Hemophagocytic lymphohistiocytosis (HLH) is a rare yet potentially fatal
systemic disease arising from uncontrolled activation of the immune
system. According to the Histiocyte Society’s 2004 guidelines, patients
must meet five of eight criteria to be diagnosed with HLH [1]. HLH
may be classified into primary and secondary. Primary, or familial, HLH
is attributed to underlying defects in genes that control natural killer
(NK) and cytotoxic T-lymphocyte (CTL) cell degranulation. Secondary HLH,
in contrast, may occur in the context of triggers, such as malignancy,
rheumatologic disease, or infection. Systemic-onset juvenile idiopathic
arthritis (SoJIA) is a well-recognized trigger of HLH and both share
overlapping features (e.g. fever and elevated ferritin). Management of
SoJIA includes the immunomodulator Anakinra, an interleukin 1 (IL-1)
receptor antagonist hypothesized to dampen an overactive immune system.
Three patients treated for HLH with concomitant SoJIA diagnosis at Cook
Children’s Medical Center between 2014 and 2019 are described below in
order to examine the role of immunomodulators in their clinical course
and outcome.
Three Hispanic patients (aged 8-15) presented with a constellation of
systemic symptoms, including fever, generalized rash, fatigue, and
weight loss. Upon fulfilment of necessary criteria and subsequent
diagnosis of HLH, they were treated accordingly with HLH-2004 protocol.
Case 3, whose HLH was suspected to be secondary to Epstein-Barr Virus
(EBV) infection, rapidly responded to treatment and, therefore, briefly
discontinued Etoposide; however, she tolerated this poorly and resumed
treatment after a six-week hiatus with the addition of weekly Rituximab
to mitigate rising EBV titers. All patients achieved remission.
Past medical history for case 3 included autoimmune disorders such as
celiac disease, type 1 diabetes and suspected idiopathic juvenile
arthritis for which she did not require ongoing care prior to presenting
with features of secondary HLH. Cases 1 and 2 were diagnosed with SoJIA
following their HLH diagnosis. Cases 1 and 3 relapsed with HLH within
months of their initial encounter. Due to their concurrent diagnosis of
SoJIA, both received daily Anakinra. Case 3 experienced rapid resolution
of symptoms. In contrast, Case 1 had unsatisfactory response of
musculoskeletal manifestations prompting switch from Anakinra to weekly
Tocilizumab—another biologic that antagonizes IL-6 receptor—with
favorable response. Case 2 was started on daily Anakinra immediately
following his diagnosis of SoJIA and has yet to relapse. In summary, all
cases have yet to experience an additional relapse following
introduction of Anakinra or Tocilizumab. Figure 1 provides the treatment
timelines for Cases 1-3 who had 5.37, 2.87, and 4.62 years of follow up,
respectively.
The diagnosis of HLH remains elusive and is often accompanied with
multiple systemic manifestations that overlap with other disorders.
Though traditional therapy for HLH includes intensive courses of
etoposide and corticosteroids, biologics represent a newer class of
medications highly effective in treating diseases with inflammatory or
immune-mediated components [2]. This case series reinforces that
immunomodulators, such as Anakinra, are promising treatment options in
pediatric patients with HLH secondary to SoJIA.