Intestinal Permeability and IgA Provoke Immune Vasculitis Linked to Cardiovascular Inflammation.

Recent experimental data and clinical, genetic, and transcriptome evidence from patients converge to suggest a key role of interleukin-1ß (IL-1ß) in the pathogenesis of Kawasaki disease (KD). However, the molecular mechanisms involved in the development of cardiovascular lesions during KD vasculitis are still unknown. Here, we investigated intestinal barrier function in KD vasculitis and observed evidence of intestinal permeability and elevated circulating secretory immunoglobulin A (sIgA) in KD patients, as well as elevated sIgA and IgA deposition in vascular tissues in a mouse model of KD vasculitis. Targeting intestinal permeability corrected gut permeability, prevented IgA deposition and ameliorated cardiovascular pathology in the mouse model. Using genetic and pharmacologic inhibition of IL-1ß signaling, we demonstrate that IL-1ß lies upstream of disrupted intestinal barrier function, subsequent IgA vasculitis development, and cardiac inflammation. Targeting mucosal barrier dysfunction and the IL-1ß pathway may also be applicable to other IgA-related diseases, including IgA vasculitis and IgA nephropathy.

Interleukin-1 Beta-Mediated Sex Differences in Kawasaki Disease Vasculitis Development and Response to Treatment.

OBJECTIVE: Kawasaki disease (KD) is the leading cause of acute vasculitis and acquired heart disease in children in developed countries. Notably, KD is more prevalent in males than females. We previously established a key role for IL (interleukin)-1 signaling in KD pathogenesis, but whether this pathway underlies the sex-based difference in susceptibility is unknown. Approach and Results: The role of IL-1 signaling was investigated in the Lactobacillus casei cell wall extract-induced experimental mouse model of KD vasculitis. Five-week-old male and female mice were injected intraperitoneally with PBS, Lactobacillus caseicell wall extract, or a combination of Lactobacillus caseicell wall extract and the IL-1 receptor antagonist Anakinra. Aortitis, coronary arteritis inflammation score and abdominal aorta dilatation, and aneurysm development were assessed. mRNA-seq (messenger RNA sequencing) analysis was performed on abdominal aorta tissue. Publicly available human transcriptomics data from patients with KD was analyzed to identify sex differences and disease-associated genes. Male mice displayed enhanced aortitis and coronary arteritis as well as increased incidence and severity of abdominal aorta dilatation and aneurysm, recapitulating the increased incidence in males that is observed in human KD. Gene expression data from patients with KD and abdominal aorta tissue of Lactobacillus caseicell wall extract-injected mice showed enhanced Il1b expression and IL-1 signaling genes in males. Although the more severe IL-1ß-mediated disease phenotype observed in male mice was ameliorated by Anakinra treatment, the milder disease phenotype in female mice failed to respond. CONCLUSIONS: IL-1ß may play a central role in mediating sex-based differences in KD, with important implications for the use of anti-IL-1ß therapies to treat male and female patients with KD.

IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model: Role of Both IL-1α and IL-1ß.

OBJECTIVE: Kawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease among US children. We have previously shown that both TLR2/MyD88 and interleukin (IL)-1ß signaling are required for the Lactobacillus casei cell wall extract-induced KD vasculitis mouse model. The objectives of this study were to investigate the cellular origins of IL-1 production, the role of CD11c(+) dendritic cells and macrophages, and the relative contribution of hematopoietic and stromal cells for IL-1 responsive cells, as well the MyD88 signaling, in Lactobacillus casei cell wall extract-induced KD mouse model of vasculitis. APPROACH AND RESULTS: Using mouse knockout models and antibody depletion, we found that both IL-1α and IL-1ß were required for Lactobacillus casei cell wall extract-induced KD. Both dendritic cells and macrophages were necessary, and we found that MyD88 signaling was required in both hematopoietic and stromal cells. However, IL-1 response and signaling were critically required in nonendothelial stromal cells, but not in hematopoietic cells. CONCLUSIONS: Our results suggest that IL-1α and IL-1ß, as well as CD11c(+) dendritic cells and macrophages, are essential for the development of KD vasculitis and coronary arteritis in this mouse model. Bone marrow chimera experiments suggest that MyD88 signaling is important in both hematopoietic and stromal cells, whereas IL-1 signaling and response are required only in stromal cells, but not in endothelial cells. Determining the role of IL-1α and IL-1ß and of specific cell types in the KD vasculitis mouse model may have important implications for the design of more targeted therapies and understanding of the molecular mechanisms of KD immunopathologies.

