Renal disease in pediatric rheumatology.

PURPOSE OF REVIEW: This review will provide updates in the outcomes in the common rheumatologic diseases with kidney involvement. Covered are also advances in therapeutics for the use of pediatric rheumatologic diseases with kidney involvement, as well as the potential kidney complications from other rheumatologic diseases and their medications. RECENT FINDINGS: Two of the more common rheumatologic diseases with kidney involvement, lupus and vasculitis, continue to show inadequate response to initial therapy of renal disease and practice continues to be driven by results of adult studies. SUMMARY: There is a continued need for pediatric specific studies in rheumatologic diseases with kidney involvement as outcomes continue to be inadequate. Despite recently approved treatments for adults with rheumatic diseases and kidney involvement, therapeutic options in pediatrics remain limited, contributing to the overall morbidity and mortality.

Efficacy of Therapeutic Apheresis for Cryoglobulinemic Vasculitis Patients with Renal Involvement: A Systematic Review.

INTRODUCTION: Therapeutic apheresis (TA) is commonly used for cryoglobulinemic vasculitis (CV) patients, but its efficacy remains uncertain. This systematic review aimed to assess the efficacy of different TA modalities, such as plasma exchange (PE), plasmapheresis (PP), and cryofiltration (CF), in treating CV patients with renal involvement. METHODS: Literature search of MEDLINE, EMBASE, and Cochrane Databases was conducted up to December 2022. Studies that reported the outcomes of TA in adult CV patients with renal involvement were assessed. The protocol for this systematic review has been registered with PROSPERO (No. CRD42023417727). The quality of each study was evaluated by the investigators using the validated methodological index for non-randomized studies (minors) quality score. RESULTS: 154 patients who encountered 170 episodes of serious events necessitating TA were evaluated across 76 studies. Among them, 51% were males, with a mean age ranging from 49 to 58 years. The CV types included 15 type I, 97 type II, and 13 type III, while the remaining patients exhibited mixed (n = 17) or undetermined CV types (n = 12). Among the treatment modalities, PE, PP, and CF were performed in 85 (56%), 52 (34%), and 17 patients (11%), respectively, with no identical protocol for TA treatment. The overall response rate for TA was 78%, with response rates of 84%, 77%, and 75% observed in type I, II, and III patients respectively. Most patients received steroids, immunosuppressants, and treatment targeting the underlying causative disease. The overall long-term renal outcome rate was 77%, with type I, II, and III patients experiencing response rates of 89%, 76%, and 90%, respectively. The renal outcomes in patients receiving PE, PP, and CF were comparable, with rates of 78%, 76%, and 81%, respectively. CONCLUSIONS: This study presents compelling evidence that combination of TA with other treatments, especially immunosuppressive therapy, is a successful strategy for effectively managing severe renal involvement in CV patients. Among the TA modalities studied, including PE, PP, and CF, all demonstrated efficacy, with PE being the most frequently employed approach.

Systemic vasculitis and headache.

PURPOSE OF REVIEW: Vasculitis refers to heterogeneous clinicopathologic disorders that share the histopathology of inflammation of blood vessels. Unrecognized and therefore untreated, vasculitis of the nervous system or so called neurovasculitides, lead to pervasive injury and disability making these disorder of paramount importance to clinicians. RECENT FINDINGS: Headache is an important clue to vasculitic involvement of central nervous system (CNS) vessels. CNS vasculitis may be primary, in which only intracranial vessels are involved in the inflammatory process, or secondary to another known disorder with overlapping systemic involvement. A suspicion of vasculitis based on the history, clinical examination, or laboratory studies warrants prompt evaluation and treatment to forestall progression and avert cerebral ischemia or infarction. There has been remarkable progress in the pathogenesis, diagnosis, and treatment of primary adult and pediatric CNS vasculitides predicated on achievements in primary systemic forms. SUMMARY: Vasculitis can be diagnosed with certainty after intensive evaluation that includes tissue confirmation whenever possible. Clinicians must choose from among the available immune modulating, suppressive, and targeted immunotherapies to induce and maintain remission status and prevent relapse, tempered by the recognition of anticipated medication side effects.

Central and Peripheral Nervous System Complications of Vasculitis Syndromes from Pathology to Bedside: Part 2-Peripheral Nervous System.

