STAT3 hyper–immunoglobulin E syndrome (STAT3-HIES) is a rare primary immunodeficiency syndrome characterized by elevated serum immunoglobulin E levels, eczema, recurrent skin and respiratory tract infections, and several gastrointestinal (GI) problems. GI manifestations, such as gastroesophageal reflux disease, dysphagia, abdominal pain, gut dysmotility, bowel perforation, eosinophilic esophagitis, and diarrhea, have been reported in 60% of patients. Until now, there was no efficient treatment that could effectively manage all aspects of the syndrome. In this report, we present the case of a 21-year-old man who suffered from undetectable pathogenic refractory diarrhea that persisted >21 days despite aggressive antibiotic and steroid treatment since he was 2 years old. STAT3 Int10(−2)A > G splicing mutation-caused STAT3-HIES was diagnosed by next-generation sequencing. The patient had suffered recurrent intestinal and colon perforations since he was 10 years old. He had received multiple surgeries and continuous systemic intravenous immunoglobulin therapy to manage his GI symptoms. However, refractory diarrhea occurring >5 to 6 times per day with severe eczematous dermatitis and frequent abscess formation remained threats to his life. Dupilumab 300 mg every 3 weeks was prescribed to control his skin problems, but the patient’s diarrhea also completely subsided. As such, it appears that dupilumab may not only effectively treat the skin inflammation but also the GI manifestation-related inflammation of STAT3-HIES refractory to traditional immunomodulators.

STAT3 hyper–immunoglobulin E syndrome (STAT3-HIES) is a rare primary immunodeficiency syndrome characterized by elevated serum immunoglobulin E (IgE), eczema, and recurrent skin and respiratory tract infections. It often includes several gastrointestinal (GI) problems. STAT3 is expressed widely and mediates many pathways, thus explaining the multisystem clinical phenotypes.1  In patients with primary immunodeficiencies, the most common presenting symptom is recurrent diarrhea.2  GI manifestations, such as gastroesophageal reflux disease, dysphagia, abdominal pain, gut dysmotility, bowel perforation, eosinophilic esophagitis, and diarrhea, have been reported in 60% of patients with STAT3-HIES.3  According to previous publications, the mainstay of treatment is the prevention of staphylococcal abscesses and pneumonias with antistaphylococcal prophylactic antibiotics, as well as the early aggressive treatment of infections.4  However, undetectable pathogenic refractory diarrhea that persisted >21 days despite aggressive antibiotic and steroid treatment has directly resulted in mortality in some cases.5  The use of intravenous immunoglobulin (IVIg) therapy seems to be helpful in controlling this inflammatory process, but there are still some patients who suffer from prolonged periods of severe and protracted diarrhea and thus require frequent hospitalization.

Dupilumab, a fully human monoclonal antibody blocking the α-subunit of interleukin 4 (IL-4) receptors that was approved recently for atopic dermatitis, has been reported as a possible drug of choice for autosomal dominant STAT3-HIES.6,7  However, there have been no reports regarding its potential effects on the systemic symptoms as well as the cutaneous manifestations of STAT3-HIES.

A 21-year-old man suffered from generalized eczematous dermatitis with refractory diarrhea since he was 2 years old. Because of his chronic refractory diarrhea, his case was complicated with severe pyoderma in the abdominal wall and a perforated colon that damaged his rectus muscularis when he was 10 years old. STAT3-HIES was diagnosed on the basis of his clinical presentation, persistent high serum IgE levels (>45 000 IU/mL), hypereosinophilia (maximum 5941 cells per μL) and STAT3 Int10(2)A > G splicing mutation detected by next-generation sequencing.

He was managed with empirical antibiotics combined with IVIg therapy for any flare-ups, in addition to being routinely managed with systemic methylprednisolone since his childhood.5  Although the number of the recurrent episodes slightly decreased after he began receiving systemic steroids with IVIg treatment, he still suffered from diarrhea >5 to 6 times per day, which had a substantial impact on his daily life. Meanwhile, because of the characteristic manifestations of STAT3-HIES, his skin continuously presented with severe generalized eczematous dermatitis with abscess formation due to concurrent Staphylococcus infections, even while receiving IVIg therapy for more than a decade.

