Gleich syndrome and eosinophilic fasciitis overlap successfully treated with mepolizumab

Gleich syndrome (GS) and eosinophilic fasciitis (EF) are very rare conditions in which eosinophils play an important pathogenetic role.1, 2 We report for the first time a patient with characteristic features of GS as well as EF who responded promptly to mepolizumab. A 56-year-old female presented with a 2-year history of 4-weekly episodes of facial edema, and remitting urticarial lesions on the neck, trunk, and extremities, which was accompanied by weight gain of about 5 kg and gastrointestinal complaints. She had a long history of bronchial asthma but no fever episodes, myalgias, or arthralgias. On examination, there were elevated erythematous urticarial lesions with peau d'orange appearance (Figure 1a,b) on the neck and shoulders and erythema on the arms, décolleté and back. There was no hyperpigmentation or skin hardening. However, the "groove sign" was positive (Figure 1c,d). A deep skin biopsy including fascia and muscle tissue obtained from the forearm revealed perivascular lymphocytic infiltrates in the upper dermis and florid eosinophilic fasciitis and myositis without signs of fibrosis/sclerosis (Figure 1e,f). Coloscopy showed slight eosinophilic infiltrates of the mucosa. During the 2-year history of her condition she had hypereosinophilia ranging from 8% to 54% (1–4), elevated lactate dehydrogenase [LDH, range: 287–612 U/L (135–214)], and increased immunoglobulin (Ig) E levels [160–968 kU/L (<100)]. Furthermore, eosinophilic cationic protein and IgG were markedly increased in the serum. Abnormal autoantibody titers for ANA, ENA, pANCA, cANCA were not found. Whole body computed tomography, lymph node ultrasound, and echocardiography did not reveal pathologies. Blood smears and bone marrow examination, including chromosome and mutation analyses, excluded hematological malignancies. Parasitoses, fungal infections, hypereosinophilic syndrome, IgG4-related disease, and Churg-Strauss syndrome were discussed as differential diagnoses.1-5 The clinic-pathological findings were most suggestive for GS/EF overlap. Despite several cycles of systemic corticosteroids, she experienced monthly flares of her condition. Because of the marked eosinophilia and recalcitrant bronchial asthma, we decided to treat her using mepolizumab 100 mg every 4 weeks, resulting in almost complete remission of her clinical symptoms (except for mild transient erythema on the neck) and normalization of eosinophils as well as LDH after four cycles. Gleich syndrome (episodic angioedema with eosinophilia) is characterized by eosinophilia, edemas, urticarial lesions, hypergammaglobulinemia, and periodically occurring weight gain. Gastrointestinal symptoms may also occur. The exact etiology of GS is still unclear, but both eosinophils and abnormalities of cytokines homeostasis seem to play a pivotal role in the pathogenesis of this condition.1 EF (Shulman syndrome) is characterized by diffuse limb swelling and subsequent fibrosis/sclerosis of the fascia. EF is often accompanied by eosinophilia and hypergammaglobulinemia and may present in a manner similar to that of systemic sclerosis. The pathogenesis of EF is unclear, but is believed to be associated with abnormal immune system responses.2 In the present case, there were several findings indicating the diagnosis of GS as well as EF. Whereas eosinophilia, edemas, and hyperimmunoglobulinemia are features of both diseases, periodic urticarial lesions, weight gain, elevated IgE levels, and gastrointestinal manifestations indicate GS.1 By contrast, the groove sign,6 peau d'orange-like lesions, and particularly abundance of eosinophilic infiltrates in the fascia and muscle are characteristic features of EF. However, we did not find clinical or histopathological evidence for fibrosis/sclerosis which is usually found in longer-standing EF. Moreover, peau d'orange appearance can also be observed in urticarial lesions.1, 2 To the best of our knowledge, eosinophilic fasciitis/myositis has not been observed in patients with GS. Given the strongly elevated eosinophil counts in the present case, however, it is conceivable that the muscular involvement has to be attributed to GS.4, 5 Since deep skin biopsies including the fascia are usually not performed to diagnose GS, eosinophilic fasciitis/myositis may be overlooked in asymptomatic patients. Management of GS as well as EF consists of the use of systemic corticosteroids, whereas exacerbations usually occur when tapered down to small doses. This also applied to the present case. Since she suffered also from asthma, we decided to treat her in label with the interleukin 5 antibody mepolizumab resulting in dramatic improvement of her symptoms and lab parameters. Before the initiation of mepolizumab her corticosteroid medication was discontinued. We found one case report on successful mepolizumab treatment of a patient with GS.7 Mepolizumab is not only successfully used in bronchial asthma but also in other eosinophil-driven conditions such as eosinophilic granulomatosis with polyangiitis, and hypereosinophilic syndromes. In conclusion, we reported a patient with clinicopathological features indicating both GS and EF. So far, GS/EF overlap has not been reported but might indicate common pathogenetic mechanisms. Mepolizumab appears to be an effective treatment for GS and EF. T.G. has received speakers and/or advisory board honoraria from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, Merck-Serono, outside the submitted work.