large-vessel vasculitis induced by pegfilgrastim

THE OffICIAL JOURNAL Of THE PORTUGUESE SOCIETy Of RHEUMATOLOGy

355

CASE BASED REVIEWS

1. Serviço de Medicina I, Clínica Universitária de Medicina I,Hospital de Santa Maria, Centro Hospitalar Universitário LisboaNorte; 2. Serviço de Reumatologia e Doenças Ósseas Metabólicas,Hospital de Santa Maria, Centro Hospitalar Universitário LisboaNorte; 3. Serviço de Imagiologia Geral, Hospital de Santa Maria, CentroHospitalar Universitário Lisboa Norte; 4. Serviço de Oncologia, Hospital de Santa Maria, Centro HospitalarUniversitário Lisboa Norte;

Keywords: Granulocyte-colony stimulating factor;Pegfilgrastim; Large-vessel vasculitis.

IntroductIon

Recombinant human granulocyte-colony stimulatingfactors (G-CSF), which include filgrastim and PEGy-lated filgrastim, induce long-acting neutrophil prolif-eration and maturation. G-CSF have been increasinglyestablished as a primary or secondary prophylaxis to re-duce the severity and duration of neutropenia in pa-tients receiving myelosuppressive cytotoxic chemother-apy who are at risk of chemotherapy-inducedneutropenic fever and potentially fatal infectious com-plications1.

G-CSF decreases all-cause mortality and increasesthe possibility of maintaining chemotherapy dose, in-tensity and density, an absolute prerequisite in curablemalignancies2. Dose-dense chemotherapy is a treatmentrequiring G-CSF that aims to achieve higher rates ofcancer cell death. It has been adopted as an adjuvanttherapy in high-risk breast cancer cases with the goalof improving outcomes3. The dose-dense doxorubicinand cyclophosphamide (ddAC) for patients with HER-2-negative breast cancer is an example of suchcases and is recommended by the National Compre-hensive Cancer Network guidelines in the United Statesof America (USA)4.

G-CSF acts on the granulocyte lineage, stimulatingneutrophil recruitment from the bone marrow to theperipheral blood, thereby promoting differentiationand maturation of these cells. The most commonly de-scribed side effects are relatively mild and include fever,bone pain, headache and fatigue5. Large-vessel vas-culitis (LVV) is a very rare adverse event in patientstreated with G-CSF, and the risk factors or relation be-tween arteritis and G-CSF remain unknown. In theUSA, G-CSF-associated aortitis has been confirmedonly in 15 cases as reported by the Adverse Event Re-

Large-vessel vasculitis induced by pegfilgrastim

AbstrAct

Granulocyte colony-stimulating factor (G-CSF) is in-creasingly being used to prevent febrile neutropenia as-sociated with chemotherapy. Large-vessel vasculitis(LVV) has been recognized as a rare side effect of G-CSF treatment. We report a case of G-CSF associatedLVV in a patient with breast cancer. While clearpathogenic mechanisms remain unknown, G-CSF maycause vasculitis due to inflammatory cytokines pro-duction. This adverse reaction should be recognized inpatients with suggestive symptoms following the ad-ministration of pegfilgrastim.

A 56-year-old woman with luminal B breast cancerwho had undergone surgery and adjuvant chemother-apy, initially with paclitaxel, was started on a doxoru-bicin plus cyclophosphamide protocol, followed bysupportive use of long-acting G-CSF pegfilgrastim. Fol-lowing the administration of pegfilgrastim, the patientdeveloped intermittent fever and was given empiric an-tibiotics in the outpatient setting with no improvement.There were no signs of cancer progression, and the con-trast-enhanced CT scan highlighted wall thickening ofthe aortic arch and the proximal segment of the sub-clavian artery, which was not present in previous imag-ing studies. The patient was diagnosed with LVV, and adifferential diagnosis was performed to rule out para-neoplastic setting, immune-mediated diseases, infec-tion or other drug-induced vasculitis. Treatment withsteroids was initiated and tapered with significant im-provement and resolution of the radiological signs ofaortitis.

