Successful dupilumab treatment for ichthyotic and atopic features of Netherton syndrome

概要

There have been some case reports of Netherton syndrome (NS) successfully treated with dupilumab recently [1-4]. We report the courses of the patients’ atopic features including the time course of serum thymus and activation-regulated chemokine (TARC), serum IgE, soluble IL-2 receptor (sIL-2R), and IL-4, and the scalp hair condition before and after dupilumab treatment. We also evaluated Clinical Ichthyosis Score (CIS) [5]. Ethics committee approval was obtained. Written informed consent was obtained from the participants. Two NS patients were enrolled: a 32-year-old female (Case 1) and a 17-year-old female (Case 2).

　Case 1 had ichthyosis linearis circumflexa with double-edged scales on the trunk and extremities (Fig. 1a). She had optic nerve inflammation at age 23 years. She had been treated with repetitive pulse prednisolone therapy four times in seven years for the optic nerve inflammation. The patient is clinically allergic to eggs, cucurbitaceous fruits and vegetables, and crustaceans. Blood samples showed a total IgE of 76633 IU/mL and a serum TARC of 2102 pg/mL. Whole-exome sequencing (WES) revealed the patient to have the compound heterozygous mutations c.1621G>T (p.Glu541*) and c.2245A>T (p.Arg749*) in SPINK5. They were confirmed by Sanger sequencing. The mutations were previously reported in patients with NS [6].

　Case 2 showed erythroderma on the face and trunk, and ichthyosis linearis circumflexa lesions on the extremities (Fig. 1c). She had received treatment with the humanized monoclonal anti-IgE antibody omalizumab at a previous hospital 10 times at age 16 years, but the response had been inadequate. She had no notable medical history. She is allergic to wheat, buckwheat, eggs, seafood, poultry, and kiwifruit. Blood samples showed a total IgE of 5781 IU/mL and a serum TARC of 1858 pg/mL. WES revealed the patient to have the previously reported homozygous nonsense mutation c.2368C>T (p.Arg790*) in SPINK5, which was confirmed by Sanger sequencing [7].

　Several treatments including oral and topical steroids had been used for many years for both patients, with limited effectiveness. Case 1 reported that her skin condition had improved temporarily and that her hair had grown longer temporarily after the steroid pulse therapy. In Case 2, omalizumab treatment was tried but it did not work much. In both patients, the dupilumab treatment was initiated at a dose of 600 mg and was re- administered every 2 weeks at a dose of 300 mg. Both patients reported marked improvements in the pruritus on the day after the initial injection. After 6 months of dupilumab therapy, the CIS, Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), and visual analogue scale (VAS) values for itching were improved (Figs. 1b, d, Fig. 2a-d). Serum IgE and TARC were decreased (Fatieig. 2e, f). sIL-2R decreased moderately, but IL-4 did not change noticeably (Supplementary Fig. 1). No adverse events from the dupilumab treatment were detected in either patient.

　The scalp hair of both patients was coarse and brittle before treatment (Case 1, Fig. 1e; Case 2, Fig. 1g). Trichoscopy showed trichorrhexis invaginata in both patients (Case 1, Fig. 1i, Supplementary Fig. 2a, c; Case 2, Supplementary Fig. 2e, g). Light microscopic and scanning electron microscopic observations of the hair shafts are presented in Supplementary Figure 3. The hair shafts were so easily breakable that Case 1 had never had a haircut, and Case 2 had not had a haircut in years. At 6 months of dupilumab treatment, the scalp hair was noticeably longer (Case 1, Fig. 1f; Case 2, Fig. 1h). Trichorrhexis invaginata was still seen, but broken hairs were less numerous and the average hair length had increased (Case 1, Fig. 1j, Supplementary Fig 2b, d; Case 2, Supplementary Fig. 2f, h). We analyzed the hair area percentage (HAP) and hair shaft diameter (HSD) as reported previously [8]. The HAP gradually increased for Case 1, but did not increase for Case 2 (Supplementary Fig. 4a, b). HSD significantly decreased in Case 1 (<0.01), although it did not change noticeably in Case 2 (Supplementary Fig. 4c, d).

　NS patients have a deficiency of serine protease inhibitor LEKTI in the stratum corneum. It results in the increased activity of serine proteases, the accelerated desquamation of corneocytes, the thinning of the stratum corneum and the breakdown of the stratum corneum barrier, which accelerates percutaneous allergen sensitization and the overproduction of pro-Th2 cytokines [9]. Patients with NS show the highest induction of Th17 pathway genes of any ichthyosis subgroup [10]. The significant atopic diathesis and Th2 cytokine profile of NS may explain the improvement by the action of dupilumab on pro-Th2 cytokines [2].

　Both patients in this study reported that their symptoms were improved in the first week after the injection of dupilumab, but that the pruritus recurred gradually in the second week. A larger injection dose or a shorter interval might be recommended for NS patients. There were discrepancies in the clinical and laboratory responses to dupilumab between the two cases (i.e., in IL-4, HAP, and HSD). As can be seen from previous case reports of treatment with dupilumab, the efficacy varies from person to person [1-4].

　This is the first report to evaluate and analyze the hair symptoms of NS patients during dupilumab therapy. Interestingly, both of NS patients in our study had episodes in which their scalp hair grew longer when their skin was in good condition. During our observational study, hair length increased with the suppression of Th-2 mediated inflammation. Although the hair shaft nodules are not completely eliminated, hair growth seems to occur when the allergic inflammation has subsided. Improvement of skin inflammation and itching is thought to reduce scratching behaviors, resulting in reduced hair breakage at the nodules from physical stress. Scalp hair symptoms are serious burdens for NS patients, affecting their quality of life, and dupilumab might be helpful in improving the hair symptoms.

　The present study suggests that the blockade of IL-4 and IL-13 signaling by dupilumab is a promising treatment for NS, although further studies enrolling a large number of NS patients are needed to confirm the efficacy of dupilumab as a treatment for NS.

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