Insights Into Chronic Itch From Shawn Kwatra, M.D.

Shawn Kwatra, M.D., professor and chair of dermatology at the University of Maryland School of Medicine, recently spoke with Managed Healthcare Executive about new discoveries in chronic itch, how treatment options are improving, and the challenges patients face in getting access to the right therapies.

Below is a Q&A with Kwatra that’s been edited for length and clarity.

Q: What are the two or three most significant advances in our understanding of chronic pruritus and its treatment over the past few years?

A: First of all, I would say that you can disrupt the itch-scratch cycle at a number of different avenues. So, we have now had the development of multiple biologic and small molecule inhibitors that are able to rapidly reduce itch. These inhibitors started with Dupixent (dupilumab), an IL-4 receptor alpha inhibitor approved in 2017, and have since expanded to IL-13 inhibitors like Adbry (tralokinumab) and Ebglyss (lebrikizumab), which more potently target IL-13. More recently, we have Nemluvio (nemolizumab), which targets IL-31, and JAK1 inhibitors, which are also important in mediating itch.

Shawn Kwatra, M.D.

What we know is that itch pathogenesis traverses both the immune system and the neural system. These treatments are targeted and safer than traditional systemic immunosuppressants. They reduce immune hyper-responsiveness and inflammation but also regulate neural activity. Nerves originating in the skin—including thinly myelinated A-delta fibers and unmyelinated C fibers—connect to the dorsal root ganglia, spinal cord, and brain, with receptors found both in the skin and dorsal root ganglia. These new treatments can block inflammation and the transmission of itch signals. So, that's been really just a tremendous breakthrough for our understanding of itch pathophysiology.

I think the second biggest break that we're understanding is that itch can be very heterogeneous. Classically, the most difficult form of itch is itch without a rash. What we know now is that an itch without a rash can actually be a result of the immune system being revved up. Our group recently published on blood biomarkers—TARC, IgE, eosinophils, and type 2 inflammatory cytokines—that are elevated in certain patients. Others may have more of a generalized neuropathic itch. We’re at the early stages of identifying biomarkers and endotypes that display in different forms.

We also know that not all itches are created equal and how people scratch can be different. You can scratch with a certain amplitude that creates a pruritic nodule, or you can scratch in a certain way that can have normal-appearing skin. Our group actually did the first genetic study of a condition called prurigo nodularis, showing genetic predispositions to developing lesions or generalized itch. So now we’re beginning to better understand and categorize the different phenotypes of itch. I think we're better understanding the different phenotypes of itch now as well.

Q: Is the traditional separation of inflammatory and neuropathic itch still valid, or is that distinction becoming less useful?

A: I think that many forms of itch involve both immune and neural involvement. In the bloodstream and in the skin, many of these cytokines, such as IL-4, IL-13, IL-31, IL-22 and JAKs are important in the bloodstream and the skin—but those same cytokine receptors are also found on nerve endings. So we’re learning a lot about the neuroimmune landscape of chronic itch.

But we’re also finding that direct damage to the somatosensory nervous system can cause a different form of neuropathic itch that doesn’t respond to immune-targeting cytokine therapies. So while neuroimmune modulation is important, we also have to recognize the role of direct nerve injury in certain cases.

Q: Are insurers limiting access to newer chronic itch treatments through prior authorization and utilization review?

A: First, it’s crucial to understand how profoundly chronic itch can impact quality of life. We recently conducted a study comparing chronic itch with other systemic conditions, and the impact was found to be as severe—or even more severe—than conditions like stroke, heart failure, or type 2 diabetes.

We also found that patients with sleep disturbance due to itch had elevated C-reactive protein levels, which suggests an increased inflammatory risk for other serious conditions, including heart attacks. Chronic itch is truly systemic.

This population also tends to be older, with comorbidities like kidney or liver disease, which makes traditional immunosuppressants such as cyclosporine or methotrexate difficult or unsafe to use. Cyclosporine, for example, can raise blood pressure and damage the kidneys. Methotrexate can cause liver damage or anemia.

So, considering the impact on quality of life, the limitations of existing treatments, and the safety profiles of newer drugs, there are many compelling reasons why managed care should be supporting access to these therapies. Patients are suffering, and these treatments can be life-changing.

Q: Are insurance-related access barriers like step therapy making it harder for patients to get appropriate treatments?

A: Sometimes, yes. We often have to include a lot of documentation in our clinical notes—things like body surface area (BSA), EASI scores, and investigator global assessments. Patients may also be required to fail certain treatments before moving forward.

For example, a patient with severe atopic dermatitis may have to try and fail both a medium- and high-potency topical steroid, as well as a non-steroidal treatment like tacrolimus, and then wait four weeks before progressing. That’s four weeks of intense suffering.

It’s frustrating because, from a clinician’s standpoint, if someone has widespread itching, why are we being required to try topical therapies first—or step through older treatments like methotrexate or phototherapy, which often aren’t as effective?

Q: Which parts of the treatment decision tree for itch are most controversial or unsettled?

A: Itch has many different phenotypes—some inflammatory, some not. For conditions with drug development programs, like atopic dermatitis or prurigo nodularis, it’s more straightforward. Chronic spontaneous urticaria and bullous pemphigoid also have options in development.

But there are many other itch disorders without any FDA-approved treatments, even though patients are severely affected. Chief among them is chronic pruritus of unknown origin. Many of these patients have high levels of type 2 inflammation and respond well to biologic therapies—but we can’t get those treatments approved.

The core problem is nomenclature. It’s not practical to require clinical trials for every single itch-related condition when so many are driven by similar underlying mechanisms. This is why we’re having trouble getting appropriate drugs covered.

Q: How do you think the challenges in gaining approval for certain itch treatments can be addressed, especially when trials for every condition aren’t feasible?

A: One of the solutions we’re working on is mapping human itch subtypes to identify where there are similarities between conditions with approved treatments and those without.

Recently, in a patient with erythroderma, we used flow cytometry to pinpoint which cytokines were upregulated and obtained a patent for a related blood test. I believe this kind of biomarker-driven phenotyping is the future of treating inflammatory skin diseases and chronic itch.

Hopefully, regulatory agencies will allow biomarker-based clinical trials, enabling us to match patients to therapies based on their unique phenotype. There’s a lot of diversity within diseases, but also shared biology across them. That’s really the heart of the issue.

Q: Does the Make America Healthy Again (MAHA) perspective, linking chronic disease to food and environment, resonate with your work in dermatology?

A: To be honest, we are starting to learn more about how the environment can modulate itch. The gastrointestinal system, for example—what you eat—can stimulate itch through vagal nerve activation. Our group recently performed gut microbiome testing and found specific fungal species in some chronic itch patients.

The skin microbiome and environmental pollutants may also stimulate nerve fibers and contribute to itch. So yes, I agree that chronic itch can be a systemic condition. Assessing environmental exposures and diet as root causes may lead to novel insights.

We recently published a study on older adults with chronic itch, many of whom had prior immune system exposures—COVID infection, COVID vaccination, PD-1 inhibitors for cancer, or shingles or the shingles vaccine. We need to study these factors longitudinally to identify modifiable environmental triggers. We’re just beginning to understand this area, but I think it offers tremendous opportunity for discovery.