Population Pharmacodynamic Modelling of the CD19+ Suppression Effects of Rituximab in Paediatric Patients with Neurological and Autoimmune Diseases.

BACKGROUND: Limited pharmacotherapy and the failure of conventional treatments in complex pathologies in children lead to increased off-label use of rituximab. We aimed to characterize the time course of CD19+ B lymphocytes (CD19+) under treatment with intravenous rituximab in children with neurologic and autoimmune diseases and to evaluate the impact of covariates (i.e., demographics, diagnosis and substitution between innovator and biosimilar product) on rituximab pharmacodynamics and disease activity. METHODS: Pre- and post-drug infusion CD19+ in peripheral blood were prospectively registered. A population pharmacodynamic model describing the time course of CD19+ was developed with NONMEM v7.4. Simulations of three different rituximab regimens were performed to assess the impact on CD19+. Logistic regression analysis was performed to identify predictors of clinical response recorded through disease activity scores. RESULTS: 281 measurements of CD19+ lymphocyte counts obtained from 63 children with neurologic (n = 36) and autoimmune (n = 27) diseases were available. The time course of CD19+ was described with a turn-over model in which the balance between synthesis and degradation rates is disrupted by rituximab, increasing the latter process. The model predicts half-lives (percent coefficient of variation, CV(%)) of rituximab and CD19+ of 11.6 days (17%) and 173.3 days (22%), respectively. No statistically significant effect was found between any of the studied covariates and model parameters (p > 0.05). Simulations of different regimens showed no clinically significant differences in terms of CD19+ repopulation times. A trend towards a lack of clinical response was observed in patients with lower CD19+ repopulation times and higher areas under the CD19+ versus time curve. CONCLUSIONS: Rituximab pharmacodynamics was described in a real-world setting in children suffering from autoimmune and neurologic diseases. Diagnosis, substitution between innovator rituximab and its biosimilars or type of regimen did not affect rituximab-induced depletion of CD19+ nor the clinical response in this cohort of patients. According to this study, rituximab frequency and dosage may be chosen based on clinical convenience or safety reasons without affecting CD19+ repopulation times. Further studies in larger populations are required to confirm these results.

Intensive Safety Monitoring of Rituximab (Biosimilar Novex® and the Innovator) in Pediatric Patients With Complex Diseases.

Although rituximab is widely used off-label for complex pediatric diseases, safety reports are limited. We aimed to report evidence of its use in clinical practice, to describe the incidence of adverse drug reactions (ADR) to rituximab biosimilar Novex® and innovator, and to identify risk factors for the development of ADR in a real-life follow-up cohort of pediatric patients with complex diseases. We conducted a prospective, longitudinal, observational, single-centre study in patients that received rituximab for any complex disease, and as part of an intensive pharmacovigilance program. Demographic, pharmacological, clinical, and drug-related data were collected for all patients. ADR-free survival, including infusion-related reactions (IRR) and delayed ADR (dADR), was estimated using Kaplan-Meier curves. Risk factors were evaluated by multivariable Cox regression models. In total, 77 patients (<19 y.o.) received 187 infusions of rituximab Novex® (n = 155) or innovator rituximab (n = 32) for neurologic (Neu), immune-hematologic-rheumatic (IHR), oncologic (O) diseases, and hematopoietic stem-cell transplantation (HSCT) or solid-organ transplantation (SOT). We recorded 29 IRR and 58 dADR that occurred in 27 (35.1%) and 29 (37.7%) patients, respectively. The respiratory tract was the most affected during IRR (29.6%) and hypogammaglobulinemia (37.9 %) was the most frequent dADR. First versus subsequent infusions (HR 5.4, CI95% 2.4-12.1, p<0.05), sex (boys vs. girls, HR 0.3, CI95% 0.1-0.8, and p<0.05), and diagnosis (Neu-IHR diseases vs. O-HSCT-SOT, HR 2.3, CI95% 1.02-5.4, and p < 0.05) were significantly associated with the development of IRR. For dADR, risk factors were diagnosis (Neu-IHR diseases vs. O-HSCT-SOT, HR 0.4, CI95% 0.2-0.9, and p < 0.05) and cumulative body surface area-normalized dosage (HR 1.0003, CI95% 1.0001-1.0006, and p < 0.05). The present is the largest real-world safety assessment of rituximab in Latin-American children with complex diseases supporting its use based on the overall acceptable safety. Identification of risk factors may contribute to optimization of off-label rituximab treatment in pediatrics.

Takayasu Arteritis.

