FormalPara Key Summary Points

Why carry out the study?

With the growing number of targeted cancer therapies, there has been an increase in the prevalence of dermatological side effects, including de novo psoriasis and flares in patients with pre-existing disease.

This review aims to highlight various classes of cancer therapeutics associated with these psoriasis manifestations, while also exploring potential underlying mechanisms.

What was learned from this study?

Discontinuation of the causative targeted therapies, such as tyrosine kinase inhibitors, was not necessary in the large majority of cases.

Approximately 13-23% of patients with immune checkpoint inhibitor-induced psoriasis ultimately required immunotherapy discontinuation.

Early detection and management of these cutaneous adverse events is necessary to decrease the likelihood of interruption to ongoing cancer treatment.

Introduction

Approximately one in three people in the developed world are diagnosed with cancer during their lifetime [1]. Cancer treatment has historically proven to be a complex and challenging process. Novel advancements in medicine continue to provide a better foundational understanding of cancer pathways and malignant cell characteristics. Numerous key molecules and immune checkpoints have been identified and are now the focus of modern molecular therapies [2]. Targeted therapies primarily function as inhibitors of specific molecules involved in intracellular molecular signaling pathways or as cellular membrane inhibitors [3]. Immune checkpoint inhibitors (ICIs) work by targeting irregularities in the immune system, suppressing their activity during DNA repair, and assisting in the death of malignant cells [4]. Although these agents have shown significant efficacy in modulating cancer progression, serious adverse effects have been identified. These can manifest as on-target toxicities, observed when the therapies inhibit their intended target, or as off-target toxicities, occurring when the therapeutic agents unintentionally inhibit other similar target-like molecules [5].

Dermatologic adverse effects (dAEs) are among the most common sequelae of targeted therapies, while the cutaneous side effects of ICIs are classified as immune-related adverse events (irAEs) due to their systemic inflammatory mechanism of action. There have been numerous reports of skin, mucosal, hair, and nail toxicities in patients receiving cancer treatment with modern therapies, regardless of the pathway involved or molecule inhibited [6]. Prior studies have reported dermatologic toxicities in > 75% of patients treated with targeted molecular therapies or immunotherapies [7]. For example, targeted therapies, such as epidermal growth factor receptor (EGFR) inhibitors, are approved for treating various cancer types but can often trigger acneiform eruptions, psoriasiform eruptions, xerosis, paronychia, and mucosal changes [7, 8]. In comparison, ICIs, such as programmed cell death receptor-1 (PD-1) and cytotoxic T-lymphocyte-associated molecule-4 checkpoint molecules (CTLA-4), can cause irAEs, such as rashes, psoriasiform eruptions, pruritus, depigmentation, and bullous diseases [9].

The mechanisms triggering psoriasis and psoriasiform eruptions in these cases are multifactorial and part of an immune-mediated dysregulation process, as discussed in this review. Psoriasis is an immune-mediated disorder of the skin that is clinically characterized by thick red plaques with a silver-scaly appearance [10]. Although the pathogenesis of psoriasis is not entirely understood, it is a condition driven by erratic T-cells and keratinocytes. The crux of psoriasis pathophysiology stems from aberrant T-cell activation, which typically consists of the Th1, Th17, and Th22 subtypes [10]. Activated T cells migrate to the dermis and epidermis, triggering an inflammatory response by inducing the release of key cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-17, IL-22, IL-23, and IL-12; these potent cytokines further drive inflammation and promote keratinocyte hyperproliferation [10]. This epidermal hyperplasia is another hallmark of psoriasis, characterized by aberrant JAK/STAT (Janus kinase-signal transducer and activator of transcription), NF-kB (nuclear factor kappa-light-chain-enhancer of activated B-cells), and MAPK (mitogen-activated protein kinase) signaling pathways. The resulting keratinocyte hyperplasia further promotes the secretion of pro-inflammatory cytokines, creating a positive feedback loop [11]. This crosstalk between keratinocyte proliferation and immune cells plays a prominent role in psoriasis pathophysiology.

