MR Vessel Wall Imaging for Atherosclerosis and Vasculitis.

Conventional imaging modalities, such as computed tomography angiography, MR angiography, transcranial Doppler ultrasonography, and digital subtraction angiography, are utilized in evaluating intraluminal or intravascular pathology of the intracranial vessels. Limitations of luminal imaging techniques can lead to inaccurate diagnosis, evaluation, and risk stratification, as many cerebrovascular pathologies contain an extrinsic vessel wall component. Furthermore, vessel wall imaging can provide information regarding extent, treatment response, and biopsy targets for vasculitis cases. Overall, while vessel wall imaging can provide robust data regarding intracranial pathologies, further prospective, multicenter studies are required to improve diagnostic application and accuracy.

To ASLO or Not to ASLO: Utility of the ASLO Test in Dermatology.

BACKGROUND: Group A Streptococcus (GAS) causes a wide spectrum of acute infections and immune-related diseases, most of which include a dermatological presentation. However, dermatological findings have a wide range of other possible etiologies. The diagnosis of GAS-related disease requires an indication of preceding GAS infection by direct culture or by measuring antistreptolysin O (ASLO) titer. OBJECTIVES: To explore the correlation between ASLO positivity and dermatological diseases. METHODS: We analyzed clinical data from all cases of patients over 18 years of age who underwent ASLO testing between the years 2016 and 2020 in the Department of Dermatology at Rambam Health Care Campus. RESULTS: Of 152 adult patients with ASLO tests, 100 had diagnoses that were potentially related to streptococcal infection. Vasculitis and psoriasis were the most suspected diagnoses. Positive ASLO test was found in 44 (29%) patients. The diagnoses showing the highest ratio of positive ASLO were psoriasis (60%), erythema nodosum (46%), skin infections (43%), Sweet syndrome (33%), and vasculitis (15%). Psoriasis types included plaque psoriasis (8 patients), guttate psoriasis (3 patients), and palmoplantar pustulosis and erythroderma (2 patients each). CONCLUSIONS: Although the applicability of ASLO for the spectrum of dermatological diseases remains unclear, our results enhance the practical relevance of the test. We showed a higher prevalence of positive ASLO tests in psoriasis and erythema nodosum cases and a lower prevalence in vasculitis. Notably, ASLO was positive in all psoriasis subtypes, suggesting high utility of the test for psoriasis.

Necrotizing mesenteric vasculitis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder which may affect the gastrointestinal system. Half of the patients with SLE experience gastrointestinal symptoms, with the most common being nausea, vomiting, anorexia, and abdominal pain. Mesenteric vasculitis is a severe and rare complication of SLE and one of the most frequent causes of severe acute abdominal pain. The authors present a case of a 57-year-old woman with SLE who was diagnosed with necrotizing mesenteric vasculitis following a urinary septic shock. The patient was treated with high-dose corticosteroid therapy and cyclophosphamide, with resolution of the clinical picture.

Anti-LAMP-2 Antibody Seropositivity in Children with Primary Systemic Vasculitis Affecting Medium- and Large-Sized Vessels.

Chronic primary systemic vasculitis (PSV) comprises a group of heterogeneous diseases that are broadly classified by affected blood vessel size, clinical traits and the presence (or absence) of anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3 (PR3) and myeloperoxidase (MPO). In small vessel vasculitis (SVV), ANCA are not present in all patients, and they are rarely detected in patients with vasculitis involving medium (MVV) and large (LVV) blood vessels. Some studies have demonstrated that lysosome-associated membrane protein-2 (LAMP-2/CD107b) is a target of ANCA in SVV, but its presence and prognostic value in childhood MVV and LVV is not known. This study utilized retrospective sera and clinical data obtained from 90 children and adolescents with chronic PSV affecting small (SVV, n = 53), medium (MVV, n = 16), and large (LVV, n = 21) blood vessels. LAMP-2-ANCA were measured in time-of-diagnosis sera using a custom electrochemiluminescence assay. The threshold for seropositivity was established in a comparator cohort of patients with systemic autoinflammatory disease. The proportion of LAMP-2-ANCA-seropositive individuals and sera concentrations of LAMP-2-ANCA were assessed for associations with overall and organ-specific disease activity at diagnosis and one-year follow up. This study demonstrated a greater time-of-diagnosis prevalence and sera concentration of LAMP-2-ANCA in MVV (52.9% seropositive) and LVV (76.2%) compared to SVV (45.3%). Further, LAMP-2-ANCA-seropositive individuals had significantly lower overall, but not organ-specific, disease activity at diagnosis. This did not, however, result in a greater reduction in disease activity or the likelihood of achieving inactive disease one-year after diagnosis. The results of this study demonstrate particularly high prevalence and concentration of LAMP-2-ANCA in chronic PSV that affects large blood vessels and is seronegative for traditional ANCA. Our findings invite reconsideration of roles for autoantigens other than MPO and PR3 in pediatric vasculitis, particularly in medium- and large-sized blood vessels.

