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OBJECTIVES: The monoclonal IL-1ß antibody canakinumab is approved for the treatment of systemic juvenile idiopathic arthritis (SJIA). Its efficacy has been proven in several trials, but not all patients show a complete and sustained response to therapy. We aimed to analyse the association of baseline serum biomarkers with treatment outcome in patients with SJIA treated with canakinumab. METHODS: Serum samples from 54 patients with active SJIA without recent macrophage activation syndrome (MAS) treated with canakinumab in an open-label response characterization study were subjected to a multiplexed bead array assay. Interesting targets from these analyses were validated by ELISA. Clinical treatment outcomes included modified paediatric ACR (pACR) 30 and 90 responses, clinically inactive disease (CID) within 15 days of treatment and sustained complete response, defined as pACR100 or CID within 15 days of treatment plus no future flare or MAS. RESULTS: In canakinumab-naïve patients most biomarkers were elevated when compared with healthy controls at baseline and some rapidly decreased by day 15 [IL-1 receptor antagonist (IL-1RA), IL-6, IL-18 and S100A12]. Responders had higher IL-18 and IFN-γ levels and lower chemokine (C-X-C motif) ligand 9 (CXCL9) levels at baseline, emphasized by the IL-18: CXCL9 and IFN-γ: CXCL9 ratios. These ratios had significant accuracy in predicting treatment responses. CONCLUSION: Differential regulation of the IL-18-IFN-γ-CXCL9 axis is observed in patients with SJIA. Higher IL-18: CXCL9 and IFN-γ: CXCL9 ratios at baseline are associated with a better clinical response to canakinumab treatment in SJIA. Future studies are needed to validate these findings and determine their generalizability to patients with recent MAS.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Artritis Juvenil/tratamiento farmacológico , Quimiocina CXCL9/sangre , Interferón gamma/sangre , Interleucina-18/sangre , Adolescente , Artritis Juvenil/sangre , Biomarcadores/sangre , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , MasculinoRESUMEN
Systemic juvenile idiopathic arthritis (sJIA) is an inflammatory disease with hallmarks of severe systemic inflammation, which can be accompanied by arthritis. Contemporary scientific insights set this paediatric disorder on a continuum with its counterpart, adult-onset Still disease (AOSD). Patients with sJIA are prone to complications, including life-threatening hyperinflammation (macrophage activation syndrome (sJIA-MAS)) and sJIA-associated lung disease (sJIA-LD). Meanwhile, the treatment arsenal in sJIA has expanded markedly. State-of-the-art therapeutic approaches include biologic agents that target the IL-1 and IL-6 pathways. Beyond these, a range of novel agents are on the horizon, some of them already being used on a compassionate use basis, including JAK inhibitors and biologic agents that target IL-18, IFNγ, or IL-1ß and IL-18 simultaneously. However, sJIA, sJIA-MAS and sJIA-LD still pose challenging conundrums to rheumatologists treating paediatric and adult patients worldwide. Although national and international consensus treatment plans exist for the treatment of 'classic' sJIA, the treatment approaches for early sJIA without arthritis, and for refractory or complicated sJIA, are not well defined. Therefore, in this Review we outline current approaches for the treatment of sJIA and provide an outlook on knowledge gaps.
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Artritis Juvenil , Enfermedades Pulmonares , Síndrome de Activación Macrofágica , Adulto , Niño , Humanos , Artritis Juvenil/complicaciones , Artritis Juvenil/tratamiento farmacológico , Factores Biológicos/uso terapéutico , Interleucina-18/uso terapéutico , Síndrome de Activación Macrofágica/tratamiento farmacológico , Síndrome de Activación Macrofágica/etiologíaRESUMEN
OBJECTIVE: Rheumatic diseases are characterized by different patterns of immune overactivation. This study investigated the correlation of whole blood type 1 interferon (IFN) stimulated gene (ISG), IL18, and CXCL9 expression with clinical disease activity in pediatric rheumatic diseases and assessed the required number of ISGs to be included in a composite type 1 IFN score. METHODS: Whole blood-derived RNA and clinical data were collected from 171 mostly pediatric patients with connective tissue diseases (CTDs), systemic autoinflammatory diseases (SAIDs), monogenic interferonopathies (IFNPs) and other inflammatory diseases, and from 38 controls. The expression of six previously established ISGs, IL18, and CXCL9 was assessed by real-time polymerase chain reaction (471 samples). Individual and composite gene expression was assessed, and correlation and threshold analyses were performed. RESULTS: Correlation between ISG expression and clinical disease activity was strongest in CTD, especially in juvenile dermatomyositis (JDM) and IFNP, and modest in patients with SAID. Threshold ISG expression levels for the detection of at least mild clinical disease activity were substantially higher in patients with systemic lupus erythematosus compared with JDM. The correlation of expression levels of limited sets of ISGs and even individual ISGs with clinical disease activity were not inferior to a composite score of six ISGs. CONCLUSION: In a real-world cohort, individual ISG expression levels robustly reflected clinical disease activity in CTD and IFNP, especially in JDM, which would simplify such analyses in clinical routine and be more cost-effective. Threshold levels varied across diseases, potentially reflecting different mechanisms of type 1 IFN overactivation.
