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.

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.

Type 1 Cryoglobulinemic Vasculitis Due to Monoclonal Gammopathy of Undetermined Significance Successfully Treated by Bortezomib Plus Dexamethasone.

Cryoglobulins are immunoglobulins that precipitate in cold conditions. Type I cryoglobulinemic vasculitis is associated with hematological malignancies. We herein report a case of steroid-resistant type 1 cryoglobulinemic vasculitis associated with monoclonal gammopathy of undetermined significance (MGUS) in a 47-year-old woman. By immunofixation of cryoglobulin, we found that the main component of cryoglobulin was the M protein due to MGUS, so treatment of MGUS was needed. Bortezomib+dexamethasone therapy resulted in a rapid decrease in cryoglobulin and improvement in the symptoms of cryoglobulinemic vasculitis. In refractory type I cryoglobulinemic vasculitis, treatment of the underlying gammaglobulinopathy should be considered.

Ocular manifestations of cryoglobulinemia: a reappraisal.

BACKGROUND/OBJECTIVES: To describe frequency and type of ocular manifestations in patients with cryoglobulinemic vasculitis (CV), as well as management approaches and outcomes. SUBJECTS/METHODS: This was a retrospective, observational, cohort study of patients who were diagnosed with CV at a single center and regularly underwent a comprehensive ocular assessment. RESULTS: Ophthalmologic manifestations were recorded in 16 patients (28%). The diagnoses included dry eye disease and primary Sjögren syndrome in 5 and 2 patients, respectively; peripheral ulcerative keratitis and anterior scleritis in 1 patient each; hyperviscosity syndrome and hypertensive retinopathy in 2 patients each; and Purtscher- like retinopathy in 3 patients. Twelve patients (75%) were anti-HCV/HCV RNA-positive, 11 of whom achieved a sustained virologic response (SVR) following treatment with interferon-α2b plus ribavirin or direct-acting antivirals. All patients were treated with ocular lubricants. Systemic therapeutic measures, including glucocorticoids, immunosuppressive and biologic agents, induced the disappearance or ≥50% reduction of cryoglobulins and major signs of vasculitis in 11 patients (68.7%). In the remaining 5 patients (31.3%), cryoglobulins and CV manifestations remained unchanged or decreased by <50%. The corresponding ophthalmologic assessment showed a variable degree of improvement in the ocular symptoms in all but 2 patients (87.5%). The best corrected visual acuity following treatment improved in 26 eyes, was unchanged in 3 eyes, and worsened in 3 eyes. CONCLUSIONS: Eye involvement is not a rare event in CV patients. A timely diagnosis and the correct employment of the available therapeutic measures may result in a favorable outcome of the ocular and extra-ocular manifestations.

[Evidence-based guidelines for the diagnosis and treatment of Kawasaki disease in children in China (2023)]. / ä¸­å›½å„¿ç«¥å·å´Žç— è¯Šç–—å¾ªè¯æŒ‡å—ï¼ˆ2023年）.

Kawasaki disease (KD) is an acute self-limiting vasculitis, and it is the most common cause of acquired heart disease in children under 5 years old. One of the improvement goals in pediatric quality control work for the year 2023, as announced by the National Health Commission, is to reduce the incidence of cardiac events and KD-related mortality in children with KD. In order to standardize the diagnosis, treatment, and long-term management practices of KD in China, and effectively prevent and reduce the incidence of coronary artery lesions and long-term adverse effects, the guideline working group followed the principles and methods outlined by the World Health Organization and referenced existing evidence and experiences to develop the "Evidence-based guidelines for the diagnosis and treatment of Kawasaki disease in children in China (2023)". The guidelines address the clinical questions regarding the classification and definition of KD, diagnosis of different types of KD, treatment during the acute phase of KD, application of echocardiography in identifying complications of KD, and management of KD combined with macrophage activation syndrome. Based on the best evidence and expert consensus, 20 recommendations were formulated, aiming to provide guidance and decision-making basis for healthcare professionals in the diagnosis and treatment of KD in children.

[Therapeutic effect of mycophenolate mofetil or cyclophosphamide in children with Henoch-Schönlein purpura nephritis of different age groups]. / ä¸åŒå¹´é¾„æ®µè¿‡æ•æ€§ç´«ç™œæ€§è‚¾ç‚Žæ‚£å„¿æŽ¥å—éœ‰é šé ¸é ¯æˆ–çŽ¯ç£·é °èƒºæ²»ç–—çš„ç–—æ•ˆå·®å¼‚åˆ†æž.

