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Abstract
Antibody-based therapies that inhibit pro-inflammatory cytokine signalling are commonly used in dermatology. Paradoxically, these biological agents may induce or exacerbate paradoxical reactions. Recently, it has been reported that the treatment of eczema with dupilumab can lead to the development of psoriasiform eruptions, which we called psoriasiform paradoxical reactions (P-PRs). Conversely, cases of eczematous paradoxical reactions (E-PRs) have also been described in patients with psoriasis treated with biologics. To summarise the case characteristics and disease features of phenotypic transition between psoriasis and eczematoid dermatitis, and to explore the mechanism or connection related to biological agents or patients' genetic characteristics, a systematic review was conducted for P-PRs in atopic dermatitis and E-PRs in patients with psoriasis treated with corresponding biological agents, respectively. We identified a series of P-PRs in 42 atopic dermatitis cases treated with dupilumab. The time to onset of P-PRs typically ranged from weeks to months, with a mean latency period of 22.65 weeks. Almost all patients presented with new-onset P-PRs. Simultaneously, we reviewed 22 articles reporting 51 patients with psoriasis with biological agent-induced E-PRs, which occurred on average at 24.47 weeks, 72.55% of them induced by IL-17A inhibitors. 48.98% (24/49) of cases reported a positive personal history of atopy, which may suggest an increased risk of biological agent-induced paradoxical eruptions. Overall, the improvement or resolution upon discontinuation of the inciting biologics was relatively common, and further studies are needed to estimate the real prevalence and unveil the pathophysiological mechanisms of these paradoxical events.
Keywords: Biological agents, eczematous paradoxical reactions, phenotypic switch, psoriasiform paradoxical reactions
Introduction 
A wide spectrum of phenotypically overlapping reaction patterns has been described, but the overlapping of psoriasiform and eczematous eruptions is the most commonly reported. Recently, dupilumab use has been associated with numerous cutaneous side effects, including psoriasiform reaction, approximately in 3.03%-3.34% of dupilumab-treated patients suffered from atopic dermatitis in different cohort studies.[1],[2],[3] Several cases of newly developed paradoxical eczematous eruptions or atopic dermatitis-like eruptions have been reported in patients with psoriasis managed with biologics, and these adverse events occur in 1.0–12.1% of patients in clinical and observational studies.[4],[5],[6] Psoriasis and eczema are thought to be diseases caused by an imbalance in the Th1/Th2 immune response with Th1 being more prominent in psoriasis and Th2 predominating in eczema.[1],[7] It has been proposed that Th1 and Th2 pathways are closely related, and blocking the Th2 response by targeting the IL-4/IL-13 signalling pathway could result in a shift towards a Th1/Th17 phenotype, leading to an inflammatory cytokine cascade and vice versa.[1] The pathogenesis of the above paradoxical reactions (PRs) associated with biological use is not clear, and to better understand and explore the mechanism, eczematous paradoxical reactions (E-PRs) and psoriasiform paradoxical reactions (P-PRs) in published literature studies are reviewed and discussed as follows.
Materials and Methods A systematic review was performed to investigate the clinical characteristics of paradoxical eruptions occurring during the treatment of psoriasis and atopic dermatitis with biological agents. A comprehensive update search was carried out in PubMed to cover literature until 1 May 2022. The keywords such as 'psoriasis', 'psoriasiform', 'eczema', 'eczematous', '(atopic) dermatitis', 'adverse reaction', 'paradoxical', 'ixekizumab', 'secukinumab', 'IL-17A', 'adalimumab', 'infliximab', 'etanercept', 'Tumor necrosis factor-α', 'TNF-a', 'guselkumab', 'ustekinumab', 'tildrakizumab', 'IL-12/23', 'IL-23', 'dupilumab' and 'IL-4' were used. Case reports and case series were screened and selected. We ruled out reports in clinical trials, observational studies and meta-analyses, and articles unavailable in English were also excluded. The references of the articles were screened to ensure the completeness of the above literature search. PRISMA flow diagrams are demonstrated in [Figure 1] and [Figure 2].
