Efficacy and safety of tumor necrosis factor inhibitors for systemic juvenile idiopathic arthritis: a systematic review.

OBJECTIVES: This systematic review assessed the efficacy and safety of tumor necrosis factor (TNF) inhibitors in patients with systemic juvenile idiopathic arthritis (JIA). METHODS: Studies were searched using PubMed, Embase, Cochrane, Ichushi-Web, and clinical trial registries (from 2000 to 2021). The risk of bias was assessed using the Cochrane Risk of Bias version 2 for randomized controlled trials (RCTs) and the manual for development clinical practice guidelines by Minds, a project promoting evidence-based medicine in Japan, for observational studies. RESULTS: One RCT and 22 observational studies were included. In the RCT on infliximab, the American College of Rheumatology pediatric (ACR Pedi) 30/50/70 responses at 14 weeks were 63.8%/50.0%/22.4%, with relative risks of 1.30 (95% confidence interval [CI]: 0.94-1.79)/1.48 (95% CI: 0.95-2.29)/1.89 (95% CI: 0.81-4.40), respectively. In the observational studies, ACR Pedi 30/50/70 responses for etanercept at 12 months were 76.7%/64.7%/46.4%, respectively. Infliximab treatment caused anaphylaxis in 17% and an infusion reaction in 23% of patients. The incidence of macrophage activation syndrome, serious infection and malignancy caused by TNF inhibitors was 0%-4%. CONCLUSIONS: Thus, although TNF inhibitors were relatively safe, they were unlikely to be preferentially administered in patients with systemic JIA because of their inadequate efficacy. Further studies, particularly well-designed RCTs, are necessary to confirm the efficacy and safety of TNF inhibitors for systemic JIA.

Efficacy and safety of abatacept for systemic juvenile idiopathic arthritis: a systematic review.

OBJECTIVES: This systematic review assessed the efficacy and safety of abatacept in patients with systemic juvenile idiopathic arthritis (JIA). METHODS: Studies published between 2000 and 2021 were searched using PubMed, Embase, Cochrane, Ichushi-Web and clinical trial registries. The risk of bias was assessed according to the manual for development clinical practice guidelines by Minds, a project to promote evidence-based medicine in Japan. RESULTS: Seven observational studies were included. American College of Rheumatology pediatric 30/50/70 responses at 3, 6 and 12 months were 64.8%/50.3%/27.9%, 85.7%/71.4%/42.9% and 80.0%/50.0%/40.0%, respectively. Outcomes on systemic symptoms, joint symptoms and activities of daily living were not obtained. No macrophage activation syndrome or infusion reaction occurred. Serious infection occurred in 2.6% of cases. CONCLUSIONS: Abatacept improved the disease activity index. In addition, abatacept was as safe as interleukin-6 (IL -6) and IL-1 inhibitors. However, both the efficacy and safety data in this systematic review should be reviewed with caution because their quality of evidence is low or very low. Further studies are needed to confirm the efficacy and safety of abatacept for systemic JIA, especially its efficacy on joint symptoms.

Successful treatment with tofacitinib for anti-melanoma differentiation-associated gene 5 antibody-positive juvenile dermatomyositis: case reports and review of the literature.

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.

Clinical Usefulness of T-Cell Receptor Vß Repertoire Analysis for Differentiating Multisystem Inflammatory Syndrome in Japanese Children From Toxic Shock Syndrome and Kawasaki Disease.

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.

Anti-Ku antibody-positive systemic sclerosis and idiopathic inflammatory myopathies overlap syndrome in children: a report of two cases and a review of the literature.

The occurrence of anti-Ku antibody-positive idiopathic inflammatory myopathy (IIM) in pediatric patients is rare, and therefore, the clinical phenotypes of this disease in such patients remain obscure. We herein report two cases of Japanese female pediatric patients with anti-Ku antibody-positive IIM. One case was unique in that it was complicated by pericardial effusion. Another patient had severe and refractory myositis with immune-mediated necrotizing myopathy. In addition, we reviewed literatures involving a total of 11 pediatric patients with anti-Ku antibody-positive IIM. The median age of the patients was 11 years, and most of them were girls. Skin rash, including erythematous nodules, malar rash, multiple brownish plaques, butterfly rash, heliotrope rash, periorbital edema, and Gottron's papules, was observed in 54.5% of the patients, scleroderma in 81.8%, and skin ulcer in 18.2%. Their serum creatine kinase level ranged from 504 to 10,840 IU/L. Furthermore, joint involvement was observed in 91% of the patients, interstitial lung disease in 18.2%, and esophageal involvement in 9.1%. All patients were treated with corticosteroids in combination with immunosuppressants. Pediatric patients with anti-Ku antibody-positive IIM had unique characteristics compared to adult patients. Skin manifestations, joint involvement and elevation of serum CK levels were more common in children than in adults. In contrast, ILD and esophageal involvement were less common in children than in adults. Although pediatric cases of anti-Ku antibody-positive IIM are rare, patients with IIM need to be tested for the presence of anti-Ku antibodies.