ACTA REUMATOL PORT. 2021;46:355-359

Costa Silva R1, Monteiro M2, Dias RP3, Silva I1, Rodrigues dos Santos J1, Vassalo T1, Rosa Martins J1, Leite I3, Abreu C4, Martins-Martinho J2, Ponte C2, Carlos Romeu J2, Peixoto L1


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Large-vesseL vascuLitis induced by pegfiLgrastim

porting System (AERS) of the Food and Drug Admin-istration (FDA)6. The Japanese Adverse Drug Eventdatabase reported a 0.47% frequency of aortitis in pa-tients treated with G-CSF (16 out of 3409)7. To ourknowledge, there are no published case reports of peg-filgrastim-associated aortitis in Portugal.

Herein, we report a case of G-CSF-induced aortitisin a patient treated for breast cancer. Although the dif-ferential diagnosis of aortitis may be challenging, thepresent case highlights how finding aortitis duringchemotherapy treatment should warrant the recogni-tion of pegfilgrastim as a possible source of inflamma-tion.

cAse report

The authors present a case of a 56-year-old female pa-tient with HER-2 negative luminal B breast cancer whounderwent lumpectomy and was receiving adjuvantchemotherapy following a multigene EndoPredict®assessment suggesting high risk of recurrence. Cancerstaging had shown no signs of invasive or metastaticdisease (pT1cN0M0) with a negative sentinel nodebiopsy and a normal computerized tomography (CT)scan.

The patient was treated according to the Oncology’schemotherapy protocol, initially with 12 cycles of pa-clitaxel during three months during which there wereno complications, followed by AC dose-dense schemewhich included doxorubicin, cyclophosphamide andsupportive use of long-acting G-CSF pegfilgrastim.Following the introduction of AC dose-dense scheme,specifically five days after doxorubicin plus cy-clophosphamide and three days after pegfilgrastim ad-ministration, she developed fever (38.7ºC) and wasgiven empiric antibiotics in the outpatient setting. Af-ter five days, given the persistence of fever, she was re-evaluated. A more comprehensive anamnesis showedthat in addition to fever, she presented malaise,lipothymia, and left cervical and pleuritic dorsal painwith left arm paraesthesia and claudication. The pa-tient was hemodynamically stable, blood pressuremeasurements performed in both arms and showedno significant difference (left arm 104/64 mmHg andright arm 106/65 mmHg), there was no pulse asym-metry and her physical exam was unremarkable, withno signs of infection. Laboratory tests showed signifi-cant elevation of inflammation markers, namely ery-throcyte sedimentation rate (103 mm/h) and C-reac-

tive protein (22.9 mg/dL), without any other abnor-malities such as elevation of tumour makers (CEA andCA 15-3) compared to the patient’s previous evalua-tion. For a more detailed evaluation, a contrast-en-hanced CT scan was performed and highlighted wallthickening of the aortic arch and the proximal segmentof the left subclavian artery, suggesting a localized vas-culitis process (Figure 1). No other abnormalities wereidentified, ruling out lesions in other vascular territo-ries, thromboembolism, signs of tumour recurrence,abnormal lymph nodes or abscesses.

The patient was diagnosed with LVV and was givenglucocorticoids, initially with methylprednisolonepulses 1g/day for three days, followed by oral pred-nisolone 60mg/day.

