Journal of Clinical & Experimental Dermatology Research
Open Access

Paradoxical Responses in Biologic Therapy for Psoriasis: Unraveling Mechanisms and Optimizing Treatment Strategies

Jingyan Kong¹, Minghui Zhao², Xiaoyu Ma^2*, Fan Yang^1* and Hongxiao Gao^{2 *}Correspondence: Xiaoyu Ma, Department of Basic Teaching and Research in Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China, Email: Fan Yang, Department of Chinese Medicine and Cosmetology, Tianjin University of Traditional Chinese Medicine, Tianjin, China, Email:

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Introduction

Psoriasis is a common chronic skin disease, primarily characterized by local skin redness, scales, and itching [1]. The prevalence of psoriasis varies among different regions and populations, but it maintains a certain level of prevalence worldwide [2]. The etiology of psoriasis is not entirely understood, but research indicates that it’s associated with aberrant activation of the immune system, genetic factors, and environmental influences [3]. Moreover, the incidence of psoriasis can increase with age, and there are gender differences, with varying rates between men and women [4].

Biologics refer to drugs with specific biological activities produced through genetic engineering. They can interfere with specific cytokines and signaling pathways in the immune system, thereby achieving therapeutic effects in psoriasis [5]. Currently, biologics have become an important treatment choice, especially for patients who are resistant or intolerant to traditional therapies. The use of biologics can significantly improve patients’ symptoms and quality of life, reduce the area and severity of skin lesions, and maintain long-term efficacy [6-8]. Despite the notable efficacy of biologics in the treatment of psoriasis, paradoxical reactions occur. For instance, the long-term use of biologics may lead to the suppression of immune function, increasing the risk of opportunistic infections [9,10]. Therefore, understanding the mechanisms of paradoxical reactions in biologic treatment is important for optimizing treatment plans and reducing treatment risks. Current studies have found that altering the dosage and administration of biologics, and the combined use of other drugs may help reduce the occurrence of paradoxical reactions [7,11].

The aim of this review is to provide a comprehensive analysis and summary of the importance and current status of biologic treatment for psoriasis, as well as the mechanisms of paradoxical reactions. Through this comprehensive analysis, we hope to provide a reference for optimizing the biologic treatment of psoriasis.

Literature Review

Common types of biologic agents used for treating psoriasis

Biologics, innovative medications with broad applications in various diseases, have proven significantly effective in the field of dermatology, especially in treating psoriasis. Currently, the biologics commonly used in dermatology for psoriasis treatment internationally include:

Tumor Necrosis Factor (TNF: Inhibitors are a class of drugs that counteract the activity of TNF. This class of biologics includes Etanercept, Infliximab, Adalimumab, golimumab, and certolizumab, among others. They inhibit TNF activity, reducing inflammation and thus alleviating the symptoms of psoriasis [12-18].

Cell inhibitors: Common drugs include Rituximab and Omalizumab. These medications inhibit the activity of B cells, reducing the production of inflammatory factors and autoantigens, thus modulating the function of the immune system and relieving the inflammatory response in psoriasis [19-21].

IL-12/23 inhibitors: Such as Ustekinumab and Briakinumab, primarily inhibit IL-12 and IL-23 to suppress the activation of Th1 and Th17 cells, thus alleviating inflammation [22,23].

Interleukin-17A (IL-17A: Inhibitors mainly include secukinumab, ixekizumab, and brodalumab. These drugs moderate the immune system by inhibiting the function of IL-17A, thereby reducing psoriasis symptoms and the inflammatory response [24,25].

IL-1 antagonists: Include, but are not limited to, Anakinra, Canakinumab, and Gevokizumab. These medications modulate the function of the immune system, alleviating inflammation and thus improving symptoms in psoriasis patients. Anakinra, a human recombinant IL-1Ra antagonist, can inhibit IL-1α and IL- β and has shown results in the treatment of Generalized Pustular Psoriasis (GPP) and patients with IL-1 receptor antagonist deficiency [26,27]. Canakinumab, an anti-IL-1β antibody, has shown benefits in the treatment of GPP [28,30]. As a novel anti- IL-1β antibody, Gevokizumab can also be used in the treatment of GPP patients [31,32].

