Clinical advancements of biologic agents in the treatment of Kawasaki disease based on its pathogenesis

http://rehabilitation.cochrane.org The aim of this commentary is to discuss the published Cochrane Review “TNF-α blockers for the treatment of Kawasaki disease in children1” by Yamaji et al., under the direct supervision of Cochrane Review Group. This Cochrane Corner is produced in agreement with the International Journal of Rheumatic Diseases by Cochrane Rehabilitation. Kawasaki disease (KD) is an acute vasculitis with unknown etiology affecting small- and medium-sized blood vessels, particularly coronary arteries, which usually occurs in early childhood up to 5 years of age.2 This condition is characterized by main clinical features including fever, swelling of cervical lymph nodes, edema or erythema of the extremities, arthritis, and mucocutaneous manifestations such as congestion of the ocular conjunctivae, and oropharyngeal swelling and reddening.3 KD has a particularly high incidence in Japanese children (264.8 per 100 000), even though it has been reported worldwide, with a male-to-female ratio of 1.5:1.4 Coronary artery abnormalities (CAAs: from dilation to aneurysm that can result in coronary artery thrombosis) are the primary cause of morbidity and mortality in patients with KD. Despite the fact that pathogenesis remains poorly understood, some mechanisms have been described, including endothelial cell activation due to increased immune response recruiting neutrophils, macrophages, lymphocytes, plasma cells, and eosinophils, as well as enhanced expression of key pro-inflammatory cytokines triggering vasculitis, such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α.5 From a functional perspective, patients might experience deconditioning after the acute phase of KD because of CAAs and impaired coronary perfusion that influence aerobic capacity and exercise performance.6 Moreover, other functional impairments, such as facial palsy, sensorineural hearing and visual loss, ataxia, as well as behavioral disorders, have been described. These complications might result in potentially irreversible functional limitations in activities of daily living and poor health-related quality of life.7-11 The main target of the acute phase of KD is suppression of inflammation and prevention of CAAs. According to available evidence, early administration of intravenous immunoglobulin (IVIG) at high doses combined with acetylsalicylic acid is the first-line treatment for KD.5, 12 However, up to 20% of patients do not respond to this therapy, requiring further interventions to prevent cardiovascular complications. Several biologics targeting inflammatory cytokines have been proposed to treat the IVIG-resistant population, including monoclonal antibodies against TNF-α because of emerging evidence about their role in reducing endothelial cell apoptosis and CAAs. However, the efficacy and safety of TNF-α in KD patients remain poorly investigated. This Cochrane Systematic Review (CSR) summarizes the available evidence about one of the available treatments for IVIG-resistant KD cases that might improve management strategies to prevent severe functional limitations in children who will become adults with disabilities. Yamaji N, da Silva Lopes K, Shoda T, Ishitsuka K, Kobayashi T, Ota E, Mori R., 2019. The aim of this Cochrane Review is to investigate the benefits and safety of TNF-α inhibitors in children affected by KD. The population addressed in this review consists of children with KD. The intervention studied was the use of TNF-α inhibitors, such as IV infliximab (single dose of 5 mg/kg) or subcutaneous etanercept (0.8 mg/kg, maximum dose 50 mg). The intervention was compared to placebo or IVIG (single dose of 2 g/kg). The main outcomes studied were: treatment resistance, intended as persistent or recurrent fever (≥38°C) not attributable to other causes occurring after more than 2 weeks after intervention; incidence of CAAs, identified through echocardiography and/or coronary angiography within 3 months of KD diagnosis; incidence of adverse effects, including infusion reactions (eg fever with chills, hypotension and/or cutaneous reactions), and infections. The Cochrane Vascular Information Specialist searched for randomized controlled trials (RCTs), without restrictions in language, publication year or publication status in the Cochrane Vascular Specialized Register, the Cochrane CENTRAL Register of Controlled Trials, MEDLINE, Embase, CINAHL and AMED databases, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials register, to 19 September 2018. The review authors also undertook reference checking of gray literature. The review included 5 RCTs, conducted in USA, Canada, Japan, and Korea, on 494 children, aged from 2 months to 13 years. Four RCTs considered infliximab as additional treatment of IVIG. The main methodological issues were the compliance bias (high rate of loss to follow-up without further description, particularly in the control group), the performance bias (poor blinding) and imbalances in the group assignments. Moreover, the certainty of evidence of all outcome measures was downgraded also because of small sample size. The authors concluded that TNF-α inhibitors may be effective in reducing both treatment resistance and infusion reaction compared to placebo or IVIG. However, considering the overall low certainty of the evidence, it is likely that further studies might change these findings. This Cochrane Review aimed to investigate efficacy and safety of TNF-α blockers in children affected by KD, demonstrating that these biologic agents have significant treatment response by more than 40% compared to placebo or additional IVIG along with a lower infusion reaction of less than 90% compared to additional IVIG. Moreover, TNF-α inhibitors do not seem to increase the incidence of infections compared to placebo or additional infusions of IVIG in the same population. According to international guidelines, infliximab, the first TNF-α inhibitor approved for the pediatric population,3, 13 may be considered as treatment options for IVIG-resistant KD patients. On the other side, this intervention may make little or no difference in reducing the incidence of CAAs. Although patients with KD tend to recover without sequelae when adequately and timely treated, affected children may have exercise intolerance as well as other functional limitations because of the potential occurrence of other conditions, particularly hearing and visual impairments, facial palsy, and ataxia,7, 8, 10, 11 thus resulting in significant burden for the patient as well as the family and/or caregivers. However, available guidelines do not consider rehabilitation approaches for KD patients, providing only indications for physical activity to be practiced. Considering the percentage of non-responders to pharmacological approaches, rehabilitation interventions should be included as an appropriate management strategy, particularly to prevent the long-term consequences of this condition. Adults with cardiovascular diseases and patients with congenital heart diseases benefit from rehabilitation programs, particularly aerobic exercise, which should also be a key intervention for counteracting deconditioning in children with KD. However, in this population the effects of exercise on cardiovascular health are little known and poorly investigated. Limited evidence suggests that exercise training is promising in KD patients, demonstrating improvement in perfusion to collateral-dependent areas when associated with anticoagulants.14 Available guidelines support non-agonistic physical activity and non-contact sport only after 8 weeks from normalization of clinical and instrumental assessments.3-13 However, since patients might still have stress-induced myocardial ischemia, it is crucial to monitor cardiovascular risk.3 From a rehabilitation perspective, this CSR does not address specific functioning outcomes, including the efficacy of interventions on arthritis. Indeed, this clinical issue should be investigated considering that it seems associated with higher systemic inflammation and IVIG resistance rates in KD patients.15 In this context, data about the efficacy of TNF-α blockers on KD-related arthritis might better define clinical benefits, considering that these drugs have demonstrated markedly improved functional outcomes in other rheumatic diseases. The author thanks Cochrane Rehabilitation and Cochrane Vascular Group for reviewing the contents of this Cochrane Corner. The author declares no conflicts of interest.

