Transient Eosinophilic Granulomatosis with Polyangiitis-Like Vasculitis During Omalizumab Therapy: A Case Report

Introduction

Omalizumab is a recombinant humanized antibody of IgG1k subclass targeted against IgE for the treatment of moderate to severe asthma. It is unclear whether omalizumab can cause eosinophilic granulomatosis with polyangiitis (EGPA), however different reports described the occurrence of EGPA while on omalizumab in patients with asthma or vasculitic urticaria. Interestingly, omalizumab is used to treat asthma in EGPA with success. We report a case of a lady, who was on omalizumab for more than 3 years presenting with EGPA like vasculitis which resolved completely after treatment with steroids and discontinuation of omalizumab.

Case Presentation

We present a case of a 67-year-old, right-handed, retired administrator female, referred urgently by her GP to the rheumatology service, with 3-days history of severe neck pain radiating to both shoulders and shoulder blades with aches in both arms. She also had a severe persistent headache in the right temporal and orbital areas. Both her headache and neck pain were severe and only marginally helped with analgesia including paracetamol, ibuprofen and codeine. She also had jaw pain on chewing as well as exquisite pain over her temple and occipital region. She had some neck stiffness but no restriction to movement of the neck or shoulders. She had no muscle stiffness or symptoms around her pelvic girdle or lower limbs. There was some blurring of vision but no visual loss or diplopia and there was no limb claudication. She also complained of episodic sore throat with odynophagia. She denied fever, sweats or weight loss; however, her appetite was reduced. There were no respiratory, gastrointestinal, urinary or neurological symptoms. There were no other extra-articular features and no history of altered sensorium. She had been on a holiday to Majorca 2 weeks prior to the presentation and had a background of severe allergic asthma and allergic rhinitis diagnosed in 1996 with multiple environmental allergies. Because of persistently raised IgE and recurrent asthma exacerbation, she was commenced on omalizumab injections in 2016. Azithromycin 250 mg three times a week was also added over the months October to April for better control. Short courses of steroids for asthma exacerbations were given once or twice a year during omalizumab therapy. She also had previous septoplasty and chronic plaque psoriasis of the extensor surfaces of the upper limb since her teenage years, tolerated and treated with calcipotriol (as monohydrate) and betamethasone (as dipropionate) ointment with the last flare up in 2009 treated with narrow-band phototherapy (UVB) and emollient creams.

Her regular medication included omalizumab 375 mg fortnightly subcutaneous injections, Symbicort 200/6 Turbo haler (120-dose) one puff twice daily and Dymista 137 µg/dose/50 µg/dose nasal spray one puff twice daily.

Family history revealed a sister with a type of vasculitis and currently on steroids. Her father suffered from osteoarthritis. She is a widow and has three children who are fit and well. She gave up smoking 40 years ago and drinks two bottles of wine a week and lives independently on her own.

On examination, she looked well, and general peripheral examination was unremarkable. Peripheral pulses were well palpable. There was no lymphadenopathy or bruit. Her blood pressure was high at 198/106 in the right arm and 198/107 in the left arm. She weighed 54 Kg. She did not have any temporal artery tenderness and both temporal arteries were well palpable, however she had some tenderness over frontal and ethmoidal sinuses. There were no peripheral stigmata of vasculitis or connective tissue diseases. The rest of the clinical examination was unremarkable including the musculoskeletal system.

A temporal artery ultrasound scan did not reveal any ultrasound evidence of temporal arteritis. Initial investigations are summarized (Table 1).

Table 1 Initial Investigation

She was admitted to the acute assessment unit for further investigations and to rule out infection before commencing her on steroids for a likely diagnosis of EGPA.

Two days later, she developed a fever and became confused. She was noted to have an ejection systolic murmur on cardiac examination. Repeat blood tests showed profound hyponatremia (Table 2). A CT scan of the head and neck followed by a brain MRI showed enhancing soft tissue mass at the right submandibular area of indeterminate nature, but was otherwise normal. Arterial spine labelling MRI, MR Venography of the cerebral veins and MR angiograph of the circle of Willis showed no acute large hemispheric subdural collection, The FLAIR suggests multiple white matter, basal ganglia, and pons as well as general subcortical changes due to underlying small vessel cerebrovascular disease. No mass effect or midline shift was seen. The paranasal sinuses demonstrate right circular mucosal thickness.

