Key Points
Question
What are the clinical and pathological features of elexacaftor-tezacaftor-ivacaftor–associated acneiform rashes in patients with cystic fibrosis?
Findings
In this case series of 16 patients, 6 experienced a new-onset acneiform rash and 10 had relapsed or worsened previous acne after a median of 45 days of elexacaftor-tezacaftor-ivacaftor treatment. Most patients had mild inflammatory and noninflammatory lesions; however, 4 patients required isotretinoin treatment, and a specific histopathological pattern of necrotizing infundibular crystalline folliculitis was found in 4 other patients.
Meaning
These findings suggest that elexacaftor-tezacaftor-ivacaftor–associated acneiform eruption is an adverse effect that dermatologists should be aware of in patients with cystic fibrosis.
This case series describes the clinicopathological features and treatment response of acneiform eruptions following elexacaftor-tezacaftor-ivacaftor treatment in patients with cystic fibrosis.
Abstract
Importance
A new treatment for cystic fibrosis combining 3 CFTR modulators—elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA)—has recently been approved for cystic fibrosis treatment. The cutaneous adverse effects following treatment with this combination are poorly described in the literature.
Objective
To describe the clinicopathological features and treatment response of ELX-TEZ-IVA–associated acneiform eruptions in patients with cystic fibrosis.
Design, Setting, and Participants
This case series study was conducted in the Dermatology Department of Cochin Hospital, Paris, France, from July 2021 to June 2022 in collaboration with the Cochin Reference Center for Cystic Fibrosis. Referred patients were examined by senior dermatologists. All patients with cystic fibrosis treated with ELX-TEZ-IVA and referred for an acneiform rash were included.
Exposures
Treatment with ELX-TEZ-IVA.
Main Outcomes and Measures
Onset of acneiform rash, type of lesions, and degree of severity, as well as treatments initiated and response, were evaluated. When performed, skin biopsies were reviewed.
Results
This study included 16 patients (11 women [68.7%]) with a median (range) age of 27 (22-38) years. Six patients (37.5%) developed new-onset acneiform rashes, whereas 10 patients (62.5%) had a relapse (5 patients) or worsening (5 patients) of previous acne. The median (range) onset of acneiform rash was 45 (15-150) days. At inclusion, 11 patients (68.7%) had facial hyperseborrhea, 15 patients (93.7%) had noninflammatory lesions, and 14 (87.5%) had inflammatory lesions of seborrheic regions. Four patients (25.0%) had severe acne with deep inflammatory lesions and pitted scars. A specific pathological pattern of necrotizing infundibular crystalline folliculitis was observed in 4 patients. Topical acne treatments, antibiotics, and isotretinoin were used successfully in these patients, resulting in partial or complete remission in 12 patients (85.7% of patients reevaluated).
Conclusions and Relevance
This case series study found that acneiform eruption is an adverse event associated with ELX-TEZ-IVA treatment in patients with cystic fibrosis. Most patients developed mild lesions. However, isotretinoin treatment may be necessary in some patients. The mechanism of ELX-TEZ-IVA–associated acneiform eruption is currently unknown, but the observation of necrotizing infundibular crystalline folliculitis in biopsied patients may guide further exploration.
Introduction
Cystic fibrosis (CF) is the most frequent, life-limiting, genetic disease in White individuals. Variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are inherited in an autosomal recessive mode.1 Recently, the management of CF has been transformed by the development of triple therapy combining 2 CFTR correctors, elexacaftor (ELX) and tezacaftor (TEZ), and a CFTR potentiator, ivacaftor (IVA), indicated for patients with at least 1 F508del CFTR variant.2 Treatment with ELX-TEZ-IVA induced significant clinical improvement with an acceptable adverse effect profile.2
Mild-to-moderate maculopapular erythematous eruptions have been described during the first weeks of treatment in 4% to 10% of patients, most commonly in women taking hormonal contraceptives.2 These exanthemas did not usually require ELX-TEZ-IVA discontinuation and were treated with supportive treatments, including antihistamines and topical steroids.
