Eosinophilic granulomatosis polyangiitis (EGPA) complicated with periaortitis, precipitating role of dupilumab? A case report a review of the literature

Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA) is an ANCA-associated vasculitis that affects small size vessels. Only four cases of periaortitis associated with EGPA have been reported in the literature. We report the case of a 67-year-old woman with EGPA who developed periaortitis 11 months after the initiation of dupilumab for uncontrolled asthma with hypereosinophilia. Complete remission of the periaortitis, and of EGPA, was obtained after switching from dupilumab to mepolizumab combined with oral prednisone therapy. Dupilumab has been associated with hypereosinophilia, that is usually asymptomatic and transitory, but symptomatic cases including EGPA were exceptionally reported. Although causality has not yet been established, caution is advisable when prescribing dupilumab for uncontrolled asthma with features that might suggest EGPA.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Periaortitis have rarely been described with Eosinophilic granulomatosis with polyangiitis.

WHAT THIS STUDY ADDS

• We describe a case of periaortitis associated with Eosinophilic granulomatosis with polyangiitis and discuss the precipitating role of dupilumab.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Caution is advisable when prescribing dupilumab for uncontrolled asthma with features that might suggest EGPA.

Introduction

Eosinophilic granulomatosis with polyangiitis (EGPA) is an ANCA-associated vasculitis (AAV) that affects small blood vessel.¹ Large vessels involvement, including periaortitis, has been described in AAVs, mainly in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).^{2 3} With regard to EGPA, only four cases of periaortitis have been reported in the literature.^4–7

Dupilumab is a human monoclonal IgG₄ antibody that targets the interleukin-4 receptor subunit α of the IL-4 and the IL-13 receptors. It is used in the treatment of atopic dermatitis, uncontrolled asthma with hypereosinophilia and chronic sinusitis with nasal polyposis.⁸ Its use has been associated with hypereosinophilia, that is usually asymptomatic and transitory, but symptomatic cases were reported, including EGPA.⁹

We report a case of EGPA with periaortitis that appeared 11 months after the initiation of dupilumab for uncontrolled asthma. We then discuss the association of periaortitis and EGPA and the potential role of dupilumab in inducing or exacerbating EGPA.

Case description

A 67-year-old female patient presented to our department in September 2022 with abdominal and back pain that was localised in the left lower quadrant and had been evolving for 3 weeks.

The patient’s medical history is relevant for severe asthma diagnosed at the age of 50, with hypereosinophilia fluctuating in numbers (12.18×10⁹/L in March 2020), nasal polyposis and chronic rhino sinusitis with crust formation and a history of polyarthritis that was diagnosed as polymyalgia rheumatica, antineutrophil cytoplasmic antibodies (ANCA) were tested negative. She was treated with inhaled corticosteroid/long-acting beta-agonis, long-acting muscarinic antagonist, oral corticosteroids and was well controlled since the introduction of dupilumab in October 2021. She also presented an episode of haemoptysis in August 2021, with a chest CT scan showing ground glass opacities in the left lower lobe.

She did not have fever, diarrhoea, haematuria or symptoms of urinary tract infection. She initially presented to the emergency department where a blood analysis showed an elevated level of C reactive protein (CRP) (22.5 mg/L), and an abdominal CT scan showed a periadventitial thickening of the aorta and the left common iliac artery. She was then referred to our department for further investigation.

She had mild diffuse joint pain and fatigue but had a stable appetite and weight. Physical examination was normal except an abdominal tenderness in the left lower quadrant without signs of peritoneal irritation, a diffuse expiratory wheezing on pulmonary auscultation and a tenosynovitis of the left elbow. ECG was normal.

Laboratory analysis revealed eosinophilia (1.09×10⁹ /L), no anaemia, an elevated CRP level (25.89 mg/L; N<5 mg/L), a serum creatinine level of 96 µmol/L. Urine analysis showed no leukocyturia, no microscopic haematuria and no proteinuria. Liver function tests were normal. Antinuclear antibodies, ANCA, rheumatoid factor and ACE were all negative. Serum protein electrophoresis showed a normal gamma fraction level. The IgG₄ level was elevated (1.9 g/L, N<0.864 g/L). Thyroid-stimulating hormone level was normal. Microbiological investigations were negative: syphilis, Coxiella, hepatitis C and B, HIV 1 and 2 serologies, blood cultures, tuberculosis interferon-gamma release assay.