IL-23 inhibitors: These are drugs that inhibit the cytokine IL-23, an important immune-mediated factor closely associated with the pathogenesis of psoriasis. Several specific drugs have been developed, including ustekinumab, guselkumab, tildrakizumab, and risankizumb. By interfering with the signaling pathway of IL-23 and inhibiting its activation effect on the immune system, these drugs achieve their therapeutic effect in psoriasis [22,33-38] (Figure 1).

Figure 1: Types and mechanisms of biologics in the treatment of psoriasis.

Mechanism of action and efficacy evaluation of biologics

The mechanism of action of biologics in psoriasis treatment primarily involves suppressing the inflammatory response, blocking T-cell activation, and inhibiting B-cell function [13]. Regarding efficacy evaluation, the Psoriasis Area and Severity Index (PASI) scoring is commonly employed to assess treatment outcomes [39,40]. Research indicates that, in the treatment of psoriasis, optimal results from biologics are generally achieved after 4-6 weeks of continuous therapy [41,42]. Despite the significant efficacy of biologics in psoriasis treatment, certain adverse reactions are associated with their use. Common side effects include infections [43], headaches [44], gastrointestinal discomfort, and allergic reactions [45-47]. Moreover, some biologics, such as Infliximab and Adalimumab, may pose a risk of malignant tumors during use [48-51]. Therefore, regular checks for complete blood count and liver and kidney function assessments are necessary during the course of psoriasis treatment with biologics to monitor potential adverse reactions.

The manifestation of paradoxical reactions in psoriasis treatment with biologics

A paradoxical reaction refers to an unexpected response that contradicts the theoretical mechanism of a drug during treatment [52]. They can be categorized into mild, moderate, and severe, based on their nature and intensity. Mild reactions may only present as transient discomfort, moderate reactions may lead to decreased treatment efficacy, and severe reactions may threaten the patient’s life [53,54]. Biologics primarily work by blocking the biological activity of inflammatory factors, thereby suppressing inflammatory responses and alleviating psoriatic lesions. However, paradoxical reactions can occur during this treatment process, such as a worsening of psoriasis or the emergence of new skin lesions, particularly common when using anti-TNF drugs [55-57]. Here is a detailed overview of various commonly used biologics:

Tumor Necrosis Factor (TNF) inhibitors: Infliximab, Etanercept, and Adalimumab have been proven effective in treating diseases such as psoriasis and psoriatic arthritis. However, some studies have pointed out potential paradoxical reactions associated with the use of TNF inhibitors, including the emergence of new or worsening psoriatic rash; gastrointestinal discomfort; increased risk of infections such as tuberculosis, fungal infections, and bacterial infections; and potential disease rebound after discontinuation of TNF inhibitors [46,58-62].

B cell inhibitors: Like Rituximab, primarily used to treat autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, it achieves disease control by selectively eliminating CD20 positive B cells. However, some studies have found that new or worsening psoriasis may occur during treatment with B cell inhibitors, posing an increased risk of certain infections such as fungal and bacterial infections, and potential disease rebound after discontinuation [63-67].

IL-12/23 inhibitors: Like Ustekinumab, a biologic used to treat moderate to severe psoriasis, it works by inhibiting the activation and proliferation of Th1 and Th17 cells. However, some studies have found paradoxical reactions may occur during treatment with IL-12/23 inhibitors, such as atypical psoriasis responses like collagenosis or psoriatic arthritis, increased risk of bacterial and viral infections, and potential triggering or worsening of some immune-mediated diseases like Crohn’s disease and ulcerative colitis, as well as headaches, upper respiratory infections, and skin irritation. [68-73].

IL-1 antagonists: Like Anakinra, used to treat some inflammatory diseases, including psoriasis. However, some studies have shown that paradoxical reactions may occur during treatment with IL-1 antagonists, manifesting as rashes, including psoriatic-like rash, reversible after discontinuation of the drug, increased risk of bacterial and viral infections, and potential triggering or worsening of some immune-mediated diseases like Cohn’s disease and ulcerative colitis [74-78].

IL-23 inhibitors: IL-23 inhibitors achieve therapeutic effects by suppressing immune responses, which could potentially suppress the patient’s immune system, thereby increasing the risk of infectious diseases [79]. Some studies have indicated that the treatment of psoriasis with IL-23 inhibitors could lead to a rebound of rash [80]. IL-23 inhibitors may also affect the efficacy of vaccines [81-84].