PURPOSE OF REVIEW: Peripheral nervous system vasculitides (PNSV) are a heterogeneous group of disorders with a clinical subset that may differ in prognosis and therapy. We provide a comprehensive update on the clinical assessment, diagnosis, complications, treatment, and follow-up of PNSV. RECENT FINDINGS: Progress in neuroimaging, molecular testing, and peripheral nerve biopsy has improved clinical assessment and decision-making of PNSV, also providing novel insights on how to prevent misdiagnosis and increase diagnostic certainty. Advances in imaging techniques, allowing to clearly display the vessel walls, have also enhanced the possibility to differentiate inflammatory from non-inflammatory vascular lesions, while recent histopathology data have identified the main morphological criteria for more accurate diagnosis and differential diagnoses. Overall, the identification of peculiar morphological findings tends to improve diagnostic accuracy by defining a clearer boundary between systemic and non-systemic neuropathies. Therefore, the definition of epineurium vessel wall damage, type of vascular lesion, characterization of lymphocyte populations, antibodies, and inflammatory factors, as well as the identification of direct nerve damage or degeneration, are the common goals for pathologists and clinicians, who will both benefit for data integration and findings translation. Nevertheless, to date, treatment is still largely empiric and, in some cases, unsatisfactory, thus often precluding precise prognostic prediction. In this context, new diagnostic techniques and multidisciplinary management will be essential in the proper diagnosis and prompt management of PNSV, as highlighted in the present review. Thirty to fifty percent of all patients with vasculitis have signs of polyneuropathy. Neuropathies associated with systemic vasculitis are best managed according to the guidelines of the underlying disease because appropriate workup and initiation of treatment can reduce morbidity. Steroids, or in severe or progressive cases, cyclophosphamide pulse therapy is the standard therapy in non-systemic vasculitic neuropathies. Some patients need long-term immunosuppression. The use of novel technologies for high-throughput genotyping will permit to determine the genetic influence of related phenotypes in patients with PNSV.

[Wounds caused by vasculitis-Current classification, diagnostics and treatment]. / Wunden durch Vaskulitiden ­ aktuelle Klassifikation, Diagnostik und Therapie.

Wounds of the skin can have very different causes. Especially in clinically atypical or non-healing wounds, the very heterogeneous group of vasculitides is of particularly important differential diagnostic significance. Nowadays, the classification of vasculitis is based on the affected vessels according to the Chapel Hill consensus conference. Thus, potentially any part of the vascular system can be affected. It becomes clear that there is often a risk of systemic diseases with high interdisciplinary relevance.Clinically, the usually very painful wounds in cutaneous vasculitis develop from necrosis and are typically surrounded by an erythematous-livid rim in the florid phase. In addition to clinical inspection, the histopathological examination of biopsies is of particular importance in the usually extensive diagnostic work-up.Therapeutically, adequate wound treatment should always be performed with a focus on pain prevention and infection prophylaxis. In the case of edema, compression therapy also supports wound healing. In addition, it is often necessary to initiate systemic treatment with immunosuppressive or immunomodulating drugs. Whenever possible, causally relevant factors and comorbidities should be diagnosed early and avoided or treated. Otherwise, there is a risk of severe or even fatal disease progression.

Medium- and Large-Vessel Vasculitis.

Systemic vasculitides are multisystem blood vessel disorders, which are defined by the size of the vessel predominantly affected, namely small, medium, or large vessels. The term "large vessel" relates to the aorta and its major branches; "medium vessel" refers to the main visceral arteries and veins and their initial branches. The most common causes of large-vessel vasculitis are giant cell arteritis and Takayasu arteritis, and those of medium-vessel arteritis are polyarteritis nodosa and Kawasaki disease. However, there is some overlap, and arteries of any size can potentially be involved in any of the 3 main categories of dominant vessel involvement. In addition to multisystem vasculitides, other forms of vasculitis have been defined, including single-organ vasculitis (eg, isolated aortitis). Prompt identification of vasculitides is important because they are associated with an increased risk of mortality. Left undiagnosed or mismanaged, these conditions may result in serious adverse outcomes that might otherwise have been avoided or minimized. The ethnic and regional differences in the incidence, prevalence, and clinical characteristics of patients with vasculitis should be recognized. Because the clinical presentation of vasculitis is highly variable, the cardiovascular clinician must have a high index of suspicion to establish a reliable and prompt diagnosis. This article reviews the pathophysiology, epidemiology, diagnostic strategies, and management of vasculitis.

