To date, no randomized placebo-controlled clinical trials have been conducted for omalizumab in 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. Keywords: bullous pemphigoid, immunology, therapeutic target, randomized controlled trials 1. Introduction Bullous pemphigoid (BP) is a chronic antibody-mediated autoimmune blistering disease which occurs at an estimated annual incidence of 6C22 newly identified cases per million of the population, and primarily affects the elderly, with an age of onset over 60 [1,2,3,4,5]. Other significant risk factors for BP include a large group of drugs, as well as neurological/psychiatric comorbidities [6]. Drug-induced/associated BP is especially on the rise, with a variety of systemic agents among the common culprits. These include diuretics (e.g., furosemide, bumetanide, spironolactone), analgesics, d-penicillamine, antibiotics (e.g., amoxicillin, ciprofloxacin), psycholeptics (phenothiazine), potassium iodide, captopril, tumor necrosis factor (TNF) inhibitors, and the antidiabetic agents metformin and dipeptidyl peptidase-4 inhibitors (DPP-4is) such as vildagliptin, sildagliptin, saxagliptin, linagliptin, alogliptin [7]. Of note, long latency may suggest that certain BPs are drug-triggered (i.e., they initiate BP immunologically, but removing the drug does not help with controlling the disease). This is in contrast to (R)-MG-132 true drug-induced skin disease, where removing the drug leads to the resolution of the disease [8]. Classic BP is characterized by tense subepidermal bullae, often along with eczematous or urticarial plaques and predominantly affects the trunk and flexural surfaces. However, atypical clinical variants still account for 20% of all patients, including only urticarial plaques or nonspecific skin findings [9]. The BP bullae are commonly (R)-MG-132 preceded by a prodrome of pruritus [10], and this might be the sole BP presentation in select patients. Oral mucosa involvement is seen in up to one-fifth of the cases [11]. Current treatment methods are limited and rely on nonspecific anti-inflammatory and immunosuppressive therapies. The choice of treatment depends on the body surface area (BSA) involvement [6], with super-potent topical corticosteroids (40 g/day tapered over 12 months, or 10C30 g/day tapered over four months), which are (R)-MG-132 equally effective but (R)-MG-132 safer than systemic corticosteroids [12,13,14,15], and therefore recommended as the first-line for management of mild-to-moderate disease (up to 25% of total BSA involvement). Given the challenging practicality of daily ointment tube administration to deliver high doses of steroids [16], immunomodulator or non-immunosuppressant options such as doxycycline with or without niacinamide, represent an alternative option in select cases of localized, noninvasive BP [17]. Doxycycline has been proven to be non-inferior to prednisone for blister control in the short term, and safer in the long-term [17,18]. For severe BP (25C50% of total BSA involvement, or significant discomfort), systemic corticosteroids with a dose of 0.5 mg/kg/day (and up to 0.75 mg/kg/day in select refractory patients) is the treatment of choice [12]. The transition from induction to maintenance therapy typically takes up to four to six weeks of gradually tapered steroid doses. These treatments notably result in debilitating side effects, with significant morbidity/mortality in the elderly patients. The most effective adjuvant agents for refractory cases include mycophenolate mofetil, the combination of tetracycline and niacinamide, azathioprine, methotrexate, dapsone, and biologics such as rituximab, omalizumab, and dupilumab [19,20,21]. First-line combination therapy with rituximab and corticosteroids significantly improves complete remission rates along with reducing the cumulative dose of steroids without Tmem27 increasing the rate of complications [21]. Intravenous immunoglobin (IVIG), mainly comprised of IgG1 and IgG2, provides an alternative, safe and effective treatment for treatment-resistant BP individuals. In Japan, human being intravenous immunoglobin is the authorized treatment for corticosteroid-refractory BP [22]. Rather surprisingly, no treatment is currently authorized by the Food and Drug Administration (FDA) for BP. 2. Immunologic Pathways in BP The pathogenesis of BP entails the combination of a mainly humoral immune response against two well-established self-antigens, as well as some contributions from cellular immunity resulting in the characteristic tense blister formation [23]. The.