Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients

Sir, Macrophage activation syndrome (MAS) belongs to the haemophagocytic lymphohistiocytic (HLH) disorders, and is one of the most feared complications of paediatric inflammatory diseases with mortality rates up to 53% [1]. Its early recognition and treatment are critical in improving outcome [2]. However, current therapeutics, including corticosteroids, ciclosporin and intravenous immunoglobulin (IVIG), do not work for all children, and the next-line treatments, such as etoposide, are associated with sepsis, a risk of secondary malignancy and up to 44% mortality rate [3]. A less immunosuppressive but effective targeted therapy is in demand. Anakinra, an IL-1 receptor antagonist, has been highly effective in treating systemic juvenile idiopathic arthritis (sJIA) [4], and MAS may occur in up to half of sJIA patients [5]. Recently, three case reports have demonstrated anakinra to effectively treat MAS as part of panniculitis, sJIA and adult onset Still’s disease [6–8]. Herein, we report the benefit of anakinra in 12 children with paediatric rheumatic disease-related MAS (prMAS). All patients at the Alberta Children’s Hospital and the Children’s Hospital of Philadelphia, who received anakinra between 2006 and 2009 for prMAS were studied retrospectively. The diagnosis of MAS was based on the combination of: (i) Ravelli’s preliminary criteria for sJIA-associated MAS [9] and (ii) HLH-2004 criteria for inherited HLH [10]. Resolution of MAS was defined by the HLH-2004 criteria [10], and included no fever, splenomegaly, cytopenia (haemoglobin ≥90 g/l, platelets ≥100 × 109/l, absolute neutrophil count ≥500 cells/µl) or hypertriglyceridaemia (>500 mg/l) and normalization of soluble CD25 (sCD25) if the test was performed. When prMAS occurred, all patients initially received corticosteroids (n = 12) and other immunosuppressants [IVIG (n = 9), ciclosporin (n = 10), etoposide (n = 2, one dose each) and etanercept (n = 1)] with limited benefit. Anakinra was given for better prMAS control. Etanercept and etoposide were discontinued when anakinra was initiated. In all other patients, anakinra was added to pre-existing MAS therapy at 2 mg/kg/day s.c. (maximum dose 100 mg/day) once daily. Laboratory measurements as per Ravelli’s and HLH-2004 criteria were measured before and after anakinra administration. CRP was additionally measured in selected patients. During hospitalization for prMAS, five patients were diagnosed with new-onset sJIA by the ILAR criteria, three patients with vasculitis using ACR criteria and one patient with acute rheumatic fever. Institutional Review Board approval was obtained from both institutions before the study for publication of the results of the case series. In total, 12 patients with prMAS were treated with anakinra between 2006 and 2009. Baseline characteristics are shown in Table 1. Before anakinra, five patients required intensive care, and potential infectious triggers were present in seven patients. All patients met diagnostic criteria for Ravelli’s sJIA-associated MAS [9]. Seven of 12 met the HLH-2004 criteria [10], including elevated ferritin (n = 12/12), haemophagocytosis in the bone marrow (n = 5/7), abnormal NK cell activity (n = 1/2) and elevated sCD25 (n = 4/6). The median hospitalization stay before anakinra was 11 (range 1–27) days. All patients achieved MAS remission after addition of anakinra within a median of 13 (range 2–19) days. Corticosteroids were discontinued by 6 weeks in seven patients. Of all laboratory parameters, CRP and ferritin correlated the best with MAS activity (Table 1). Median (interquartile range) CRP (n = 9/12) 2 days before the use of anakinra was 125 (95.5–183.5) mg/l compared with median 6.8 (1.9–8.9) mg/l 5 days after the use of anakinra (P = 0.0039). Patients were followed for a median of 22 (range 2–40) months, and all were in remission of MAS at the final follow-up with excellent control of the underlying rheumatic disease. There were no noted side effects from anakinra administration. Baseline patient characteristics, selected laboratory results pre- and post-anakinra and eventual outcome aFerritin (normal range 10–110) is expressed as μg/l and CRP (normal range 0–8) is expressed as mg/l. Time ‘0’ refers to initiation of anakinra. Known rheumatic diagnoses before development of MAS: sJIA in Patients 3, 4, and 9. Potential infectious triggers: positive anti-streptolysin A-titre in Patients 1, 3, 6, 7 and 