Much like psoriasis, cancer biology is also characterized by cellular hyperproliferation and a complex immune environment. Modern targeted therapeutics have revolutionized the landscape of cancer care, with agents targeting patient-specific receptors, immune checkpoints, and tumor signaling pathways. Many of these anti-neoplastic targets also overlap with those involved in psoriasis, especially given the shared mechanisms in the two processes. Both tumor and psoriasis control involve a fine balance between cell proliferation and regulation, along with immune activation and suppression. Given the delicate nature of this balance, it is posited that targeted cancer therapeutics may have varying effects on psoriasis presentation, ranging from therapeutic improvement to exacerbation to new-onset psoriasis. In this review, we aim to highlight the management of de novo or pre-existing psoriasis in patients treated with ICIs and targeted anti-neoplastic therapies.

Methods

The PubMed database was searched using the search terms “psoriasis” AND “cancer treatment,” resulting in the retrieval of 1363 studies published from 2008 to 2023. Title, abstract, and full-text screenings were carried out by five of the authors (LO, VM, GS, RC, KN) in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Fig. 1). To refine the selection, we employed the subsequent exclusion criteria: (1) studies written in languages other than English; (2) studies about cancer treatments without a focus on psoriasis; (3) non-evidence-based commentary or opinion pieces, and (4) studies discussing cancer risk as a result of treatment with immunotherapy. Studies discussing the treatment of psoriasis in the context of several malignancies were included. In cases where there was a lack on consensus among the reviewers, consensus was achieved through shared discussion.

Fig. 1
figure 1

PRISMA diagram of literature search. PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

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Standardized data extraction was performed for each eligible study. The data extracted included the following variables: study design, sample size, patient characteristics (age, gender, skin type, localization of affected skin, comorbidities), psoriasis treatment details (e.g., dosing, duration), and key clinical outcomes (e.g., response rates, adverse effects).

This study did not require ethical approval from a medical ethics committee as it is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Results

Relationship Between Psoriasis and Targeted Therapies

Epidermal Growth Factor Receptor Inhibitors

Epidermal growth factor receptor inhibitors are targeted immunotherapy agents which are currently used to treat many malignancies, such as breast, colon, lung, and pancreatic cancer [12, 13]. EGFR signaling pathways regulate cell differentiation, proliferation, and migration; they are also overexpressed in various epithelial cancers [12]. EGFR inhibitors decrease the activation and autophosphorylation of tyrosine kinase, inhibiting the intracellular signal transduction pathways essential to tumor growth [12]. Dysregulated EGFR pathways have also been implicated in the pathophysiology of psoriasis, with EGFR overexpression found in the epidermis of active psoriatic lesions [14,15,16]. EGFR ligands have also been shown to increase IL-17A-induced expression of psoriasis signature genes [17]. Additionally, several studies have reported the increased activity of EGFR downstream signaling, like RAS-MAPK or JAK-STAT, in psoriatic lesions [18].

Given the overlapping roles of this receptor, the mechanisms by which EGFR inhibitors target neoplasms may also therapeutically affect psoriasis. For example, there have been many case reports of dramatic therapeutic improvement of psoriasis in patients with cancer treated with EGFR tyrosine kinase inhibitors, such as erlotinib [19,20,21,22] and lapatinib [24], and with EGFR monoclonal antibodies, such as cetuximab [23,24,25] and panitumumab [26, 27]. In several of these case reports, the use of a single agent was effective in even treating patients with refractory chronic psoriasis [22, 25]. This clinical response supports the role of EGFR overexpression in psoriasis-related skin lesions. It has also been theorized that the EGFR tyrosine kinase inhibitor erlotinib treats psoriasis by inhibiting TNF-α [28]. By inhibiting T-cell proliferation and activation, erlotinib prevents the secretion of this proinflammatory cytokine, resolving psoriasis [28]. Indeed, several patients with non-small cell lung cancer (NSCLC) and lung adenocarcinoma have experienced either complete resolution or significant improvement of psoriasis-related symptoms after erlotinib monotherapy [19, 22, 28].

Interestingly, there have been two reported cases of cetuximab-induced psoriasis, one of which was a rare pustular form [29, 30]. This paradoxical presentation of psoriasis may be due to an imbalance in downstream molecular pathways upon EGFR blockade, resulting in the induction of alternative keratinocyte proliferation signaling [30]. Both patients were effectively treated with topical steroids, without needing to discontinue cetuximab. Osimertinib, a third-generation EGFR inhibitor, has also been associated with one case of pre-existing psoriasis exacerbation [31]. Due to the severe toxic desquamating psoriatic skin reaction, osimertinib was discontinued and the patient’s lesions were largely cleared by a 10-week course of UVB phototherapy. It is important to note the historical association between EGFR inhibitors and dermatological toxicities, such as the papulopustular rash affecting 70–90% of patients. While these reactions are more common in first- and second-generation therapeutics, these side effects coupled with the variability in psoriasis response make EGFR inhibitors a less attractive option for psoriasis monotherapy. However, in patients with concurrent malignancy and psoriasis, these targeted therapies may be a valid choice.

