody-associated vasculitis and immune complex small-vessel vasculitis, (4) variable-vessel vasculitis, (5) single-organ vasculitis, (6) vasculitis associated with systemic disease, and (7) vasculitis associated with probable aetiology. Moreover, representative pathological findings of vasculitis-related diseases and non-inflammatory vasculopathy not mentioned in the CHCC2012 are also presented. This will be useful for clinicians to refer to typical pathological findings of vasculitis in daily practice.

Vasculitis reumatoidea como manifestación extraarticular en dos casos / Rheumatoid vasculitis as an extra articular manifestation in two cases

La vasculitis reumatoidea es un proceso inflamatorio poco frecuente que confiere una morbilidad y mortalidad significativa en pacientes con artritis reumatoidea (AR). Presenta una incidencia de 0,7 a 5,4% de los casos de AR y hasta un 40% de mortalidad a 5 años, siendo la manifestación extraarticular de mayor gravedad1,2. Se caracteriza por el desarrollo de vasculitis necrotizante; ocurre típicamente en pacientes masculinos con AR seropositiva de larga data, nodular y erosiva, tabaquistas y, en general, tiene mal pronóstico. Se presenta una serie de casos, paciente masculino y femenino con AR y manifestaciones extraarticulares, necrosis digital y compromiso multiorgánico, interpretados como cuadros de vasculitis reumatoidea, realizando tratamiento de referencia con inmunosupresores.

Rheumatoid vasculitis is a rare inflammatory process that confers significant morbidity and mortality in patients with rheumatoid arthritis (RA); it has an incidence of 0.7 to 5.4% of RA cases and up to 40% mortality at five years, making it the most serious of all the extra-articular manifestations of RA1,2. It is characterized by the development of necrotizing vasculitis, it typically occurs in male patients with long-standing seropositive RA, erosive nodular, smokers and generally has a poor prognosis. A series of cases is presented, male and female with RA and extra-articular manifestations, digital necrosis and multiorgan system involvement, interpreted as rheumatoid vasculitis, undergoing treatment with immunosuppressants.

[HLA-B58.01 and allopurinol hypersensitivity renal vasculitis in a Chinese patient]. / HLA-B58.01 et vascularite rénale d'hypersensibilité à l'allopurinol chez un patient chinois.

INTRODUCTION: Allopurinol, widely used in the treatment of hyperuricemia and gout, has been shown to cause severe cutaneous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, as well as systemic reactions such as DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). The HLA-B*5801 allele is known to be a risk factor for severe cutaneous manifestations of hypersensitivity to allopurinol, mostly in Asian populations. OBSERVATION: We report the observation of a 47-year-old Chinese patient, with no previous medical history, carrying the HLA-B*5801 allele, who developed an isolated allopurinol hypersensitivity necrotizing renal vasculitis without cutaneous manifestations. DISCUSSION: . The identification of this allele should be proposed before prescribing allopurinol in patients originating from certain regions of Asia, and the imputability of allopurinol should be evoked in case of necrotizing renal vasculitis, even without associated cutaneous involvement.

Severe cutaneous necrotizing vasculitis with postinfectious glomerulonephritis secondary to peripherally inserted central catheter bloodstream infection.

Peripherally Inserted Central Catheters (PICCs) are widely used for hospitalized patients particularly in the oncological and hematological field. PICCs are a safe alternative to central venous catheters, mainly for medium- and long-term therapy.

Polyarteritis Nodosa: State of the art.

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that preferentially affects medium-sized vessels. The idiopathic form has become rare. Its treatment relies on corticosteroid therapy and is combined with cyclophosphamide infusions for severe forms. Secondary PANs were mainly associated with hepatitis B virus infection; they were treated with plasma exchange and antivirals in combination with short-term corticosteroid therapy. Other secondary forms of PAN are now becoming more common, such as those due to blood disorders. More recently, a monogenic form linked to adenosine deaminase-2 mutations has been identified. It requires treatment with TNF inhibitors to decrease the occurrence of ischemic central nervous system complications, which make it serious. Once remission is obtained, relapses are typically rare during PAN and affect 28% of idiopathic PANs, within an average of 26 months from the diagnosis. The prognosis has improved considerably, with 5- and 10-year survival rates of 83% and 74%.

