Granulocyte colony-stimulating factor-induced aortitis with temporal arteritis and monoarthritis

Abstract

We present the case of a patient in his 80s receiving gemcitabine-cisplatin therapy for bladder cancer who developed neutropenia and was treated with filgrastim. In 10 days, the patient developed a mild fever with left jaw claudication and right knee arthritis. Contrast-enhanced CT findings indicated aortitis. Prednisolone was started for granulocyte colony-stimulating factor (G-CSF)-induced aortitis, and symptoms and elevated serum inflammatory markers resolved rapidly, allowing early discontinuation of prednisolone. Right knee arthritis relapsed at the initial follow-up. Contrast-enhanced CT revealed aortitis had disappeared. Therefore, recurrence of G-CSF-induced arthritis was suspected; prednisolone was resumed for 29 days without relapse. Most previous reports of G-CSF-induced aortitis have described inflammation of the aorta, carotid arteries and subclavian arteries; however, G-CSF-induced aortitis may present with more peripheral symptoms, such as temporal arteritis and knee arthritis. Furthermore, G-CSF-induced aortitis reportedly responds well and rapidly to prednisolone, although early discontinuation may lead to relapse.

Background

Recombinant human granulocyte colony-stimulating factors (G-CSF) are widely used to treat neutropenia induced by anticancer chemotherapy. Large-vessel vasculitides have previously been reported as rare adverse events of G-CSF treatment.^1–3 Most previous reports have described inflammation of the aorta, carotid arteries and subclavian arteries,^{2 4} but to our knowledge, only one case of G-CSF-induced aortitis with temporal arteritis has been reported; there are no reported cases of G-CSF-induced aortitis with arthritis. Here, we report a case of G-CSF-induced aortitis with left temporal arteritis and right knee arthritis.

Case presentation

A male patient in his 80s was referred to our outpatient clinic for suspected aortitis. The patient had been undergoing a third course of gemcitabine-cisplatin therapy for bladder cancer with multiple lymph node metastases at the urology department of our hospital for thirty days preceding admission. Sixteen days before admission, he was diagnosed with neutropenia with pancytopenia (absolute neutrophil count; ANC 479/µL) and had been treated with four subcutaneous injections of 75 µg of biosimilar products of filgrastim 16, 15, 14 and 11 days before admission according to the Japanese guideline.⁵ After the fourth injection, the patient’s ANC was 982/µL. The patient had a persistent mild fever (37.0℃–37.5℃) for the 7 days before admission, and right knee pain and loss of appetite appeared 5 days before admission. Two days before admission, the patient saw his urologist for follow-up of neutropenia. The urologist investigated the patient’s fever. A laboratory test 2 days before admission revealed a high C reactive protein (CRP) level of 24 mg/dL. Contrast-enhanced CT scan revealed increased adipose tissue density around the aortic arch and the proximal region of the left subclavian artery (figure 1A). On the admission day, the urologist referred the patient to our clinic for suspected aortitis. The patient could normally walk unassisted, but on his initial visit on the admission day, he used his spouse’s walker due to knee pain. In addition to bladder cancer, his medical history included dyslipidaemia and hypertension, and he was taking atorvastatin, telmisartan and amlodipine. The patient had no known history of autoimmune/rheumatological disorder. He was alert, and his body temperature was 37.0°C, blood pressure 113/50 mm Hg, pulse rate 89 beats/min and respiratory rate 14/min. Physical examination revealed left scalp pain and left jaw claudication but no obvious temporal artery thickening on palpation and vision loss. The patient did not have morning stiffness or shoulder pain, and the painful arc test, Neer test and Hawkins test were bilaterally negative. No tenderness was observed in the large or small joints of the upper extremity. Swelling, warmth and tenderness in the right knee joint were noted. The rest of the physical examination was normal.

Figure 1.

(A) Contrast-enhanced thoracic CT (delayed phase) on the day of admission revealed increased adipose tissue density around the aorta (arrow), suggesting inflammation in this region. (B) Contrast-enhanced thoracic CT (arterial phase) 19 days after admission, after the inflammatory response had recurred, revealed that the periaortic adipose tissue density elevation had disappeared, and the findings were not suggestive of aortitis.

