Successful treatment of checkpoint inhibitor‐associated bullous pemphigoid with dupilumab in a patient with angiosarcoma

Dear Editor, Immune checkpoint inhibitors (ICI) have established in the treatment of numerous tumor entities. However, non-specific immune activation often leads to adverse events that can manifest themselves in all organ systems and most frequently affect the skin.1 Cutaneous side effects develop comparatively early, usually occurring in the first 6 weeks after the start of therapy. The most common cutaneous manifestation is maculopapular exanthema, less frequently dermatoses such as vitiligo, psoriasis, lichenoid dermatoses, or blistering diseases including bullous pemphigoid (BP) can occur.1, 2 We report on a 65-year-old patient with osseous metastatic angiosarcoma. Following the initial diagnosis of angiosarcoma in November 2016, the patient was treated with chemotherapy, which yielded a good response. In the further course, osseous metastasis occurred, so chemotherapy with gemcitabine and dacarbazine was initiated. As the disease progressed under this treatment, ICI therapy was initiated with the combination of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab and the programmed cell death (PD)-1 inhibitor nivolumab. The efficacy of the combination therapy has been described for angiosarcoma with an overall response rate of 25%.3, 4 A possible explanation for the efficacy of ICI in angiosarcoma could be the tumor inflammation signature present in some patients as well as a high tumor mutation burden.4, 5 With initially good tolerability of ICI therapy, partial remission of angiosarcoma could be achieved. However, 132 weeks (corresponding to 2 years, 7 months) after initial administration, pruritic skin changes and blisters appeared on arms, back, and décolleté (Figure 1a, b). Mucous membranes were not affected. A sample biopsy with direct immunofluorescence (DIF) showed subepidermal clefts and linear deposits of C3 and IgG along the basement membrane zone (Figure 2). Indirect immunofluorescence revealed circulating IgG autoantibodies with linear binding to the basement membrane. BP180-NC16A was elevated in ELISA. This confirmed the diagnosis of BP,6 which we evaluated in association with the ICI. ICI therapy was therefore paused and oral steroid pulse therapy with prednisolone 80 mg (1 mg/kg body weight) was initiated. New blisters did not appear during this treatment. Since a longer-term pause in ICI would have been prognostically unfavorable for the patient due to the metastatic angiosarcoma, initiation of steroid-sparing therapy was necessary in order to reduce the steroid dose quickly and continue sustained ICI therapy as promptly as possible. The BP guideline recommends azathioprine, dapsone, doxycycline, methotrexate and mycophenolate mofetil as steroid-sparing systemic therapies.7 However, no specific recommendations for ICI-associated BP or tumor patients are made in the guideline.7 Combining ICI with antibiotic therapies can potentially lead to a loss of efficacy.8 The use of antibiotic therapy during ICI has been associated with poorer progression-free survival.9 These negative effects were primarily observed for antibiotic treatments before the start of ICI and for broad-spectrum antibiotics.8, 10, 11 This could be due to a change in the gut microbiome caused by antibiotic therapy.9 Overall, restraint in the use of antibiotics under ICI is recommended,8 which is why we decided against long-term treatment with doxycycline in this case. The long-term use of broad immunosuppression should also be avoided, both due to the underlying malignant disease and during ICI therapy, in order to minimize the potentially negative influence on the antitumor effect of ICI. Hence the immunosuppressants recommended in the BP guideline (e.g. azathioprine or methotrexate) also represent unfavorable treatment options for the patient and were avoided in this case.12, 13 Therapy with the interleukin (IL)-4/IL-13 inhibitor dupilumab has been described in the literature as a successful treatment option for BP as well as for ICI-associated BP and is listed as a treatment option in the European BP guideline.2, 14-19 Th2 cell-mediated inflammatory responses are thought to be involved in the loss of tolerance to BP180. Dupilumab modulates the Th2 cytokines IL-4 and IL-13, the levels of which are often elevated in both serum and blister fluid in BP patients.14 A retrospective study showed a 92.3% response to dupilumab in patients with BP, and complete healing was achieved in 53.8%.19, 20 Against this background, we decided to initiate therapy with dupilumab one week after the start of steroid pulse therapy, in the standard dosage approved for moderate to severe atopic dermatitis (300 mg subcutaneously every 2 weeks). After introduction of the antibody therapy, the oral steroid was gradually tapered off and ICI therapy was resumed. Under dupilumab therapy, even after continuation of ICI therapy, there was no recurrence of BP (Figure 2c, d). Successful treatment of the immune-mediated side effects allowed the patient to continue effective treatment of his tumor disease. BP is one of the rare cutaneous side effects of ICI and has been associated with PD-1/PD-L1 inhibitors and the primary tumor entities malignant melanoma, bronchial carcinoma, urothelial carcinoma, and cutaneous squamous cell carcinoma.1 To date, neither the occurrence of BP under ICI in angiosarcoma nor the successful treatment of ICI-associated BP in angiosarcoma with dupilumab has been described. The occurrence of initial skin changes has been reported with a mean duration of 21 weeks (range 1–88) from first administration, while blisters occur on average after 27.5 weeks (range 3–104).21 Therefore, in our case, blisters appeared unusually late. Due to the sometimes prolonged period of time between initiation of therapy and the appearance of skin changes, it is not always easy to understand this relationship. However, as immune-mediated side effects can generally occur up to one year after discontinuation of therapy, a possible association should always be considered in such patients.1, 21 To date, no significant clinical or dermatohistopathological differences between idiopathic and ICI-associated BP have been identified, apart from the increased incidence in males and more frequent mucosal involvement.22 However, there are indications that ICI-associated BP can persist for up to several months after discontinuation of ICI, presumably due to persistent immune activation.1 Due to the underlying tumor disease, discontinuation of ICI is not desirable in many cases, so being able to fall back on effective treatment options that are compatible with tumor diseases is of high relevance. Due to the combination with steroid pulse therapy, the therapeutic success in our case cannot be attributed to dupilumab alone. Hence, this should be seen as a possible limitation. Nevertheless, our case shows that the use of dupilumab for immune-mediated BP can be an effective treatment option with few side effects and should be considered, in particular, if immunosuppressive or antibiotic therapy is to be avoided. Here, management of side effects under ICI is largely independent of the tumor entity. Open access funding enabled and organized by Projekt DEAL. None.