A case of polymorphic dermal angiitis in a B-cell chronic lymphocytic leukemia patient during rituximab therapy.

The aim of the study is to describe a case is of clinical interest as the first known occurrence of skin vasculitis during rituximab treatment. The article describes a case of polymorphic dermal angiitis, a combination of hemorrhagic and ulcerative-necrotic forms against the background of rituximab treatment in a 53-year-old woman suffering from chronic lymphocytic leukemia (b-CLL). During four hours after the 5th intravenous administration of rituximab, the appearance of painful rashes on the skin of both shins of a patient was observed. In the following few days, a progression of the pathological skin process was noted. The treatment with prednisolone in the amount of 50 mg/day, amoxicillin and clavulanic acid in the amount of 1000 mg twice per day and Diflucan in a dosage of 50 mg/day for 15 days was prescribed. In a local therapy, wet-drying bandages with antiseptic solutions, combined topic glucocorticosteroid preparations, drugs that improve trophic and tissue regeneration were recommended. After discharge, the patient continued to receive prednisolone in the amount of 50 mg/day for 14 days with a slow decrease in the dosage of the drug until the withdrawal under the supervision of a dermatologist. The described experience of how combined forms of polymorphic dermal angiitis are developing can be considered a result of toxic drug response to rituximab.

A Spotlight on Drug-Induced Vasculitis.

PURPOSE OF REVIEW: Drug-induced vasculitis (DIV) is a rare form of vasculitis related to the use of various drugs. DIV primarily affects small to medium size vessels, but it can potentially involve vessels of any size. Differentiating between primary systemic vasculitis and DIV can be challenging; however, it is crucial, so that the offending agent can be discontinued promptly. RECENT FINDINGS: The clinical phenotype of DIV is protean and depends on the size of the affected vessels. It ranges from arthralgias, to an isolated cutaneous rash, to severe single or multi-organ involvement. While withdrawal of the offending drug is the most important step in management, a significant number of patients require immunosuppressive therapy for varying periods of time. DIV can affect any vascular bed size, leading to protean vasculitic syndromes. Increased awareness among general practitioners, specialty, and subspecialty physicians is crucial for early recognition, and withdrawal of drug for better outcomes.

[Cryoglobulinemic vasculitis]. / Kryoglobulinämische Vaskulitis.

Cryoglobulinemic vasculitis (CV) is a rare immune complex disease of small vessels (capillaries, venules or arterioles) with detection of cryoglobulins (CG). These are serum proteins that precipitate at temperatures below the normal body temperature. The laboratory diagnostics are logistically challenging because the temperature of the blood sample must be maintained continuously at 37 °C until arrival in the laboratory to prevent early precipitation of the proteins with adsorption to corpuscular blood components. Cryoglobulins can be divided into three classes (types I-III), with each class associated with specific underlying diseases and symptom complexes. Cryoglobulinemia can be caused by hematological, virological or autoimmune diseases and mixed forms also occur. The most common cause to date is a hepatitis C infection. Treatment of the underlying disease is obligatory, with antiviral treatment of hepatitis C offering the rare possibility of causal treatment. Depending on the severity of cryoglobulinemia, immunosuppressive therapy is indicated to prevent permanent damage caused by the inflammation.

Vasculitis in Patients With Sarcoidosis: A Single-Institution Case Series of 17 Patients.