Risk of Stroke in Systemic Necrotizing Vasculitis: A Nationwide Study Using the National Claims Database.

Objective: Evidences indicate that the risk of stroke is increased in autoimmune rheumatic diseases. This study aimed to investigate the incidence of stroke in patients with systemic necrotizing vasculitis (SNV) using the national health database. Methods: Data were obtained from the Korean National Claims database between 2010 and 2018 to identify incident SNV [anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and polyarteritis nodosa (PAN)] cases. The standardized incidence ratio (SIR) and incidence rate ratio (IRR) were calculated to estimate the risk of stroke in patients with SNV compared to the general population and among disease subgroups. Time-dependent Cox's regression analysis was performed to identify risk factors for stroke. Results: Among 2644 incident SNV cases, 159 patients (6.0%) were affected by stroke. The overall risk of stroke was significantly higher in patients with SNV compared to the general population (SIR 8.42). Stroke event rates were the highest within the first year of SNV diagnosis (67.3%). Among disease subgroups, patients with microscopic polyangiitis (MPA) exhibited higher IRR compared to PAN (adjusted IRR 1.98). In Cox's hazard analysis, older age and MPA were associated with higher risk of stroke [hazard ratio (HR) 1.05 and 1.88], whereas the administration of cyclophosphamide, azathioprine/mizoribine, methotrexate, and statins were protective in stroke (HR 0.26, 0.34, 0.49, and 0.50, respectively). Conclusion: A considerable number of SNV patients experienced stroke, especially in the early phase of disease. Older age and MPA diagnosis were associated with elevated risk of stroke, while the administration of immunosuppressive agents and statins was beneficial in preventing stroke.

[TAFRO syndrome and cutaneous necrotizing vasculitis]. / Syndrome TAFRO et vascularite nécrosante cutanée : une association inédite.

INTRODUCTION: TAFRO syndrome is a systemic inflammatory syndrome in the spectrum of Castleman's disease, associating thrombocytopenia, anasarca, fever, renal failure and/or reticulin myelofibrosis and organomegaly. Its association with necrotizing cutaneous vasculitis has not yet been reported. CASE REPORT: A 69-year-old woman presented with weight loss, fever, anasarca, organomegaly, lymphadenopathy, anuria and extensive necrotic livedo occurring after acute diarrhea. Biology showed anemia, thrombocytopenia, renal failure, hypergammaglobulinemia, a circulating B-lymphocyte clone, hypoparathyroidism and autoimmune hypothyroidism. The skin biopsy showed small vessel vasculitis with fibrinoid necrosis. Methylprednisolone infusions associated with tocilizumab were ineffective and the patient became anuric. Rituximab and plasma exchanges associated to corticosteroids allowed remission for 2 months. Combination of rituximab, cyclophosphamide and dexamethasone resulted in a prolonged remission. CONCLUSION: We report here the first case of severe cutaneous necrotizing vasculitis in a patient suffering from TAFRO syndrome. The possible resistance to tocilizumab should be known.

Multiple renal infarctions in a patient caused by granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA) is a small-vessel vasculitis that is highly associated with anti-neutrophil cytoplasmic antibodies. GPA carries an increased risk of organ infarction, but renal infarction is rare. We herein describe a case of multiple renal infarctions caused by GPA. A 66-year-old man presented with hearing loss, nasal discharge, fatigue, and weight loss for several months. Cross-sectional contrast-enhanced computed tomography images revealed multiple low-attenuation areas in both kidneys. He subsequently developed fever and impaired renal function. Blood serum was positive for cytoplasmic anti-neutrophil cytoplasmic antibody and a renal biopsy showed granulomatous necrotizing vasculitis. He was diagnosed with GPA and treated with high-dose corticosteroids, plasma exchange, and cyclophosphamide. The patient ultimately entered clinical remission.