Drug package inserts for ELX-TEZ-IVA also mention a 2% to 5% risk of acneiform rash, and this adverse effect is frequently reported by online communities of patients with CF. Yet, to our knowledge, no studies have characterized acneiform rash in patients with CF treated with ELX-TEZ-IVA. Here, we report 16 cases of new-onset or relapsing or worsening acneiform eruptions following this treatment.
Methods
We conducted a retrospective case series study. Inclusion criteria were adults with CF (aged ≥18 years) treated with ELX-TEZ-IVA who presented with an acneiform rash between July 2021 and June 2022 and were referred to the Dermatology Department of Cochin Hospital (Paris, France). The exclusion criterion was refusal of consent. Verbal patient consent was obtained in accordance with French Bioethics Law for retrospective noninterventional research studies. According to French law, formal ethics committee approval was not required for this study. The objective was to describe the clinical and pathological characteristics of these acneiform eruptions and their response to treatment. The medical information collected for this study is presented in Table 1 and Table 2. When performed, skin biopsies were reviewed. The CARE reporting guidelines for case series were followed.3
Table 1. Patients’ Clinical Characteristics.
| Variable | Patients, No./total No. (%) (N = 16) |
|---|---|
| Sex | |
| Female | 11/16 (68.7) |
| Male | 5/16 (31.3) |
| Age, median (range), y | 27 (22-38) |
| Fitzpatrick skin type | |
| I | 1/15 (6.6) |
| II | 10/15 (66.7) |
| III | 4/15 (26.7) |
| IV-VI | 0/15 |
| Body mass index, mean (SD)a | 21.6 (1.1) |
| History of insulin resistance or diabetes | 7/16 (43.7) |
| History of tobacco or cannabis smoking | 2/16 (12.5) |
| History of polycystic ovary syndrome | 1/11 (9.1) |
| Oral contraceptives | 3/11 (27.3) |
| Long-term azithromycin treatment | 12/16 (75.0) |
| Family history of acne | 3/15 (20.0) |
| Personal history of acne | 10/16 (62.5) |
| Previous treatment for acne | |
| None or over-the-counter acne products | 7/10 (70.0) |
| Topical treatments | 1/10 (10.0) |
| Oral antibiotics | 1/10 (10.0) |
| Isotretinoin | 1/10 (10.0) |
| Previous treatment by IVA and lumacaftor | 8/16 (50.0) |
| Acneiform eruption following IVA and lumacaftor | 0/8 |
| Maculopapular rash following ELX-TEZ-IVA | 3/16 (18.7) |
| Delay between ELX-TEZ-IVA and maculopapular rash, median (range), d | 7 (7-10) |
| Delay to obtain maculopapular rash complete remission, median (range), d | 15 (10-15) |
| Acneiform eruption following ELX-TEZ-IVA | |
| New-onset acneiform eruption | 6/16 (37.5) |
| Relapse of preexisting acne | 5/16 (31.3) |
| Worsening of preexisting acne | 5/16 (31.3) |
| Delay between ELX-TEZ-IVA and acneiform eruption, median (range), d | 45 (15-150) |
| Clinical features | |
| Hyperseborrhea | 11/16 (68.7) |
| Noninflammatory lesions | 15/16 (93.7) |
| Open comedones | 9/16 (56.2) |
| Closed comedones | 12/16 (75.0) |
| Inflammatory lesions | 14/16 (87.5) |
| Papules | 14/16 (87.5) |
| Pustules | 12/16 (75.0) |
| Nodules | 4/16 (25.0) |
| Postinflammatory hyperpigmentation | 9/16 (56.2) |
| Scars | 4/16 (25.0) |
| Affected areas | |
| Face | 13/16 (81.2) |
| Chest | 10/16 (62.5) |
| Back | 11/16 (68.7) |
| Acneiform eruption severity level (Global Acne Severity Scale) | |
| 1 (Almost no lesions) | 1/16 (6.3) |
| 2 (Mild) | 8/16 (50.0) |
| 3 (Moderate) | 3/16 (18.7) |
| 4 (Severe) | 4/16 (25.0) |
| 5 (Very severe) | 0/16 |
Abbreviation: ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor.
Body mass index is calculated as weight in kilograms divided by height in meters squared.
