Abstract
Introduction
Biological drugs (BD) and Janus kinase inhibitors (JAKi) have revolutionized the treatment of diverse dermatoses. However, there are concerns regarding their safety, especially the risk of cancer and opportunistic infections. Here, we discuss the risk of cancer associated with the BD and JAKi used in dermatology.
Methods
A narrative review was carried out. All relevant articles evaluating the risk of cancer associated with BD or JAKi and published between January 2010 and February 2024 were selected.
Results
Multiple large studies have evaluated the association between BD, JAKi and cancer risk. However, there is a lack of prospective, comparative studies. Overall, patients undergoing BD and JAKi present a cutaneous cancer incidence similar to that in the general population. The drugs more strongly associated with non-skin cancer risk were anti-tumor necrosis factor (anti-TNFs) agents and JAKi (especially tofacitinib and oral ruxolitinib). This risk appears to increase with age, the presence of other factors (such as chronic immunosuppression from previous drugs or other comorbidities), and specific diseases such as rheumatoid arthritis (RA) and myelodysplastic syndrome. Conversely, BD such as interleukin (IL)-17 and IL-23 inhibitors may even reduce the risk of some visceral and hematological malignancies. In patients with dermatological conditions such as psoriasis and atopic dermatitis, the risk of malignancies may be lower than in other subgroups, and probably comparable to the general population.
Conclusions
The incidence of cancer in patients undergoing BD or JAKi is generally low. This incidence can be higher in elderly patients with RA or myelodysplastic syndrome, and in those undergoing prolonged therapy with tofacitinib or ruxolitinib (oral), or anti-TNF agents.
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Avoid common mistakes on your manuscript.
In general, biological drugs and Janus kinase inhibitors (JAKi) are considered safe regarding the risk of cancer. |
The incidence of cancer may be increased in patients undergoing prolonged treatment with with anti-tumor necrosis factor (anti-TNF) agents, tofacitinib and oral ruxolitinib (possibly more so with these latter two agents). |
Cancer incidence may be increased in elderly patients or those with other factors, such as chronic immunosuppression from previously administered drugs. |
Overall, the risk of cancer in patients with dermatological conditions (such as psoriasis, psoriatic arthritis, or atopic dermatitis) is low, and could be lower than in other subgroups (such as those with rheumatoid arthritis or myelodysplastic syndrome), and possibly comparable to the general population. |
Introduction
Conventional immunosuppressants such as corticosteroids, cyclosporine, methotrexate, or azathioprine present a significant burden of side effects (AEs) [1], including cytopenias (methotrexate or azathioprine), renal dysfunction or hypertension (cyclosporine), and an elevated incidence of cutaneous and extracutaneous neoplasms and opportunistic infections in patients undergoing long-term therapy [2]. Biologic drugs (BD) have revolutionized the management of multiple dermatoses [3]. BD target specific protein receptors, and are typically administered subcutaneously or intravenously. They present a more selective action, and tend to have a more favorable safety profile [4]. Diverse BD are available in dermatology, including inhibitors of tumor necrosis factor alpha (anti-TNF), interleukin (IL)-4 (anti-IL-4), IL-17 (anti-IL-17), and IL-23 (anti-IL-23), among others. BD have been linked to AEs such as generic reactions at injection sites, flu-like symptoms, or respiratory, gastrointestinal, and genitourinary infections [5]. Anti-TNF drugs have been associated with severe reactivation of latent tuberculosis infection (LTBI), reactivation of the hepatitis B virus (HBV), and the occurrence of cutaneous and extracutaneous neoplasms [6].