Takayasu arteritis is an idiopathic granulomatous vasculitis of the aorta and its main branches and it constitutes one of the more common vasculitides in children. Inflammation and intimal proliferation lead to wall thickening, stenotic or occlusive lesions, and thrombosis, while destruction of the elastica and muscularis layers originates aneurysms and dissection. Carotid artery tenderness, claudication, ocular disturbances, central nervous system abnormalities, and weakening of pulses are the most frequent clinical features. The diagnosis is usually confirmed by the observation of large vessel wall abnormalities: stenosis, aneurysms, occlusion, and evidence of increased collateral circulation in angiography, MRA or CTA imaging. The purpose of this revision is to address the current knowledge on pathogenesis, investigations, classification, outcome measures and management, and to emphasize the need for timely diagnosis, effective therapeutic intervention, and close monitoring of this severe condition.

[Autoinflammatory diseases]. / Enfermedades autoinflamatorias.

The monogenic autoinflammatory diseases are rare, genetic disorders resulting in constitutive innate immune defects leading to excessive response to danger signals, spontaneous activation of inflammatory mediators or loss of inhibitory regulators. During the past 15 years, a growing number of monogenic inflammatory diseases have been described and their respective responsible genes identified. The proteins encoded by these genes are involved in the regulatory pathways of inflammation and are mostly expressed in cells of the innate immune system. Although a group of patients exhibit episodic systemic inflammation (periodic fevers), these disorders are mediated by continuous overproduction and release of pro-inflammatory mediators, notably IL-1ß, and are best considered as autoinflammatory diseases rather than periodic fevers. The most common autoinflammatory diseases are familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyperimmunoglobulin D syndrome (MKD/HIDS) and the cryopyrin-associated periodic syndromes (CAPS). Clinical features often include fever, cutaneous rash, serosal involvement and acute phase reactants. Autoantibodies are usually absent but may accompany certain syndromes. Diagnosis remains clinical and is based on the different phenotypic features. Genetic diagnosis is of utmost importance, but must be performed judiciously and interpreted cautiously. Treatment with biologic agents that block proinflammatory cytokines, particularly IL-1, has proved to be dramatically effective in many patients. Still, in many cases of autoinflammation no genetic abnormalities are detected and treatment remains suboptimal, raising the question of novel pathogenic mutations in unexplored genes and pathways.

Enfermedades autoinflamatorias / Autoinflammatory diseases

Las enfermedades autoinflamatorias monogénicas son desórdenes raros que resultan en defectos del sistema inmune innato, originando excesiva respuesta a señales de peligro, activación espontánea de vías inflamatorias o pérdida de reguladores inhibitorios. En los últimos 15 años un creciente número de enfermedades inflamatorias monogénicas han sido descriptas y sus respectivos genes responsables identificados. Las proteínas codificadas por estos genes están involucradas en las vías regulatorias de la inflamación y están expresadas fundamentalmente en las células del sistema inmune innato. Si bien un grupo de pacientes exhibe inflamación sistémica episódica (fiebres periódicas), estos desórdenes están mediados por una continua sobreproducción y liberación de mediadores pro-inflamatorios -especialmente la interleucina 1beta- y su conceptualización como enfermedades autoinflamatorias es preferible por sobre la de fiebres periódicas. Las enfermedades más frecuentes son fiebre mediterránea familiar (FMF), TRAPS, deficiencia de mevalonatocinasa/síndrome de hiper IgD (MKD/HIDS) y los síndromes periódicos asociados a criopirina (CAPS). Sus características clínicas frecuentemente incluyen fiebre, erupciones cutáneas, compromiso de serosas y reactantes de fase aguda. Los autoanticuerpos están usualmente ausentes pero pueden observarse en ciertos síndromes. El diagnóstico es clínico y se basa en las características fenotípicas. El diagnóstico genético es muy importante pero debe ser realizado de manera juiciosa e interpretado con cautela. El tratamiento con agentes biológicos que bloquean citocinas pro-inflamatorias, particularmente IL-1, ha demostrado ser efectivo en muchos pacientes. Sin embargo, en otros tantos casos no se descubren anormalidades genéticas y el tratamiento es subóptimo, planteando la posibilidad de mutaciones patogénicas en genes y vías aún no explorados.

The monogenic autoinflammatory diseases are rare, genetic disorders resulting in constitutive innate immune defects leading to excessive response to danger signals, spontaneous activation of inflammatory mediators or loss of inhibitory regulators. During the past 15 years, a growing number of monogenic inflammatory diseases have been described and their respective responsible genes identified. The proteins encoded by these genes are involved in the regulatory pathways of inflammation and are mostly expressed in cells of the innate immune system. Although a group of patients exhibit episodic systemic inflammation (periodic fevers), these disorders are mediated by continuous overproduction and release of pro-inflammatory mediators, notably IL-1β, and are best considered as autoinflammatory diseases rather than periodic fevers. The most common autoinflammatory diseases are familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyperimmunoglobulin D syndrome (MKD/HIDS) and the cryopyrin-associated periodic syndromes (CAPS). Clinical features often include fever, cutaneous rash, serosal involvement and acute phase reactants. Autoantibodies are usually absent but may accompany certain syndromes. Diagnosis remains clinical and is based on the different phenotypic features. Genetic diagnosis is of utmost importance, but must be performed judiciously and interpreted cautiously. Treatment with biologic agents that block proinflammatory cytokines, particularly IL-1, has proved to be dramatically effective in many patients. Still, in many cases of autoinflammation no genetic abnormalities are detected and treatment remains suboptimal, raising the question of novel pathogenic mutations in unexplored genes and pathways.

