Version May 2024
INTRODUCTION — Bullous pemphigoid is an autoimmune cutaneous blistering disease characterized by autoantibody deposition at the epithelial basement membrane zone. The disorder most frequently affects older adults and classically presents with generalized, pruritic, urticarial plaques and tense, subepithelial blisters (picture 1A-D).
Topical corticosteroids, systemic corticosteroids, and doxycycline are the mainstays of initial treatment for bullous pemphigoid. Additional immunomodulatory therapies are often added to minimize the adverse effects of chronic corticosteroid therapy or to augment improvement in the disease.
The management of bullous pemphigoid will be reviewed here. The epidemiology, pathogenesis, potential triggers, clinical features, and diagnosis of bullous pemphigoid are discussed separately.
●(See "Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid".)
●(See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)
The management of mucous membrane pemphigoid is also reviewed separately.
●(See "Management of mucous membrane pemphigoid".)
●(See "Ocular cicatricial pemphigoid".)
TREATMENT GOALS — Treatment of bullous pemphigoid is generally recommended as the disease can cause discomfort, is a risk factor for infection, and often negatively affects quality of life [1].
The major goals for the treatment of bullous pemphigoid include:
●Decrease blister formation and pruritus
●Promote healing of blisters and erosions
●Improve quality of life
These goals are fulfilled through a therapeutic regimen that attenuates autoantibody production and antibody-mediated inflammation while minimizing the risk for serious, drug-induced, adverse effects. In addition, careful skin care and referrals to appropriate specialists for mucosal involvement may help to manage and minimize morbidity. (See 'General skin care' below and 'Indications for referral' below.)
PRETREATMENT ASSESSMENT — The pretreatment evaluation should include assessments for:
●The possibility of drug-induced bullous pemphigoid
●Mucosal involvement warranting specialist referral
Identification of drug-induced disease — Drug-induced bullous pemphigoid presents with clinical, histopathologic, and immunopathologic findings consistent with bullous pemphigoid and may develop several months or more than one year after ingestion of the inciting medication [2]. Although drug-induced disease likely accounts for a small proportion of cases of bullous pemphigoid, a wide variety of drugs have been associated with the development of this disease (table 1) [3,4]. Examples of drugs with the strongest associations with bullous pemphigoid include gliptins, programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors, loop diuretics, and penicillins [4,5]. (See "Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Infections and drugs'.)
●Patient evaluation – The evaluation for drug-induced bullous pemphigoid consists of a careful medication history. Examples of findings that may be more strongly associated with drug-induced bullous pemphigoid than classic bullous pemphigoid include younger patient age, the development of bullae on normal-appearing skin, and histopathologic findings of intraepidermal vesicles, necrotic keratinocytes, or thrombus formation [3]. Similar to classic bullous pemphigoid, pruritus and eczematous lesions may precede blistering.
●Drug management – Drugs suspected of inducing bullous pemphigoid should be promptly discontinued whenever feasible. In addition, patients typically require the initiation of medical therapy to suppress cutaneous inflammation and blistering. Similar to classic bullous pemphigoid, topical and systemic corticosteroids are the mainstays of treatment. (See 'Approach to management' below.)
Data from case reports and case series suggest that many patients respond rapidly to medical treatment and cessation of the inciting drug, achieving remission within six weeks, after which treatment can be tapered [3]. However, other patients develop a chronic and persistent course, resembling classic bullous pemphigoid [3]. (See 'Approach to management' below and 'Initial therapy' below.)
Further study is necessary to clarify the impact of the cessation of gliptin therapy. Although the time to achieve disease control and relapse rates did not differ among patients who ceased or continued gliptin therapy in a retrospective study that included 108 patients with gliptin-associated bullous pemphigoid, a retrospective study of 40 patients with gliptin-associated bullous pemphigoid found a higher rate of complete remission after three months among patients who ceased gliptin therapy (65 versus 5 percent) [6,7].
Indications for referral — The management of bullous pemphigoid is a multidisciplinary affair that ideally consists of management by a dermatologist in conjunction with the patient's primary care clinician.
When there is known or suspected mucosal involvement of the ocular, esophageal, pharyngeal, or laryngeal mucosa, referral to appropriate specialists is advised:
●Ophthalmology – Prompt referral is indicated for patients with signs of ocular involvement. Examples of suggestive findings include itching or burning sensations in the eyes or visual changes.
