FormalPara Key Summary Points

CTCL risk in the setting of biologic therapy in the management of psoriasis has not been well characterized.

In clinical trials, the incidence of CTCL was not significantly increased with the use of biologic therapy relative to placebo.

In psoriasis registries, only a single case of CTCL has been reported.

Of the CTCL cases reported in the literature, most were in the setting of TNF inhibitor use.

No cases of CTCL were reported with the use of IL-23 inhibitors.

Introduction

Psoriasis is a common, multisystem inflammatory disease characterized by erythematous, scaling patches, and plaques. Psoriasis affects roughly 125 million people worldwide (3% prevalence) and is associated with comorbidities such as psoriatic arthritis, cardiovascular disease, diabetes mellitus, and obesity [1, 2]. The underlying pathogenesis involves dysregulated cutaneous immunity with dysfunction of T1 and T17 cells, dendritic cells, keratinocytes, fibroblasts, and macrophages. This results in keratinocyte hyperproliferation and the production of proinflammatory cytokines such as interleukin (IL)-17, IL-23, tumor necrosis factor-alpha (TNFα), and interferon-gamma (IFNγ) [1, 3, 4].

Our improved understanding of the inflammatory molecular pathways involved in psoriasis has led to the development and US Food and Drug Administration (FDA) approval of multiple biologic therapies. These therapies target the cytokine-mediated pathogenesis of psoriasis and are approved for the treatment of moderate-to-severe psoriasis [5]. The main classes of biologics include TNFα inhibitors, IL-17 inhibitors, IL-23 inhibitors, and IL-12/23 inhibitors.

An important consideration for using biologic agents is their safety profiles. The efficacy of a biologic agent in treating psoriasis must be weighed against potential adverse events [6]. Through clinical trials and post-marketing surveillance, multiple adverse events have been reported. Reported events include injection site reactions, infections, heart failure, and malignancy [7, 8]. The goal of this review is to focus on one particular type of malignancy, which is cutaneous T cell lymphoma (CTCL).

Methods

Prior to initiating the study, a protocol outlying the study goals, search strategy, and plan for analysis was established. First, the US National Library of Medicine clinical trials database (clinicaltrials.gov) was queried to identify phase 3 and phase 4 clinical trials of the 12 biologic agents currently FDA approved for psoriatic disease. Incident cases of CTCL were recorded. Fisher’s exact test was performed to elucidate differences in rates of CTCL between patients receiving biologic medication and patients receiving placebo. A p value less than 0.05 was considered statistically significant.

Next, publications involving psoriasis biologic registry studies were identified via a PubMed (MEDLINE) search. Search criteria included psoriasis AND registr* AND biologic* NOT (clinical trial NOT case series) AND (safety OR malignancy OR cancer OR CTCL OR mycosis fungoides) AND (*name of psoriasis registry). Psoriasis registries examined included Corrona/CorEvitas, BADBIR, BIOBADADERM, BioCAPTURE, PsoReg, PSOLAR, Child-Capture, Psocare, Psonet, DERMBIO, PsoRA, PsoBest, MPR, AMC Psoriasis Registry, Australasian Psoriasis Registry, Swedish National Psoriasis Registry, Swiss Dermatology Network of Targeted Therapies, PsoREP, PsoBioTeq, Clalit Health Service Database, PSODIT, PSOREAL, and SDNB. The incidence of CTCL was analyzed. References were reviewed to identify potentially omitted studies.

Finally, a systematic review was performed by two individuals (M.S.D. and R.K.S.). This study was conducted in accordance with the Preferred Reporting Items for Systematic Review (PRISMA) guidelines (Supplementary Fig. 1). Articles involving psoriasis biologics and CTCL were identified in PubMed (MEDLINE) and Embase from inception through October 28, 2022 using a combination of terms: psoriasis AND (lymphoma OR mycosis fungoides OR cutaneous T-cell lymphoma OR non-Hodgkin T-cell lymphoma) AND (“tumor necrosis factors” OR “tumor necrosis factor*” OR “tumor necrosis factor alpha” OR guselkumab OR risankizumab OR tildrakizumab OR etanercept OR infliximab OR adalimumab OR golimumab OR certolizumab pegol OR brodalumab OR “anti-IL-17” OR secukinumab OR ixekizumab OR “anti-IL-23” OR ustekinumab OR “anti TNF alpha” OR “anti TNF”). Comprehensive review articles and references were reviewed to identify potentially omitted studies. The search was limited to publications in English and human participants.

