Summary: New research shows that an FDA-approved rheumatoid arthritis drug can reduce severe, unexplained chronic itch by blocking immune signals that directly activate nerve cells in the skin.
FDA-approved arthritis drug may work in new ways to fight itch
Chronic itch causes persistent, often debilitating scratching, but its underlying mechanisms have been difficult to pin down. Researchers at Washington University School of Medicine in St. Louis report evidence that immune signaling molecules directly activate sensory neurons in the skin to produce chronic itch, and that blocking a specific neuronal signaling pathway can relieve symptoms in people with chronic idiopathic pruritus—itch with no identifiable cause.
In a small clinical observation tied to laboratory work, five patients with severe chronic idiopathic pruritus experienced major reductions in itch after receiving tofacitinib (Xeljanz), a JAK inhibitor approved to treat rheumatoid arthritis. These patients had not responded to prior anti-inflammatory treatments, yet within a month of starting tofacitinib they reported dramatic symptom relief, including better sleep and reduced scratching. The team published the findings in Cell in September 2017.
Senior investigator Brian S. Kim, MD, co-director of Washington University’s Center for the Study of Itch, emphasizes both the promise and the caution: the results are encouraging but derived from a small number of patients. Larger clinical trials are needed to confirm the effectiveness and safety of targeting neuronal JAK signaling for chronic itch.
The new work helps explain clinical success seen with other therapies such as dupilumab (Dupixent) for atopic dermatitis. The investigators found that drugs like dupilumab and tofacitinib can act directly on nerve cells, interrupting immune-to-nerve communication that produces the sensation of itch, rather than solely suppressing general inflammation.
Chronic itch affects up to 15 percent of the population and is commonly linked to inflammatory skin diseases such as eczema and psoriasis, as well as systemic disorders including kidney failure, liver disease, some cancers, and nerve disorders. Cases without clear inflammatory causes—chronic idiopathic pruritus—are especially difficult to treat because standard anti-inflammatory measures, such as topical steroids, are often ineffective.
Laboratory studies in mice and analyses of human tissue led the team to identify a specific immune molecule, interleukin-4 (IL-4), as a direct activator of sensory neurons. The researchers showed that IL-4 binds to receptors on sensory neurons and increases neuronal responsiveness to multiple pruritogens (itch-inducing agents). Mechanistically, IL-4 activates the intracellular protein JAK1 within neurons, and JAK1 signaling proved to be critical for persistent itch.
To test the neuron-specific role, the team engineered mice whose sensory neurons could not respond to IL-4. Those mice did not scratch in response to stimuli that normally provoke itch, supporting the idea that neuronal IL-4Rα and downstream JAK1 drive chronic itching behavior. These animal results translated into the clinical observation that JAK inhibitors such as tofacitinib can markedly reduce itch in patients whose symptoms previously did not respond to other immunosuppressive therapies.
The combined animal and human data point to JAK1 in neurons as a promising therapeutic target for multiple forms of chronic itch, including chronic idiopathic pruritus. In the small group of patients treated with tofacitinib, average itch severity dropped by nearly 80 percent. Investigators note that the ideal goal is to develop treatments that block neuronal itch signaling without compromising systemic immune function; future studies will examine whether JAK inhibitors can be modified or delivered in ways that achieve that balance.
This study demonstrates an evolutionarily conserved mechanism in which classical immune signaling pathways are co-opted by the sensory nervous system to drive chronic itch. The research highlights type 2 cytokines—particularly IL-4—as direct activators of sensory neurons and identifies neuronal IL-4Rα and JAK1 signaling as essential contributors to persistent itch. Clinical observations in a small set of refractory itch patients showed substantial improvement with JAK inhibitor therapy, supporting the translational potential of targeting neuronal immune signaling.
Funding: Research support came from multiple US National Institutes of Health institutes and centers, including the National Center for Advancing Translational Sciences, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Heart, Lung, and Blood Institute. Additional funding was provided by the American Skin Association, the Doris Duke Charitable Foundation, and a research grant from LEO Pharma.
Publication: The full study, “Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch,” reports both the mechanistic laboratory findings and the preliminary clinical observations that support JAK1 as a therapeutic target for chronic itch.