KFD, an uncommon benign disease of necrotizing histiocytic lymphadenitis, usually occurs in young East Asian females, with a male/female ratio of 1:1.26–4 in three adult cohorts [
9‐
11]. However, most studies found that KFD in children has a male predominance, with a male/female ratio of 1.13–2.25:1 [
3‐
5], except for two studies based on Korean children [
12,
13], of which male/female ratios were 1:1 and 1:1.32, respectively. Some studies have reported that the median age of onset for children with KFD is between 8.1 and 13.2 years [
3,
4,
13]. We also reviewed all 47 pediatric patients with KFD diagnosed in our hospital between April 2014 and July 2021. Among them, 31 were boys, and 16 were girls, with a male/female ratio of 1.9:1 and a median age of 10 years.
KFD may be associated with the proliferation of CD8
+ T lymphocytes induced by autoimmunity, infection, and other factors. It may also be related to the participation of interferon-gamma and interleukin 6; however, the exact pathogenesis is unclear [
14]. In clinical manifestations, the most common symptoms of KFD were lymphadenopathy, fever, rash, fatigue, or arthritis and hepatomegaly or splenomegaly [
2]; various skin manifestations, including facial erythema, leukocytoclastic vasculitis, alopecia, and oral ulcerations, have also been described in KFD patients [
15], which lack specificity compared with many chronic conditions, including SLE. An early study carried out by Imamura M et al. hypothesized that KFD might represent a self-limited, SLE-like autoimmune state due to various infectious agents, indicating that KFD and SLE might have a certain relationship in the occurrence mechanism. The two may also need to be carefully differentiated in diagnosis [
16]. Some studies reported that the rate of KFD with or developed to SLE ranges from 1.3% to 7% [
5,
12,
13,
17]. Moreover, there have also been reports of SLE diagnosed before (18%), simultaneously (51%), and after KFD (31%) [
18]. Among the 47 patients with KFD in our hospital, only the two girls reported in this article had concurrent SLE and KFD as the initial manifestation. Subsequently, they developed into MAS, with the incidence of KFD with an SLE of 4.3%. According to reports, 12%–26% of patients with SLE experience lymphadenopathy at some point during the clinical stage and treatment [
19‐
21]. Lymph node involvement is usually cervical, localized, and moderately enlarged, with a diameter of 1–2 cm in KFD, whereas lymph nodes are usually soft, mobile, generalized, and of varied size in SLE [
22‐
24]. Lymph nodes biopsy is the gold standard for differential diagnosis. Patchy paracortical necrosis, karyorrhexis, and scarce plasma cells are the characteristics of KFD in histological findings [
9]. The immunohistochemical analysis of KFD is positive for myeloperoxidase, lysozyme, CD68, and CD163. However, the presence of hematoxylin bodies, an abundance of plasma cells, the Azzopardi phenomenon (hematoxylin staining nuclear material), and sparse CD8
+ T cells indicate SLE lymphadenitis [
25]. The lymph node biopsy of our patients revealed paracortical necrosis without hematoxylin bodies, and immunohistochemistry showed lysozyme and CD68 were positive, which is compatible with KFD. In laboratory indicators, most patients with KFD have normal laboratory findings; however, some may have leukopenia (especially granulocytopenia; 20–58% of cases), leukocytosis (2–5% of cases), anemia, elevated ESR, elevated CRP, elevated LDH, elevated AST and ALT, and atypical lymphocytes in the peripheral blood, which need to be distinguished from other diseases [
25]. Moreover, ANA is positive in 30% of patients with KFD, whereas anti-extractable nuclear antigen antibodies are generally negative [
22]. Sopeña B et al. also found that patients with KFD-SLE had a higher probability of experiencing leukopenia, pancytopenia, anti-Ro/SSA antibodies, and positive anticardiolipin antibody immunoglobulin G than those with SLE alone [
18]. Therefore, children diagnosed with KFD should be routinely tested for autoantibodies to identify the high-risk group for SLE occurrence timely.
Because KFD is related to rheumatic disease, hemophagocytic lymphohistiocytosis associated with KFD was regarded as KFD-MAS. It has been reported that the incidence of KFD-MAS was 30.8%, with more frequent glucocorticoid treatment and longer hospital stays [
26]. Moreover, it is worth noting that MAS is also a complication of SLE, which often occurs in the early stage of onset, with an incidence rate of 0.9%–4.6% [
27]. However, it is rare for all to occur simultaneously in one patient. There were only two reports of KFD disease associated with SLE and MAS [
28,
29], except for the two cases we reported in this article. Among them is a 17-year old boy who experienced KFD-MAS at first and developed SLE 6 weeks later with no follow-up condition described after SLE [
28]. The other is a 50-year-old man who experienced KFD, SLE, MAS, and neuropsychiatric lupus almost simultaneously but died due to severe infection [
29]. This article reported two pediatric patients’ disease courses and detailed follow-up outcomes. It is difficult to distinguish between MAS and SLE flare since the two conditions have similar characteristics, including blood cytopenia, skin rash, fever, lymphadenopathy, splenomegaly, and neurological symptoms. The overlapping clinical manifestations may impede the identification of early MAS and result in the delay of the most appropriate treatment. Therefore, attention should be given to the occurrence of MAS in patients with SLE with unexplained fever and cytopenia, accompanied by significantly increased SF levels. SF may be a remarkable index because it increases when MAS occurs and decreases rapidly after controlling the disease [
8].
Furthermore, we reported the prognosis of two patients, one with ILD and the other with neuropsychiatric lupus. Combined with the fatal case reported by other authors mentioned above, these suggested that patients with SLE with KFD as the initial manifestation may experience a more severe cytokine storm and organ involvement. Intravenous methylprednisolone pulse therapy is considered the first-line treatment [
30]; however, there has been no conclusion on which immunosuppressive agent is preferable for MAS in SLE. Several studies found that CYC and CsA had a similar effect in SLE-MAS [
31‐
33]; Kumakura et al. found CYC was beneficial in comparison with CsA [
34]. Gavand et al. found CYC or etoposide should be used for uncontrolled or severe forms in SLE-MAS [
30]. In addition, a review of the latest follow-up outcome of the two patients in our report showed that both benefited from CYC, and organ involvement was controlled. These outcomes show that the treatment of patients with KFD as the initial manifestation, developing into SLE and MAS, should be more aggressive, particularly in choosing immunosuppressive agents.
In conclusion, although SLE with KFD as the initial manifestation is rare, more attention should be paid to it as it may aggravate during the treatment, be more prone to developing into MAS, and can lead to the involvement of important organs. High-dose methylprednisolone pulse therapy combined with CYC may effectively control the disease and improve prognosis.