Aspirin and IVIG are the recommended initial therapy in KD (12). As the pathology of KD consists of an immune-mediated panvasculitis of small and medium-sized muscular arteries, corticosteroids with their well-known and strong anti-inflammatory properties are expected to be of benefit. The available literature is contradictory (13, 14, 15), even though the RAISE study has provided evidence for the advantage of corticosteroids plus intravenous immunoglobulin in high-risk patients with KD (16).
This may well be due to the different modes of using steroids in KD. Some use it as ‘rescue therapy’ (administered in children who fail initial IVIG therapy), whereas others address ‘primary therapy’ (corticosteroids administration as a component of first-line therapy, which may or may not include IVIG) (17). The differences between these studies could also have been due to the differing dose of aspirin (30 mg/kg vs. 80–100 mg/kg) or steroids (prednisolone 2 mg/kg/thrice-a-day vs. IV methylprednisolone 30 mg/Kg once-a-day), or even IVIG (1 g/Kg/day for 2 days vs. 2 g/Kg once). However, none of the previous studies has used the regimen, which we had to use due to pressing circumstances. Due to resource constraints, in this study, we could only use aspirin and corticosteroids, and follow-up showed significant coronary artery improvement and the presence of only one patient with a small-sized coronary aneurysm in each group.
Corticosteroid therapy has undoubtedly earned a place among the therapeutic regimens for KD. The link between the systemic immune response seen in the acute phase of KD and subsequent damage to the coronary arteries may be related to TNF-α and its downstream effector molecules as the key players in mediating coronary artery damage. Several factors, such as prolonged fever and younger and older age, have been identified as part of the high-risk phenotype for poor coronary artery outcomes in KD (18). In this study, we included patients aged six months to five years, and the duration of fever and the acute phase of the disease was relatively similar between the two groups, so we had no additional factor in increasing the risk of coronary artery involvement.
In some previous studies, the use of steroids in the treatment of KD (first-line or refractory cases) has also been shown to reduce the duration of fever cessation and normalization of CRP (15, 19, 20, 21).
Masaru et al. showed the changes in the inflammatory cytokine levels in the IVMP group compared with additional IVIG induced faster resolution of fever. The stronger suppression of MCP-1 and TNF-α levels by IVMP is noteworthy for preventing coronary artery lesions (10).
Corticosteroids have been considered contraindicated in KD because of a higher incidence of coronary aneurysms in the group treated with corticosteroids than in the untreated group (22). However, this finding can be criticized on several points, including drug dosage, being insufficient due to its oral administration, and the timing of the initiation of the steroid therapy being too late. As discussed above, anti-inflammatory agents are not used conventionally in sufficient amounts. Pulsed administration regimens have renewed interest in corticosteroids, particularly very high doses of 250–1000 mg methylprednisolone (MP) for one to five days, as they are reported to be well-tolerated, more immunomodulatory than immunosuppressive, and safe, with only minor dose-related side effects (23, 24). The type I interferon pathway is affected in patients treated with pulse corticosteroids but not oral corticosteroids. Pulse corticosteroids markedly but transiently decreased the number of plasmacytoid dendritic cells (25).
In our study, the frequency of coronary artery involvement in the steroid pulse group in the two weeks after treatment was not significantly different from before treatment. As mentioned in the results section, patients in IVMP treated group, like patients receiving standard treatment with IVIG, had a marked improvement in coronary artery involvement and had the same percentage and type of involvement at the end of the study.
According to a study by Kijima et al., intravenous methylprednisolone pulse could significantly reduce coronary artery damage in children with KD (26). Shinohara et al. also showed a possible role of corticosteroids in treating the acute phase of KD (20). Swati Singhal et al. described the course of a one-year-old child with KD who was treated with aspirin and corticosteroids as the initial therapy, and follow-up showed the presence of a small-sized coronary aneurysm (27).
The most compelling evidence for steroid use in KD comes from the meta-analysis done by Wooditch et al. (13). They performed a meta-analysis of 862 children and found a significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroids and aspirin with/without IVIG compared with aspirin alone or with IVIG. Newer studies are now testing steroid plus IVIG-aspirin combination in those not responding to the initial therapy or those likely to have a more resistant disease (15, 16, 28, 29).
Based on the available evidence, this lack of efficacy of corticosteroids in first-line combination therapy in some patients may be due to reduced corticosteroid receptor gene expression on mRNA in these populations (15).
The basic idea of our pulse therapy was to prevent or suppress the process of aneurysm development by treating coronary angiitis, which may underlie coronary changes in KD, using large doses of corticosteroids parenterally within a relatively short period in the early stage of the disease. The present study indicates that steroid pulse therapy is effective in patients having some dilating changes of the coronary arteries and patients in whom an aneurysm formation is developing. Theoretically, such a treatment should be initiated before any dilative lesions appear in the acute phase of KD. In the acute phase, the activation of the innate immune system is demonstrated cytokine storm. In IVIG-resistance KD patients and patients with coronary artery involvements, TNFα, IL6 is higher than IVIG-Responder patients.(30, 31) Methylprednisolone pulses, especially in suppressing the innate immune system during the acute phase of KD, may have a more pivotal role in inhibiting progressive coronary involvements than IVIG as the first-line treatment.
It should be emphasized that we found no significant side effects in any patient and that there was no convincing evidence that steroids made the coronary lesions worse.
Therefore, at present, intense corticosteroid pulse therapy for the coronary artery's inflammatory process may be used to prevent or minimize any tragic sequel of KD. Further evaluation with more sample size might be more valuable for IVIG and IVMP comparisons as the first-line treatment in KD, especially in anticipation of IVIG-resistance patients.
This is the first study on IVMP pulse therapy as first line treatment of KD, alone as a clinical trial study. However, Single blind study and 2 month follow-up are the main limitation of this study