Non-trivial - despite proven and new system therapies

Chronic pruritus can occur at any age and affect different groups of patients. A guideline-based approach is advisable in order to determine the cause and provide the best possible treatment for those affected. The therapeutic landscape is in a state of flux – as evidenced, among other things, by the recently approved drugs for the indication areas of nephrogenic pruritus and prurigo nodularis.

Pruritus not only occurs in the context of skin diseases such as atopic dermatitis or psoriasis, but numerous patients with internal medical conditions also suffer from this distressing symptom. The lifetime prevalence of chronic pruritus – i.e. persisting for at least 6 weeks – is around 20%, explained PD Dr. med. Simon Müller, Medical Director Inpatient Dermatology, University Hospital Basel [1]. Those affected often suffer from a massively impaired quality of life, accompanied by increased stress levels, anxiety disorders and depression.

Classification – “International Forum for the Study of Itch” (IFSI)

To find an explanation for pruritus, a structured, guideline-based approach is recommended because the spectrum of possible causative ashes is broad, the speaker said. The current S2k guideline suggests using the IFSI classification of chronic pruritus [2,3]. In the first step, the patient is assigned to a clinical group (IFSI I-III) and in the second step, differential diagnostic categories of the possible underlying disease are elicited. According to IFSI, chronic pruritus can be classified into the following groups:

IFSI I: Chronic pruritus on primary lesional (altered) skin: in the presence of skin disease (previously: pruritus cum materia).
IFSI II: Chronic pruritus on primarily non-lesional (unchanged) skin: without initial presence of skin lesions (previously: pruritus sine materia).
IFSI III: Chronic pruritus with severe scratch lesions: Predominance of chronic scratch lesions (for example, chronic prurigo, lichen simplex) that do not allow classification into the first or second group

The differential diagnostic categories are as follows: dermatological diseases, systemic diseases (including drug-induced pruritus), neurological diseases, psychological/psychosomatic diseases, multifactorial (i.e., more than one cause), pruritus of unclear etiology. In cases of chronic pruritus on primarily non-lesional skin, internal, neurological, and psychological/psychosomatic disorders or drug-induced pruritus should be considered first [3].

Individual treatment plan with symptom-targeted measures

The following course of therapy is recommended: first, the affected person should be informed about general pruritus-relieving measures and diagnostically clarified for possible underlying diseases. In parallel with the diagnosis, the initiation of a stepwise, symptomatic therapy is useful (Tab. 1) [3]. In order to achieve the best possible risk-benefit profile, it is suggested that the treatment plan be individually tailored, taking into account age, diseases and medication, as well as the severity of the symptoms and the limitations of health-related quality of life. Selective, second-generation peripheral H1- receptor antagonists (e.g., loratadine, cetirizine, desloratadine, levocetirizine, or bilastine) are widely used as antipruritic agents. Unlike first-generation H1 receptor blockers, they are generally well tolerated and have little depressant or sedative effect.

Biologics and JAK-i inhibit proinflammatory signaling pathways

Chronic pruritus is based on complex pathophysiological mechanisms, with different mediator systems, immune and non-immune cells, and nerve fiber classes interacting to initiate and maintain sensitization processes in the skin and peripheral and central nervous systems [4]. Newer approaches to the systemic treatment of pruritus focus on blocking proinflammatory interleukins, such as IL(interleukin)-4/IL-13/IL-31 or the JAK/STAT** pathway [5]. Relevant expression of IL-4 and IL-13 has been demonstrated mainly in inflammatory skin diseases such as atopic dermatitis (and chronic nodular prurigo and prurigo nodularis, respectively. IL-31 is discussed in humans particularly in pruritus in the context of atopic dermatitis, cutaneous T-cell lymphoma, psoriasis, and purigo nodularis.

** JAK/STAT=Januskinase/”signal transducers and activators of transcription”.

Prurigo nodularis – Dupilumab and nemolizumab score well

Prurigo nodularis (PN) involves itchy nodules on the skin. The exact etiology of the disease is not yet clear. Presumably, PN develops in patients with chronic and severe pruritus of various etiologies in response to repeated scratching. Dupilumab (^Dupixent®) received an indication extension from Swissmedic based on the PRIME trial program for adults with moderate-to-severe PN [6]. The effects of this monoclonal antibody are based on binding to the α-subunit of the interleukin (IL)-4 receptor and the IL-13 receptor. In the double-blind, placebo-controlled phase III PRIME and PRIME2 trials, 311 adults with uncontrolled prurigo nodularis were randomized 1:1 to 300 mg dupilumab every two weeks or placebo [7]. In the PRIME trial, a ≥4-point reduction in the Worst-Itch Numeric Rating Scale [WI-NRS] was achieved at week 24 by 60.0% in the dupilumab study arm, compared with 18.4% with placebo (95% confidence interval (CI): 27.8-57.7; p<0.001). In the PRIME2 trial, 37.2% and 22.0% of patients achieved a ≥4-point reduction in WI-NRS at week 12, respectively (95% CI; 2.3-31.2; p=0.022).