●Gastroenterology – Referral to a gastroenterologist for assessment for esophageal involvement is indicated for patients with dysphagia.
●Otolaryngology – Referral to an otolaryngologist is indicated for patients with signs of laryngeal, pharyngeal, or nasal mucosa involvement. Hoarseness of the voice or difficulty speaking suggest laryngeal involvement. Pharyngeal involvement may present with dysphagia. Symptoms of nasal obstruction may suggest nasal involvement.
APPROACH TO MANAGEMENT
Overview of therapeutic approach — Immunosuppressants and other anti-inflammatory medications are the mainstays of pharmacologic therapy for bullous pemphigoid. Patients may require treatment for up to several years.
Much of the morbidity and mortality related to bullous pemphigoid results from the combined effect of patient comorbidities and adverse effects of treatment, rather than from direct effects of the disease. Therefore, treatment should be conservative, incorporating the minimal amount of medication required to achieve remission and careful consideration of drug toxicity.
Selection of initial treatment — Initial treatment for bullous pemphigoid typically consists of one of the following as the primary mode of therapy:
●High-potency topical corticosteroid (eg, clobetasol propionate)
●Oral corticosteroid (eg, prednisone or prednisolone)
Each of these approaches is appropriate, with efficacy data to support achievement of disease control in a majority of patients. Consideration of feasibility of treatment, risk for adverse effects, relative efficacy, and patient preference influence selection.
Although high-potency topical corticosteroid therapy (twice-daily application of clobetasol propionate) is highly effective for bullous pemphigoid and associated with lower mortality and risk for severe complications compared with oral prednisone (1 mg/kg per day) in patients with extensive bullous pemphigoid [8], challenges with administration limit use of this approach to therapy in some settings. Adherence to topical corticosteroid therapy can be challenging, with treatment success dependent upon the ability of a patient of advanced age or a caregiver to apply a topical corticosteroid to extensive areas of skin daily. The preference or need for an easily administered treatment commonly leads to the selection of an oral corticosteroid or doxycycline for initial therapy. (See 'Initial therapy' below.)
For patients for whom topical corticosteroid monotherapy is not utilized, selection between prednisone and doxycycline often rests upon consideration of tolerance for risk for adverse effects and disease severity. Doxycycline may be less likely to induce rapid remission compared with oral prednisone but has a more favorable side effect profile [9]. (See 'Tetracyclines' below.)
The favorable side effect profile prompts us to select doxycycline, rather than oral prednisone, for the initial treatment of milder presentations of bullous pemphigoid (eg, localized bullous pemphigoid or development of only a few new bullae per day). We typically add use of a topical corticosteroid on affected areas in an attempt to augment the response to doxycycline. Other tetracyclines, such as tetracycline and minocycline, are alternatives to doxycycline. Doxycycline and other tetracyclines are sometimes given in conjunction with nicotinamide (niacinamide), an active form of vitamin B3 with anti-inflammatory properties. (See 'Tetracyclines' below.)
Clinician approaches to extensive disease (eg, widespread skin involvement or development of many new bullae per day) differ. While some experts consider oral prednisone the preferred initial oral treatment for this population, others consider a trial of oral doxycycline a reasonable initial approach given data supporting efficacy in some extensive bullous pemphigoid patients and the drug's favorable side effect profile [9]. Limited data suggest that initial treatment with methotrexate may also be effective as a primary treatment for bullous pemphigoid [10].
Incorporation of corticosteroid-sparing therapy — Due to the chronic nature of bullous pemphigoid and the multiple adverse effects of systemic corticosteroids, corticosteroid-sparing agents (eg, doxycycline, dapsone, methotrexate, mycophenolate, azathioprine) are often added to an oral corticosteroid regimen following achievement of disease control in an attempt to facilitate corticosteroid tapering. Alternatively, given the common delay in onset of effect of corticosteroid-sparing therapies, the corticosteroid-sparing agent and oral corticosteroid are started simultaneously. (See 'Treatment tapering and cessation' below and 'Corticosteroid-sparing therapy' below.)