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OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of inflammatory joint disorders with a chronic-remitting disease course. Treat-to-target approaches have been proposed but monitoring disease activity and predicting the response to treatment remains challenging. METHODS: We analyzed biomarkers and their relationship to outcome within the first year after JIA diagnosis in the German Inception Cohort of Newly diagnosed patients with JIA (ICON-JIA). CRP, CXCL9, CXCL10, CXCL11, erythrocyte sedimentation rate, G-CSF, IL-6, IL-17A, IL-18, MCP-1, MIP-1α, MMP-3, S100A8/A9, S100A12, TNFα, and TWEAK were measured at baseline and 3 months later. RESULTS: Two-hundred-sixty-six JIA patients with active disease at baseline were included, with oligoarthritis and rheumatoid factor-negative polyarthritis representing the most frequent categories (72.9%). Most biomarkers were elevated in JIA compared to healthy pediatric controls. Patients with systemic JIA had higher CRP, S100A8/A9 and S100A12 levels compared to other JIA categories. Baseline levels of TWEAK, G-CSF and IL-18 were lower in oligoarthritis patients with disease extension within 1 year. Increased baseline levels of CRP, S100A8/A9, S100A12 and ESR were associated with the subsequent addition of biologic disease-modifying antirheumatic drugs (DMARDs). Higher baseline ESR, G-CSF, IL-6, IL-17A and TNF levels indicated an increased risk for ongoing disease activity after 12 months. CONCLUSION: Our data demonstrate that elevated baseline levels of CRP, S100A8/A9 and S100A12 as well as increased ESR are associated with the necessity to escalate therapy during the first 12 month of follow-up. Furthermore, biomarkers related to Th17 activation may inform on future disease course in previously treatment-naïve JIA patients.
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Antirreumáticos , Artritis Juvenil , Sedimentación Sanguínea , Proteína C-Reactiva/análisis , Quimiocinas/sangre , Proteínas S100/sangre , Adolescente , Antirreumáticos/inmunología , Antirreumáticos/uso terapéutico , Artritis Juvenil/sangre , Artritis Juvenil/diagnóstico , Artritis Juvenil/epidemiología , Artritis Juvenil/fisiopatología , Femenino , Alemania/epidemiología , Humanos , Pruebas Inmunológicas/métodos , Inflamación/sangre , Masculino , Administración del Tratamiento Farmacológico/normas , Monitorización Inmunológica/métodos , Gravedad del Paciente , Valor Predictivo de las Pruebas , PronósticoRESUMEN
We report an 11-year-old boy with a longstanding history of recurrent pyoderma gangrenosum and abnormal wound healing who eventually developed a fatal invasive fungal infection. This article emphasizes the importance to consider leukocyte adhesion deficiency type 1 in the differential diagnosis of patients with recurrent skin ulcers.
