Granulocyte colony-stimulating factors and aortitis: A rare adverse event
Authors: Allison Lardieri, Lynda McCulley, Steven Christopher Jones, Daniel Woronow
Journal: American Journal of Hematology (2018)

Aortitis is a rare disorder involving inflammation of one or more layers of the aortic wall and is a risk factor for acute aortic syndromes, including aortic dissection and rupture.1 It presents with nonspecific symptoms such as abdominal pain, back pain, fever, malaise, and elevated inflammatory markers, which make diagnosis challenging. Aortitis can be classified as either infectious or noninfectious. Infectious causes are rarer than noninfectious, which include rheumatologic disorders such as giant cell arteritis and Takayasu arteritis.1 We report a case series of fulminant aortitis associated with the use of granulocyte colony-stimulating factor (G-CSF), a myeloid growth factor indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae. We searched the FDA adverse event reporting system (FAERS) and the medical literature through April 5, 2018 for post-marketing cases of aortitis in patients treated with G-CSFs. In addition to filgrastim and pegfilgrastim, the biologic tbo-filgrastim and the biosimilar filgrastim-sndz were included in this search, as well as lipegfilgrastim and lenograstim, two chemically distinct G-CSFs that are only available outside of the US. Cases were included if there was a temporal exposure to a G-CSF and a diagnosis of aortitis was reported by a health care professional. Cases were excluded if the adverse event was not aortitis, aortitis was attributed to an alternate etiology, or insufficient information was provided. We identified 15 FAERS cases of G-CSF associated aortitis that met our case definition, four of which were also published in the literature. Nine cases were associated with the long acting pegfilgrastim, four with filgrastim, and one with lenograstim. Twelve cases occurred in women and the mean patient age was 62 years old. Table 1 summarizes the cases. France 20044 Filgrastim/5 d Stem cell donor WBC 41.1 CRP 30 Germany 2013 Pegfilgrastim/1 d Neutropenia Japan 2016 Filgrastim/1 d Neutropenia Israel 20166 Filgrastim/4 d Stem cell donor WBC 10.3 CRP "positive" United States 20162 Filgrastim/8 d Neutropenia WBC 11.4 CRP 68.2 Japan 2016 Pegfilgrastim/1 d Neutropenia WBC 11.7 CRP 30.1 Japan 2016 Pegfilgrastim/1 d Neutropenia WBC 21.8 CRP 35.9 Japan 2016 Filgrastim/6 d Neutropenia WBC 8.7 CRP 25.4 Japan 2017 Lenograstim/ "several times" Neutropenia Not reported Japan 2017 Pegfilgrastim/1 d Neutropenia WBC 18.3 CRP 25.4 Japan 2017 Pegfilgrastim/1 d Neutropenia Japan 2017 Pegfilgrastim/1 d Neutropenia WBC 60.4 CRP 30.8 Japan 2017 Pegfilgrastim/1 d Neutropenia WBC 18.6 CRP 33.3 Japan 20173 67/F Pegfilgrastim/1 d Neutropenia WBC 22.3 CRP 20.2 Japan 2017 Pegfilgrastim/1 d Neutropenia Aortitis presented rapidly (6-15 days) after G-CSF administration in 14 cases, in contrast to nondrug associated aortitis, where onset tends to be subacute and can range from months to years. Fourteen cases reported nonspecific findings such as fever, epigastric pain, or malaise; and these cases were subsequently found to have elevated inflammatory markers (eg, C-reactive protein [CRP], white blood cell count [WBC]). Diagnosis is based on clinical presentation and cross-sectional aortic imaging; most commonly computed tomography (CT) or magnetic resonance imaging (MRI). On cross-sectional imaging, inflammation within the aortic wall manifests as concentric wall thickening. Fourteen cases were confirmed by diagnostic imaging (CT with or without MRI) and most had supporting laboratory values such as elevated CRP (n = 9) or WBC (n = 13). Case reports by Adiga et al, and Sato et al, describe cases with baseline imaging where the aorta was normal compared to imaging conducted after G-CSF administration.2, 3 G-CSF therapy was discontinued in all cases, and aortitis resolved within 11 days to 15 months. Resolution was achieved in six cases after anti-inflammatory treatment (eg, steroids, nonsteroidal anti-inflammatory drugs). One case (Sato et al.) noted a dissection of the descending aorta (Stanford Type B dissection), which was successfully managed medically.3 One case of pegfilgrastim-associated aortitis described a positive rechallenge where suspected aortitis and fever occurred when pegfilgrastim was readministered. Thirteen cases excluded infectious etiologies and 11 cases reported administering an antibiotic before or during the diagnosis of aortitis, all of which were nonresponders. In all cases, aortitis was unlikely attributed to underlying disease or other drugs. Two cases received G-CSF as a stem cell donor, one of which was an otherwise healthy 55-year old female who developed aortitis 6 days after her initial dose of filgrastim.4 All patients with an underlying cancer diagnosis (n = 13) received chemotherapy concomitantly with the G-CSF product. Cases received a variety of chemotherapeutic agents, (bevacizumab, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, pertuzumab, rituximab, trastuzumab, and vincristine) none of which have been associated with aortitis. None of the cases had a history of aortic disease. To our knowledge, this is the largest case series supporting a causal association between aortitis and G-CSF use. G-CSFs are relatively safe, however vasculitides such as cutaneous vasculitis and Sweet's syndrome have been reported in patients treated with G-CSFs.5 Manifestations of vasculitis generally developed simultaneously with an increase in absolute neutrophil count (ANC) and abated with ANC decrease. Potential mechanisms for G-CSF induced aortitis include upregulation of neutrophil function, secondary release of cytokines, and damage from toxic metabolites released by neutrophils.6 G-CSF administration may induce activation of interleukin with subsequent pathologic Th17 cell generation.6 The case published by Sato et al, reported a serum cytokine analysis where interleukin 6 (IL-6) levels were increased when the patient developed aortitis and subsequently decreased when aortitis resolved.3 Additionally, the relative short onset latency in 14 cases, observed improvement in all cases upon G-CSF cessation, and one potential case of positive rechallenge, are supportive of a causal association. Aortitis is a serious condition which can lead to aortic dissection. Because the signs and symptoms of aortitis are nonspecific and the potential outcome very serious, it is important that providers be aware that aortitis has been reported in patients receiving G-CSF. The sponsor recently updated the warnings and precautions section of filgrastim and pegfilgrastim prescribing information to include aortitis. It may occur as early as the first week after start of therapy and manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (eg, CRP and WBC). Consider aortitis in patients who develop these signs and symptoms without known etiology and discontinue G-CSF if aortitis is suspected.7