Immunosuppressive corticosteroid-sparing therapies, such as azathioprine, mycophenolate, and methotrexate, are often reserved for patients who presented with extensive bullous pemphigoid (eg, widespread skin involvement or development of many new bullae per day). The decision to add an immunosuppressant should not be taken lightly given that these drugs may cause serious adverse effects. In some older adults, the risks of adding a corticosteroid-sparing immunosuppressant may exceed those of maintaining low-dose prednisone therapy (eg, 5 mg per day or less). (See 'Corticosteroid-sparing therapy' below.)
Refractory disease — Therapeutic options for bullous pemphigoid refractory to the treatments above include a variety of biologic therapies. Examples include rituximab, omalizumab, dupilumab, and intravenous immune globulin (IVIG). We typically use these therapies when patients fail to respond to standard therapy, morbidity from systemic corticosteroid therapy occurs, or tapering of prednisone to less than 10 mg per day is not feasible despite use of corticosteroid-sparing therapies. (See 'Refractory disease' below.)
Assessing response to therapy — The primary method for assessing the response of bullous pemphigoid to treatment is the clinical assessment. Specific features to assess include the presence of skin lesions of bullous pemphigoid, the occurrence of new lesion development or lesion expansion, the rate of healing of existing lesions, the presence of pruritus, and the current medication regimen. For patients in whom pre-existing skin lesions, the development of new or expanding skin lesions, or pruritus have resolved, the duration of resolution should also be assessed. (See 'Treatment tapering and cessation' below.)
Comparing baseline serum bullous pemphigoid antibody levels with subsequent levels may have value as an adjunct to clinical assessment. The level of bullous pemphigoid antigen 180 (BP180) antibodies in serum usually correlates with the clinical activity of bullous pemphigoid [11,12]. In addition, marked decreases in BP180 antibody levels and lesser decreases in bullous pemphigoid antigen 230 (BP230) antibody levels have been detected soon after the start of topical corticosteroid treatment [13]. Limited data suggest an association between BP180 antibody levels and risk for relapse [14,15]. (See 'Treatment tapering and cessation' below and 'Prognosis' below and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Enzyme-linked immunosorbent assay'.)
Use of precise descriptors of response is recommended for clinical studies. In 2012, a panel of international experts proposed unifying outcome definitions to support comparisons of therapeutic outcomes of studies [16]. The validated score known as the Bullous Pemphigoid Disease Area Index (BPDAI) is used in specialized clinics for bullous pemphigoid patients to quantify their responses to treatments. The BPDAI activity score correlates well with the BP180 antibody titer.
Treatment tapering and cessation — The clinical assessment guides the timing for tapering or cessation of therapy. The primary finding that supports the initiation of tapering is referred to as the "end of the consolidation phase" in clinical studies:
●End of the consolidation phase – No new lesions or pruritic symptoms have occurred for at least two weeks, and most (approximately 80 percent) of established lesions have healed [16].
Although data to confirm the best approach to the use of serum antibody levels to guide therapy are lacking, observed correlations among antibody levels, clinical activity, and disease relapse have contributed to the use of periodic measurement of serum BP180 antibody levels as an adjunct to the physical examination in clinical practice [11-15]. Approaches have included awaiting substantial reductions from pretreatment levels to support reductions in therapy and following trends in an attempt to predict disease exacerbations that may warrant increases in therapy. Additional study is needed to explore the use of BP180 antibody levels for informing changes in therapy. (See 'Assessing response to therapy' above.)
Tapering is generally performed slowly, with progressive reductions of treatment doses (eg, 5 mg reduction in prednisone dose) every two to four weeks in conjunction with close clinical follow-up. Tapering continues provided 80 percent of lesions have healed, there are less than three lesions that heal spontaneously within one week, and there is no pruritus. Awaiting blister-free skin prior to tapering may prolong treatment and increase risk for treatment-related side effects, particularly with oral corticosteroids.
Discontinuation of treatment may be attempted once patients have remained in complete remission (absence of new or established lesions or pruritus) on minimal therapy for at least two months [16]. Examples of doses considered minimal therapy include:
●Clobetasol propionate – ≤20 g of clobetasol propionate per week
●Prednisone – ≤0.1 mg/kg per day
●Azathioprine – ≤0.7 mg/kg per day (patients with normal thiopurine S-methyltransferase [TPMT] level)
●Mycophenolate mofetil – ≤500 mg per day
●Mycophenolic acid – ≤360 mg per day
●Methotrexate – ≤5 mg per week
●Dapsone – ≤50 mg per day
●Doxycycline – 100 mg twice daily
Our general approach to recurrences during tapering or following treatment cessation is as follows:
●Recurrence of mild disease activity (eg, <3 new lesions within one month) – Return to the preceding lowest effective treatment dose.