Further investigation with Doppler ultrasoundshowed no relevant abnormalities of the temporal, fa-cial and axillary arteries. Primary LVV was consideredunlikely, considering the patient’s age and lack of pre-vious symptoms suggestive of giant cell arteritis (GCA),such as headache or visual disturbances, or symptomsof polymyalgia rheumatica. A differential diagnosiswith secondary aortitis was performed. Complemen-tary exams including anti-nuclear antibodies (ANA)panel, rheumatoid factor, anti-CCP, anti-MPO andanti-PR3 autoantibodies were negative and comple-ment levels were normal. Furthermore, the patient hadno manifestations of other immune-mediated diseases,specifi cally systemic lupus erythematosus, rheumatoidarthritis, spondyloarthropathies, Behçet’s disease,IgG4- -related disease or sarcoidosis. No microorgan-isms such as bacteria or fungi were identified in bloodcultures; transthoracic echocardiogram had no vege-tations; a negative Interferon Gamma Release Assay(IGRA) excluded tuberculosis; and serologies forSalmonella, Syphilis, Brucella, varicella zoster virus, he -patitis B and C virus were negative for active infection.

A significant improvement was observed with res-olution of symptoms and reduction of inflammatorymarkers (erythrocyte sedimentation rate 61 mm/h andC-reactive protein 4.8 mg/dL) after five days of gluco-corticoids which were then tapered. Considering theacute onset of symptoms following the pegfilgrastimadministration, absence of vasculitis signs in CT scansprior to this drug and the rapid response to glucocor-ticoids, a diagnosis of pegfilgrastim-induced LVV wasmade. After hospital discharge, the patient was evalua -ted by the assistant Oncologists and the chemothera-py regimen was adjusted excluding pegfilgrastim. CTscan re-evaluation after four weeks showed complete

FIgure 1. Contrast-enhanced computed tomography (A – axial, B – coronal, and C – sagittal reconstruction planes) shows wall thickening of the aortic arch (yellow arrows) and leftsubclavian artery (blue arrows) with perivascular fat stranding (yellow asterisk).


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resolution of the aortitis signs (Figure 2) and at the timeof this manuscript the patient remains without LVV re-currence.

dIscussIon

Previous reports of G-CSF-induced arteritis show thatpatients present with high-grade fever, increased C--reac tive protein levels and erythrocyte sedimentationrate, which represent non-specific markers of inflam-mation. When infections or immune-mediated diseases

are ruled out, imaging modalities like CT scan, mag-netic resonance imaging and positron emission to-mography play a major role in attaining a successfuldiagnosis and should be performed as early as possiblewhen aortitis is suspected. Although the precise mech-anism of G-CSF-induced aortitis remains uncertain, ithas been demonstrated that CSF-producing cell linesco-produce and activate pro-inflammatory cytokinessuch as interleukin-1 (IL-1), IL-6, IL-23, with subse-quent pathological activation of Th17 cells, antigen-specific CD4+ T cells and neutrophils, which may beinvolved in the development of vasculitis8,9.

The revised International Chapel Hill ConsensusConference nomenclature of vasculitis from 2012 is the


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most widely used system for describing vasculitis10. Theetiological diagnosis of aortitis is challenging andshould include primary LVV – Takayasu’s arteritis(TAK) and GCA – and secondary vasculitis associatedwith systemic disease. TAK occurs more frequently be-fore the age of 40 years and GCA often occurs after theage of 50 years. However, in this present case the pa-tient did not meet the 1990 American College ofRheumatology classification criteria for neither disease.

Secondary vasculitis may arise due to various caus-es, including infections, immune-mediated diseases,drug reaction and cancer. The diagnosis of drug-in-duced vasculitis requires the exclusion of all other po-tential causes of vasculitis and is frequently not easy toconfirm. In our case, infection was ruled out, no symp-toms or autoantibodies that would indicate an im-mune-mediated disease were present and there wereno signs of active cancer. Paraneoplastic vasculitis(PNV) represents 2%–5% of all types of vasculitis andoccurs in approximately 1 in 80800 solid tumours11.

The most common site for PNV is the skin, and almosthalf of all cases appear as a leukocytoclastic vasculitisand are often accompanied with progression of cancer,neither of which were present in this case, making it anunplausible cause for LVV12. LVV was unlikely at-tributed to other drugs, namely doxorubicin and cy-clophosphamide which were administered at the timeof pegfilgrastim, since none of those have been linkedwith aortitis6.

