Emerging Biomarkers and Therapeutic Strategies for Refractory Bullous Pemphigoid

Abstract

Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disorder in the elderly. Systemic and topical use of glucocorticoids and immunosuppressants has been shown to be effective in most patients. However, refractory BP patients are challenged to clinicians with severe clinical symptoms, resistance to treatment, and high relapse rate. How to predict and assess the refractory and severity of bullous pemphigoid is the key issue in clinical practice, and the urgent need for precision medicine in refractory patients is driving the search for biomarkers and biologics. Recently, some biomarkers, such as the level of specific autoantibodies and released cytokines, have been proposed as the potential parameters to reflect the disease severity and predict the treatment response and relapse of refractory BP. Moreover, new biologics targeting pathogenic antibodies, complement, Th2 axis, eosinophils, and Th17 axis have shown potent efficacy on refractory BP. Here, we review the literature and give an overview of emerging biomarkers and therapeutic strategies for refractory bullous pemphigoid to improve the prognosis of the patient.

Keywords: biologics; biomarkers; bullous pemphigoid; prognosis; refractory; relapse; severity.

Figure 1

The main pathogenic mechanism of blister formation in patients with BP: Autoimmune abnormalities such as dysfunction of Th cells and Treg cells lead to the production of anti-BP180 autoantibodies, among which BP180IgG and IgE are the main pathogenic antibodies for blister formation. (1) Mechanical damage: Both BP180IgG and IgE could bind to the NC16A domain of BP180, resulting in BP180 internalization, thus decreasing the adhesion; (2) Inflammatory injury: BP180IgG and IgE could also activate keratinocytes to release IL-8 and other cytokines by binding to BP180. Moreover, BP180IgG and IgE also activate mast cells in a complement-dependent or independent way to release cytokines and mMCP-4. These above cytokines and mMCP-4 recruit and activate inflammatory cells dominated by eosinophils and neutrophils to magnify the inflammatory response of skin lesions and cause tissue damage; (3) Specific pathways of mast cell activation: BP180IgG and IgE directly activate mast cells by binding to FcγR or FcϵR of mast cells. BP180IgG binding BP180 also activate the complement cascade pathway to produce C5a, which binds to the C5aR of mast cells and indirectly causes mast cell activation.