ANCA in patients with systemic lupus erythematosus. A cross sectional study in Brazilian patients and review of literature.

BACKGROUND: Antineutrophil cytoplasmatic antibodies (ANCA) have been detected in patients with systemic lupus erythematosus (SLE). In this study, we investigated the presence of ANCA in a sample of Brazilian SLE patients and its possible associations with clinical and serological outcomes. Additionally, we reviewed the literature of on ANCA in SLE. RESULTS: The presence of ANCA was detected in 130 patients using indirect immunofluorescence (IIF). The test was positive in 29.9% of the cases (17.6% pANCA and 11.5% cANCA). Male sex and peripheral vasculitis were more prevalent in the ANCA-positive sample. cANCA was associated with lupus anticoagulant and pANCA had a positive association with peripheral vasculitis and a negative association with anti- SSB/La antibodies. In the 22 studies included in the literature review, a wide range of ANCA positivity was found (13% to 81.1% by IIF and 0 to 22.2% by ELISA). ANCA was associated with renal damage in the Asian population. Although other associations have been found in isolated studies, they were not consistently reported. CONCLUSIONS: The ANCA prevalence found in this Brazilian sample was within the range reported in the literature and these autoantibodies were more frequent in males and in patients with vasculitis. The literature showed controversial results on the association between ANCA and SLE disease activity or clinical characteristics.

Syndrome of inappropriate antidiuretic hormone release secondary to central nervous system coccidioidomycosis with vasculitis.

A man in his 60s presented to the clinic due to night sweats and weight loss following pneumonia. He was found to have hyponatraemia due to a syndrome of inappropriate antidiuretic hormone (SIADH). CT of the thorax was concerning for pulmonary nodules. He was ultimately diagnosed with pulmonary coccidioidomycosis (CM) and started on fluconazole 400 mg daily with improvement in symptoms. Due to the report of headaches, head MRI was conducted which suggested central nervous system (CNS) involvement. Cerebrospinal fluid analysis was consistent with CNS CM and head magnetic resonance angiography confirmed the presence of CNS vasculitis. Fluconazole dose was increased to 800 mg daily which the patient continued to tolerate and showed improvement. This report depicts a case of SIADH associated with CNS CM with vasculitis and demonstrates the importance of high clinical suspicion for SIADH secondary to CNS CM in the setting of hyponatraemia and headache.

Frosted branch angiitis in a patient with systemic juvenile idiopathic arthritis: a case report.

BACKGROUND: Frosted branch angiitis is a retinal vascular condition that is associated with a viral infection or autoimmune disorders like Crohn's disease, systemic lupus erythematosus, and Behcet's disease. Frosted branch angiitis presents with vascular inflammation, retinal edema, and severe retinal vascular sheathing. We present a case of systemic juvenile idiopathic arthritis, an autoinflammatory disease, presenting with frosted branch angiitis. REPORT OF CASE: A 14-year-old female with systemic juvenile idiopathic arthritis and a history of bilateral anterior uveitis developed acute unilateral vision loss and was found to have frosted branch angiitis complicated by branch retinal vein occlusion. She underwent an extensive serology workup and aqueous viral PCR to rule out other possible autoimmune and viral etiologies for forested branch angiitis. She received systemic and intravitreal antiviral treatment due to positive CMV IgM initially. However, the clinical picture improved following the use of a higher dose of oral steroids and the switch of the immunosuppressive agent to a TNF-a inhibitor. CONCLUSION: To our knowledge, this would be the first case in the literature demonstrating a systemic juvenile idiopathic arthritis patient presenting with frosted branch angiitis. Infectious causes still must be ruled out, especially CMV, as it is the most common cause of secondary frosted branch angiitis.

