A Review of the Immunologic Pathways Involved in Bullous Pemphigoid and Novel Therapeutic Targets

Abstract

Bullous pemphigoid (BP) is a rare, chronic antibody-mediated autoimmune blistering disease primarily affecting the elderly, with an age of onset over 60. Current treatment options are limited and involve the use of corticosteroids and immunosuppressants, but their long-term use is associated with significant morbidity and mortality. In Japan, human intravenous immunoglobin is approved for the treatment of corticosteroid-refractory BP. However, no treatment option is approved by the Food and Drug Administration for the management of BP. Therefore, developing effective therapies free of debilitating side effects is imperative. In this review, we summarize the main immunologic pathways involved in the pathogenesis of BP, with an emphasis on the role of eosinophils, immunoglobulins, cytokines such as the interleukin (IL)-4 and IL-5, and complements. We further discuss the latest advances with novel therapeutic targets tested for the management of BP. Ongoing efforts are needed to run well-designed controlled trials and test the efficacy and safety of investigational drugs while providing much-needed access to these medications for refractory patients who will not otherwise be able to afford them as off-label prescriptions.

Intravenous immunoglobulins in infantile dyshidrosiform bullous pemphigoid refractory to steroids and dapsone

“…3,5 Dapsone is the mostly used steroid sparing agent (70%), effectively inhibiting neutrophilic chemotaxis and activity, and being well tolerated. 3,6 Occasionally, IBP may be refractory to systemic corticosteroids and dapsone, as in the present case: IVIGs (2 g/kg/4w) may be of aid F I G U R E 1 Clinical presentation of dyshidrosiform bullous pemphigoid in a 1-month-old boy: tense hemorrhagic bullae, partially ruptured and forming erosions and crusts, on the patient's foot in these circumstances, rapidly and safely leading to clinical improvement. 2,3 In literature cases of IBP treated with IVIGs are anecdotal, reporting variable dosages, (200-1000 mg/kg/day), number (1-7), duration (1-5 days) of infusion-courses and intervals between courses (2-5 weeks).…”

“… 3 , 5 Dapsone is the mostly used steroid sparing agent (70%), effectively inhibiting neutrophilic chemotaxis and activity, and being well tolerated. 3 , 6 …”

Bullous Pemphygoid and Novel Therapeutic Approaches

“…Currently, there is an ongoing phase 2/3 randomized double-blind placebo-controlled trial for dupilumab administration in BP (NCT04206553) [ 37 ].…”

Successful pharmacological intervention at different levels of the complement system in an in vitro complement fixation model for bullous pemphigoid

“…10 Therefore, selective inhibition of C5a-C5aR1 axis, for example by avacopan or avdoralimab, might be more interesting thereby leaving the potentially beneficial C5a-C5aR2 interaction intact. 32 In fact, avdoralimab is currently evaluated in a phase 2 clinical trial (NCT04563923) with an enrolment target of 40 BP patients. Future studies should be aimed to investigate the efficacy of both drugs in inhibiting complement activation in BP.…”