Patients with very early-onset systemic juvenile idiopathic arthritis exhibit more inflammatory features and a worse outcome.

OBJECTIVE: Systemic juvenile idiopathic arthritis (SJIA) frequently leads to disability and damage. Predictive factors for a poor outcome include persistent systemic features and younger age at onset. We describe and analyze disease features in patients with early-onset (EO) SJIA (disease onset before age 18 mo) and compare them to patients with later-onset (LO) disease. METHODS: Clinical features at onset, activity measures (occurrence of macrophage activation syndrome, remission), and outcome measures for disability [Childhood Health Assessment Questionnaire (CHAQ) ≥ 0.5] and damage [radiographic joint destruction, Juvenile Arthritis Damage Index (JADI) score, growth retardation] observed during followup were analyzed retrospectively in patients with SJIA followed for ≥ 3 years since disease onset. RESULTS: In total 132 patients were included. SJIA started at age ≤ 18 months in 19 (14%) patients and at a later age in 113 (86%) children. At onset, serositis (p < 0.01) and hepatomegaly (p < 0.05) were more frequent in EO patients, who also exhibited lower hemoglobin levels (p < 0.03) and higher platelet counts (p < 0.03) than patients with LO. Macrophage activation syndrome occurred in 20 patients (11 EO and 9 LO; p < 0.0001). Remission was achieved by 49 patients (37%; 4 EO and 45 LO). At last visit, destructive hip disease (p < 0.04), growth retardation (p < 0.01), radiographic damage (p < 0.02), and disability (p < 0.04) were more frequent in patients with EO disease, who had higher JADI scores (p < 0.003). CONCLUSION: Patients with EO exhibited a more aggressive and destructive disease course than patients with LO SJIA.

Clinical remission in patients with systemic juvenile idiopathic arthritis treated with anti-tumor necrosis factor agents.

OBJECTIVE: To assess the frequency of clinical remission in a cohort of patients with systemic juvenile idiopathic arthritis (JIA) who received continuous anti-tumor necrosis factor (TNF) therapy; and to identify potential predictors of remission. METHODS: Patients with systemic JIA who were treated with anti-TNF agents for > 6 months were studied. Demographic and nosologic variables recorded at the start of anti-TNF therapy were analyzed. Association between early variables and occurrence of remission was evaluated through Cox proportional hazard regression analysis. RESULTS: Forty-five patients were included (30 girls), median age 9 years (range 2-17 yrs), age at disease onset 5 years (range 0.5-15), disease duration 3 years (range 0.5-13). Twenty-one (47%) children showed systemic symptoms at the start of anti-TNF therapy. Patients received therapy for 24 months (range 6-88): 45 (100%) were given etanercept, 17 (38%) infliximab, and 5 (11%) adalimumab, in combination with methotrexate. Anti-TNF switching was performed in 22 (49%) children. Eleven (24%) met definition criteria for remission while taking etanercept (n = 8), infliximab (2), or adalimumab (1). Remission occurred following 26 (range 9-65) months of therapy. Flares occurred in 5 (45%) patients 2 to 14 months after remission was first recorded. Absence of systemic symptoms at the start of therapy and fulfillment of improvement criteria at Month 3 were associated with remission in univariate analysis; no variable showed any association in multivariate analysis. CONCLUSION: Twenty-four percent of patients with systemic JIA experienced remission with anti-TNF therapy, but only 13% experienced sustained benefit.

Use of adalimumab in patients with juvenile idiopathic arthritis refractory to etanercept and/or infliximab.

To analyse the effectiveness and safety of adalimumab in a group of patients with juvenile idiopathic arthritis (JIA) who had failed treatment with etanercept and/or infliximab in a single paediatric rheumatology clinic. Patients with JIA with active polyarthritis refractory to metotrexate (MTX) (> or =20 mg/m2/week) for at least 3 months and to etanercept (up to 1 mg/kg twice weekly) and/or infliximab (up to 10 mg/kg every 4 weeks) for at least 6 months were included. All patients received adalimumab 24 mg/m2/week concomitantly with MTX 7.5-10 mg/week. Evaluation of efficacy included improvement as defined by the ACR paediatric 30 criteria, 50% and 70% improvement and remission. Six patients were included. Three patients met improvement criteria; 50% and 70% improvement occurred in two children. Improvement was sustained for 12, 24 and 36 months, respectively. Remission occurred in one patient. Adalimumab was discontinued due to lack of efficacy in three patients. No side effects were observed. Adalimumab appears to be effective and safe in patients with JIA refractory to other anti-TNF agents. Further controlled studies are needed in order to assess efficacy of adalimumab in children with refractory JIA.