BCR-ABL Inhibitors

Tyrosine kinase inhibitors (TKI) associated with psoriasis also include those targeting BCR-ABL, a fusion protein implicated in chronic myelogenous leukemia and acute lymphoblastic leukemia. Imatinib, a first-generation molecule inhibiting multiple tyrosine kinases, including BCR-ABL, has been reported to both induce and exacerbate psoriasis [32,33,34,35]. The majority of these skin lesions resolved after imatinib discontinuation along with combinations of topical steroids, antihistamines, and UVB phototherapy. In two cases, suppression was achieved with methotrexate and vitamin D analogs without any interruption of imatinib therapy [33,34,35]. Upon dermatological improvement, most patients were started on second-generation TKIs, such as nilotinib or dasatinib [32, 35, 36]. Nilotinib-induced psoriasis in patients without cutaneous history was documented in four cases, typically emerging around 2 months after the initiation of treatment [37,38,39,40]. In three of these four cases, nilotinib administration was uninterrupted [37,38,39]; in the fourth case, one patient was switched from nilotinib to dasatinib, which further exacerbated psoriasis vulgaris and required discontinuation [40]. The resolution of psoriasis with topical corticosteroids and vitamin D derivatives was reported in two cases [39, 40], while either subcutaneous or oral methotrexate administration was required in the other two cases [37, 38]. In contrast, there have also been reports of psoriasis improvement during treatment with imatinib—a therapeutic effect observed in even intractable psoriasis [41, 42].

The relationship between TKIs and psoriasis may be explained by the imbalance of regulatory T lymphocytes (Tregs). Tregs play a central role in the pathophysiology of psoriasis, with their dysfunction resulting in the inadequate suppression of inflammatory Th17 cells [43, 44]. Similarly, TKIs, such as imatinib and nilotinib, have been shown to suppress the proliferation and function of Tregs in a dose-dependent manner [45, 46]. This disruption in Treg homeostasis may explain the induction of psoriasis following TKI therapy. On the other hand, the proposed mechanism for imatinib-associated psoriasis improvement is thought to be due to TKI inhibitory effects on effector T-cell subsets. Imatinib has been shown to inhibit the tyrosine kinase Lck, which is essential for T-cell activation and proliferation [47]. This inhibition can block signaling in both regulatory and effector T cells; however, when the balance is skewed towards a decrease in effector T cells, this exerts an immunosuppressive effect that is protective against autoimmune diseases like psoriasis [48]. Shifts in these T-cell populations appear to determine the contrasting outcomes in psoriatic lesions and warrant further exploration in the context of TKI therapies.

Vascular endothelial growth factor Inhibitors

Vascular endothelial growth factor (VEGF) is another target with similar trends. Similar to EGFR, VEGF is overexpressed on psoriatic keratinocytes, contributing to epidermal hyperplasia and angiogenesis in the dermis [27, 49, 50]. As a result, immunotherapy against this receptor would be expected to relieve psoriasis-related symptoms. Indeed, complete remission of psoriasis has been reported with both bevacizumab and sorafenib monotherapy [49, 51]. Monotherapy with sunitinib in patients with renal cell carcinoma has also been reported to result in improved psoriatic symptoms [52, 53]. However, paradoxical results have also been observed. Sorafenib monotherapy has induced psoriasis and psoriasiform eruptions in several patients with malignancies, ranging from hepatocellular carcinoma to acute myeloid leukemia [50]. Interestingly, of the eight sorafenib-associated psoriasis presentations, five were of the rare pustular type. The causative agent was discontinued in three patients, while treatment with topical steroids, in combination with UVB phototherapy and vitamin D3, was effective in improving all cases. Other VEGF inhibitors, such as bevacizumab, have also been reported to have contrasting effects on psoriatic lesions. For example, although complete remission of psoriasis has been observed with bevacizumab monotherapy, the opposite has also been reported: blocking of VEGF in one patient had no effect on psoriasis-related symptoms whereas subsequent EGFR inhibition resulted in dramatic improvement [27, 51]. Thus, despite VEGF being integral to the hyperplasia and vascularization necessary for psoriasis, VEGF may not be the most ideal target [27, 49, 50].

