Paradoxical reactions to biologicals for psoriasis

KEYWORDS:

• Paradoxical reactions
• biologicals
• psoriasis
• psoriasiform eruption
• eczematous eruption
• alopecia
• psoriatic arthritis
• hidradenitis suppurativa
• treatment

1. Introduction

The growing availability of target therapies for psoriasis (biologicals) has dramatically changed the prognosis of the disease. Currently, the therapeutic goal is represented by a complete or almost complete skin clearance, given biologicals’ selective mechanism of action toward specific key cytokines. Anyway, the widespread use of biologicals has led to the increasing report of the so-called paradoxical reactions (PRs), defined as the de novo occurrence or worsening of an immune-mediated inflammatory disease during treatment with a targeted biologic agent that is commonly employed to treat the idiopathic counterpart of the drug-induced reaction [1]. They mainly include paradoxical psoriasis and psoriatic arthritis, inflammatory bowel disease (IBD), and eczematous eruption but also lupus-like reactions, alopecia areata (AA), lichen planus (LP), hidradenitis suppurativa (HS), pyoderma gangrenosum, sarcoidosis-like reactions, vitiligo, and bullous pemphigoid (BP) [1]. PRs’ onset time is usually estimated to be between weeks or months from the inciting biological agent start, usually subsiding upon its discontinuation [2]. It is supposed that biologicals may imbalance cytokine pattern, toward another immune response [1]. The most involved biologicals are anti-tumor necrosis factor (TNF), but evidence has been increasing toward anti-interleukin (IL)12/23, IL17, and IL23 [3]. Herein we briefly present and discuss the described paradoxical reactions to biologicals for psoriasis, focusing on less investigated ones.

2. Skin reactions

2.1. Psoriasiform reactions

Psoriasiform PRs (P-PRs) are among the most described paradoxical reactions during biologicals. Overall, anti-TNF agents represent the major culprit, with an incidence varying from 3.8% to 10.7% [2–4]. Of the class, the most inciting agent is represented by infliximab (>50% of cases), followed by adalimumab (30%) and etanercept (11%) with few cases associated with certolizumab and golimumab (<2.5%) [2]. Onset time was reported to vary between 1 month and 10 years from anti-TNF start with both the occurrence of de novo psoriasis or flares, histologically showing atypical psoriasis features such as spongiosis and eosinophils [2]. Morphologically, P-PRs usually resemble plaque type or pustular psoriasis, but other subtypes may occur (mean time: 16.4 months) [2]. As regards anti-IL12/23, P-PRs are an exceptional finding during ustekinumab since only 9 cases have been reported after approximately 3.1 months from treatment start [2]. Similarly, a few more cases have been described with anti-IL17 (mainly secukinumab 6/10, less likely with brodalumab 2/10 and ixekizumab 2/10), occurring with an average onset time of 4.9 months (range 1–16) [2]. To date, no P-PRs have been described under anti-IL-23 agents.

2.1.1. Psoriasiform alopecia

Psoriasiform alopecia (PA)-PR is mostly reported in association with anti-TNF, usually requiring treatment discontinuation due to the risk of evolution in scarring alopecia [5]. Moreover, PA was exceptionally reported under ustekinumab (n = 1, onset time: 18 months) and ixekizumab (n = 1, onset time: 6 months). In both cases, biologic was discontinued [6,7]. Currently, no cases of PA-PR under brodalumab, secukinumab, or anti-IL23 have been described. Clinically and histologically, PA-PR may present with overlapping features of primary psoriatic alopecia and alopecia areata; hence, a thorough history is mandatory to classify this condition [5].

2.2. Eczematous reactions

Eczematous PRs (E-PRs) are the second most common paradoxical reactions occurring during biologicals for psoriasis. Of the anti-TNF, infliximab was responsible for ~70% of cases, while 24.5% occurred during adalimumab, with rare reports with other drugs of the same class [2]. Mean onset time was 22.7 months (range 1–54) [2]. Contrarily, cases under anti-IL17 are increasing with a shorter onset time (mean: 3.8–13.5 months) and higher severity, usually imposing treatment discontinuation [8]. Interestingly, among anti-IL17, ixekizumab was the major culprit, over secukinumab, and lastly brodalumab. The low incidence-rate of E-PRs with brodalumab may be justified by the IL17RA binding and inhibition of multiple cytokines, including the isoform-c that appears involved in the psoriasis pathogenesis, as compared to the other class members [2]. Of note, no cases of E-PRs were reported for tildrakizumab, while few were described for ustekinumab, risankizumab, and guselkumab [2,9].

2.3. Sarcoid-like reactions and granulomatous reactions

Granulomatous reactions include sarcoid-like (S-PRs), granuloma annulare (GA), and interstitial granulomatous drug-reactions [2]. Although rarely, they have been associated with anti-TNFs (S-PRs mainly etanercept, GA mainly adalimumab), ustekinumab, and anti-IL17 [ixekizumab (S-PRs), and secukinumab (S-PRs and GA)] [2]. The onset time is long, approximately 2 years on average, and the manifestations tend to persist, notwithstanding treatment withdrawal [2].