Global damage in systemic juvenile idiopathic arthritis: preliminary early predictors.

OBJECTIVE: To assess damage in systemic juvenile idiopathic arthritis (sJIA) by the use of the Juvenile Arthritis Damage Index (JADI) and to identify early predictors of global, articular, and extraarticular damage. METHODS: Forty-seven consecutive patients with sJIA with a disease duration > 24 months were assessed for damage in a cross-sectional evaluation. The JADI was administered by 2 pediatric rheumatologists. Damage was defined as JADI score >or= 1. Early clinical variables were retrieved from clinical records, and they included demographic, clinical, and laboratory characteristics. Univariate analysis was used to select candidate predictors to be included in multiple logistic regression. RESULTS: Twenty (43%) patients exhibited damage: 18 (38%) patients had articular and 9 (19%) extraarticular damage. JADI score ranged between 0 and 24. Cervical spine arthritis and corticosteroid usage occurring in the first 6 months of the disease course were found as predictors of damage. Damage scores correlated with number of joints with limited motion, and with functional disability. CONCLUSION: Articular damage is the main component of global damage in patients with sJIA. Early cervical spine involvement and corticosteroid usage may identify patients with sJIA at risk of developing damage.

Hepatitis A-associated macrophage activation syndrome in children with systemic juvenile idiopathic arthritis: report of 2 cases.

OBJECTIVE: We describe two 3-year-old patients with systemic juvenile idiopathic arthritis (SJIA) who developed hepatitis A-associated macrophage activation syndrome (MAS). One patient showed MAS as the presenting manifestation of SJIA, while MAS complicated SJIA during the second year of the disease course in the other child. Both girls presented with fever, jaundice, hepatosplenomegaly, neurological involvement, mucosal hemorrhage, and purpura. Cytopenias, hypofibrinogenemia, and hemophagocytosis confirmed the diagnosis. After aggressive treatment with high-dose corticosteroids and immunosuppressants one patient entered remission while the other one died. Hepatitis A virus may induce severe MAS in SJIA.

Síndrome de activación macrofágica en pacientes con artritis idiopática juvenil sistémica: análisis de 17 casos observados en un hospital terciario / Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis: analysis of 17 cases followed in a tertiary hospital

Introducción. El síndrome de activación macrofágica (SAM) es una grave complicación de ciertas enfermedades reumáticas, especialmente la artritisidiopática juvenil sistémica (AIJS). El objetivo deeste trabajo es describir las manifestaciones clínicas y bioquímicas de pacientes con AIJS que desarrollaron SAM, así como su respuesta a diferentes esquemas terapéuticos.Población, material y métodos. Estudio observacional y restrospectivo de un grupo de niños con diagnóstico de AIJS que desarrollaron un SAM entre1993 y 2007. El diagnóstico de SAM se realizó sobre la base de elementos clínicos, bioquímicos y,en algunos casos, histopatológicos.Resultados. Se incluyeron 17 pacientes (14 niñas).La edad de los niños varió entre 1 y 16 años (mediana10 años). El SAM se desarrolló en el primer año de evolución de AIJS en 10 niños (en 6 fue la manifestacióninicial). Sus principales características fueron:fiebre continua (100%), hepatomegalia (100%),esplenomegalia (76%), erupción cutánea (59%),adenomegalias (53%), hemorragias (53%), compromisodel sistema nervioso central (SNC) (41%),edemas (29%); enzimas hepáticas elevadas (94%),plaquetopenia (76%), eritro sedimentación normal (76%), hipertrigliceridemia (71%), coagulopatía65%), leucopenia (59%), hipofibrinogenemia (47%);se halló hemofagocitosis en 9 de 13 (69%) pacientes biopsiados. El tratamiento incluyó corticosteroides en altas dosis en 17 (100%) casos, inmunosupresoresen 6 (35%). Doce (71%) pacientes remitieron y 529%) fallecieron en fallo multisistémico. Conclusiones. El SAM es un síndrome de variable gravedad que ocasiona morbimortalidad significativa.La presencia de fiebre continua, hepatosplenomegalia,coagulopatía, compromiso del SNC,citopenias hemáticas y normalización de la eritro sedimentaciónen un niño con AIJS deben despertar lasospecha diagnóstica, aun sin evidencia de hemofagocitosis.

