Unveiling a suspected dupilumab‐induced neuropathy in pediatric eosinophilic esophagitis

The prevalence of eosinophilic esophagitis (EoE) has increased dramatically in the pediatric population since 1976 (8.18/100,000 from 1976 to 2001 and 74.42/100,000 from 2017 to 2022).1 Although this disease is more frequent, therapy remains challenging due to low rates of remission with standard therapies (proton pump inhibitors, swallowed topical corticosteroids, and elimination diets) as well as the high recurrence rate of the disease.2 Elimination diets are often effective when the incriminating food is identified but are difficult to maintain considering the impact on quality of life. Dupilumab is a relatively new therapy that was officially approved by the FDA in May 2022 for the treatment of EoE in adolescents aged 12 years and older and weighing at least 40 kg.3 It has shown promising results in the treatment of EoE by reducing clinical symptoms and improving histological, molecular, and endoscopic response.2 A recent phase 3 trial has also demonstrated the efficacy and safety of this medication at a 1-year follow-up with no neurological symptoms reported except for headaches in 3%–8% of patients, compared to 12% in the placebo group and muscle pain associated with injections.4 More recently, on 25 January 2024, the FDA also approved dupilumab for the treatment of pediatric patients with EoE aged 1–11 years and weighing at least 15 kg.5 We present the case of a patient who developed significant paresthesias after months of using dupilumab that spontaneously resolved with discontinuation of treatment. An informed consent was obtained from the patient's legal guardian. A 9-year-old male patient with severe and refractory EoE and eosinophilic gastritis developed neurological symptoms after using dupilumab. The patient had a history of asthma at a young age, multiple type 1 food allergies, and was diagnosed with EoE, gastritis and an enteritis of the duodenal bulb at 6 years old while undergoing desensitization for his food allergies. He proved refractory to all treatments for his EoE and also had a history of a type 1 allergy to proton pump inhibitors (PPIs). Extensive elimination diets proved unsuccessful, except for an 8-week trial of an exclusive amino acid-based formula that was deemed unsustainable as a long-term treatment. He began dupilumab at 7 years and 8 months of age and experienced significant improvement in his gastrointestinal symptoms while on the medication. On dupilumab, his macroscopic esophagitis score (EREFS) decreased from 5 to 1, and he had approximately 20 eosinophils per high-power field (HPF) in the distal esophagus, 16 months after starting dupilumab compared with his peak eosinophil count of greater than 80 eos/HPF. Approximately 9 months after starting dupilumab, he developed paresthesias in his proximal legs and torso. The symptoms worsened when dupilumab injections were increased from every 4 weeks to every 2 weeks. The symptoms became severe, and he was unable to participate in sports. The medication was discontinued 2 years after initiation and all symptoms drastically improved within 7 weeks. He underwent a neurological evaluation, and a diagnosis of dupilumab-induced neuropathy was deemed the most likely diagnosis. Extensive investigations (magnetic resonance of the spine, nerve conduction studies of six nerves in the lower limbs, and blood work including vitamin levels) were performed to rule out other diagnosis and found to be normal. The patient was scheduled for a skin biopsy to rule out a small-fiber neuropathy, but the biopsy was canceled since all symptoms had improved prior to the dermatology consultation. Although the diagnosis could not be confirmed definitively, the relationship with the discontinuation of the medication makes the diagnosis of dupilumab-induced neuropathy most plausible. Even though data are very scarce on a possible immunological mechanism, it has been suggested that inhibition of TH2-mediated inflammation by blocking IL-4 and IL-13 with dupilumab could result in a shift toward TH1- or TH17-mediated inflammation. The increase in TH1 and TH17 could contribute to the expression of type 1 inflammation-mediated disorders, such as Guillain–Barré syndrome or psoriasis.6, 7 The same mechanism could also be plausible with dupilumab-induced neuropathy as theorized by other authors.8 This patient is the only pediatric case with peripheral neuropathy reported, but adult patients with similar symptoms have been described. The first patient reported was a 38-year-old Chinese man treated for uncontrolled atopic dermatitis with dupilumab.9 He was started on dupilumab every 2 weeks with excellent improvement in his eczema. Approximately 18 months into the treatment, he developed weakness in his upper limbs with reduced reflexes. He had a nerve conduction study that showed an early acute inflammatory demyelinating polyradiculopathy that resolved with dupilumab cessation and IVIg induction. Two months later, he had a relapse with distal sensory disturbance, and he was diagnosed with a chronic inflammatory demyelinating polyradiculopathy. The second reported patient was a 53-year-old woman treated with dupilumab for severe refractory allergic asthma.8 She developed edema and numbness in her wrist and ankle 2 h after her second injection (injection administered in the abdomen). Each following injection was accompanied by numbness that lasted for a few days at first and later became persistent. A nerve conduction study showed reduced sensory nerve action potentials for the median and ulnar nerves suggesting axonopathies. Extensive investigations were performed to rule out other diagnosis and came back negative. Numbness resolved spontaneously after 6 months of dupilumab withdrawal and a diagnosis of dupilumab-induced peripheral neuropathy was proposed. These two adult cases are the only published reports of dupilumab-associated neuropathies, and our patient is the first pediatric case reported. Although the specific symptoms varied and appeared at different time points, the increase in TH1 and TH17 is a scientifically plausible theory that could explain the clinical presentation of these patients with neuropathies. All cases described to date are limited by the lack of a rechallenge with dupilumab after symptom resolution and, in the present case, by the absence of biopsy. Considering the significant functional impact, it is understandable that patients prefer not to resume the medication. While recognizing the uncertainty of the causal relationship with dupilumab, physicians should be aware of the potential association and remain vigilant for peripheral neurologic symptoms developing in patients while on therapy. With the more widespread use of dupilumab in clinic, it will be critical for physicians to keep reporting rare potential adverse events that may have been missed in clinical trials. Hugo Gagnon: Writing – original draft; conceptualization; investigation; visualization; validation; methodology; writing – review and editing; project administration. Cam-Tu Émilie Nguyen: Investigation; writing – review and editing; methodology. Afshin Hatami: Writing – review and editing; methodology; investigation. Philippe Bégin: Writing – review and editing; methodology; investigation. Kelly Grzywacz: Conceptualization; investigation; writing – review and editing; supervision; project administration; methodology; validation; visualization. No author received funding for this manuscript. Dr Hugo Gagnon has no conflict of interest to declare. Dr Kelly Grzywacz has participated in two advisory boards for Sanofi/Regeneron. She will co-chair a pediatric advisory board in June 2024. Dr Cam-Tu Émilie Nguyen is a subinvestigator in a clinical trial on Friedreich ataxia for PTC therapeutics at the Centre Hospitalier Universitaire Sainte-Justine. Dr Afshin Hatami: Advisory board consultant or conference honorarium or research support from Sanofi, Pfizer, Novartis, Abbvie, Galderma, Sun pharma, Bosch-Health, Leo pharma, Bristol-Myers Squibb, Bioderma outside the submitted work. Dr Philippe Bégin reports research personal fees from Novartis, Pfizer, Sanofi, DBV Technologies, ALK, and Aralez outside the submitted work and research support from Novartis, Regeneron, and Sanofi outside the submitted work.

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