Upadacitinib leading to resolution of refractory mucosal erosions in a case of pemphigus vulgaris

Pemphigus vulgaris (PV) is an intraepithelial autoimmune bullous disease (AIBD), in which IgG autoantibodies against desmoglein-1 (Dsg1) and desmoglein-3 (Dsg3) lead to cutaneous and mucosal erosions, respectively.1 In 80% of cases, patients will present with oral mucosal lesions, later developing cutaneous lesions.1 Treatment includes systemic corticosteroids and steroid-sparing agents (azathioprine, mycophenolate mofetil, rituximab, or IVIG).2 Treatment remains uncertain because of insufficient clinical trials and uniform outcome measures.2 Recent studies suggested Janus kinase (JAK) inhibitors may be useful in treating AIBD, including PV.3 Herein, we describe the treatment of PV with upadacitinib. A 64-year-old man with a several-month history of PV (outside-biopsy proven) presented to the clinic after hospital discharge amid a severe flare. He had received one dose of rituximab and was on prednisone 80 mg/daily. Examination revealed erythematous erosions on the face, extremities, trunk, and oral mucosa (Figure 1a). He admitted to a 15-pound weight loss as the oral lesions led to decreased PO intake. Laboratories revealed a Dsg1 of 84.9 U/ml and Dsg3 of 152.3 U/ml. Mycophenolate mofetil (MMF), 500 mg/twice daily, was prescribed. A second rituximab infusion was dosed 2 weeks after the first. Two months later, new erosions were noted. Monthly IVIG was initiated, and MMF was increased to 3 g/daily, with rituximab every 6 months. After one dose of IVIG, the active cutaneous and oral lesions improved. Prednisone taper was initiated, while MMF, IVIG, and rituximab were continued. The patient was doing well off prednisone but then had a COVID-19 infection, after which PV flared with new oral and cutaneous lesions (Figure 1b). High-dose prednisone was initiated while continuing with IVIG, rituximab, and MMF. Flaring continued, so MMF was transitioned to mycophenolic acid 720 mg/twice daily. After several months of treatment, his skin continued to improve; however, the oral erosions persisted, and Dsg1 and Dsg3 remained elevated. Due to a lack of improvement in the oral mucosal lesions and poor quality of life, off-label upadacitinib 15 mg/daily was prescribed in conjunction with rituximab and IVIG. Mycophenolic acid was discontinued (Figure 2a,c). Two months later, the oral lesions continued to heal, and no new lesions developed. PO intake was improved. After 6 months of therapy with upadacitinib, no new cutaneous or mucosal lesions occurred, and previous lesions had healed (Figure 2b,d). Recent laboratories showed a Dsg1 of 17.9 U/ml (normal) and a Dsg3 of 176.2 U/ml. Although clinically improved, elevated Dsg3 indicates active disease; therefore, upadacitinib 15 mg/daily is continued with IVIG monthly and rituximab biyearly to manage the disease. Herein, upadacitinib showed promise as one agent used in combination with rituximab and IVIG to induce clinical remission of mucosal PV while preventing the formation of new cutaneous lesions, allowing discontinuation of long-term oral corticosteroids. PV patients with high corticosteroid exposure have a dose-dependent risk of cataracts and fractures. Corticosteroid-free remission remains a goal in PV treatment.4 Upadacitinib is a selective JAK1 inhibitor. This family of proteins conducts pro-inflammatory signals and induces the production of cytokines. Dsg3-reactive helper T cell (Th)1 and Th2 cells are active in PV.5 Aberrant Th1 cells potentiate an inappropriate immunomodulatory response, resulting in overexpression of IFN-γ. Th2 cells secrete IL-4, a cytokine that stimulates B-cell proliferation, leading to immunoglobulin switch, a vital component of PV pathogenesis. Other cytokines, such as IL-6, IL-8, IL-10, IL-12, and IL-15, may also be elevated in PV patients.5 Importantly, these cytokines utilize the JAK-STAT family of proteins to drive inflammation, demonstrating a potential therapeutic target for upadacitinib in PV. Although limited, we hope this report can add to the literature regarding the use of JAK inhibitors in pemphigus disease. Long-term follow-up and randomized clinical trials are necessary. The results detailed here may motivate future studies concerning PV treatment with upadacitinib. Patient consent was obtained for the publication of this manuscript.