Objective: To analyze the clinical characteristic of systemic juvenile idiopathic arthritis (sJIA) patients with Kawasaki disease like onset symptom. Methods: A case-control study was performed. A total of 24 patients with sJIA with Kawasaki disease-like symptoms at the Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University from January 2018 to August 2024 were selected as the Kawasaki disease combined with sJIA group. A total of 96 patients with Kawasaki disease as the Kawasaki disease group and 83 patients with sJIA were selected as the sJIA group. The general information, clinical manifestations, laboratory examinations and complications of the patients were compared among the 3 groups. Differences between groups were assessed by Mann-Whitney U test or Kruskal-Wallis H test and Chi-square test or Fisher's exact test. Results: There were significant differences in age and fever course between Kawasaki disease combined with sJIA groups, Kawasaki disease groups, and sJIA groups (3.4 (2.5, 7.3) vs. 3.4 (1.9, 4.8) vs. 8.8 (5.1, 11.7) years, 24.5 (18.0, 37.3) vs. 23.0 (18.0, 31.0) vs. 7.0 (6.0, 8.0) d, Z=67.09, 138.24, both P<0.05). Among the 24 cases of Kawasaki disease combined with sJIA, 20 cases (83%) had joint symptoms and 9 cases (38%) had conjunctival congestion. There were significant differences in the incidence of coronary artery injury between Kawasaki disease combined with sJIA group, Kawasaki disease group and sJIA group (58% (14/24) vs. 44% (42/96) vs. 6% (5/83), χ2=40.50, P<0.05). There were significant differences in the risk of macrophage activation syndrome between Kawasaki disease combined with sJIA group, sJIA group and Kawasaki disease group (17% (4/24) vs. 10% (8/83) vs. 0, P<0.05). In the Kawasaki disease combined with sJIA group, 11 cases (46%) did not respond after 2 courses of intravenous immunoglobulin (IVIG) treatment, and 21 cases (88%) used glucocorticoids. The use rate of high-dose hormones in the Kawasaki disease combined with sJIA group was higher than that in the sJIA group (29% (7/24) vs. 5% (4/83), χ2=12.95, P<0.05). In the group of Kawasaki disease combined with sJIA group, 17 cases (71%) used biological agents, 1 case used adalimumab, and 16 cases received tocilizumab treatment, of which 4 cases were allergic to tocilizumab. In the group of Kawasaki disease combined with sJIA, 11 cases (46%) treated with tocilizumab were followed up regularly for 1 month, and 10 cases were effective. Conclusions: Children with sJIA who present with Kawasaki disease-like clinical symptoms have clinical features of Kawasaki disease and sJIA. Children with Kawasaki disease who present at a young age, have a long fever course, are accompanied by joint symptoms, and are IVIG-resistant need to be alert to the possibility of sJIA and receive timely treatment with hormones and biological agents.