Figure 1: PRISMA flow diagram summarising article review and selection process for P-PRs in patients with atopic dermatitis receiving dupilumab
Figure 2: PRISMA flow diagram summarising article review and selection process for E-PRs in patients with psoriasis receiving biologics Results Psoriasiform paradoxical reactions (P-PRs)
A total of 26 articles (18 case reports and 8 case series reports), 42 patients met the inclusion criteria, including 41 patients with new-onset P-PRs and one patient with worsening pre-existing psoriasis [Supplementary Table 1]. The mean age of these patients was 42.33 years and ranged from 17 to 92 years. Males accounted for 54.76% (23/42) of all cases. All patients responded well to the treatment of atopic dermatitis with biological agents before the appearance of paradoxical lesions. Only one case had a family history but not a personal history of psoriasis.
Clinical characteristics
These P-PRs were manifested in initially unaffected skin and exhibited a new or different morphology from their original presentation of atopic dermatitis. Extremities were the most susceptible, with an incidence of 69.05%, followed by the trunk (52.38%) and scalp (21.43%). The latency period from dupilumab initiation to psoriasis onset much varied, and the mean time was 22.65 weeks after biological initiations.
Histopathological characteristics
Only 33 of the 42 cases were confirmed by histological evaluation, which mainly showed acanthosis, parakeratosis, minimal spongiosis, a dense superficial dermal perivascular infiltration of lymphocytes and histiocytes with dilated capillary, and these findings were consistent with psoriasiform reactions and were clinically classified as psoriasiform eruptions or psoriasis.
Management
P-PRs led to the suspension of dupilumab in 32.5% (13/40) of patients, and then, alternative topical corticosteroids (38.46%) or systemic therapy (38.46%) were started; 76.92% of patients achieved significant improvement or complete resolution, and 15.38% of patients achieved improvement. Of the remaining 27 patients with a continuation of dupilumab, 12 patients were referred for treatment effects, 41.67% (5/12) of patients achieved complete remission or significant improvement, 33.33% (4/12) of patients achieved remission or improvement, 25% (3/12) of patients were ineffective and received systemic therapy, one patient achieved complete resolution and two patients were unresponsive.
Eczematous paradoxical reactions (E-PRs)
We reviewed E-PRs in 51 cases of patients with psoriasis treated with IL-17A inhibitors, IL-12/23 inhibitors, IL-23 inhibitors or TNF-α inhibitors [Table 1]. Data from studies suggested that E-PRs were more common with IL-17A inhibitors than with any other inhibitors. In this review, we observed that IL-17A inhibitors resulted in 72.55% (37/51) of E-PRs, and secukinumab was the most common culprit (52.94%); ixekizumab accounted for 19.61%, followed by TNF-α (11.76%), IL-12/23 (11.76%) and IL-23 (3.92%) inhibitors [Supplementary Table 2]. The mean age of patients was 52.27 years (ranged 20–89 years), and 62.75% were males. Before the onset of the E-PRs, all patients responded well to biologics. 48.98% (24/49) of cases reported a positive personal history of atopy (atopic dermatitis, allergy, asthma or allergic rhinitis). Of the 14 patients who had serum antibodies and routine blood tests, 78.57% (11/14) and 42.86% (6/14) of patients had high IgE levels and eosinophilia, respectively.
Table 1: Biologics for cases with psoriasis that contain eczematous paradoxical reactions (E-PRs) as a treatment adverse event
Clinical characteristics
Clinical features of these E-PRs were consistent with eczematous eruptions in 28 patients (54.9%) and atopic dermatitis in 22 patients (43.14%), and one patient had dyshidrotic hand dermatitis. The time to onset of E-PRs typically ranged from weeks to months after treatment initiation, whereas it could occur up to 4–5 years later in two cases. Overall, these eruptions occurred on average at 24.47 weeks and mainly affected the extremities (including the flexural areas) and trunk in 84.31% and 56.86% of cases, respectively. Patients were always affected by varying degrees of itching or burning. 62.75% of patients had a sense of itching from the eruptions, and 9.8% of patients felt burning.