2.4. Hidradenitis suppurativa

HS-PR is a rare entity described under anti-TNF, especially adalimumab [3]. Cases with ustekinumab and secukinumab have been recently described [10]. The mean onset time is 12 months (range 1–120), and the severity is mild since the most affected patients were in Hurley stage I and II [11,12]. Also, in association with HS, patients usually develop other inflammatory diseases [11].

2.5. Others (alopecia areata, vitiligo, lichen planus, lupus-like reaction, and bullous pemphigoid)

AA-PR may occur with anti-TNF, particularly adalimumab, after a mean of 16.7 months of treatment (range 0.04–89) [2]. It usually occurs together with other PRs, and the most common form is patchy AA [12]. Five and four cases of AA-PR have been reported following treatment with ustekinumab or anti-IL23 and anti-IL17, respectively, with a mean onset time of 6.2 months (range 3–10) and 6.8 months (range 2–13) [2]. Lupus-like reactions (L-PRs) are uncommon findings (<0.18%) during treatment with anti-TNF, ustekinumab, and secukinumab [2]. They may manifest as systemic lupus erythematosus or isolated cutaneous lupus. Concerning vitiligo, the association with biologicals is controversial, although reported under anti-TNF, ustekinumab, and secukinumab [3,13]. As for lichenoid reactions, in the form of LP, oral LP, or lichen planopilaris, TNF-inhibitors and secukinumab have been depicted as inciting drugs [3]. BP-PR is a very rare manifestation. Globally, 13 cases have been reported during treatment with TNF inhibitors [mean time to onset 9.3 months (range 0.1–36)], whereas 4 and one case were described during treatment with ustekinumab [mean time to onset 7.8 months (range 1–18)] and anti-IL17 (mean time to onset: 0.25 months) respectively [2].

3. Systemic reactions

3.1. Paradoxical psoriatic arthritis (PsA)

Paradoxical PsA is a growing recognized entity that may occur under all biologicals currently available for psoriasis, with an incidence between 8.1% and 9.4%, according to the studies [3,14]. This suggests that the underlying pathogenetic mechanism does not rely on a specific cytokine blockade and is yet to be clarified [14]. It usually involves peripheral articulations (hands and feet), less likely is the spondyloarthropathy or the combination of both [3,14]. Severity is usually mild to moderate [14]. However, given the great variability in methodology of existing studies, it is difficult to differentiate between paradoxical-PsA and new-onset PsA under biologicals, so further investigation is needed.

3.2. Inflammatory bowel disease

IBD is considered a paradoxical manifestation under anti-TNF, occurring prominently with etanercept (80% of cases) [3]. IBD manifesting under anti-IL17 is not considered paradoxical, but rather an adverse event [3].

3.3. Drug-induced uveitis

Uveitis has been reported under all TNF-inhibitors, especially with etanercept, and is often in association with spondylarthritis [15]. The intra-class biological switch seems not associated with uveitis recurrence [15].

4. Expert opinion

PRs represent an increasing challenge for dermatologists as they may threaten the ongoing biological treatment, notwithstanding its efficacy on the psoriatic disease. Indeed, they can complicate the clinical pictures, interrupting the therapeutical strategy and often requiring additional and specific medications. To date, several studies have pointed out the potential mechanisms of action underlying PRs: indeed, they can be the results of either a cytokine imbalance, an immune response pattern shift (Th1> Th2 and vice versa), a collection of activated innate and adaptive immune cells in the skin or a dysfunction of regulatory T-cells. Given the growing introduction and employment of biologicals, these reactions are expected to increase, and physicians should be aware of them to undertake the best treatment strategy that, on the one hand, safeguards psoriasis status and, on the other hand, tackles the new manifestation. Indeed, the management should be chosen balancing the severity of psoriasis and PR: in case of mild-to-moderate skin-PRs, the inciting agent can be maintained, and topicals, phototherapy, or systemic treatments (e.g. methotrexate and acitretin) added; for moderate-to-severe skin PRs or those with systemic involvement, the replacement of inciting biological with one from a different class is preferred with/without an additional therapy. Of note, the development of PRs during treatment with biologics may only be due to coincidence in some cases, probably related to psoriasis and its clinical implications with respect to the drug itself. Anyway, the occurrence of PRs has a positive effect: they let shed a light on the complex interaction between the host genetic predisposition, the pathogenesis of immune-mediated diseases, and the spectrum of action of target therapies. Also, given the current unpredictability and variety of PRs, rigorous research is warranted in detailing their pathogenesis so as to identify predisposing factors on which stratifying patients at risk, meeting the goals of personalized medicine. The future objective should be the identification of biomarkers that could predict PRs development, limiting their impact.

5. Conclusion

PRs are unexpected and unpredictable events that may occur anytime during treatment with biologicals. Understanding their pathogenetic mechanism will deepen the knowledge on the diseases themselves and help identify biomarkers predictive of PRs to stratify patients in the therapeutic decision process.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by E Camela, L Potestio and M Megna. The first draft of the manuscript was written by E Camela, L Potestio and M Megna, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. All authors contributed equally to the manuscript and read and approved the final version of the manuscript.

Additional information

Funding

This paper was not funded.