Systemic <scp>JAK</scp> inhibitors for treatment of cutaneous manifestations in a patient with <scp> <i>SPINK5</i> </scp> variants: A case report and review of the literature

Netherton syndrome (NS) is an autosomal recessive erythrodermic primary atopic condition caused by loss-of-function SPINK5 variants.1, 2 SPINK5 encodes lympho-epithelial kazal-type 5 (LEKTI). Reduced LEKTI in NS leads to unopposed protease activity, causing skin barrier impairment (Figure 1).1, 2 NS presents with ichthyosis, erythroderma, trichorrhexis invaginata, atopy, recurrent herpes and/or bacterial infections, autoimmunity, elevated IgE, eosinophilia, Th2 predominance, decreased memory B cells, specific antibody deficiency, and/or reduced NK cell function.1, 2 Multiple treatments have been trialed for NS.3-5 Five previously published case reports describe the use of systemic JAK inhibitors for the cutaneous manifestations of NS.6-9 Here, we describe a patient with two novel SPINK5 variants of uncertain significance (VUS), treated with systemic JAK inhibitors, without significant improvement in cutaneous disease. We also summarize previous reports of JAK inhibitor use for patients with Netherton syndrome/SPINK5 variants. The patient is a 17-year-old male with severe atopic dermatitis, peanut allergy, and allergic rhinoconjunctivitis. Atopic dermatitis was diagnosed at 1–2 months old, and it was described as very erythematous and inflamed, involving the neck, elbows, wrists, and dorsum of the feet. He had persistent severe cutaneous symptoms (large lichenified, scaly, hypopigmented plaques on extremities; diffuse erythematous and dry plaques on trunk and face) (Figure 1). Rashes were refractory to topical corticosteroids, topical calcineurin inhibitors, emollients, and dupilumab 300 mg every 2 weeks. He had a severe peanut allergic reaction at 10 months old and was admitted to the intensive care unit for management. The most recent peanut skin prick testing performed in adolescence showed a 14 mm wheal × 16 mm flare, serum-specific peanut IgE = 4.24 kU/L, and Ara h 2-specific IgE = 4.91 kU/L. He has a history of dermatographism and spontaneous urticaria. He had chronic nasal congestion and recurrent herpes simplex virus (HSV) keratitis (Figure 1) diagnosed when he was a young child. He experienced significant symptomatic improvement in rhinoconjunctivitis symptoms with aeroallergen immunotherapy (AIT) and initially tolerated injections. However, he experienced anaphylaxis (urticaria, rhinoconjunctivitis, and hypotension) treated with intramuscular epinephrine after receiving his AIT maintenance dose (0.5 mL of the 1:1 vial). The patient desired AIT continuation, and despite significant AIT dose reduction and cetirizine 20 mg pre-treatment, he developed urticaria about 30 min after every subsequent AIT injection, requiring AIT cessation. The patient is 50% Native American and 50% European. His mother has urticaria and environmental allergies, and his maternal grandmother has a food allergy. The family history was negative for known inborn errors of immunity or other genetic conditions. Given the patient's multiple, severe atopic conditions, lack of dupilumab response, and recurrent HSV keratitis, there was concern for an inborn error of immunity. Baseline laboratory studies demonstrated an elevated IgE (1378 IU/mL) and normal IgG (929 mg/dL), IgA (183 mg/dL), IgM (75 mg/dL), baseline tryptase (3.1 μg/L), and absolute eosinophil count (0.4 K/μL). A targeted 429-gene panel for inborn errors of immunity demonstrated two heterozygous VUS in SPINK5. The SPINK5 c.2390G > T (p.Gly797Val) variant (paternal inheritance) is not reported in gnomAD, CADD = 23.9, and Polyphen-2 HumDiv and HumVar designations are “Probably damaging.” The SPINK5 c.1499G > A (p.Arg500Gln) variant (maternal inheritance) is not reported in gnomAD, CADD = 16.1, and Polyphen-2 HumDiv and Polyphen-2 HumVar designations are “Possibly damaging” and “Benign,” respectively. The genetic changes are documented in multiple mammalian species, which may indicate that they are non-deleterious. His asymptomatic brother was negative for both SPINK5 variants, increasing