Kawasaki disease is a systemic vasculitis with a risk of developing coronary artery lesions if left untreated. Kawasaki disease can be diagnosed clinically with classical symptoms (conjunctivitis, rash, lymphadenopathy, mucositis, edema of hands and feet), but predicting the risk of developing coronary artery aneurysm remains challenging. The coronary sequelae of Kawasaki disease have significant morbidity and mortality and are the second most common cause of acquired cardiac disease in children. Several genetic and immune factors are involved in the inflammation of coronary artery lesions in Kawasaki disease. Inositol trisphosphate 3-Kinase (ITPKC), Foxp3+, circular RNAs, mannose-binding lectin 2 (MBL2), complement factor H (CFH), kininogen 1 (KNG1), serpin family C member 1 (SERPINC1) and fibronectin 1 (FN1) are the essential genes identified in the pathogenesis of coronary artery lesions in Kawasaki disease. The addition of methylprednisolone to a combination of aspirin and intravenous immunoglobulins and biological agents like anakinra, etanercept, infliximab, and immunosuppressants like cyclosporine prevents the occurrence of coronary artery aneurysms in Kawasaki disease. Since the coronary artery lesions form the second most common cause of acquired cardiac disease in children and the incidence of myocardial infarction is a late complication, the risk stratification for coronary artery aneurysms and follow-up protocols for the prevention of cardiac thrombosis were proposed by the American Heart Association in 2017.