As the appropriate treatment for pegfilgrastim-in-duced LVV, G-CSF discontinuation can lead to recov-ery and, notably, glucocorticoid administration hasbeen reported to be effective13. In our patient, given theextension of LVV with risk of progression to aorticaneurysm formation and potentially fatal dissection orrupture, glucocorticoids were promptly started havingruled out infectious. The patient also had lipothymia,which could represent a symptom of subclavian stealsyndrome from the subclavian artery involvementproximal to the vertebral artery origin. There was analtered vascular haemodynamic phenomenon that re-sulted in retrograde blood flow in the ipsilateral verte-bral artery toward the upper arm, distal to the subcla-vian artery narrowing, where decreased blood pressurehad been established.

Having ruled out other causes for secondary LVV,considering the onset of symptoms following the peg-filgrastim administration, rapid clinical and radiologi-cal improvement after glucocorticoid initiation and thefact that vasculitis did not recur after G-CSF therapywas stopped, strongly imply that in our case LVV wascaused by pegfilgrastim. Accordingly, the chemother-apy scheme was adjusted with suspension of pegfil-grastim, as re-administration of G-CSF entails a risk ofvasculitis recurrence14.

One of the possible mechanisms by which exoge-nous administration of G-CSF may induce LVV in-cludes stimulation of the proliferation and differentia-tion of neutrophil precursors and enhancement ofneutrophil chemotaxis15. G-CSF may have a primingeffect in human neutrophils. Interestingly, viable hu-man neutrophils after priming with granulocyte/macrophage colony-stimulating factor (GM-CSF) andsubsequent stimulation of toll-like receptor 4 (TLR4)or complement component 5a (C5a) receptor were ableto generate neutrophil extracellular traps (NETs)16. C5avia interaction with its cellular receptor on neutrophilsurface leads to changes in the neutrophil cell shapeand membrane formability that allows the neutrophilnot only to transform into a migratory cell and invade

FIgure 2. Contrast-enhanced computed tomography showingcomplete resolution of the aortitis signs.(A – axial and B – coronal reconstruction planes).


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inflammatory sites but also clear pathogens and de-bris17. Mavrilimumab is a fully humanized monoclon-al antibody targeting GM-CSF receptor alpha (GM-CS-FR�) currently ongoing clinical trials as treatment ingiant cell arteritis and could have a potential use in druginduced LVV in the future.

In summary, we report a case of arteritis associatedwith G-CSF, which may be potentially under-recog-nized due to its rarity. However, it is crucial to correct-ly identify the presence of aortitis, given its risk of pro-gression to an acute aortic syndrome which can belife-threatening. Clinicians should be increasinglyaware of this serious adverse effect for which gluco-corticoid administration is effective.

correspondence to

Ryan Costa SilvaRua Professor Eduardo Araújo Coelho, N°5, 1° EsquerdoE-mail: [email protected]

reFerences

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8. Sugai Y, Toyoguchi Y, Kanoto M, Kirii K, Hiraka T, Konno Y, etal. Clinical and image features: large-vessel vasculitis after gran-ulocyte colony stimulating factor administration. Acta Radiol.2020: 284185120931685

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10. Jennette JC, Falk RJ, Bacon PA et-al. 2012 revised Internation-al Chapel Hill Consensus Conference Nomenclature of Vas-culitides. Arthritis Rheum. 2013;65 (1): 1-11

11. Park HJ, Ranganathan P, Neoplastic and paraneoplastic vas-culitis, vasculopathy and hypercoagulability. Rheum Dis ClinN Am.2011; 37:593–606

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14. Nakamura J, Nishi TM, Yamashita S, Nakamura H, Sato K, OdaY, et al. Pegfilgrastim-associated large-vessel vasculitis devel-oped during adjuvant chemotherapy for breast cancer: A casereport and review of the literature. J Oncol Pharm Pract.2020:1078155220910800

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large-vessel vasculitis induced by pegfilgrastim

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