●Recurrence of greater than mild disease activity (eg, development of ≥3 lesions per month that do not heal within one week, extension of established lesions, or daily pruritus) – Return to dose that preceded the last effective treatment dose; if this fails or patient presented with extensive disease activity, return to initial effective dose. Add a corticosteroid-sparing systemic agent for patients who are not already receiving one and change the corticosteroid-sparing agent for patients who are already receiving one.
Determining treatment failure — Treatment failure may be defined as continued development of nontransient lesions, continued extension of existing lesions, failure of existing lesions to begin to heal, or continued pruritus despite an adequate course of treatment.
Bullous pemphigoid tends to respond to treatment quickly, usually within one month of receipt of appropriate therapeutic doses. Examples of points after which treatment failure may be assumed include [16]:
●Clobetasol propionate – 40 g per day for four weeks
●Prednisone – 0.75 mg/kg per day for at least three weeks (with or without other therapies)
●Azathioprine – 2.5 mg/kg per day for four weeks (patients with normal TPMT levels)
●Mycophenolate mofetil – 40 mg/kg per day for four weeks (patients with normal renal function)
●Methotrexate – 15 mg per week for four weeks (patients >60 kg and without major renal impairment)
●Dapsone – 1.5 mg/kg per day for four weeks
●Tetracyclines – Full therapeutic dosing for four weeks
General skin care — The best approach to the care of blistered skin is not established. In our experience, daily rupturing of tense blisters seems to reduce lateral extension of the blister edges.
We instruct patients and caregivers to:
●Cleanse blisters with alcohol prior to rupturing them with a sterile needle or blade. The puncture is best placed in the most gravitationally dependent area of the blister to facilitate drainage.
●Leave the overlying epithelial layer (blister roof) in place. The epithelium acts as a natural wound dressing.
●Cover open erosions with nonstick dressings to reduce pain and risk for infection.
Superinfection is a significant concern in patients with bullous pemphigoid, particularly when numerous skin lesions are present and systemic immunosuppressants are being utilized for treatment. Patients and caregivers should be informed about the warning signs of infection (eg, purulent drainage, worsening redness, or pain) to facilitate prompt diagnosis and treatment.
Oral involvement — Oral mucosal involvement, which usually manifests as oral erosions, occurs in 10 to 30 percent of patients with bullous pemphigoid [17]. Similar to mucous membrane pemphigoid, oral mucous membrane involvement in bullous pemphigoid can often be managed with topical corticosteroid therapy. (See "Management of mucous membrane pemphigoid".)
In addition, our experience suggests that mucous membrane involvement frequently improves during systemic therapy for cutaneous disease.
INITIAL THERAPY — Corticosteroids, administered topically or systemically, and oral doxycycline are the mainstays of initial therapy. (See 'Selection of initial treatment' above.)
Topical corticosteroids — High-potency topical corticosteroids (group 1) are utilized for bullous pemphigoid (table 2). The ability of patients to obtain and administer topical therapy is a major factor for selection of this mode of therapy (see 'Selection of initial treatment' above):
●Administration – A superpotent topical corticosteroid, such as clobetasol propionate 0.05% cream, is typically applied twice daily. Patients with generalized or widespread involvement apply 20 to 30 g of clobetasol propionate per day to the entire skin surface of the trunk and extremities. Patients with limited skin involvement can apply treatment to the affected areas.
Achievement of disease control is expected within one month. Patients who fail to improve are transitioned to systemic therapy.
Patients who achieve stable disease control are candidates for treatment tapering. We typically begin to taper topical corticosteroid use after two weeks of stable disease control and progressively reduce the frequency of application. (See 'Assessing response to therapy' above and 'Determining treatment failure' above and 'Treatment tapering and cessation' above.)
