Pain and Itch: The Neuroimmune Burden of Psoriasis

Pain and itch are among the most distressing symptoms reported by psoriasis patients, yet they receive far less attention than the visible signs of the disease. Both are mediated by a complex neuroimmune dialogue between sensory nerve fibres, immune cells, and keratinocytes, the same cross-talk described in Section 28.8 (neuroimmunology). This chapter examines the molecular mechanisms underlying these symptoms and the therapeutic implications.

18.1 The Neuroscience of Psoriatic Itch

Pruritus (itch) is reported by 60–90% of psoriasis patients and is frequently cited as the single most bothersome symptom, more troublesome even than visible plaques. Psoriatic itch differs from itch in other conditions (such as eczema) in its mechanisms, and current treatments often fail to adequately control it.

The neuro-immune itch circuit in psoriasis involves several key molecular players:

IL-31 and its receptor. IL-31, produced by Th2 cells and activated macrophages, acts through the IL-31 receptor A (IL-31RA) expressed on sensory neurons in the dorsal root ganglia (DRG), the clusters of nerve cell bodies that relay sensory information from the skin to the spinal cord. IL-31 binding triggers intracellular calcium release and ERK1/2 phosphorylation in these neurons, directly generating itch signals (Jaworecka et al., 2025).

TRPV1 and TRPA1 channels. Transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) are ion channels on sensory nerve endings that detect heat, chemicals, and inflammatory mediators. In psoriatic skin:

• TRPV1 is upregulated, lowering the threshold for itch and pain perception.
• Nerve growth factor (NGF), which is elevated in psoriatic lesions (Section 28.8), further sensitises TRPV1 channels by lowering their activation threshold.
• The skin microbiota stimulates NGF production in mast cells, adding a microbial contribution to itch generation (Takahashi & Yamasaki, 2023).

Neuropeptide amplification. When TRPV1+ nerve endings are activated, they release substance P and CGRP (calcitonin gene-related peptide), the same neuropeptides described in the neuroimmunology section (Section 28.8). Substance P activates mast cells via the NK1 receptor, causing degranulation and release of histamine, tryptase, and further inflammatory mediators. CGRP amplifies IL-23/IL-17 signalling. This creates a neurogenic inflammation loop: itch signals generate more inflammation, which generates more itch.

Emerging therapeutic targets for itch:

Target	Agent	Status	Mechanism
TRPV1	Asivatrep (PAC-14028)	Phase 2/3	Topical TRPV1 antagonist; inhibits heat and capsaicin-mediated itch signalling
NK1R	Serlopitant	Phase 2 completed (programme discontinued)	Blocks substance P signalling; showed significant itch reduction vs placebo in psoriasis (PSORIXA trial) but development halted for strategic reasons
IL-31RA	Nemolizumab	FDA-approved (Dec 2024, atopic dermatitis)	Anti-IL-31RA antibody; the most clinically advanced anti-itch biologic; being explored for psoriatic itch
JAK pathway	Ruxolitinib cream	Approved (atopic dermatitis)	Topical JAK inhibitor; reduces itch-associated cytokine signalling

Research stage: Emerging. Evidence strength: Moderate. Preclinical mechanisms well-established; early clinical data for anti-itch agents, though most are not yet specifically approved for psoriatic itch.

18.2 Pain in Psoriasis and Psoriatic Arthritis

Pain in psoriasis extends beyond the joint involvement of PsA (Section 15). Cutaneous pain (burning, stinging, and soreness of psoriatic plaques) is reported by 42% of patients and is distinct from itch, though both share some neural pathways.

A 2025 study of 114 psoriatic arthritis patients systematically characterised pain mechanisms and found (Akdeniz et al., 2025):

• Central sensitisation (amplified pain processing in the spinal cord and brain) was present in 43% of patients
• Neuropathic pain (pain from nerve damage or dysfunction) was present in 23.5%
• Fibromyalgia (widespread pain with central sensitisation) was diagnosed in 25.5%

Pain mechanisms in psoriasis follow a progression:

1. Peripheral nociception: Inflammatory mediators (TNF-α, IL-17, IL-1β, prostaglandins) directly activate nociceptors (pain-sensing nerve endings) in the skin via TRPV1 and TRPA1 channels. This produces the burning and stinging sensation of active plaques.

2. Peripheral sensitisation: Prolonged inflammation lowers the activation threshold of nociceptors through phosphorylation of TRPV1 by protein kinase C (PKC), protein kinase A (PKA), and calcium/calmodulin-dependent kinase II (CaMKII). Stimuli that would normally be painless (light touch, warm water) become painful. This phenomenon is called allodynia (Puig et al., 2024).

3. Central sensitisation: Persistent nociceptive input from the periphery causes maladaptive changes in spinal cord dorsal horn neurons, including increased excitability and expansion of receptive fields. This amplifies pain perception beyond the original stimulus and beyond the original body region, which explains why some patients experience widespread pain.

4. Peripheral polyneuropathy: Psoriasis and PsA are associated with increased risk of peripheral polyneuropathy, meaning damage to the small nerve fibres that detect temperature and pain. This may contribute to the persistent burning and tingling sensations patients report.

Clinical implications: Pain in psoriasis is often undertreated because clinicians attribute it solely to joint disease (and therefore consider it rheumatology’s domain) or dismiss it as secondary to itch. Recognising the central sensitisation component matters because it responds poorly to conventional analgesics and anti-inflammatory biologics. It may require targeted approaches such as duloxetine, pregabalin, or cognitive behavioural therapy for chronic pain.

Research stage: Emerging. Evidence strength: Moderate. Cross-sectional studies with mechanistic characterisation; pain phenotyping studies now being conducted.

18.3 Current Limitations and Future Directions

Current biologic therapies, while effective at clearing skin plaques and reducing joint inflammation, have limited impact on neurological symptoms. Patients who achieve PASI 90 or PASI 100 may still report residual itch, pain, and burning. There are three likely reasons:

1. Biologics target immune pathways but not neural pathways: IL-17 and IL-23 blockade reduces immune-mediated inflammation but doesn’t directly modulate sensory nerve sensitisation or neuropeptide release.
2. Structural nerve changes persist: The hyperinnervation of psoriatic skin (increased nerve fibre density, see Section 28.8) may take longer to resolve than epidermal thickening, or may not resolve at all after chronic disease.
3. Central sensitisation is self-sustaining: Once established, central pain amplification can persist independently of the original peripheral stimulus.

This represents a significant unmet therapeutic need. Future approaches may include:

• Anti-itch biologics (nemolizumab, asivatrep) used as adjuncts to standard psoriasis biologics
• Topical neuromodulators targeting TRPV1 or NK1R
• Combination strategies addressing both immune and neural components simultaneously
• Neuromodulation techniques (transcutaneous electrical nerve stimulation, acupuncture) as adjunctive therapies for chronic pain

Research stage: Experimental. Evidence strength: Low. This section describes an unmet need with early-pipeline approaches; no dedicated trials of anti-itch/anti-pain agents specifically in psoriasis have completed Phase 3.