Possible drug reaction with eosinophilia and systemic symptoms after spironolactone therapy for clinical hyperandrogenism: a case report

Abstract

Objective

To present a case of possible drug reaction with eosinophilia and systemic symptoms (DRESS) after spironolactone and to review existing literature on serious cutaneous adverse reactions to spironolactone.

Design

Case report and literature review

Subject

A 29-year-old woman with hyperandrogenism who developed a febrile, pruritic, generalized rash 1 week after initiating spironolactone.

Exposure

Discontinuation of spironolactone

Main Outcome Measures

Resolution of symptoms, RegiSCAR diagnostic assessment for DRESS

Results

Symptoms resolved after discontinuation and recurred upon two separate rechallenges. Although laboratory and histopathological data were not available to definitively confirm the diagnosis of DRESS, clinical features were suspicious for DRESS on the basis of RegiSCAR criteria. The patient met five diagnostic criteria, which would classify this as a “possible” case. Other reported cutaneous reactions to spironolactone include linear immunoglobulin A bullous dermatosis and erythema multiforme.

Conclusion

Clinicians should be aware of the rare but potentially serious risk of DRESS in patients treated with spironolactone. Prompt recognition, drug discontinuation, and supportive management are essential. Diagnostic confirmation with laboratory studies and skin biopsy should be pursued in suspected cases.

Hyperandrogenism refers to an excess of androgens, most commonly testosterone, and may present with hirsutism, acne, alopecia, and oligomenorrhea or amenorrhea. The most common cause is polycystic ovary syndrome (PCOS), with a prevalence of 6%–15% depending on the diagnostic criteria (1, 2).

Combined oral contraceptive pills and lifestyle modifications are first-line treatments for hyperandrogenism. For patients with suboptimal response after 6 months, antiandrogens such as spironolactone are considered appropriate second-line agents according to the 2023 International Evidence-Based Guideline (3). Spironolactone is a dose-dependent androgen receptor antagonist that may also inhibit 5-α-reductase. Frequently reported adverse effects include nausea, breast tenderness, nipple discharge, menorrhagia, and headache (4). Although generally well tolerated, spironolactone has been rarely associated with cutaneous hypersensitivity reactions.

We present a case of spironolactone-induced cutaneous hypersensitivity in a patient with hyperandrogenism, with symptom recurrence upon two separate rechallenges. We also review the differential diagnosis and relevant literature, including reported cases of drug reaction with eosinophilia and systemic symptoms (DRESS) and other dermatologic reactions to spironolactone. Given the limited number of documented cases, each new report contributes valuable insight into the clinical spectrum of spironolactone-related hypersensitivity.

Case report

A 29-year-old nulligravid woman presented for management of hyperandrogenism. She presented with bothersome acne and terminal hair growth on the abdomen despite 5 years of combined oral contraceptive (COC) use. Before COC initiation, she had regular, monthly menstrual cycles. She had no evidence of virilization. Alternate causes of hyperandrogenism, including congenital adrenal hyperplasia, Cushing syndrome, androgen-secreting tumors, hypothyroidism, hyperprolactinemia, and exogenous androgen exposure, were excluded by history, physical examination, laboratory testing, and pelvic ultrasound. Given polycystic ovaries seen on ultrasound, she was diagnosed with PCOS. Because of persistent acne and hirsutism, spironolactone 100 mg daily was initiated. She was not taking any other medications or supplements apart from COCs.

Her past medical history included a rash after amoxicillin use. She also had a history of an allergic rash on her face and had a positive skin patch test to balsam, cetrimide, chloroxylenol, formaldehyde, chlorhexidine, amidoamine, and p-methylaminophenol. She had no personal or family history of autoimmune disease.

One week after starting spironolactone, she presented to urgent care with fever (39.2 °C), fatigue, facial edema, and a pruritic rash that began on the trunk and spread to the extremities. She denied other medications aside from acetaminophen for fever. Physical examination revealed facial edema, aphthous ulcers on the buccal mucosa, and blanching 1–2 mm papules on the face, chest, arms, and legs, sparing the palms and soles (Fig. 1A and B). No lymphadenopathy was appreciated.

Figure 1.

(A) Day 1 of pruritic, morbilliform generalized rash that started on the trunk and spread to the extremities. (B) Erythema spread to the extremities but spared the palms and soles.

Infectious workup was negative for influenza A/B, streptococcus, Epstein-Barr virus, COVID-19, and measles. Given spontaneous improvement and lack of other findings, a viral exanthem was initially suspected.

Spironolactone was discontinued, and supportive care with acetaminophen, antihistamines, and oral hydration was provided. Within days, her fever resolved, but the rash coalesced into dusky macules covering more than 50% of her body surface area, particularly on the lower extremities (Fig. 2A and B). She also developed bilateral leg paresthesia, interfering with sleep. Gabapentin 300 mg nightly was initiated.

Figure 2.

(A) The rash began coalescing and became macular. (B) After defervescing, the papules became dusky in appearance. (C) After 29 days of the initial rash, desquamation occurred.

