Two seminal RCTs conducted by Joly and colleagues with a total of 653 patients confirmed the efficacy and safety of superpotent topical corticosteroids in controlling moderate and severe BP, in addition to improving survival. Joly et al. in 2002 showed that topical clobetasol propionate (0.05%, 40 g/day) cream was significantly superior to oral prednisone (1 mg/kg/day) for extensive disease (more than ten new blisters per day) in terms of overall survival at 1 year (76% vs 58%; p = 0.02) [17]. Topical clobetasol propionate cream was applied over the whole body (excluding the face) twice daily until disease control was achieved for 15 days, after which the dose was reduced by 15% every 3 weeks and ceased after 12 months. The topical regimen also had improved rates of disease control at 3 weeks (99% vs 91%; p = 0.02), reduced severe side effects (29% vs 54%; p = 0.006) and a shorter duration of hospitalisation (mean 17 vs 25 days; p = 0.002) compared with oral prednisone. In patients with moderate disease (fewer than ten new blisters per day), no significant differences were found between clobetasol propionate cream (0.05%, 40 g/day) and oral prednisone (0.5 mg/kg/day) regarding overall survival or adverse effects, with excellent disease control in both groups (100% vs 95%, respectively). Importantly, this study had good methodology in terms of adequate power and randomisation. A limitation which may have introduced bias was the non-blinded nature of the study, which potentially could have influenced assessments of disease control, but is likely to have had little impact on the primary endpoint of overall survival [21].

The same group, in 2009, demonstrated the benefits of a milder regimen of clobetasol propionate cream (0.05%, 10–30 g/day based on disease severity and weight) with a shorter duration of treatment (4 months), compared to the standard regimen of 40 g/day tapered over 12 months [22]. The milder regimen, which allowed a reduction in the cumulative dose of corticosteroids of 71%, was efficacious and non-inferior to the standard regimen in terms of disease control (100% vs 98%) for both moderate and severe disease. Significantly, after adjusting for age and functional status, patients with moderate BP treated with the mild regimen had a twofold decrease in mortality and life-threatening adverse effects (such as sepsis and cardiovascular disorders) during the first year of treatment compared with those on the standard regimen (hazard ratio 0.54, 95% confidence interval 0.30–0.97; p = 0.039). This may offset the slightly higher rate of relapse observed in the mild compared with the standard regimen group (43% vs 35%). The study additionally found a reduced basal cortisol response during treatment, supporting the hypothesis that the efficacy of superpotent topical corticosteroids could in part be due to systemic effects. A recent longitudinal study in 100 BP patients potentially supports the systemic role of topical corticosteroids in inducing immune suppression and inhibiting autoantibody synthesis [23]. Treatment with superpotent topical corticosteroids induced a marked decrease within 60 days in serum levels of anti-BP180 and to a lesser extent anti-BP230, which corresponded with clinical improvement. Given that the RCT in 2002 found topical corticosteroids had fewer side effects but greater efficacy than prednisone, it is possible that systemic steroid levels due to percutaneous absorption are low but have a sustained action [17, 22].

The studies above contribute strong evidence of the efficacy and safety of superpotent topical corticosteroids for BP, which is reflected in clinical practice guidelines. Twice-daily whole-body application (excluding the face) of clobetasol propionate 0.05% cream or ointment (10–40 g/day) is recommended by a European consensus as the first-line treatment for both mild and generalised BP [24]. Treatment should begin tapering 15 days after disease control, which has standard definitions according to an international panel of experts (see Murrell et al. for details [25]), with cessation of treatment after 4–12 months. For localised disease, treatment of lesional skin only is recommended, although this regimen has not been validated in controlled studies [24].

The implementation of the above recommendations is potentially limited by practical factors, which are important to consider when choosing treatment. Disadvantages of topical corticosteroid treatment include difficult application in bedridden patients, poor compliance and higher cost (up to 110 times the price of prednisone) [13, 16, 26]. In these cases, systemic steroids are recommended as first-line therapy instead, despite their higher rates of adverse events [16].

Adjuvant therapy with other treatments, for example, with steroid-sparing agents, is recommended for consideration only in patients who are intolerant or resistant to topical corticosteroid treatment [7]. Newer research is investigating the utility of adding adjuvant therapies that are cheap, well-tolerated and also effective in BP to improve the practical use of topical corticosteroids in the future. For example, clobetasol propionate and betamethasone dipropionate have been used to initially induce remission in BP, followed by long-term maintenance with low-dose methotrexate [27, 28].

Internationally, the modes of practice for the management of BP vary, which may be partially explained by the practical considerations discussed above. Some health systems, such as in France and the Netherlands, subsidise the cost of medications and nursing assistance, which may encourage the use of topical corticosteroids in these countries [26]. An international survey found that topical corticosteroid monotherapy was preferred in BP by 52.4% of clinician responders in the Netherlands compared with only 27% in Germany and 14.4% in the UK [29]. A similar survey of dermatologists in the UK found the majority of responders only used topical corticosteroids for localised BP (98%), rather than generalised BP (34%) [30].