9. Patient 1 met the criteria for ARF and also had positive PCR for EBV. Patient 10 had positive monospot. Patient 5 developed Escherichia coli septicaemia at the time of MAS after having been hospitalized with pulmonary haemorrhage and acute renal failure requiring dialysis. bPatients who met <5 out of 8 HLH-2004 criteria. Three patients (Patients 3, 4 and 7) did not have a bone marrow biopsy, and NK function assessment was not available for these same patients. sCD25 was not measured in three patients (Patients 3, 11 and 12). cBoth these patients with known sJIA were on etanercept when they developed MAS. Etanercept was discontinued as soon as MAS was diagnosed. dThis patient was initially suspected of Kawasaki disease, and was treated with IVIG and aspirin before diagnosis of MAS and sJIA. eThis patient had received etanercept for MAS after incomplete response to IVIG, Csp and CS, with no improvement. fDetailed data for corticosteroid taper were not available for these two patients. ICU: intensive care unit; ARF: acute rheumatic fever; KD: Kawasaki disease; ND: not done; NA: not available; Mpred: methylprednisolone; Csp: ciclosporin; Eto: etoposide; CS: corticosteroids. Baseline patient characteristics, selected laboratory results pre- and post-anakinra and eventual outcome aFerritin (normal range 10–110) is expressed as μg/l and CRP (normal range 0–8) is expressed as mg/l. Time ‘0’ refers to initiation of anakinra. Known rheumatic diagnoses before development of MAS: sJIA in Patients 3, 4, and 9. Potential infectious triggers: positive anti-streptolysin A-titre in Patients 1, 3, 6, 7 and 9. Patient 1 met the criteria for ARF and also had positive PCR for EBV. Patient 10 had positive monospot. Patient 5 developed Escherichia coli septicaemia at the time of MAS after having been hospitalized with pulmonary haemorrhage and acute renal failure requiring dialysis. bPatients who met <5 out of 8 HLH-2004 criteria. Three patients (Patients 3, 4 and 7) did not have a bone marrow biopsy, and NK function assessment was not available for these same patients. sCD25 was not measured in three patients (Patients 3, 11 and 12). cBoth these patients with known sJIA were on etanercept when they developed MAS. Etanercept was discontinued as soon as MAS was diagnosed. dThis patient was initially suspected of Kawasaki disease, and was treated with IVIG and aspirin before diagnosis of MAS and sJIA. eThis patient had received etanercept for MAS after incomplete response to IVIG, Csp and CS, with no improvement. fDetailed data for corticosteroid taper were not available for these two patients. ICU: intensive care unit; ARF: acute rheumatic fever; KD: Kawasaki disease; ND: not done; NA: not available; Mpred: methylprednisolone; Csp: ciclosporin; Eto: etoposide; CS: corticosteroids. We report resolution of severe prMAS following addition of anakinra to conventional immunosuppressive therapy. In these severely ill patients, anakinra was chosen over HLH-2004 treatment with etoposide and high-dose dexamethasone because of concern for sepsis, potential future malignancy and the high mortality rate associated with this protocol [3]. The clinical response was dramatic and rapid, occurring within days. All patients fully recovered, including five who had required intensive care support. In sJIA-related MAS, the mortality rate was reported in 2001 as 28% [2], yet all our patients with sJIA did well. Our three patients with vasculitis and one with rheumatic fever-associated MAS also remitted. Ravelli’s 2005 preliminary MAS criteria [9] allowed for early confirmation of MAS, although we also utilized ferritin, sCD25 and NK cell activity from the HLH-2004 criteria to confirm the diagnosis [10]. We attribute the excellent outcome in our patients to early diagnosis and immediate therapeutic intervention, including early use of anakinra. As all patients were treated with anakinra and traditional therapies, it is possible that the combination of medications contributed to the resolution of MAS. We therefore recommend anakinra in combination with high-dose corticosteroids, ciclosporin and IVIG, rather than as a sole agent. Further studies with larger patient numbers are required to better define the promising role of anakinra in the management of prMAS. Funding: P.M.M.’s work was partially supported by the University of Calgary Starter Grant. Disclosure statement: The authors have declared no conflicts of interest.

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