More recently, Janus kinase inhibitors (JAKi) have emerged. JAKi are a series of proteins essential for intracellular signaling of various cytokines, and play a crucial role in regulating the immune system and inflammation [7]. Currently, six molecules have been approved for use in dermatology: upadacitinib, baricitinib, abrocitinib, ritlecitinib, deucravacitinib, and topical ruxolitinib. Off-label uses have been reported for multiple dermatoses, and the approval of these drugs for diverse inflammatory dermatoses is anticipated (Table 1) [8]. As JAKi block intracellular signaling, they could theoretically reduce systemic AEs, when compared to conventional immunosuppressants [7]. However, concerns have recently arisen about their safety profile. In September 2021, the Food and Drug Administration (FDA) reviewed the post-marketing safety trial results comparing tofacitinib with anti-TNF in rheumatoid arthritis (RA), and concluded that tofacitinib posed a higher risk of major cardiovascular events (MACE), thromboembolic events, malignant neoplasms, and death. Based on these results, a boxed warning was issued, which also extended to other JAKi [8, 9].
In the first part of this review, we will discuss the available evidence regarding the relationship between BD and JAKi used for dermatological disorders, and the risk of cancer.
Methods
We conducted a narrative review of the literature. Searches were performed on MEDLINE and Google Scholar from January 2010 to February 2024 using the following key terms: “cancer,” “malignancy,” “skin cancer,” “melanoma,” “anti-TNF,” “etanercept,” “infliximab,” “adalimumab,” “certolizumab,” “golimumab,” “anti IL-17,” “secukinumab,” “ixekizumab,” “brodalumab,” “bimekizumab,” “anti IL-23,” “guselkumab,” “tildrakizumab,” “risankizumab,” “anti IL-12/23,” “ustekinumab,” “anti IL-1,” “anti CD-20,” “rituximab,” “anti IL-4/13,” “dupilumab,” “tralokinumab,” “anti IgE,” “omalizumab,” “anti IL-31,” “nemolizumab,” “JAK inhibitors,” “abrocitinib,” “upadacitinib,” baricitinib,” “ruxolitinib,” “tofacitinib,” “deucravacitinib,” “ritlecitinib.”
The search was directed to articles written in Spanish and English. These articles were screened based on their abstracts, and selected according to their relevance after reading the studies. Observational studies, clinical trials, post-trial analysis studies, systematic reviews (SR), and meta-analyses (MA) were included. Two authors (MMP and DMC) carried out the search and article selection. The procedures followed here are in accordance with the standards of the committee on ethical human experimentation and with the Helsinki Declaration of 1975, as revised in 1983. We have not used patients' names, initials, or hospital numbers. This article 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
Anti-TNF and Cancer Risk (Table 2)
Anti-TNFs
We found 50 studies on anti-TNF agents and the risk of cancer. Among them, 34 include anti-TNF as a group (≥ 3 drugs of this class) [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44], with four on etanercept (ETN) therapy [45,46,47,48], two on infliximab (IFX) [49, 50], six on adalimumab (ADA) [46, 51,52,53,54,55], three on certolizumab [56,57,58], and one on golimumab treatment [56]. Globally, the risk of cancer could be slightly increased with the use of anti-TNF agents, especially for non-melanoma skin cancer (NMSC) and in patients with other risk factors (increased age, comorbidities).
An MA of randomized controlled trials (RCTs) (n > 15,000) published in 2011, including patients treated with ADA, ETN, or IFX for diverse pathologies, showed that the only tumor associated with anti-TNF was non-melanoma skin cancer (NMSC) [relative risk (RR) of 2.02 (95% CI: 1.11–3.95)], with no differences among the three drugs [10]. This risk was especially relevant in patients with rheumatoid arthritis (RA). Anti-TNFs presented a significant risk when compared with non-biological disease-modifying antirheumatic drugs (nbDMARDs). In 2015, a multicenter prospective study (n > 10,000) compared the risk of solid organ malignancies in RA patients treated with anti-TNF to that in patients treated with nbDMARDs. After adjusting for differences in baseline characteristics, there was no significant difference between treatments: hazard ratio (HR) 0.83 (95% CI 0.64–1.07). Furthermore, there was no difference in the RR of cancer for any of the individual anti-TNF [16]. A multicenter retrospective study with 4500 patients suggested that individuals with RA undergoing anti-TNF treatment might even have a lower risk of cancer than those treated with nbDMARDs. The adjusted HR (95% CI) was significantly lower in the anti-TNF cohort than in the nbDMARD cohort for gastrointestinal cancer (0.432; 0.235–0.797), breast cancer (0.146; 0.045–0.474), and genitourinary cancer (0.220; 0.059–0.820) [33]. Regarding inflammatory bowel disease (IBD), in 2022, a multicenter retrospective study with > 30,000 patients showed that the risk of colorectal cancer could even be decreased in patients under anti-TNF treatment for ≥ 10 years (HR, 0.41; 95% CI, 0.20–0.86). [31] However, other studies have linked anti-TNF in IBD patients with the risk of lymphomas, especially when combined with other treatments [29, 37].