A Patient with Necrotizing Vasculitis Related to Sarcoidosis, which Was Diagnosed via Immunohistochemical Methods Using Propionibacterium acnes-specific Monoclonal Antibodies.

Propionibacterium acnes (P. acnes) is a commensal bacterium indigenous to the skin. Previous reports have suggested that infection with P. acnes causes sarcoidosis, a systemic granulomatous disease. We present the case of a 63-year-old woman who developed subcutaneous nodules. A skin biopsy revealed necrotizing vasculitis and noncaseating granulomas, which are characteristic of sarcoidosis. Immunohistostaining revealed a P. acnes skin infection, which led to the diagnosis of sarcoidosis. Minocycline treatment resolved the infection and improved the patient's symptoms. We herein report a case in which immunohistochemistry was useful in the diagnosis of sarcoidosis.

Granulomatosis with polyangiitis (Wegener's).

Granulomatosis with polyangiitis (GPA) (Wegener) is a necrotizing vasculitis combining inflammation of the vascular wall and peri- and extravascular granulomatosis. Clinically, GPA is characterized in its full form by ENT signs, lung, and kidney involvement. One of the key features of GPA is the presence of ANCAs-cytoplasmic in approximately 90% of systemic forms and in 50% of localized forms-directed against proteinase 3 in most cases. PR3-ANCAs are highly specific to GPA and therefore have a high diagnostic value. Treatment of GPA is based on a combination of corticosteroids and cyclophosphamide or rituximab, which allows remission to be achieved in more than 80% of cases. Azathioprine was the most widely used maintenance treatment, but low-dose semi-annual rituximab maintenance infusions further decrease relapses with acceptable safety. Nevertheless, relapses occur in more than 50% of cases. One of the biggest treatment challenges is the occurrence of side effects, the severity and frequency of which are often linked to the prolonged treatment course, which is difficult to avoid.

Handgrip strength is a comorbidity marker in systemic necrotizing vasculitides and predicts the risk of fracture and serious adverse events.

OBJECTIVE: Sarcopenia has been associated with poor outcomes in various medical and surgical conditions. However, its impact in systemic necrotizing vasculitides (SNV) had never been characterized. We aimed to assess the prevalence, associated factors and prognostic impact of sarcopenia in SNV. METHODS: Patients with SNV were successively included in a prospective longitudinal study assessing comorbidities. At inclusion, we evaluated sarcopenia by assessing skeletal muscle mass index using DXA and muscle strength using handgrip strength. Vasculitis and treatments-related events were recorded and analysed using Cox models. RESULTS: One hundred and twenty patients were included. At inclusion, low handgrip strength (<30 kg for men and 20 kg for women) was identified in 28 (23%) patients, while no patient exhibited low skeletal muscle mass index (<7.23 kg/m2 for men and 5.67 kg/m2 for women). Low handgrip strength was associated with age (P <0.0001), type of vasculitis (P =0.01), vasculitis damage index (P =0.01), history of falls (P =0.0002), osteoporosis (P =0.04), low serum albumin (P =0.003) and prealbumin (P =0.0007), high CRP (P =0.001), high FRAX® tool (P =0.002) and low bone mineral density at femoral neck (P =0.0002). After median follow-up of 42 months, low handgrip strength was associated with higher risk of bone fracture [HR 4.25 (1.37-13.2), P =0.01] and serious adverse events [HR 2.80 (1.35-5.81), P =0.006]. CONCLUSION: Handgrip strength is associated in SNV with nutritional status and comorbidities such as bone disease, and seems to predict, as in other medical conditions, the risk of fracture and serious adverse events during follow-up. In contrast, assessment of skeletal muscle mass index in this population remains uncertain.

Ferroptosis and Necroptosis in the Kidney.