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors, such as those targeting PD-1, are revolutionizing cancer care and are increasingly indicated for various malignancies and adjuvant settings. The PD-1 axis, in combination with the programmed death ligand 1 (PDL-1), plays a crucial role in inhibiting T-cell response and promoting immune tolerance. Various cancers, such as melanoma and small-cell lung cancer, can express PD-1 and enable tumor evasion from the immune system [54, 55]. A growing body of ICIs are being utilized in cancer care, targeting molecules like PD-1, PD-L1, and CTLA-4. However, the increased T-cell activation from ICIs can result in immune-related adverse events, with cutaneous reactions such as maculopapular rashes, which are among the most prevalent adverse effects [56]. Psoriasis, while relatively uncommon, has also been reported in this setting, possibly due to PD-1 being a key regulator of T-cell activation and autoimmunity [54, 57, 58]. Previous studies have also shown decreased PD-1 expression by keratinocytes in psoriatic epidermis, suggesting local negative regulation of T cells [58].

It has been reported that ICI-associated psoriasis or psoriasiform reactions accounted for 3.8% of all cutaneous toxicities in the EudraVigilance drug safety database [59]. The majority of these patients had a previous history of psoriasis and were primarily managed with topical steroids [59]. On the contrary, a multicenter retrospective study reported a fourfold higher prevalence of ICI-mediated psoriasis exacerbations compared to de novo cases [60]. Additionally, ICI interruption and ultimate discontinuation were found in 18% of cases, with adjustments in treatment more likely when affected body surface area (BSA) was > 10% [60]. This mirrors trends seen in recent systematic reviews that report an ICI interruption rate of 16–58%, with permanent discontinuation among 13.6–22.9% patients [61, 62]. The predominant treatment modality was topical steroids, with other agents, including acitretin, systemic steroids, and biologics, used to treat refractory cases [61, 62]. Interestingly, while patients who received systemic steroids were widely observed to achieve complete psoriasis remission, they were also seen to have higher rates of ICI discontinuation—likely correlating with psoriasis severity [61, 62].

The use of systemic steroids in the context of ICI-mediated psoriasis has been controversial. Patients treated with systemic steroids for ICI-induced psoriasis did show clinical response, but this was accompanied by significant side effects and exacerbations during tapering [60, 62]. Furthermore, systemic steroids may interfere with the beneficial immunoproliferative effects of ICIs, ultimately contributing to the discontinuation of ICIs in neoplastic patients [60]. However, exceptions exist in the literature. For example, successful treatment has been observed in cases with steroid-refractory irAEs after ustekinumab and guselkumab administration, despite theoretical reductions in the anti-tumor activity conferred by IL-12 and IL-23 [60]. Additionally, IL-17A inhibition with secukinumab has also demonstrated good clinical response in cases where patients had an initial suboptimal response to systemic corticosteroids [63]. However, secukinumab may result in a loss of anti-tumoral efficacy in patients receiving immunotherapy treatment [64]. It is important to note that while these case reports provide promising results, larger sample sizes are needed to demonstrate clinical efficacy of agents such as ustekinumab, guselkumab, and secukinumab in the setting of steroid-refractory irAEs. Non-immunosuppressive agents, such as acitretin and phototherapy, are also reported as potential alternatives in patients with steroid-refractory irAEs [62]. Another treatment option for ICI-mediated psoriasis is apremilast, especially among patients with disease refractory to conventional topical and UV therapy. Regarding the discontinuation of ICI, current guidelines recommend ICI interruption if the patient presents with grade 3 psoriasis, classified as a BSA > 30% with moderate to severe symptoms [65]. In clinical practice, the decision to continue, interrupt, or restart ICI treatment is highly individualized, and takes into account tumor response, severity of cutaneous reaction, and overall patient health.

Conclusions

This review aims to summarize the complex interplay between targeted cancer therapy and psoriasis. Our systematic literature review identified EGFR, BCR-ABL, VEGF, and immune checkpoints as targets implicated in both tumor growth and psoriasis. For each drug class, we highlight therapeutic indications, shared biological mechanisms, clinical reports of drug-associated psoriasis presentations, and management options for cutaneous reactions.