Investigations

Laboratory test on the admission day revealed markedly elevated CRP of 22.51 mg/dL (reference range: 0.00–0.14 mg/dL) and erythrocyte sedimentation rate of >110 mm/hour (reference range: 2–10 mm/hour). Head and neck vascular ultrasound (on the admission day) showed no obvious arterial wall thickening in either of the temporal arteries. Contrast-enhanced MRI on the admission day revealed mild contrast effects on the walls of the aortic arch, the proximal region of both common carotid arteries and the proximal region of the brachiocephalic artery, but no significant wall thickening was observed. Although contrast effects were noted in more distal and smaller vessel walls and lumens near vessel walls, circumferential wall thickening was not evident. MR angiography allowed good visualisation of the external carotid arteries and temporal arteries. Fluorodeoxyglucose positron emission tomography/CT was not performed. Left temporal artery biopsy (TAB) 3 days after admission revealed destruction of elastic fibres and fibrosis in the arterial wall. No findings strongly suggestive of vasculitis, such as inflammatory cell infiltration, fibrin deposition or granuloma formation, were observed. Funduscopic examination revealed no obvious findings of ischaemic optic neuropathy, retinal ischaemia or vascular occlusion. Although the patient had decreased visual acuity in the left eye, this was attributed to cataracts or glaucoma. Two sets of blood cultures taken on the admission day were negative. Right knee arthrocentesis was not performed during hospitalisation. His serum IgG4 level was high at 436 mg/dL (reference range: 11–121 mg/dL), but serological markers for syphilis and hepatitis B and C were negative, as was cryoglobulin. No hypocomplementaemia was observed. Antinuclear antibody titre was high (1:160), but anti-DNA and anti-CCP antibodies were negative. PR3-ANCA and MPO-ANCA were also negative.

Differential diagnosis

• Idiopathic large-vessel vasculitides (eg, giant cell arteritis (GCA), Takayasu’s arteritis): The patient had aortitis with left jaw claudication; therefore, the possibility of GCA should be considered. However, TAB did not reveal typical pathological findings of GCA, and only two of the 1990 ACR classification criteria were met. Polymyalgia rheumatica, often associated with GCA, was not strongly suspected because this case did not meet the clinical criteria other than negative anti-CCP antibody, although it met the required criteria of the ACR (The American College of Rheumatology) and EULAR (The European Alliance of Associations for Rheumatology) classification criteria. Furthermore, as described below, in this case, we achieved corticosteroid discontinuation in 47 days. Based on previous reports,⁶ in cases with GCA the median time of corticosteroid taper to achieve oral prednisolone (PSL) level of 5 mg/day is 7.5 months. Additionally, the EULAR guideline for the management of large-vessel vasculitis⁷ recommends that corticosteroid should be tapered to 5 mg/day (PSL-equivalent) or less after a year. The clinical course of this case, in which corticosteroid target level was achieved in a short time, is atypical for GCA, making the diagnosis of GCA less likely.

• Infectious aortitis: Aortitis caused by pathogenic microorganisms such as Salmonella could be a possible differential diagnosis, but two sets of blood cultures taken on the admission day were negative; thus, this diagnosis was considered unlikely.

• Large-vessel vasculitides associated with infectious diseases (syphilis, hepatitis B, hepatitis C): This was considered unlikely as serological markers were negative.

• IgG4-related large-vessel vasculitis: Although the patient’s IgG4 level was high, it was within five times the upper limit of normal, without hypocomplementaemia, and other findings of IgG4-related disease were absent, so it was considered unlikely.

• Large-vessel vasculitis as a side effect of chemotherapeutic agents: Cases of vasculitis associated with gemcitabine, which was included in the patient’s chemotherapy regimen, have been reported,^{8 9} and this may be a possible differential diagnosis.

• Paraneoplastic large-vessel vasculitis: Cases of vasculitides, such as GCA, have been reported as paraneoplastic syndromes. However, paraneoplastic vasculitides reportedly show a poor response to steroid therapy, and treatment of the underlying malignancies is required to alleviate vasculitis symptoms.¹⁰

Although large-vessel vasculitides caused by other aetiologies listed above were considered as differential diagnosis, a presumptive diagnosis of G-CSF-induced aortitis was made since symptoms had developed approximately 10 days after G-CSF administration and the patient’s history was typical. The Naranjo Adverse Drug Reactions Probability Scale¹¹ was developed to assess the probability that a suspected drug caused adverse drug reactions. In this case, the score was 6, falling into the ‘probable’ category. This scoring result also supports our diagnosis. This patient had symptoms of left scalp pain and jaw claudication, but the TAB result did not strongly suggest vasculitis. However, considering the estimated sensitivity of TAB at 77%,¹² this might have been false-negative, and G-CSF-induced aortitis with temporal arteritis was clinically diagnosed.

Treatment

Following a tentative diagnosis of G-CSF-induced aortitis, the patient was started on PSL 60 mg/day on admission day. The patient was afebrile (<37°C) after admission, and left jaw claudication and right knee arthritis were resolved 3 days after admission. According to previous reports,¹³ it is suggested that G-CSF-induced aortitis would resolve within approximately 10 days to 1 month after onset with or without corticosteroid administration; in this case, the clinical course was considered good at this point, so rapid tapering was selected. A laboratory test performed 10 days after admission revealed a CRP level of 0.49 mg/dL, and the patient was discharged home 11 days after admission as his clinical course was good. PSL was tapered off and discontinued 14 days after admission.

