Skin Related Paradoxical Adverse Events (Mainly Psoriasis) During Il-17 Blockage: A Systematic Review

Alexandra Maria Giovanna Brunasso^1*, Martina Montinari¹

¹Dermatology, Villa Scassi Hospital ASL3, Genoa, Italy

*Correspondence author: Alexandra Maria Giovanna Brunasso, Dermatology, Villa Scassi Hospital ASL3, Genoa, Italy; Email: giovanna.brunasso@asl3.liguria.it; Giovanna.brunasso@gmail.com

Published Date: 30-06-2023

Copyright© 2023 by Brunasso AMG, et al. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Background: Paradoxical Adverse Events (PAEs) during biological therapy are characterized by the onset of a new inflammatory disease or by the exacerbation of the preexisting condition (with a different morphology or localization) while treating the patient with a class-agent proven efficacious for both conditions. They can be divided in two subgroups: “true PAE” characterized by the previously proven efficacy of the biological agent for the PAE and “borderline PAE” defined by the development of an inflammatory condition where the biological agent has not a proven efficacy.

Methods: systematic search of English databases in order to identify true and borderline-skin PAE under anti IL-17 therapy.

Results: We retrieved 58 patients affected by skin-PAE during anti-IL-17 therapy, 40 cases classified as True-PAE and 18 as Borderline-PAE., with a mean age of onset of 51 years. Secukinumab was the most frequent agent associated to skin-PAE and mean onset of the skin-PAE was 18 weeks.

Conclusion: True-skin-PAE occur during anti Il-17 therapy, the underlaying immunological mechanism is not yet known, but pustular variants of psoriasis seem to be more prevalent; withdrawal of the anti-IL-17 therapy has been mainly performed and other therapies such as anti-IL-23 biologics seem to control both the underlying disease and the true-skin-PAE. Further studies are needed in order to better understand the immunological mechanism involved.

Keywords: Psoriasis; Palmoplantar Psoriasis; Palmoplantar Pustulosis; Plaque Psoriasis; Brodalumab; Ixekizumab; Secukinumab; IL-17

Introduction

Paradoxical Adverse Events (PAEs) during biological therapy are characterized by the onset of a new inflammatory disease or by the exacerbation of the preexisting condition (with a different morphology or localization) while treating the patient with a class-agent proven efficacious for both conditions [1,2]. Toussirot, et al., have proposed a classification of PAE in two subgroups: “true PAE” characterized by the previously proven efficacy of the biological agent for the PAE (for example, new onset of pustular psoriasis and plaque psoriasis during the treatment with a proven efficacious agent for an inflammatory condition that also has well known efficacy in treating psoriasis) and “borderline PAE” defined by the development of an inflammatory condition where the biological agent has not a proven efficacy in phase-3 clinical trials and registration, despite a rationale for its use (for example, Behcets disease, pyoderma gangrenosum, alopecia areata, vitiligo, sarcoidosis, hidradenitis suppurativa) [1-3].

Induction or worsening of psoriasis was initially noted almost 20 years ago in patients with Inflammatory Bowel Disease (IBD), Rheumatoid Arthritis (RA) and Ankylosing Spondylitis (AS) treated with each of the available TNF-α inhibitors, reporting a 5% prevalence that clearly exceeds the 1-2% prevalence expected by chance [3]. In most cases, psoriasis appearing during anti-TNF-α therapy shows a pustular palmoplantar pattern that has been considered a class effect of TNF-α blocking agents rather than a drug-specific adverse event [3]. The mechanism underlying this paradoxical phenomenon seems to be related to the increased production of Interferon (IFN)-γ after TNF-α blockage, as IFN-γ is a key element in the induction of innate forms of psoriasis, mainly acute psoriasis and erythrodermic, guttate and might play also a role in pustular variants such as palmoplantar pustulosis [3].

