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Abstract
Macrophage activation syndrome (MAS) is a frequent complication of adult-onset Still’s disease (AOSD) and is characterised by organ dysfunction, cytopenia and coagulopathy. There are few data regarding the use of granulocyte colony-stimulating factor (G-CSF) as a treatment for neutropenia in MAS due to AOSD. This case describes a previously healthy mid-20s patient who was diagnosed with AOSD and subsequently MAS. Although his clinical symptoms and ferritin levels responded well to steroids, interleukin-1 inhibition and Janus kinase inhibition, he developed prolonged and profound neutropenia for which he received one dose of G-CSF. His MAS flared markedly, requiring intensive immunosuppression and significantly prolonging his hospital stay. This report illustrates that G-CSF carries the risk of worsening inflammation leading to MAS, particularly in auto-inflammatory conditions such as AOSD.
- Autoimmunity
- Immunology
- Rheumatology
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Background
Adult-onset Still’s disease (AOSD) is a rare auto-inflammatory condition that classically presents with quotidian fevers, evanescent truncal-predominant cutaneous eruptions and inflammatory arthritis or arthralgia. Macrophage activation syndrome (MAS) is a form of secondary haemophagocytic lymphohistiocytosis (HLH) that occurs in the setting of rheumatic disease and occurs in 5%–19.5% of patients with AOSD.1 2 A retrospective, single-centre study of 118 patients found that neutropenia (neutrophil count <1.0 × 109) occurred in 17.8% of patients with MAS.3 Despite this frequency, there is a paucity of literature specifically addressing the management of neutropenia due to MAS.
We report the first case that describes an exacerbation of MAS due to granulocyte colony-stimulating factor (G-CSF) in a patient being treated for active MAS secondary to AOSD. Though the exact relationship between exogenous G-CSF administration and the initiation or worsening of an autoinflammatory state remains unknown, there is significant evidence that G-CSF does play a pro-inflammatory role in autoimmune arthritis and vasculitis, and potentially in the pathogenesis of AOSD itself.4 5 This report reinforces the need to thoroughly weigh the risks and benefits before proceeding with G-CSF treatment in a persistently neutropenic AOSD patient with or without MAS.
Case presentation
A previously healthy man in his mid-20s without any significant past medical history presented to the emergency department with a 3-month history of daily subjective fevers, night sweats, 25-pound weight loss, rash and sore throat. Despite the duration and severity of symptoms, his presentation had been delayed by insurance and immigration status. He denied any recent travel or sick contacts. A review of systems was unrevealing.
The initial examination was pertinent for sinus tachycardia with a heart rate of 120 beats per minute and a temperature of 100°F. On physical examination, he had a right knee joint effusion and a rash on the upper trunk.
Investigations
Initial blood work was significant for neutrophilic leukocytosis, mildly elevated liver function tests and elevated ferritin (table 1). Infectious workups for hepatitis A, hepatitis B, hepatitis C and cytomegalovirus were negative. Epstein–Barr virus IgG was positive, but IgM was not elevated, inconsistent with acute infection. F-actin antibody, antimitochondrial antibody, rheumatoid factor and antinuclear antibody titre were negative as well. Synovial fluid analysis of the right knee revealed a white blood cell count of 10.05 × 109/L with 97% neutrophils. Blood culture and synovial culture were negative. CT of chest/abdomen/pelvis showed diffuse hepatomegaly. At this point, the patient met both major and minor diagnostic criteria for adult-onset Still’s disease using both Yamaguchi and Fautrel criteria.6 7 Adult-onset Still’s, however, remains a diagnosis of exclusion, so further tissue biopsy was pursued to rule out malignancy or other connective tissue diseases.
Trend of white blood count (WBC), absolute neutrophil count (ANC) and macrophage activation syndrome (MAS) labs from hospital days 1–45. HScore is a diagnostic calculator to determine the risk of having haemophagocytic lymphohistiocytosis/macrophage activation syndrome
A liver biopsy was performed on Day 9, demonstrating Kupffer cell hyperplasia with the presence of erythrophagocytosis (figure 1), definitively confirming a diagnosis of AOSD with superimposed MAS.
Iron staining of liver biopsy specimen demonstrating erythrophagocytosis by liver macrophages.