Table 2. Treatments for ELX-TEZ-IVA–Associated Acneiform Eruptions.
| Variable | Patients, No./total No. (%) (N = 16) |
|---|---|
| All treatments for ELX-TEZ-IVA–associated acneiform eruptions | |
| None or over-the-counter acne products | 0/16 |
| Topical treatments | 15/16 (93.7) |
| Oral antibiotics | 6/16 (37.5) |
| Doxycycline | 3/16 (18.7) |
| Azithromycin | 3/16 (18.7) |
| Isotretinoin | 4/16 (25.0) |
| Treatment sequences | |
| First line, topical treatments | 9/16 (56.3) |
| First line, simultaneous topical treatments and oral antibiotics | 2/16 (12.5) |
| First line, topical treatments; second line, oral antibiotics | 1/16 (6.2) |
| First line, topical treatments; second line, oral antibiotics; third line, isotretinoin | 3/16 (18.7) |
| First line, isotretinoin | 1/16 (6.2) |
| Acneiform eruption status at last follow-up | |
| Complete remission | 5/14 (35.7) |
| Partial remission | 7/14 (50.0) |
| Stable disease | 1/14 (7.1) |
| Progressing disease | 1/14 (7.1) |
| Delay to obtain complete remission, median (range), d | 90 (60-180) |
Abbreviation: ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor.
Results
Sixteen patients with CF treated with ELX-TEZ-IVA were referred for an acneiform rash. Their median (range) age was 27 (22-38) years, and 11 (68.7%) were women. Other clinical characteristics are listed in Table 1.
Overall, 10 patients (62.5%) reported a personal history of acne in adolescence, including 1 patient who had been treated with isotretinoin. Before initiation of ELX-TEZ-IVA, 5 patients reported no residual acne, whereas 4 reported persistent mild lesions and 1 moderate lesions; 8 of 16 patients (50.0%) had previously been treated with IVA and lumacaftor. The remaining 6 patients (37.5%) had no personal history of acne (Table 1). During treatment with ELX-TEZ-IVA, 6 patients (37.5%) experienced new-onset acneiform eruption and 10 patients (62.5%) had relapsed (5 patients) or worsened (5 patients) acne after a median (range) of 45 (15-150) days. Of note, 12 patients (75.0%) were also treated with azithromycin (250 mg thrice weekly) to prevent CF exacerbations. Eleven patients (68.7%) had facial hyperseborrhea, 15 (93.7%) had noninflammatory lesions (open and/or closed comedones), and 14 (87.5%) had inflammatory lesions (papules, pustules, and/or nodules). Nine patients (56.2%) had postinflammatory hyperpigmentation, and 4 (25.0%) had pitted scars. The severity of these acneiform eruptions assessed using the Global Acne Severity Scale4 was mild to moderate (50.0% grade 2 and 18.7% grade 3) (Figure, A and B, and Table 1). Affected areas included facial seborrheic areas in 13 patients (81.2%), chest in 10 patients (62.5%), and back in 11 patients (68.7%) (Table 1). Of note, 4 patients (25.0%) described spontaneous improvement of acneiform lesions without discontinuation of ELX-TEZ-IVA.
Figure. Clinical and Pathological Features of Elexacaftor-Tezacaftor-Ivacaftor–Associated Acneiform Eruption.
A and B, Clinical pictures show inflammatory and noninflammatory lesions observed in a patient. C, Skin biopsy demonstrated a dilated hair follicle containing a pale crystalline material in its lumen. D, An inflammatory infiltrate composed of neutrophils, histiocytes, and giant cells organized around keratin debris is seen around the ruptured hair follicle. E, Birefringent crystalline deposits are visible under polarized light.
Skin biopsy of inflammatory papules was performed in 4 patients. Interestingly, all 4 biopsies showed evidence of acute folliculitis with a perifollicular inflammatory infiltrate of neutrophils occasionally. In addition, histopathologic features of necrotizing infundibular crystalline folliculitis (NICF) were observed in all 4 biopsies, showing dilated follicular ostia with birefringent crystalline material (Figure, C-E). Pityrosporum species spores were observed in 1 patient, and gram-positive cocci were seen in another.