The cost of topical corticosteroids (generally higher than prednisone) and limited access to these agents may inhibit the use of topical corticosteroids in some clinical settings. In the United States, cost often inhibits use of topical corticosteroids as the primary therapy.
●Efficacy – Randomized trials have compared clobetasol propionate with systemic corticosteroid therapy as well as different regimens of clobetasol propionate therapy:
•Topical versus systemic corticosteroids – The use of topical corticosteroids as monotherapy for bullous pemphigoid is supported by a multicenter, randomized trial (n = 341) that found that patients with extensive bullous pemphigoid (n = 188, defined as >10 new bullae per day) treated with topical clobetasol propionate 0.05% cream had better clinical outcomes than patients with extensive bullous pemphigoid treated with prednisone [8]. This included higher one-year survival rates (76 versus 58 percent), a higher likelihood of achieving disease control by day 21 (99 versus 91 percent), and a lower frequency of severe complications (29 versus 54 percent).
Among the patients with moderate bullous pemphigoid (n = 153, defined as ≤10 new bullae per day), the differences between the topical and systemic therapy groups for one-year survival (both 69 percent), likelihood of disease control by day 21 (100 versus 95 percent, respectively), and severe complications (32 versus 38 percent, respectively) were not statistically significant.
The regimen for clobetasol propionate 0.05% cream consisted of a total daily dose of 40 g that was given through twice-daily applications of clobetasol to the entire cutaneous surface. Prednisone was given as 0.5 mg/kg per day for moderate disease and 1 mg/kg per day for severe disease. Treatment was continued in this manner until 15 days after disease control. Subsequently, clobetasol was gradually reduced over the course of 12 months. The dose of prednisone was reduced by 15 percent every three weeks until treatment was discontinued after 12 months.
•Higher versus lower doses of clobetasol propionate – The findings of a randomized trial suggest that doses lower than 40 g per day of clobetasol propionate may be sufficient for achieving disease control [18].
In a randomized trial that included 312 patients with newly diagnosed bullous pemphigoid treated with clobetasol propionate 0.05% cream, a milder regimen (10 to 20 g per day for moderate disease and 20 to 30 g per day for extensive disease until 15 days after disease control, then tapered to discontinuation over four months) was as effective for attaining control of moderate and extensive bullous pemphigoid as the regimen used in the trial above (40 g per day tapered slowly over 12 months) [18]. Disease control was achieved by day 21 in 98 versus 100 percent of patients, respectively. Relapses were more likely to occur during the one-year trial in patients in the less aggressive treatment group; however, this group discontinued treatment after 4 months rather than 12 months. One-year, disease-free survival rates were 30 versus 45 percent, respectively.
After adjustments were made for patient age and general health status (Karnofsky score), a statistically significant reduction in the risk for mortality and life-threatening, adverse effects was detected among patients with moderate bullous pemphigoid who were treated with the milder regimen compared with those treated with the higher-dose regimen (hazard ratio [HR] 0.54, 95% CI 0.30-0.97). A significant difference in these factors was not seen among patients with extensive disease (HR 1.18, 95% CI 0.76-1.82).
•Adverse effects – High-potency topical corticosteroids can result in cutaneous atrophy, striae, and folliculitis. (See "Topical corticosteroids: Use and adverse effects", section on 'Cutaneous'.)
Adrenal suppression is an additional concern with the extensive application of topical corticosteroids [19-21]. However, among a subset of 28 patients evaluated for adrenal suppression in the dose-comparison trial above, only 5 of 18 patients in the mild regimen group (28 percent) and 1 of 8 patients in the higher-dose regimen group (12 percent) had positive cosyntropin tests (an indicator of adrenal sufficiency) after seven days of therapy [18]. (See "Topical corticosteroids: Use and adverse effects", section on 'Systemic'.)
The adverse effects of topical corticosteroids are reviewed in greater detail separately. (See "Topical corticosteroids: Use and adverse effects".)
Systemic corticosteroids — Systemic corticosteroids are typically administered orally. Prednisone and prednisolone are commonly prescribed, though other formulations may also be effective [22,23]:
●Administration – The optimal regimen for systemic corticosteroid therapy is unclear. We typically treat patients with prednisone or prednisolone with starting doses ranging from 0.5 mg/kg to 0.75 mg/kg per day, with the initial starting dose dependent on the severity of disease and patient comorbidities. The need for measures to reduce risk for treatment-related complications, such as osteoporosis or gastrointestinal adverse effects, should be reviewed. (See "Major adverse effects of systemic glucocorticoids", section on 'General treatment considerations and monitoring'.)