Regarding dermatological indications, a single-center retrospective study (n = 280) demonstrated that the incidence of NMSC in psoriasis patients treated with anti-TNF was higher than in those with RA treated with anti-TNF [HR 6.0 (1.6–22.4 95% CI)]. This could be explained by different baseline characteristics between the groups (e.g., previous phototherapy in psoriasis patients) [15].
Regarding patients with a history of cancer, an SR and MA, including 3807 patients under anti-TNF therapy (with dermatological and non-dermatological disorders) versus 7972 controls, all those with a previous history of cancer, showed that the pooled RR of new or recurrent cancer was not significantly different between the groups (IRR 0.90; 95% CI 0.59–1.37) [28].
The risk of malignancies has also been evaluated in pediatric and young adult patients under anti-TNF therapy. Overall, the risk was low and comparable to the general population [48, 50].
Anti-TNF Versus JAK Inhibitors or Other Therapies
A multicenter retrospective study (n > 3500) revealed that the rates of malignancies were higher with rituximab than with infliximab [18]. Other comparative studies have suggested a higher incidence of cutaneous and extracutaneous cancers with JAKi (especially tofacitinib) when compared to anti-TNF agents [34, 38, 41, 43, 44]. An MA including 62 RCTs and 16 observational studies (n > 35,000) concluded that JAKi were associated with a higher incidence of malignancy (IRR 1.50; 95% CI 1.16–1.94), both NMSCs and non-NMSCs, than anti-TNFs [44]. However, other studies have shown a similar incidence of cancer with anti-TNF drugs and JAKi [35, 40, 47].
Anti IL-17 and Cancer Risk (Table 3)
We found six studies analyzing the relationship between anti-IL-17 drugs or IL-17 receptor (R) inhibitors (IL-17i) and the risk of cancer. Among them, four studies that simultaneously investigated various IL-17i [39, 59,60,61], including > 140,000 patients in total, showed that the incidence of neoplasms with these agents was very low, both cutaneous and non-cutaneous cancer. In fact, anti-IL-17 could even confer a decreased risk of certain neoplasms in patients with psoriasis, compared to the native population [61].
Regarding secukinumab, in 2021, an analysis of 49 RCTs and post-marketing surveillance data, including > 15,000 patients with psoriasis, PsA, and/or ankylosing spondylitis (AS), reported an exposure-adjusted incidence rate (EAIR) of malignancy of 0.85 per 100 persons treated per year [95% CI 0.74–0.98] in secukinumab-treated patients, a relatively low incidence at 5 years of follow-up [62]. Similar results were observed with ixekizumab [63].
Anti IL-17 Versus Anti-TNF
A population-based study published in 2024 (n > 40,000) revealed that patients undergoing anti-TNF treatment had an increased risk of cancer compared to those receiving anti-IL-17 and IL-23 drugs. Anti-IL17 could even decrease the risk of malignancies, especially non-Hodgkin lymphoma (NHL), colorectal cancer, ovarian cancer, hepatobiliary cancer, melanoma, and basal cell carcinoma [61].