Varying international mortality rates of BP may also influence the relative benefits of topical compared with oral corticosteroids between countries. In the USA, which has a high rate of oral corticosteroid use in BP, a study reported a 1-year survival of 89% [31]. This was significantly higher than the 1-year survival rates reported in the literature, including that of 76% and 58% reported in French patients treated with topical and oral steroids, respectively, in Joly et al.’s 2002 study [13, 17, 18, 26]. These differences may be attributed to the different demographics, patient comorbidities and treatment practices (hospital vs outpatient) of BP between countries, highlighting the need to consider individual circumstances before recommending treatment [13, 26].

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are mucocutaneous blistering diseases caused by autoantibodies directed against cellular adhesion molecules, resulting in intra-epidermal blistering. In contrast to BP, high-dose systemic corticosteroids are currently the first-line treatment for pemphigus, although adverse side effects may sometimes limit their use [32, 33]. Potent topical preparations are advocated as monotherapy in selected cases of mild or limited (particularly mucosal) disease or as an adjunct to help reduce doses of systemic therapy [32, 33].

Given the rarity of pemphigus, high-quality evidence from large RCTs is scarce. Support for topical corticosteroid use is largely derived from case reports and expert recommendations [3, 33]. Efficacy however appears limited when superpotent topical corticosteroids are used as monotherapy. For example, Dumas et al. in a small study (three PV patients, four PF patients) found that 10 g/day of clobetasol propionate cream 0.05% applied to lesional skin and mucosal lesions (betamethasone valerate 0.1% was used on the face) failed in three patients (two PV patients, one PF patient), necessitating systemic treatment [34]. Treatment efficacy may be increased in patients who at baseline have negative or low levels of autoantibodies [35].

Oral lesions in pemphigus are particularly difficult to treat and slower to heal than skin lesions, given the continuous trauma inherent in the oral environment [36]. Potent topical corticosteroid preparations can be used as adjuvant therapy to limit the systemic side effects of oral corticosteroids [32, 33]. Topical preparations recommended include soluble betamethasone sodium phosphate mouthwashes (0.5 mg tablet in 10 mL water) used four times a day, hydrocortisone (2.5 mg) lozenges and sprayed asthma inhalers (beclomethasone dipropionate 50–200 ug or budesonide 50–200 ug [32]. For isolated mucosal lesions, triamcinolone acetonide (0.1% in adhesive dental paste) and clobetasol propionate can be used [32, 37]. Intralesional/perilesional triamcinolone injections may be effective for recalcitrant oral lesions [36] and were shown in one study in oropharyngeal PV patients who were treated concomitantly with systemic steroids to reduce the total amount of corticosteroids and the time to remission by 27 days [38].

Mucous membrane pemphigoid (MMP) encompasses a group of inflammatory subepithelial blistering diseases that can affect a variety of mucocutaneous surfaces [39]. Treatment is largely guided by clinical experience and uncontrolled studies, with a paucity of evidence from RCTs demonstrating the efficacy of most interventions in MMP, including topical therapy [40]. Experts recommend consideration of the site and severity of disease to guide treatment. Topical corticosteroids can be used as monotherapy in patients with low-risk disease, defined as disease limited to the oral cavity, or oral mucosa and skin, given these sites are less likely to scar [39, 41]. In severe disease characterised by other mucosal involvement (ocular, pharyngeal, oesophageal and laryngeal mucosae) or in acute exacerbations, systemic corticosteroids are still recommended as the first-line treatment [39, 42, 43].

A variety of moderate-to-high potency topical corticosteroid regimens have been recommended for oral disease. These include clobetasol propionate and betamethasone valerate gels and ointments, which are easy to apply to the mucosa, and dexamethasone mouthwashes (5 mL of 100 g/mL in a 5 min swish-and-spit regimen) used two to four times per day [3, 39–41]. Adherence of medication to the mucosa can be enhanced by drying the mucosa with soft tissue paper before each application, compounding with Orabase [44] and having one application directly before bed, as oral secretions are reduced during sleep [39]. Oral insertable vinyl prosthetic devices made by dentists can also facilitate application and provide some occlusion, which can increase potency of the corticosteroids [37, 39, 41].

Topical corticosteroids may also be beneficial for skin lesions, and steroid sprays and inhalers may be used in nasal, pharyngeal and oesophageal disease [43]. Topical regimens have limited efficacy in controlling ocular disease and should be initiated in consultation with an ophthalmologist [43]. Intralesional triamcinolone acetonide injections every 2–4 weeks have been used for recalcitrant lesions of both the skin and mucosa; however, its use is potentially limited by the lack of long-term benefit and undesirable side effects, such as cataract formation when used near ocular surfaces [39, 41, 43].

Pemphigoid gestationis (PG) is an autoimmune blistering disease of pregnancy characterised by autoantibodies against BP180 in the dermal-epidermal junction of the skin [45]. As in other AIBD, evidence is limited on corticosteroid use in the disease, particularly as pregnant patients are often excluded from interventional studies.

Systemic therapy is the mainstay of management, although small case studies and retrospective reviews support the use of potent topical corticosteroids in localised PG and mild disease, including those with early urticarial lesions or premenstrual flares [45, 46]. In these studies, clobetasol propionate 0.05% or betamethasone dipropionate 0.05% was applied twice daily. Topical corticosteroid use in pregnancy is safe, with a Cochrane review finding no significant association with congenital abnormalities, preterm delivery or stillbirth [47]. The review did link potent topical corticosteroid use with low birth weight, although the risk may only increase significantly when high doses are used [47–49] or when the amount of potent topical corticosteroid exceeds 300 g [50].