Coronary arteritis, a complication of Kawasaki disease (KD), can be refractory to immunoglobulin (IVIG) treatment. To determine the most effective alternative therapy, we compared the efficacy of different agents in a mouse model of KD. Vasculitis was induced by injection of Candida albicans water-soluble fractions (CAWS) into a DBA/2 mouse, followed by administration of IVIG, etanercept, methylprednisolone (MP), and cyclosporine-A (CsA). At 2 and 4 weeks, the mice were sacrificed, and plasma cytokines and chemokines were measured. CAWS injection induced active inflammation in the aortic root and coronary arteries. At 2 weeks, the vasculitis was reduced only by etanercept, and this effect persisted for the subsequent 2 weeks. At 4 weeks, IVIG and CsA also attenuated the inflammation, but the effect of etanercept was more significant. MP exerted no apparent effect at 2 or 4 weeks. The suppressive effect exerted by etanercept on cytokines, such as interleukin- (IL-)6, IL-12, IL-13, and tumor necrosis factor-α (TNF-α), was more evident than that of others. The extent of arteritis correlated with the plasma TNF-α levels, suggesting a pivotal role of TNF-α in KD. In conclusion, etanercept was most effective in suppressing CAWS-induced vasculitis and can be a new therapeutic intervention for KD.

Kawasaki disease (KD) is an acute febrile illness that primarily affects children under five years of age and can lead to coronary artery aneurysms if left untreated. High-dose intravenous immunoglobulin (IVIg) is the standard treatment. However, approximately 10%–20% of patients are refractory to this therapy and require additional treatments, including biologic agents such as infliximab, etanercept, or anakinra. As the use of these biologic agents has increased in recent years, concerns have been raised that biologics may suppress immune responses, potentially compromising the safety and immunogenicity of subsequent vaccinations, particularly live-attenuated vaccines. This study outlines the principles of vaccination in children with KD who have received biologic therapy. Key factors such as pharmacokinetics, mechanisms of action, and the duration of immunosuppressive effects should be considered when determining the optimal timing for vaccination. In patients with KD, biologics are typically administered once, often following IVIg, which may reduce the risk of vaccine-related adverse events while still allowing for adequate antibody responses. Further research is needed to establish evidence-based guidelines for safe and effective immunization in these patients.

BackgroundThe COVID-19-associated multisystem inflammatory syndrome in children (MIS-C) is characterized by Kawasaki disease (KD)-like features and circulatory shock [1]. The genesis of SARS-CoV-2 variants triggered successive waves of mass infections...

Previous chapters described initial and rescue treatment for patients with Kawasaki disease. Other immunosuppressive agents, such as biological agents, methotrexate, cyclophosphamide, and plasma exchange, may also be effective for patients with Kawasaki disease. However, most of these agents have not been carefully evaluated for their efficacy in suppressing inflammation due to Kawasaki disease and preventing formation of coronary artery lesions, and most of the present evidence is from case reports or case series. Further research is needed before recommendations can be developed for these agents.

Systemic vasculitis is characterized by blood vessel inflammation which may lead to tissue injury from vascular stenosis, occlusion, aneurysm, and/or rupture. Apart from relatively common vasculitides such as Henoch-Schönlein purpura (HSP) and Kawasaki's disease (KD), most of the primary vasculitic syndromes are rare in childhood, but are associated with significant morbidity and mortality. New classification criteria for childhood vasculitis have recently been proposed and validated. The cause of most vasculitides is unknown, although it is likely that a complex interaction between environmental factors such as infections and inherited host responses trigger the disease and determine the vasculitis phenotype. Several genetic polymorphisms in vasculitis have now been described that may be relevant in terms of disease predisposition or development of disease complications. Treatment regimens continue to improve, with the use of different immunosuppressive medications and newer therapeutic approaches such as biologic agents. We provide an overview of paediatric vasculitides focusing on HSP, KD, and polyarteritis nodosa (PAN). Key differences (where relevant) between paediatric and adult vasculitis are highlighted. In addition we discuss new emerging challenges particularly in respect to the long-term cardiovascular morbidity for children with systemic vasculitis, and emphasize the importance of future international multicentre collaborative studies to further increase and standardize the scientific base of investigating and treating childhood vasculitis.