Anti IL-23 and Cancer Risk (Table 3)
We found 11 studies that evaluated the risk of cancer in patients treated with IL-23 inhibitors (IL-23i): three studies simultaneously investigated various drugs [59,60,61], three focused on guselkumab [64,65,66], two on tildrakizumab [67, 68], and three on risankizumab [69,70,71].
The majority of studies indicate a very low incidence of neoplasms, comparable or even lower than the general population [59,60,61]. Similar findings were shown individually for guselkumab [64,65,66], tildrakizumab [67, 68], and risankizumab [69,70,71]. The previously mentioned population-based study by Kidrin et al. [61] showed that patients under IL-23i experienced a decreased risk of NHL (HR, 0.39; 95% CI, 0.19–0.78; p = 0.006) and hepatobiliary cancer (HR, 0.44; 95% CI, 0.31–0.62; p < 0.001). A recent SR and MA, including 19 observational studies and > 18,000 individuals, compared the incidence of malignancies among patients undergoing anti IL-17, anti IL-23, ustekinumab, or JAKi, and showed that the incidence of NMSC was higher in patients undergoing JAKi when compared to those receiving anti IL-17, ustekinumab, or anti IL-23, but was similar for other types of tumors [60].
Ustekinumab (Anti IL-12/23) and Cancer Risk (Table 3)
We found three studies evaluating ustekinumab and the risk of malignancies. They revealed a very low risk [32, 60, 72]. An analysis of four clinical trials (> 3000 individuals) showed that the rate of cancer was similar in patients receiving a placebo [32, 72].
Anti CD-20 and Cancer Risk (Table 4)
We found five studies that evaluated the relationship between rituximab (RTX) and neoplastic risk [18, 20, 24, 73, 74]. A multicentric retrospective study with 3762 individuals with RA showed that the crude rates of malignancies were highest among the users of RTX and nbDMARD, and lowest among patients treated with IFX [18]. A multicenter retrospective study on 130,315 RA patients did not revealed an overall increased risk of melanoma following exposure to rituximab [24]. Similar results were observed in a global company safety database that included 409,706 patients, where data showed no evidence of an increased risk of malignancy of any type following rituximab treatment in patients with RA [74].
Anti IL-4/13 and Anti IL-13 and Cancer Risk (Table 4)
We found four studies that evaluated the risk of malignancies with dupilumab [75,76,77,78] and three with tralokinumab [79,80,81] An SR and MA including 22 observational studies in patients with AD under dupilumab (anti-IL-4/13) revealed that no cases of malignancy were reported [75]. Strikingly, Mota et al., using worldwide real data in safety databases (VigiBase®) (n > 10,000,000), linked dupilumab to cases of cutaneous T-cell lymphoma [relative odds ratio (ROR) = 11.11] [78]. This association was not found in other studies [75,76,77].
Regarding tralokinumab (anti-IL-13), a post hoc analysis of clinical trials on 1174 patients with AD found nine neoplasms in the group under biologic treatment [79].
Anti IL-31 and Cancer Risk (Table 4)
We found two studies that assessed the relationship between nemolizumab and cancer [82, 83]. An SR with MA, including eight RCTs (809 patients with AD), did not reveal an increased risk of cancer in individuals under nemolizumab therapy [82].
Anti Ig-E and Cancer Risk (Table 4)
We found five studies (four of them were SR) evaluating the relationship between neoplasms and omalizumab. In all the included studies, cancer rates among patients exposed to omalizumab were not higher than in the general population [84,85,86,87,88].
Anti IL-1 (Anakinra, Canakinumab, Rilonacept) and Cancer Risk
We found five studies on anti-IL-1 agents and the risk of cancer: two analyzing various anti-IL-1 [89, 90], two on canakinumab [91, 92] and one on rilonacept [93]. All of the studies, including an SR with > 10,000 patients with cryopyrin-associated periodic syndromes (CAPS) treated with anti-IL-1 therapy, showed that these drugs did not increase the rate of neoplasms compared to the general population [90].
