名媛直播

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease."

Recent advances in the treatment of chronic urticaria have dramatically improved symptom control. However, standard doses of second-generation, histamine type 1 (H1)-receptor antihistamines leave at least , 32% of whom remain symptomatic after dose increases and the addition of omalizumab (Xolair).

The burden of chronic urticaria for patients and society is substantial, and current treatment options are still limited, noted Pavel Kolkhir, MD, of the IM Sechenov First Moscow State Medical University in Russia, and co-authors in a . "Novel targeted treatments are needed."

This mast cell-mediated skin disease, characterized by the sudden appearance of itchy wheals, angioedema, or both, is defined by a duration of 6 weeks or longer. The two main subtypes -- chronic spontaneous urticaria (CSU; 80% of cases) and chronic inducible urticaria (CinDU) -- affect up to 1% of the world's population and can have a big negative impact on quality of life. Although about 50% of patients with CSU have spontaneous remission within 5 years, many require long-term treatment.

"I would say we're kind of behind the curve in terms in developing treatments for urticaria," Alison Ehrlich, MD, of Foxhall Dermatology and Research Center in Washington, D.C., told 名媛直播. "When you look at what's been approved, there's a dearth of clinical tools against what's available for the treatment of psoriasis and atopic dermatitis."

Therapies for chronic urticaria should address the underlying mechanism of disease and the signals or biomarkers that drive it, said Torsten Zuberbier, MD, PhD, of Charité–Universitätsmedizin Berlin in Germany, and colleagues, writing in a 2024 . "Treatments that prevent, delay, or slow the progression of chronic urticaria and induce disease remission are needed. Such treatments should lead to step-down therapy, long-term chronic urticaria remission, or cure after drug withdrawal."

The for the management of urticaria recommends a step-up approach, with first-line H1-antihistamines and dose increases of up to four times the standard dose. When 2-4 weeks of antihistamine therapy doesn't achieve adequate symptom control, omalizumab, the recombinant humanized immunoglobulin (Ig) G1k monoclonal antibody against IgE, can be added as second-line therapy. The 300 mg standard dose, delivered by subcutaneous injection, can be increased to a maximum of 600 mg.

A systematic of the effectiveness of omalizumab in daily clinical practice highlighted data for its high degree of effectiveness and positive safety profile in daily clinical practice. "It's certainly a good therapy," Jonathan I. Silverberg, MD, PhD, MPH, director of clinical research at George Washington University School of Medicine and Health Sciences in Washington, D.C., told 名媛直播.

Still, he noted, about 20% of his patients are omalizumab-refractory, and there is also a "theoretical concern about anaphylaxis."

In addition, symptoms may return when treatment with H1-antihistamines and/or omalizumab ends. "Patients come off and go back to square one," Silverberg said. "So the question is where do you go after that? We turn to things like cyclosporine, although we generally try not to."

In patients with refractory symptoms after 6 months of omalizumab, the guideline recommends adding cyclosporine to an H1-antihistamine until complete response is achieved. Cyclosporine controls CSU symptoms quickly, but more than 50% of patients have dose-dependent such as nephrotoxicity and hypertension, so monitoring is essential.

"We need safer and more effective oral options for second- and third-line treatment," Silverberg said.

Novel therapies such as Bruton's tyrosine kinase (BTK) inhibitors, anti-cytokine therapies, and mast cell depletion are promising for chronic urticaria. Currently, there are 52 drugs in development for chronic urticaria, according to GlobalData, a data analysis firm headquartered in London.

Even so, experts warn that many of these drugs are not even close to being ready for prime time. "Overall, more studies are needed to assess the efficacy and safety of these emerging drugs," said Gil Yosipovitch, MD, of the University of Miami Miller School of Medicine in Coral Gables, Florida, and co-authors in a 2023 .

Most new therapies address antihistamine-refractory and omalizumab-refractory disease, supported by new data on the impact of CSU endotypes on treatment. A of biomarkers for type I and type IIb autoimmune CSU endotypes, for instance, revealed that the co-existence of autoimmune and autoallergic mechanisms was a driver of response to omalizumab compared with the presence of a single class of autoantibody.

Therapies that target endotype-specific mechanisms may be most effective, and could outperform standard therapies, said Zuberbier and co-authors. In the meantime, they advised clinicians to select optimal treatment for individual patients based on the presence of type 2 co-morbidities and evidence of type 2 cytokine skewing and other biomarkers, such as total IgE.

There are also several omalizumab biosimilars under investigation for CSU patients with IgE antibodies to allergens or auto-allergens, as well as those with IgE-mediated co-morbidities. Among these:

• : In May 2024, this became the first omalizumab biosimilar approved in Europe, for use in omalizumab-refractory CSU, allergic asthma, and chronic rhinosinusitis with nasal polyps.