Itch-related distress – consider antidepressants
Numerous studies show that chronic pruritus considerably reduces the quality of life of those affected. “The prevalence of depression and anxiety disorders is high in this patient population,” explained PD Dr. Simon Müller, Dermatology, University Hospital Basel. A viable screening tool is Whooley’s 2-question test (“In the past month, have you often felt down, sadly depressed, or hopeless?” and “In the past month, have you had significantly less pleasure and joy in doing things you usually enjoy?”). If depressive symptoms are predominant and the patient wants an improvement in sleep, Dr. Müller uses the tricyclic antidepressant trimipramine; if anxiety symptoms are predominant and the patient suffers from sleep problems, on the other hand, he uses trazadone – an antidepressant from the group of serotonin antagonists with simultaneous serotonin reuptake inhibition (SARI). When depression or anxiety is present but sleep improvement is not desired, sertraline, a selective serotonin reuptake inhibitor with relatively few side effects, can be used.

to [1,11]

The anti-IL-31 receptor antibody nemolizumab is not yet on the market in Switzerland, but remarkable results have been achieved in clinical trials. In a phase II study, nemolizumab resulted in a 4.5-point (-53.0%) reduction in itch in patients with moderate-to-severe PN at week 4 compared with baseline, compared with 1.7 points (-20.2%) with placebo (p<0.001) [8].

Nephrogenic pruritus – μ- and κ-opioid receptors.

According to the multinational DOPPS (“Dialysis Outcomes and Practices Patterns Study”) cohort, more than 40% of dialysis patients suffer from moderate to very severe pruritus [9]. “The pathogenesis of nephrogenic pruritus is relatively complex,” Dr. Müller reported. A disturbance in the endogenous opioid system such as overstimulation of central μ-opioid receptors or antagonism of peripheral κ-opioid receptors is thought to be significantly involved. Difelikefalin (^Kapruvia®) – an active ingredient from the opioid receptor agonist group – was approved in Switzerland in 2022 for the treatment of pruritus in adult hemodialysis patients [6]. The antipruritic effects are due to selective agonism at kappa opioid receptors. The drug is administered intravenously. Unlike μ-receptor agonists, difelikefaline cannot be abused as a narcotic and does not induce respiratory depression [10].

Congress: Joint advanced training BE-BS-ZH

Literature:

“1, 2, 3 – Itching soon over? Proven and new system therapies”, PD Dr. med. Simon Müller, Joint Continuing Education and Training of the dermatological clinics Bern, Basel, Zurich. Inselspital Bern, 25.05.2023.
International Society for the Study of Itch (IFSI), www.itchforum.net,(last accessed 09.08.23).
Ständer S, et al: S2k guideline: diagnosis and therapy of chronic pruritus. JDDG 2022; 20(10): 1386-1402.
Cevikbas F, Lerner EA: Physiology and pathophysiology of itch. Physiol Rev 2020; 100: 945-982.
Agelopoulos K, et al: Neurobiology of pruritus: new concepts. Die Dermatologie 8/2022. www.springermedizin.de,(last accessed 09.08.23).
Drug Information, www.swissmedicinfo.ch,(last accessed 09.08.23).
Yosipovitch G, et al: Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials. Nat Med 2023: 29: 1180-1190.
Ständer S, et al: Trial of nemolizumab in moderate-to-severe prurigo nodularis. NEJM 2020; 382(8): 706-716.
Rayner HC, et al: International comparisons of prevalence, awareness, and treatment of pruritus in people on hemodialysis. Clin J Am Soc Nephrol 2017; 12: 2000-2007.
Pharmawiki, www.pharmawiki.ch,(last accessed 09.08.2023).
Whooley MA, et al: Case-finding instruments for depression. Two questions are as good as many. J Gen Intern Med 1997; 12: 439-445.
Tutka K, et al: Skin microbiome in prurigo nodularis. International Journal of Molecular Sciences 2023; 24(8): 7675. www.mdpi.com/1422-0067/24/8/7675,(last accessed 09.08.2023).