In the last decade, the role of apoptosis in the pathophysiology of acute kidney injury (AKI) and AKI to chronic kidney disease (CKD) progression has been revisited as our understanding of ferroptosis and necroptosis has emerged. A growing body of evidence, reviewed here, ascribes a central pathophysiological role for ferroptosis and necroptosis to AKI, nephron loss, and acute tubular necrosis. We will introduce concepts to the non-cell-autonomous manner of kidney tubular injury during ferroptosis, a phenomenon that we refer to as a "wave of death." We hypothesize that necroptosis might initiate cell death propagation through ferroptosis. The remaining necrotic debris requires effective removal processes to prevent a secondary inflammatory response, referred to as necroinflammation. Open questions include the differences in the immunogenicity of ferroptosis and necroptosis, and the specificity of necrostatins and ferrostatins to therapeutically target these processes to prevent AKI-to-CKD progression and end-stage renal disease.

Multiple ulcerations and perforation in the small intestine after steroid treatment in eosinophilic granulomatosis with polyangiitis: a case report and literature review.

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly called Churg-Strauss syndrome, is an uncommon disease with pathological features consisting of systemic necrotizing vasculitis, eosinophilic infiltration, and granulomatous or nongranulomatous extravascular eosinophilic inflammation. EGPA preferentially affects certain organ systems, including the airways, peripheral nerves, heart, kidney, and gastrointestinal tract. Although gastrointestinal involvement, such as ulcerations, is common in EGPA, gastrointestinal perforation is relatively uncommon and is associated with a poor prognosis. Ulceration, perforation, and stenosis of the gastrointestinal tract are assumed to be the result of ischemia caused by vasculitis. The histological finding in the biopsy specimens of EGPA is generally only eosinophil infiltration, and vasculitis is not often seen. Therefore, in biopsy specimens, it is difficult to distinguish eosinophilic gastroenteritis from the gastrointestinal involvement of EGPA. In addition, in general, steroid therapy is the first-choice treatment for EGPA, but some reports have described the frequent occurrence of acute ulcer or perforation of the gastrointestinal tract in association with steroid treatment. We herein report an EGPA patient who was treated with steroid therapy and subsequently developed perforation of the small intestine.

A homogeneously enhancing mass evolving into multiple hemorrhagic and necrotic lesions in amoebic encephalitis with necrotizing vasculitis.

BACKGROUND: Granulomatous amoebic encephalitis (GAE) is a rare and mostly fatal disease. Without specific symptoms, laboratory findings, or radiologic characteristics, establishing a correct diagnosis is challenging. In many cases of GAE, multiple ring-enhancing lesions with perifocal edema are observed on magnetic resonance imaging (MRI); a solitary and homogeneously enhancing mass masquerading as a malignant lymphoma that evolved into multiple hemorrhagic and necrotic lesions has rarely been reported in GAE. CASE DESCRIPTION: An immunocompetent 68-year-old man presented with transient right hemiparesis due to epilepsy. MRI revealed a well- and homogeneously enhancing mass with perifocal edema and restricted diffusion in the left parietal subcortical region. As malignant lymphoma was suspected based on MRI findings and an elevated ß2-microglobulin level in the cerebrospinal fluid, an open biopsy was performed; the pathological diagnosis was inconclusive but suggested a granulomatous disease. Although steroid therapy was administrated, subsequently the mass lesion gradually enlarged. After a second surgery for removal of the mass lesion, multiple hemorrhagic and necrotic lesions developed at the primary site and additionally in the brainstem. The patient entered a comatose state and died 3 months after admission. Histopathological examination and polymerase chain reaction analysis of the specimen revealed posthumously GAE caused by Balamuthia mandrillaris with necrotizing vasculitis. CONCLUSION: A solitary mass lesion initially mimicked a malignant lymphoma, and subsequently evolved into multiple hemorrhagic and necrotic lesions detected on T2*-weighted and susceptibility-weighted imaging. Such serial changes noted on MRI seem characteristic and suggestive of necrotizing vasculitis of GAE.