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Cicatriz/patología , Piodermia Gangrenosa/complicaciones , Piodermia Gangrenosa/patología , Biopsia , Niño , Cicatriz/etiología , Cicatriz/inmunología , Resultado Fatal , Humanos , Síndrome de Deficiencia de Adhesión del Leucocito/complicaciones , Síndrome de Deficiencia de Adhesión del Leucocito/inmunología , Síndrome de Deficiencia de Adhesión del Leucocito/patología , Masculino , Piodermia Gangrenosa/inmunología , Recurrencia , Piel/inmunología , Piel/patologíaRESUMEN
To report on the efficacy of rituximab (RTX) therapy in standard treatment-refractory, chronic Henoch-Schönlein purpura, a retrospective chart review of 3 pediatric patients treated with RTX for severe refractory chronic Henoch-Schönlein purpura was performed. All 3 patients responded to 1 or 2 courses of RTX without serious adverse events.
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Anticuerpos Monoclonales/uso terapéutico , Vasculitis por IgA/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Adolescente , Corticoesteroides/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Niño , Resistencia a Medicamentos , Femenino , Humanos , Masculino , Estudios Retrospectivos , Rituximab , Índice de Severidad de la EnfermedadRESUMEN
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.
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Antirreumáticos/uso terapéutico , Artritis Juvenil/sangre , Artritis Juvenil/tratamiento farmacológico , Calgranulina A/sangre , Calgranulina B/sangre , Proteína S100A12/sangre , Adolescente , Biomarcadores/sangre , Niño , Preescolar , Femenino , Humanos , Quimioterapia de Mantención/métodos , Masculino , Brote de los Síntomas , Factores de Tiempo , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Privación de TratamientoRESUMEN
Wegener's granulomatosis (WG) is a chronic, relapsing, systemic necrotizing vasculitis with typical pathologic findings of granulomatous inflammation and pauci-immune vasculitis. Untreated, the condition has a very high mortality, and contemporary treatment strategies carry a high risk of treatment-related morbidity. Antineutrophil cytoplasmic antibodies (ANCA) play a central role in the pathogenesis of the disease. It is unclear how ANCA develop, but B cells are of major importance in the disease pathogenesis as precursors of ANCA-producing plasma cells and, possibly, also as antigen-presenting and cytokine-producing cells. Therefore, the use of B-cell depletion therapy, e.g., with rituximab appears to be an attractive treatment option in WG. Several small clinical trials and case reports show promising results with a high rate of clinical remissions achieved in patients that were refractory to or intolerant of conventional treatment regimens. However, granulomatous manifestations seemed to be less responsive to B-cell depletion therapy. B-cell depletion therapy was generally well tolerated. A large prospective, randomized, double-blind clinical trial evaluating the efficacy of B-cell depletion therapy in WG is pending.
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Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Anticuerpos Monoclonales/uso terapéutico , Linfocitos B , Granulomatosis con Poliangitis/terapia , Inmunosupresores/uso terapéutico , Depleción Linfocítica/métodos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales de Origen Murino , Linfocitos B/inmunología , Enfermedad Crónica , Granulomatosis con Poliangitis/inmunología , Granulomatosis con Poliangitis/fisiopatología , Humanos , Inmunosupresores/efectos adversos , Depleción Linfocítica/efectos adversos , RituximabRESUMEN
BACKGROUND: Juvenile Dermatomyositis (JDM) is a rare pediatric autoimmune disease with broad variations of the individual course. Data on the optimal management are mostly lacking. Currently treatment decisions are often based on experts' opinions. In order to develop consensus-based treatment strategies for JDM in Germany a survey was pursued to analyze the current clinical practice. METHODS: An online survey addressing all members of the Society for Pediatric Rheumatology (GKJR) in Germany and Austria and pediatric neurologists with expertise in JDM was performed in February/March of 2016. The questionnaire consisted of 5 case scenarios including diagnostic criteria, treatment of moderate, severe and refractory JDM, using either multiple choice or a 5-point Likert scale. Basic descriptive statistics were used to analyze the findings. RESULTS: The survey was completed by 60 pediatric rheumatologists and 7 pediatric neurologists experienced in the management of JDM. Typical findings allowing a diagnosis were considered to be: typical skin changes, proximal muscle weakness, MRI findings, elevated muscle enzymes, nailfold capillary changes, presence of calcinosis and muscle biopsy. Regarding induction treatment of moderate/severe JDM: 59%/74% opted for intermittent intravenous methylprednisolone (IVMP) pulse therapy, and 21%/40% for conventional high-dose oral glucocorticoids. Methotrexate (MTX) was the preferred disease-modifying conventional anti-rheumatic drug (cDMARD) for moderate and severe JDM. Regarding the management of refractory moderate or severe JDM, intravenous immune globulins, mycophenolate mofetil and rituximab were preferred treatment options. CONCLUSION: There is consensus about the diagnosis of JDM strongly supported by classic clinical and MRI findings. There is great variety in the treatment of JDM in Germany regarding both induction and maintenance therapy. The development of consensus-based treatment strategies for JDM based on harmonization of current clinical practice is essential in order to allow comparative effectiveness research in the future.