Introduction. Macrophage activation syndrome is a severe complication of certain rheumatic diseases, mainly systemic juvenile idiopathic arthritis (SJIA).The objective of this presentation is to describe the clinical and biochemical features of patients with SJIA who developed MAS, and their response to different therapeutic regimes. Population, materials and methods. Retrospective, observational analysis of children with a diagnosis of SJIA who developed MAS between 1993 and 2007. Diagnosis of MAS was formulated based upon clinical, biochemical and, in some cases, histopathological evidence. Results. Seventeen children (14 girls) were included. Age varied between 1 and 16 years (median 10 years). MAS developed during the first year of AIJS course in 10 children (it was the presenting manifestation in 6). Its main features were: continuous fever (100%), hepatomegaly (100%), splenomegaly (76%), cutaneous rash (59%), lymphadenopathy (53%), hemorrhage (53%), CNS involvement (41%), edema (29%); elevated liver enzimes (94%), thrombocytopenia (76%), normal sedimentation rate (76%), hypertriglyceridemia (71%), coagulopathy (65%), leukopenia (59%), hypofibrinogenemia (47%); hemofagocytosis was found in 9 out of 13 (69%) patients who underwent biopsy. High-dose corticosteroids were prescribed in 17 cases and immunosupressants in 6. Twelve patients remitted and 5 died due to multiorgan failure. Conclusions. MAS is a syndrome of variable severity that may cause significant morbimortality. Presence of continuous fever, hepatosplenomegaly, coagulopathy, CNS involvement, cytopenias and normal sedimentation rate in a child with AIJS should prompt diagnosis, even without evidence of hemophagocytosis. Immunosuppressive therapy was effective in the majority of the studied patients.

Síndrome de activación macrofágica en pacientes con artritis idiopática juvenil sistémica: análisis de 17 casos observados en un hospital terciario / Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis: analysis of 17 cases followed in a tertiary hospital

Introducción. El síndrome de activación macrofágica (SAM) es una grave complicación de ciertas enfermedades reumáticas, especialmente la artritisidiopática juvenil sistémica (AIJS). El objetivo deeste trabajo es describir las manifestaciones clínicas y bioquímicas de pacientes con AIJS que desarrollaron SAM, así como su respuesta a diferentes esquemas terapéuticos.Población, material y métodos. Estudio observacional y restrospectivo de un grupo de niños con diagnóstico de AIJS que desarrollaron un SAM entre1993 y 2007. El diagnóstico de SAM se realizó sobre la base de elementos clínicos, bioquímicos y,en algunos casos, histopatológicos.Resultados. Se incluyeron 17 pacientes (14 niñas).La edad de los niños varió entre 1 y 16 años (mediana10 años). El SAM se desarrolló en el primer año de evolución de AIJS en 10 niños (en 6 fue la manifestacióninicial). Sus principales características fueron:fiebre continua (100%), hepatomegalia (100%),esplenomegalia (76%), erupción cutánea (59%),adenomegalias (53%), hemorragias (53%), compromisodel sistema nervioso central (SNC) (41%),edemas (29%); enzimas hepáticas elevadas (94%),plaquetopenia (76%), eritro sedimentación normal (76%), hipertrigliceridemia (71%), coagulopatía65%), leucopenia (59%), hipofibrinogenemia (47%);se halló hemofagocitosis en 9 de 13 (69%) pacientes biopsiados. El tratamiento incluyó corticosteroides en altas dosis en 17 (100%) casos, inmunosupresoresen 6 (35%). Doce (71%) pacientes remitieron y 529%) fallecieron en fallo multisistémico. Conclusiones. El SAM es un síndrome de variable gravedad que ocasiona morbimortalidad significativa.La presencia de fiebre continua, hepatosplenomegalia,coagulopatía, compromiso del SNC,citopenias hemáticas y normalización de la eritro sedimentaciónen un niño con AIJS deben despertar lasospecha diagnóstica, aun sin evidencia de hemofagocitosis.(AU)

Introduction. Macrophage activation syndrome is a severe complication of certain rheumatic diseases, mainly systemic juvenile idiopathic arthritis (SJIA).The objective of this presentation is to describe the clinical and biochemical features of patients with SJIA who developed MAS, and their response to different therapeutic regimes. Population, materials and methods. Retrospective, observational analysis of children with a diagnosis of SJIA who developed MAS between 1993 and 2007. Diagnosis of MAS was formulated based upon clinical, biochemical and, in some cases, histopathological evidence. Results. Seventeen children (14 girls) were included. Age varied between 1 and 16 years (median 10 years). MAS developed during the first year of AIJS course in 10 children (it was the presenting manifestation in 6). Its main features were: continuous fever (100%), hepatomegaly (100%), splenomegaly (76%), cutaneous rash (59%), lymphadenopathy (53%), hemorrhage (53%), CNS involvement (41%), edema (29%); elevated liver enzimes (94%), thrombocytopenia (76%), normal sedimentation rate (76%), hypertriglyceridemia (71%), coagulopathy (65%), leukopenia (59%), hypofibrinogenemia (47%); hemofagocytosis was found in 9 out of 13 (69%) patients who underwent biopsy. High-dose corticosteroids were prescribed in 17 cases and immunosupressants in 6. Twelve patients remitted and 5 died due to multiorgan failure. Conclusions. MAS is a syndrome of variable severity that may cause significant morbimortality. Presence of continuous fever, hepatosplenomegaly, coagulopathy, CNS involvement, cytopenias and normal sedimentation rate in a child with AIJS should prompt diagnosis, even without evidence of hemophagocytosis. Immunosuppressive therapy was effective in the majority of the studied patients.(AU)