IL-17 plays a key role in the pathogenesis of psoriasis and Psoriatic Arthritis (PsA). Protein levels of IL-17A, IL-17C, and IL-17F in lesional psoriatic skin are significantly increased when compared to non-lesional skin [4]. The IL-17 pathway plays a pivotal role in the inflammatory cycle of psoriasis. When an individual with a genetic predisposition gets into contact with trigger factor for psoriasis (mainly infections), the adaptive immune system initiates an immunologic cascade. Myeloid dendritic cells initiate the release of IL-12 and IL-23 (being the role of Il-23 essential in the whole process). IL-23 enhances the survival, differentiation, and activation of Th17 cells, which secrete IL-17 cytokines. IL-17 promotes keratinocyte proliferation and the production of psoriasis-related cytokines, chemokines, and antimicrobial peptides [4].

In the last five years, anti-IL-17 therapies have been routinely prescribed, while increasing their use diverse adverse events not reported during Randomized Clinical Trials (RCT) have emerged [4].

In the literature we can find isolated reports of skin related PAE associated to IL-17 blockage with Secukinumab (a recombinant fully human IgG1κ monoclonal antibody against IL-17A), Ixekizumab (a humanized IgG4 monoclonal antibody against IL-17A) and Brodalumab (a human monoclonal IL-17 receptor antibody (RA) antibody), but well-designed studies are missing and focus on this argument has not been given; for this reason, we decided to conduct the present systematic review of the literature in order to collect all of such cases in order to characterized general features, outcomes and to highlight this new emerging condition.

Materials and Methods

We followed PRISMA criteria and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. No ethical approval was requested. We performed a systematic search of English databases (PubMed, Embase and Web of Science) from January 2000 until March 2022, using the following keywords and [MESH FORMS]: “palmoplantar pustulosis” and/or “paradoxical”  and/or “pustular” and/or “new onset psoriasis” and/or “pyoderma gangrenosum” and/or “Behcet” and/or “alopecia areata” and/or “vitiligo” and/or “hidradenitis suppurativa” and/or “sarcoidosis” and/or “brodalumab” and/or “secukinumab” and/or “ixekizumab” No exclusion criteria were applied. Articles in English, German and Spanish were reviewed.

Data Extraction and Quality Assessment

Two reviewers (ABV and MM) independently screened all the identified studies and any disagreement was discussed and resolved. The following information was collected and analyzed for each case: demographics (age, sex), primary disease diagnosis, previous biological therapy, type of skin-PAE, previous PAE under other biological therapies, trigger molecule (Secukinumab, Ixekizumab or Brodalumab), time to onset of skin-PAE, time to withdrawal of trigger molecule and outcome of skin-PAE.

Definition of Cases Included and Excluded

We included all cases found that fullfeed the definition of “true”- or “borderline”-PAE. We excluded cases of eczematous reactions or atopic dermatitis or photosensitive skin reactions, because anti IL-17 agents have not a proven efficacy in the treatment of such conditions in a considerable way (in a phase-2 RCT, secukinumab failed to obtain improvement in atopic dermatitis) and only sporadic cases report their utility [5]. Recently Cardarola, et al., have reviewed such conditions in depth [6]. According with the literature, some specific adverse events as, lichenoid reactions, cutaneous vasculitis and subacute lupus erythematosus, occurring during biological therapy were not considered as PAE and excluded from the review, because of the possible underlying mechanisms related with immunogenicity, immune complex deposition and autoantibodies formation that are not primarily related to the Th17 pathway and cannot be classified as paradoxical [1].

We also excluded cases of flared psoriasis during anti Il-17 because they did not fulfill the criteria for PAE such as exacerbation of the preexisting condition with a different morphology or localization, therefore we excluded the cases that represented a secondary failure of therapy or loss of efficacy.

Results

We retrieved 40 publications describing a total of 58 patients affected by skin-PAE during anti-IL-17 therapy (Secukinumab, Ixekizumab and Brodalumab). The articles retrieved are case series, case reports and retrospective observational studies. We identified 220 reports, 65 were assessed for eligibility and only 40 publications fulfilled the requirements for the present systematic review [6-45]. The majority of the articles retrieved are case series, case reports and retrospective observational studies. The overview of the research strategy and a Flow chart of the systematic literature search according to PRISMA guidelines published in 2021 is illustrated on Fig. 1.