IL-17A inhibitors: Some studies have found that IL-17A inhibitors may lead to the occurrence of novel diseases during the treatment of psoriasis, and the use of IL-17A inhibitors may increase the risk of inflammatory bowel diseases (such as Cohn’s disease and ulcerative colitis) [85]. Some research also indicates that some patients may experience disease rebound, worsening condition after discontinuation of IL-17A inhibitors [86]. Additionally, some patients may develop resistance to these drugs, leading to a gradual decline in treatment efficacy (Figure 2).

Figure 2: Paradoxical responses in psoriasis biologic therapy.

Impact of paradoxical reactions on treatment efficacy and quality of life

Paradoxical reactions can potentially affect the treatment outcome, prolonging or exacerbating the course of psoriasis, thereby impacting patients’ quality of life. These reactions may also instill fear and resistance towards the medication in patients, lowering their adherence to the treatment, and thus influencing the overall treatment efficacy. During the administration of biologics, it is important to regularly conduct safety assessments, closely monitor the emergence of paradoxical reactions, and if severe reactions occur, the use of the drug should be immediately discontinued and alternative treatment options should be sought.

The treatment efficacy of biologics can be assessed through a variety of indices, including the Psoriasis Area and Severity Index (PASI), Patient Global Assessment (PGA) [87] and the Health-Related Quality of Life (HRQoL) [88]. The degree of improvement in these indices post-biologic treatment can reflect the efficacy of the medication. Furthermore, long-term follow-up of patients is necessary to monitor the durability of treatment effects and the occurrence of paradoxical reactions. Hence, paradoxical reactions in the treatment of psoriasis with biologics not only concern the selection and usage of drugs but also involve a comprehensive evaluation of treatment efficacy and safety, requiring the joint attention and handling of both physicians and patients.

Mechanisms underlying paradoxical reactions

The role and regulatory mechanisms of the immune system in the treatment of psoriasis with biologics: The development and progression of psoriasis are associated with immune system abnormalities [89]. Biologics treat psoriasis by modulating the immune system to suppress inflammatory responses. Studies have shown that biologics can effectively control the development of psoriasis by regulating the balance of cytokines such as Th1, Th2, and Th17 [90,91], as well as by modulating the functions of antigen presentation, phagocytosis, and natural killer cells [92,93]. Additionally, biologics can activate anti-inflammatory signaling pathways, such as NF-kB inhibitors and STAT3 inhibitors, to alleviate skin inflammation [94-97] (Figure 3).

Figure 3: Biomarkers and signaling pathways associated with paradoxical responses to biological agents.

Biomarkers and signaling pathways associated with paradoxical reactions to biologics

Paradoxical reactions, characterized by a worsening or relapse of symptoms after the use of biologics, is a common phenomenon in the treatment of psoriasis [7,98,99]. The mechanisms underlying these reactions are not fully understood but may be related to the immunoregulatory effects of biologics, individual differences, and environmental factors [100,101]. Certain biomarkers and signaling pathways, such as cytokines, chemokines, inflammatory mediators, and oxidative stress responses, may play key roles in paradoxical reactions. Monitoring these biomarkers and signaling pathway alterations can help in early identification and prevention of paradoxical reactions [100,102-104]. Psoriasis is a complex inflammatory disease whose pathophysiology involves numerous signaling pathways and cell types, including T cells, keratinocytes, dendritic cells, and myriad cytokines like Tumor Necrosis Factor (TNF) and Interleukins (ILs) [105-108]. Biologics target these signaling pathways and cytokines to treat psoriasis, but sometimes they may trigger paradoxical reactions.

Cytokines: Cytokines like TNF-α and the IL-23/IL-17 axis play an important roles in psoriasis. Biologics such as TNF-α inhibitors and IL-17 inhibitors can effectively alleviate symptoms. However, some patients may experience worsening of their condition after using these agents, possibly due to the activation of other inflammatory pathways or compensatory increase in cytokines [75,109-111].

Chemokines: Chemokines such as CXCL8 and CCL20 can guide inflammatory cells to the skin, exacerbating inflammation. Biologics can mitigate symptoms by inhibiting these chemokines, but in some cases, they may induce the expression of other chemokines, exacerbating the condition [112-116].

Inflammatory mediators: Inflammatory mediators, including various prostaglandins and leukotrienes, play a key role in inflammatory responses. Biologics can alleviate symptoms by inhibiting these mediators, but in some instances, they may trigger the production of other inflammatory mediators, worsening the condition [117-122].

