Varghese et al. Allergy Asthma Clin Immunol (2021) 17:58 Allergy, Asthma & Clinical Immunology https://doi.org/10.1186/s13223-021-00561-2 CASE REPORT Open Access Efect of omalizumab for autoimmune progesterone dermatitis refractory to bilateral oophorectomy: a case report Akshay Varghese1* , Terri Paul2, Harold Kim3, Stan Van Uum2, Peter Vadas4 and Alescia Azzola1 Abstract Background: Autoimmune progesterone dermatitis (APD) is a rare skin condition caused by sensitivity to high levels of progesterone secreted during the luteal phase of the menstrual cycle. This may be due to various pathophysiological mechanisms including a Type I and Type IV hypersensitivity reaction. Here we present the case of a patient with APD whose episodic fares were controlled by the addition of omalizumab, after a bilateral oophorectomy failed to resolve her symptoms. Case Presentation: A 34-year-old female presented to our Endocrine clinic with marked Cushingoid features secondary to high-dose oral prednisone prescribed for APD diagnosed 6 years earlier. She frst developed a pruritic maculopapular rash on her arms and legs just after the birth of her second child in 2009. The rash was also associated with headaches and difuse angioedema. Symptoms occurred for 1–2 weeks, in a cyclical fashion, during the luteal phase of each menstrual cycle and subsided within a few days after menses. The severity of symptoms increased as time went on, and fare-ups began to also include dyspnea, nausea, vomiting and abdominal pain. Her symptoms improved with administration of oral prednisone, but she continued to experience breakthrough symptoms. After multiple failed treatment modalities, she elected bilateral oophorectomy in 2018. However, her symptoms of APD persisted and she still required high-dose oral prednisone. Her condition was further complicated by vasomotor menopausal symptoms and progressive iatrogenic Cushing’s syndrome. She eventually was started on Omalizumab, which suppressed further recurrences of APD symptoms and allowed her to wean of prednisone. Vasomotor menopausal symptoms responded well to the addition of conjugated estrogens with bazedoxifene. However, her symptoms of difuse bony pain and arthralgias which started whilst on prednisone have persisted in spite of discontinuing prednisone. Conclusions: To our knowledge, this is only the third case of APD which was successfully treated with Omalizumab and the frst case where a bilateral oophorectomy failed to resolve symptoms of APD in the literature. This case also demonstrates the complications of vasomotor menopausal symptoms secondary to a bilateral oophorectomy, as well as the adverse efects of long-term glucocorticoid therapy. Keywords: Autoimmune progesterone dermatitis, Bilateral oophorectomy, Omalizumab Background Autoimmune progesterone dermatitis (APD) is a rare condition, with a literature review from 2016 *Correspondence: [email protected] 1 Division of Internal Medicine, Northern Ontario School of Medicine, documenting approximately 90 cases [1]. Patients with Sudbury, ON, Canada APD are sensitive to the high levels of progesterone Full list of author information is available at the end of the article secreted during the luteal phase of the menstrual cycle © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Varghese et al. Allergy Asthma Clin Immunol (2021) 17:58 Page 2 of 5 [2]. Depending on whether the reaction is IgE-mediated, or T-cell mediated, APD can present in various forms, such as eczema, folliculitis, and erythema multiforme, but can also progress to more acutely severe manifestations such as dyspnea and anaphylaxis [2]. Symptom onset is typically 1 week prior to menses and symptoms resolve a few days after the onset of menstruation [3, 4]. Although the pathogenesis of the disease is not yet fully understood, it has been postulated to involve Type I and Type IV hypersensitivity reactions [4]. Progesterone has been noted to stimulate immunoglobulin E (IgE)- mediated mast cell degranulation [2, 5]. Additionally, progesterone sensitivity may be also due to cell-mediated Fig. 1 Acute angioedema—patient photograph, consent obtained immunity, due to prior uptake of progesterone by antigen-presenting cells and stimulation of T-helper cells [4]. Furthermore, cross-reactivity with other endogenous steroid hormones such as 17-α-hydroxy-progesterone abdominal cramping. All symptoms continued to follow may also be a plausible mechanism for increased the identical luteal phase cyclical onset of presentation. progesterone sensitivity in APD patients [1]. For several years, she was treated with numerous Te diagnosis of APD is based on the unique cyclical medications, including frst and second generation H1 appearance of symptoms during a menstrual cycle. If and H2 histamine antagonists, tricyclic antidepressants, APD is IgE-mediated, the diagnosis is confrmed by calcineurin inhibitor immunosuppressant therapy a positive wheal and fare response to skin testing with and psoralen and ultraviolet A (PUVA) therapy. progesterone [6]. Various treatment options have been Tese treatments were all unsuccessful in improving described for APD, including gonadotrophin-releasing her symptoms. She was eventually started on oral hormone (GnRH) agonists (suppressing progesterone prednisone in doses of up to 100 mg daily. Symptomatic production), oral contraceptives, tamoxifen, improvement was achieved with corticosteroid use, antihistamines, prednisone, dapsone, thalidomide, but pre-menstrual fare-ups would still occur quite azathioprine and danazol [7–9]. However, if these often. After three years of persistent symptoms, she was therapies fail, or cause intolerable side efects, a bilateral referred to an Immunologist who established a likely oophorectomy can be performed as a more durable diagnosis of autoimmune progesterone dermatitis with solution [7]. potential catamenial anaphylaxis. Tis was confrmed using a progesterone skin test. Her serum tryptase at baseline was low at 2.8 Ug/L (3.8–11.4 Ug/L). Case Presentation She was then started on a trial of a low-dose oral contraceptive pill, which contained 0.02 mg ethinyl A 34-year-old female with pronounced Cushingoid estradiol and 0.1 mg of levonorgestrel, in an attempt to features presented to our Endocrinology clinic in 2018. be desensitized to progesterone. High dose prednisone She had been taking high dose oral prednisone for a was prescribed for fare-ups. Tis was an attempt to diagnosis of severe autoimmune progesterone urticaria, wean her of prednisone. After 6 months, there was still refractory to bilateral oophorectomy. no improvement in her symptoms. Te reintroduction A raised pruritic macular erythematous rash initially of antihistamine therapy, intensifed up to quadruple appeared on her arms and legs in 2009, two to three therapy, as well as a trial of cyclosporine therapy also did days after the birth of her second child. Tis rash was not allow for adequate prednisone taper. Gonadotropin- associated with headaches, and difuse angioedema of releasing hormone (GnRH) therapy was also her hands, feet, lips, and eyelids (Fig. 1). Te pruritic rash recommended. However, the patient declined additional continued to occur in a cyclical fashion, appearing one medical therapies. Due to the long-term use of high-dose to two weeks prior to each menses and resolving within prednisone, she developed Cushingoid features including a few days of menstruation onset. Six months after the moon face, violaceous striations, alopecia, and central post-partum period, in tandem with the return of her adiposity Fig. 2—left panel). menstrual cycles, her symptoms quickly progressed from ( Due to the progressive side efects of prednisone as well cyclic urticaria to systemic symptoms such as dyspnea. as persistent symptoms, she elected to undergo a bilateral Her fare-ups also coincided with nausea, dizziness, and oophorectomy at age 34 in June 2018. Tere was short Varghese et al. Allergy Asthma Clin Immunol (2021) 17:58 Page 3 of 5 post-oophorectomy. To our knowledge, this is the frst case where a bilateral oophorectomy procedure may have failed to resolve symptoms of APD. However, one potential publication bias could indeed be a lack of reporting of non-responsive cases. Tree months following bilateral oophorectomy, she presented to our Endocrine clinic for an initial consultation for Cushing syndrome while being treated with 50 mg of daily prednisone. In search of a prednisone sparing treatment for her APD, we initiated Omalizumab (Xolair) monoclonal