Systemic vasculitis is characterized by blood vessel inflammation which may lead to tissue injury from vascular stenosis, occlusion, aneurysm, and/or rupture. Apart from relatively common vasculitides such as IgA vasculitis (Henoch–Schönlein purpura (HSP)) and Kawasaki’s disease (KD), most of the primary vasculitic syndromes are rare in childhood, but are associated with significant morbidity and mortality. New classification criteria for childhood vasculitis have recently been proposed and validated. The cause of most vasculitides is unknown, although it is likely that a complex interaction between environmental factors such as infections and inherited host responses trigger the disease and determine the vasculitis phenotype. Several genetic polymorphisms in vasculitis have now been described that may be relevant in terms of disease predisposition or development of disease complications. Treatment regimens continue to improve, with the use of different immunosuppressive medications and newer therapeutic approaches such as biologic agents. We provide an overview of paediatric vasculitides focusing on HSP, KD, and polyarteritis nodosa (PAN). Key differences (where relevant) between paediatric and adult vasculitis are highlighted. In addition we discuss new emerging challenges particularly in respect to the long-term cardiovascular morbidity for children with systemic vasculitis, and emphasize the importance of future international multicentre collaborative studies to further increase and standardize the scientific base of investigating and treating childhood vasculitis.

GIH clinical research 2003–2004: The year in review

Background: The Etanercept as Adjunctive Treatment for Acute Kawasaki Disease study, a phase 3 randomized placebo-controlled clinical trial, evaluated etanercept, a TNF-alpha inhibitor, as an adjunct to IVIg for Kawasaki Disease (KD). In children presenting with coronary artery (CA) aneurysm, etanercept resulted in reduction in progression of CA dilation and earlier aneurysm regression compared to placebo. Following study conclusion, our institution implemented etanercept as a first line IVIg adjunctive treatment for patients presenting with early CA aneurysm formation. Hypothesis: Real world use with etanercept as adjunct to IVIg in children with KD and CA aneurysm shows high patient compliance, is safe and results in early CA regression. Methods: We reviewed charts and echocardiograms for all children admitted to Seattle Children’s Hospital from 5/2019 to 4/2024 and treated with etanercept for KD with CA aneurysms at presentation (Z-score ≥2.5 per AHA aneurysm definition). Etanercept is injected subcutaneously at 0.8 mg/kg with IVIg at diagnosis and then with 2 repeat weekly doses at outpatient visits. Results: Thirty-six patients with KD and CA aneurysms received at least one dose of etanercept. Sixteen (44%) were &lt;1 year of age, 17 (47%) were diagnosed with incomplete KD and 5 (14%) were ‘IVIg refractory.’ Four patients responded to a second IVIg dose and two patients received additional biologic agents. Thirty-two patients completed the 3-dose course of etanercept, with outpatient doses administered 6.6±1.5 days (mean±SD) and 13.5±2.3 days after the first. Seven patients had giant CA aneurysms (Z-score ≥10) requiring anticoagulation. In patients with giant aneurysms and at least 6-month follow-up, all aneurysms regressed to below the threshold for requiring anticoagulation beyond aspirin. Of 31 children with long-term follow-up echocardiograms available, 19 had complete resolution (Z-score &lt;2.5) of CA dilation by 6 months, 22 by 1 year, and 29 by 2-year follow-up. No severe or serious adverse events were attributed to etanercept. Conclusions: Etanercept for KD with early CA aneurysms was delivered safely and with high compliance. CA aneurysm regression occurred in most patients with marked reduction in giant CA aneurysms by 6 months. These real-world data support the use of etanercept as an intensification therapy for preventing persistence of CA aneurysms in KD.

Due to the well known toxicities of cyclophosphamide, substantial interest exists in finding other therapies to treat primary systemic vasculitis. Biologic agents have been proposed as an alternative to cyclophosphamide for these disorders because of their recent success in treating other rheumatic diseases. This article reviews the current state-of-the-art therapy with regards to the use of biologic agents as treatments for systemic vasculitis. The greatest amount of experience with these agents for the treatment of systemic vasculitis is with antitumor necrosis factor agents, pooled intravenous immunoglobulin, and anti-B-cell therapies such as rituximab. Intravenous immunoglobulin is already a standard therapy for Kawasaki's disease, but should also be considered for the treatment of vasculitis associated with antineutrophil cytoplasmic antibodies when standard therapies are either ineffective or contraindicated. Early experience with tumor necrosis factor inhibitors indicates that they may be effective for the treatment of Takayasu's arteritis, but their role in the treatment of other forms of vasculitis remains controversial. Early experience with rituximab for the treatment of several forms of vasculitis has been quite promising, but must be confirmed by ongoing randomized clinical trials. Biologic agents represent the next evolution in treatment for the primary systemic vasculitides. Greater understanding of these diseases has allowed us to move further away from nonspecific, highly toxic therapies toward a more directed approach. As our experience with these agents increases, they will likely form the keystone of treatment in the near future.