Treatment
The patient was started on prednisone 40 mg daily on day 4 for AOSD. He was eventually started on interleukin-1 inhibition with continuous intravenous anakinra 300 mg/day on day 10 for MAS due to worsening clinical and laboratory parameters. Despite the escalation of therapy, MAS laboratory values worsened. From day 23 to 27, he was treated with ruxolitinib 15 mg twice daily and eventually one dose of emapalumab 2 mg/kg with improvement in clinical status and serological markers for MAS. The rationale for this treatment regimen was based on literature review and personal experience of successfully treating MAS. T cell overproduction of interferon-γ and activation of the JAK-STAT pathway have been shown to be the final common pathway in the pathogenesis of HLH/MAS.8 Ruxolitinib, thus, targets STAT1 phosphorylation and has been shown not only to be effective at controlling relapsed MAS but also to have better efficacy than single cytokine targets such as anti-IL-6 tocilizumab.8 9
On day 27, neutropenia (absolute neutrophil count (ANC) of 0.9 × 109/L (normal: 1.7–7.0 × 109/L)) was noted. Bone marrow biopsy on day 29 showed no evidence of haematological malignancy and reconfirmed the diagnosis of macrophage activation syndrome with significant haemophagocytosis (figure 2). Over the next week, ferritin levels decreased from the peak of 263 978.30 ng/dL on day 27 to a nadir of 8936 ng/dL on day 37. Anakinra was decreased to 300 mg/day by day 38. Ruxolitinib was decreased to once-daily dosing on day 36. Neutropenia, however, persisted with an ANC of 0.0 × 109/ L. At this point, the patient had been neutropenic for 2 weeks. Despite his decreasing ferritin levels and otherwise improving clinical symptoms, this persistent neutropenia was felt to be due to the continued haemophagocytosis occurring in his bone marrow as a result of MAS.
Bone marrow biopsy specimen demonstrating the presence of red blood cells within the cytoplasm of polynucleated cells.
While otherwise close to hospital discharge, he could not be discharged because of concern for infection. One dose of G-CSF 300 mcg was administered on day 40. On day 41, the white blood cell (WBC) count had risen to 12.0 × 109/L and the ANC to 2.0 × 109/L. Despite this initial response, on day 42, the patient was febrile to 103.2 F with an increase in ferritin to 23 087 ng/dL. The WBC count eventually peaked at 54.1×109/L on day 44 and ferritin rose to 148 488.50 ng/dL on day 45. In response to rising ferritin and fevers, ruxolitinib and anakinra dosing were again increased. Eventually, a second dose of emapalumab 2 mg/kg needed to be administered on day 63.
Outcome and follow-up
The patient’s inflammatory markers and other laboratory parameters including liver function tests began to downtrend from day 67 onward. He was discharged on day 87 on a regimen of prednisone 60 mg daily, ruxolitinib 15 mg daily and once-monthly subcutaneous canakinumab 150 mg due to better patient affordability.
Discussion
We describe a case of significant exacerbation of AOSD-related MAS following a single dose of G-CSF. To the best of our knowledge, this is the first case of such an exacerbation to be reported in association with AOSD-related MAS.
While G-CSF is the standard of care for chemotherapy-induced or radiotherapy-induced neutropenia, there are few data regarding the use of G-CSF for neutropenia in MAS, which typically responds to anti-inflammatory therapy. There is only one case report of a patient with acute MAS in the setting of AOSD receiving G-CSF for neutropenia. Despite receiving 16 consecutive days of G-CSF for febrile neutropenia, this patient did not experience a flare of symptoms or significant alterations in lab values.10 On the other hand, three case reports have documented a new onset of MAS after single doses of G-CSF treatment for neutropenia due to SLE,11 mantle cell lymphoma12 and myelodysplastic syndrome.13 Two case reports have demonstrated worsening of pre-existing haemophagocytosis and haemophagocytic syndrome after a dose of G-CSF,14 15 though neither of these cases were related to AOSD. These limited and contradictory reports are the only available literature regarding the use of G-CSF in relation to MAS flares.
In oncologic cases, G-CSF is recommended for patients with high risk for infection-associated complications, prolonged (>10 days) or profound (<100 cells/µL) neutropenia, age >65, clinically documented infection, prior episode of febrile neutropenia or hospitalisation at the time of the development of fever.16 With these factors in mind, G-CSF was felt to be an appropriate and necessary therapy in this patient, whose neutropenia had persisted for weeks after relative quiescence of his MAS had been accomplished.
