Induction of sustained remission and reversal of pathologic transcriptome achieved with tezepelumab in an adolescent with eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a chronic, type 2 inflammatory disorder defined clinically by symptoms of esophageal dysfunction and histologically by esophageal eosinophilia with ≥ 15 eosinophils per high power field (hpf). Incidence and prevalence of EoE are increasing over time¹. Pharmacologic treatments for EoE have only recently achieved approvals for use.

Thymic stromal lymphopoietin (TSLP) is an epithelial derived cytokine that mediates type 2 immune responses, contributing to the pathogenesis of allergic diseases including asthma, atopic dermatitis, allergic rhinitis, and EoE². TSLP expression is increased in the esophageal epithelia of patients with EoE³. It was recently demonstrated that in individuals with EoE, there is a greater proportion of esophageal derived memory CD4+ T cells that expressed receptor to TSLP. Expression of these receptors increased in response to stimulation by TSLP both in the esophagus and in circulation. Further, the number of circulating TSLP responsive CD4+ T cells correlated with the degree of esophageal eosinophilia, supporting the potential therapeutic benefits of TSLP inhibition in EoE⁴.

Tezepelumab is an anti-TSLP human monoclonal antibody that is approved by the U.S. Food and Drug Administration for the add-on maintenance treatment of severe asthma in adults and adolescents⁵. Additionally, there is a phase 3 clinical trial (CROSSING) recruiting patients to evaluate the efficacy and safety of tezepelumab in patients with EoE⁶.

In this case report, we describe an adolescent patient whose active EoE responded to treatment with tezepelumab prescribed for his asthma. Human biopsy samples were obtained after informed consent, under the auspices of the Institutional Review Board (IRB) of Cincinnati Children’s Hospital Medical Center. Participant enrollment complied with ethical regulations in accordance with the IRB-approved protocol. Informed consent was obtained from the patient and guardian to publish this case report with its accompanying visual elements.

Assessment of the patient’s disease at multiple time points before and after treatment with tezepelumab was conducted using objective measures including EoE Endoscopic Reference Scores (EREFS), EoE Histologic Scoring System (EoE-HSS), and EoE Diagnostic Panel (EDP) from available specimens. EREFS is a validated measure that grades the severity of implicated EoE endoscopic findings at 2 to 3 levels of the esophagus and includes edema, rings, exudate, furrows, and strictures⁷. In this case, endoscopies were blindly scored by a pediatric gastroenterologist utilizing pictures and videos. EoE-HSS is a validated scoring system that assesses histologic features present in the esophageal mucosa affected by EoE. As compared to peak eosinophil count, the composite EoE-HSS score better discerned treatment status utilizing clinical biopsies obtained from a large cohort of patients with EoE⁸. Higher EREFS and EoE-HSS scores indicate more severe or extensive endoscopic and histologic abnormalities, respectively. EDP is a validated 96 gene quantitative PCR array of 94 transcripts differentially expressed in EoE performed on esophageal biopsies. The EDP score was calculated by previously described methods and higher scores indicate a trend toward normalization of the pathologic gene expression⁹. Table 1 summarizes these assessed objective measures of disease activity.

Table 1.

Summary of analyzed measures.

Date of endoscopy	PEC (eos/hpf)	Total EoE-HSS (grade/stage)	EREFS composite	EDP score
Initial evaluation (8 years before tezepelumab initiation) Age 8	56 (distal), 1 (proximal)	N/A	6-1-2-6-0	11.3
6 months before tezepelumab initiation Age 15	74 (distal), 43 (proximal)	Distal: 0.42/0.38 Proximal: 0.48/0.38	6-0-3-6-0	69.5
Initiated tezepelumab
9 months after tezepelumab initiation Age 17	10 (distal), 2 (proximal)	Distal: 0.14/0.14 Proximal: 0.19/0.19	3-1-1-2-0	N/A
21 months after tezepelumab initiation Age 18	3 (distal), 0 (proximal)	Distal: 0.21/0.21 Proximal 0.10/0.10	3-1-0-0-0	308.7

Summary of evaluated objective measures of EoE disease activity by time point relative to tezepelumab initiation.