Editorial on the Research Topic Pathophysiological and clinical advances in asthmatic inflammation from the nasopharynx to the peripheral airway in the respiratory tract systems Asthmatic airway inflammation is associated with many diseases, ranging from the upper to the lower respiratory tract, such as eosinophilic chronic sinusitis with nasal polyps (ECRSwNP), childhood and adult asthma, eosinophilic bronchiolitis/pneumonia, and eosinophilic granulomatosis with polyangiitis (EGPA). Various biological agents have been introduced for patients refractory to oral corticosteroid-based therapy. However, the mechanism of asthma-related inflammation remains obscure, and overcoming this intractable disease remains challenging. In this Research Topic, we focused on various asthmatic inflammatory diseases to deepen the understanding of underlying complicated pathological mechanisms, and the efficacy of the latest biologics against asthmatic inflammation. An in vivo study has demonstrated the beneficial effects of classical hypoglycemic agent, metformin, in metabolic syndrome, cancer, and chronic inflammation and tissue-remodeling through AMPK-dependent or AMPK-independent mechanisms (Saisho, 2015; Wu et al., 2021) . Furthermore, metformin alleviates airway inflammation in asthmatic patients with obesity (Guo et al., 2021) . As shown in Figure 1 , Ma et al. clarified the mechanisms of metforminmediated improvement in the airway inflammatory cell infiltration by restoring AMPKα activity using ovalbumin-sensitized asthmatic mice. Articles and reviews on this Research Topic are summarized in Figure 1 ; Table 1 , respectively. Moreover, Iwashita et al. demonstrated that type IV collagen, an extracellular matrix protein, suppresses MUC5AC secretion by regulating integrin α2 and β1 expression in the lungs and increases Akt and ERK phosphorylation using ovalbumin-sensitized asthmatic mice. This study was consistent with a previous in vitro study (Iwashita et al., 2010) . These in vivo studies indicate that alternative treatment options may be promising for refractory asthmatic inflammatory diseases.

Objective: To explore the latest research methods and information on the diagnosis and treatment of Kawasaki disease. Methods: A total of 50 papers related to Kawasaki disease were collected from databases such as CNKI, the Internet, and PubMed for analysis and summary. Results: In recent years, the research progress in the diagnosis and treatment of Kawasaki disease worldwide has been rapid, mainly focusing on five aspects: etiology and pathogenesis, diagnosis, treatment guidelines, expert consensus, and long-term management. The main pathogenesis theories include genetic susceptibility and infection trigger hypotheses, with the core role of the IL-1 pathway being clarified, and a deeper understanding of incomplete Kawasaki disease relying on ultrasound and biomarkers (NT-proBNP); the Z-score assessment has been promoted. The treatment mainly involves the use of biological agents such as infliximab and anakinra as standard second-line options; for high-risk patients, initial combination with hormones has become a new strategy. Conclusion: Further strengthening of basic and clinical research on Kawasaki disease is still needed. Future research directions will focus on finding specific etiological factors and diagnostic biomarkers; developing more precise individualized initial treatment plans to minimize drug resistance and coronary artery damage; and deepening the understanding of the mechanisms of long-term sequelae and optimizing management strategies for the pre-adult period.

BackgroundJuvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood, divided into several subgroups. The sJIA could be presented by monocyclic, polycyclic or persistent polyarticular clinical course....