Clinical characteristics of children with Juvenile Systemic Sclerosis: follow-up of 23 patients in a single tertiary center.

BACKGROUND: Juvenile systemic sclerosis (JSS) is a multisystem connective tissue disease characterized by skin fibrosis and internal organ involvement. It has a low prevalence, even in a tertiary facility setting. The purpose of the present study is to describe and analyze the clinical and laboratory characteristics of a group of children with JSS followed in a single center. METHODS: Clinical charts of children with a diagnosis of JSS who were seen at a tertiary referral center between 1995 and 2005 were reviewed. Clinical features were recorded and analysed. RESULTS: Twenty-three patients who met preliminary classification criteria for JSS were included. Age at first symptom attributable to JSS was 6 (1-14) years, The first symptom attributable to JSS was Raynaud's phenomenon in 14 cases. Proximal sclerosis (23 patients, 100%), sclerodactyly (21, 91%), Raynaud's phenomenon (19, 83%), and periungual capillaropathy (17, 74%) were the most consistent clinical findings during follow-up. Respiratory involvement occurred in two thirds of our patients, and it manifested as dyspnea as well as abnormal imaging and/or pulmonary function tests; pulmonary hypertension was an infrequent finding. Dysphagia was the commonest gastrointestinal symptom (9 patients, 39%). The most frequent musculoskeletal symptom was arthralgia (14 children, 6%); symmetrical arthritis was found in 8 (35%) patients. Periungual capillary abnormalities were evident during physical examination in 17 children; capillaroscopy revealed abnormalities in all 19 examined patients. ANA were present in 17 (74%) children: homogeneous pattern was the most frequent (8 patients), nucleolar (5) and speckled (4) were less common. CONCLUSION: Raynaud's phenomenon heralds the beginning of the disease. Capilaroscopy is a major adjuvant in the diagnosis, since autoantibody determination may not offer sensitive and specific markers. Skin and vascular manifestations are the most common clinical features, while internal organ involvement is more rare. Cardiopulmonary disease is the most frequent visceral involvement, leading to significant morbidity.

Poliarteritis nodosa cutánea posestreptocócica: un simulador de la fiebre reumática / Pos-streptoccal cutaneous polyarteritis nodosa: a mimic of rheumatic fever

RESUMEN Introducción. La poliarteritis nodosa cutánea es una enfermedad inflamatoria que compromete vasos medianos de piel y, en ocasiones, de nervios periféricos y músculos. La frecuente presencia de artritis puede originar errores diagnósticos. El objetivo fue describir los hallazgos clínicos en pacientes con esta enfermedad.Población, material y métodos. Se trató de un estudio descriptivo. Se incluyeron 10 niños con diagnóstico de poliarteritis nodosa cutánea y evidencias de infección reciente por estreptococo betahemolítico del grupo A. Los datos se recolectaron retrospectivamente.Resultados. Todos los pacientes presentaban fiebre,púrpura y nódulos subcutáneos en el debut de la enfermedad. Nueve tuvieron artritis. Las articulaciones afectadas fueron predominantemente grandes,de miembros inferiores y la duración de la inflamación articular varió entre 10 y 90 días. Seis pacientes mostraron un patrón aditivo de afección articular y en tres fue migratorio. La articulación más frecuentemente afectada fue la rodilla. Se observó leucocitosis y elevación de los reactantes de fase aguda en todos los pacientes. Los nueve niños con artritis cumplían con los criterios diagnósticos de Jones para fiebre reumática. Todos recibieron tratamiento con m menos prednisona y profilaxis con penicilinabenzatínica. Se observaron 17 recaídas en 8 de los pacientes, 12 de ellas relacionadas con nuevas infecciones por estreptococo y fallas en la profilaxis. Conclusiones: La artritis de la poliarteritis nodosa cutánea posestreptocócica puede remedar a la de la fiebre reumática. La erupción purpúrica y nódulos cutáneos rojizos y dolorosos orienta fuertemente hacia el diagnóstico, que se confirma por el hallazgo de inflamación de vasos medianos en la dermis

