Introduction

Pruritus, defined as an unpleasant sensation that provokes the desire to scratch, may range in severity from mild to disabling.1 It is frequently associated with significant impairments in sleep, concentration, mood, and quality of life. Severe or chronic forms of pruritus can contribute to significant psychological morbidity, including depression, anxiety, social withdrawal, reduced work productivity, and, in some cases, suicidal ideation.2,3,4 Despite the widespread impact of pruritus across dermatologic and systemic conditions, many therapeutic options remain inadequate, especially for patients with intractable symptoms.5

Targeting the "Itch Cytokine"

Interleukin-31 (IL-31) has emerged as a key cytokine in the pathogenesis of pruritus, acting directly on sensory neurons regardless of the underlying cause. Nemolizumab, a monoclonal antibody targeting the IL-31 ”itch” receptor, is FDA-approved for the treatment of prurigo nodularis and atopic dermatitis. Emerging evidence suggests that its clinical utility may extend beyond these approved indications.5

A retrospective case series examined medical records of 70 patients treated with nemolizumab for chronic pruritus. The cohort included individuals with a wide range of dermatological and systemic conditions, including atopic dermatitis, nummular dermatitis, hand dermatitis, dermatographia/urticaria, cutaneous mastocytosis, neuropathic itch, subacute prurigo, immunologic eruptions of aging, scrotal and vulvar/anal pruritus, notalgia paresthetica, acquired cutaneous brachioradial pruritus, scabies, postscabetic id hypersensitivity, lichenoid amyloidosis, pernio, granulomatous dermatitis, burning, neuropathic skin pain, burning mouth syndrome, neurogenic rosacea, lymphoma- and leukemia-associated pruritus, and erythromelalgia.5 Each patient received an initial 60 mg dose of nemolizumab, followed by monthly doses of 30 or 60 mg. Patients were followed for an average of 73 days.5

Clinical response was defined as either a ≥2-point reduction in Numerical Rating Scale (NRS) or a ≥50% reduction in symptom severity from baseline. Nearly all patients (96%) experienced meaningful symptom improvement and continued therapy beyond the study period. While two patients (one with notalgia paresthetica and one with brachioradial pruritus) initially failed to respond, the case of brachioradial pruritus later demonstrated improvement after five months.5

"Yin-Yang" Relationship of Cytokines and Paradoxical Reactions

Many pruritic disorders are driven by Th2-type inflammation, which is mediated by cytokines such as IL-4 and IL-13. Biologic agents including dupilumab, tralokinumab, and lebrikizumab inhibit these cytokines and are effective in reducing pruritus in conditions such as atopic dermatitis, chronic spontaneous urticaria, and prurigo nodularis. However, suppression of Th2 signaling may shift the immune balance and unmask latent Th1- or Th17-driven diseases such as inflammatory arthritis. For instance, dupilumab has been associated with new-onset or exacerbated psoriatic arthritis in susceptible individuals.

Conversely, agents that inhibit IL-17 (e.g., secukinumab, ixekizumab, and bimekizumab) may shift the immune response toward a Th2-dominant state, potentially exacerbating or triggering atopic conditions. This reciprocal relationship has been described as a "yin-yang" balance between Th1, Th17, and Th2 immunity (Figure 1&2).6

In some cases, selective cytokine blockade may result in paradoxical reactions, defined as unusual skin reactions due to imbalances in immune responses (Figure 3). These reactions have been observed as the development of psoriasis-like skin reactions in patients undergoing treatment for eczema (e.g. TNFi and dupilumab), or eczema-like skin reactions in patients undergoing treatment for psoriasis, most commonly with the use of TNFi, IL-17, IL12/23, or IL-23 blockade. Occurring within weeks to months of treatment initiation, these paradoxical reactions affect approximately 1% of all patients undergoing such treatments. These reactions are thought to arise from immune imbalance due to inhibition of one pathway, thereby promoting unchecked activity of another.

In addition to psoriasiform eruptions, reported paradoxical reactions include arthralgias, neurosarcoidosis, granulomatosis with polyangiitis amongst patients with asthma, and oral and cutaneous lichen planus. Transient eosinophilia, with absolute eosinophil counts >1500µL, has also been observed and typically resolves without intervention.6 Furthermore, inhibition of IL-13 may impact mucosal immunity. IL-13 plays a critical role in maintaining goblet cells, which are responsible for mucous production in the conjunctiva. Consequently, blockade of IL-13 by agents such as dupilumab, tralokinumab, or lebrikizumab can lead to ocular adverse events, including conjunctivitis and dry eye.7 Overall, this variety of paradoxical reactions emphasizes the delicate equilibrium of the “yin-yang” relationship between the T-helper cell pathways.

Investigating Medical Causes Before Prescribing

Before initiating nemolizumab, clinicians should conduct a thorough evaluation to exclude systemic causes of pruritus, especially in patients without primary skin lesions. In the case series, 20% of patients had renal insufficiency, 36% had diabetes or prediabetes, and several had hematologic malignancies.5 Pruritus may precede the diagnosis of conditions such as Hodgkin lymphoma or chronic kidney disease, and prompt recognition may be life-saving.1

Recommended screening evaluations include a complete blood count with differential, comprehensive metabolic panel, hemoglobin A1c, calcium, uric acid, lactate dehydrogenase (LDH), and serologies for HIV, hepatitis C, and syphilis. Additional assessments may include serum protein electrophoresis, chest x-ray, and skin biopsy with T-cell gene rearrangement studies for suspected lymphoma.5

Adverse Effects Associated with Nemolizumab

The majority of patients in the retrospective series tolerated nemolizumab well. One patient with recalcitrant mycosis fungoides experienced erythroderma and facial swelling, which was attributed to withdrawal of abrocitinib, although the patient no longer reported skin pain or pruritis.5 Overall, nemolizumab has demonstrated a favorable safety profile.

Literature reports have documented cutaneous adverse events in 30% to 50% of patients, including psoriasiform eruptions, exacerbation of underlying dermatitis, urticaria, acne, and fungal infections.8 However, other studies suggest that the incidence of adverse events amongst patients receiving nemolizumab therapy is comparable to placebo.9

Transforming the Landscape of Itch Treatment

Nemolizumab represents a significant advancement in the treatment of chronic pruritus. By targeting IL-31, a cytokine that acts directly on sensory neurons, nemolizumab offers a novel approach distinct from upstream immunomodulators, with the benefit of rapid and targeted relief. This agent has shown promise in diverse clinical settings, including idiopathic pruritus, malignancy-associated itch, pruritus of chronic kidney disease, vulvar and scrotal itch, and neuropathic pruritus.5

Further studies should explore nemolizumab’s efficacy in off-label indications, characterize long-term safety, and identify optimal patient selection criteria. For dermatologists, nemolizumab offers a novel and potentially transformative approach to addressing itch–one of the most burdensome symptoms in dermatologic care.