Automated whole slide morphometry of sural nerve biopsy using machine learning.

AIM: The morphometry of sural nerve biopsies, such as fibre diameter and myelin thickness, helps us understand the underlying mechanism of peripheral neuropathies. However, in current clinical practice, only a portion of the specimen is measured manually because of its labour-intensive nature. In this study, we aimed to develop a machine learning-based application that inputs a whole slide image (WSI) of the biopsied sural nerve and automatically performs morphometric analyses. METHODS: Our application consists of three supervised learning models: (1) nerve fascicle instance segmentation, (2) myelinated fibre detection and (3) myelin sheath segmentation. We fine-tuned these models using 86 toluidine blue-stained slides from various neuropathies and developed an open-source Python library. RESULTS: Performance evaluation showed (1) a mask average precision (AP) of 0.861 for fascicle segmentation, (2) box AP of 0.711 for fibre detection and (3) a mean intersection over union (mIoU) of 0.817 for myelin segmentation. Our software identified 323,298 nerve fibres and 782 fascicles in 70 WSIs. Small and large fibre populations were objectively determined based on clustering analysis. The demyelination group had large fibres with thinner myelin sheaths and higher g-ratios than the vasculitis group. The slope of the regression line from the scatter plots of the diameters and g-ratios was higher in the demyelination group than in the vasculitis group. CONCLUSION: We developed an application that performs whole slide morphometry of human biopsy samples. Our open-source software can be used by clinicians and pathologists without specific machine learning skills, which we expect will facilitate data-driven analysis of sural nerve biopsies for a more detailed understanding of these diseases.

Leukocytoclastic Vasculitis Localized to the Uterine Cervix.

Patients with gynecologic vasculitis should be evaluated for systemic disease as prognosis and treatment can vary depending on systemic involvement versus isolated disease. Leukocytoclastic vasculitis is a rare, immune-mediated small-vessel vasculitis. Leukocytoclastic vasculitis of the uterine cervix with systemic involvement has not previously been reported. A 25-year-old female with abnormal cervical cancer screening presented for colposcopy. Biopsies were notable for dysplasia and concurrent leukocytoclastic vasculitis. The patient later recalled a recurrent rash of her lower extremities, suspicious for systemic disease. Patients with gynecologic vasculitis should be evaluated for systemic involvement because prognosis and treatment differ from that of isolated disease. Additionally, leukocytoclastic vasculitis of the uterine cervix may be associated with both hormonal contraception and infections such as human papillomavirus, and any resulting cervical dysplasia should be monitored for progression and treated accordingly.

[Biologicals in rheumatology: an overview of mechanisms of action and applications]. / Biologicals in de reumatologie.

The development of biological disease-modifying anti-rheumatic drugs (bDMARDs) has been a breakthrough in rheumatology. In this article, the general principles of bDMARD-treatment will be described based on 2 patient cases. Most bDMARDs inhibit cytokines: signaling molecules that transmit messages within the immune system. Because specific cytokines play a dominant role in different rheumatic diseases, this determines which agent is used for which indication. Another group of bDMARDs targets B cells, and is increasingly used for the treatment of SLE and vasculitis. Finally, we will briefly discuss side effects and precautions to provide an optimal overview for understanding rheumatologic bDMARD-treatment.

Prospects of targeting JAK/STAT signal transduction pathways for vasculitis.

