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Infliximab Therapy and the Central Nervous Demyelination in Patients with Kawasaki Disease

Sagara, Yuka MD*; Muneuchi, Jun MD*; Shimabukuro, Wataru MD*; Joo, Masahiko MD*; Yoshino, Miwa MD*; Nakamura, Ryoko MD*; Yoneda, Toru MD*; Sugitani, Yuichiro MD*; Watanabe, Mamie MD*; Mizushima, Akira MD; Takahashi, Yasuhiko MD*

The Pediatric Infectious Disease Journal: August 2019 - Volume 38 - Issue 8 - p e185–e187
doi: 10.1097/INF.0000000000002296
Brief Reports
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We performed brain magnetic resonance imaging in 14 patients with Kawasaki disease who were treated with infliximab (IFX) at 56 months of age (32–62 months of age) and 23 months (5–35 months) after IFX therapy. Magnetic resonance imaging showed no finding of the central nervous demyelination. IFX therapy is not related to central nervous demyelination in patients with Kawasaki disease.

From the Departments of *Pediatrics

Radiology, Japan Community Healthcare Organization Kyushu Hospital, Kitakyushu, Japan.

Accepted for publication January 8, 2019.

The authors have no funding or conflicts of interest to disclose.

Address for correspondence: Jun Muneuchi, MD, Department of Pediatrics, Japan Community Healthcare Organization Kyushu Hospital, 1-8-1 Kishinoura, Yahatanishi-ku, Kitakyushu, Fukuoka 806-8501, Japan. E-mail: jmune@msn.com.

Kawasaki disease (KD) is an acute systemic vasculitis syndrome primarily affecting small- and medium-sized arteries, particularly the coronary arteries. Recently, infliximab (IFX), a TNF-α (tumor necrosis factor-alpha) antagonist, has been used in patients with KD refractory to the conventional combination therapy with intravenous immunoglobulin and oral aspirin.1,2 However, previous studies have shown the induction of cerebral nervous demyelination among patients with autoinflammatory diseases who were treated with TNF-α inhibitors.3,4 We therefore studied brain magnetic resonance imaging (MRI) to evaluate the central nervous demyelination in patients with KD who were treated with IFX.

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PATIENTS AND METHODS

This study was approved by the institutional review board. Among a total of 424 patients with KD admitted to our institution between 2007 and 2017, 36 patients (8%) with KD refractory to the conventional combination therapy were treated with IFX. We performed brain MRI in 14 patients (9 males) from whom or whose guardians provided informed consents.

Brain MRI was performed using a 1.5-T system (Siemens, Munich, Germany). T1-weighted axial images (time to repetition: 440–650; time to echo: 15) and T2-weighted axial images (time to repetition: 3000; time to echo: 20–120) were obtained routinely in 3- to 5-mm-thick slice. In addition to these conventional images, 3-dimensional time-of-flight magnetic resonance angiography was obtained. Image processing was generated using a maximum-intensity-projection algorithm.

Results are expressed as median values following interquartile ranges.

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RESULTS

Demographic data of the subjects are shown in Table 1. Age at onset of KD was 23 months (7–40 months). Seven patients (50%) were treated with IFX during infancy: at 6 months of age (5–8 months of age). The day of illness at the initial treatment and administration of IFX was 2 (1–5) and 8 (7–10), respectively. The risk scores for coronary arterial aneurysms (Kurume and Gunma scores) and maximum serum level of C-reactive protein were also shown in Table 1.5,6 There were 2 patients who required plasma exchange because IFX therapy was ineffective. The day of defervescence was 10 (9–13). Z score of the coronary arterial diameter was 5.55 (4.88–6.71). A total of 7 patients developed coronary arterial aneurysms.

TABLE 1

TABLE 1

During the follow-up period of 63 months (52–65 months), there were no patients who developed neurologic complaints nor signs among 13 patients. Brain MRI was performed at 56 months of age (32–62 months of age) and 23 months (5–35 months) after the treatment with IFX. There were 5 patients who underwent MRI within 6 months after the treatment with IFX. Brain MRI showed no finding of demyelination in these subjects. In 1 patient, there was small cerebral arterial aneurysm in the right internal carotid artery (Fig. 1), but the causal relationship between KD and cerebral aneurysm was unclear.

FIGURE 1

FIGURE 1

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DISCUSSION

The present study demonstrates that brain MRI showed no evidence of the central nervous demyelination in children, including infants, with KD after IFX. TNF-α inhibitors have been established as an essential therapeutic option for several inflammatory diseases. Although infectious complications are well-known, neuroinflammatory demyelinating disorders such as multiple sclerosis, myelitis and optic neuritis also have been considered as possible complications associated with IFX therapy.3,4 French rheumatologists’ nationwide survey showed that 33 demyelinating disorders occurred in patients with inflammatory rheumatic diseases who were treated with TNF-α inhibitors. The relationship between the treatment with TNF-α inhibitors and nervous demyelination was not definitive, but the majority of rheumatologists believed this to be a causal relationship.4 The precise pathophysiology of demyelination after the treatment with TNF-α inhibitors remains unclear. The lack of entry of TNF-α agents into the central nervous system can attenuate TNF-α–mediated demyelination, and prolonged exposure to TNF-α antagonist enhances the antigen-specific T-cell response, or myelin-specific T-cell response, in the peripheral nervous system, which can impact the central nervous system resulting in the central nervous demyelination.7 Our results suggest that the single-dose administration of IFX for KD probably does not elicit such immunologic reactions resulting in the central nervous demyelination. Otherwise, we performed brain MRI at a median of 23 months after IFX therapy and within 6 months of IFX therapy in only 5 patients. It is possible that there could have been an abnormal finding, if brain MRI had been performed earlier.

In the present study, there was a 2-year-old girl whose MRI showed a small cerebral aneurysm (shown in Fig. 1). She had recurrent KD refractory to intravenous immunoglobulin at 4 months, 2 years and 3 years of age. Serial brain MRI showed no remarkable change in the cerebral aneurysm. Muneuchi et al8 previously reported brain MRI findings in patients with KD before the introduction of IFX therapy: in that study, there were no findings of cerebral arterial aneurysms. It is unlikely that the cerebral aneurysms occur in patients with KD. Because our cohort consists of small number of patients, the further evaluation of brain MRI should be performed in these patients.

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REFERENCES

1. Burns JC, Mason WH, Hauger SB, et al. Infliximab treatment for refractory Kawasaki syndrome. J Pediatr. 2005;146:662–667.
2. Burns JC, Best BM, Mejias A, et al. Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease. J Pediatr. 2008;153:833–838.
3. Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum. 2001;44:2862–2869.
4. Seror R, Richez C, Sordet C, et al; Club Rhumatismes et Inflammation Section of the SFR. Pattern of demyelination occurring during anti-TNF-α therapy: a French national survey. Rheumatology (Oxford). 2013;52:868–874.
5. Kobayashi T, Inoue Y, Takeuchi K, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. 2006;113:2606–2612.
6. Egami K, Muta H, Ishii M, et al. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr. 2006;149:237–240.
7. Kaltsonoudis E, Voulgari PV, Konitsiotis S, et al. Demyelination and other neurological adverse events after anti-TNF therapy. Autoimmun Rev. 2014;13:54–58.
8. Muneuchi J, Kusuhara K, Kanaya Y, et al. Magnetic resonance studies of brain lesions in patients with Kawasaki disease. Brain Dev. 2006;28:30–33.
Keywords:

Kawasaki disease; infliximab; intravenous immunoglobulin; complication; central nervous system

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