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Dermatomiositis/tratamiento farmacológico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Antirreumáticos/uso terapéutico , Austria , Niño , Consenso , Dermatomiositis/diagnóstico , Alemania , Glucocorticoides/uso terapéutico , Humanos , Inmunoglobulinas Intravenosas , Neurólogos , Reumatólogos , Encuestas y CuestionariosRESUMEN
BACKGROUND: The goal of this study was to apply the varicella zoster virus (VZV) vaccine to patients with pediatric rheumatic diseases (PRD) at risk for severe chickenpox, without interrupting their current immunosuppression, including biological agents, using an immunological-based pre-vaccination checklist to assure safety. A pre-vaccination checklist was implemented to ensure adequate immune competence prior to immunization. METHODS: This prospective study included seronegative patients (VZV-IgG ≤200 mIU/ml) and patients who had previously received only a single dose of VZV vaccine. All vaccinees demonstrated clinically inactive PRD. Patients were categorized according to their actual treatment in low-intensity IS (LIIS) and high-intensity IS (HIIS) including biological therapy. The pre-vaccination checklist defined thresholds for the following basic laboratory tests: white blood cell count ≥3000/mm3, lymphocytes ≥1200/mm3, serum IgG ≥500 mg/dl, IgM ≥20 mg/dl, tetanus toxoid antibody ≥0.1 IU/ml. In case of HIIS additional specifications included a CD4+ lymphocyte count ≥200/mm3 and a positive T-cell function (via analyzable positive control of a standard tuberculosis interferon-gamma-release-assay (TB-IGRA) indicating mitogen-induced T cell proliferation). Patients who met the criteria of the pre-vaccination checklist received the first and/or second VZV vaccination. Immunologic response and side effects were monitored. RESULTS: Twenty-three patients were recruited of whom nine had already received one VZV immunization before initiating IS. All patients met the pre-vaccination checklist criteria despite ongoing IS. There was no overall difference in VZV-IgG levels when comparing the LIIS (n=9) and HIIS (n=14) groups. In total, 21 patients (91%) showed a positive vaccination response, after the first immunization the median VZV-IgG across all patients was 224 (59-1219) mIU/ml (median (range)), after booster immunization it increased to 882 (30-4685) mIU/ml. Two patients in the HIIS group failed to raise positive VZV-IgG, despite booster immunization. All nine patients receiving only the second immunization on IS reached high titers of VZV-IgG >500 mIU/ml (1117 (513-4685) mIU/ml). There were no cases of rash or other vaccine-induced varicella disease symptoms and no evidence of PRD flare. CONCLUSIONS: VZV vaccination is safe and largely immunogenic in children with ongoing IS fulfilling an immunological based pre-vaccination checklist. This new approach is based on immunologic function rather than on type of medications. TRIAL REGISTRATION NUMBER: ISRCRTN trial registration number 21654693 , date of registration February 12, 2018, retrospectively registered.