Despite ongoing symptoms, the patient independently restarted spironolactone 5 days after the initial symptom presentation. Within 30 minutes, she developed new urticarial lesions and discontinued the medication (Fig. 3A). After 29 days, the initial rash desquamated (Fig. 2C) and completely resolved.

Figure 3.

(A) Urticarial lesions appeared within 30 minutes after the first rechallenge of spironolactone. (B) Rash on bilateral lower extremities recurred within 12 hours after rechallenging spironolactone.

Five months later, she again self-initiated spironolactone. Twelve hours after a single 100 mg dose, she developed a morbilliform, nonblanching rash limited to the lower extremities (Fig. 3C). She also experienced warmth and peripheral edema, but no fever. The rash self-resolved within 7 days without coalescence or desquamation.

Informed consent

The investigators declare that informed consent was obtained from the patient for publication of this report and any accompanying images.

Discussion

This case demonstrates a reproducible cutaneous hypersensitivity reaction to spironolactone in a patient with clinical hyperandrogenism, with symptom recurrence after two distinct rechallenges. The timing and presentation implicate spironolactone as the causative agent.

Drug reaction with eosinophilia and systemic symptoms is a rare, potentially life-threatening drug hypersensitivity reaction characterized by widespread rash, fever, eosinophilia, lymphadenopathy, and potential multiorgan involvement (5). Skin findings often affect more than 50% of the body surface and may present as maculopapular or polymorphous eruptions. Pruritus and facial edema are common; oral mucosal lesions occur in up to 50% of cases (5). Symptoms may reappear rapidly upon reexposure to the offending drug.

The RegiSCAR (European Registry of Severe Cutaneous Adverse Reactions) group developed standardized diagnostic criteria for DRESS on the basis of clinical, laboratory, and histopathologic findings (5). Applying the RegiSCAR criteria to our patient yields a total score of 3: fever ≥38.5 °C (0), skin rash affecting >50% of the body surface area (+1), facial edema and scaling/desquamation (+1), and symptom resolution >15 days (0), and alternative diagnoses excluded (+1). Our score of 3 is consistent with a “possible” case of DRESS. Laboratory testing or histopathologic examination would have enhanced diagnostic clarity; however, these were not performed, as DRESS was not considered at the time of her urgent care visit.

Early recognition and withdrawal of the offending agent are critical in managing DRESS. Supportive care is typically sufficient in mild cases. Corticosteroids may be indicated with systemic involvement. Severe cases may require advanced therapies such as intravenous immunoglobulin or plasma exchange (5).

To our knowledge, only four cases of spironolactone-induced DRESS have been reported in the literature (6, 7, 8, 9). Spironolactone-induced DRESS was first reported in 2004 in a 58-year-old man with heart failure with decreased ejection fraction. Skin histology was consistent with drug eruption, and spironolactone was the confirmed culprit via skin patch testing. His rash resolved after taking oral prednisone (6). In a 17-year-old exposed to spironolactone for acne vulgaris, violaceous, nonblanching macules developed over her proximal extremities that coalesced into patches as with our patient. She developed transaminitis, and skin biopsy was consistent with DRESS (7). Another 58-year-old man taking spironolactone for hypertension developed biopsy-proven DRESS with elevated creatinine and proteinuria. Analogous to our case, spironolactone was confirmed as the cause after accidental rechallenge of spironolactone. Within 2 days of retaking the medication, he developed erythroderma with eosinophilia (8). Other reported spironolactone-associated cutaneous reactions include linear immunoglobulin A bullous dermatosis, which can be distinguished from DRESS with skin biopsy for histology and direct immunofluorescence, and erythema multiforme (Fig. 4) (10, 11, 12).

Figure 4.

Left: Linear IgA bullous dermatosis. (From Philip et al. [10]. Reprinted by permission of the publisher. Licensed under CC BY 4.0.) Right: Erythema multiforme. (From Hafsi et al. [12]. Reprinted by permission of the publisher. Licensed under CC BY-NC-ND 4.0.)

Conclusion

Spironolactone is commonly used for the management of clinical hyperandrogenism and is generally well tolerated. Rare but potentially serious cutaneous adverse reactions, including DRESS, can occur. In this case, the reproducibility of symptoms upon rechallenge supports a causal association with spironolactone, despite the absence of confirmatory laboratory or histopathologic findings. Early recognition, prompt discontinuation of the offending agent, and supportive care are essential. When DRESS is suspected, laboratory evaluation and skin biopsy should be performed to facilitate accurate diagnosis and guide management.

This case adds to the limited literature on spironolactone-associated DRESS and reinforces the importance of pharmacovigilance when prescribing medications for hyperandrogenism, particularly in patients with a complex allergy history. Broader awareness of such reactions can facilitate earlier diagnosis and safer care.

CRediT Authorship Contribution Statement

Sandy Hoang: Writing – original draft. Danielle Strom: Writing – review & editing. Kathleen M. Brennan: Writing – review & editing, Supervision.

Declaration of Interests

S.H. has nothing to disclose. D.S. has nothing to disclose. K.M.B. has nothing to disclose.