Dear editor:
Systemic inhibitors of mechanistic target of rapamycin (mTOR) have antiproliferative, antiangiogenic, and immunosuppressive properties. In dermatology, they are effective for managing certain vascular anomalies and genodermatoses, notably tuberous sclerosis complex (TSC).1 Compared to cancer patients or transplant recipients, TSC patients are prescribed mTOR inhibitors at lower doses and their treatment regimens are less likely to include other drugs that may induce similar side effects. We aimed to assess the range and frequencies of dermatologic side effects in individuals taking oral mTOR inhibitors for TSC.
We performed a retrospective cross-sectional analysis of TSC patients evaluated at the National Institutes of Health Clinical Center between 2004 and 2019. Adults fulfilling clinical criteria for TSC were included if treated for at least one month with oral mTOR inhibitor and excluded if taking concomitant immunosuppressive therapy. All patients were evaluated by a dermatologist (T.N.D.), and severity of changes was graded according to the common terminology criteria for adverse events version 5.0.
Thirty individuals (29 females, 1 male; median age:39 years, range:25–57 years) met inclusion criteria. Twenty-three were treated with oral sirolimus (median dose:2 mg/day, range:1–9 mg/day) for pulmonary lymphangioleiomyomatosis (LAM), a TSC-associated disorder that occurs predominantly in women, and seven with oral everolimus (median dose: 5 mg/day, range:2–10 mg/day) for pulmonary LAM and/or renal angiomyolipomas. Median duration of therapy was 5 years (range:0.5–15 years). For those taking sirolimus, median trough serum level was 7.2 ng/mL (range:2–34 ng/mL).
Twenty-nine individuals (97%) presented with or reported modifications of the skin, soft tissues, mucous membranes, nails, or hair within one month to nine years following initiation of therapy. The most common dermatologic side effects, each of which occurred in over half of patients, were oral ulceration and acneiform eruptions (Table 1). Oral ulcers appeared as discrete mucosal aphthae. Acne-like lesions were erythematous, inflammatory papules and nodules on the scalp, face, and back. Nearly half of patients developed hand or lower extremity edema. Eight (27%) individuals experienced impaired wound healing following injury or surgery, including two with slow healing following skin biopsies, one who developed thigh seromas after a motor vehicle accident, and one who developed an abdominal wall seroma following surgery. Eight (27%) individuals experienced folliculitis; of these, two eventually developed furunculosis and one developed cellulitis requiring oral antibiotic treatment. Herpes zoster virus and tinea infection occurred in two individuals each. Six (20%) patients developed localized xerotic and/or pruritic lesions, mostly on the hands. Some individuals experienced increased waviness of scalp hair, decreased scalp hair density, or brittle nails (Table 1). All side effects were grade 1 or 2 severity except for one individual who had to discontinue sirolimus treatment due to painful oral ulcers (grade 3).
Table 1:
Dermatologic changes observed in a cohort of 30 individuals taking oral mechanistic target of rapamycin inhibitor therapy.
| Dermatologic change | Number of individuals out of 30 (%) | Sirolimus (n=23) | Everolimus (n=7) | ||
|---|---|---|---|---|---|
| n (%) | Median dose (mg/day) | n (%) | Median dose (mg/day) | ||
| Any | 29 (97) | 22 (96) | 2 | 7 (100) | 5 |
| Oral ulceration | 21 (70) | 16 (70) | 2 | 5 (71) | 5 |
| Acneiform lesions | 18 (60) | 14 (61) | 2 | 4 (57) | 6.25 |
| Edema of extremities | 14 (47) | 9 (39) | 2 | 5 (71) | 2.5 |
| Impaired wound healing | 11 (37) | 8 (35) | 2.5 | 3 (43) | 2.5 |
| Infection | 9 (30) | 9 (39) | 3 | 0 | -- |
| Folliculitis | 8 (27) | 8 (35) | 2.5 | 0 | -- |
| Folliculitis developing into furunculosis | 2 (7) | 2 (9) | 3 | 0 | -- |
| Folliculitis developing into cellulitis | 1 (3) | 1 (4) | 3 | 0 | -- |
| Herpes zoster virus | 2 (7) | 2 (9) | 2.5 | 0 | -- |
| Tinea | 2 (7) | 2 (9) | 3 | 0 | -- |
| Xerotic or pruritic patch/plaque | 6 (20) | 4 (17) | 1.75 | 2 (29) | 5 |
| Scalp hair change | 3 (10) | 3 (13) | 2 | 0 | -- |
| Decreased hair density | 3 (10) | 3 (13) | 2 | 0 | -- |
| Increased hair waviness | 2 (7) | 2 (9) | 2 | 0 | -- |
| Brittle nails | 3 (10) | 2 (9) | 2 | 1 (14) | 2.5 |
| Ganglion cyst | 2 (7) | 2 (9) | 2 | 0 | -- |
Oral ulceration was experienced by the majority of patients in our study and has been frequently reported in prior prospective trials. mTOR inhibitor-associated stomatitis appears similar to aphthous ulceration and distinct from oral mucositis caused by chemotherapy.2 Acneiform eruptions have been reported in about one-quarter of patients taking mTOR inhibitors;3 our findings suggest that this may be more common than previously considered. Prior trials have also reported infections, particularly of the respiratory tract,1,2 and our results indicate that skin and soft tissue infections may occur. Remarkably, 20 (67%) individuals experienced changes relating to the pilosebaceous unit, including changes in hair growth. This may result directly from mTOR inhibition through effects on hair follicle stem cells and hair follicle cycling,4 or indirectly through inhibition of signaling through epidermal growth factor (EGF).5 Several hair-related side effects, including acne,6 trichomegaly,7 and scalp hair changes,7 have been associated with EFG inhibitors. A potential limitation of our study is partial reliance on patient history for documenting side effects. Furthermore, the retrospective nature of the study limited our ability to assess the timing and dose-dependence of side effects.
Dermatologic side effects of oral mTOR inhibitors are common but generally do not necessitate treatment discontinuation. For side effects that are particularly bothersome or complicated, routine monitoring by dermatologists can be vital for optimizing quality of life during therapy. Painful mouth ulcers that hinder oral intake may lead to poor nutrition. Patients may benefit from avoidance of foods that may traumatize the oral mucosa as well as topical corticosteroids or analgesics.8 Acneiform eruptions, which may be painful and cause psychologic distress, may be managed with conventional acne therapies.5 Patients should be cautioned regarding the risks of poor wound healing and cutaneous infections prior to undergoing skin biopsies. For individuals who are refractory to direct management of dermatologic side effects, dosage reduction or transient discontinuation of treatment may be pursued, especially if the risks of stopping therapy outweigh the benefits.
Funding:
This research was funded in part by the Intramural Research Program, National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI). This research was also made possible by the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, and other private donors. For a complete list, visit the foundation website at http://www.fnih.org. Additionally, this work was funded by the Doris Duke Charitable Foundation Clinical Research Mentorship grant #2018042.
Footnotes
Conflicts of interest: None declared
Consent: Each participant provided written informed consent under the protocols 00-H-0051, 95-H-0186, 96-H-0100, and/or 82-H-0032, all of which were approved by the National Heart, Lung, and Blood Institute’s Institutional Review Board.
This work was presented at the 2019 International Tuberous Sclerosis Complex Research Conference, June 20–22, 2019, Toronto, Ontario, Canada.
Publisher's Disclaimer: Disclaimer: The opinions and assertions expressed herein are those of the authors and do not necessarily reflect the official policy or position of the Uniformed Services University, the Department of Defense, or the National Institutes of Health.
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