Poliarteritis nodosa cutánea posestreptocócica: un simulador de la fiebre reumática / Pos-streptoccal cutaneous polyarteritis nodosa: a mimic of rheumatic fever

RESUMEN Introducción. La poliarteritis nodosa cutánea es una enfermedad inflamatoria que compromete vasos medianos de piel y, en ocasiones, de nervios periféricos y músculos. La frecuente presencia de artritis puede originar errores diagnósticos. El objetivo fue describir los hallazgos clínicos en pacientes con esta enfermedad.Población, material y métodos. Se trató de un estudio descriptivo. Se incluyeron 10 niños con diagnóstico de poliarteritis nodosa cutánea y evidencias de infección reciente por estreptococo betahemolítico del grupo A. Los datos se recolectaron retrospectivamente.Resultados. Todos los pacientes presentaban fiebre,púrpura y nódulos subcutáneos en el debut de la enfermedad. Nueve tuvieron artritis. Las articulaciones afectadas fueron predominantemente grandes,de miembros inferiores y la duración de la inflamación articular varió entre 10 y 90 días. Seis pacientes mostraron un patrón aditivo de afección articular y en tres fue migratorio. La articulación más frecuentemente afectada fue la rodilla. Se observó leucocitosis y elevación de los reactantes de fase aguda en todos los pacientes. Los nueve niños con artritis cumplían con los criterios diagnósticos de Jones para fiebre reumática. Todos recibieron tratamiento con m menos prednisona y profilaxis con penicilinabenzatínica. Se observaron 17 recaídas en 8 de los pacientes, 12 de ellas relacionadas con nuevas infecciones por estreptococo y fallas en la profilaxis. Conclusiones: La artritis de la poliarteritis nodosa cutánea posestreptocócica puede remedar a la de la fiebre reumática. La erupción purpúrica y nódulos cutáneos rojizos y dolorosos orienta fuertemente hacia el diagnóstico, que se confirma por el hallazgo de inflamación de vasos medianos en la dermis (AU)

Recaídas de artritis crónica juvenil luego de la suspensión de atenercept / Flares in juvenile chronic artritis after withdrawal of etanercept

Introducción. El etanercept es un medicamento bloqueante del factor de necrosis tumoral de probada eficacia y seguridad en el tratamiento de la artritis crónica juvenil de curso poliarticular refractariaal tratamiento con otros fármacos, comometotrexato. Sin embargo, se desconoce qué ocurrecon la actividad de la enfermedad luego de la suspensión de etanercept en pacientes que responden al tratamiento. Objetivo. Describir la evolución de la artritis crónica juvenil de curso poliarticular en pacientes que mejoraron con etanercept y que posteriormente suspendieron el tratamiento. Población, material y métodos. Se evaluaron pacientes con artritis crónica juvenil de curso poliarticular refractaria al metotrexato que recibieron etanercepty mejoraron. Se incluyeron los pacientes que debieron suspender el tratamiento con etanercept porcausas no médicas.Se evaluaron en sucesivas visitas diferentes indicadores clínicos de actividad y la eritrosedimentación; se definieron, además, mejoría y recaída. Se compararon los valores de esos indicadores en lasvisitas inmediatamente anteriores y posteriores a lasuspensión de etanercept...

Introduction. Etanercept is a drug that blocks tumor necrosis factor-alpha, of proven efficacy and safety in the treatment of polyarticular juvenile chronic arthritis refractory to other treatments, such as methotrexate. However, disease activity after discontinuation in patients who respond to etanercept is unknown. Objective. To describe the clinical course of polyarticular course juvenile chronic arthritis in patients who responded to etanercept and subsequently discontinued the treatment. Population, materials and methods. Patients with polyarticular juvenile chronic arthritis refractory to methotrexate who received etanercept and experienced an improvement. Patients who had to discontinue treatment with etanercept for nonmedical reasons were included. Several clinical measures of activity and erythrocyte sedimentation rate were assessed in consecutive visits; definitions of improvement and relapse were provided. Comparisons of the values of these measures were done between visits recorded before and after etanercept withdrawal. Results. Of 20 patients with juvenile chronic arthritis (17 with systemic onset, 2 with polyarticular onset, and 1 with oligoarticular onset) who reached improvement with etanercept treatment, 7 (all with systemic arthritis) had to discontinue this treatment 5.5 months after its initiation. In all cases, interruption of treatment was due to social security termination of drug supply. These 7 patients showed relapse within one month after etanercept withdrawal. In all cases, the relapse was especially characterized by an increase in the number of swollen joints, the number of joints with limitation in range of motion, and in the erythrocyte sedimentation rate. Reappearance of fever and cutaneous rash was observed in one patient. Of the 13 patients who did not suspend treatment with etanercept, 6 showed relapses (all had systemic onset arthritis). Conclusions. Withdrawal of etanercept treatment in patients with...