OBJECTIVES: To investigate the difference in the therapeutic effect of mycophenolate mofetil (MMF) or cyclophosphamide (CTX) in children with Henoch-Schönlein purpura nephritis (HSPN) of different age groups. METHODS: A retrospective analysis was conducted on the clinical data of 135 children with HSPN who were treated with MMF or CTX in the Department of Nephrology, Children's Hospital Affiliated to Capital Institute of Pediatrics, from October 2018 to October 2020. According to the immunosuppressant used, they were divided into two groups: MMF group and CTX group, and according to the age, each group was further divided into two subgroups: ≤12 years and >12 years, producing four groups, i.e, the ≤12 years MMF subgroup (n=30), the >12 years MMF subgroup (n=15), the ≤12 years CTX subgroup (n=71), and the >12 years CTX subgroup (n=19). All children were followed up for at least 12 months, and the above groups were compared in terms of clinical outcomes and the incidence rate of adverse reactions. RESULTS: There was no significant difference in the complete response rate between the MMF group and the CTX group after 3, 6, and 12 months of treatment (P>0.05). There were no significant difference in the complete response rate and the incidence rate of adverse reactions between the >12 years MMF subgroup and the ≤12 years MMF subgroup at 3, 6, and 12 months of treatment (P>0.05). The >12 years CTX subgroup had a significantly lower complete response rate than the ≤12 years CTX subgroup at 6 and 12 months of treatment (P<0.05). The >12 years CTX subgroup had a significantly higher incidence rate of adverse reactions than the >12 years MMF subgroup (P<0.05). CONCLUSIONS: The efficacy and adverse reactions of MMF are not associated with age, but the efficacy of CTX is affected by age, with a higher incidence rate of adverse reactions. CTX should be selected with caution for children with HSPN aged >12 years.

Limping as Presenting Symptom of Multisystem Inflammatory Syndrome in Children (MIS-C): a Case Report of Large Vessel Vasculitis in MIS-C.

Background: Multisystem Inflammatory Syndrome of children (MIS) is a pathological condition that occurs in response to a SARS-CoV-2 infection, the syndrome has been described as a "Kawasaki disease"-like illness and the spectrum of associated abnormalities, including vascular complications, remain to be fully defined. Objective: The aim of this article was to present a case of MISC presented with limping and associated with large vessel vasculitis. Case presentation: In this article we present a case of 10-year-old male presented to emergency department complaining of limping of one-week duration and left hip pain, associated with high grade prolonged fever, abdominal pain and weight loss. The patient was ill looking, couldn't bear weight and was admitted to pediatric intensive care unit. Laboratory workup have rule out infectious and malignant causes as well as known rheumatological causes. Inflammatory markers were elevated. Ultrasound, Doppler ultrasound, CT scan of the affected hip showed evidence of vasculitis extending from the left femoral artery reaching the left common iliac artery with intramural thrombus. According to WHO criteria the patient diagnoses was MIS-C. treatment was started immediately with IVIG and steroids in addition to anticoagulants, dramatic improvement was noticed within 24 hours. Patient was discharged after 10 days of hospitalization. Conclusion: MIS-C is a new emerging medical diagnosis after the pandemic of COVID-19. it is described a Kawasaki-like syndrome that affect small to medium vessels. This case reports a large vessel vasculitis associated with MIS-C, it helps the understand the extend of this new syndrome and the variety of complaints that may result from large vessels involvement.

[Clinicopathological characteristics and key therapeutic options for liver involvement with vasculitis].

Vasculitis, involving any levels of vessels throughout the body, has variable nonspecific clinical presentation and complicated classification, hence, the diagnose is difficult. The liver is not the major organ involved, so it is prone to overlook vasculitis-associated liver injuries. The main manifestations of vasculitis involving the liver include abnormal liver biochemistry test (mainly increase of cholestatic liver enzymes), portal hypertension, and hepatic occupying lesions. Treatment principles are primarily directed at systemic immunosuppressive therapy for vasculitis. This review summarized the classification of vasculitis, major presentations of liver involvement in vasculitis, and the principles of treatment, to improve the awareness of the rare vascular diseases.

Association between Factor XIII Activity and Clinical Course in Pediatric Patients with Immunoglobulin A Vasculitis.