The CT aortic angiography showed the hypodense circumferential irregular infiltration of the infrarenal abdominal aorta and the common and external left iliac arteries without significant luminal narrowing, compatible with periaortic fibrosis (figure 1A). The left renal pelvis and ureter were dilated being in contact with the infiltration around the iliac artery. The periaortic and peri-iliac artery fibrosis was highly metabolic on the Fluorodesoxyglucose positron emission tomography (FDG PET)(figure 1B). A sinus CT scan showed polypoidal lesions in the maxillary sinuses and the left sphenoid sinus.

Figure 1.

Axial CT scan during arterial phase (A) showing an irregular circumferential thickening around subrenal aorta (arrows) without significant luminal narrowing. FDG-PET-CT axial views (B) showing highly metabolic involvement of the left common iliac artery. After 6 months of corticosteroid therapy, follow-up non-contrast CT scan (C) shows complete regression of the irregular thickening around the aorta (arrowheads), and follow-up FDG-PET-CT (D) shows no residual hypermetabolism around the left common iliac artery, compatible with complete morphologic and inflammatory response. FDG-PET, fluorodesoxyglucose positron emission tomography.

A biopsy of the periaortic mass was performed and showed a fibroinflammatory tissue with non-specific subacute inflammatory changes. There was no granuloma, no signs of malignity, no vasculitis lesions, no eosinophilic cells, no storiform fibrosis. There were no IgG₄+ plasma cells excess on the immunohistochemical studies with anti-IgG, IgG₄ and anti-CD138, in the limit of the small number of plasma cells present. Culture of the specimen remains sterile.

The final diagnosis was a periaortitis associated with an EGPA. The patient was treated with oral corticosteroid, at a dose of 0.5 mg/kg/day (30 mg/day) of prednisone and was switched to mepolizumab (100 mg every 4 weeks) due to the potential role of dupilumab in inducing or exacerbating EGPA.

After 6 months, the patient was still taking steroids at a dose of 5 mg per day and mepolizumab. She did not have abdominal or back pain. She had no asthma attacks or other clinical manifestations of EGPA. Eosinophilic count was normal and CRP level was normal. The FDG PET scan showed a complete remission of the periaortitis (figure 1C,D).

Discussion

As a part of the aetiological differential diagnosis of periaortic fibrosis, secondary causes must be ruled out before the condition is termed chronic periaortitis (CP) (infections, neoplasia, radiotherapy, major abdominal surgery or trauma, histiocytosis and drug induced).¹⁰ CP per se is an inflammatory condition that originates in the adventitia of the aortic wall and then extends to the periaortic space, forming a fibroinflammatory tissue that usually develops around the infrarenal abdominal aorta and the common iliac arteries.¹⁰ Depending on the aspect of the aorta (dilated or not), three different conditions can be described in CP: idiopathic retroperitoneal fibrosis, inflammatory abdominal aortic aneurysms and perianeurysmal retroperitoneal fibrosis.¹⁰ CP can be isolated or associated with other conditions such as organ-specific autoimmune disorders, systemic autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis and small vessel vasculitis) and IgG₄-related disease (IgG₄ RD).¹⁰ In our case, the two main diagnoses that could be discussed were EGPA and IgG4 RD.

EGPA is an AAV that affects small blood vessels, together with GPA and MPA.¹ However, although rare, large vessels involvement, including aortitis and periaortitis, has been described in AAVs, mainly in GPA and MPA,^{2 3} and is usually non-stenosing, consisting of perivascular soft tissue masses, aneurysms, dissection and rupture.³ With regard to EGPA, to our knowledge, only four cases of periaortitis have been reported in the literature,^4–7 and are summarised in table 1. The suggested underlying pathophysiology is a vasa-vasoritis of the aorta.⁴ In our case, the patient met the ACR 2022 criteria for EGPA.

Table 1.