Vasculitis is the inflammation of blood vessels caused by autoimmunity and/or autoinflammation, and its etiology and pathogenesis remain largely unknown. The Janus kinase (JAK) and Signal transduction Transcription Activator (STAT) signal transduction pathways are a group of molecules involved in the major pathways by which many cytokines exert and integrate their functions, and their dysregulation has been implicated in the pathogenesis of a variety of autoimmune diseases. However, current data supporting the role of the JAK/STAT pathway in the development of vasculitis is limited. In terms of treatment, glucocorticoids and immunosuppressants have been the standard therapy. However, because of the huge burden of treatment side effects, people have long waited for new treatment options. JAK inhibitors reduce the production of multiple cytokines and inhibit inflammation by targeting the JAK/STAT pathway, and have the advantage of rapidly acting in oral formulations, reducing glucocorticoid dependence and associated adverse events, especially in refractory cases. Therefore, JAK inhibitors are expected to be a promising drug for the treatment of vasculitis.

Comparison of characteristics of muscle magnetic resonance imaging findings in patients with antineutrophilic cytoplasmic antibody-associated vasculitis and polyarteritis nodosa.

AIM: This study aimed to analyze the muscle magnetic resonance imaging (MRI) findings of patients with antineutrophilic cytoplasmic antibody-associated vasculitis (AAV) and polyarteritis nodosa (PAN) presenting with clinical symptoms in the extremities. METHODS: Retrospective analysis was conducted on short tau inversion recovery MRI findings, with a focus on intramuscular vessels displaying abnormal perivascular signals, in 22 and eight patients with AAV and PAN, respectively. The number per unit area (4 cm2) and diameter of abnormal vessels on muscle MRI were compared between patients with AAV and those with PAN. Cut-off values, clinical sensitivity, and specificity for these indices were calculated from the receiver operating characteristic curves to distinguish between AAV and PAN, and the relationship between the indices and clinical findings in AAV was analyzed. RESULTS: The number of abnormal vessels per unit area was significantly higher in AAV compared to PAN (p < .05). Additionally, the diameter of the abnormal vessels was significantly higher in PAN than in AAV (p < .05). The presence of >6.44 abnormal vessels per unit area or ≤3.61 mm diameter of abnormal vessels was able to predict AAV (sensitivity, 0.955; specificity, 0.625). AAV patients with peripheral neuropathy exhibited a significantly higher number of abnormal vessels per unit area than those without peripheral neuropathy (p < .05). CONCLUSIONS: Muscle MRI can detect small- to medium-vessel vasculitis and be a valuable tool for distinguishing between patients with AAV and PAN experiencing clinical symptoms in the extremities.

Extrahepatic manifestations of HCV where do we stand? / Manifestaciones extrahepáticas del VHC. ¿Dónde nos encontramos?

Hepatitis C virus (HCV) infection has been associated as up 40–70% of patients with extrahepatic manifestations (EHM) and 36 different syndromes. These could be attributed to the fact that HCV is lymphotropic, particularly B lymphotropic, and not merely hepatotropic, and could trigger immunological alterations indirectly by exerting a chronic stimulus on the immune system with production of immunoglobulins having rheumatoid activity forming immune complexes and production of cryoglobulins. Cryoglobulinemoa plays a pivotal role in producing most EHM of HCV such as vasculitis, glomerulonephritis, arthritis and neuropathies. Less frequently; while less frequently, the direct viral cytopathic effect could lead to EHMs independent of cryoglobulinemia. The mainstay of treatment of EMH has been antivirals, since interferon era to direct-acting drugs era, with no differences between the two eras, despite the better virological response. Longer evaluation of virological response and clinical investigation with longer follow-ups are necessary.(AU)

