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PURPOSE: Histiocytic necrotizing lymphadenitis (HNL) is an inflammatory disease of unknown etiology clinically characterized by painful lymphadenopathy. This study aimed to investigate the role of interferon (IFN)-α in the pathogenesis of HNL and the clinical significance of serum IFN-α levels for the diagnosis and monitoring of HNL disease activity. METHODS: This study enrolled 47 patients with HNL and 43 patients with other inflammatory diseases that require HNL differentiation including malignant lymphoma (ML), bacterial lymphadenitis, and Kawasaki disease. Expression of IFN-stimulated genes (ISGs) and MX1 in the lymph nodes was measured by real-time quantitative reverse transcription polymerase chain reaction and immunofluorescence staining, respectively. Enzyme-linked immunosorbent assay was used to quantify serum cytokine levels. The results were compared with the clinical features and disease course of HNL. RESULTS: Patients with HNL had a significantly elevated ISG expression in the lymph nodes compared with those with ML. MX1 and CD123, a specific marker of plasmacytoid dendritic cells (pDCs), were colocalized. In patients with HNL, serum IFN-α levels were significantly elevated and positively correlated with disease activity. The serum IFN-α level cutoff value for differentiating HNL from other diseases was 11.5 pg/mL. CONCLUSION: IFN-α overproduction from pDCs may play a critical role in HNL pathogenesis. The serum IFN-α level may be a valuable biomarker for the diagnosis and monitoring of disease activity in patients with HNL.
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Células Dendríticas , Linfadenitis Necrotizante Histiocítica , Interferón-alfa , Ganglios Linfáticos , Humanos , Linfadenitis Necrotizante Histiocítica/diagnóstico , Linfadenitis Necrotizante Histiocítica/sangre , Linfadenitis Necrotizante Histiocítica/inmunología , Masculino , Interferón-alfa/sangre , Femenino , Niño , Adolescente , Adulto , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Preescolar , Ganglios Linfáticos/patología , Proteínas de Resistencia a Mixovirus/genética , Proteínas de Resistencia a Mixovirus/metabolismo , Proteínas de Resistencia a Mixovirus/sangre , Adulto Joven , Persona de Mediana Edad , Linfoma/diagnóstico , Linfoma/inmunología , Linfoma/sangre , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/inmunología , Síndrome Mucocutáneo Linfonodular/sangre , Biomarcadores/sangre , Citocinas/sangre , Citocinas/metabolismoRESUMEN
OBJECTIVE: Recently, the Pediatric Rheumatology International Trials Organization (PRINTO) has proposed revisions to the current International League of Associations for Rheumatology (ILAR) criteria for systemic juvenile idiopathic arthritis (s-JIA). Interleukin (IL)-18 overproduction plays a significant role in the pathogenesis of s-JIA. This study aimed to evaluate the performance of the PRINTO criteria compared with the ILAR criteria and determine whether serum IL-18 levels improve their diagnostic performances. METHODS: Overall, 90 patients with s-JIA and 27 patients with other febrile disease controls presenting with a prolonged fever of > 14 days and arthritis and/or erythematous rash were enrolled. The ILAR and PRINTO classification criteria were applied to all patients and examined with expert diagnoses. Enzyme-linked immunosorbent assay was used for measuring serum IL-18 levels. RESULTS: The PRINTO criteria had higher sensitivity but lower specificity than the ILAR criteria (sensitivity: PRINTO 0.856, ILAR 0.533; specificity: PRINTO 0.259, ILAR 0.851). With the addition of serum IL-18 levels ≥ 4,800 pg/mL, the sensitivity of the ILAR criteria and specificity of the PRINTO criteria were improved to 1.000 and 1.000, respectively. PRINTO plus serum IL-18 levels ≥ 4,800 pg/mL showed the highest value in Youden's index (sensitivity - [1 - specificity]). CONCLUSION: Serum IL-18 levels could improve the diagnostic performance of the PRINTO and ILAR criteria for s-JIA. The PRINTO criteria plus serum IL-18 levels ≥ 4,800 pg/mL could be the best diagnostic performance for s-JIA.
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OBJECTIVES: To validate the correlation between laboratory markers reflecting disease activity of macrophage activation syndrome (MAS) and serum cytokine levels and identify the valuable laboratory markers that change over time for a prompt MAS diagnosis. METHODS: Serum cytokine levels were determined by enzyme-linked immunosorbent assay and compared with laboratory markers reflecting MAS disease activity.The changes in values were evaluated from the acute phase of systemic juvenile idiopathic arthritis (s-JIA) to MAS diagnosis. RESULTS: CXCL9 was significantly correlated with aspartate aminotransferase (AST), lactate dehydrogenase (LDH), D dimer, and urine ß2 microglobulin levels. sTNF-RII was significantly correlated with platelet counts, AST, LDH, D dimer, and ferritin levels. Significant changes in platelet count, LDH, and D dimer levels were observed. Decreased platelet counts were the most valuable indicator for MAS diagnosis. CONCLUSION: Monitoring the laboratory markers that change over time, particularly decreased platelet counts, was valuable for the prompt MAS diagnosis in s-JIA.