Interleukin-1ß is crucial for the induction of coronary artery inflammation in a mouse model of Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease in US children. Untreated, children may develop coronary artery aneurysms, myocardial infarction, and sudden death as a result of the illness. Up to a third of KD patients fail to respond to intravenous immunoglobulin, the standard therapy, and alternative treatments are being investigated. Genetic studies have indicated a possible role for interleukin (IL)-1ß in KD. We therefore explored the role of IL-1ß in a murine model of KD. METHODS AND RESULTS: Using an established mouse model of KD that involves injection of Lactobacillus casei cell wall extract (LCWE), we investigated the role of IL-1ß and caspase-1 (activated by the inflammasome and required for IL-1ß maturation) in coronary arteritis and evaluated the efficacy of IL-1 receptor antagonist as a potential treatment. LCWE-induced IL-1ß maturation and secretion were dependent on the NLRP3 inflammasome in macrophages. Both caspase-1-deficient and IL-1 receptor-deficient mice were protected from LCWE-induced coronary lesions. Injection of recombinant IL-1ß into caspase-1-deficient mice restored the ability of LCWE to cause coronary lesions in response to LCWE. Furthermore, daily injections of the IL-1 receptor antagonist prevented LCWE-mediated coronary lesions up to 3 days after LCWE injection. CONCLUSIONS: Our results strongly suggest that caspase-1 and IL-1ß play critical roles in the development of coronary lesions in this KD mouse model, blocked by IL-1 receptor antagonist. Therefore, anti-IL-1ß treatment strategies may constitute an effective, more targeted treatment of KD to prevent coronary lesions.

Marked acceleration of atherosclerosis after Lactobacillus casei-induced coronary arteritis in a mouse model of Kawasaki disease.

OBJECTIVE: The purpose of this study was to investigate whether Lactobacillus casei cell wall extract-induced Kawasaki disease (KD) accelerates atherosclerosis in hypercholesterolemic mice. Method and Results- Apolipoprotein E knockout or low-density lipoprotein receptor knockout mice were injected with Lactobacillus casei cell wall extract (KD mice) or PBS, fed high-fat diet for 8 weeks, and atherosclerotic lesions in aortic sinuses, arch (AC), and whole aorta were assessed. KD mice had larger, more complex aortic lesions with abundant collagen, and both extracellular and intracellular lipid and foam cells, compared with lesions in control mice despite similar cholesterol levels. Both apolipoprotein E knockout KD and low-density lipoprotein receptor knockout KD mice showed dramatic acceleration in atherosclerosis versus controls, with increases in en face aortic atherosclerosis and plaque size in both the aortic sinuses and AC plaques. Accelerated atherosclerosis was associated with increased circulating interleukin-12p40, interferon-γ, tumor necrosis factor-α, and increased macrophage, dendritic cell, and T-cell recruitment in lesions. Furthermore, daily injections of the interleukin-1Ra, which inhibits Lactobacillus casei cell wall extract-induced KD vasculitis, prevented the acceleration of atherosclerosis. CONCLUSIONS: Our results suggest an important pathophysiologic link between coronary arteritis/vasculitis in the KD mouse model and subsequent atherosclerotic acceleration, supporting the concept that a similar relation may also be present in KD patients. These results also suggest that KD in childhood may predispose to accelerated and early atherosclerosis as adults.

Takayasu arteritis presenting in the context of active tuberculosis: a pediatric case.