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Lista de Verificación/métodos , Vacuna contra la Varicela/administración & dosificación , Varicela/inmunología , Herpesvirus Humano 3/inmunología , Enfermedades Reumáticas/inmunología , Adolescente , Factores Biológicos/administración & dosificación , Factores Biológicos/efectos adversos , Vacuna contra la Varicela/efectos adversos , Niño , Preescolar , Femenino , Alemania , Humanos , Huésped Inmunocomprometido/inmunología , Inmunoglobulina G/sangre , Masculino , Estudios Prospectivos , Vacunación/efectos adversos , Vacunación/métodosRESUMEN
BACKGROUND: Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in childhood and a major cause of morbidity among children with pediatric rheumatic diseases. The management of JDM is very heterogeneous. The JDM working group of the Society for Pediatric Rheumatology (GKJR) aims to define consensus- and practice-based strategies in order to harmonize diagnosis, treatment and monitoring of JDM. METHODS: The JDM working group was established in 2015 consisting of 23 pediatric rheumatologists, pediatric neurologists and dermatologists with expertise in the management of JDM. Current practice patterns of management in JDM had previously been identified via an online survey among pediatric rheumatologists and neurologists. Using a consensus process consisting of online surveys and a face-to-face consensus conference statements were defined regarding the diagnosis, treatment and monitoring of JDM. During the conference consensus was achieved via nominal group technique. Voting took place using an electronic audience response system, and at least 80% consensus was required for individual statements. RESULTS: Overall 10 individual statements were developed, finally reaching a consensus of 92 to 100% regarding (1) establishing a diagnosis, (2) case definitions for the application of the strategies (moderate and severe JDM), (3) initial diagnostic testing, (4) monitoring and documentation, (5) treatment targets within the context of a treat-to-target strategy, (6) supportive therapies, (7) explicit definition of a treat-to-target strategy, (8) various glucocorticoid regimens, including intermittent intravenous methylprednisolone pulse and high-dose oral glucocorticoid therapies with tapering, (9) initial glucocorticoid-sparing therapy and (10) management of refractory disease. CONCLUSION: Using a consensus process among JDM experts, statements regarding the management of JDM were defined. These statements and the strategies aid in the management of patients with moderate and severe JDM.
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Dermatomiositis/tratamiento farmacológico , Antirreumáticos/uso terapéutico , Austria , Niño , Consenso , Dermatomiositis/diagnóstico , Manejo de la Enfermedad , Alemania , Glucocorticoides/uso terapéutico , Humanos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Systemic juvenile idiopathic arthritis (SJIA) is an autoinflammatory disease associated with chronic arthritis. Early diagnosis and effective therapy of SJIA is desirable, so that complications are avoided. The PRO-KIND initiative of the German Society for Pediatric Rheumatology (GKJR) aims to define consensus-based strategies to harmonize diagnostic and therapeutic approaches in Germany. METHODS: We analyzed data on patients diagnosed with SJIA from 3 national registries in Germany. Subsequently, via online surveys and teleconferences among pediatric rheumatologists with a special expertise in the treatment of SJIA, we identified current diagnostic and treatment approaches in Germany. Those were harmonized via the formulation of statements and, supported by findings from a literature search. Finally, an in-person consensus conference using nominal group technique was held to further modify and consent the statements. RESULTS: Up to 50% of patients diagnosed with SJIA in Germany do not fulfill the International League of Associations for Rheumatology (ILAR) classification criteria, mostly due to the absence of chronic arthritis. Our findings suggest that chronic arthritis is not obligatory for the diagnosis and treatment of SJIA, allowing a diagnosis of probable SJIA. Malignant, infectious and hereditary autoinflammatory diseases should be considered before rendering a diagnosis of probable SJIA. There is substantial variability in the initial treatment of SJIA. Based on registry data, most patients initially receive systemic glucocorticoids, however, increasingly substituted or accompanied by biological agents, i.e. interleukin (IL)-1 and IL-6 blockade (up to 27.2% of patients). We identified preferred initial therapies for probable and definitive SJIA, including step-up patterns and treatment targets for the short-term (resolution of fever, decrease in C-reactive protein by 50% within 7 days), the mid-term (improvement in physician global and active joint count by at least 50% or a JADAS-10 score of maximally 5.4 within 4 weeks) and the long-term (glucocorticoid-free clinically inactive disease within 6 to 12 months), and an explicit treat-to-target strategy. CONCLUSIONS: We developed consensus-based strategies regarding the diagnosis and treatment of probable or definitive SJIA in Germany.
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Artritis Juvenil/diagnóstico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Antirreumáticos/uso terapéutico , Artritis Juvenil/tratamiento farmacológico , Factores Biológicos/uso terapéutico , Niño , Preescolar , Consenso , Bases de Datos Factuales , Alemania , Glucocorticoides/uso terapéutico , Humanos , Sistema de RegistrosRESUMEN
Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.
