Chronic prurigo is associated with persistent papules and nodules on the skin and is now defined as a disease in its own right. However, this was not always the case: for decades, prurigo was characterized by misconceptions and misunderstandings. In this context, prurigo was also referred to as “Cindarella disease”. In the meantime, research efforts have borne fruit, so that an approved biologic is currently available and further systemic active substances are in advanced phases of clinical development.
When chronic pruritus develops into chronic prurigo due to an itch-scratch cycle, this is often associated with a high level of distress (Box). Nowadays, prurigo chronica et nodularis is referred to as a neuroinflammatory dermatosis characterized by chronic itching (>persisting for 6 weeks), as well as a positive history of repeated scratching and the development of prurigo lesions, explained Prof. Mirjana Maiwald, MD, from the Hautärzte-Zentrum am Zürisee, Zurich [1]. While prurigo simplex subacuta is characterized by scratched papules, the nodular subtype is dominated by scratched nodules. Classic localizations are the extremities and accessible regions of the trunk (“butterfly sign”) [1,2]. “Prurigo is an independent disease and not a variant of another dermatosis,” emphasized the speaker, explaining that prurigo had previously been mistakenly regarded as a subtype of atopic dermatitis [1]. The Prurigo Activity and Severity Score (PAS) can be used to objectively document the severity and extent of chronic prurigo (CPG) [3]. Traditional therapies such as topical topicals, UV treatment, antidepressants or GABA agonists have proven to be insufficiently effective in the majority of cases.
Prurigo is often associated with a considerable impairment of quality of life; the agonizing itching can lead to emotional stress, sleep disorders and social isolation. The “burden of disease” can be very high. The incidence of arterial hypertension, diabetes mellitus and dyslipidemia is increased and those affected often also suffer from psychological disorders such as anxiety and depression. Interestingly, there is an association between prurigo and back pain, as well as neural sensitization disorders such as fibromyalgia, irritable bowel syndrome and interstitial cystitis, reported Prof. Maiwald [1]. |
Complex interaction of the skin, immune and nervous systems
CPG can occur at any age and affect different patient groups, although it is a disease that occurs more frequently in advanced age [3]. The underlying etiology of CPG is usually multifactorial and can include dermatologic, systemic, neurologic and psychiatric causes, although sometimes the causes remain unexplained [4]. Neuronal sensitization to itching results in a chronic cycle of itching and scratching followed by new prurigo lesions that is difficult to break. A cascade of inflammatory processes is involved in the pathomechanism (Fig. 1). Various immune cells infiltrate the skin of prurigo lesions, leading to the release of inflammatory cytokines and pruritogens. As a result, keratinocytes proliferate and release pruritogens, which leads to hyperplasia of nerve fibers and the release of neuropeptides and other neuroimmunomodulators. This leads to an intensification of the itch-scratch cycle. Although scratching causes the itching to subside in the short term, it induces mechanical damage to the peripheral nerve fibers, which promotes the recurrence of itching. Chronic pruritus leads to considerable subjective suffering for those affected, which can result in restrictions in health-related quality of life such as sleep disorders, anxiety, depression, stigmatization and/or social withdrawal [3]. The guideline recommends that patients with all forms of CPG should be treated according to the following pillars:
- Symptomatic antipruritic therapy
- Interdisciplinary diagnosis and treatment of the underlying disease
- Treatment of secondary secondary symptoms of pruritus (e.g. psychological/psychotherapeutic treatment if corresponding comorbidities are present).
The sensation of itching is subjective and can therefore only be recorded by self-report. Using the numerical rating scale (NRS), itching can be classified on a scale of 0-10 (usually in relation to the period of the previous 24 hours).
Dupilumab and nemolizumab effectively reduce pruritus and skin lesions
The primary treatment goals of antipruritic therapy include itch relief and interruption of the established itch-scratch cycle. In the short or medium term, the aim is to heal the prurigo lesions, explained the speaker, stating: “The era of modern prurigo therapy began with the approval of the first biologic for this indication” [1]. Dupilumab targets the IL-4Rα subunit of the interleukin (IL)-4 receptors, thereby inhibiting IL-4 and IL-13 signaling. In Switzerland, dupilumab (Dupixent®) is officially approved for the treatment of prurigo nodularis [5]. In pivotal studies, treatment with this monoclonal antibody showed a significant improvement in itching, quality of life, sleep, skin pain and mental health. The safety profile of dupilumab is excellent, so that nothing stands in the way of its use in elderly and/or multimorbid patients, the speaker reported [1]. Nemolizumab – an interleukin (IL)-31 receptor blocker – is another promising antibody: in the phase III OLYMPIA 2 study, it led to a significant reduction in pruritus intensity and skin lesions compared to placebo [6]. The ongoing OLYMPIA LTE study is investigating the efficacy and safety of long-term treatment. Nemolizumab has not yet been approved in Switzerland (status of information 19.07.2024).