the likelihood that the patient's variants contribute to his presentation. Taken together, the available data and models predicting pathogenicity of his SPINK5 variants are mixed. Microscopic evaluation of the patient's eyebrow hair demonstrated unevenly spaced nodes along the hair shaft, though not entirely characteristic of the “bamboo” or “golf tee” hair appearance described in trichorrhexis invaginata. For severe eczematoid plaques, he was prescribed upadacitinib 15 mg/day, and it was recommended to continue his topical regimen. He initially experienced improvement in the extent of plaques and degree of pruritus. However, upadacitinib was discontinued after 3 months because the cutaneous improvement was not sustained, and he developed diarrhea, a known adverse effect of upadacitinib. Stool pathogen testing was negative. He transitioned to abrocitinib 100 mg/day for 2 months and continued twice daily topical medium-potency corticosteroid on the body, topical calcineurin inhibitor on the face, and emollients on the face and body. There was no significant change in eczematoid plaques. Abrocitinib was increased to 200 mg/day for 3 months. He was advised to use a high-potency corticosteroid on the body twice daily for 3 days at a time for severe plaques, with a step-down to medium-potency corticosteroids. He continued twice daily topical calcineurin inhibitor on the face and twice daily emollient on the body and face. Though there was a minor reduction in pruritus with the increased abrocitinib dose, there was no improvement in the severity/extent of the plaques. Abrocitinib was discontinued. There was no recurrence of HSV keratitis or evidence of other HSV disease while on JAK inhibitors. Our patient had two novel SPINK5 VUS and a clinical presentation aligning with previously described cases of NS. The patient had widespread ichthyosis and cutaneous scaling, multiple severe atopic conditions, recurrent HSV keratitis, elevated total IgE, and two variants in SPINK5. His cutaneous disease was refractory to upadacitinib, abrocitinib, dupilumab, high- and medium-potency topical corticosteroids, topical calcineurin inhibitors, and emollients. In addition to other immunologic therapies,3, 4 there are recent reports of oral JAK inhibitor use (abrocitinib,7 upadacitinib,4, 6, 9 and tofacitinib10) in NS, which are summarized in Table 1. 17-year-old male (patient presented) Unlike the patient presented here whose variants result from substitutions, most of the previously described patients for whom genetics are reported had SPINK5 deletions. Three previously reported patients failed secukinumab and dupilumab prior to JAK inhibitor therapy.6-8 The patient managed with abrocitinib had a sustained response at 3 months,7 but the patients treated with upadacitinib did not have a persistent response beyond 18, 9 or 26 months. The genetic variant of the child treated with tofacitinib is unknown, and his response was sustained up to 8 weeks after starting therapy. Mechanistically, JAK1 inhibition is expected to reduce pSTAT1, which is upregulated in NS.10 Similar to some previously reported cases, our patient did not have a substantial response to systemic JAK inhibitors. The reported response to this class of medications is mixed, and further research is needed regarding long-term effectiveness and safety in patients with Netherton syndrome/SPINK5 variants. This case adds to the growing body of literature about systemic JAK inhibitors for the management of severe cutaneous manifestations associated with SPINK5 variants. Bridget E. Wilson: Writing – original draft; writing – review and editing. Theresa A. Grebe: Writing – review and editing; supervision. Supraja Prakash: Data curation. Cindy S. Bauer: Conceptualization; writing – review and editing; supervision. No funding was required for the preparation of this article. The authors decalre no conflicts of interest. Informed consent was obtained from the patient's mother to submit this case for publication. The patient provided assent for the submission of his case for publication. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/pai.70039.