A Scoping Review Protocol to Explore the Use of Interleukin-1-Targeting Drugs for the Treatment of Dermatological Diseases: Indications, Mechanism of Action, Efficacy, and Safety

Research into inflammatory disease pathophysiology facilitates the development of increasingly selective pharmaceutical agents that are highly effective but may also be expensive and have serious side effects. Autoinflammation is driven by endogenous danger signals, metabolic mediators, as well as cells and cytokines of the innate immune system, including interleukin (IL)-1, IL-8, and tumor necrosis factor (TNF)-α [1]. IL-1 is a proinflammatory cytokine that is pathogenically involved in the development of skin diseases. The IL-1 pathway is balanced by activating/promoting agents such as the receptor I (IL-1RI) agonist isoforms IL-1α and IL-1β as well as natural inhibitors of excessive inflammatory responses such as IL-1Ra (a competitive inhibitor of IL-1α and IL-1β) and IL-1RII (which acts as a decoy receptor). While IL-1α initiates the inflammatory process, both isoforms are responsible for propagating and maintaining it [2].

IL-1 is a proinflammatory cytokine involved in skin homeostasis. In the skin, it is mainly expressed in keratinocytes [3], but it can also be found in melanocytes, Langerhans cells, and Merkel cells. Two agonist isoforms encoded by genes located at different loci on chromosome 2 target the IL-1 receptor: IL-1α and IL-1β [4]. These are secreted in the endoplasmic reticulum independently of the Golgi apparatus after inflammasome activation [5]. The precursor of IL-1α, pro-IL-1α, is biologically active, is expressed more with inflammation, and can reside in the cytoplasm, nucleus, or membrane of a producer cell. The precursor of IL-1β, pro-IL-1β, is biologically inactive until processed by intracellular caspase-1 in inflammasomes or by extracellular neutrophilic proteases such as elastase, chymase, granzyme A, cathepsin G, and proteinase [6]. IL-1 has two receptors: IL-1RI and IL-1RII. Signal transduction caused by IL-1 occurs exclusively through IL-1RI. IL-1α, IL-1β, and extracellular pro-IL-1α inhibit IL-1RI with the same affinity. Signal transduction is initiated by IRAK activation, which in turn activates transcription factors such as nuclear factor kappa B (NF-κB), c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase (JNK-MAPK) signaling [7]. There are natural inhibitors of excessive inflammatory responses such as IL-1Ra and IL-1RII. IL-1Ra acts as a competitive inhibitor of IL-1α and IL-1β and exists in two isoforms: the soluble glycosylated extracellular isoform (sIL-1Ra), which is predominantly produced by activated macrophages and monocytes, and the nonglycosylated intracellular isoform (icIL-1Ra), which is produced mainly by Kupffer cells [8]. The nonglycosylated isoform regulates intracellular IL-1-dependent responses. IL-1RII functions as a decoy receptor since it lacks a Toll/IL-1R (TIR) domain [9].

With respect to their biological functions, IL-1 isoforms are generally active during stress responses, inflammation onset, and immune response activation, and they partake in gene expression regulation. They also intervene in carcinogenesis and tumor progression by regulating angiogenesis. These functions can be performed selectively by one isoform alone or can be initiated by one isoform and perpetuated by another, exerting effects at the local (IL-1α) or systemic (IL-1β) level [10]. The regulation of IL-1 can be affected by different factors, both genetic and acquired. Genetic factors include mutations such as IL-1β 511 (CT) polymorphism, IL-1α-889 (C → T) polymorphism, and melanocortin 1 receptor (MC1R) gene polymorphism. These can result in differences in immune response or susceptibility to different diseases. Alternatively, ultraviolet radiation A and B, human papillomavirus infection, skin barrier integrity alteration, and exposure to certain chemicals have been found to be related to dysregulation of the IL-1 pathway [4].

IL-1 pathway alterations have been associated with the onset and progression of several dermatological diseases, including psoriasis [11], atopic dermatitis [12], neutrophilic diseases (e.g., Sjögren’s syndrome, pyoderma gangrenosum, Sweet syndrome, or subcorneal pustular dermatosis) [13], as well as the development of neoplastic diseases such as actinic keratosis, Bowen’s disease, cutaneous epidermoid carcinoma, or melanoma [14]. Research conducted regarding the pathophysiological mechanisms for these diseases has led to the development of selective pharmaceutical agents such as anakinra (a recombinant IL-1Ra that competes with IL-1R agonists for its receptor), rilonacept (which acts as a soluble decoy preventing the activation of IL-1RI [15]), canakinumab (a human monoclonal antibody targeting IL-1β [16]), or, more recently, MABp1 (an anti-IL-1α monoclonal antibody [17]). However, given the broad expression and systemic functions of IL-1β and IL-1R, it is questionable whether the long-term effects of these drugs are tolerable. Another drawback of these inhibitors is that they have been associated with bacterial infections, thus limiting their use. From this perspective, anti-IL-1α may have a clinical advantage since they are applied locally rather than systemically, thus potentially limiting adverse effects [10].

The available evidence on the use of IL-1 pathway-modulating agents for the treatment of dermatological diseases is scarce but growing. However, while randomized clinical trials currently represent the best source of evidence, they are not always available, thus making it necessary to obtain secondary evidence. Integrating the optimal research evidence available with clinical experience and patient values has been shown to improve care, health, and cost outcomes [18]. This is likely because evidence-based guidelines rank interventions based on cost-effectiveness, which allows us to discard ineffective alternatives, improve patient status over the long term, avoid complications and additional treatments, and identify measures for disease prevention. Thus, it is necessary to scientifically synthesize the breadth of studies derived from primary research. The secondary scientific research methodology applied depends on the type of research question being asked and the urgency of the response [19]. They can be divided into the following categories: (1) systematic reviews, which question the effectiveness of an intervention; (2) rapid reviews, when time is a critical factor; (3) scoping reviews, which provide an overview of a broad field; and (4) realistic reviews, which are designed to determine how and why complex social interventions function. Specifically, a scoping review is a form of scientific synthesis that addresses an exploratory research question aimed at mapping key concepts and identifying research gaps related to a defined area or field by systematically searching, selecting, and synthesizing existing knowledge [20]. These studies aim to synthesize and present the available evidence, to identify and make recommendations about specific areas of research, and finally to explore the possibility of carrying out systematic reviews on the specific questions formulated.

Here, we aimed to establish a methodology for broadly synthesizing the available evidence on the indications for and the mechanisms of action, efficacies, and safety of IL-1 pathway-targeting drugs that are used to treat dermatological diseases.