Consensus Treatment Plans for Severe Pediatric Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: There is no standardized approach to the treatment of pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Because of the rarity of pediatric AAV, randomized trials have not been feasible. The present study of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) was undertaken to establish consensus treatment plans (CTPs) for severe pediatric AAV to enable the future study of comparative effectiveness and safety. METHODS: A workgroup of CARRA members (rheumatologists and nephrologists) formed the AAV Workgroup. This group performed a literature review on existing evidence-based treatments and guidelines for the management of AAV. They determined that the target population for CTP development was patients <18 years of age with new-onset granulomatosis with polyangiitis (GPA), microscopic polyangiitis, or renal-limited AAV (eosinophilic GPA was excluded), with presentation confined to those with severe disease (i.e., organ- or life-threatening). Face-to-face consensus conferences employed nominal group techniques to identify treatment strategies for remission induction and remission maintenance, data elements to be systematically collected, and outcomes to be measured over time. RESULTS: The pediatric AAV Workgroup developed 2 CTPs for each of the remission induction and remission maintenance of severe AAV. A glucocorticoid-weaning regimen for induction and maintenance, a core data set, and outcome measures were also defined. A random sample of CARRA membership voted acceptance of the CTPs for remission induction and remission maintenance, with a 94% (75 of 80) and 98% (78 of 80) approval rate, respectively. CONCLUSION: Consensus methodology established standardized CTPs for treating severe pediatric AAV. These CTPs were in principle accepted by CARRA-wide membership for the evaluation of pragmatic comparative effectiveness in a long-term registry.

Pyoderma gangrenosum-like ulceration as a presenting feature of pediatric granulomatosis with polyangiitis.

BACKGROUND: Granulomatosis with polyangiitis (GPA) is an anti-neutrophilic cytoplasmic antibody-associated vasculitis affecting small to medium-sized vessels and involves most commonly the kidneys and the respiratory tract. Skin involvement can be seen in up to 50% of children with GPA and is the initial presenting symptom in 7.7%. Pyoderma gangrenosum (PG)-like ulcers are rarely described as a skin manifestation in GPA and very few cases have been reported previously in children. CASE PRESENTATION: We describe 3 new pediatric cases of GPA with PG-like ulcerations. The median age at first symptom was 15 years. Two patients had PG-like ulceration as their initial presentation; additional symptoms eventually led to the diagnosis of GPA 2-24 months later. In 1 case, proteinase 3 (PR3) was negative when first tested, but converted to positive when systemic symptoms emerged; in the other 2 cases PR3 was positive at presentation. All 3 patients had prominent facial lesions. None of the patients responded to treatment with antibiotics or medications commonly used to manage PG, including corticosteroids and cyclosporine. All patients had excellent responses to rituximab. An electronic database literature review was performed and 4 previously reported cases were identified. We assessed the clinical characteristics, serology, and response to treatment of the previously reported and our newly diagnosed cases. CONCLUSION: PG-like ulceration is a rare presentation of pediatric GPA which may precede classic systemic GPA symptoms. The predominance of facial ulcer, granulomatous and neutrophilic inflammation on skin biopsy and lack of response to PG treatments are characteristic of GPA-associated PG-like ulcers. Our review suggests that treatment with rituximab may be needed to improve the skin lesions. Recognizing that PG-like ulcerations can occur in pediatric GPA may result in timely diagnosis, appropriate treatment and improved prognosis.

Kawasaki Disease: Beyond IVIG and Aspirin.

Kawasaki disease (KD) is a vasculitis syndrome of unknown etiology, affecting medium-sized vessels and occurring primarily in young children. It is a self-limited illness classically presenting with fever, conjunctivitis, mucocutaneous lesions, and cervical adenopathy. However, vasculitis of coronary arteries with aneurysm formation may occur, leading to morbidity and rarely mortality. Prompt diagnosis of KD is essential as early treatment with intravenous immune globulin (IVIG) decreases the occurrence and severity of coronary vasculitis. This article reviews the clinical characteristics of KD, laboratory assessment, echocardiogram findings, and recommended initial medical therapy. Complications of KD are discussed, including KD refractory to IVIG, the presence of shock or macrophage activation syndrome (MAS), and short/long-term cardiac sequelae. The medical management of these complications is reviewed. Although improved treatment of KD has resulted in a decrease of coronary artery vasculitis over the past 3 decades, KD remains the most common cause of acquired heart disease in children. [Pediatr Ann. 2019;48(10):e400-e405.].