JAK Inhibitors and Cancer Risk (Table 5)
JAK Inhibitors (ALL) and Cancer Risk
We found 46 studies on JAKi agents and the risk of cancer. Among them, 11 included JAKi as a group (≥ 2 drugs of this class) [35, 40,41,42,43,44, 60, 94,95,96,97,98]. An SR and MA from 2020, encompassing 82 RCTs with over 66,000 RA patients, revealed that the incidence rates of malignancies (excluding NMSC) were 0.89 per 100 person-years, which is slightly higher than would be expected in the general population (0.5–0.6 per 100 person-years) [95]. Jalles et al., utilizing data from VigiBase®, a French pharmacovigilance database that reports skin cancers (> 100,000 registered cases), revealed a disproportionality signal for squamous cell carcinoma (SCC) with ruxolitinib and tofacitinib, for melanoma with ruxolitinib and tofacitinib, and Merkel cell carcinoma with ruxolitinib and tofacitinib, and only for Merkel cell carcinoma with baricitinib [96].
Anti-JAKi Versus Biologics
A retrospective study involving nearly 5000 patients reported that the incidence of malignancies in RA patients was not increased with JAKi use compared with anti-TNF therapy [35]. This finding has been supported by other studies [42, 43]. However, some studies have reported a higher incidence of neoplasms in patients undergoing JAKi treatment compared to anti-TNF [41, 44], including a recent multicenter retrospective study (n > 36,000) which concluded that compared to anti-TNF, JAKi were associated with an increased incidence of cancer (incidence rate ratio 1.50; 95% CI 1.16–1.94), both NMSCs and non-skin cancer [44].
JAK-1 Inhibitors (Abrocitinib, Upadacitinib) and Cancer Risk
We found nine studies on the risk of neoplasms with selective JAK 1 (JAK-1) inhibitors: three focusing on abrocitinib [77, 99, 100] and six on upadacitinib [55, 101,102,103,104,105]. In the three studies with abrocitinib, including 787 patients with AD, no cases of cancer were reported [77, 99, 100]. Regarding upadacitinib, a recent SR including 25 RCTs (> 10,000 patients) reported that most of the RCTs did not find a significant increase in the rate of malignancies with upadacitinib therapy when compared to placebo or to anti-TNFs [101, 103, 105]. However, an extended study of a phase 3 RCT (493 patients with RA) showed a higher rate of neoplasia in the 12 mg/day group, mainly at the expense of NMSC [102]. An SR with 11 RCTs and > 50,000 patients (including patients with RA, PsA, and spondyloarthritis) revealed a dose-dependent increase in the incidence of NMSC in RA patients treated with upadacitinib, but not in patients with spondyloarthritis or PsA. The incidence of other types of cancer was not increased [104].
JAK-1 and JAK-2 Inhibitors (Baricitinib, Ruxolitinib) and Cancer Risk
We found 11 studies: one on ruxolitinib and baricitinib [106], four studies on baricitinib [107,108,109,110], and six studies on ruxolitinib [111,112,113,114,115,116]. Regarding baricitinib, the incidence of cancer was low, and there was no higher rate of malignancies when compared to the reference population in studies involving RA [107] (n = 3770), AD [108] (n = 2636), or alopecia areata (AA) (n > 1300) [109, 110].
Concerning oral ruxolitinib, an agent traditionally used in hematological disorders such as myelofibrosis and polycythemia vera, diverse studies have demonstrated an increased incidence of secondary neoplasms [111, 112]: a multicentric retrospective study on 700 patients with myelofibrosis revealed that 11.4% of cases developed a neoplasm after starting ruxolitinib and 50% were NMSC [112]. Other studies have also shown an increased incidence of NMSC, especially SCC [113,114,115]. NMSCs have also been reported with the use of topical ruxolitinib in RCTs on patients with vitiligo, although all cases were considered unrelated to the treatment [116]. A recent study that reviewed nearly 14,000 patient-years of post-marketing safety data from the first year following market approval of ruxolitinib cream found four NMSC in two patients [116].
