Tuberous sclerosis complex (TSC) is a genodermatosis of autosomal dominant inheritance characterized by the multisystemic formation of hamartomatous tumors. The disease is caused by mutations in the TSC1 and TSC2 genes, leading to constitutive activation of mTORC1. This stimulation translates into uncontrolled cell proliferation and differentiation, resulting in the appearance of hamartomas in different tissues (such as skin, brain, and kidneys) and that are responsible for the clinical characteristics of these patients. The direct implication of the mTOR pathway in the pathogenesis of this disease has prompted the use of different mTOR inhibitors to palliate the skin and systemic manifestations. The good outcomes with oral everolimus in the treatment of subependymal giant cell astrocytomas8 and renal angiomyolipomas9 have led to these indications being added the labeling of this drug. Recent studies have also shown these drugs to be effective, with a good safety profile, in the treatment of lymphangioleiomyomatosis,10 leading to approval by the Food and Drug Administration of this indication in the case of sirolimus.11

Among the multiple skin manifestations of TSC, hypomelanotic macules and facial angiofibromas (FAs) are the most frequent. Traditionally, treatment of FA was based on local destructive techniques such as CO2 laser or electrocoagulation, but these are associated with a high risk of sequelae.12 The substantial improvement observed in FA in a patient in treatment with oral sirolimus13 led to the use of different topical formulations for treatment with concentrations ranging from 0.015% to 1%.14–17 Good outcomes were attained with this regimen (Fig. 3), while minimizing potential side effects associated with systemic sirolimus administration. Local irritation was only observed in patients in whom a solution was applied (4.8% of cases),18 with the other formulations being well tolerated. Sirolimus has also been used topically with good response in hypomelanotic macules19 and in a patient with subungual fibromas.20 The topical formulation of everolimus has only been used in an isolated patient with FA.21

Figure 3.

Patient with facial angiofibroma associated with tumorous sclerosis before (a) and 6 months after starting treatment with topical sirolimus (b).

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RASopathies are developmental abnormalities caused by germline mutations in the RAS/MAPK pathway. They are characterized by a broad spectrum of skin and systemic manifestations.22 Neurofibromatosis and Legius, Noonan, Leopard, and cardiofaciocutaneous syndromes are all considered RASopathies. The link between the RAS/MAPK pathway and the PI3K/Akt/TSC/mTOR pathway has aroused interest in mTOR inhibitors as possible therapeutic alternatives in these patients. In a recent phase ii clinical trial, the use of oral sirolimus showed a modest decrease in plexiform neurofibroma growth with acceptable toxicity.23 Currently, a phase ii clinical trial is ongoing to investigate administration of oral everolimus in patients with neurofibromatosis type 1, while another phase i trial of the use of topical sirolimus for skin manifestations of this RASopathy has been completed although the results are not yet available.

Birt-Hogg-Dubé syndrome is characterized by mutations in the folliculin gene, which is implicated in the mTOR pathway. These patients have facial trichofolliculomas, lesions very similar to facial angiofibromas in TSC. However, topical application of sirolimus was of no benefit in these patients.24

Familial multiple discoid fibroma, which was initially included in the spectrum of Birt-Hogg-Dubé syndrome, is a rare entity characterized by early onset in the facial region of fibrovascular tumors denoted discoid fibromas. An article has been published describing improvement in the lesions of 2 twins with this disorder after treatment with 1% topical sirolimus.25

Pachyonychia congenita is a disorder of autosomal dominant inheritance characterized by the appearance of painful focal palmoplantar keratoderma, subungual hyperkeratosis, epidermoid cysts, and oral leukokeratosis. It can present in a range of clinical forms depending on the mutations present in the genes responsible for encoding keratins K6a, K6b, K6c, K16, and K17. Sirolimus has been demonstrated to inhibit keratinocyte proliferation by blocking keratin K6a expression. Clinically, sirolimus has been associated with an ostensible improvement in plantar keratoderma in 3 patients treated with oral sirolimus.26 These findings have prompted a clinical trial with topical sirolimus for the treatment of this plantar keratoderma.

