Dupilumab as a treatment for bullous pemphigoid in a liver transplant recipient: A case report

Abstract

Bullous pemphigoid is a common subepidermal autoimmune bullous disease that affects the skin and mucous membranes. It is more prevalent in the elderly, often resulting in significant morbidity and mortality. Bullous pemphigoid is rare in solid organ transplant recipients but presents unique challenges due to their underlying immunosuppression, which increases the risks of infection and adverse drug reactions. Herein, we present the first reported case of dupilumab successfully treating bullous pemphigoid in a liver transplant recipient.

Introduction

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease caused by autoantibodies against proteins at the dermal–epidermal junction. ¹ Although no precipitating factors are identified in most cases, it may be triggered by medications, trauma, or skin infection. ² Since the condition involves immune system malfunction, mainstay treatment involves systemic or topical corticosteroids targeting inflammation and suppressing the immune system. However, as BP is a longstanding and chronic condition and systemic corticosteroids have several significant side effects, ³ it is unfavorable to provide long-term high-dose corticosteroids. Therefore, steroid-sparing agents are often added in clinical practice to facilitate corticosteroid tapering and discontinuation once the disease is under control. More recently, the treatment of recalcitrant BP has involved adjuvant biologic drugs, such as rituximab, which is an immunosuppressant, and dupilumab and omalizumab, which are immunomodulators.^1,4 Dupilumab is a biologic without immunosuppressive effects and has recently been shown to be associated with improved clinical symptoms and a favorable safety profile in patients with BP.^4–6

Although rare, cases of BP in renal and liver transplant recipients have been reported, and they tend to be partially resistant to systemic steroid therapy.^7–10 Linking organ transplantation to BP, it has been hypothesized that a chronic allogeneic process resulting from immune cross-reactivity between the skin and the transplanted organ leads to the development of autoantibodies in organ allografts, or that immunosuppressants that reduce interleukin-2 (IL-2) gene expression may suppress the number of regulatory T cells and modify autoantibody induction, in addition to increasing infection risk, which may trigger autoimmunity.^2,8,10 As solid organ transplant recipients (SOTRs) are already immunocompromised, providing more immunosuppressors for comorbid BP can weaken their immune system further, making immunomodulatory biologics, such as dupulimab, a good candidate for treatment.^4,11 Here, we report the first case of a SOTR with BP successfully treated with the addition of dupilumab to her course of treatment.

Case report

A 70-year-old female presented to our transplant dermatology clinic with complaints of pruritic lesions on the face and lower legs for the past few months, as well as new-onset painful lesions with discharge on the right side of the neck. The patient had a history of many comorbidities, along with a liver transplant 29 years ago due to fulminant hepatitis B infection. She was on cyclosporine 125 mg b.i.d. as her anti-rejection medication, leading to chronic immunosuppression.

On examination, she had a 1 cm tense blister on the right lateral neck and eczematous plaques on the face and legs. Biopsy was performed and was consistent with BP, demonstrating subepidermal bullae with abundant eosinophils and direct immunofluorescence findings of focal linear immunoglobulin G (IgG) and complement component 3 at the dermal–epidermal junction. The patient continued to develop more blisters on the neck and scalp.

Therefore, treatment began with doxycycline 100 mg b.i.d., niacinamide 500 mg b.i.d., mometasone furoate ointment, and mupirocin ointment. This controlled the BP, leading to no bullous lesions after 5 weeks. However, she presented to the emergency department 4 months later due to increasingly generalized lesions across her body with mucous membrane involvement, and was started on prednisone 50 mg q.d. With a gradual taper to 30 mg q.d. after 3 weeks, she experienced an acute worsening of her BP with active development of new lesions (Figure 1). She presented to the transplant dermatology clinic with widespread intact and ruptured blisters all over the body and was systematically unwell with pain and several comorbidities, prompting hospital admission for disease and infection control. Prednisone was increased to 60 mg q.d., mycophenolate mofetil 500 mg b.i.d. was given as a steroid-sparing agent, and the dosage of cyclosporine was also increased. The patient was hospitalized for 8 weeks due to superinfection of BP lesions and the need for significant nursing time and expertise for management and dressings.

Figure 1.

Multiple tense bullae present on the left upper arm, along with erosion and crusting on an erythematous base during BP flare.

Since she was on baseline immunosuppressive medication due to liver transplant, it was expected that she might have a milder BP disease course. However, it remained difficult to treat. As improvement was slow and she was on high doses of immunosuppressants, a steroid-sparing non-immunosuppressive agent was considered. At the beginning of the eighth week, she was started on dupilumab 300 mg injection every 2 weeks. Patient was seen 3 weeks after discharge from the hospital, and her BP was very well-controlled (Figure 2). Currently, 10 months after initiating dupilumab, she is maintaining control of her BP and is on 5 mg prednisone q.d., back to her original dose of cyclosporine, and her mycophenolate mofetil has been stopped.

Figure 2.

Resolution of BP lesions on the left upper arm was seen at 4 weeks after dupilumab initiation.

Discussion

Dupilumab, an IL-4 receptor alpha antagonist, is a human monoclonal antibody that inhibits IL-4 signaling via the type 1 receptor and both IL-4 and IL-13 signaling via the type 2 receptor, further inhibiting the release of proinflammatory cytokines, chemokines, and IgE. ¹² IL-4 and IL-13 are the key cytokines of the type 2 helper T-cell (T_H2)-mediated immune response, which plays a key role in the pathogenesis of BP. ¹³ BP is characterized by IgG and IgE autoantibodies against structural proteins of the dermal–epidermal junction, specifically hemidesmosomal proteins BP antigen 180 (type XVII collagen) and BP antigen 230.^14,15 Elevated IgE serum levels and deposits along the basal membrane zone have been found in patients with BP. ¹⁵ Although originally indicated for atopic dermatitis, dupilumab has shown effectiveness as an off-label medication for BP,^16–18 among numerous other chronic dermatological conditions. ¹⁹ Dupilumab induces the inhibition of IL-4 and IL-13 signal transduction, leading to a reduced T_H2-type response.^5,20

BP disproportionately affects elderly patients, who often have multiple comorbidities, and their therapeutic options are often limited.^1,21 The disease has been rarely reported in SOTRs.^7–10 Although our patient was on immunosuppressive medications due to her liver transplant, which may have helped to inhibit her autoimmune response, she had a severe BP disease course. In fact, immunosuppressive medication in transplant patients may modify their immune response and induce BP. ² Furthermore, prescribing additional immunosuppressive medications may lead to immunocompromisation, increasing the risk of infection. Our case is the first where dupilumab was used to treat recalcitrant BP in a transplant recipient and demonstrates the potential of dupilumab as a therapeutic option for BP in transplant recipients who already have a weakened immune system or as an additional therapy when immunosuppressive agents fail. These encouraging outcomes support the need for innovative, targeted treatments for SOTRs with skin disease. However, additional research is urgently required to validate the safety and efficacy of biologic therapies in this high-risk patient population.