Takayasu arteritis (TA) is a large-vessel vasculitis, most commonly presenting in young adults and more rarely in pediatric patients. An apparent association between TA and Mycobacterium tuberculosis has been noted previously, although this potential relationship is not yet understood. We present the case of a 16-year-old Haitian girl diagnosed with TA, originally presenting in the context of active tuberculosis. Our patient has been treated with antituberculosis therapy, corticosteroids, methotrexate, and rituximab to control her continued active vasculitis. With this case report, we seek to promote further exploration of the apparent association between TA and tuberculosis, as further clarification of the nature of this relationship may lead to the development of more targeted therapies and better outcomes for TA patients.

Diagnosis of the mucopolysaccharidoses.

The mucopolysaccharidoses (MPSs) often present a diagnostic challenge, particularly for patients who have more slowly progressive disease phenotypes, as early disease manifestations can be subtle or non-specific. However, certain types of bone and joint involvement should always prompt consideration of an MPS diagnosis, such as early joint involvement without classic inflammatory features or erosive bone lesions, claw hand, spinal deformities or dysostosis multiplex. All such patients should be referred to a geneticist or metabolic specialist for diagnostic evaluation. The earlier the diagnosis is made, the better the potential outcome of treatment. Each type of MPS is associated both with deficient activity of a specific lysosomal enzyme that degrades specific glycosaminoglycans (GAGs) and with abnormalities in urinary GAG excretion. MPS patients usually excrete excess GAG in urine and/or have different relative proportions of types of GAG in urine as compared with age-matched normal subjects. Although urinary GAG analyses (both quantitative and qualitative) can suggest the most likely type of MPS, diagnosis must be confirmed by enzyme assay. Multiple assays may be necessary to identify the disease subtype. Correct identification of the MPS type is essential to guide treatment and management decisions.

Morphea, diabetes mellitus type I, and celiac disease: case report and review of the literature.

An 11-year-old girl with a history of diabetes mellitus type I and celiac disease presented with multiple, depressed patches of purple-brown skin on the right lower extremity and central back, with histopathologic features of early morphea. Though morphea may coexist with other autoimmune diseases, its presentation with both diabetes mellitus type I and celiac disease has not yet been described.

Poststreptococcal reactive arthritis in children: a retrospective study.

The duration of treatment and appropriate guidelines for antibiotic prophylaxis for children with poststreptococcal reactive arthritis (PSRA) have not been determined. The authors performed a retrospective chart review of 40 children with PSRA and examined their clinical features at initial evaluation and at 6, 12, and 24 months. At baseline, 18% (n = 7) had a finding noted on the echocardiogram. Although most patients developed cardiac findings early on in the course of their disease, 2 patients with a normal baseline echocardiogram may have developed findings after 12 months of follow-up. The mean duration of prophylaxis was 22 months. During the follow-up period, there was improvement in Physician's Global Assessment, number of patients with arthralgia, tender and swollen joints, erythrocyte sedimentation rate, anti-streptolysin O, and anti-DNAse B antibody titers. The authors conclude that marked improvement in clinical features and laboratory values was seen over time. Patients may benefit with long-term cardiac follow-up.

Myocardial fibrosis after adrenergic stimulation as a long-term sequela in a mouse model of Kawasaki disease vasculitis.

Kawasaki disease (KD), the leading cause of acquired cardiac disease among children, is often associated with myocarditis that may lead to long-term myocardial dysfunction and fibrosis. Although those myocardial changes develop during the acute phase, they may persist for decades and closely correlate with long-term myocardial sequelae. Using the Lactobacillus casei cell wall extract-induced (LCWE-induced) KD vasculitis murine model, we investigated long-term cardiovascular sequelae, such as myocardial dysfunction, fibrosis, and coronary microvascular lesions following adrenergic stimuli after established KD vasculitis. We found that adrenergic stimulation with isoproterenol following LCWE-induced KD vasculitis in mice was associated with increased risk of cardiac hypertrophy and myocardial fibrosis, diminished ejection fraction, and increased serum levels of brain natriuretic peptide. Myocardial fibrosis resulting from pharmacologic-induced exercise after KD development was IL-1 signaling dependent and was associated with a significant reduction in myocardial capillary CD31 expression, indicative of a rarefied myocardial capillary bed. These observations suggest that adrenergic stimulation after KD vasculitis may lead to cardiac hypertrophy and bridging fibrosis in the myocardium in the LCWE-induced KD vasculitis mouse model and that this process involves IL-1 signaling and diminished microvascular circulation in the myocardium.