Records were then screened by title and abstracts with duplicate records removed. Articles deemed relevant or potentially relevant were selected for full-text review. Disagreement between (M.S.D. and R.K.S.) were resolved through discussion and the resultant conclusions were unanimous. For the systematic review, studies were eligible if they were observational cohort studies, case series, or case reports with a full-text article or conference abstract available. Patients must have been treated with a biologic for psoriasis and a report of adverse events (e.g., CTCL, etc.) must have been included in the publication. We limited our systematic analysis to include all forms of CTCL. Studies that did not specify subtype of malignancy or, more specifically, subtype of lymphoma were excluded. We avoided including the same cases more than once (e.g., multiple articles referencing the same cases of CTCL). For quality assessment, two independent reviewers (R.K.S., M.S.D.) performed initial screening of studies. No filters or limits were utilized during the study selection process. Discrepancies in eligibility criteria were resolved by an additional reviewer (W.L.). Data abstraction was performed by M.S.D., and quality assessment was performed by two independent authors (K.G.E., J.Q.J.). All randomized controlled trials included were manually assessed by two independent authors (R.K.S., J.Q.J.) for risk of bias in six different domains. Bias assessment outcomes were compiled using the Cochrane Review Manager application.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Results

Phase 3 and 4 Trials

Data from 116 phase 3 trials of psoriasis biologics were analyzed (Supplementary Table 1 and Supplementary Fig. 2). Out of 35,801 patients with psoriasis who received a psoriasis biologic in the active arm of a phase 3 trial, two were diagnosed with CTCL (Table 1). Out of the 4519 patients who received placebo, none were diagnosed with CTCL. The biologics used in the two cases of CTCL were secukinumab and ustekinumab. These two cases were diagnosed during weeks 0–12 of the study period when the patients were receiving the study drug. The patient treated with secukinumab received 300 mg subcutaneous loading doses weekly for five weeks (weeks 0, 1, 2, 3, 4) and then every four weeks until week 28 (weeks 8, 12, 16, 20, 24, 28) [9]. The CTCL case associated with ustekinumab was retrospectively determined by the investigator to have existed prior to the administration of the biologic, but had been incorrectly diagnosed as psoriasis [10]. The patient treated with ustekinumab received 90 mg subcutaneous doses at weeks 0, 4, and then every 12 weeks until week 52. Depending on PGA evaluation at week 12, this patient may have been given an extra 90 mg dose at week 12, but it is unknown if this patient received the supplemental dose [11].

Table 1 Cases of CTCL reported in phase 3 clinical trials of psoriasis biologics
Full size table

Fisher’s exact test was performed to assess for any difference between the collective active drug group (all biologics combined) and placebo group. The test showed that there was no significant association between biologic administration and incidence of CTCL (p > 0.05).

Data from 34 phase 4 trials of psoriasis biologics were analyzed (Supplementary Table 2). Out of 5440 patients who received a biologic in these trials, 0 cases of CTCL were reported (Table 2).

Table 2 Cases of CTCL reported in phase 4 clinical trials of psoriasis biologics
Full size table

Review of Psoriasis Registries

Initial search for psoriasis registry studies in the Medline database yielded 68 total articles. Of these articles, 37 were excluded on the basis of title and abstract, leading to the identification of 31 articles for full-text review. Ultimately, 11 publications investigating adverse events reported in registry studies were included after full text-review (Table 3). Safety data was reported on 34,111 patients. Only one case of CTCL (mycosis fungoides subtype) was reported. This case was reported in the PSOLAR Registry study [12]. This registry study included the following biologic medications: adalimumab, infliximab, etanercept, and ustekinumab. However, the identity of the specific biologic associated with this reported case of CTCL was not available and additional clinical details of this case were not reported.