Hamartomatous polyposis syndromes include a group of genetic disorders of autosomal dominant inheritance, characterized by the development of gastrointestinal hamartomatous polyps, as well as other extradigestive manifestations including different dermatological conditions.27 These syndromes of hamartomatous polyposis include PTEN-associated hamartoma tumor syndrome, which covers a heterogenous group of clinical disorders sharing a PTEN germline mutation that suppresses the PI3K-Akt axis. A phase ii clinical trial of the use of oral sirolimus in patients with PTEN-associated tumor hamartoma syndrome has been completed and we are awaiting the results.

Klumpen et al.28 treated a patient with Peutz-Jeghers syndrome who developed a pancreatic carcinoma with oral everolimus. They observed a partial improvement in the tumor and the colonic polyps disappeared but the authors did not report on the effect on the patient's lentigines.

In cases in which juvenile polyposis syndrome is associated with SMAD4 mutations, the hereditary hemorrhagic telangiectasia or Rendu-Osler-Weber syndrome may also be present. There is a report of 1 case in which sirolimus led to remission of both the skin lesions and the intestinal lesions.29

Capillary vascular malformations are congenital malformations that may appear sporadically or associated with genetic syndromes such as Sturge-Weber syndrome. Related to GNAQ mutations, up to 70% of cases associated with Sturge-Weber syndrome present activation of the Akt pathway.30 Recently, the results of a phase ii clinical trial have been published in which patients with capillary vascular malformations associated with Sturge-Weber syndrome were treated with pulsed dye laser light and topical rapamycin. The areas to which the combined therapy was applied showed a greater response compared with those treated with laser light only or placebo.31

Posterior fossa malformations–hemangiomas–arterial anomalies–cardiac defects–eye abnormalities–sternal cleft and supraumbilical raphe syndrome (more commonly known as PHACE syndrome) is characterized by association of large facial hemangiomas and other underlying vascular disorders, such as posterior fossa brain malformations, cerebral artery abnormalities, and cardiac, aortic, and ocular disorders. The large deformation and functional problems arising from these hemangiomas, as well as safety issues observed with the use of oral propanol in some of these patients, have prompted a search for therapeutic alternatives. A case has been published of good cutaneous response with oral sirolimus; no complications were observed in the other vascular disorders.32

Kaposiform hemangioendothelioma is an uncommon childhood vascular tumor that can infiltrate deep structures such as muscle or bone. It is associated with the Kassabach-Merrit phenomenon, and is life-threatening. Sirolimus33 and everolimus34 have led to a decrease in or stabilization of the size of the lesions, as well as control of the associated symptoms (thrombocytopenia, coagulopathy) in isolated cases of kaposiform hemangioendothelioma refractory to other treatments.

Case reports have been published of the use of sirolimus in other vascular abnormalities, such as lymphatic and venous malformations,33 benign lymphangioendotheliomas,35 hemangioendotheliomas associated with Mafucci syndrome,36 blue rubber bleb nevus syndrome,37 and complex vascular malformations.

Graft versus host disease (GVHD) is a complication that can present in up to 80% of allogeneic stem cell transplant procedures. In a recent metaanalysis, treatment with sirolimus was shown to be useful in preventing the development of acute GVHD, with no signs of a decrease in relative risk in the chronic form.38 Both sirolimus39 and everolimus40 have been shown to be effective in controlling the symptoms of chronic GVHD with low rates of graft dysfunction and thrombotic microangiopathy. In addition, sirolimus showed promising results in patients with acute corticosteroid-resistant GVHD.41 However, mTOR inhibitors remain second-line therapies in the management of acute and chronic GVHD, behind corticosteroids whether used alone or in combination with calcineurin inhibitors.42,43 In a study in 34 patients with chronic sclerodermatous GVHD,44 mTOR inhibitors achieved an overall response rate of 76%, and so the authors considered sirolimus and everolimus as a good therapeutic option in these particularly refractory forms of the disease.

These results in patients with chronic GVHD have prompted the use of mTOR inhibitors in sclerosing diseases. Su et al.45 conducted a pilot clinical trial in 18 patients with diffuse systemic sclerosis in whom sirolimus showed a similar efficacy to methotrexate.