Rituximab for severe refractory pediatric Wegener granulomatosis.

We describe a case of pediatric Wegener granulomatosis initially treated with cyclophosphamide and oral corticosteroids resulting in remission for 5 years. Of note in this case is relapse with severe pulmonary disease treated with multiple regimens, all unsuccessful. Patient achieved remission with rituximab infusion therapy. This demonstrates how rituximab may be beneficial for childhood-onset Wegener granulomatosis unresponsive to conventional therapy. The case is followed by a review of the current treatment options.

CD8+ T Cells Contribute to the Development of Coronary Arteritis in the Lactobacillus casei Cell Wall Extract-Induced Murine Model of Kawasaki Disease.

OBJECTIVE: Kawasaki disease (KD) is the leading cause of acquired heart disease among children in developed countries. Coronary lesions in KD in humans are characterized by an increased presence of infiltrating CD3+ T cells; however, the specific contributions of the different T cell subpopulations in coronary arteritis development remain unknown. Therefore, we sought to investigate the function of CD4+ and CD8+ T cells, Treg cells, and natural killer (NK) T cells in the pathogenesis of KD. METHODS: We addressed the function of T cell subsets in KD development by using a well-established murine model of Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis. We determined which T cell subsets were required for development of KD vasculitis by using several knockout murine strains and depleting monoclonal antibodies. RESULTS: LCWE-injected mice developed coronary lesions characterized by the presence of inflammatory cell infiltrates. Frequently, this chronic inflammation resulted in complete occlusion of the coronary arteries due to luminal myofibroblast proliferation (LMP) as well as the development of coronary arteritis and aortitis. We found that CD8+ T cells, but not CD4+ T cells, NK T cells, or Treg cells, were required for development of KD vasculitis. CONCLUSION: The LCWE-induced murine model of KD vasculitis mimics many histologic features of the disease in humans, such as the presence of CD8+ T cells and LMP in coronary artery lesions as well as epicardial coronary arteritis. Moreover, CD8+ T cells functionally contribute to the development of KD vasculitis in this murine model. Therapeutic strategies targeting infiltrating CD8+ T cells might be useful in the management of KD in humans.

TLR2 and MyD88 contribute to Lactobacillus casei extract-induced focal coronary arteritis in a mouse model of Kawasaki disease.

BACKGROUND: Kawasaki disease is the most common cause of acquired cardiac disease and acute vasculitis in children, targets the coronary arteries, and can occasionally be fatal. The pathogenesis and the molecular mechanisms remain unknown. After injection of Lactobacillus casei cell-wall extract (LCCWE), mice develop a focal coronary arteritis that histopathologically resembles Kawasaki disease, but the mechanism remains unclear. Here, we tested the hypothesis that signaling by Toll-like receptors (TLRs) through their key downstream adaptor molecule myeloid differentiation factor 88 (MyD88) is required for the cellular activation and coronary arteritis produced by LCCWE. METHODS AND RESULTS: Bone marrow-derived macrophages from TLR2- or MyD88-deficient mice were unresponsive to LCCWE-induced stimulation. In contrast, macrophages obtained from TLR4-deficient mice produced the same amount of interleukin-6 as macrophages from wild-type mice after stimulation with LCCWE. Intraperitoneal injection of LCCWE produced severe focal coronary arteritis in TLR4(-/-) and C57BL/6 control mice but not in TLR2(-/-) or MyD88(-/-) mice. Collectively, these results indicate that LCCWE is a potent inducer of nuclear factor-kappaB via TLR2 but not TLR4 and that this activation proceeds via the MyD88-dependent signaling pathway. In vivo studies suggest that TLR2(-/-) mice are protected from LCCWE-induced coronary arteritis and that this protection is mediated through the adaptor molecule MyD88. CONCLUSIONS: Our results provide important insights into the molecular signaling in this mouse model of coronary arteritis. We show here that LCCWE-induced coronary arteritis is dependent on intact TLR2 and MyD88 signaling.