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Artritis Juvenil , Síndrome de Activación Macrofágica , Humanos , Citocinas , Síndrome de Activación Macrofágica/etiología , Biomarcadores , Productos de Degradación de Fibrina-Fibrinógeno , Activación de MacrófagosRESUMEN
OBJECTIVES: To investigate the clinical significance of serum cytokine profiles for differentiating between Kawasaki disease (KD) and its mimickers. METHODS: Patients with KD, including complete KD, KD shock syndrome (KDSS), and KD with macrophage activation syndrome (KD-MAS), and its mimickers, including multisystem inflammatory syndrome in children, toxic shock syndrome, and Yersinia pseudotuberculosis infection, were enrolled. Serum levels of interleukin (IL)-6, soluble tumor necrosis factor receptor type II (sTNF-RII), IL-10, IL-18, and chemokine (C-X-C motif) ligand 9 (CXCL9) were measured using enzyme-linked immunosorbent assay and compared them with clinical manifestations. RESULTS: Serum IL-6, sTNF-RII, and IL-10 levels were significantly elevated in patients with KDSS. Serum IL-18 levels were substantially elevated in patients with KD-MAS. Patients with KD-MAS and KD mimickers had significantly elevated serum CXCL9 levels compared with those with complete KD. Area under the receiver operating characteristic curve analysis showed that serum IL-6 was the most useful for differentiating KDSS from the others, IL-18 and CXCL9 for KD-MAS from complete KD, and CXCL9 for KD mimickers from complete KD and KD-MAS. CONCLUSION: Serum cytokine profiles may be useful for differentiating between KD and its mimickers.
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Citocinas , Síndrome Mucocutáneo Linfonodular , Choque Séptico , Síndrome de Respuesta Inflamatoria Sistémica , Infecciones por Yersinia pseudotuberculosis , Síndrome Mucocutáneo Linfonodular/sangre , Síndrome Mucocutáneo Linfonodular/diagnóstico , Citocinas/sangre , Humanos , Interleucina-6/sangre , Quimiocina CXCL9/sangre , Síndrome de Activación Macrofágica/sangre , Síndrome de Activación Macrofágica/diagnóstico , Masculino , Femenino , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Diagnóstico Diferencial , Choque Séptico/sangre , Choque Séptico/diagnóstico , Infecciones por Yersinia pseudotuberculosis/sangre , Infecciones por Yersinia pseudotuberculosis/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Síndrome de Respuesta Inflamatoria Sistémica/diagnósticoRESUMEN
OBJECTIVES: Myositis-specific autoantibodies (MSAs) define distinct clinical subsets of idiopathic inflammatory myopathies (IIMs). The anti-nuclear matrix protein 2 (NXP2) antibody, a MSA detected in juvenile/adult IIMs, has been reported to be associated with a high risk of subcutaneous calcinosis, subcutaneous oedema and internal malignancies. The study aimed to clarify the clinical features of anti-NXP2 antibody-positive IIMs in detail. METHODS: This was a multicentre retrospective observational study on 76 anti-NXP2 antibody-positive patients. The antibody was detected via a serological assay using immunoprecipitation and western blotting. The patients were selected from 162 consecutive Japanese patients with IIMs. RESULTS: The cohort of anti-NXP2 antibody-positive IIMs included 29 juvenile patients and 47 adult patients. Twenty-seven (35.5%) patients presented with polymyositis phenotype without dermatomyositis-specific skin manifestations (heliotrope rash or Gottron sign/papules); this was more common in the adults than children (48.9% vs 15.8%, P < 0.01). Nine (11.8%) patients had subcutaneous calcinosis, and 20 (26.3%) patients had subcutaneous oedema. In addition, the proportion of patients with muscle weakness extending to the distal limbs was high (36 patients [47.4%]) in this cohort. Adult patients had a higher prevalence of malignancy than the general population (age-standardized incidence ratio of malignancies: 22.4). CONCLUSION: Anti-NXP2 antibody-positive IIMs, which include dermatomyositis sine dermatitis, are characterized by atypical skin manifestations and extensive muscular involvement.
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Autoanticuerpos/sangre , Proteínas de Unión al ADN/inmunología , Enfermedades Musculares/complicaciones , Enfermedades Musculares/inmunología , Factores de Transcripción/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of tacrolimus in patients with juvenile idiopathic arthritis (JIA). METHODS: We retrospectively analysed 27 patients with JIA who received tacrolimus therapy at the Department of Pediatric Rheumatology of the Tokyo Medical and Dental University between April 2019 and August 2020. We collected background and clinical characteristics at the time of add-on tacrolimus therapy initiation (baseline; Month 0) and after 3, 6, and 12 months. The primary outcome was successful medication reduction after 12 months. Patients requiring reduced and additional treatments were assigned as 'did not require additional treatment patients' and 'required additional treatment patients', respectively. The Wilcoxon signed-rank test was used to evaluate the continuous distribution of laboratory data and Juvenile Arthritis Disease Activity Score-27 at 3, 6, and 12 months relative to baseline values. Statistical significance was set as p < .05. RESULTS: Among the 27 included cases, 17 patients were classified as did not require additional treatment patients, and there was a significant improvement in Juvenile Arthritis Disease Activity Score-27 scores in this group (p < .05). No patients presented tacrolimus-related adverse events throughout the study period. CONCLUSION: Tacrolimus is an effective and safe therapeutic alternative for approximately 60% of patients with JIA.