The patient initially presented to care with persistent vomiting as a three year-old toddler which led to the diagnosis of EoE. The patient had failed to achieve histologic remission despite trials of multiple food eliminations of commonly implicated food antigen triggers, prompting transfer of care to our center. Subsequently, the patient was able to achieve histological and clinical remission with swallowed budesonide in suspension used in combination with high dose proton pump inhibitor. However, EoE histologic and clinical remission were not sustained, despite escalating doses of budesonide up to 1mg twice daily and PPI therapy up to 40mg twice daily, believed to be partly due to poor medication adherence in the setting of psychosocial stressors. During this period, the patient experienced intermittent symptoms of difficulty swallowing and heartburn. Six months prior to initiation of tezepelumab, the now 15 year-old patient underwent an esophagogastroduodenoscopy (EGD) which demonstrated thickening, furrowing, and exudate throughout the esophagus. Biopsies from this EGD demonstrated esophageal eosinophilia with up to 65 eosinophils/hpf in addition to other pathological findings consistent with EoE.

In consideration of the patient’s active EoE and difficult-to-manage asthma, his allergist prescribed dupilumab (loading dose of 400mg, followed by 200mg every 2 weeks) in addition to concurrent EoE treatment with omeprazole 20mg twice daily. However, with the administration of the first dose of subcutaneous dupilumab, the patient demonstrated an immediate adverse reaction characterized by dizziness, numbness, tingling, and mild hypotension despite previously tolerating other injected medications well. Following this event, the patient was instead prescribed subcutaneous tezepelumab 210mg every 4 weeks. Since initiation more than 2 years ago, he has tolerated the monthly tezepelumab injections well without reported side effects. He has never required esophageal dilation.

On the first evaluation after initiating tezepelumab, EGD with biopsies demonstrated improved composite EREFS and histologic remission with <15 eosinophils/hpf. Clinically, the patient reported resolution of dysphagia,, with only occasional reflux symptoms relieved by as needed use of calcium carbonate. On re-evaluation one year later – and one year after discontinuing concurrent omeprazole treatment – EGD with biopsies demonstrated further improvement in composite EREFS score and sustained histologic remission with further reduction in peak esophageal eosinophil counts. At that time, the patient reported full resolution of all previously reported gastrointestinal symptoms. Accordingly, Figure E1 depicts improvement in endoscopic findings of disease with corresponding EREFS scores and Figure E2 depicts histologic findings from available esophageal biopsies with corresponding EoE-HSS scores.

Further analysis of the patient’s distal esophageal biopsies demonstrated that treatment with tezepelumab led to a reversal of the pathologic EoE transcriptome as measured by EDP. The EDP score improved from 11.3 and 69.55 during active EoE disease states prior to tezepelumab initiation to 308.7 after tezepelumab initiation when EoE remission was achieved. More specifically, treatment reversed expression of notable genes downstream of TSLP and related to type 2 inflammation. These include genes related to inflammatory chemokines/cytokines (CCL26, CXCL1, CXCL6, CXCL8, IL13) implicated in EoE pathogenesis. Additionally, many EDP assessed genes related to ion channels, remodeling, and proliferation improved toward normalized expression after treatment (Figure 1). These molecular level changes are in accordance with existing knowledge of TSLP role in allergic diseases, however, a single case is not sufficient to identify mechanistic underpinnings of Tezepelumab in EoE².

Figure 1.

EoE Transcriptomic Analysis by EDP. Heatmaps of EoE downregulated and upregulated gene expression normalized to log(10). Genes grouped by function.

In addition to eliminating the need for any additional concurrent EoE therapies with tezepelumab treatment, the patient has been able to eliminate the need for asthma maintenance inhalers and reduce the frequency of albuterol rescue inhalers to 1–2 occasions annually.

To our knowledge, we report the first documented case of tezepelumab successfully inducing sustained clinical, histopathologic, and endoscopic remission of EoE. The evidence for potential therapeutic benefit of tezepelumab in EoE is strengthened by the molecular analysis of this patient’s biopsies using EDP. Further controlled clinical trials should be pursued to evaluate the short- and long-term efficacy and safety of tezepelumab in patients with EoE.

Clinical Implications:

Tezepelumab use for asthma successfully induced and sustained eosinophilic esophagitis remission and reversed its pathologic transcriptome. This case provides insight into the mechanistic underpinnings of type 2 inflammation in EoE and the clinical utility of targeting these pathways for treatment.