Comment
Sorafenib is an oral tyrosine kinase inhibitor that blocks tumor cell proliferation and angiogenesis due to its activity against vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, stem cell growth factor receptor, and rapidly accelerated fibrosarcoma kinases.11 It is primarily used for the treatment of solid tumors, such as advanced renal cell carcinoma, unresectable HCC, and thyroid carcinoma, and more recently has been expanded for treatment of AML due to potential inhibition of FMS-like tyrosine kinase 3 receptor. Although dermatologic toxicity is a common adverse event during treatment with sorafenib,11 reports of psoriasiform drug eruptions are rare.
Review of Cases
Based on our literature search, there are 10 previously reported cases of psoriasiform drug eruption secondary to sorafenib. Of the 13 total cases (including the 3 patients in this report), 7 patients had a history of psoriasis; most were middle-aged men; and the treatment with sorafenib was for solid tumors, primarily HCC with the exception of patient 3 from the current report who was treated for AML (Table). In all cases, the dose of sorafenib ranged from 200 to 800 mg daily. In 5 cases, HFSR preceded (as with patient 2 in the current report) or presented concurrently (as with patient 1 in the current report) with the onset of psoriasiform rash.1,3,5
Of the 13 total cases, patients with a history of psoriasis generally developed the eruption in a shorter period of time after starting sorafenib (eg, days to 2 months) compared to those without a history of psoriasis (eg, 2 to 9 months)(Table), suggesting that patients with preexisting psoriasis more rapidly developed the drug eruption than patients without a history. In these patients with a history of psoriasis, all had long-standing mild to moderate stable plaque psoriasis, with the exception of 1 case in which the type of psoriasis was not described (Table).7 The presentation of the drug eruption following sorafenib varied from psoriasiform drug eruption (5 patients, including patient 3),2,3,6,9 pustular psoriasis (5 patients, including patient 2),4,7,8,10 and plaque psoriasis (3 patients, including patient 1).1,5 Interestingly, 5 of 6 patients with a history of plaque psoriasis presented with pustular psoriasis or psoriasiform drug eruption after treatment with sorafenib.4-6,8-10 These results suggest a causal relationship between sorafenib and exacerbation of preexisting psoriasis.
In the 13 total cases, treatments included mid- to high-potency topical steroids (10 cases), UVB or NB-UVB phototherapy (7 cases), and discontinuation of sorafenib (10 cases)(Table). All of these treatments led to improvement of the eruption with the exception of 1 case in which hand involvement was recalcitrant to therapy.9 Of the 10 cases in which sorafenib was discontinued, rechallenge at a lower dose was performed in 6 cases (including patient 1)3,4,6,7,9 with recurrence of psoriasiform rash seen in 5 cases (including patient 1)(Table).4,6,7,9 These data strongly implicate sorafenib as the direct cause of these psoriasiform eruptions. In the 3 cases in which sorafenib was not discontinued (including patient 3), there was notable improvement of the eruption with NB-UVB phototherapy.1,2
Vascular endothelial growth factor is overexpressed on psoriatic keratinocytes, contributes to epidermal hyperplasia, and induces angiogenesis in the dermis.12 The development of psoriasiform eruptions in patients treated with sorafenib seems paradoxical, as this drug has been considered as potential therapy for psoriasis due to its ability to block VEGF receptor signaling. Indeed, an improvement of psoriasis has been reported in 1 case of a patient treated with sorafenib13 and in multiple patients with psoriasis treated with other VEGF antagonists (eg, bevacizumab).14 The underlying mechanisms by which sorafenib induced or exacerbated psoriasis are not entirely clear. Palmoplantar hyperkeratosis, keratosis pilaris–like eruption, multiple cysts, eruptive keratoacanthomas, and squamous cell carcinoma have been described in patients treated with sorafenib, supporting the hypothesis that treatment with sorafenib alters keratinocyte proliferation and differentiation.15 In addition, B-Raf inhibitors such as imatinib are known to induce or exacerbate psoriasiform dermatitis.16 The activity of sorafenib resulting in psoriasis may be specific to RAF kinase inhibition, as there are no reports in the literature that describe psoriasiform dermatitis with agents that preferentially block other sorafenib targets such as VEGF receptor, stem cell growth factor receptor, or platelet-derived growth factor receptor. Future studies are needed to fully elucidate the underlying mechanisms by which sorafenib induces or exacerbates psoriasiform dermatitis and whether the severity of the drug eruption correlates with the antitumor efficacy of sorafenib.
Conclusion
Although psoriasiform drug eruptions secondary to sorafenib are not life-threatening, they impact quality of life with associated pain, pruritus, infection, and limitation of daily activities. Dose reduction or discontinuation of sorafenib resulted in resolution of the psoriasiform dermatitis; however, as demonstrated in 3 cases (including patient 3),1,2 psoriasiform dermatitis can be managed while maintaining the patient on sorafenib so that treatment of the malignancy is not compromised.