Pediatric anti-NMDA receptor encephalitis with catatonia: treatment with electroconvulsive therapy.

BACKGROUND: Anti-NMDA receptor encephalitis, an autoimmune disease associated with antibodies against N-methyl-D-aspartate (NMDA) receptors, is being diagnosed more frequently, especially in children and young adults. Acute neurological and psychiatric manifestations are the common presenting symptoms. Diagnosing anti-NMDA receptor encephalitis is often challenging given the wide range of clinical presentation, and may be further complicated by its overlap of symptoms, brain MRI changes, and CSF findings with other entities affecting the brain. Even though diagnosis can be made by identifying antibodies in immune-mediated encephalitis, the diagnosis may be delayed by weeks to months. Delay in initiation of treatment with immune suppressive therapies is shown to be associated with adverse outcomes. Malignant catatonia is a severe and life-threatening state associated with anti-NMDA receptor encephalitis. It is often inadequately assessed and may not respond to immunosuppressive treatment. CASE PRESENTATION: We present a confirmed case of anti-NMDA receptor encephalitis in a 16 year old girl who had severe critical neurological and psychiatric manifestations, including malignant catatonia and autonomic instability. Our patient continued to manifest malignant catatonia despite the initiation of prompt, aggressive immune suppressive therapies, including corticosteroids, plasmapheresis, intravenous gammaglobulin and rituximab, as well as treatment with high-dose benzodiazepines. Once electroconvulsive therapy (ECT) began, she had a robust response with resolution of her catatonia. Six weeks after treatment with eight ECT cycles, she had returned to her normal baseline cognitive and motor function. CONCLUSIONS: ECT was an effective and well-tolerated therapy in our patient, and should be considered for the treatment of children with anti-NMDA receptor encephalitis whose catatonia does not respond to immunosuppression and benzodiazepines.

Serum S100A8/A9 and S100A12 Levels in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis: Relationship to Maintenance of Clinically Inactive Disease During Anti-Tumor Necrosis Factor Therapy and Occurrence of Disease Flare After Discontinuation of Therapy.

OBJECTIVE: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti-tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA). METHODS: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti-TNF withdrawal. Spearman's rank correlation test, Mann-Whitney U test, Kruskal-Wallis test, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti-TNF withdrawal. RESULTS: Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = -0.36). CONCLUSION: Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular-course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare.

Pilot study comparing the childhood arthritis and rheumatology research alliance consensus treatment plans for induction therapy of juvenile proliferative lupus nephritis.

BACKGROUND: To reduce treatment variability and facilitate comparative effectiveness studies, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) published consensus treatment plans (CTPs) including one for juvenile proliferative lupus nephritis (LN). Induction immunosuppression CTPs outline treatment with either monthly intravenous (IV) cyclophosphamide (CYC) or mycophenolate mofetil (MMF) in conjunction with one of three corticosteroid (steroid) CTPs: primarily oral, primarily IV or mixed oral/IV. The acceptability and in-practice use of these CTPs are unknown. Therefore, the primary aims of the pilot study were to demonstrate feasibility of adhering to the LN CTPs and delineate barriers to implementation in clinical care in the US. Further, we aimed to explore the safety and effectiveness of the treatments for induction therapy. METHODS: Forty-one patients were enrolled from 10 CARRA sites. Patients had new-onset biopsy proven ISN/RPS class III or IV proliferative LN, were starting induction therapy with MMF or IV CYC and high-dose steroids and were followed for up to 24 months. Routine clinical data were collected at each visit. Provider reasons for CTP selection were assessed at baseline. Adherence to the CTPs was evaluated by provider survey and medication logs. Complete and partial renal responses were reported at 6 months. RESULTS: The majority of patients were female (83%) with a mean age of 14.7 years, SD 2.8. CYC was used more commonly than MMF for patients with ISN/RPS class IV LN (vs. class III), those who had hematuria, and those with adherence concerns. Overall adherence to the immunosuppression induction CTPs was acceptable with a majority of patients receiving the target MMF (86%) or CYC (63%) dose. However, adherence to the steroid CTPs was poor (37%) with large variability in dosing. Renal response endpoints were exploratory and did not show a significant difference between CYC and MMF. CONCLUSIONS: Overall, the immunosuppression CTPs were followed as intended in the majority of patients however, adherence to the steroid CTPs was poor indicating revision is necessary. In addition, our pilot study revealed several sources of treatment selection bias that will need to be addressed in for future comparative effectiveness research.