• UB-221: In a phase I study, the addition of this IgE neutralizing antibody to antihistamine therapy relieved symptoms in patients with CSU with no adverse events.

• GBR-310: Data analysis is underway following completion of a phase I biosimilarity study in healthy control individuals.

• : A randomized phase III study is underway to compare the efficacy of this IgE inhibitor against that of omalizumab in patients with antihistamine-refractory CSU.

Of all the new therapies, two in particular are likely to be approved for antihistamine-unresponsive chronic urticaria within the next 1-2 years, Zuberbier and colleagues predicted. The first is dupilumab (Dupixent), approved by the FDA for use in atopic dermatitis in 2017 and asthma in 2018. In the phase III , dupilumab improved symptom control compared with placebo in antihistamine-resistant CSU (CUPID A), but not in omalizumab-refractory or -intolerant CSU (CUPID B).

Experts also predict that dupilumab, which inhibits interleukin (IL)-4 and IL-13 signaling, could become an alternative treatment to omalizumab as second-line therapy.

Most physicians treating refractory chronic urticaria are already using dupilumab off-label, said Silverberg. "I think that overall, it's encouraging to have another therapy coming soon for this disorder."

The other strong contender for early approval in antihistamine-refractory chronic urticaria is remibrutinib, a next-generation, selective, reversible, oral BTK inhibitor. Although severe adverse events were reported with early BTK inhibitors, this potent small molecule, which inhibits IgE-mediated response, appears to be safer and to work in both antibody-dependent and antibody-independent chronic urticaria.

In the phase III , remibrutinib rapidly improved symptoms compared with placebo in patients with antihistamine-resistant CSU and had a favorable safety profile, including balanced liver function, for up to 52 weeks. The BTK inhibitor fenebrutinib had encouraging results in a randomized phase II I of antihistamine-refractory CSU.

"Remibrutinib has the potential to offer patients and physicians a well-tolerated oral treatment that provides early and lasting efficacy," said Martin Metz, MD, PhD, of Charité–Universitätsmedizin Berlin, in a from Novartis.

Other anti-cytokine therapies under investigation could be candidates for off-label use in treatment-refractory chronic urticaria, Zuberbier and co-authors predicted. These include:

• IL5-blocking agents such as mepolizumab (Nucala), reslizumab (Cinqair), and benralizumab (Fasenra)

• Secukinumab (Cosentyx), an IL-17 blocker

• UB-221, an IL-23 blocker

Notably, mast cell depletion with anti-tyrosine kinase receptor KIT therapy might be helpful for chronic urticaria, regardless of the underlying disease mechanism. A phase I randomized controlled in 35 patients with antihistamine-resistant CSU showed that intravenous barzolvolimab, a monoclonal anti-KIT antibody, reduced symptoms within 1 week. Transient adverse events were mild to moderate and included hair color and taste change.

Briquilimab, another anti-KIT mAb, is being studied in adults with omalizumab-intolerant or omalizumab-refractory CSU.

"Barzolvolimab and other anti-KIT therapies represent a novel approach for treatment of chronic urticaria that has the potential to help all patients with chronic urticaria, irrespective of endotype," said Zuberbier and co-authors. "The consequence of long-term KIT inhibition or suppression of mast cell number at different sites should be further investigated."

In another , Metz and colleagues said that mast cell silencing has even more potential than mast cell depletion because of greater selectivity and less toxicity. Other mast cell silencers in development include AK006, which is directed against Siglec-6, and LY3454738, directed against CD200R.

"It's a very exciting time in the field, and I think there will be a lot of change as more therapies come to market," Jenny Murase, MD, of the University of California, San Francisco and director of Medical Dermatology Consultative Services and Patch Testing for the Palo Alto Foundation Medical Group, told 名媛直播. "Medicines like Xolair and Dupixent are very safe to use in children and elderly patients, and it's likely that once registry data become available, we'll be able to show that they're also very safe to use in pregnancy."

Read previous installments in this series:

Part 1: Urticaria/Hives: The Search Continues for Causes

Part 2: Keys to Diagnosis of Urticaria

Part 3: Chronic Spontaneous Urticaria and Autoimmunity

Part 4: Case Study: Terrible Recurrent Itchy Wheals All Over This Woman's Body

Part 5: Managing Comorbidities in Chronic Urticaria

Part 6: What's New in the Treatment of Chronic Urticaria?

Part 7: Special Considerations in Treating Urticaria in Pregnant or Lactating Patients

Part 8: Case Study: Sudden Urticaria After a Stroke

Part 9: Managing Urticaria in Children and Elderly Patients

Part 10: Clues to Improving the Quality of Life of Patients with Chronic Urticaria

Part 11: Defining Treatment Success in Chronic Spontaneous Urticaria