OBJECTIVES: Vasculitis in patients with sarcoidosis is rare and can affect any sized blood vessel. Limited information describing this association is available. METHODS: A single-institution medical records review study was performed reviewing all patients with a diagnosis code for sarcoidosis and vasculitis between January 1, 1998, and December 31, 2019. Data were abstracted regarding diagnosis, treatment, and outcomes from medical records. Patients were diagnosed with vasculitis based on biopsy and/or arterial imaging. Comparison between patients presenting with large and/or medium vessel vasculitis (L/MVV) versus patients with only small vessel vasculitis (SVV) was performed. RESULTS: Seventeen patients were identified during the study period. Nine patients (56% female) had L/MVV, and 8 (50% female) had SVV. Sarcoidosis preceded vasculitis in 4 (44%) L/MVV and 3 (38%) SVV. The mean ± SD age at sarcoidosis diagnosis was 53.2 ± 17.8 and 51.9 ± 11.4 years, and the mean ± SD age at vasculitis diagnosis was 57.4 ± 19.6 and 59.0 ± 13.4 years in L/MVV and SVV, respectively. Number of organ systems involved by sarcoidosis was similar (median [interquartile range], 3 [1-4] L/MVV vs 2.5 [1.75-3.25] SVV). The mean length of follow-up was 11.5 ± 12.8 in L/MVV and 13.1 ± 14.3 years in SVV. Complete response to therapy for vasculitis was observed in 8 of 9 with L/MVV and 7 of 8 with SVV. Four patients with SVV were able to stop all immunosuppression as compared with only 1 patient with L/MVV at the last follow-up. CONCLUSIONS: This series observed a comparable number of patients with L/MVV and SVV. Although a variety of treatments were used, most patients achieved remission regardless of vessel size affected. Clinicians should be aware of the overlap between sarcoidosis and vasculitis.

[Cutaneous Vasculitides - Clinical Manifestations, Diagnosis, and Aetiology]. / Kutane Vaskulitiden.

Cutaneous Vasculitides - Clinical Manifestations, Diagnosis, and Aetiology Abstract. Vasculitides are a heterogeneous group of diseases that are classified differently, for example according to the size of the affected vessel or according to primary and secondary causes. The skin is most frequently affected; it can be involved both as single organ vasculitis and in the context of systemic forms. The combination of skin lesions, their anatomical location and information on the time course provide clues for a differential diagnosis. Purpura, blisters, necrosis, ulcerations and possibly a livedo are characteristic manifestations. Constitutional symptoms such as weight loss, exhaustion, fever, and arthralgias are indicative of a systemic form. It is important to differentiate vasculitides from vasculopathies, which can manifest similarly. The most common form in adults is cutaneous leukocytoclastic angiitis, in children IgA vasculitis (Schönlein-Henoch purpura). Various triggers are possible: infections, drugs, autoimmune diseases, and malignancies, whereby up to 50% remain etiologically unexplained. Skin biopsies and laboratory parameters, if necessary supplemented with imaging, are important steps in the clarification process. Treatment is primarily directed at the elimination of a possible triggering cause. Idiopathic cutaneous leukocytoclastic angiitis usually resolves spontaneously; treatment is symptomatic. In more severe cases, topical corticosteroids or calcineurin antagonists are primarily used. In case of therapeutic resistance, systemic immunosuppressants are recommended.

Etiologic dilemma and challenges of management of nodular vasculitis in tertiary health-care facility: A case report.

Nodular vasculitis is a rare inflammatory disease of the skin and subcutaneous fat tissue, characterized by crops of small, tender, erythematous nodules on the legs, mostly on the calves and shins. We present a 17-year-old adolescent female who presented with a six-month history of cough; recurrent fever and bilateral lower limb multiple ulcerated nodules of 1-month duration. Clinical examination revealed generalized lymphadenopathy with bilateral pitting leg edema which had multiple nodules and discoid ulcers extending from the groin to the ankles and discharging purulent fluid. Tests for human immunodeficiency virus and tuberculosis were negative. Histology of nodule biopsy revealed extensive caseous and coagulative fat necrosis, granulomatous inflammation with epitheloid macrophages and multinucleated giant cells surrounding the necrosis, and lymphoid infiltration of vessel walls with fibrous thickening of the intima, typical of Whitfield-type erythema induratum. There was initial but very transient response to antibiotic treatment, with further deterioration and eventual death from overwhelming sepsis.

Localized Forms of Vasculitis.

