Are TNF‐α blockers effective and safe for Kawasaki disease in children? A Cochrane Review summary with commentary

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.

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