Risk, Timing, and Predictors of Disease Flare After Discontinuation of Anti-Tumor Necrosis Factor Therapy in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis With Clinically Inactive Disease.

OBJECTIVE: To determine the frequency, time to flare, and predictors of disease flare upon withdrawal of anti-tumor necrosis factor (anti-TNF) therapy in children with polyarticular forms of juvenile idiopathic arthritis (JIA) who demonstrated ≥6 months of continuous clinically inactive disease. METHODS: In 16 centers 137 patients with clinically inactive JIA who were receiving anti-TNF therapy (42% of whom were also receiving methotrexate [MTX]) were prospectively followed up. If the disease remained clinically inactive for the initial 6 months of the study, anti-TNF was stopped and patients were assessed for flare at 1, 2, 3, 4, 6, and 8 months. Life-table analysis, t-tests, chi-square test, and Cox regression analysis were used to identify independent variables that could significantly predict flare by 8 months or time to flare. RESULTS: Of 137 patients, 106 (77%) maintained clinically inactive disease while receiving anti-TNF therapy for the initial 6 months and were included in the phase of the study in which anti-TNF therapy was stopped. Stopping anti-TNF resulted in disease flare in 39 (37%) of 106 patients by 8 months. The mean/median ± SEM time to flare was 212/250 ± 9.77 days. Patients with shorter disease duration at enrollment, older age at onset and diagnosis, shorter disease duration prior to experiencing clinically inactive disease, and shorter time from onset of clinically inactive disease to enrollment were found to have significantly lower hazard ratios for likelihood of flare by 8 months (P < 0.05). CONCLUSION: Over one-third of patients with polyarticular JIA with sustained clinically inactive disease will experience a flare by 8 months after discontinuation of anti-TNF therapy. Several predictors of lower likelihood of flare were identified.

Malignancy in Pediatric-onset Systemic Lupus Erythematosus.

OBJECTIVE: To determine cancer incidence in a large pediatric-onset systemic lupus erythematosus (SLE) population. METHODS: Data were examined from 12 pediatric SLE registries in North America. Patients were linked to their regional cancer registries to detect cancers observed after cohort entry, defined as date first seen in the clinic. The expected number of malignancies was obtained by multiplying the person-years in the cohort (defined from cohort entry to end of followup) by the geographically matched age-, sex-, and calendar year-specific cancer rates. The standardized incidence ratio (SIR; ratio of cancers observed to expected) was generated, with 95% CI. RESULTS: A total of 1168 patients were identified from the registries. The mean age at cohort entry was 13 years (SD 3.3), and 83.7% of the subjects were female. The mean duration of followup was 7.6 years, resulting in a total observation period of 8839 years spanning the calendar period 1974-2009. During followup, fourteen invasive cancers occurred (1.6 cancers per 1000 person-yrs, SIR 4.13, 95% CI 2.26-6.93). Three of these were hematologic (all lymphomas), resulting in an SIR for hematologic cancers of 4.68 (95% CI 0.96-13.67). SIR were increased for both male and female patients, and across age groups. CONCLUSION: Although cancer remains a relatively rare outcome in pediatric-onset SLE, our data do suggest an increase in cancer for patients followed an average of 7.6 years. About one-fifth of the cancers were hematologic. Longer followup, and study of drug effects and disease activity, is warranted.

Clinical practice variation and need for pediatric-specific treatment guidelines among rheumatologists caring for children with ANCA-associated vasculitis: an international clinician survey.