Figure 1: Overview of the research strategy (according the PRISMA 2020 Statement).

The patients identified with skin-PAE were 58 in total, 40 cases classified as True-PAE and 18 as Borderline-PAE. Regarding sex distribution 21 males and 30 females (in seven cases sex was not available) were reported, being males 45% (20/44) and females 55% (24/44) of the whole cohort (Table 1). Mean age of onset of skin-PAE was 51 years.

Table 1: Skin-PAE during anti IL-17 therapy.

Psoriasis and Psoriatic Arthritis (PsA) were the most common primary disease treated with IL-17 blocking agents, psoriasis 64% (37/58), concomitant psoriasis and PsA 19% (11/58), followed by anchylosing spondylitis (AS) with 7% (4/58), Generalized Pustular Psoriasis (GPP) with 3,5% (2/58), and concomitant PPP in 3,55% (2/58), Spondyloarthropathy 1,7% (1/58), hidradenitis suppurativa 1,7% (1/58) in one case such information was not available (Table 1).

Secukinumab was the most frequent agent associated to skin-PAE (67%, 39/58) followed by Ixekizumab (20%, 12/58) and Brodalumab 7/58(12%).

A total of 64 skin-PAE were recorded, one patient developed simultaneously four different skin-PAEs (PPP, inverse psoriasis, vitiligo and hidradenitis suppurativa) during Brodalumab-therapy and three patients recorded two skin-PAEs during Secukinumab (2 patients) and one case under Brodalumab. All of the cases of multiple skin-PAEs involved the new onset of pustular forms of psoriasis.

True skin-PAE manifested mainly as PPP in 33% (18/58) of patients and as other forms of psoriasis in 67%, 27/40 (plaque, plantar, inverse, palmoplantar plaque, GPP, scalp, nail, eye-lid, erythrodermic, acrodermatitis of Hallopeau, psoriasiform eruption, psoriasiform alopecia) Table 2.  Between the 40 cases classified as True-PAE in 45% of patients (18/40) a variant of pustular psoriasis was described, mainly PPP (78%, 14 cases), but also GPP and in one case ACH Table 2. Borderline skin-PAE were recorded in 31% of cases (18/58): new onset of Behcet´s disease, pyoderma gangrenosum, diffuse alopecia/alopecia areata, vitiligo and hidradenitis suppurativa Table 2.

Table 2: Type of paradoxical event and patient distribution.

In 7% (4/58) of cases a previous skin-PAE was recorded as follows: palmoplantar plaque psoriasis by adalimumab, dermatomyositis during adalimumab, PPP by adalimumab and alopecia areata during Certolizumab pegol [32,37]. Table 1 mean onset of the skin-PAE was 18 weeks, range: 1 week to 24 months after the first dose of anti-IL-17 therapy. 60% (35/58) of patients discontinued anti IL-17 therapy due to skin-PAE and 28% (16/58) did not interrupt it; in 7 cases (12%) withdrawal or continuation was not reported. Between patients that withdrew anti-IL-17 therapy, 20% were switched with improvement to anti IL-12/23 (Ustekinumab: 7/35) or to anti-IL-23 in 9% (Guselkumab: 3/35), or to an anti-TNF-a in 14% of cases (5/35) and to other anti-IL-17 agent in two cases (6%). In 7 cases cyclosporine was introduced (Table 1).

Discussion

After extensive review of the available literature, we found 58 patients affected by 64 episodes of skin-PAE during anti IL-17 therapy, 40 of those cases can be classified as true-PAE, with an almost equal distribution between genders and a mean age of onset of 51 years. The most frequent agent associated to skin-PAE was Secukinumab, such finding can be explained by its earlier approval for both psoriasis and PsA in comparison with Ixekuzumab and Brodalumab and its broader use worldwide. The mean time to skin-PAE onset was 18 weeks, but with a great variability between one week to 24 months after the first administered dose of anti-IL-17 therapy.