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Enfermedad Granulomatosa Crónica/genética , Mutación con Pérdida de Función , Fosfoproteínas/deficiencia , Fosfoproteínas/genética , Adolescente , Adulto , Alelos , Niño , Preescolar , Femenino , Técnicas de Inactivación de Genes , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/metabolismo , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Linaje , Fagocitos/inmunología , Fagocitos/metabolismo , Fagocitos/microbiología , Fenotipo , Fosfoproteínas/metabolismo , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción Genética , Adulto JovenRESUMEN
BACKGROUND: High-dose intravenous immune globulins (IVIg) are frequently used in refractory juvenile dermatomyositis (JDM) but are often poorly tolerated. High-dose recombinant human hyaluronidase-facilitated subcutaneous immune globulins (fSCIg) allow the administration of much higher doses of immune globulins than conventional subcutaneous immune globulin therapy and may be an alternative to IVIg. The safety and efficacy of fSCIg therapy in JDM is unknown. CASE PRESENTATION: In this retrospective case series, five patients with steroid-refractory severe JDM were treated with high-dose fSCIg due to IVIg adverse effects (severe headaches, nausea, vomiting, difficult venous access). Peak serum IgG levels, muscle enzymes, the childhood myositis assessment scale and adverse effects were retrieved for at least 6 months following intiation of fSCIg. Data were analyzed by descriptive statistics. Patients initially received fSCIg 1 g/kg every 14 days, resulting in median IgG peak levels of 1901 mg/dl (1606-2719 mg/dl), compared to median IgG peak and trough levels while previously receiving IVIg of 2741 mg/dl (2429-2849 mg/dl) and 1351 mg/dl (1156-1710 mg/dl). Additional antirheumatic therapies consisted of low-dose glucocorticoid therapy, methotrexate, mycophenolate mofetil and/or rituximab. Two patients maintained clinically inactive disease and three patients had only a partial treatment response. In the three patients with partial treatment response, fSCIg 1 g/kg was then given on days 1 and 6 of every 28-day cycle resulting in IgG peak levels of between 2300-2846 mg/dl (previously 1606-1901 mg/dl on the biweekly regimen), resulting in clinically inactive disease in two of the three patients. There were no relevant adverse effects that limited continuation of fSCIg treatment. CONCLUSIONS: High-dose fSCIg is well-tolerated in patients with JDM and high peak serum IgG levels can be achieved which may be important for treatment success. High-dose fSCIg may therefore be an alternative to high-dose IVIg and deserves further study. TRIAL REGISTRATION: This is a case series and data were retrospectively registered.
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Dermatomiositis , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Hialuronoglucosaminidasa , Inmunoglobulinas Intravenosas , Tejido Subcutáneo , Permeabilidad de la Membrana Celular/efectos de los fármacos , Niño , Dermatomiositis/tratamiento farmacológico , Dermatomiositis/inmunología , Dermatomiositis/fisiopatología , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Femenino , Humanos , Hialuronoglucosaminidasa/administración & dosificación , Hialuronoglucosaminidasa/farmacocinética , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoglobulinas Intravenosas/efectos adversos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Inmunomodulación , Masculino , Monitorización Inmunológica/métodos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacocinética , Tejido Subcutáneo/efectos de los fármacos , Tejido Subcutáneo/inmunología , Resultado del TratamientoAsunto(s)
Anticuerpos Monoclonales/uso terapéutico , Enfermedades Autoinmunes/tratamiento farmacológico , Linfocitos B/efectos de los fármacos , Factores Inmunológicos/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Enfermedades Autoinmunes/inmunología , Linfocitos B/metabolismo , Niño , Evaluación de Medicamentos , Monitoreo de Drogas/métodos , Humanos , Rituximab , Resultado del TratamientoAsunto(s)
Conducta del Adolescente , Conducta Infantil , Trastornos del Conocimiento/diagnóstico , Cognición , Vasculitis por Lupus del Sistema Nervioso Central/diagnóstico , Pruebas Neuropsicológicas , Adolescente , Edad de Inicio , Niño , Preescolar , Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/psicología , Humanos , Vasculitis por Lupus del Sistema Nervioso Central/epidemiología , Vasculitis por Lupus del Sistema Nervioso Central/psicología , Neuroimagen , Valor Predictivo de las Pruebas , Factores de RiesgoRESUMEN