Histopathological characteristics
The diagnosis of E-PRs was confirmed by histology in a limited number of cases in our review, and half of the diagnoses were judged by clinical experience. Pathological examination was performed in 26 (50.98%) of 51 patients with E-PRs, histological evaluation in 15 cases was consistent with a clinical diagnosis of eczematous reaction and histopathological manifestations in 11 cases were accorded with atopic dermatitis. 23 cases did not perform the examination, and two cases were unspecified.
Management
E-PRs led to the suspension of biological agents in 68.75% (33/48) of cases for whom this information was available, 33.33% (11/33) of patients chose topical therapy (data on treatment effect were incomplete), and 42.42% (14/33) of patients received systemic therapy, of which 66.67% (4/6) of patients achieved improvement (the effect of treatment for eight individuals was not reported). 15.15% (5/33) of patients switched biologics, and 80% (4/5) of patients had their rash disappear. In the remaining 15 cases with a continuation of biologics, E-PRs were treated with topical or oral corticosteroids that were mostly sufficient for the remission of E-PRs.
Discussion Both psoriasis and atopic dermatitis are chronic T-cell-mediated inflammatory diseases with reverse effects in shared pathways influencing epidermal differentiation and immune response.[8] Psoriasis is characterized by a typical overproduction of IL17A/F and IL23. While in atopic dermatitis or eczema, Th2 polarization is more prominent, characterized by overproduction of IL-4 and IL-13.
It is now considered that psoriasiform eruption is one of the most frequently observed PRs associated with dupilumab[9] and has appeared in approximately 3.03%-3.34% of patients with atopic dermatitis.[1],[2],[3] Inversely, with the increased use of biological therapies for psoriasis, several cases of new-onset E-PRs have been reported, including atopic dermatitis, eczema or eczema-like dermatitis, with the prevalence ranging from 1.0% to 12.1% in different biological clinical trials and observational studies.[4],[5],[6]
We reviewed P-PRs occurring in atopic dermatitis patients with the therapy of dupilumab and E-PRs occurring in patients with psoriasis treated with adalimumab, infliximab, ixekizumab, secukinumab, ustekinumab, guselkumab or tildrakizumab. Potential immunological mechanisms and management of PRs were also considered. Factors common to some reported cases included a prior history of atopy or psoriasis, eosinophilia and raised serum IgE. Among the above factors, we found that a personal history of atopy may help in predicting patients who may experience E-PRs. E-PRs of 48.98% (24/49) of cases occurred in patients with a personal history of atopy (dermatitis, allergies or asthma). Although the data were limited, it appeared that patients with psoriasis with at least one pre-existing Th2-mediated disease might be more prone to developing eczema during targeted biological therapy, as reported in the previous studies.[10],[11] E-PRs typically occurred from weeks to months after treatment initiation, but they could occur up to 4–5 years later, and the average latent period was 24.47 weeks. Sachiko reported a case of paradoxical lichenified eczema occurring after 210 weeks of ustekinumab treatment.[12] E-PRs mainly affected the extremities (84.31%, including the flexural areas) and trunk (56.86%). IgE is a common mediator of allergic diseases, and high serum IgE level is the result of exaggerated Th2 cell response.[13] However, it was shown that IL-17A could promote B-cell activity and function and increase IgE production,[14] and raised IgE has been reported in 46% of patients with psoriasis.[15],[16],[17] We found that 78.57% of psoriasis patients with E-PR had elevated IgE, much higher than that of previously reportedwhether IgE can be served as a clue to predict E-PRs remained to be discussed. In addition, P-PRs appeared in the skin of various locations, mostly in previous atopic dermatitis-unaffected sites, although there had an aggravation of pre-existing psoriasis lesions after dupilumab initiation in one case. Regardless of the severity and duration of atopic dermatitis, dupilumab-induced P-PRs mainly tended to develop within 1 year upon treatment, with a mean time of 22.65 weeks. Brumfiel systematically reviewed 43 atopic dermatitis patients after dupilumab treatment and reported that the mean incubation period from dupilumab initiation to P-PRs onset was 3.7 months.[18]
