BTK-Inhibition Considered for Dermatologic Conditions

Pedro Mendes-Bastos, MD

An evaluation into Bruton’s tyrosine kinase (BTK), a member of the TEC kinase family, found that the inhibitors could help address the shortcomings of monoclonal antibody treatments for immune-mediated dermatological conditions such as chronic spontaneous urticaria (CSU), pemphigus, and systemic lupus erythematosus.

Investigators led by Pedro Mendes-Bastos, MD, Dermatology Center at Hospital CUF Descobertas, Portugal, also believed that BTK inhibitors could improve understanding of the pathophysiological roles of mast cells, basophils, and B cells in these conditions.

The potential benefits of these inhibitors had been suggested in some autoimmune and allergic conditions including immune-mediated dermatological diseases, though the risk-to-benefit profile of “first generation” BTK inhibitors could not be extrapolated from emerging, non-oncological indications.

Despite this, Descobertas and colleagues reviewed the current understanding of the role of the BTK pathway and consider the potential value of pharmacological inhibition of BTK as a therapeutic strategy.

Chronic Spontaneous Urticaria

Chronic spontaneous urticaria has affected approximately 1% of the worldwide population, with an increasing trend showing over time.

Sleep deprivation, sexual dysfunction, limitations on daily life, and reduced performance at work or school have all been linked to the condition, and a lack of understanding of underlying cause has precluded development of curative treatments.

Regarding licensed treatments, omalizumab has shown a complete hive response rate of 26%, compared with 30-51% with ligelizumab, an anti-IgE.

Investigators noted that novel treatment options with improved effectiveness are warranted. Considering that BTK is involved in both known pathway that result in the degranulation of skin mast-cells, which are the key pathogenic driver of CSU, the rationale for BTK inhibition has remained strong.

Additionally, the antibody production in B cells associated with BTK inhibitors have led to increased potential for efficacy in both auto-allergic and autoimmune CSU.

Pemphigus

Pemphigus is an autoantibody-driven skin disease which can manifest in 3 major forms including pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. Pemphigus vulgaris remains the most common of the 3 forms.

Though rituximab is considered a very effective treatment option, it requires intravenous administration that results in B-cell depletion, which could contribute to higher rates of severe infections.

Currently, targeted approaches such as the use of engineered human cytoxic chimeric autoantigen receptor (CAAR)-T cells to eradicate B cells producing autoantibodies are under clinical investigation.

With BTK playing a prominent role in responses of autoreactive B cells, BTK inhibitors could represent a therapeutic option for pemphigus.

Other Skin Conditions

Though CSU and pemphigus are considered the main focus for the potential of BTK inhibition, investigators believe other chronic inflammatory skin diseases such as hidradenitis suppurativa, systemic lupus erythematosus, and atopic dermatitis could also benefit from the therapeutic approach.

The immunopathogenesis of HS is poorly understood, though plasma cells have been identified as a potential therapeutic target. Additionally, characterization of the inflammatory response in HS using proteomic and transcriptomic approaches revealed enrichment of BTK signaling, which investigators believe support the value of BTK inhibition.

This inhibition therapy has also been considered for the treatment of cutaneous, renal, and articular manifestations of systemic lupus erythematosus, and remains 1 of a myriaf of therapeutic strategies under investigation for the treatment of atopic dermatitis along with Janus kinase inhibitors.

Regarding atopic dermatitis, the triggering of BTK-dependent signaling is a direct result of the production of cytokines such as thymic stromal lymphopoietin, which is brought on by the penetration of antigens through the impaired dermatological barriers.

“The development of treatments for immune-mediated dermatological conditions presents a particular challenge: a successful therapy must be effective but also boast a tolerability profile that is acceptable for the long-term treatment of a chronic condition that affects quality of life but does not significantly reduce life expectancy,” the team wrote. “BTK inhibitors present themselves as promising candidates for this role.”

The study,"Bruton's tyrosine kinase inhibition—an emerging therapeutic strategy in immune-mediated dermatological conditions," was published online in Allergy.