Table 3 CTCL cases identified in psoriasis biologic registries
Full size table

Systematic Literature Review

The Medline and Embase search for reported cases of CTCL yielded 294 articles. Of these articles, 31 duplicates were excluded, and 263 publications were screened on the basis of title and abstract. Subsequently, 135 articles were excluded, leading to the identification of 126 articles for full-text review. Ultimately, 28 publications reporting CTCL cases in the setting of psoriasis biologic treatment were included after full text-review (Supplementary Fig. 1). In total, 38 cases of CTCL with 48 distinct biologic exposures were reported (Table 4). Eight patients had been treated with two or more biologics prior to CTCL diagnosis. Mycosis fungoides was specifically listed as the diagnosis in 28 of the cases. The average patient age was 53 years (21 male, 7 female, 10 unspecified gender). The most frequently reported overall CTCL stage at time of diagnosis was stage 1 (10/38). Five cases were diagnosed at stage 2, one case at stage 3, and seven cases at stage 4.

Table 4 Systematic review: CTCL cases
Full size table

TNF inhibitors were used in the majority of the CTCL cases reported (34/38). Adalimumab was the biologic agent with the greatest number of CTCL cases reported (17). Other biologic exposures with reported CTCL cases include etanercept (11), secukinumab (6), ustekinumab (6), infliximab (6), ixekizumab (1), and an unspecified psoriasis biologic (1). No cases of CTCL were reported with IL-23 inhibitor use. The average duration with a biologic medication prior to CTCL diagnosis was 11 months. The five most frequent therapies utilized in the management of CTCL diagnosed in these patients were acitretin, narrow-band UVB, bexarotene, interferon alpha, and histone deacetylase inhibitors (e.g., romidepsin). Examples of other treatments used include total skin electron beam therapy (TSEBT), PUVA, methotrexate, prednisone, electrophoresis, and various other chemotherapeutic agents (e.g., doxorubicin).

Of the 38 cases reported from all sources, five patients died of their CTCL disease (Table 4). Each of these patients was diagnosed with CTCL after the administration of the biologic medication. In each of these cases, a TNF inhibitor was involved. One of the five patients had also received ustekinumab after a trial of a TNF inhibitor (adalimumab).

Discussion

Psoriasis is a chronic, systemic inflammatory disease associated with comorbidities including psoriatic arthritis, heart failure, multiple sclerosis, mood disorders, and malignancy [13,14,15]. The greatest concern for malignancy in the setting of biologic use has been with the TNF inhibitor class of biologics. This concern may in part be related to the observation of TNFα’s activity against tumors in laboratory models [16]. TNFα is a predominant cytokine in the inflammatory cascade and was initially recognized for its ability to lyse tumors in vitro and in mouse models [16]. TNF appears to be critical in CD8 lymphocyte- and natural killer cell-mediated killing of tumor cells [17]. Introduction of TNFα has been shown to cause thrombosis and necrosis of blood vessels feeding neoplastic cells [18]. However, TNFα has shown both tumor-inhibiting and tumor-promoting effects [19].

The majority of the concern for malignancy now likely stems from clinical trial data, observational studies, and meta-analyses, which report an increased risk of some types of cancer, particularly systemic lymphoma in rheumatoid arthritis and nonmelanoma skin cancer in rheumatoid arthritis and psoriasis in the setting of TNF inhibitor use [17, 18, 20,21,22,23]. For example, a relatively small registry study in Sweden demonstrated an increase in lymphoma in patients with rheumatoid arthritis treated with TNF inhibitor therapies [24]. It is important to note, however, that results have varied and that other studies have not been able to confirm an increased risk malignancy in the setting of biologic therapy use (TNF inhibitors included) [8, 17, 21, 22]. Regarding systemic lymphoma specifically, multiple large registry- and population-based studies have not been able to demonstrate an increased risk in the setting of biologic use [19,20,21,22, 25,26,27,28].