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Antirreumáticos , Artritis Juvenil , Antirreumáticos/uso terapéutico , Artritis Juvenil/tratamiento farmacológico , Niño , Humanos , Estudios Retrospectivos , Tacrolimus/uso terapéutico , Resultado del TratamientoAsunto(s)
Vasculitis por IgA , Vasculitis , Humanos , Inmunoglobulinas Intravenosas , Inmunoglobulina A , IntestinosAsunto(s)
Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Deleción Cromosómica , CromosomasAsunto(s)
Pérdida Auditiva , Hipertensión , Lupus Eritematoso Sistémico , Nefritis Lúpica , Pielonefritis , Femenino , Humanos , Mareo , Pielonefritis/complicaciones , Pielonefritis/diagnóstico , Edema , Hipertensión/complicaciones , Hipertensión/diagnóstico , Pérdida Auditiva/diagnóstico , Pérdida Auditiva/etiologíaAsunto(s)
Artritis Infecciosa , Lupus Eritematoso Sistémico , Sínfisis Pubiana , Antibacterianos/uso terapéutico , Artritis Infecciosa/diagnóstico , Artritis Infecciosa/tratamiento farmacológico , Humanos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Sínfisis Pubiana/diagnóstico por imagenAsunto(s)
Enfermedad de Crohn , Síndromes Mielodisplásicos , Espondilitis Anquilosante , Adolescente , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/diagnóstico , Humanos , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/diagnóstico , Espondilitis Anquilosante/complicaciones , Espondilitis Anquilosante/diagnósticoAsunto(s)
Azetidinas/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Artropatías/tratamiento farmacológico , Purinas/uso terapéutico , Pirazoles/uso terapéutico , Sulfonamidas/uso terapéutico , Enfermedad Injerto contra Huésped/diagnóstico por imagen , Enfermedad Injerto contra Huésped/etiología , Humanos , Artropatías/diagnóstico por imagen , Artropatías/etiología , Imagen por Resonancia Magnética , Masculino , Adulto JovenRESUMEN
Although the clinical efficacy of tofacitinib has been reported in adult patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (Ab+) dermatomyositis, data on its use in refractory juvenile dermatomyositis (JDM) are scarce. We describe two female Japanese patients with anti-MDA5 Ab + JDM and rapidly progressive interstitial lung disease who achieved remission by adding tofacitinib to existing immunosuppressive drugs and present a literature review. While both patients received various immunosuppressive or anti-inflammatory treatments for induction therapy, remission could not be achieved. Subsequently, tofacitinib was administered to reduce the Krebs von den Lungen-6 level 5 months after diagnosis in one patient; the other patient received tofacitinib 4 months after diagnosis to reduce ferritin levels and skin manifestations. Subsequently, both patients achieved remission, and prednisolone was withdrawn. Tofacitinib reduced the interferon signature associated with dermatomyositis/JDM disease progression and exerted a therapeutic effect on dermatomyositis/JDM. We found six published cases from five articles of tofacitinib for refractory anti-MDA5 Ab + JDM. Except for one case of herpes simplex meningitis, the other cases, including ours, had improved disease activity without severe adverse events, and steroids and immunosuppressive medicines could be tapered. Tofacitinib could be considered an available therapy for refractory anti-MDA5 Ab + JDM.
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Dermatomiositis , Helicasa Inducida por Interferón IFIH1 , Piperidinas , Pirimidinas , Humanos , Dermatomiositis/tratamiento farmacológico , Dermatomiositis/inmunología , Femenino , Helicasa Inducida por Interferón IFIH1/inmunología , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Piperidinas/administración & dosificación , Piperidinas/uso terapéutico , Autoanticuerpos , Resultado del Tratamiento , Niño , Inmunosupresores/uso terapéutico , Inmunosupresores/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
The specific expansion of T-cell receptor ß chain variable region (TCR-Vß21.3 + ) CD4 + and CD8 + T cells was observed in Japanese patients with multisystem inflammatory syndrome in children. In contrast, these findings were not observed in patients with toxic shock syndrome and Kawasaki disease. T-cell receptor ß chain variable region repertoire analysis to detect specific expansion of Vß21.3 + T cells might be useful for differentiating multisystem inflammatory syndrome in children from toxic shock syndrome and Kawasaki disease.
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COVID-19/complicaciones , Síndrome Mucocutáneo Linfonodular , Choque Séptico , Síndrome de Respuesta Inflamatoria Sistémica , Niño , Humanos , Síndrome Mucocutáneo Linfonodular/diagnóstico , Choque Séptico/diagnóstico , Japón , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/análisis , Linfocitos T CD8-positivos , Linfocitos T CD4-PositivosRESUMEN
OBJECTIVE: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. METHODS: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. RESULTS: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)-unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti-tumor necrosis factor-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy. CONCLUSION: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment.