Inflammation-promoting pruritogenic cytokines as a therapeutic target

There are various triggers for the initial itching in prurigo nodularis (PN). If those affected give in to the scratching impulse, the pruritus intensifies, as this stimulates nerve and inflammatory cells. This leads to a vicious circle and contributes to a chronification of the symptoms. The complex interaction between the skin, immune system and nervous system is becoming increasingly better understood. Based on this, new anti-inflammatory therapy options were developed and tested.

“We have reached a turning point in the management of prurigo nodularis,” says PD Dr. med. Simon Müller, Medical Director of Inpatient Dermatology, University Hospital Basel and Chair of the symposium [1]. This skin disease, which is characterized by agonizing itching and itchy skin nodules, has been in the shadows for a long time, but in recent years it has become a “hot topic” in connection with the development of new treatment options. This is also shown by a look at the number of scientific publications on prurigo nodularis (PN) in PubMed, which has risen sharply within a short period of time. According to epidemiological data, PN has a higher prevalence in people over the age of 50, with women being affected more frequently than men [1].

Agonizing itching hits the mind

PD Dr. med. Manuel P. Pereira, Charité Universitätsmedizin Berlin, spoke about the etiopathogenesis, diagnosis and treatment of PN [1]. The etiology of PN can be dermatologic, systemic, neurologic, psychiatric/psychosomatic, multifactorial or of undetermined cause [1]. Peripheral and central sensitization to the chronic itching contributes to the chronicity of the disease. The diagnosis of PN is primarily made clinically if these three main criteria are met [2–4]:

Chronic pruritus over a period of ≥6 weeks
History of chronic and severe itching and/or signs of repeated scratching or rubbing (e.g. excoriations and scars)
Presence of itchy, nodular lesions.

The severity of the skin lesions can be assessed using the IGA score. “The itching is moderate to severe in most patients,” reported the speaker [1]. Predilection sites are the upper and lower extremities, but the back can also be affected. The “Burden of Disease” should also be recorded during the diagnostic clarification. The burden of disease associated with PN is high, patients often suffer from sleep disorders and depressive symptoms, and their overall quality of life is impaired.

Atopic diathesis increases the risk of PN

“Nodules are the most common lesions, but others such as papules and plaques are also found,” says Dr. Pereira. The number of itchy lesions ranges from a few to several hundred. In general, there is a bilateral distribution. “Normally you can see scratch marks,” says the speaker. In addition to excoriations and crusting, this also includes lichenification, hyper- and hypopigmentation [4–6]. Typical is the recess of interscapular areas (so-called “butterfly sign”), as these are less accessible for scratching, especially in the back area [5].

“Another important aspect is the distinction between atopic dermatitis and prurigo nodularis,” explained the speaker. One difference concerns the morphology of the lesions; prurigo is characterized by nodules, while atopic dermatitis (AD) is characterized by eczematous lesions, but PN and AD can coexist in the same patient [1,7]. PN often occurs with atopic dermatitis or pronounced atopic skin diathesis [8]. Histopathologically, dermal fibrosis and a dense inflammatory infiltrate in the dermis are characteristic of PN [1].

Pathophysiology of PN is complex

“In pathophysiology, the interaction between keratinocytes, immune cells and skin nerves is very important,” explained Dr. Pereira. Various immune cells, including eosinophils, neutrophils, T cells, macrophages and mast cells, infiltrated the lesional skin, triggering the release of inflammatory cytokines and pruritogens [9]. The skin has a high density of peripheral afferent nerve fibers. The itch signals from the skin are transmitted to the central nervous system [10]. In addition, the interaction between the immune cells and the neurotransmitter-activated peripheral sensory nerve fibers leads to neuroinflammation in the skin and persistent itching [9]. The inflammatory mediators released by immune cells include interleukin (IL)-4, which is released by Th2 cells, among others. However, IL-13 and IL-31 also act as pro-inflammatory messengers in PN. These mediators have a direct effect on the skin nerves, but also contribute to neuronal sensitization. “All of these processes intensify the itching and contribute to the chronicity,” Dr. Pereira concluded [1].

Dupilumab as a new beacon of hope

The guidelines recommend stage-adapted treatment of PN [14,15]. When therapies that only act locally on the treated skin (e.g. topical corticosteroids and topical calcineurin inhibitors) reach their limits, systemic treatment is indicated. Dupilumab (^Dupixent®) was granted an indication extension by Swissmedic this year for adults with moderate to severe PN for whom prescription topical therapies are not effective [11]. Dupilumab is a biologic that precisely targets the inflammatory response and the mechanism of itch development and has been shown to be effective and safe in the PRIME and PRIME 2 clinical trials in 311 adults with moderate to severe PN [11]. Treatment with dupilumab 300 mg (q2w)** showed clinically meaningful and statistically significant improvements in itching and skin lesions compared to placebo.

** q2w = every 2 weeks

In the PRIME study, for example, 44.0% achieved a reduction of ≥4 points in the Worst-Itch Numeric Rating Scale (WI-NRS) at week 12 after baseline, compared with 15.8% under placebo [12]. Over time, this proportion increased considerably in the verum group: at week 24, the corresponding rates were 60.0% and 18.4% respectively. PRIME2 also showed a significant difference in this endpoint at week 12 with 37.2% with dupilumab vs. 22.0% with placebo, which was accentuated by week 24. The safety signals corresponded to the known safety profile of dupilumab. A subgroup analysis showed that both atopic and non-atopic PN patients benefit from treatment with dupilumab (Fig. 1). [1,12].

Further drug candidates are in the pipeline, including the anti-IL-31 receptor antibody Nemolizumab. This monoclonal antibody has so far delivered convincing results in clinical trials. Ruxolitinib cream is a topical JAK inhibitor that is currently being investigated in phase III trials, and two oral JAK inhibitors, abrocitinib and povorcitinib, are also undergoing clinical trials (phase II trials) [13]. Nalbuphine and vixarelimab are also being tested in ongoing clinical trials [13].

Congress: SGDV Annual Congress

Literature:

“The long Way to a Hot Topic”, PD Dr. med. Simon Müller, Dupi or not to be – that is the new question in prurigo nodularis, Symposium 9, Sanofi, SSDV Congress, 06.-08.09.2023.
Pereira MP, et al; EADV Task Force Pruritus group members. European academy of dermatology and venereology European prurigo project: expert consensus on the definition, classification and terminology of chronic prurigo. J Eur Acad Dermatol Venereol 2018; 32(7): 1059-1065.
Ständer HF, et al: Diagnostic and treatment algorithm for chronic nodular prurigo. J Am Acad Dermatol 2020; 82(2): 460-468.
Misery L. Chronic prurigo. Br J Dermatol 2022; 187(4): 464-471.
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Yosipovitch G, et al.: Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials. Nat Med 2023; 29(5): 1180–1190.
Müller S, Zeidler C, Ständer S: Chronic Prurigo Including Prurigo Nodularis: New Insights and Treatments. Am J Clin Dermatol 2023, https://doi.org/10.1007/s40257-023-00818-z
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