Pharmacotherapy of lupus nephritis in children: a recommended treatment approach.

Systemic lupus erythematosus (SLE) is a multisystem inflammatory disease of unknown aetiology, which is characterised by recurrent disease flares that may affect any organ system. Renal involvement remains one of the chief causes of morbidity and mortality in children with lupus. Nephritis occurs in approximately two-thirds of patients, ranging from mild glomerulitis to life-threatening occurrences of diffuse proliferative glomerulonephritis. As lupus nephritis is a condition of no single aetiology, there is no single cure. Corticosteroids, although still the first line of treatment, are increasingly being superseded by cytotoxic drugs, in particular cyclophosphamide and corticosteroid-sparing agents. Newer agents such as mycophenolate mofetil, although effective in the treatment of lupus in adults, are less effective in children. Standard of care for highly active lupus nephritis in children remains intravenous cyclophosphamide, although preliminary experience suggests that the addition of rituximab may allow for remission induction with a reduction in cumulative cyclophosphamide dose. Combination therapies and newer agents appear promising for the future as our understanding of the immune system and its dysregulation in SLE improves. In this review, we discuss the current standards of care, newer therapies currently in use, and emerging treatments still undergoing development and investigation. We conclude by discussing our guidelines for treatment at the present time and suggestions for the comprehensive care of children with lupus nephritis.

Systemic and localized scleroderma in children: current and future treatment options.

Scleroderma is a group of rare and complex diseases with varied clinical manifestations. The most obvious manifestation of the diseases is skin hardening and sclerosis. Scleroderma can be divided into two main subgroups: systemic and localized. The systemic form, also known as systemic sclerosis, involves diffuse skin involvement and potentially severe visceral involvement. Localized scleroderma on the other hand is more common in children and usually confined to a specific region of the body with no internal organ involvement. The juvenile forms of systemic sclerosis and localized scleroderma are important conditions in children because of the clinical severity and substantial mortality of systemic scleroderma and the major growth defects associated with childhood-onset localized disease even if the active disease itself is self-limited. The pathogenic pathways of the various forms of scleroderma are only partially defined, but the main defect in scleroderma is abnormal collagen deposition leading to eventual fibrosis in the skin as well as multiple organ systems such as the heart and lungs in juvenile systemic sclerosis. Therapeutics are divided into three main subgroups for systemic sclerosis: antifibrotics, anti-inflammatories, and vasodilators. For localized disease, anti-inflammatories, vitamin D analogs, and UV irradiation have been investigated. However, the infrequency of scleroderma in the pediatric population plus the fact that this disease is very often self-limiting makes randomized controlled trials very difficult. It is for this reason that most data on treatment modalities for this disease have been extrapolated from studies in adult patients. There is no one therapy for systemic sclerosis or localized scleroderma that has proven to be very effective or significantly disease modifying. However, current therapeutic strategies must be initiated early in the disease course for maximum beneficial clinical effects. New interventions such as autologous stem cell transplant and cytokine-directed therapies are under investigation as potential treatments for this complex disease.

Anaphylaxis to anakinra in a pediatric patient with systemic juvenile idiopathic arthritis successfully treated with canakinumab: a case-based review.