BACKGROUND: Immunoglobulin A vasculitis is a systemic form of vasculitis that predominantly affects children. Factor XIII activity is decreased in some cases, and several reports have shown an association between abdominal pain and decreased factor XIII activity. However, the clinical significance of decreased factor XIII activity in pediatric immunoglobulin A vasculitis has not been fully elucidated. This study aimed to identify the association between factor XIII activity and the clinical course of pediatric patients with immunoglobulin A vasculitis. METHODS: Forty-four pediatric patients, admitted to Kita-Harima Medical Center with a clinical diagnosis of immunoglobulin A vasculitis between October 1, 2013 and September 30, 2022, were retrospectively reviewed, and 22 patients were analyzed. The patients' background characteristics and clinical course were compared between the normal and decreased factor XIII activity (<70%) groups. RESULTS: The group with decreased factor XIII activity showed a significantly increased duration of hospitalization (14 [6-36] vs. 7 [5-13] days, p = 0.01), total glucocorticoid dose (prednisolone 22.7 [4.9-55.5] vs. 10.1 [3.4-19.6] mg/kg, p = 0.02), and duration of glucocorticoid administration (19 [4-85] vs. 10 [3-15] days, p = 0.03). Correlational analyses showed that these three parameters were negatively correlated with factor XIII activity. CONCLUSIONS: Factor XIII activity was negatively correlated with the duration of hospitalization, total glucocorticoid dose, and duration of glucocorticoid administration. Factor XIII activity is not only associated with abdominal symptoms but also may be a marker to predict the overall trajectory of acute-phase treatment in pediatric patients with immunoglobulin A vasculitis.

A narrative review of potential drug treatments for nephritis in children with IgA vasculitis (HSP).

Immunoglobulin A (IgA) vasculitis (IgAV, also known as Henoch-Schoenlein purpura, HSP) is the most common vasculitis of childhood. It usually presents with a simple, self-limiting disease course; however, a small subset of patients may develop kidney involvement (IgAV-N) which occurs 4-12 weeks after disease onset and is the biggest contributor to long-term morbidity. Treatment currently targets patients with established kidney involvement; however; there is a desire to work towards early prevention of inflammation during the window of opportunity between disease presentation and onset of significant nephritis. There are no clinical trials evaluating drugs which may prevent or halt the progression of nephritis in children with IgAV apart from the early use of corticosteroids which have no benefit. This article summarises the latest scientific evidence and clinical trials that support potential therapeutic targets for IgAV-N that are currently being developed based on the evolving understanding of the pathophysiology of IgAV-N. These span the mucosal immunity, B-cell and T-cell modulation, RAAS inhibition, and regulation of complement pathways, amongst others. Novel drugs that may be considered for use in early nephritis include TRF-budesonide; B-cell inhibiting agents including belimumab, telitacicept, blisibimod, VIS649, and BION-1301; B-cell depleting agents such as rituximab, ofatumumab, and bortezomib; sparsentan; angiotensin converting enzyme inhibitors (ACE-Is); and complement pathway inhibitors including avacopan, iptacopan, and narsoplimab. Further clinical trials, as well as pre-clinical scientific studies, are needed to identify mechanistic pathways as there may be an opportunity to prevent nephritis in this condition. Key Points • Kidney involvement is the main cause of long-term morbidity and mortality in IgA vasculitis despite the current treatment recommendations. • The evolving understanding of the pathophysiology of IgA vasculitis is allowing exploration of novel treatment options which target underlying immune pathways. • Novel treatments currently being trialled in IgA nephropathy may have benefit in IgA vasculitis due to the similarities in the underlying pathophysiology, such as TRF-budesonide, B-cell modulators, and complement inhibitors. • Further studies, including clinical trials of novel drugs, are urgently needed to improve the long-term outcomes for children with IgA vasculitis nephritis.

Cytomegalovirus colitis unmasking human immunodeficiency virus infection as a cause of IgA vasculitis.

BACKGROUND: Human immunodeficiency virus (HIV) has a protean clinical picture, in rare instances manifesting as systemic autoimmune disorders such as vasculitides. HIV-induced autoimmune diseases often do not respond well to systemic immunosuppressive therapy. Opportunistic infections may occur in patients with either acquired immunodeficiency syndrome (AIDS) or heavy immunosuppressive treatment, and can further complicate the clinical presentation. CASE PRESENTATION: A patient presenting with immunoglobulin A (IgA) vasculitis (IgAV) with treatment-refractory purpuric skin rash and suspect intestinal vasculitis was discovered to have AIDS. HIV was the trigger of IgAV, and cytomegalovirus (CMV) colitis mimicked intestinal vasculitis. Antiretroviral treatment improved both CMV colitis and the control of the autoimmune disease. CONCLUSIONS: An autoimmune disease relapsing despite adequate immunosuppressive treatment and/or the presence of recurrent severe opportunistic infections may be clues to an underlying HIV infection.