PURPOSE OF REVIEW: To provide an updated review on epidemiology, clinical manifestations, diagnostic assessment, treatment, and prognosis of localized vasculitis, following the 2012 Revised International Chapel Hill Consensus Conference Nomenclature on single-organ vasculitis. RECENT FINDINGS: Localized, single-organ vasculitides encompass a group of rare conditions in which there is no evidence of concomitant systemic vasculitis. Most data on this topic derives from case reports and small case series. Although some aspects of these diseases, such as clinical manifestations and histologic findings, have already been extensively investigated, there is still a lack of robust data concerning the pathogenesis, epidemiology, and treatment. Localized vasculitides may have a wide range of clinical features depending on the organ affected. The inflammatory process may have a multifocal/diffuse or unifocal distribution. Diagnosis is usually based on histopathology findings and exclusion of systemic vasculitis, which may frequently pose a challenge. Further research on treatment is warranted.

The Challenging Management of Cancer: An Immunonephrologist's Perspective.

INTRODUCTION: Onconephrology is an emerging medical subspecialization that focuses on the numberless interrelations between cancer and kidney diseases. Tumor cells evade immune surveillance through activation of immune checkpoint pathways that suppress antitumor immune responses. By blocking checkpoints, new anticancer agents disrupt immune homeostasis but potentially induce immune-mediated diseases. Nephrologists and nephroimmunologists should be able to treat the nephrotoxic sequelae of cancer therapy and ensure continuation of the life-saving treatment. METHODS: Thirty-seven renal biopsies have been carried out over 42 months in oncologic patients, that is, 5.2% of the total native renal biopsies were carried out in the same period. The commonest diagnoses (>6 cases) were interstitial tubular nephritis, membranous glomerulopathy, IgA nephropathy, vasculitis, and focal and segmental glomerulosclerosis. CASE PRESENTATION: Three example cases, including focusing on key questions which could involve the nephrologists are reported in detail. They include a cancer-related Goodpasture Syndrome, the peculiar toxic effects of pemetrexed on tubular cells, and the intriguing relationship between bevacizumab and cryoglobulinemic glomerulonephritis. CONCLUSION: As shown by these 3 example cases, nephrologists need to be open-minded with regard to kidney biopsy in order to get a timely diagnosis. Nephrologists also need to improve their knowledge of cancer biology and therapy in order to prevent kidney problems, manage therapy-related immune-mediated disorders, and improve patient life expectancy.

IgA Vasculitis: Etiology, Treatment, Biomarkers and Epigenetic Changes.

IgA, previously called Henoch-Schönlein vasculitis, is an essential immune component that drives the host immune response to the external environment. As IgA has the unique characteristic of a flexible response to broad types of microorganisms, it sometimes causes an autoreactive response in the host human body. IgA vasculitis and related organ dysfunction are representative IgA-mediated autoimmune diseases; bacterial and viral infections often trigger IgA vasculitis. Recent drug developments and the presence of COVID-19 have revealed that these agents can also trigger IgA vasculitis. These findings provide a novel understanding of the pathogenesis of IgA vasculitis. In this review, we focus on the characteristics of IgA and symptoms of IgA vasculitis and other organ dysfunction. We also mention the therapeutic approach, biomarkers, novel triggers for IgA vasculitis, and epigenetic modifications in patients with IgA vasculitis.

IL-1-dependent electrophysiological changes and cardiac neural remodeling in a mouse model of Kawasaki disease vasculitis.

Kawasaki disease (KD) is the leading cause of acquired heart disease in children. In addition to coronary artery abnormalities, aneurysms and myocarditis, acute KD is also associated with echocardiogram (ECG) abnormalities in 40-80% of patients. Here, we show that these ECG changes are recapitulated in the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model. LCWE-injected mice developed elevated heart rate and decreased R wave amplitude, with significant differences in prolonged ventricular repolarization. LCWE-injected mice developed cardiac ganglion inflammation, that may affect the impulse-conducting system in the myocardium. Furthermore, serum nerve growth factor (NGF) was significantly elevated in LCWE-injected mice, similar to children with KD vasculitis, associated with increased neural remodeling of the myocardium. ECG abnormalities were prevented by blocking interleukin (IL)-1 signaling with anakinra, and the increase in serum NGF and cardiac neural remodeling were similarly blocked in Il1r1-/- mice and in wild-type mice treated with anakinra. Thus, similar to clinical KD, the LCWE-induced KD vasculitis mouse model also exhibits electrophysiological abnormalities and cardiac neuronal remodeling, and these changes can be prevented by blocking IL-1 signaling. These data support the acceleration of anti-IL-1 therapy trials to benefit KD patients.