Diverse phenotypes of psoriasis, mainly pustular forms were described as Skin-PAE, in 33% of cases PPP was recorded and in 67% of patients, other form of psoriasis, including acrodermatitis of Hallopeau, GPP, palmoplantar plaque psoriasis, eye-lid psoriasis, nail and scalp psoriasis, inverse and erythrodermic psoriasis were seen. True-skin-PAE were all psoriasis-related, interestingly, we found an increased frequency (45%) of pustular variants of psoriasis, much higher than the prevalence of pustular psoriasis in general population and in accordance to previously reported skin-PAE during anti-TNF-a therapies [2] Borderline (non-psoriatic) skin-PAE were mainly neutrophilic dermatoses as Behcet´s disease and Pyoderma Gangrenosum, accounting for 18% of all skin-PAE.

It is worth to notice that the majority of patients (77%) who experienced a skin-PAE during anti IL-17 therapy were previously treated with other biologicals (not naïve to biological therapy), in first-line patients were treated with TNF-a blockers in 79% of cases and in only 17% (4 cases) a previous skin-PAE was recorded (recurrent skin PAE during two different mechanism of action). In 83% of IL-17 related skin-PAE the previous use of a TNF-a blocker did not trigger such reaction, suggesting a different or specific immunological mechanism related to anti-IL-17 Skin-PAE. We have to consider that patients that were switched from TNF-a blockers to anti-IL-17, experienced a lack of efficacy during the former and we would like to underline that the vast majority of skin-PAE appear while the primary disease is under optimal control, advocating a diverse immunological pathway involved. Such findings make us state that skin-PAE usually appears while the putative biological agent demonstrates efficacy in controlling the primary disease. For the cases with recurrent skin-PAEs we hypothesize a genetic predisposition. Considering the high frequency of pustular psoriasis variants between skin-PAE is probable that the immunological mechanism differs from the one in chronic plaque psoriasis. Probably an immunological imbalance cause by the Th17 downregulation contributes to the up-regulation of IL-36 cytokines that have been recognized as essential to pustular psoriasis pathogenesis under a specific genetic background. In contrast to classical pustular psoriasis, paradoxical pustular psoriasis under anti-TNF-a and anti Il-17 therapy, as demonstrated in this systematic review, tend to complete remission after the withdrawal of the offending agent and are not prone to become recurrent as it would be expected, suggesting a transitory immunological imbalance. Exactly as with pustular variants of psoriasis, paradoxical psoriasis seems to be slightly more frequent in females.

The mean time of onset of skin-PAE during anti Il-17 therapy was 18 weeks, it can be considered as delayed making us think that trigger factors might contribute to such a late onset. In the four cases where recurrent skin-PAE were recorded the mean time of onset was 6 weeks, significantly shorter if compared to the rest, suggesting as previously discussed a genetic predisposition/background. Similar time of onset has been reported for paradoxical psoriasis during anti TNF-a therapies where the onset might range from few days to several months [46-48]. 

In two-thirds of cases anti-IL-17 withdrawal was performed, with complete improvement without systemic therapy in 3 cases (10%), with effective switch to anti IL-23 therapies in 34%, switch to anti-TNF-a in 17% and introduction of cyclosporine in 24%. Such data suggests that IL-23 blockers might be a safe and efficacious option for patients affected by skin-PAE. Interestingly the switch to an anti-TNF-a therapy did not trigger another skin-PAE suggesting an alternative mechanism involved in anti-IL-17 and anti-TNF-a induced paradoxical events.

The onset of unexpected and antagonistic reactions associated with these targeted therapies reveals the complexity of the immunogenetic pathways involved in human disease. A paradox provokes fresh thought about a contradictory event.

Conclusion

True-skin-PAE occur not only under anti TNF-a therapy but also during anti Il-17 therapy, the underlaying immunological mechanism is not yet known, but pustular variants of psoriasis seem to be more prevalent than in general population; withdrawal of the anti-IL-17 therapy has been mainly performed and other therapies such as anti-IL-23 biologics seem to control both the underlying disease and the true-skin-PAE. Further studies are needed in order to better understand the immunological mechanism involved and eventually the genetical predisposition to such reactions. 

Conflict of Interest

The authors have no conflict of interest to declare.

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