TKIs, such as EGFR, BCR-ABL, and VEGF inhibitors, play a crucial role in regulating the complex molecular signaling pathways involved in tumor growth. Similarly, these pathways also have an impact on psoriasis keratinocyte proliferation, as evidenced by the cutaneous disease improvement seen in many patients treated with these anti-neoplastic agents. For example, clinical improvement with EGFR inhibitor monotherapy has even been observed in recalcitrant psoriasis cases. On the contrary, there have also been reports of psoriasis exacerbations and even new-onset disease in patients receiving these TKIs. This paradoxical presentation has been posited to be due to the delicate balance involved in both keratinocyte proliferation and immune regulation. For example, while the EGFR blockade of downstream signals can decrease keratinocyte proliferation, it may also place adaptive pressure to enhance alternative pathways for cell growth. Other TKIs, such as imatinib and nilotinib, can impact the immune environment by affecting the proportion of regulatory and effector T cells—with the direction of skew predicting whether psoriasis will be improved or exacerbated. These contrasting responses further underscore the equilibrium required between cellular growth and immune surveillance. In the setting of TKI-induced psoriasis exacerbation, the cases largely resolved with the use of topical steroids, often in conjunction with vitamin D derivatives. UVB phototherapy was also another common adjunct treatment modality with high efficacy. Discontinuation of the causative TKI agent was not necessary in the large majority of cases given the relatively high drug safety profile, anti-tumor efficacy, and manageable nature of the psoriasis flares.

The growing class of ICIs has also been associated with psoriasis presentations. The enhanced immune activity required for anti-tumor effect has been posited to nonspecifically affect the skin, with maculopapular rashes being one of the most common side effects. ICI-associated psoriasis, while less prevalent, has been reported in various case reports, drug safety databases, and multi-institutional studies. This presentation is likely due to disruptions in the PD-1/PD-L1 axis, which dampens inhibitory immune response and results in exacerbations of autoimmune diseases like psoriasis. Management of these cutaneous immune-related adverse events also involves the use of topical corticosteroids. The utilization of systemic oral steroids in this setting has been controversial, especially given the potential of disrupted ICI efficacy. Rather, biologics or non-immunosuppressive agents, such as acitretin and phototherapy, are recommended as first-line treatments for cases refractory to topical steroids. Current guidelines also recommend ICI interruption if > 30% of the BSA is affected by psoriasis. Our review of the literature suggests that approximately 13–23% of patients with ICI-induced psoriasis required ultimate immunotherapy discontinuation. Numerous factors may have played into this cessation, such as cancer treatment efficacy, other IrAEs, and patient preferences. A collaboration between oncologists and dermatologists may help the decision-making regarding treatment continuation in the setting of cutaneous toxicities.

In conclusion, we provide a summary of the relationship between targeted cancer therapeutics and psoriasis, reviewing mechanisms underlying different drug classes, the contrasting effects on psoriasis manifestations, and effective treatment modalities. This discussion becomes increasingly relevant as the landscape of targeted cancer therapeutics continues to expand, with rapidly increasing number of drug approvals and growing indications. As these anti-neoplastic agents become more utilized, the prevalence of associated side effects like psoriasis will likely increase. The early detection and management of these cutaneous adverse events is necessary to decrease the likelihood of cancer treatment interruption. On the other hand, it is important to note the beneficial impact that anti-neoplastic treatment may have on some patients with coexisting psoriasis. Given the shared underlying processes driving both diseases, greater clinical awareness may help to identify new targets and assess clinical efficacy of cancer therapeutics in psoriasis treatment. While seemingly paradoxical, the relationship between targeted cancer therapeutics and psoriasis can offer powerful insights that may advance the fields of both oncology and dermatology. Finally, quality of life is an extremely important consideration in patients with psoriasis with a history of malignancy. There is a tremendous psychological burden associated with these diagnoses, and patient comfort and preference must be given full consideration in these cases. There is a complex interplay between the mechanisms of psoriasis and cancer, and this interplay requires input across several healthcare specialties. Due to the relatively unpredictable risk of adverse dermatologic reactions with several of the agents listed above, careful follow-up and monitoring for symptoms are crucial.