Childhood vasculitis.

Vasculitis is a challenging disease for paediatricians. Certain vasculitides are quite common in children whereas others are much rarer compared with adults. The most common vasculitides in childhood are IgA-associated vasculitis (Henoch-Schönlein purpura) and Kawasaki disease, which are usually self-limiting vasculitides although children do develop complications as a result. We now have much better knowledge of how to manage these patients and prevent the deleterious complications. This review provides an up-to-date discussion on childhood vasculitides, including diagnosis, treatment and follow-up strategies, together with a comparison with vasculitides in adults. It also discusses the newly defined monogenic vasculitides that often present during early childhood.

IgA vasculitis and anti-GBM disease: two ends of a spectrum of immune complex vasculitis.

Two immune complex vasculitides, IgA vasculitis (IgAV) and anti-GBM disease, represent polar extremes with regard to our understanding of disease pathogenesis, standardized management protocols and outcomes. This report compares our current approach to these uncommon entities in adults. Both diseases demonstrate degrees of small vessel necrosis and glomerular crescent formation. IgAV has an antibody response directed against unknown antigens, is often treated conservatively and has poorly studied long term renal outcomes. By contrast, anti-GBM disease presents with rapidly progressive glomerulonephritis and often results in end stage renal failure, despite intensive immunosuppression. Rarely, some cases of anti-GBM disease may be IgA predominant and bind other α-chains present in the GBM, but their clinical course is as for other anti-GBM disease patients but not IgAV, suggesting that the antigenic target rather than the antibody subclass is the critical factor in determining disease outcome. However, both conditions are associated with increased mortality in adults and result in significant chronic kidney disease and hypertension.

Cardiovascular Manifestations of Systemic Vasculitides.

PURPOSE OF REVIEW: Vasculitis can cause heart disease and are associated with premature atherosclerosis, causing increased morbidity and mortality. Consequently, it is important to know how they can affect the cardiovascular system in order to detect and treat the abnormalities in earlier phases. RECENT FINDINGS: A clear increasing trend of inpatient burden of myocardial infarction and thromboembolic events in granulomatosis with polyangiitis has been observed lately. Behçet's disease has been linked to an increased risk of atrial fibrillation. Studies showing increased atherosclerosis and thromboembolic phenomena in vasculitis are continuously published. Improvement in imaging techniques has consistently showed that subclinical cardiovascular involvement is frequent. Vasculitis may affect seriously the cardiovascular system causing an important increase in morbidity and mortality. Subclinical involvement is frequent. Early treatment with immunosuppression and sometimes surgery, is of paramount importance to improve the prognosis.

Pregnancy Outcomes in Systemic Vasculitides.

PURPOSE OF REVIEW: In recent years, improvements in the recognition of primary vasculitides and increased treatment options have led to greater survival rates and a better quality of life for patients. Therefore, pregnancy in women with vasculitis has become a more frequent consideration or event. Literature on pregnancy outcomes in this population has grown and allowed us, in this article, to review the effects of pregnancy on disease activity, as well as maternal and fetal outcomes for each type of vasculitides. RECENT FINDINGS: Successful pregnancies in patients with vasculitides are possible, especially when conception is planned, and the disease is in remission. The risk of vasculitis flare is highly dependent on the type of vasculitis, but overall limited. The most frequent complication associated with large-vessel vasculitis (mainly Takayasu arteritis) is hypertension and preeclampsia. Preterm deliveries and intrauterine growth restriction occur more frequently with small- and medium-vessel vasculitis. Pregnancies in patients with vasculitis should be considered high risk and followed by a multidisciplinary team with expertise in the field. Flares should be managed as in the non-pregnant population, while avoiding medications with unknown safety in pregnancy or known teratogens. Although commonly prescribed for the prevention of preeclampsia, there is limited evidence supporting the use of low-dose aspirin for pregnant women with vasculitis. Prospective registries or studies are needed, to better assess the value of aspirin, the place and long-term impact of new biologics and, to identify predictors of pregnancy outcomes other than disease status at conception.