The response to treatment is usually rapid. In one randomized trial that compared treatment with clobetasol propionate with treatment with prednisone, 95 and 91 percent of patients with moderate or extensive bullous pemphigoid, respectively, who were treated with prednisone (0.5 to 1 mg/kg per day) achieved disease control by 21 days [8].
If patients do not demonstrate improvement within two to three weeks, we typically add a corticosteroid-sparing systemic agent (if the patient is not already receiving one) and increase the dose of prednisone to 0.75 mg/kg per day for patients receiving less than 0.75 mg/kg per day. (See 'Corticosteroid-sparing therapy' below.)
Following achievement of disease control, the systemic corticosteroid can be tapered slowly, typically over the course of several months. (See 'Assessing response to therapy' above and 'Treatment tapering and cessation' above and 'Determining treatment failure' above.)
●Efficacy – A trial in which patients with bullous pemphigoid (n = 341) were randomly assigned to either clobetasol propionate or oral prednisone therapy supports the efficacy of prednisone for achieving disease control in patients with bullous pemphigoid [8]. However, compared with clobetasol propionate, prednisone therapy was associated with a slightly lower likelihood of achieving disease control at day 21, lower one-year survival rates, and greater risk for severe complications among patients with extensive bullous pemphigoid (patients developing >10 new bullae per day). Details of this trial are described above. (See 'Topical corticosteroids' above.)
The findings of another randomized trial suggest that doses greater than 0.75 mg/kg of prednisone or prednisolone per day may not be more effective for achieving disease control. A multicenter, randomized trial (n = 50) that compared starting prednisolone doses of 0.75 mg/kg per day and 1.25 mg/kg per day for bullous pemphigoid did not find a statistically significant difference in the proportion of patients in the 0.75 mg/kg group and the 1.25 mg/kg group who achieved clear skin by day 21 (58 versus 64 percent, respectively) [23,24].
●Adverse effects – Systemic corticosteroid therapy can lead to serious acute and long-term side effects [25]. The adverse effects of systemic corticosteroid therapy are reviewed separately. (See "Major adverse effects of systemic glucocorticoids".)
Certain populations have elevated risk for systemic corticosteroid side effects. (See "Major adverse effects of systemic glucocorticoids", section on 'Assessment for preexisting comorbid conditions'.)
Measures to prevent osteopenia should be implemented in patients receiving chronic systemic corticosteroid therapy. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Tetracyclines — Tetracycline antibiotics (eg, doxycycline, tetracycline, minocycline), alone or in combination with nicotinamide (niacinamide), have been utilized for the treatment of bullous pemphigoid [26-32]:
●Administration – We typically treat adults with doxycycline at a dose of 100 mg twice daily. Alternatives to doxycycline include minocycline 100 mg twice daily and tetracycline 500 mg four times daily, although availability of tetracycline is limited. We treat with doxycycline based upon greater evidence to support efficacy and a more favorable side effect profile in comparison with minocycline.
Whether coadministration of tetracycline antibiotics with nicotinamide is superior to treatment with a tetracycline antibiotic alone is unclear. We do not typically add nicotinamide. Studies of tetracycline for bullous pemphigoid have often included coadministration with nicotinamide, but nicotinamide was not used in a randomized trial that compared doxycycline with oral prednisolone [9].
●Efficacy – Few randomized trials have evaluated these therapies. Doxycycline was beneficial in a randomized trial that compared doxycycline and oral prednisolone (BLISTER trial). In the trial, 253 adults with bullous pemphigoid (with at least three clinically significant blisters) were randomly assigned to receive either doxycycline (200 mg per day) or prednisolone (0.5 mg/kg per day) as initial treatment [9]. Application of a potent topical corticosteroid (mometasone furoate) to active lesions was permitted during the first three weeks and after six weeks.
