To our knowledge, the present study is the first to report the clinical characteristics and long-term outcomes of childhood-onset PAN in Korea and analyse the utility of the FSS and BVAS in paediatric patients. Given the partial accordance of our findings with those of previous researchers, we believe that our study provides useful data related to the clinical manifestations of childhood-onset PAN.
Previous studies [6, 12, 20] have reported that skin involvement and arthralgia/arthritis are more common in children than in adults with PAN. In contrast, weight loss and renal, gastrointestinal, and neurologic involvement appear to be more common in adults with PAN. In the largest multicentre study to date, which included 110 paediatric patients with PAN (63 with systemic PAN) [6], 92% of patients exhibited cutaneous lesions, while 71.4%, 43%, 33.3%, 14%, and 11% exhibited myalgia, hypertension, central nervous system involvement, cardiac involvement, and pulmonary involvement, respectively. In another large paediatric series including 69 patients with systemic PAN [21], presenting features by organ system were as follows: skin involvement in 88%, myalgia in 83%, arthralgia/arthritis in 75%, weight loss in 64%, fever in 60%, renal involvement in 19%, severe gastrointestinal involvement in 10%, and central nervous system involvement in 10%. In accordance with previous findings, skin and joint symptoms were noted in most of our patients, although rates of myalgia were lower in our study. These findings suggest that cutaneous manifestations with nonspecific systemic symptoms in children necessitate referral to a specialist in paediatric rheumatology or dermatology to ensure prompt clinical diagnosis.
Laboratory features including serum creatinine, urinalysis, liver function tests, and muscle enzyme concentrations were largely non-specific and included elevated ESR and hs-CRP in most cases. However, these findings are neither sensitive nor specific for the diagnosis of PAN. That is, there are no laboratory findings that can be used to definitely diagnose either childhood- or adult-onset PAN. Evidence suggests that childhood-onset PAN affects girls more than boys, in contrast to adult-onset PAN [8, 20, 21]. Although we enrolled only a small number of patients, the prevalence of PAN appeared slightly higher in boys (n = 6) than in girls (n = 3). While previous studies have reported mortality rates ranging from 1–4% [6, 21], no deaths were observed during our study period.
We also evaluated BVAS and FFS in our patients. No patients exhibited involvement of the mucous membranes, eyes, ears, nose, throat, chest, or cardiovascular system (used for BVAS assessment). Skin manifestations, especially Raynaud’s phenomenon with or without digital necrosis, were observed in six and five patients at diagnosis and at the first relapse, respectively. For the BVAS, Raynaud’s phenomena are not considered, and the contribution of skin symptoms is relatively small. However, Raynaud’s phenomena and skin symptoms greatly influenced the treatment strategies adopted for our patients. These findings suggest that more detailed subdivisions of skin manifestations are required to develop a new vasculitis scoring system for children. The highest FFS (2 points) was observed in Patient 2, who experienced hemiplegia due to cerebral bleeding and haematoma as well as several relapses. Fortunately, disease activity in Patient 2 has been well controlled with low-dose prednisolone, azathioprine, and methotrexate. Although this finding indicates that the FFS may be useful for predicting mortality in both childhood- and adult-onset PAN, our study was limited by the small number of included patients. As few patients exhibited multi-organ involvement, it was difficult to assess the utility of the FFS in paediatric patients.
The most appropriate treatments for PAN remain to be determined. Given the rarity of the disease, no treatment guidelines have been established, especially for children. In our study, four patients initially presented with Raynaud’s phenomena in the fingers. Finger amputation was necessary in two of these patients due to delayed diagnosis (Fig. 2a). In contrast, two patients who had been diagnosed earlier recovered without the need for amputation (Fig. 2b). These findings suggest that early diagnosis and aggressive intervention can help to improve long-term outcomes. Initial treatment with corticosteroids is important achieving remission in patients with adult-onset PAN, and steroid monotherapy is currently recommended for patients with mild PAN [22, 23]. In addition, cyclophosphamide is considered to induce remission, and immunosuppressive agents such as azathioprine or methotrexate are recommended to maintain remission or as steroid-sparing agents [24]. For induction, all patients in the present study were treated with high-dose corticosteroids or corticosteroid pulse therapy. The degree of multi-organ involvement and the response to initial treatment are the principal determinants for the addition of cyclophosphamide, IVIG, or infliximab. Given the lack of controlled studies, IVIG treatment for vasculitis has been restricted to patients exhibiting resistance to corticosteroids and immunosuppressive therapy [25]. Both steroids and cyclophosphamide are associated with several side effects when used in children, including growth problems, metabolic syndrome, adverse psychological effects, hypertension, infection, malignancy, and infertility [26–28]. In the present study, we also observed adverse drug reactions including Cushingoid face (n = 3), hypertension (n = 3), infection (n = 2), osteoporosis (n = 1), and haemorrhagic cystitis (n = 1). These complications are particularly worrisome for children with many years of life ahead of them. Although we did not detect late complications such as malignancy or infertility in our study, physicians should screen for signs of infertility and malignancy in patients exposed to cyclophosphamide.
Recent reports have highlighted the safety and efficacy of the anti-TNF-α inhibitor infliximab in patients with PAN [29, 30]. Indeed, treatment of skin necrosis with infliximab appeared effective in our study. Although not used in the current study, the interleukin-6 blocker tocilizumab has also shown promise for the treatment of vasculitis [31, 32]. Strategies that aim to reduce the treatment burden as much as possible should be a major goal for physicians when attempting to achieve remission. Furthermore, paediatricians should closely monitor growth, psychological status, and long-term outcomes in patients with childhood-onset PAN.
Multiple cases of systemic and cutaneous PAN have been identified in some Georgian Jewish or German families, consistent with an autosomal recessive inheritance-induced mutation in the adenosine deaminase 2 (ADA2)-encoding gene CECR1 (cat-eye syndrome chromosome region candidate 1) [4]. The discovery of this association between ADA2 and vasculitis has led to reconsideration in most cases of childhood-onset PAN. Hence, it remains critical to evaluate family history and identify ADA2 mutations when considering a diagnosis of PAN, as anti-TNF-α agents and ADA2 replacement therapy may be warranted in some cases [30].
This study has several strengths. First, all patients were managed by two expert physicians affiliated with Seoul National University Children’s Hospital, helping to ensure homogenous referral and treatment patterns among patients. In addition, patients were followed up for a relatively long period of time, allowing us to better characterise disease status based on clinical and laboratory information. Despite these strengths, the study possesses some limitations of note, including its single-centre retrospective design, which prevented us from assessing correlations between various treatment strategies and final outcomes. Furthermore, we were unable to perform a comprehensive multivariate analysis including clinical manifestations, FFS, and BVAS due to the small number of included patients. Lastly, we cannot exclude the potential for bias due to the inclusion of patients with more severe disease, who may be more likely to consult at tertiary referral centres.