PAN-JAK Inhibitors (Tofacitinib) and Cancer Risk
Twelve studies were found that assessed the risk of cancer with the administration of the JAK-1, JAK-2, JAK-3, and TYK-2 inhibitor tofacitinib [34, 36, 38, 47, 117,118,119,120,121,122,123,124]. Diverse studies reported that the incidence of neoplasms with tofacitinib was low and similar to the general population, including NMSC [117,118,119,120,121, 123, 124]. A recent SR and MA including 26 controlled studies (22 RCTs) showed that the RR for any cancer with tofacitinib therapy compared to any control treatment was 1.06 (95% CI, 0.86–1.31; p = 0.95). When comparing tofacitinib to either placebo or biological therapy, no difference was found in the overall cancer risk (versus placebo, RR = 1.04; 95% CI, 0.44–2.48; p = 0.95; versus biological drugs, RR = 1.06; 95% CI, 0.86–1.31; p = 0.58). However, when tofacitinib was compared to anti-TNF, the overall cancer RR was 1.40 (95% CI, 1.06–2.08; p = 0.02). For skin cancer, the RR was 1.30 (95% CI, 0.22–5.83; p = 0.88). In conclusion, a slightly higher risk was found in patients treated with tofacitinib than in those treated with anti-TNF agents [122]. Similar findings were reported in a randomized, open-label, non-inferiority, post-authorization, safety endpoint trial with 1455 RA patients comparing tofacitinib to anti-TNF [HR 1.48 (95% CI, 1.04–2.09)] [34], and in a study that reviewed data from real practice (> 80,000 patients) [36].
TYK-2 Inhibitors (Deucravacitinib) and Cancer Risk
We found two studies (n = 666 and n = 1519) on the association of cancer and deucravacitinib in patients with psoriasis. Neither article reported a higher incidence of malignancies with this drug than in the general population [125, 126].
JAK-3 and TYK Inhibitors (Ritlecitinib) and Cancer Risk
An SR including four RCTs and > 1000 patients with AA revealed no higher rate of cancer with ritlecitinib in individuals aged ≥ 12 years. In this study, the risk of NMSC was not specifically analyzed [127].
Discussion
Biologics and Cancer Risk
TNF-α is a cytokine with pleiotropic activity, and plays a crucial role in inflammation, exhibiting pro-inflammatory characteristics and influencing various aspects of inflammation and immune regulation. Concerns have arisen about the potential induction of immunotolerance by anti-TNF treatment, leading to the development of malignancies [128]. However, we found a low risk of cancer with these agents, higher in RA patients with other comorbidities such as advanced age, exposure to other immunosuppressants, and/or hematological disorders [10, 11]. When comparing anti-TNF with other BD, evidence suggested that treatment with anti-IL-17 or anti-IL-23 may have a lower cancer risk than anti-TNF, potentially even lower than the general population [61]. This could be attributed to a pro-tumor role of IL-17 or IL-23, as suggested by some studies [129]. Regarding other BD such as IL-4/13 (dupilumab), IL-13 (tralokinumab), CD-20 (rituximab), IgE R (omalizumab), IL-12/23 (ustekinumab), and IL-31 (nemolizumab) inhibitors, as well as anti-IL-1, IL-5, and IL-6, no higher risk of cancer was found compared to the general population or to other biologics.
Regarding anti IL-4/13, concerns have been raised about the association of dupilumab with certain lymphoproliferative processes. This was initially based on cases of patients treated with dupilumab and subsequently diagnosed with cutaneous T-cell lymphomas (LCCT). However, recent studies have indicated no clear association, with most cases likely being diagnostic errors, initially diagnosed as AD but later confirmed as LCCT [130].