Normocomplementemic urticarial vasculitis in a patient with multiple sclerosis on glatiramer acetate.

Glatiramer acetate is one of the oldest and safest disease modifying therapies used to treat relapsing-remitting multiple sclerosis. Urticarial vasculitis is a rare complication of treatment with glatiramer acetate, having been reported by only two others previously. Here, we describe a case of normocomplementemic urticarial vasculitis diagnosed on skin punch biopsy in a patient with multiple sclerosis treated with glatiramer acetate for five years. Upon treatment with steroids and an antihistamine along with discontinuation of glatiramer acetate, the urticaria resolved.

Managing Immunosuppression in Vasculitis Patients in Times of Coronavirus Disease 2019.

The coronavirus disease 2019 (COVID-19) pandemic has led to the emergence of multiple challenges in the care of patients with systemic rheumatic diseases. Patients with vasculitis represent a group of particular concern due to existing risk factors which include a higher burden of comorbidities and specific immunosuppressive therapies used for treatment. Vaccination and the use of other risk mitigation strategies are crucial for the care of these patients. This review provides an overview of existing evidence to contribute to the understanding and specific requirements of the treatment and management of patients with vasculitis during the time of COVID-19.

Steroid sparing in vasculitis: Myth or reality?

Glucocorticoids are the cornerstone of therapy for all forms of vasculitis. However, glucocorticoid treatment carries with it the risk of glucocorticoid toxicity. Recent research efforts in vasculitis have emphasized investigation into strategies that reduce glucocorticoid exposure. These strategies include the adoption of rapid-acting steroid-sparing agents, reduced-dose glucocorticoid induction regimens, the early introduction of steroid-sparing agents for maintenance therapy, and the extension of maintenance therapy to minimize glucocorticoid exposure associated with disease relapse. These are critical advances to move us toward the goal of glucocorticoid-free treatment of vasculitis. The evidence supporting each of these strategies and directions for future research are explored.

Clinical, radiological and laboratory characteristics of central nervous system histoplasmosis: A systematic review of a severe disease.

BACKGROUND: The knowledge of central nervous system (CNS) histoplasmosis is limited to case reports and series. OBJECTIVES: Our objective was to synthesise clinical, radiological and laboratory characteristics of CNS histoplasmosis to improve our understanding of this rare disease. METHODS: We performed a systematic review using Pubmed/MEDLINE, Embase and LILACS databases accessed on March 2023 without publication date restrictions. Inclusion criteria comprised: (1) histopathological, microbiological, antigen or serological evidence of histoplasmosis; (2) CNS involvement based on cerebrospinal fluid pleocytosis or neuroimaging abnormalities. We classified the certainty of the diagnosis in proven (CNS microbiological and histopathological confirmation), probable (CNS serological and antigen confirmation) or possible (non-CNS evidence of histoplasmosis). Metaproportion was used to provide a summary measure with 95% confidence intervals for the clinical, radiological and laboratory characteristics. Chi-squared test was used to compare mortality between pairs of antifungal drugs. RESULTS: We included 108 studies with 298 patients. The median age was 31 years, predominantly male, and only 23% were immunocompromised (134/276, 95%CI: 3-71), mainly due to HIV infection. The most common CNS symptom was headache (130/236, 55%, 95%CI: 49-61), with a duration predominantly of weeks or months. Radiological presentation included histoplasmoma (79/185, 34%, 95%CI: 14-61), meningitis (29/185, 14%, 95%CI: 7-25), hydrocephalus (41/185, 37%, 95%CI: 7-83) and vasculitis (18/185, 6%, 95%CI: 1-22). There were 124 proven cases, 112 probable cases and 40 possible cases. The majority of patients presented positive results in CNS pathology (90%), serology (CSF: 72%; serum: 70%) or CSF antigen (74%). Mortality was high (28%, 56/198), but lower in patients who used liposomal amphotericin B and itraconazole. Relapse occurred in 13% (23/179), particularly in HIV patients, but less frequently in patients who used itraconazole. CONCLUSION: Central nervous system histoplasmosis usually presents subacute-to-chronic symptoms in young adults. Neuroimaging patterns included not only focal lesions but also hydrocephalus, meningitis and vasculitis. Positive results were commonly found in CSF antigen and serology. Mortality was high, and treatment with liposomal amphotericin B followed by itraconazole may decrease mortality.