Outcome and follow-up

At the follow-up outpatient visit, 19 days after admission, the patient had right knee arthralgia, and swelling and warmth were noted in the same area. Arthrocentesis of the right knee revealed non-prominent mononuclear and polynuclear cells, and it was crystal-negative and culture-negative. Laboratory tests revealed elevated CRP (4.93 mg/dL), which raised suspicion of aortitis recurrence, and contrast CT was performed; however, the CT findings suggestive of periaortic inflammation had resolved (figure 1B). PSL 10 mg/day was resumed, and right knee arthritis had resolved by the time of the outpatient visit, 26 days after admission. The PSL dose was tapered off and discontinued 47 days after admission. After that, the patient showed no recurrence of symptoms.

Discussion

In the present case, the patient developed aortitis with left temporal arteritis and right knee arthritis after G-CSF administration. Despite a good response to corticosteroid administration, inflammation relapsed after hospital discharge, necessitating steroid administration resumption. Thus, unlike previously reported cases, in this case, G-CSF-induced aortitis presented with more peripheral symptoms and required a longer course of treatment.

Most previous reports of G-CSF-induced aortitis have described inflammation of the aorta, carotid arteries and subclavian arteries.^{2 4} However, this case suggests that G-CSF-induced aortitis may also cause temporal arteritis. To our knowledge, only one case of G-CSF-induced aortitis with temporal artery inflammation has previously been reported.⁴ In the present case, the patient had left jaw claudication and left temporal pain, both of which are symptoms of temporal arteritis, at the time of his initial visit to our outpatient clinic. Biopsy revealed findings suggestive of postinflammatory changes, although these changes were atypical for temporal arteritis. G-CSF-induced aortitis may also present with inflammation of the temporal arteries, as indicated by the fact that GCA, an idiopathic large-vessel vasculitis, presents with aortitis and temporal arteritis.

Furthermore, G-CSF-induced aortitis can cause knee arthritis in addition to vasculitis symptoms. In this case, right knee arthritis was present at the initial visit and at the first follow-up outpatient visit after discharge. Right knee arthrocentesis was not performed during hospitalisation, although it should have been done to rule out septic arthritis. We performed right knee arthrocentesis at the first follow-up visit because arthritis recurred. There have been case reports of crystalline arthritis attacks and rheumatoid arthritis exacerbation after G-CSF administration,^14–16 but the knee arthrocentesis at the first follow-up visit in this case was negative for crystals, and the patient did not have rheumatoid arthritis. Arthralgia has also been reported as an adverse effect of filgrastim^{17 18}; however, to our knowledge, no case of arthritis associated with G-CSF administration has been reported. The mechanism by which G-CSF administration causes aortitis is unclear; however, some previous studies have discussed the possibility that G-CSF induces vasculitis by activating immune mediators.¹³ This case suggests that knee arthritis can be a complication of G-CSF-induced aortitis, probably because of the inflammatory response-eliciting effects of G-CSF.

In addition, inflammation induced by G-CSF, including aortitis, may persist longer than that which was previously reported. Previous reports of G-CSF-induced aortitis have noted that remission can be achieved within a short time frame,^{1 4 19} generally from 10 days to 1 month¹³ after the onset of the disease. This feature is only partially applicable to this case. In our patient, subjective symptoms disappeared, and the inflammatory response decreased rapidly, leading to early hospital discharge (11 days after admission) and discontinuation of corticosteroid administration (14 days after admission). However, at a follow-up outpatient visit, the patient showed signs of relapse of inflammation without obvious imaging findings of aortitis, and corticosteroid administration was resumed. We, therefore, suggest that the proinflammatory effects of G-CSF that cause aortitis may persist for a longer time.

The association between underlying cancer types and the incidence of G-CSF-induced aortitis is still unclear. Previous case reports^{2 20} with literature review suggest an association with breast cancer as an underlying malignancy in G-CSF-induced aortitis cases. An analysis of the Japanese Adverse Drug Event Report database²¹ showed high ORs for breast cancer, ovarian cancer and malignant lymphoma. In the same study, no cases of bladder cancer, such as in our case, were reported. However, because this adverse event is rare, the association between underlying cancer types and incidence remains to be evaluated.

An increasing number of case reports of G-CSF-induced aortitis have been published in the past decade. This condition typically presents as inflammation of the aorta and its proximal branches, occurring approximately 10 days after G-CSF administration. It responds well to corticosteroid therapy or may resolve quickly without corticosteroid administration.^{1 4} However, atypical presentations and clinical courses of G-CSF-induced aortitis exist, as in this case, in which inflammation relapsed after corticosteroid discontinuation, and aortitis was accompanied by temporal arteritis and knee arthritis. Further studies and reports are required in the future.

Learning points.

• Granulocyte colony-stimulating factor (G-CSF)-induced aortitis can present with symptoms of temporal arteritis, such as jaw claudication.

• Monarthritis, which is distinct from crystalline arthritis or exacerbation of chronic arthritis, may be observed during the clinical course of G-CSF-induced aortitis.

• G-CSF-induced aortitis responds well to corticosteroids and resolves rapidly; however, early discontinuation of corticosteroids may lead to a relapse of inflammation.

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