JAK Inhibitors and Cancer Risk
JAKi block multiple cytokines and intracellular pathways of immunosurveillance. The disruption of immunosurveillance could increase the risk of cancer [8]. In our review, some studies demonstrated a higher incidence of cancer, particularly of NMSC, in patients undergoing JAKi, especially with tofacitinib and ruxolitinib, [96]. This may be secondary to the less selective inhibition of tofacitinib (JAK-1, JAK-2, JAK-3, and TYK-2) and ruxolitinib (JAK-1 and JAK-2). However, the patients receiving these drugs may have clinical characteristics (elderly with myelodysplastic syndrome for ruxolitinib and RA patients for tofacitinib) rendering them prone to the development of malignancies. The association of oral ruxolitinib with SCC is noteworthy and has been shown in several case series, often involving high-risk and poor-prognosis tumors [114]. This should be considered in patients undergoing ruxolitinib and presenting with other risk factors for cutaneous cancer [113,114,115].
For the rest of JAKi, the overall association with cancer was limited and comparable to the general population, although a slightly higher rate of NMSC has been reported with upadacitinib, which is dose-dependent and only in RA [104].
Cancer Risk: Biologics Versus JAK Inhibitors
Multiple studies have attempted to compare the incidence of cancer in patients undergoing BD (especially anti-TNF) and JAKi. Although some have demonstrated a similar incidence [35, 42, 55], most have revealed a higher cancer incidence in patients treated with JAKi than those with anti-TNF or other BD [34, 38, 40, 41, 44, 47, 60]. This risk seems higher particularly for NMSC [41], in patients under prolonged therapy [38], in RA individuals [34, 38, 47], and in patients using tofacitinib [34, 47] or ruxolitinib [114]. However, it is important to emphasize that the overall safety profile of JAKi is favorable and generally superior to other classic immunosuppressants (systemic corticosteroids, azathioprine, methotrexate, cyclophosphamide) [8]. Additionally, the higher incidence of neoplasms has been mainly observed in patients with extra-dermatological disorders (RA and myelodysplastic syndrome), who tend to be older, with more comorbidities, and have undergone prior therapy with multiple immunosuppressants [8]. Nevertheless, new guidelines evaluating the safety of JAKi and certain BD are needed. Recently, the Pharmacovigilance Risk Assessment Committee proposed measures to address severe side effects linked to JAKi in immune-mediated inflammatory diseases [131]. These and other measures may provide a more comprehensive understanding of JAKi and other BD.
Limitations
Our study has several limitations. First, it is a narrative review rather than a systematic one. Second, not all JAKi and BD available were included. The risk of sonidegib, vismodegib, and immunotherapy was not assessed. However, efforts were made to include as many drugs as possible. Third, a significant portion of the included studies evaluated rheumatological conditions (such as RA, PsA, or spondyloarthropathies), digestive disorders (IBD), or hematological conditions (such as myelodysplastic syndromes), and these patients may present comorbidities or an intrinsic cancer risk that may differ from that of dermatologic patients. Fourth, there is limited literature on newer drugs (e.g., abrocitinib) and a reduced follow-up interval with these agents. Lastly, many studies globally assessed cancer incidence without specific mention of cutaneous cancer, as most reported studies focused on non-dermatological conditions. All these factors make the generalization of reported findings and their conclusions difficult.
Conclusions
The drugs most strongly associated with cancer risk are anti-TNF agents and JAKi (specifically tofacitinib and ruxolitinib). BD and JAKi tend to represent an incidence of cutaneous cancer similar to the general population.
When comparing BD with JAKi, the latter seem to be associated with a higher risk of malignancies. This risk appears to increase with age, with the presence of other factors such as chronic immunosuppression from previous drugs or other comorbidities, and with specific diseases such as RA and myelodysplastic syndrome. In patients with dermatological conditions (such as psoriasis, PsA, AD), this risk may be lower than in other subgroups and possibly comparable to the general population.
Data Availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
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Mansilla-Polo, M., Morgado-Carrasco, D. Biologics Versus JAK Inhibitors. Part I: Cancer Risk. A Narrative Review. Dermatol Ther (Heidelb) 14, 1389–1442 (2024). https://doi.org/10.1007/s13555-024-01166-4
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DOI: https://doi.org/10.1007/s13555-024-01166-4