Oxidative stress responses: Oxidative stress responses can trigger inflammatory reactions and exacerbate skin lesions. Biologics can improve the condition by inhibiting oxidative stress responses, but in certain cases, they may disrupt the intracellular antioxidant mechanisms, worsening the condition [123-126].

Genetic and environmental factors in paradoxical reactions

Genetic and environmental factors play critical roles not only in the pathogenesis of psoriasis but also in the occurrence of paradoxical reactions. Studies have shown the presence of polymorphisms in multiple genes in patients with psoriasis, which may be related to the sensitivity of psoriasis to biologics [127]. Polymorphism in the HLA-Cw6 gene has been found to be associated with the reactivity of psoriasis to TNF-α inhibitors [128]. Another study found that polymorphisms in IL23R and IL12B genes might influence the sensitivity of psoriasis patients to IL-23 inhibitors [129]. Environmental factors such as infections, lifestyle, and psychological stress could also affect the occurrence of paradoxical reactions [130-132]. Smoking and alcohol consumption could potentially impact the efficacy and safety of biologics [133]. Furthermore, infections may lead to a decrease in the therapeutic effect of biologics and even trigger severe adverse reactions [134]. Therefore, a comprehensive understanding of the role of genetic and environmental factors in paradoxical reactions is vital for optimizing psoriasis treatment plans.

Strategies for managing and preventing paradoxical reactions

Firstly, for the identification and assessment of paradoxical reactions, careful observation of symptom changes and adverse reactions during the treatment process is necessary. Simultaneously, a holistic evaluation should be conducted in conjunction with individual differences and specific disease characteristics. Necessary information could be gathered through medical history inquiries, physical examinations, and relevant laboratory tests to promptly identify and assess the occurrence and severity of paradoxical reactions. Secondly, various strategies can be employed in managing and treating paradoxical reactions. On one hand, the drug dosage and frequency of use could be reduced or adjusted to minimize the occurrence and severity of adverse reactions [8,135,136]. On the other hand, adjunctive treatment measures, such as local care, physiotherapy, and traditional Chinese medicine, could be used to alleviate adverse reactions and promote disease improvement [137-140]. Lastly, for the prevention of paradoxical reactions and personalized treatment strategies, a multi-faceted approach is needed. Firstly, patients should be guided to adopt good lifestyle habits, including regular sleep and meal schedules, balanced diet, and moderate exercise, to enhance immune resistance [141]. Psychological regulation is also vital to maintain a positive mental and emotional state, which could be achieved through psychological counseling and support. Moreover, personalized treatment is of paramount importance. Treatment plans should be customized based on the patient’s disease characteristics and individual differences to achieve optimal therapeutic outcomes [142].

Psoriasis is a chronic inflammatory skin condition characterized primarily by patchy red skin covered with white scales. Patients often experience symptoms such as itching and dryness, which tend to worsen during the winter and lighten during the summer [3].Currently, significant progress has been made in the treatment of psoriasis using biologics. These biologics work by modulating the immune system functions, reducing the inflammatory response, and thus improving patient symptoms. However, a number of paradoxical reactions may occur during the biologic treatment of psoriasis, including immune suppression, infection, and diminished vaccine response. The mechanisms of biologic treatment primarily function by inhibiting inflammatory mediators and regulating immune cell functions [143-145]. However, the specific mechanisms warrant further exploration and research. In terms of future research prospects and recommendations, current studies are primarily focused on clinical observations and case studies. Future research could delve deeper into the pathogenesis of psoriasis, mechanisms of biologic therapy, and the occurrence mechanisms of paradoxical reactions. Moreover, multi-center and large-scale clinical studies can be conducted to more comprehensively and objectively assess the efficacy and safety of biologic treatments [146,147]. In conclusion, biologic treatment for psoriasis is currently an effective therapeutic approach, albeit potential paradoxical reactions may occur during the treatment process. Future research can further explore the treatment mechanisms and conduct more extensive and in-depth clinical studies.

Conclusion

In conclusion, the management and prevention of paradoxical reactions in psoriasis can be effectively addressed through identification and assessment, management and treatment, as well as prevention strategies and personalized treatment approaches. The implementation of these strategies requires considering the patient’s disease characteristics and individual differences to enhance treatment outcomes and improve the patients’ quality of life.

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