Table 2 Further Investigations

An EEG was requested based on a neurologist’s advice to rule out encephalitis. It showed bi-frontal abnormalities with emphasis on the left and possible minor temporal involvement. There was no evidence to point strongly to diffuse encephalitis, however focal encephalitis was possible but the distribution of abnormalities was not typical of herpes simplex and there were no periodic complexes to point to this condition. She was started on acyclovir which was discontinued after 3 days as lumbar puncture was normal with no growth after 48 hrs and cerebrospinal fluid (CSF) polymerase chain reaction (PCR) for Herpes simplex type 1 and 2, varicella zoster, parvovirus and enterovirus was negative.

To investigate the murmur, an Echocardiogram showed mild Aortic Regurgitation (AR), small pericardial effusion, no haemodynamic compromise, normal size and function of both ventricles. A neck ultrasound showed dilated ducts in the submandibular salivary gland (SMG) and both parotid glands, and multinodular thyroid. As EGPA has pulmonary involvement a Chest x-ray was requested followed by high-resolution computed tomography (HRCT) scan which showed central bronchial dilatation, abnormal inflammatory/atelectasis in the left apex, no focal mass lesion in this area.

Treatment and Referrals

The below table lists the treatments recommended by each department on referral (Table 3).

Table 3 Referrals and Treatments

Outcome and Follow-Up

During the 8-months follow-up period, she continued to improve gradually and was weaned off steroids which were given for a total of 4 months after her admission. However, she was concomitantly experiencing increasing cough and mucous production but coping relatively well. Repeat blood tests, including inflammatory markers as well as eosinophilic count and Myeloperoxidase antibodies (MPO) were taken and were all back to normal range remaining so when repeated 2 months after steroid discontinuation. Her sodium levels remained within normal range. She was seen in the respiratory outpatient clinic and was started on prophylactic azithromycin during wintertime along with her usual inhaler and nasal spray. Moreover, she was advised not to restart omalizumab at this time.

Discussion

EGPA is a systemic necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium vessels and associated with asthma and eosinophilia.¹

There are no clinical diagnostic criteria for EGPA, however, for research purposes, the American College of Rheumatology 1990 criteria suggests the presence of EGPA if four or more of six clinical criteria in the setting of vasculitis were met: Asthma, Peak peripheral eosinophilia of >10% of the total WBC count, Peripheral neuropathy attributable to a systemic vasculitis, transient pulmonary infiltrates on chest radiographic imaging, paranasal sinus abnormality, blood vessel biopsy demonstrating extravascular eosinophils.² Our case does not fully fulfil the criteria for EGPA; however, the atypical presentation of PMR like symptoms, raised inflammatory markers, high MPO antibodies titre, eosinophilia, pulmonary infiltrates and the resolution of symptoms and abnormal biochemical markers with steroids and omalizumab discontinuation, point to the diagnosis. Vasculitis induced syndrome of inappropriate antidiuresis (SIAD) is another aspect of this atypical presentation. Histological diagnosis in this case was not applicable and the rapid response to steroids did not prompt more invasive tests.

Differential diagnosis includes infections such as toxocariasis, strongyloides stercoralis, HIV and aspergillus species, drug-induced eosinophilia, hypereosinophilic syndromes (HES), and paraneoplastic eosinophilia. In our case, serology for Lyme disease, HIV, syphilis, and spinal fluid PCR were tested initially, but because the patient improved shortly after commencing steroids, there was no need to test for parasitic infections despite her recent travel history. Hyper eosinophilic syndrome is a disease of exclusion characterized by persistently raised eosinophilic count for at least 6 months with multisystem involvement, in our case, the eosinophilic count return to normal in less than 4 months.

Omalizumab has been implicated as a trigger for EGPA mainly during steroids withdrawal for asthmatic patients.^3–9 However, as an exceptional option for patients with severe asthma and urticarial vasculitis, it can also be used in patients with EGPA in this context 0.¹⁰⁻¹² Rechallenging with omalizumab can still be an option for patients with severe allergic asthma and raised IgE who do not respond to other treatment modalities.

Patient Informed Consent

Written informed consent was obtained from the patient described in this report to have the case details published. Institutional approval was not required to publish the case details.