BACKGROUND: Because pediatric antineutrophil cytoplasmic antibody-associated vasculitis is rare, management generally relies on adult data. We assessed treatment practices, uptake of existing clinical assessment tools, and interest in pediatric treatment protocols among rheumatologists caring for children with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). METHODS: A needs-assessment survey developed by an international working group of pediatric rheumatologists and two nephrologists was circulated internationally. Data were summarized with descriptive statistics. Pearson's chi-square tests were used in inferential univariate analyses. RESULTS: The 209 respondents from 36 countries had collectively seen ~1600 children with GPA/MPA; 144 had seen more than two in the preceding 5 years. Standardized and validated clinical assessment tools to score disease severity, activity, and damage were used by 59, 63, and 36%, respectively; barriers to use included lack of knowledge and limited perceived utility. Therapy varied significantly: use of rituximab rather than cyclophosphamide was more common among respondents from the USA (OR = 2.7 [1.3-5.5], p = 0.0190, n = 139), those with >5 years of independent practice experience (OR = 3.8 [1.3-12.5], p = 0.0279, n = 137), and those who had seen >10 children with GPA/MPA in their careers (OR = 4.39 [2.1-9.1], p = 0.0011, n = 133). Respondents who had treated >10 patients were also more likely to continue maintenance therapy for at least 24 months (OR = 3.0 [1.4-6.4], p = 0.0161, n = 127). Ninety six percent of respondents believed in a need for pediatric-specific treatment guidelines; 46% supported adaptation of adult guidelines while 69% favoured guidelines providing a limited range of treatment options to allow comparison of effectiveness through a registry. CONCLUSIONS: These data provide a rationale for developing pediatric-specific consensus treatment guidelines for GPA/MPA. While pediatric rheumatologist uptake of existing clinical tools has been limited, guideline uptake may be enhanced if outcomes of consensus-derived treatment options are evaluated within the framework of an international registry.

Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegener's): An ARChiVe Cohort Study.

OBJECTIVE: To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. RESULTS: In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. CONCLUSION: Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.

Safety and immunogenicity of the quadrivalent HPV vaccine in female Systemic Lupus Erythematosus patients aged 12 to 26 years.

BACKGROUND: Women with SLE have higher rates of persistent human papilloma virus (HPV) infections and precancerous lesions than healthy women. HPV vaccine is safe and effective in healthy females aged 9-26 years. There are limited data on the safety and immunogenicity of HPV vaccine in females with SLE, and none in adolescents with SLE. Our study evaluates the safety and immunogenicity of recombinant quadrivalent HPV vaccine, Gardasil, in adolescents and young women with SLE. METHODS: This is a prospective, open-label study. Exclusion criteria included disease exacerbation within past 30 days; rituximab or cyclophosphamide within 6 months; pregnancy. Vaccine was administered at months 0, 2, and 6. Physical examination, SLEDAI scores and laboratory studies were performed at months 0, 2, 4, 6 and 7. Each patient's SLEDAI scores and laboratory profile in the year prior to vaccine administration were used as controls for that patient. Primary outcome measures were change in SLEDAI and mean HPV antibody titers. RESULTS: 27 patients, 12 to 26 years, were enrolled; 20 completed the study. Nine had mild/moderate lupus flares. Mean SLEDAI scores decreased from 6.14 pre-vaccination to 4.49 post-vaccination (p = 0.01). Of 12 patients with lupus nephritis, two experienced worsening renal function during/after the study and progressed to renal failure within 18 months of the study. Both had Class IV lupus nephritis with high chronicity scores (≥ 8) on renal biopsies performed within one year prior to study entry. Seropositivity post-vaccine was >94% for HPV 6, 11, 16 and 18. CONCLUSIONS: Quadrivalent HPV vaccine seems generally safe and well tolerated in this series of adolescents and young women with SLE, with no increase in mean SLEDAI scores. Progression to renal failure in two patients was most likely secondary to pre-existing severe renal chronicity and not secondary to HPV vaccination. Immunogenicity to the quadrivalent HPV vaccine was excellent, with the seropositivity rate >94% in all four HPV types.

Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase.

Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 with the guanine nucleotide exchange factor Vav1. The model predicts that NCF2/H389 residue interacts with Vav1 residues E509, N510, E556, and G559 in the ZF domain of Vav1. Furthermore, replacing H389 with Q results in 1.5 kcal/mol weaker binding. To examine the effect of the NCF2 H389Q mutation on NADPH oxidase function, site-specific mutations at the 389 position in NCF2 were tested. Results show that an H389Q mutation causes a twofold decrease in reactive oxygen species production induced by the activation of the Vav-dependent Fcγ receptor-elicited NADPH oxidase activity. Our study completes the chain of evidence from genetic association to specific molecular function.