The exact mechanism by which G-CSF administration can initiate or worsen an auto-inflammatory state has yet to be definitively elucidated, but its use comes with calculated risks. It is known to reactivate inflammation in malignancy-associated haemophagocytic lymphohistiocytosis.17 It has been shown to positively correlate with CRP and ferritin5 and is thought to mobilise phenotypically immature and, therefore, possibly more dysfunctional granulocytes.10 It can potentiate leucocyte phagocytosis18 and lead to histiocytic bone marrow proliferation.19 There is also evidence that G-CSF plays a pro-inflammatory role in autoimmune arthritis, vasculitis and potentially AOSD itself,4 5 including as a biomarker of severe AOSD with the risk for MAS.18 In AOSD, serum G-CSF has been shown to positively correlate with CRP and ferritin.5 Additionally, AOSD patients who develop MAS have higher serum G-CSF levels than those who do not.20 In this case, G-CSF treatment resulted in the resolution of the patient’s neutropenia but appeared to have caused a flare of his MAS requiring a prolonged hospital stay and intensified treatment.
Despite the strong association in the literature between G-CSF administration and the triggering or reactivation of MAS, and the close temporal linkage between G-CSF administration and the worsening of disease in our patient, we recognise some possible limitations.
The use of anakinra in AOSD has been shown to rapidly and dramatically reduce serum ferritin levels.21 22 Perhaps, this caused an underestimation of disease activity prior to G-CSF administration. Our approach was based on clinical manifestations, as well as laboratory values (eg, absence of tachycardia, fever, rash and improvement in AST, triglycerides and fibrinogen) with an overall decrease in HScore from a height of 263 (>99% probability of HLH/MAS) to 145 (16%–25% probability of HLH/MAS) by the day of G-CSF administration. We felt that the decrease in ferritin prior to G-CSF administration represented improved control of inflammation rather than masking by anakinra.
The development of MAS has also been reported to be triggered by cytokine inhibitor therapy in some AOSD patients. In this case, however, MAS was diagnosed on liver biopsy the day prior to starting anakinra. Additionally, a recent meta-analysis has shown that AOSD patients treated with tocilizumab, an IL-6 inhibitor, have a higher incidence of MAS than those treated with anakinra.23
Finally, in the days before the marked exacerbation of MAS, the immunosuppressive regimen was decreased, raising the question as to whether his disease flare was not due to G-CSF administration alone. Given that his steroid dose had last been decreased on day 30, 12 days prior to the first evidence of a MAS flare on day 42, it seems unlikely that inadequate steroid dosing was the cause. Ruxolitinib dosing was halved on day 36, and anakinra dosing was steadily titrated down from day 30 to day 40. It is possible that these did contribute to the severity of the subsequent MAS flare. However, given the short duration of both therapeutic actions, a disease flare might have presented itself sooner than 12 days after the start of the anakinra taper and 6 days after the ruxolitinib decrease.
In summary, we report a case of G-CSF exacerbation of AOSD-associated MAS. It is possible that the increased myelopoiesis and the release of myeloid cells into the circulation, including immature and dysfunctional cells, with the concomitant increased phagocytic activity of those cells, exacerbated his underlying macrophage dysfunction. We are highlighting that G-CSF carries the risk of worsening auto-inflammatory conditions such as AOSD and MAS. The risks and benefits need to be carefully weighed before proceeding with G-CSF treatment in a persistently neutropenic AOSD patient with or without MAS.
Learning points
The development of persistent neutropenia in a patient with adult-onset Still’s disease (AOSD) should raise concern for new or worsening macrophage activation syndrome (MAS).
Neutropenia in a hospitalised patient who is receiving immunosuppressive agents could lead to the development of a severe, potentially life-threatening infection. Before using G-CSF to treat this neutropenia, it is imperative to determine the aetiology and consider other underlying conditions.
In the case of autoimmune conditions such as SLE or auto-inflammatory conditions such as haemophagocytic lymphohistiocytosis/MAS, G-CSF does not appear to be a benign option and might carry the risk of worsening inflammation.
In patients with AOSD, this risk may be even higher as G-CSF has been implicated in disease pathogenesis.
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References
Footnotes
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms and critical revision for important intellectual content: AP, CB and PP. EG approved the manuscript and acted as the guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.