Case reports describing CP in EGPA

Reference	Hervier et al4 2008	Fujii and Hidaka5 2012	Kumari et al6 2021	Kondo et al7 2021
Age	42 years	68 years	63 years	50 years
Sex	Male	Male	Male	Female
ANCA	Negative	Negative	p-ANCA 1:80 c-ANCA (MPO-PR3) negative	Negative
EGPA manifestations	Worsening asthma and nasal polyps	Asthma, pulmonary infiltrates, purpura, mononeuritis multiplex, renal dysfunction	Asthma, chronic rhinosinusitis, eosinophilic enteritis	Polyneuropathy, sinusitis, asthma
CP type	Aortitis with vasa-vasoritis	Soft tissue mass surrounding the aorta from its subphrenic abdominal portion to the proximal common iliac arteries	Fusiform aneurysm of the infrarenal abdominal aorta, surrounded by stranding and haziness, that ruptured the following day (confined rupture with periaortic inflammatory thickening) warranting surgical intervention.	Retroperitoneal fibrosis with membranous nephropathy
Histopathology	Autopsy: necrotising myocarditis with medium-sized vessel vasculitis and a large eosinophilic infiltrate—aortitis with granulomatous and necrotising angiitis of the vasa-vasorum	Skin and kidney: eosinophilic vasculitis	Aortic wall: aortitis, periaortitis and eosinophilic vasculitis of small vessels with rare fibrinoid necrosis but no granuloma	Irregular abdominal mass: fibrous tissue with inflammatory cell infiltration containing eosinophils Kidney: diffuse and granular capillary wall staining for IgG (IgG4>IgG1) and C3
Time from EGPA diagnosis to CP onset	Simultaneous	Simultaneous	11 years (patient had refused therapy)	Simultaneous
Treatment	Not applicable	Corticosteroids	Patient declined immunosuppressive therapy	Prednisolone, cyclosporine, Mizoribine and intravenous immunoglobulins
Outcome	Death	Good clinical and biological results, improvement of the periaortic lesion	Not reported	Complete remission

ANCA, antineutrophil cytoplasmic antibodies; CP, chronic periaortitis; EGPA, eosinophilic granulomatosis with polyangiitis.

The second hypothesis that can be discussed in our case is IgG₄-RD. Indeed, it is known that IgG4 levels can be elevated in EGPA patients without IgG₄-RD and can be associated with EGPA disease activity and organ involvement.¹¹ Furthermore, IgG₄ RD is considered as a diagnosis of exclusion; in other words, EGPA must be excluded before IgG₄ RD can be diagnosed.¹² However, in a retrospective case series, Danlos et al point to the possibility of an overlap syndrome between AAV and IgG₄ RD.¹³ In this retrospective multicentre observational study including of 18 patients fulfilling the criteria for IgG₄-RD and AAV criteria, 14 cases were GPA, 3 MPA and only 1 EGPA. Interestingly, 50% of the patients (9 patients) had CP. Our patient had mild increased level of IgG₄, but no IgG₄ on the biopsy, nor storiform fibrosis or obliterative phlebitis. Given the whole presentation, we did not retain the diagnosis of Ig₄-RD.

Lastly, our case highlighted the potential role of dupilumab in inducing or exacerbating EGPA. Our patient developed CP 11 months after the introduction of dupilumab and without change in her corticosteroids dose. In our case, EGPA was probably pre-existing before the onset of dupilumab, as she had uncontrolled asthma with hypereosinophilia, a history of polyartritis and haemoptysis with ground glass opacities. Thus, dupilumab may have exacerbated her EGPA. Dupilumab allowed a good control of her steroid dependent asthma that was previously poorly controlled.

Dupilumab is a human monoclonal IgG4 antibody that targets the interleukin-4 receptor subunit α (IL-4Rα) of the IL-4 and the IL-13 receptors,⁸ thus inhibiting their signalling. Hypereosinophilia has been described in 4%–25% of patients treated with dupilumab. It is usually transitory, resolving in 6 months in 86% of affected patients, but symptomatic cases were reported.⁹ Olaguibel et al reviewed the electronic pharmacovigilance database of the European Medical Agency and found, till 19 March 2022, 61 cases of EGPA reported while on dupilumab.⁹ In the LIBERTY NP SINUS-52 clinical trial, two cases of EGPA were reported on dupilumab, one during dupilumab use and one more than 300 days after a single dose.¹⁴ Table 2 summarises six case reports describing EGPA diagnosed after initiation of dupilumab.^15–20 In the case presented by Anai et al, dupilumab was first switched to mepolizumab after EGPA onset, and reintroduced later concomitantly with mepolizumab given the insufficient control of asthma, with good results, pointing to the possibility of combination therapy.¹⁹

Table 2.