Clinical significance of serum cytokine profiles for differentiating between Kawasaki disease and its mimickers.

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.

The dynamics of laboratory markers reflecting cytokine overproduction in macrophage activation syndrome complicated with systemic juvenile idiopathic arthritis.

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.

An infant with A20 haploinsufficiency presenting with periodic fever syndrome: A case report.

A20 haploinsufficiency (HA20) is an early-onset autoinflammatory disease caused by loss-of-function variants of the TNFAIP3 gene, which encodes the protein A20. HA20 is typically characterized by Behçet's disease-like clinical symptoms, and patients usually present with a family history. Herein, we report a case of HA20 in a pediatric patient, presenting with periodic fever, abdominal pain, and vomiting, with no family history. This patient also harbored a novel heterozygous frameshift variant c.677del (p.Pro226LeufsTer2) of TNFAIP3. We initiated treatment with an anti-tumor necrosis factor-α agent that did not induce symptom resolution; we thus administered combination therapy, including prednisolone. Remission was then successfully achieved. We suggest that HA20 should be considered when an autoinflammatory disease is suspected and periodic fever syndrome is present, even in the absence of a family history of HA20 or Behçet's disease-like symptoms.

Infliximab treatment for refractory COVID-19-associated multisystem inflammatory syndrome in a Japanese child.

Patients with multisystem inflammatory syndrome in children (MIS-C) can develop clinical features resembling Kawasaki disease (KD). A full picture of MIS-C in East Asia which has higher incidence of KD than other regions remains unclear. We report on a 15-year-old Japanese boy with refractory MIS-C who was successfully treated with infliximab. A Japanese boy who was diagnosed with coronavirus disease 2019 (COVID-19) before a month developed MIS-C with fulfilling six principal symptoms of KD. Laboratory data showed extreme hyperferritinemia (11,404 ng/mL), besides lymphopenia and thrombocytopenia. The patient was refractory to initial therapy with intravenous immunoglobulin (IVIG; 2 g/kg), aspirin, and prednisolone. He was therefore administered a second IVIG (2 g/kg) and infliximab (5 mg/kg) on days 7 and 8 from the onset of fever, respectively, which resulted in an improvement of clinical symptoms. Only four Japanese cases with MIS-C were reported and all of them were responsive to IVIG. The hyperferritinemia in this case was distinctive from previously reported MIS-C cases in Japan and other cohorts and may be associated with refractoriness to IVIG therapy. Marked elevation of circulating ferritin levels is known to be induced by tumor necrosis factor-α, which plays a key role in the pathogenesis of both KD and MIS-C. Thus, for MIS-C patients with hyperferritinemia, early intervention with adjunctive infliximab may induce a more rapid resolution of inflammation and improve outcome. Because MIS-C may be heterogeneous with respect to immunopathology, genetic background, clinical phenotypes and response to therapies, optimized treatment strategies according to immunopathogenesis are required.

Apoptosis inhibitor of macrophage as a biomarker for disease activity in Japanese children with IgA nephropathy and Henoch-Schönlein purpura nephritis.