Activation of the PI3K/Akt/mTOR pathway in psoriatic plaques and perilesional skin46 has led to speculation about the potential use of mTOR inhibitors in psoriasis. A clinical trial provided evidence that the combination of sirolimus at subtherapeutic doses of cyclosporin (1.25mg/Kg) was as effective as high-dose cyclosporin, but with a better renal safety profile. However, when used in monotherapy, these agents did not produce any improvement in psoriasis.47 Likewise, the use of topical sirolimus at much higher concentrations than those used in other indications (2.2%-8%) has not shown any clinically relevant effects.48 There are only 2 clinical cases of oral everolimus use in patients with psoriasis.49,50 In both cases, the agent was combined with other immunosuppressants (cyclosporin and tacrolimus) that the patients had been taking previously to avoid graft rejection.

The use of sirolimus for prevention of suprabasal acantholysis in an animal model51 would explain the possible beneficial effect of mTOR inhibitor use in pemphigus vulgaris. However, current evidence in blistering diseases is limited to 3 cases of oral pemphigus treated with topical sirolimus without any improvement,52 and a case of pemphigus vulgaris treated with sirolimus in combination with high doses of intravenous immunoglobulins during the maintenance phase.53 Everolimus has recently been linked to the induction of 2 cases of bullous pemphigoid,54 and so the possible beneficial role of mTOR inhibitors in autoimmune bullous diseases has been brought into question

There is only 1 clinical study in patients with oral erosive lichen planus. In that study, Soria et al.55 treated 7 women with topical sirolimus. They obtained a complete response in 4 patients and a partial response in 3, and the formulation was well tolerated.

Although there are isolated cases of patients with basal-cell carcinoma treated with everolimus,56 prevention of nonmelanoma skin cancer is one the main uses of mTOR inhibitors. Several clinical trials have shown a decrease in the incidence of nonmelanoma skin cancer in transplant patients in treatment with sirolimus in comparison with calcineurin inhibitors. In a metaanalysis of 5876 transplant patients in 21 clinical trials, Knoll et al.57 observed a risk reduction for developing nonmelanoma cancer of 56%, as well as an overall decrease in the risk of cancer at any site in patients in treatment with sirolimus. The study showed a greater risk reduction in patients treated with other immunosuppressive therapies who subsequently switched to sirolimus.

There are 3 phase ii clinical trials with metastatic melanoma in which everolimus was administered in combination with other biologic agents such as bevacizumab,58 or associated with monochemotherapy (temozolomide)59 or polychemotherapy (paclitaxel+carboplatin).60 Although the combination with bevacizumab showed a modest benefit, with a response rate of 12% and stable disease in 58% of the patients, the use of everolimus with cytostatic agents did not show any benefit at all.

The association of temsirolimus with sorafenib in patients with metastatic melanoma was not efficaceous,61 whereas in combination with bevacizumab better results were obtained in patients without the BRAF mutation.62

Sirolimus has been shown to be extremely effective in the treatment of skin and visceral involvement in Kaposi sarcoma in transplanted patients,63 and this has led some authors to consider the agent as the first-choice immunosuppressant in this subgroup of patients and even to use it topically.64

The limited experience with the use of everolimus in patients with Kaposi sarcoma is, on the other hand, more controversial. Although isolated clinical trials have been reported in which complete resolution of skin and systemic lesions has been attained,65 a recent clinical trial in 11 patients with classic Kaposi sarcoma showed limited efficacy66 with the onset of new lesions during treatment.

In vitro studies have shown excessive activation of the mTOR pathway in cells of patients with Sézary syndrome and cutaneous T cell lymphomas, suggesting that mTOR inhibitors may be a possible therapeutic alternative.

Witzig et al.67 recently published a phase ii clinical trial in which patients with T-cell lymphomas were treated with oral everolimus. Seven of these had stage iiB (6) and stage iii (1) mycosis fungoides. Three of these (43%) attained partial response. Currently, there is a phase ii clinical trial ongoing to investigate treatment of refractory cutaneous T-cell lymphomas with everolimus.