Case reports describing EGPA cases diagnosed after dupilumab initiation

Reference	Sex	Age	Reason for prescribing DPM	Time from DPM initiation to EGPA onset	EGPA manifestations	ANCA status	Histopathology	Corticosteroids tapered before or during EGPA onset?	Switch from anti-IL5/IL5R to DPM?	Corrective treatment
Persaud et al15 2022	M	58 years	Chronic sinusitis	1–2 weeks	Weakness, arthralgia, skin rash, lung and renal involvement	pANCA MPO (+)	Skin (eosinophilic vasculitis) and renal (pauci-immune glomerulonephritis)	No	No	High dose MPL for 3 days then oral prednisone, plan for long-term RTX
Tanaka et al16 2022	M	50s	Asthma and eosinophilic rhinosinusitis with nasal polyposis	5 months	High-grade fever, dyspnoea, interstitial pneumonia	(−)	Transbronchial lung biopsy: interstitial pneumonia with eosinophilia and no vasculitis.	No	No	High-dose MPL for 3 days then prednisolone 1 mg/kg
Murag et al17 2021	M	41 years	Uncontrolled asthma	3 months	polyneuropathy and lung involvement	(−)	None	possible	No	Switch from Dupilumab to MPZ
Milne et al18 2022	M	63 years	Severe persistent asthma and nasal polyposis	7 months	Fatigue, purpura, pulmonary nodules, eosinophilic myocarditis	(−)	Skin (small-vessel vasculitis with eosinophilic infiltrate)	Yes	Yes (MPZ)	High-dose MPL for 3 days then oral prednisone. CYC than AZA and MPZ
Anai et al19 2022	M	42 years	Uncontrolled asthma	3 weeks	Fever, sinusitis, lung involvement	(−)	Transbronchial lung biopsy: eosinophilic pneumonia, possible features of healed arteritis	?	Yes (MPZ then benralizumab)	High dose MPL for 3 days then oral prednisolone, intravenous CYC and MPZ instead of DPM (reintroduced later)
Eger et al20 2021	F	63 years	Uncontrolled asthma	After 8 administrations of dupilumab	Dysarthria, left-sided neurological deficit, bilateral pulmonary consolidations	(−)	None	Yes (cautiously)	Yes (Benralizumab)	Increase in prednisone dose, switch from DPM to MPZ

ANCA, antineutrophil cytoplasmic antibodies; AZA, azathioprine; CYC, cyclophosphamide; DPM, dupilumab; EGPA, eosinophilic granulomatosis with polyangiitis; F, female; M, male; MPL, methylprednisolone; MPZ, mepolizumab; RTX, rituximab.

The pathophysiology of the hypereosinophilia induced by dupilumab can be partially explained by an inhibition of the migration of eosinophils to tissues without inhibition of the eosinophilopoiesis, resulting in accumulation of eosinophils in the blood.⁹ However, this mechanism cannot fully explain the pathophysiology since eosinophils were found in tissues in patients developing EGPA while on dupilumab.⁹ Whether dupilumab induces EGPA or whether it accelerates the course of a previously non diagnosed ANCA-negative EGPA is still unclear.

Finally, we did not find any case of a periaortitis caused by dupilumab. On the contrary, there are some reports of effective treatment with dupilumab in IgG4-RD.²¹

Conclusion

In conclusion, we presented a case of an EGPA with periaortitis that appeared 11 months after initiation of dupilumab. Periaortitis can be an atypical manifestation of EGPA. EGPA has been described in patients treated with dupilumab, but causality has not yet been established. Caution is advisable when prescribing dupilumab for uncontrolled asthma with features that might suggest EGPA.

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