BACKGROUND: To evaluate the apoptosis inhibitor of macrophage (AIM) deposition patterns on the kidneys of children with IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (HSPN) and to investigate the clinical usefulness of serum and/or urinary AIM levels as biomarkers for the disease activity. METHODS: Immunohistochemical study was performed in the kidneys of 37 patients with IgAN and 10 patients with HSPN. Serum and urinary AIM levels in the patients and 20 healthy controls (HCs) were quantified by enzyme-linked immunosorbent assay. The results were compared with clinical features. RESULTS: In patients with IgAN and HSPN, AIM expression was observed in various areas, including the glomerular mesangial and capillary areas, the proximal and distal tubular epithelial cells, and on infiltrating macrophages in the glomeruli and interstitial areas. Serum and urinary AIM levels were significantly elevated in these patients compared with the HCs. Urinary AIM levels were positively correlated with the histological severity and degree of proteinuria and hematuria as well as urinary ß2 microglobulin and urinary N-acetyl-ß-D-glucosaminidase levels. CONCLUSIONS: AIM plays an important role in the pathogenesis of IgAN and HSPN. Urinary AIM levels can potentially reflect active renal inflammation in these diseases and may represent a useful biomarker for disease activity. IMPACT: Urinary AIM levels may represent a useful biomarker for disease activity of IgAN and HSPN. AIM expression was observed in the glomeruli, tubular epithelial cells, and infiltrating macrophages in glomeruli and interstitial area. U-AIM/Cr were significantly correlated not only with proteinuria, hematuria, and u-ß2MG and u-NAG levels but also with the activity index of histological findings in kidney biopsy specimens. Our results can emphasize the important role of AIM in the pathogenesis of IgAN and HSPN.

Comparison of serum cytokine profiles in macrophage activation syndrome complicating different background rheumatic diseases in children.

OBJECTIVES: To compare the cytokines involved in the development of macrophage activation syndrome (MAS) in different background rheumatic diseases and to identify serum biomarkers for MAS diagnosis. METHODS: Serum neopterin, IL-6, IL-18 and soluble TNF receptor (sTNFR) type I (sTNFR-I) and type II (sTNFR-II) levels were determined using ELISA in 12 patients with SLE, including five with MAS; 12 patients with JDM, including four with MAS; 75 patients with Kawasaki disease (KD), including six with MAS; and 179 patients with systemic JIA (s-JIA), including 43 with MAS. These results were compared with the clinical features of MAS. RESULTS: Serum neopterin, IL-18 and sTNFR-II levels were significantly higher during the MAS phase than during the active phase in patients with all diseases. Furthermore, serum sTNFR-I levels were significantly higher during the MAS phase than during the active phase in patients with SLE, KD and s-JIA. Receiver operating characteristic (ROC) curve analysis revealed that serum sTNFR-I levels for SLE, serum IL-18 levels for JDM, and serum sTNFR-II levels for KD and s-JIA had the highest areas under the ROC curve. Serum levels of these cytokines were significantly and positively correlated with serum ferritin levels. CONCLUSIONS: Overproduction of IFN-γ, IL-18 and TNF-α might be closely related to the development of MAS. Serum levels of sTNFR-I for SLE, IL-18 for JDM, and sTNFR-II for KD and s-JIA might be useful diagnostic markers for the transition from active phase to MAS.

Clinical Significance of Serum Galactose-Deficient IgA1 Level in Children with IgA Nephropathy.

This study was aimed at investigating the clinical significance of serum galactose-deficient IgA1 (Gd-IgA1) levels measured by a novel lectin-independent enzyme-linked immunosorbent assay (ELISA) using an anti-Gd-IgA1 monoclonal antibody (KM55) as a disease-specific biomarker for IgA nephropathy (IgAN) in children. Thirty-three children with IgAN, 40 with non-IgA glomerular diseases, and 38 age-matched healthy controls (HCs) were enrolled. Serum Gd-IgA1 levels were quantified by ELISA using KM55. Results were statistically compared with clinical features and pathological findings of IgAN. Serum Gd-IgA1 levels were significantly elevated in children with IgAN compared with children with non-IgA glomerular diseases and HCs. Serum Gd-IgA1 levels in children with IgAN were positively correlated with serum total IgA levels. However, the serum Gd-IgA1/total IgA ratio (Gd-IgA1/IgA) was also significantly elevated in children with IgAN. Serum Gd-IgA1 levels in children with IgAN increased in an age-dependent manner. The cutoff value of serum Gd-IgA1 levels for differentiating IgAN from non-IgA glomerular diseases was 3236 in children < 12 years and 5284 in children ≥ 12 years, respectively. In contrast, serum Gd-IgA1/IgA was age-independent. The cutoff value of serum Gd-IgA1/IgA for differentiating IgAN from non-IgA glomerular diseases was 0.2401. Serum Gd-IgA1 levels were negatively correlated with eGFR and positively correlated with mesangial IgA deposition. In contrast, serum Gd-IgA1/IgA levels were not correlated with any clinical parameters of IgAN. In conclusion, serum Gd-IgA1 levels were significantly elevated in children with IgAN. However, those levels were age-dependent; therefore, serum Gd-IgA1 levels classified by age and/or serum Gd-IgA1/IgA might have diagnostic values in children with IgAN.