Further systemic active ingredients with promising data
Vixarelimab is a dual inhibitor of IL-31 and oncostatin M beta receptor. The results of a phase IIa study were published in 2023 [7]. This study included 18-75-year-old patients with moderate to severe pruritus, defined as a WI-NRS** score ≥7 at screening and a mean weekly WI-NRS score ≥5 in the two subsequent weeks before randomization. Study participants were randomized 1:1 to once-weekly vixarelimab 360 mg (720 mg loading dose) or placebo. Participants were stratified by gender and atopy status. The modified intent-to-treat analysis population included data from 23 participants in the vixarelimab group and 26 participants in the placebo group. At week 8, there was a -50.6% reduction in LS& mean WI-NRS score in the treatment arm compared to baseline, compared to -29.4% in the placebo arm (p=0.03). A reduction of ≥4 points in the WI-NRS score was achieved by 52.2% with vixarelimab compared to 30.8% with placebo (p=0.11). Vixarelimab also proved to be superior to placebo in terms of sleep disturbance relief (p=0.02).
** WI-NRS = Worst Itch-Numeric Rating Scale
& LS= “Least squares” (method of least squares)
Phase II data on the Janus kinase inhibitor abrocitinib was also recently published [8]. The study included 10 patients with prurigo nodularis (PN) and 10 patients with chronic pruritus of unknown origin(CPUO). The mean PP-NRS score at baseline was 9.2 (SD 1.0) in the PN group and 8.2 (SD 1.2) in the CPUO group. With abrocitinib, the PP-NRS$ values decreased by week 12 by 78.3% for PN (95% CI, -118.5 to -38.1; p<0.001) and by 53.7% for CPUO (95% CI; -98.8 to -8.6; p=0.01). From baseline to week 12, 8 out of 10 patients with PN and 6 out of 10 patients with CPUO achieved an improvement of at least 4 points in the PP-NRS. There was a significant improvement in quality of life (DLQI) in both groups.
$ PP-NRS = Peak Pruritus Numerical Rating Scale
Promising data are also available on nalbuphine (agonist at the κ-opioid receptor and partial antagonist at the µ-opioid receptor); a phase II study with an open extension phase showed a significant reduction in pruritus with a twice-daily dose of 162 mg [11]. Other systemic agents currently under investigation are ruxolitinib cream and povorcitinib, both of which are JAK-i agents. The efficacy and safety of ruxolitinib cream is currently being investigated in a multicenter, international phase III trial [12]. A 12-week double-blind placebo-controlled treatment period is followed by a 40-week open-label extension phase.
Congress: Zurich Dermatology Training Days (ZDFT)
Literature:
- “Prurigo chronica et nodularis”, Prof. Dr. med. Mirjana Maiwald, ZDFT, 22.06.2024.
- Thünemann J, et al: Chronic prurigo. JDDG 2024; 22(6): 813-823.
- Ständer S, et al.: S2k Leitlinie: Diagnostik und Therapie des chronischen Pruritus. JDDG 2022; 20(10): 1386–1402.
- 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. JEADV 2018; 32(7): 1059-1065.
- Swissmedic: Medicinal product information, www.swissmedicinfo.ch,(last accessed 19.07.2024)
- Kwatra SG, et al; OLYMPIA 2 Investigators. Phase 3 Trial of Nemolizumab in Patients with Prurigo Nodularis. N Engl J Med 2023; 389(17): 1579-1589.
- Sofen H, et al: Efficacy and safety of vixarelimab, a human monoclonal oncostatin M receptor β antibody, in moderate-to-severe prurigo nodularis: a randomized, double-blind, placebo-controlled, phase 2a study. EClinicalMedicine 2023 Feb 3; 57: 101826.
- Kwatra SG, et al: Efficacy and Safety of Abrocitinib in Prurigo Nodularis and Chronic Pruritus of Unknown Origin: A Nonrandomized Controlled Trial. JAMA Dermatol 2024; 160(7): 717-724.
- Wong L-S, Yen Y-T: Chronic Nodular Prurigo: An Update on the Pathogenesis and Treatment. International Journal of Molecular Sciences 2022; 23(20): 12390. www.mdpi.com/1422-0067/23/20/12390#,(last accessed 19.07.2024)
- Müller S, Zeidler C, Ständer S: Chronic Prurigo Including Prurigo Nodularis: New Insights and Treatments. Am J Clin Dermatol 2024; 25(1): 15-33.
- Weisshaar E, et al: Efficacy and safety of oral nalbuphine extended release in prurigo nodularis: results of a phase 2 randomized controlled trial with an open-label extension phase. JEADV 2022; 36(3): 453-461.
- Cochrane Central Register of Controlled Trials: NCT05764161.
DERMATOLOGIE PRAXIS 2024; 34(4): 40-41 (published on 30.8.24, ahead of print)