INTRODUCTION: Previous observations suggest that active systemic juvenile idiopathic arthritis (sJIA) is associated with a prominent erythropoiesis gene-expression signature. The aim of this study was to determine the association of this signature with peripheral blood mononuclear cell (PBMC) subpopulations and its specificity for sJIA as compared with related conditions. METHODS: The 199 patients with JIA (23 sJIA and 176 non-sJIA) and 38 controls were studied. PBMCs were isolated and analyzed for multiple surface antigens with flow cytometry and for gene-expression profiles. The proportions of different PBMC subpopulations were compared among sJIA, non-sJIA patients, and controls and subsequently correlated with the strength of the erythropoiesis signature. Additional gene-expression data from patients with familial hemophagocytic lymphohistiocytosis (FHLH) and from a published sJIA cohort were analyzed to determine whether the erythropoiesis signature was present. RESULTS: Patients with sJIA had significantly increased proportions of immature cell populations, including CD34+ cells, correlating highly with the strength of the erythropoiesis signature. The erythropoiesis signature strongly overlapped with the gene-expression pattern in purified immature erythroid precursors. The expansion of immature cells was most prominently seen in patients with sJIA and anemia, even in the absence of reticulocytosis. Patients with non-sJIA and anemia did not exhibit the erythropoiesis signature. The erythropoiesis signature was found to be prominent in patients with FHLH and in a published cohort of patients with active sJIA, but not in patients with inactive sJIA. CONCLUSIONS: An erythropoiesis signature in active sJIA is associated with the expansion of CD34+ cells, also is seen in some patients with FHLH and infection, and may be an indicator of ineffective erythropoiesis and hemophagocytosis due to hypercytokinemia.
Asunto(s)
Artritis Juvenil/genética , Artritis Juvenil/patología , Eritropoyesis/genética , Perfilación de la Expresión Génica , Leucocitos Mononucleares/patología , Adolescente , Anemia/genética , Anemia/metabolismo , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Artritis Juvenil/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Citocinas/sangre , Femenino , Humanos , Leucocitos Mononucleares/inmunología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/metabolismo , Masculino , Estudios Prospectivos , Receptores de Transferrina/metabolismoRESUMEN
Kawasaki disease (KD) characteristically presents with prolonged, remittent fever in addition to other clinical findings. We report the case of a 3-month-old boy who developed characteristic manifestations of KD and coronary aneurysms in the absence of fever. This case report underlines the difficulty to diagnose KD in young infants.
Asunto(s)
Fiebre , Síndrome Mucocutáneo Linfonodular/diagnóstico , Aneurisma Coronario/etiología , Humanos , Lactante , Masculino , Síndrome Mucocutáneo Linfonodular/patología , Síndrome Mucocutáneo Linfonodular/fisiopatologíaRESUMEN
OBJECTIVE: To determine whether neutrophil gelatinase-associated lipocalin (NGAL) can predict worsening of global and renal disease activity in childhood-onset systemic lupus erythematosus (SLE). METHODS: One hundred eleven patients with childhood-onset SLE were enrolled in a longitudinal, prospective study with quarterly study visits and had at least 3 study visits. At each visit, global disease activity was measured using 3 external standards: the numerically converted British Isles Lupus Assessment Group (BILAG) index, the SLE Disease Activity Index 2000 update score, and the physician's assessment of global disease activity. Renal and extrarenal disease activity were measured by the respective domain scores. The disease course over time was categorized at the most recent visit (persistently active, persistently inactive, improved, or worsening). Plasma and urinary NGAL levels were measured by enzyme-linked immunosorbent assay, and urinary NGAL levels were standardized to the urinary creatinine concentration. The longitudinal changes in NGAL levels were compared with the changes in SLE disease activity using mixed-effect models. RESULTS: Significant increases in standardized urinary NGAL levels of up to 104% were detected up to 3 months before worsening of lupus nephritis (as measured by all 3 external standards). Plasma NGAL levels increased significantly by as much as 26% up to 3 months before worsening of global SLE disease activity as measured by all 3 external standards. Plasma NGAL levels increased significantly by 26% as early as 3 months prior to worsening of lupus nephritis as measured by the BILAG renal score. CONCLUSION: Serial measurement of urinary and plasma NGAL levels may be valuable in predicting impending worsening of global and renal childhood-onset SLE disease activity.