La infección por el virus hepatitis C (VHC) se ha asociado a 40-70% de los pacientes con alguna manifestación extrahepática (MEH) y 36 síndromes diferentes, atribuibles a que el VHC es linfotrópico, particularmente linfotrópico B, y no simplemente hepatotrópico. El VHC podría desencadenar alteraciones inmunológicas al ejercer un estímulo crónico del sistema inmunológico con producción de inmunoglobulinas con actividad reumatoide y formación de complejos inmunes y crioglobulinas. Estas desempeñan un papel fundamental en la mayoría de las MEH como vasculitis, glomerulonefritis, artritis y neuropatías, mientras, menos frecuentemente, el efecto citopático viral directo podría conducir a MEH independientes de crioglobulinas. El principal tratamiento de las MEH ha sido el antiviral, desde la era del interferón hasta la de los fármacos de acción directa, sin diferencias entre las dos épocas, a pesar de la mejor respuesta virológica. Son necesarias evaluaciones más prolongadas de la respuesta virológica e investigación clínica con seguimientos más largos.(AU)

Peripheral retinal finding on fluorescein angiography in neuronal ceroid lipofuscinosis type 2 (CLN2).

Classically, peripheral vascular changes in the retina in patients with neuronal ceroid lipofuscinosis type 2 (CLN2) are described as vascular attenuation seen in the late stages of disease on the Weill Connell Ophthalmic Severity Score (WCOSS) staging system. We describe isolated, mild, peripheral vasculitis with peripheral arteriolar dropout identified by fluorescein angiography in patients with a WCOSS grade of stage 2. We believe this vasculitis represents an early vasodegenerative phase of disease that leads to the vascular attenuation seen in later stages of the disease.

Idiopathic membranous nephropathy and synchronous mononeuritis multiplex secondary to idiopathic small vessel vasculitis.

Membranous nephropathy has been associated with demyelinating polyneuropathies and antiglomerular membrane disease; however, an association with vasculitic neuropathy has not been described. This case describes a patient with biopsy-proven idiopathic membranous nephropathy and synchronous mononeuritis multiplex secondary to idiopathic small vessel vasculitis, who presented with lower limb microvascular ischaemia, peripheral neuropathy and active urinary sediment. Her extensive non-invasive screening for immunological disease and radiological investigations for occult malignancy were unremarkable. The patient received intravenous methylprednisolone and intravenous rituximab induction therapy resulting in complete remission of both the idiopathic membranous nephropathy and small vessel vasculitis at 7 months post treatment.

Inhibition of IL-1 Ameliorates Cardiac Dysfunction and Arrhythmias in a Murine Model of Kawasaki Disease.

BACKGROUND: Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis often associated with cardiac sequelae, including arrhythmias. Abundant evidence indicates a central role for IL (interleukin)-1 and TNFα (tumor necrosis factor-alpha) signaling in the formation of arterial lesions in KD. We aimed to investigate the mechanisms underlying the development of electrophysiological abnormalities in a murine model of KD vasculitis. METHODS: Lactobacillus casei cell wall extract-induced KD vasculitis model was used to investigate the therapeutic efficacy of clinically relevant IL-1Ra (IL-1 receptor antagonist) and TNFα neutralization. Echocardiography, in vivo electrophysiology, whole-heart optical mapping, and imaging were performed. RESULTS: KD vasculitis was associated with impaired ejection fraction, increased ventricular tachycardia, prolonged repolarization, and slowed conduction velocity. Since our transcriptomic analysis of human patients showed elevated levels of both IL-1ß and TNFα, we asked whether either cytokine was linked to the development of myocardial dysfunction. Remarkably, only inhibition of IL-1 signaling by IL-1Ra but not TNFα neutralization was able to prevent changes in ejection fraction and arrhythmias, whereas both IL-1Ra and TNFα neutralization significantly improved vasculitis and heart vessel inflammation. The treatment of L casei cell wall extract-injected mice with IL-1Ra also restored conduction velocity and improved the organization of Cx43 (connexin 43) at the intercalated disk. In contrast, in mice with gain of function of the IL-1 signaling pathway, L casei cell wall extract induced spontaneous ventricular tachycardia and premature deaths. CONCLUSIONS: Our results characterize the electrophysiological abnormalities associated with L casei cell wall extract-induced KD and show that IL-1Ra is more effective in preventing KD-induced myocardial dysfunction and arrhythmias than anti-TNFα therapy. These findings support the advancement of clinical trials using IL-1Ra in patients with KD.