https://orcid.org/0000-0003-0452-8710
Dear Editor,
The treatment with tumor necrosis factor-alpha (TNF-alfa) inhibitors has drastically changed the prognosis of many dermatological conditions, including psoriasis and hidradenitis suppurativa (HS). Nevertheless, biological therapies have not been free of adverse events, such as paradoxical reactions (PR) (Citation1). PRs are defined as the onset or exacerbation of a pathological condition during biological therapy that is used to treat that disease. The most common cutaneous paradoxical events include psoriasiform manifestations, eczematous eruptions, and pustular reactions. It is presumed that in some cases biological drugs may lead to a shift in the immune response cytokine pattern. In particular, the blockage of the TNF-alfa pathway may result in increased activation of the Th17 pathway (Citation2). Paradoxical reactions usually develop in weeks or months after the start of the biological treatment and do not spontaneously recede after discontinuation, requiring a specific treatment (Citation3).
We report the case of a 46-year-old female patient affected by HS with lesions localized in the inguinal region, intergluteal cleft, and left axilla. She was previously treated with corticosteroid infiltrations and topical and systemic antibiotic therapies with poor disease activity control. Because of the clinical severity (Hurley Stage III) and the significant impairment of her quality of life, we decided to prescribe adalimumab biosimilar 40 mg, administered according to the summary of product characteristics as screening blood exams were all within normal ranges.
After 8 weeks of treatment with adalimumab, we observed an initial improvement in skin lesions, with the persistence of a singular active nodule at the left axilla and scarring in the intergluteal cleft. After 22 weeks of therapy with adalimumab, the patient started to develop a paradoxical adverse reaction. We observed an exudating patch of alopecia with peripheral scaling on the vertex and desquamation of the palms and soles. Considering the development of these manifestations, in agreement with the patient, we decided to stop therapy with adalimumab. Besides, we prescribed topical therapy with daily applications of clobetasol propionate 500 mcg/ml as an ointment for the palms and soles and as a solution for the scalp.
After two weeks the patient came back to our Department showing extensive alopecic patches covering most of her scalp. The exposed skin appeared intensely erythematous and scaly. Moreover, on the palms and soles, we observed several pustules on erythematous and scaly skin.
We diagnosed a psoriasiform paradoxical reaction (P-PR) and psoriasiform alopecia (PA). Given the poor response to topical steroids, we decided to complement the topical treatment with ixekizumab 80 mg, a high-affinity monoclonal antibody that targets interleukin-17A, whose efficacy in pustular psoriatic conditions, rapidity of action, and excellent safety profile had been widely described in the literature (Citation4). Moreover, monoclonal antibodies against the IL-17 pathway have shown promising responses in HS trials.
After 4 weeks of treatment with ixekizumab, we observed a dramatic reduction of inflammation of the scalp. The palms and soles showed mild desquamation and rare pustules. An initial diffuse regrowth of the hair, without frank alopecic patches, was observed after 8 weeks from the first dose of ixekizumab. The patient had still a mild desquamation on the palms and hyperkeratotic patches on the soles without any pustular lesion. At week 16, we observed a complete resolution of the alopecia, while only faint erythema persisted on the soles. We decided to interrupt the treatment with topical clobetasol. To date, the patient has completed one year of treatment with ixekizumab without any relapse of both psoriasis and HS ( and ).
Figure 1. a) Erythema, scaling and alopecia on the scalp of a 46-year-old woman after 22 weeks of treatment with adalimumab; b) complete remission of the alopecia after 16 weeks of treatment with ixekizumab.
Figure 2. a-b) Paradoxical pustular psoriasis of the soles, emerging after 22 weeks of treatment with adalimumab; c) complete skin clearance after 16 weeks of treatment with ixekizumab.
The increased use of biological drugs has led to a higher incidence of PR, representing a challenge in clinical practice. The pathogenesis of these reactions is still unclear, but many hypotheses have been raised: they may be caused by a cytokine imbalance, a shift in immune response patterns, and an impairment in regulatory T-cells function. As described in the literature, Anti-TNF alpha agents are the most involved in paradoxical reactions (Citation5). This can be explained by the role in cross-regulation of TNF- alfa and Interferon-alfa (IFN-alfa); TNF-alfa regulates IFN-alfa production, the blockage of TNF-alfa sustains plasmacytoid dendritic cells (pDCs) production of IFN-alfa, resulting in the onset of psoriasis (Citation6).
The management of PRs should be proportional to the severity of the event, in mild reactions it is not required to interrupt the inciting drug, and topical or systemic therapies can be added. However, in the event of moderate-to-severe reactions as in our case, it is recommended to replace the therapy.
The blockage of TNF alpha leads to increased activity of IFN alpha and therefore of pDCs, therefore, the principal strategy in counteracting anti-TNF alpha-induced PRs may be blocking the Th-17 pathway. In our case, we opted for an anti-IL17 agent to achieve a rapid resolution of the lesions.
Paradoxical reactions are unanticipated events that can happen at any time during treatment with biological drugs. Gaining insight into the underlying mechanisms of these reactions can enhance our understanding of the diseases and can help to stratify patients in the therapeutic decision-making process. Anti-IL-17 drugs could represent a valuable treatment option in these cases, due to their activity on different immune-mediated skin conditions.
Disclosure statement
L. Gargiulo has received research grants from Almirall. A. Costanzo has served as an advisory board member, consultant and has received fees and speaker’s honoraria or has participated in clinical trials for Abbvie, Almirall, Biogen, LEO Pharma, Lilly, Janssen, Novartis, Pfizer, Sanofi Genzyme, and UCB-Pharma. A. Narcisi has served on advisory boards, received honoraria for lectures and research grants from Almirall, Abbvie, Leo Pharma, Celgene, Eli Lilly, Janssen, Novartis, Sanofi‐Genzyme, Amgen and Boehringer Ingelheim. The other authors have nothing to disclose.
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References
- Camela E, Potestio L, Fabbrocini G, et al. Paradoxical reactions to biologicals for psoriasis. Expert Opin Biol Ther. 2022;22(12):1–3. doi:10.1080/14712598.2022.2153593.
- Miyagawa F. Pathogenesis of paradoxical reactions associated with targeted biologic agents for inflammatory skin diseases. Biomedicines. 2022;10(7):1485. doi:10.3390/biomedicines10071485.
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- Puig L, Gulliver W. Adverse reactions to biologics. In: Puig L, Gulliver W, editors. Adverse reactions to biologics. Current problems in dermatology. Vol. 53. Basel: Karger; 2018. p. 49–63.
- Palucka AK, Blanck J-P, Bennett L, et al. Cross-regulation of TNF and IFN-α in autoimmune diseases. Proc Natl Acad Sci USA. 2005;102(9):3372–3377. doi:10.1073/pnas.0408506102.