Recaídas de artritis crónica juvenil luego de la suspensión de atenercept / Flares in juvenile chronic artritis after withdrawal of etanercept

Introducción. El etanercept es un medicamento bloqueante del factor de necrosis tumoral de probada eficacia y seguridad en el tratamiento de la artritis crónica juvenil de curso poliarticular refractariaal tratamiento con otros fármacos, comometotrexato. Sin embargo, se desconoce qué ocurrecon la actividad de la enfermedad luego de la suspensión de etanercept en pacientes que responden al tratamiento. Objetivo. Describir la evolución de la artritis crónica juvenil de curso poliarticular en pacientes que mejoraron con etanercept y que posteriormente suspendieron el tratamiento. Población, material y métodos. Se evaluaron pacientes con artritis crónica juvenil de curso poliarticular refractaria al metotrexato que recibieron etanercepty mejoraron. Se incluyeron los pacientes que debieron suspender el tratamiento con etanercept porcausas no médicas.Se evaluaron en sucesivas visitas diferentes indicadores clínicos de actividad y la eritrosedimentación; se definieron, además, mejoría y recaída. Se compararon los valores de esos indicadores en lasvisitas inmediatamente anteriores y posteriores a lasuspensión de etanercept...(AU)

Introduction. Etanercept is a drug that blocks tumor necrosis factor-alpha, of proven efficacy and safety in the treatment of polyarticular juvenile chronic arthritis refractory to other treatments, such as methotrexate. However, disease activity after discontinuation in patients who respond to etanercept is unknown. Objective. To describe the clinical course of polyarticular course juvenile chronic arthritis in patients who responded to etanercept and subsequently discontinued the treatment. Population, materials and methods. Patients with polyarticular juvenile chronic arthritis refractory to methotrexate who received etanercept and experienced an improvement. Patients who had to discontinue treatment with etanercept for nonmedical reasons were included. Several clinical measures of activity and erythrocyte sedimentation rate were assessed in consecutive visits; definitions of improvement and relapse were provided. Comparisons of the values of these measures were done between visits recorded before and after etanercept withdrawal. Results. Of 20 patients with juvenile chronic arthritis (17 with systemic onset, 2 with polyarticular onset, and 1 with oligoarticular onset) who reached improvement with etanercept treatment, 7 (all with systemic arthritis) had to discontinue this treatment 5.5 months after its initiation. In all cases, interruption of treatment was due to social security termination of drug supply. These 7 patients showed relapse within one month after etanercept withdrawal. In all cases, the relapse was especially characterized by an increase in the number of swollen joints, the number of joints with limitation in range of motion, and in the erythrocyte sedimentation rate. Reappearance of fever and cutaneous rash was observed in one patient. Of the 13 patients who did not suspend treatment with etanercept, 6 showed relapses (all had systemic onset arthritis). Conclusions. Withdrawal of etanercept treatment in patients with...(AU)

Manifestaciones clínicas severas relacionadas con anticuerpos antifosfolipídicos en pacientes pediátricos con enfermedades autoinmunes / Severe clinicas manifestations relates to antiphospholipid antibodies in pediatric patients with autoimmune diseases

Introducción.Los anticuerpos anticardiolipinas(aCL)se han relacionado con diversas manifestaciones clínicas,de distinto grado de severidad,en pacientes portadores de enfermedades autoinmunes.El objetivo de este trabajo fue establecer la frecuencia y características de los cuadros graves relacionados con AcL en pacientes pediátricos con enfermedades autoinmunes.Población,Pacientes con enfermedades autoinmunes en quienes se detectó Acl en al menos dos oportunidades,que concurrieron a un servicio de inmunología en los años 1994 a 1998.Material y Métodos,Se trata de un trabajo retrospectivo,observacional y analítico.Se revisaron y analizaron las historias clínicas de los pacientes,y se evaluaron las siguientes variables:demográficas,manifestaciones clínicas,tratamiento y evolución,anticuerpos antinucleares(AAN)antiENA,C3 y C4.Se utilizó un conjunto de criterios clínicos y de laboratorio para evaluar actividad lúpica(SLEDAI)Los anticuerpos aCL fueron determinados por ELISA.Se consideraron valores positivos:GPL > 15U(positivso intenso >80 U)y MPL >5U(positivo intenso >40 U)También se observó en cada caso la presencia o ausencia de anticuagulant lúpico(AL)Conclusiones,Pueden existir manifestaciones clínicas variadas y graves en presencia de distintos títulos de aCL en niños con enfermedad autoinmune.De todas formas,la presencia de estos anticuerpos no asegura su participación exclusiva en la patogenia de los fenómenos clínicos descriptos,ya que otros trastornos debidos a la enfermedad autoinmune de base pueden participar en la génesis de esta complicaciones