The collective data on CTCL from phase 3 and 4 clinical trials, registry studies, and a systematic review of two biomedical literature databases provide additional insight into the risk of CTCL in the setting of biologic therapy use for psoriasis. Our study suggests that the risk of incident CTCL in the setting of biologic use is low. Only two cases of CTCL, one of which may have been CTCL misdiagnosed as psoriasis, were reported in phase 3 and phase 4 clinical trials and only one case of CTCL was reported in a psoriasis biologic registry publication. This is significant as over 25,000 patients in the phase 3 clinical trials and over 5000 patients in the phase 4 clinical trials received a biologic.

Nonetheless, 38 cases of CTCL from case reports and case series were found in our systematic review. Eight of these cases were associated with exposure to two or more biologics. Most of the cases of CTCL occurred in the setting of TNF inhibitor use (34/38). The single agent with the highest number of cases was adalimumab with 17 reported. It is important to note that adalimumab, infliximab, and etanercept were approved for treatment of plaque psoriasis prior to biologics in the IL-17, IL-12/23, and IL-23 inhibitor classes. Therefore, we have had more time to observe patient outcomes with the TNF inhibitor class.

A total of seven cases of CTCL were reported with use of IL-17 inhibitors (secukinumab, ixekizumab) and six cases were reported with IL-12/23 inhibitor (ustekinumab) use. Interestingly, no cases of CTCL were reported with IL-23 inhibitor use in patients with plaque psoriasis. Other studies on IL-23 safety data are consistent with our findings [29,30,31]

Several obstacles are present for establishing the true malignancy risk for biologics and other therapies. First, analyses of malignancy risk will often reference SIR, comparing the risk of malignancy in a psoriasis cohort compared to a reference cohort. These unfortunately do not differentiate between malignancy risk associated with biologic therapy and the malignancy risk associated with psoriasis. This is particularly pertinent as psoriasis has been associated with an increased risk of malignancy when compared with the general population in studies of large healthcare databases [32, 33].

Another specific challenge is the assessment of cancer risk in patients with a history of cancer. Patients with cancer are often excluded from participating in clinical trials because of concern about an intervention potentially causing a new malignancy, instigating a recurrence, or exacerbating an existing malignancy. As a result, clinicians treating patients with cancer and concurrent psoriasis are often unable to make confident, evidence-based recommendations for these patients.

Conclusion

Overall, it is important to recognize that biologic agents are associated with various adverse effects, some of which are potentially serious. However, it is also important to assess these risks in the context of the potential benefits of biologics, as well as in the context of potential comorbidities associated with uncontrolled disease. This study demonstrates that the risk of CTCL is extremely low in the setting of biologic use for psoriasis, with no CTCL yet reported with IL-23 inhibitor use. When considering a biologic, clinicians need to factor in the extent of psoriatic disease and all of the associated risks for each individual patient.

Limitations

This analysis is limited by the relatively short exposure to trial drug and placebo per clinical trial protocols. As phase 3 and 4 studies are limited in duration, certain outcomes like CTCL may take a longer period of time to develop. Next, registries oftentimes only include patients with psoriasis and do not include a placebo group for comparison. Reporting bias may also affect the results.

Additionally, we found eight cases in which patients were exposed to multiple biologic agents (Table 4). In three of these cases, information regarding the timing of the biologic treatments in relation to the diagnosis of CTCL was unavailable. These cases are marked with an asterisk in Table 4.

Future Directions

While this study focused on incident CTCL with biologic use, clinicians may face the question of whether to use biologics in patients with psoriasis and a known diagnosis of CTCL. A similar concern may exist when treating patients with malignancy in remission. Therefore, it would be useful to identify studies in the future with patients who had CTCL prior to administration of a biologic to see if biologics therapy could be safely used in this specific population.