Because of the patient’s refractory skin condition and intestinal complications, he underwent treatment with dupilumab at a dosage of 300 mg every 3 weeks combined with IVIg. After the dupilumab therapy, his generalized eczematous skin condition and folliculitis were significantly improved (Fig 1) and his eczema area severity index score and total body surface area changed from 13.1 and 20% to 0 and 0% after 9 doses of dupilumab therapy (Fig 2). Most importantly, the patient’s refractory diarrhea totally subsided from the frequency of >5 to 6 times per day after the dupilumab therapy. In addition to this significant clinical improvement, a laboratory examination revealed a marked decrease in his serum IgE level (76 900 IU/mL decreased to 34 200 IU/mL) and hypereosinophilia (1518 cells per μL decreased to 408 cells per μL) during the follow-up period after the 9 doses of dupilumab treatment. During a follow-up period of 6 months of dupilumab therapy, his skin and intestinal conditions continued to improve and displayed nearly complete remission without adverse effects.

FIGURE 1

STAT3-HIES–caused severe eczematous dermatitis. A, Severe eczematous dermatitis with disseminated abscesses before dupilumab use; B, complete symptom resolution after dupilumab use for 6 months.

FIGURE 1

STAT3-HIES–caused severe eczematous dermatitis. A, Severe eczematous dermatitis with disseminated abscesses before dupilumab use; B, complete symptom resolution after dupilumab use for 6 months.

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FIGURE 2

Atopic dermatitis severity scores and frequency of diarrhea after start of dupilumab therapy. BSA, body surface area; EASI, eczema area severity index.

FIGURE 2

Atopic dermatitis severity scores and frequency of diarrhea after start of dupilumab therapy. BSA, body surface area; EASI, eczema area severity index.

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Although GI symptoms of STAT3-HIES are rarely mentioned, previous studies have reported that nearly 60% of patients with STAT3-HIES exhibit GI manifestations.3  Multiple patients with STAT3-HIES have also been found to have evidence of underlying GI dysmotility and colonic perforation. The pathophysiology for these manifestations may be related to abnormal connective tissue remodeling and impaired mucosal healing in patients with STAT3 deficiency that cause abnormal levels of matrix metalloproteinases. In addition, impaired mucosal wound healing has been seen in murine models with deletion of STAT3.8,9  Moreover, interleukin 18/interleukin 22/STAT3 pathway deregulation plays an important role in intestinal dysbiosis and inflammation.10 

The optimal therapy for these GI disorders has yet to be determined. The use of oral or topical corticosteroid therapy in this population is limited by the high risk of infection. Moreover, although proton pump inhibitors and Histamine-2 receptor blockers have been prescribed for long-term acid suppression for gastroesophageal reflux disease, the benefits of these treatments must be weighed against the associated risk of osteoporosis.3  IVIg therapy has been used to control refractory diarrhea, but it cannot totally stop this symptom.5 

A transient increasing eosinophil number was observed in many patients with atopic dermatitis who received dupilumab therapy.11  The increase in blood eosinophil counts is considered to be related to the hypothesis that dupilumab blocks IL-4 and interleukin 13 function in eosinophil survival, activation, and recruitment to tissues but not egress from bone marrow, which is influenced by interleukin 5. Therefore, it has been speculated that initial treatment with dupilumab may result in a transient increase in circulating blood eosinophil counts.12  Moreover, according to previous studies, the number of eosinophiles was back to normal range in most of the patients with atopic dermatitis after a few months of dupilumab treatment,12  which was similar to our patient. However, the reason the patient did not have transient increase in eosinophils in his early phase of dupilumab therapy may be related to his extremely high baseline eosinophil level (up 30%–40%).

To our knowledge, this is the first report regarding the successful treatment of STAT3-HIES with refractory atopic dermatitis and intestinal complications by dupilumab. The possible underlying mechanism might be related to restoration of the barrier function of GI epithelium after IL-4 was blocked and the subsequent microbiome modification due to the GI environment change after dupilumab use.13  A further investigation to determine the immune mechanism of STAT3-HIES after IL-4 blockage is needed. Furthermore, the important finding of this report was that dupilumab may not only work on the skin inflammation but also on the inflammation of systemic organs, including the GI system, of hyper-IgE–related disorders, such as asthma, allergic rhinitis, eosinophilic gastroenteritis, and hyper-IgE syndrome.

Dr Lu collected data, conducted the initial analyses, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Lee provided patient’s baseline genetic data and reviewed and revised the manuscript; Dr Chung conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

Dupilumab has an excellent therapeutic effect on STAT3-HIES with severe diarrhea.

GI

gastrointestinal

IgE

immunoglobulin E

IL-4

interleukin 4

IVIg

intravenous immunoglobulin

STAT3-HIES

STAT3 hyper– immunoglobulin E syndrome

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.