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Inflammation, Histamine, and Itching in MPN: Why the Symptom Is More Than Skin-Deep

Itching—known medically as pruritus—is one of the most common and burdensome symptoms in myeloproliferative neoplasms (MPNs). For many patients, the itching is not mild or occasional, but burning, stinging, tingling, or electric, often triggered by water, heat, exercise, temperature changes, or even stress. In polycythemia vera (PV), the phenomenon is so characteristic that it has its own name: aquagenic pruritus.

But why does a bone marrow cancer cause such intense itching? The answer lies in a complex interplay between inflammation, mast cells, histamine release, microvascular dysfunction, and JAK-STAT signaling—all hallmark features of MPN biology.

Why Itching Happens in MPN

Most itch starts in the skin, but MPN-related itching starts deeper—in the immune system and circulatory system, and only then reaches the skin.

Several mechanisms have been implicated:

1. Chronic Inflammation as a Disease Driver

MPNs are chronic inflammatory cancers. Malignant stem cells release cytokines such as:

  • IL-6

  • IL-31

  • TNF-α

  • IFN-γ

These cytokines sensitize peripheral nerves, making them more likely to fire itch signals in response to minor stimuli. Elevated cytokine levels have been correlated with fatigue, night sweats, bone pain, and itching in multiple cohorts.

2. JAK-STAT Signaling and Neural Sensitivity

MPN driver mutations—especially JAK2 V617F—result in persistent JAK-STAT pathway activation. This doesn’t just affect blood production; it also influences:

  • mast cell activation

  • cytokine production

  • neuropathic itch pathways

This is one reason JAK inhibitors reduce itching even when they don’t completely normalize blood counts.

3. Histamine and Mast Cell Activation

MPN patients have been shown to exhibit increased mast cell activity in the skin and microvasculature. Mast cells release:

  • histamine

  • tryptase

  • leukotrienes

Histamine binds to H1 and H4 receptors, triggering nerve signals that the brain perceives as itch. Mast cell mediator levels are often elevated in PV and MF, and symptoms can overlap with mast cell activation syndromes.

4. Microvascular and Nitric Oxide Dysfunction

Aquagenic itching in PV is strongly linked to:

  • microvascular constriction

  • altered nitric oxide signaling

  • erythrocytosis-related blood viscosity changes

This helps explain why itching can worsen:

  • after showers

  • after exercise

  • in warmth

  • at night

  • during stress

These are all contexts where blood flow and temperature shift rapidly.

Why Water Triggers Aquagenic Itch

Water does not “cause” the itch directly. Instead, water triggers:

  • rapid temperature change

  • microvascular dilation

  • mast cell degranulation

  • nerve stimulation

Interestingly, even cold showers can trigger pruritus in some PV patients, confirming that the mechanism is not simply heat.

How This Symptom Impacts Patients

MPN-associated itching can significantly impair quality of life. Patients frequently report:

  • sleep disruption

  • anxiety about bathing

  • avoidance of swimming or exercise

  • social withdrawal

  • dermatologic self-injury from scratching

In multiple surveys, itching ranks among the top three most burdensome MPN symptoms, often reported alongside fatigue and splenic discomfort.

Why Antihistamines Often Don’t Fully Work

Standard antihistamines (H1 blockers) can offer partial relief, but many PV and MF patients find they are not enough. This is because itch is not solely histamine-dependent—cytokines like IL-31 are potent pruritogens independent of histamine.

This is why therapies that target JAK-STAT, rather than histamine receptors alone, may provide more meaningful relief.

Treatments That May Help

Treatment depends on the severity of symptoms and the type of MPN.

1. JAK Inhibitors

JAK inhibitors such as ruxolitinib and fedratinib have shown significant reduction in pruritus scores across multiple trials—including in patients who previously failed antihistamines.

2. Phlebotomy (in PV)

Phlebotomy reduces hematocrit, lowers blood viscosity, and can improve aquagenic itch in some patients.

3. Cytoreductive and Targeted Therapy

Agents such as hydroxyurea, interferon-α, or ropeginterferon alfa-2b may also reduce pruritus by decreasing malignant clone activity.

4. Adjunctive Approaches

Some patients report benefit from:

  • selective serotonin reuptake inhibitors (SSRIs)

  • UV-B phototherapy

  • H1 + H2 antagonist combinations

  • leukotriene inhibitors

  • mast-cell–stabilizing supplements (e.g., quercetin)

More research is needed to establish standardized protocols.

When Itching Signals Disease Progression

Increasing pruritus may correlate with:

  • worsening inflammation

  • inadequate hematologic control

  • splenomegaly

  • elevated cytokines

For this reason, itching should be documented and monitored—not dismissed as a minor dermatologic issue.

Conclusion

MPN-related itching is a hallmark symptom rooted in inflammation, histamine biology, mast cell activation, and JAK-STAT signaling, not simply dry skin or benign allergies. Understanding the mechanisms behind it not only validates patient experience, but also points to more effective treatment options.

Scientific Sources

 

  1. Luque LFM, et al.
    Key Role of Inflammation in Myeloproliferative Neoplasms: Lessons for Pathogenesis and Treatment.
    This review discusses pruritus, cytokine release, mast cell degranulation, prostaglandins, leukotrienes, histamine, and inflammatory contributions to MPN symptoms, especially itching.

  2. Kiladjian JJ, et al. (2015)
    Ruxolitinib for the Treatment of Patients with Polycythemia Vera: Symptom and Pruritus Outcomes.
    In this clinical analysis, ruxolitinib treatment is associated with significant reductions in pruritus and other symptoms by Week 4, sustained long-term.

  3. Le Gall-Ianotto C., et al. (2025)
    Ruxolitinib and Hydroxycarbamide Are the Most Efficient Drugs to Reduce Aquagenic Pruritus Intensity in a Real-World Cohort of Patients With Myeloproliferative Neoplasms.
    This observational cohort demonstrates improvement in aquagenic pruritus intensity with ruxolitinib and cytoreductive therapy.

  4. Szepietowski JC, et al. (2018)
    Aquagenic Pruritus in Polycythemia Vera.
    A clinical characterization showing aquagenic pruritus is a common, burdensome symptom in PV, often preceding diagnosis and affecting life quality.

  5. Hashimoto T. (2019)
    Itching as a Systemic Disease: Mast Cells, Histamine, and Pruritic Cytokines.
    A broader immunology review describing mast cells, histamine, leukotrienes, and IL-31 as pruritogenic mediators relevant to systemic pruritus.

  6. Cuthbert D. (2019)
    Polycythemia Vera-Associated Complications: Mast Cells, Histamine, and Pruritogenesis.
    A comprehensive analysis of mast cell involvement in MPN itching and release of pruritogenetic mediators in PV patients.

  7. Mesa RA, et al. (2016)
    Changes in Quality of Life and Disease-Related Symptoms with Ruxolitinib in Polycythemia Vera Patients Resistant/Intolerant to Hydroxyurea.
    This patient-reported outcomes article shows ruxolitinib improves symptom burden, including itching, in many PV patients.

  8. Scarpellini M., Le Gall-Ianotto C., et al. (2019)
    Aquagenic Pruritus in Essential Thrombocythemia.
    Describes water-triggered itching occurring in ET similar to PV, expanding the pruritus phenotype across MPN subtypes.