Idiopathic hypereosinophilic syndrome with eosinophilic cellulitis-like cutaneous involvement treated with mepolizumab and dapsone.

Introduction

Hypereosinophilic syndromes (HES) are a heterogeneous group of rare entities characterized by sustained blood eosinophilia with secondary tissue damage that can affect several organs, including the skin. Systemic corticosteroid therapy is considered the mainstay of treatment. However, numerous side effects limit its long-term use. Anti–interleukin (IL) 5 monoclonal agents, such as mepolizumab, have shown to be an effective alternative treatment for HES.

In this report, we present a case of idiopathic HES with marked cutaneous involvement reminiscent of eosinophilic cellulitis (Wells syndrome), showing complete recovery with the combination therapy of dapsone and mepolizumab.

Case report

A 40-year–old Caucasian woman without known medical history first presented to the dermatology clinic in 2005 with erythematous vesicular plaques on her right wrist and left concha (Fig 1). A complete blood count revealed hypereosinophilia at an absolute eosinophil count of 6.9 × 109/L. Skin biopsies revealed a prominent dermal eosinophilic infiltrate with flame figures consistent with eosinophilic cellulitis. Rapid improvement was observed after the initiation of prednisone.

Fig 1

Erythematous vesicular plaques on the patient’s right wrist at initial presentation in 2005.

Subsequently, she presented over the course of a 14-year period with highly polymorphic skin relapses for which no specific triggers were identified, affecting various anatomic sites accompanied by low-grade fever, general malaise, and eosinophilia ranging from 1.3 to 9.9 × 109/L (Fig 2). Skin biopsies were repeated during a cutaneous relapse in 2011, which revealed an eosinophil-rich dermal infiltrate and flame figures without vasculitis (Fig 3). A perilesional direct immunofluorescence test was negative. Ten years after the initial diagnosis, in 2015, she presented with a massive exudative pleural effusion. Her blood count at that time showed absolute eosinophil counts ranging from 1.3 to 1.5 × 109/L. No infectious or neoplastic causes were found, and she spontaneously recovered over a few weeks after therapeutic thoracentesis. She also underwent a below-knee amputation because of terminal ischemia of her left lower limb secondary to atherosclerotic disease. Histopathologic analysis did not demonstrate eosinophil-related endothelial damage.

Fig 2

Cutaneous relapse presenting as large necrotic plaques on the patient’s left arm and treated with oral prednisone in 2006. At this point of time, the patient had no long-term treatment.

Fig 3

Skin biopsy of an ulcerated papule on the patient’s right axilla revealed an eosinophil-rich dermal infiltrate and flame figures during a relapse in 2011.

In 2015, given the extracutaneous manifestations, full rheumatology and hematology workups were performed to rule out a secondary cause of eosinophilia. She had no lymphocytosis but rather had an unremarkable comprehensive metabolic panel. Serum immunoglobulins, immunoglobulin E measurement, as well as tryptase level were all within normal limits. Tests for antinuclear antibodies, antineutrophilic cytoplasmic antibodies, hepatitis B and C, human immunodeficiency virus, and other infections (including parasites) were negative. Serum protein electrophoresis and immunofixation failed to demonstrate a monoclonal spike. Molecular genetic studies were all negative, including FIP1L1-PDGFRA and BCR-ABL1 fusion genes, JAK2 V617F mutation, as well as FGFR1, PDGFRB, and receptor gamma and beta gene rearrangements. Flow cytometry failed to reveal a monoclonal lymphocytic population. IL-5 levels were not measured. A bone marrow aspiration and biopsy showed eosinophilia with normal cellularity according to her age. Echocardiogram was normal. Repeated computed tomography scans of the thorax, abdomen, and pelvis performed in 2012, 2015, and 2019 were negative for lymphadenopathy or internal malignancy. The blood hypereosinophilia persisting for several years, the bone marrow eosinophilia, as well as the pulmonary involvement with a negative thorough etiologic workup were highly suggestive of idiopathic HES.

Intermittent courses of prednisone 50 mg daily slowly tapered over a few weeks were given multiple times over a 10-year period. In 2006, minocycline (100 mg twice daily) was given for a few months, and in 2008, tetracycline (1500 mg per day divided into 3 doses) was tried for 10 days without improvement. Dapsone (100 mg twice daily) was subsequently initiated for 2 years but failed to prevent relapses. In 2019, mepolizumab was initiated at a dose of 100 mg subcutaneous monthly, resulting in the normalization of blood hypereosinophilia and the disappearance of cutaneous lesions. In the first 8 months of therapy, she had 2 cutaneous relapses of neutrophilic dermatosis-like plaques on her abdomen, back, and right lower limb in the absence of systemic symptoms. Skin biopsies revealed persistent eosinophils at one site and another biopsy showed a prominent neutrophilic infiltrate. Oral dapsone was then reintroduced at a lower dose (100 mg daily), showing no recurrence after 11 months of follow-up.

Discussion

HES comprise a spectrum of disorders defined by hypereosinophilia and variable organ involvement. The skin may be affected predominantly. Cutaneous manifestations are nonspecific, including angioedema, urticaria, eczematous and lichenoid eruptions, prurigo-like lesions, as well as bullous lesions. Eosinophilic cellulitis (Wells syndrome) is a distinct eosinophilic dermatosis typically presenting with cellulitis-like plaques that can last for weeks or years and heal without scarring. Hypereosinophilia may be present, but no other organ is involved beside the skin as opposed to HES. However, there is significant overlap between the 2 entities, and cases of idiopathic HES presenting with skin manifestations reminiscent of eosinophilic cellulitis have been described, as shown in our patient.

IL-5 is the most specific IL that positively influences the maturation, differentiation, mobilization, and survival of eosinophils. Mepolizumab is a humanized immunoglobulin G1 anti–IL-5 monoclonal antibody that binds IL-5 with high affinity and specificity to prevent from associating with the IL-5 eosinophilic receptor. It is a Food and Drug Administration–approved treatment for HES at a dose of 300 mg subcutaneously every 4 weeks. In our patient who had no significant organ damage, mepolizumab at a lower dose of 100 mg subcutaneously every 4 weeks was chosen, because it had been reported to be successful in treating patients with eosinophilic cellulitis. The dose of 100 mg, also used in severe eosinophilic asthma, may be considered to treat selected patients with idiopathic HES showing predominant cutaneous manifestations without significant systemic involvement.

Interestingly, our patient presented mild cutaneous relapses after the initiation of mepolizumab. A skin biopsy performed during a cutaneous relapse showed the persistence of dermal eosinophils but also a predominant neutrophilic infiltrate, for which dapsone was chosen. Of note, in HES, tissue persistence of eosinophils has been reported even at high doses of mepolizumab (750 mg intravenously). Furthermore, a prospective study on patients with allergic asthma treated with mepolizumab (750 mg intravenously) showed that eosinophils in the bronchial mucosa can remain activated despite treatment, because they have persistent cellular activation markers and receptors related to the IL-5 cytokines. Thus, patients may still present clinical exacerbations despite a reduced number of circulating and tissue eosinophils.

In conclusion, HES are a spectrum of diseases involving sustained hypereosinophilia and secondary organ damage. The initial presentation can rarely manifest as eosinophilic cellulitis-like plaques. The treatment of HES is challenging, and lower doses of mepolizumab may be a relevant option in patients with predominant cutaneous involvement.

Conflicts of interest

None disclosed.