The pathogenesis of PRs associated with biological use is not clear, and there are various views on the possible mechanism. As most well described in a few studies, the abnormal immune polarisation of T-cell subsets leads to the conversion of the immunophenotype. It was hypothesised that the Th1 and Th2 pathways were closely related in that blocking the Th2 response by targeting the IL-4/IL-13 signalling pathway could result in a shift towards a Th1/Th17 immune response and vice versa, while a study proposed that environmental antigens maybe the shared risk factors of both Th1-mediated autoimmune disease and Th2-mediated atopic disease in the same individual.[19] Genome-wide association studies have found that psoriasis and atopic dermatitis may have some overlapping risk alleles that regulate the proliferation and differentiation of epidermal cells and modulate general cutaneous inflammatory immunity.[20],[21],[22] In a few molecular studies of PRs, it was interesting to note that IL-17A had been found to be higher in the skin of patients with atopic dermatitis compared with normal controls,[23],[24] and also, as the case of allergic contact dermatitis,[25],[26] it may induce immune dysregulation by amplifying the inflammatory response and promote the occurrence of E-PRs.[23] Furthermore, some scholars found that IL-17C could trigger an autocrine loop of stimulation on keratinocytes,[27] which may be responsible for Th2- and Th17-driven skin inflammation.[28] There has been propaedeutic evidence that IL-17C antibodies could be effective in the treatment of atopic dermatitis.[29] Interestingly, IL-17 inhibitor drugs can increase the infection of Staphylococcus aureus on the skin surface because they inhibit the expression of antimicrobial peptides in keratinocytes, Munera-Campos et al. speculated that it might play a role in paradoxical atopic dermatitis.[30] Naoko also demonstrated that the percentage of Staphylococci, Streptococci and Corynebacterium increased in AD skin lesions of psoriasis patients after IL-17i treatment.[31] Recently, Napolitano et al. argued that IL-22 may be a key mediator in the pathogenesis of E-PRs induced by anti-IL-17 agents.[32]
On the other side, dupilumab may contribute to immune response shifts; it might motivate the IL-12- and IL-23-secreting dermal dendritic cells, and these signalling events can promote the differentiation of naive CD4+ T cells towards Th1 and Th17 cells, causing the secretion of TNF-α and IL-17A, thereby driving the occurrence and development of P-PRs.[33],[34] Cytokine RNA in situ hybridisation was conducted to demonstrate an association between dupilumab therapy and newly developed P-PRs by some researchers, showing de novo IL-17A, reduced IL-13 and IL-4 and increased IL-23A expression in the biopsy of psoriasiform eruptions induced by dupilumab.[35],[36],[37] Researchers quantified the expression of various cytokines on biopsy specimens, which would be a promising method for the diagnosis of dupilumab-induced psoriasis.
To our knowledge, this is the largest review of PRs (P-PRs or E-PRs) occurring in psoriasis or atopic dermatitis patients with the treatment of biological agents, and we summarised relatively consistent features of a phenotype switch from atopic eczema to psoriasis and from psoriasis to atopic dermatitis. Our review suggested that E-PRs were more commonly induced by IL-17A inhibition than any other inhibitors, especially secukinumab, and we guessed that it may be related to the widespread use of secukinumab and ixekizumab in patients with psoriasis. The majority of cases with E-PRs discontinued the implicated biologics owning to severe itching symptoms, and they mostly achieved a successful improvement. Those with an atopic predisposition would be more at risk of developing PRs. Elucidation of mechanisms and risk factors would contribute to optimal therapy selection for individual patients.
Limitations of this review, common to most systematic reviews of the literature, are retrospective analysis and lacking control groups. Therefore, further studies are needed to estimate the real prevalence and unveil the pathophysiological mechanisms of these paradoxical events.
Acknowledgement
LYY was responsible for the literature search, data analysis and manuscript preparation. We thanked Prof. LH for providing the ideas, designing and revising this manuscript and Prof. ZFR for supporting and approving this manuscript.
Abbreviations
PRs = paradoxical reactions; P-PRs = psoriasiform paradoxical reactions; E-PRs = eczematous paradoxical reactions
Financial support and sponsorship
This study was supported by the Academic Promotion Programme of Shandong First Medical University (2019LJ002), the Key Research and Development Programme of Shandong Province (2021LCZX07) and the Shandong Provincial Clinical Research Center for Dermatovenereology.
Conflicts of interest
There are no conflicts of interest.
References 
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