Treatment sequences are presented in Table 2. Topical treatments (monotherapy or retinoid and benzoyl peroxide combination) were prescribed for 15 patients (93.7%), whereas 6 patients (37.5%) were secondarily prescribed oral antibiotics and 4 (25.0%) were prescribed isotretinoin (Table 2). Doxycycline was used in 3 patients, and an increase in azithromycin dose to 500 mg thrice weekly was tested in 3 patients. Although doxycycline treatment showed transient improvement, azithromycin showed only limited improvement. Isotretinoin was highly effective in all 4 patients who received it. Because isotretinoin safety profile was unknown in patients treated with ELX-TEZ-IVA, it was started at a low dose (0.1-0.2 mg/kg/day) and gradually increased with monthly biological monitoring. The overall safety profile was good except for 2 cases of increased creatine kinase (CK) levels greater than 10 times the upper limit of normal that occurred at 0.3 to 0.5 mg/kg/day. Increased CK levels are also a common adverse effect of ELX-TEZ-IVA; therefore, the sole responsibility of isotretinoin was uncertain. Both patients were male and had exercised a few days before the blood test. They were asymptomatic, and no admission was necessary. The CK levels decreased rapidly after temporary discontinuation of isotretinoin and physical activity. In these patients, isotretinoin was continued at low dose because increased CK levels relapsed after dose escalation. Overall, partial or complete remission was achieved in 12 patients (85.7% of patients reevaluated). In those who achieved complete remission, the median (range) delay was 90 (60-180) days after treatment (Table 2).
Discussion
In this case series study, we reported 16 patients with CF who experienced mild-to-moderate acneiform eruption while being treated with ELX-TEZ-IVA. Further studies will be needed to assess the exact frequency of this adverse event. The choice of treatment should be based on the assessment of severity using validated clinical scores such as the Global Acne Severity Scale.4 Topical or systemic acne treatments were followed by an improvement in most cases. Isotretinoin can be used in patients with severe acneiform lesions by starting at a low dose (0.2 mg/kg/day) and carefully monitoring the specific risk of increased CK levels.
The imputability of ELX-TEZ-IVA in the development of these acneiform eruptions appears high (Naranjo score of 9).5 Indeed, 2 patients stopped ELX-TEZ-IVA because of acne or anxiety, which was followed by a complete disappearance of acneiform lesions. Conversely, acneiform lesions relapsed when ELX-TEZ-IVA was resumed in 1 patient. Although patients with CF are generally aware of this adverse effect, only 2 cases of ELX-TEZ-IVA–associated acneiform rash have been described in the literature.6,7 Acneiform lesions have also been described as an adverse effect of IVA on drug package inserts. However, 8 of 16 patients (50.0%) had previously been treated with IVA and lumacaftor without any cutaneous adverse effect. This suggests a greater imputability of ELX or TEZ.
Histopathological evidence of acute neutrophilic folliculitis and NICF was found in 4 patients. In the literature, approximately 20 cases of NICF have been described since the description of this entity in 1999.8,9 Some cases have been described in patients with acne,10 and crystal formation appears to be common in acne comedones.11 The pathogenesis of NICF remains largely unknown. However, polarizable crystals may result from esterification of cholesterol in sebum by gram-positive cocci bacteria, including Cutibacterium acnes and Pityrosporum species10; NICF may represent aberrant differentiation of infundibular progenitors in response to destructive folliculitis.12 In addition, 2 cases of NICF have been described in patients receiving targeted therapies such as VEGF or EGFR inhibitors for metastatic adenocarcinoma,13 and 1 in a patient receiving anti-PD1 immune checkpoint inhibitor.14 Thus, the description of acneiform lesions on ELX-TEZ-IVA treatment suggests a potential role of CTFR in follicular and sebaceous homeostasis. The CFTR protein was previously shown to be expressed in sebaceous glands.15 Whether ELX-TEZ-IVA–associated acneiform eruption could also be related to changes of sweat composition is an interesting hypothesis that would require further exploration.
Limitations
Limitations of this retrospective study include the small size of the cohort, the lack of a comparison group, and the absence of a dermatological evaluation before ELX-TEZ-IVA treatment.
Conclusions
This case series study suggests that treatment with ELX-TEZ-IVA may cause an acneiform rash in patients with CF with a specific histopathological pattern of NICF. Treatments with topical retinoids or benzoyl peroxide, doxycycline, or oral isotretinoin seem to be effective.
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