We present the case of a 2-year-old boy with a history of necrotizing enterocolitis (NEC) with ileostomy diagnosed with systemic juvenile idiopathic arthritis (sJIA) at 10 months of age controlled on anti-interleukin-1 (anti-IL-1) therapy (anakinra). At 17 months of age, ileostomy reversal and bowel re-anastomosis was scheduled with anakinra discontinued 3 days prior to the surgery and steroids initiated in its place. Ten days postoperatively, anakinra was re-started for signs of sJIA flare. Three months later, he developed persistent peripheral eosinophilia and subsequent anaphylactic reaction 6 months postoperatively. The patient safely tolerated an alternative anti-IL-1 agent (canakinumab). Anaphylaxis to anakinra has not been previously reported in the pediatric literature. This case highlights an important issue in a pediatric patient with sJIA: safety of an alternate anti-IL-1 agent, following development of allergy to one initial agent.

A prospective study comparing infection risk and disease activity in children with juvenile idiopathic arthritis treated with and without tumor necrosis factor-alpha inhibitors.

Tumor necrosis factor-alpha (TNF-α) inhibitors are effective treatment for juvenile idiopathic arthritis (JIA) but may increase infection rates. However, active JIA may also render patients vulnerable to infection. In this study, we prospectively assessed infection rates in JIA patients treated with and without TNF-α inhibitors and correlated disease activity with infection risk. TNF-α inhibitor-naïve JIA subjects were followed up for 12 months. Subjects initiated on TNF-α inhibitors after enrollment were analyzed in the TNF group. Subjects treated without TNF-α inhibitors were analyzed in the non-TNF group. Questionnaires captured mild or severe infections. JIA disease activity by Childhood Health Assessment Questionnaire (CHAQ) disability index/pain score and physician joint count/global assessment was recorded. Twenty TNF and 36 non-TNF subjects were analyzed. The total infection rate ratio for TNF versus non-TNF group subjects was 1.14 (95% CI, 0.78-1.66; p = 0.51). The average rate of infections per month was 0.29 for TNF and 0.24 for non-TNF subjects. No severe infections or hospitalizations occurred in either group. Secondary infectious outcomes were also similar between groups. Controlling for study group, an increase in CHAQ pain score correlated with an increase in several infectious outcome measures. Our results suggest no difference in infection rates between JIA subjects treated with and without TNF-α inhibitors. Additionally, JIA disease activity may have contributed to infection risk in our cohort, irrespective of immunosuppressive therapy. Future analysis of the relationship between treatment regimens, disease activity, and infection rates may help to further delineate predictors of infection risk in JIA patients.

Unrecognized Celiac Disease in Children Presenting for Rheumatology Evaluation.

BACKGROUND AND OBJECTIVES: Current clinical guidelines do not consider patients with rheumatic conditions to be at high risk for celiac disease (CD) despite numerous reported associations between the two in adults and children. The objective of this study was to evaluate the prevalence of CD among patients presenting for pediatric rheumatology evaluation. METHODS: A total of 2125 patients presenting for initial evaluation by the Division of Pediatric Rheumatology at the Hospital for Special Surgery between June 2006 and December 2013 were screened for CD as a part of the standard initial serologic evaluation. The charts of these patients were evaluated retrospectively at the end of this period. RESULTS: 36 patients (30 girls, 6 boys, mean age 9.4 ± 4.3 years, range 2-16 years) received a diagnosis of CD after serologic testing and evaluation by pediatric gastroenterology. Eight additional patients with known diagnoses of CD presented during this time period. The total prevalence of CD over this 6.5-year period was 2.0%. The most common presenting complaints among patients diagnosed with CD were myalgias, arthralgias, and rash. Less frequently, patients reported gastrointestinal complaints including abdominal pain, nausea, and diarrhea. All patients reported improvement or complete resolution of their musculoskeletal symptoms after initiation of a gluten-free diet. CONCLUSIONS: This study identified 36 new cases of CD among children presenting for rheumatology evaluation, for an overall prevalence rate of 2.0%. The majority of patients who ultimately received a diagnosis of CD presented with extraintestinal manifestations. These results underscore the importance of screening children presenting for rheumatology evaluation for CD.