At six weeks, doxycycline was noninferior to prednisolone based upon the specified noninferiority margin of a 37 percent difference in effect. In the doxycycline group, 83 of 112 patients (74 percent) achieved treatment success (three or fewer significant blisters) compared with 92 of 101 patients (91 percent) in the prednisolone group. The adjusted difference in effect was 18.6 percent (90% CI 11.1-26.1). In addition, over 52 weeks, fewer severe, life-threatening, or fatal events occurred in the doxycycline group than in the prednisolone group (22 of 121 patients [18 percent] compared with 41 of 113 patients [36 percent], respectively). The adjusted difference in effect was 19 percent (95% CI 7.9-30.1).
In addition, a small, unblinded, randomized trial did not find significant differences in efficacy between prednisone and tetracycline plus nicotinamide in patients with bullous pemphigoid. In the randomized trial (n = 20), eight weeks of tetracycline (500 mg four times per day) plus nicotinamide (500 mg three times per day) was compared with prednisone (40 to 80 mg per day) [29]. Out of the 14 patients treated with tetracycline and nicotinamide, there were five complete responses, five partial responses, one failure to respond, and one case of worsening disease. Two patients were unavailable for follow-up. Among the six patients treated with prednisone, one had a complete response and the remainder responded partially to therapy. A larger, blinded, randomized trial is necessary to confirm the comparative efficacy of these regimens.
●Adverse effects – Common side effects of tetracyclines include photosensitivity and gastrointestinal distress. Long-term treatment with tetracyclines is contraindicated in children under the age of nine years due to adverse effects on tooth development. Nicotinamide therapy is occasionally associated with headaches or gastrointestinal distress.
CORTICOSTEROID-SPARING THERAPY — Data to support the efficacy of drugs (eg, tetracyclines, dapsone, azathioprine, mycophenolate, methotrexate) for corticosteroid-sparing therapy in bullous pemphigoid are limited. However, in clinical practice, these drugs are commonly used to facilitate tapering and discontinuation of oral corticosteroids. The corticosteroid-sparing agent is often added a few weeks prior to the start of tapering or at the start of oral corticosteroid therapy.
Selection — The tolerability of nonimmunosuppressant agents, such as doxycycline and dapsone, makes them favorable options for corticosteroid-sparing therapy, particularly for patients with milder presentations of bullous pemphigoid (eg, localized disease or history of active disease manifesting as only a few new blisters per day) and patients who are unlikely to tolerate risks of immunosuppressive therapy.
Immunosuppressants, such as azathioprine, mycophenolate, and methotrexate, are typically reserved for patients with a history of extensive bullous pemphigoid (eg, widespread skin involvement or development of many new bullae per day) or patients who fail to improve with or cannot tolerate nonimmunosuppressive, corticosteroid-sparing therapies. We typically attempt treatment with doxycycline prior to considering use of immunosuppressant therapies.
Tetracyclines — In addition to use as primary therapies for bullous pemphigoid, tetracycline antibiotics can also be employed as corticosteroid-sparing agents. Dosing is similar to use as primary therapy. Efficacy data, treatment regimens, and adverse effects for tetracyclines are reviewed above. (See 'Tetracyclines' above.)
Dapsone
●Administration – Dapsone is usually initiated at a low dose (eg, 25 or 50 mg per day in adults) and titrated upward as tolerated.
●Efficacy – Support for a corticosteroid-sparing effect of dapsone comes from an open trial in which 54 patients with bullous pemphigoid were randomly assigned to receive methylprednisolone (0.5 mg/kg per day) in combination with either azathioprine (1.5 or 2.5 mg/kg per day based upon thiopurine S-methyltransferase [TPMT] activity) or dapsone (1.5 mg/kg per day) [33]. Methylprednisone was tapered to discontinuation as tolerated prior to tapering azathioprine or dapsone. Five patients in the azathioprine group and three patients in the dapsone group achieved the primary endpoint of discontinuation of methylprednisolone after a median time of 251 and 81 days, respectively. There was a nonstatistically significant trend towards a lower median cumulative methylprednisolone dose in the dapsone group compared with the azathioprine group (1.92 versus 2.65 g). The small study size may have contributed to the lack of statistical significance. The number of adverse effects was similar in the two groups.
Additional support for benefit of dapsone comes from a 2009 review of published case reports and case series that found clinical improvement documented in 139 of 170 patients who were treated with dapsone (50 to 300 mg per day) alone or in combination with topical corticosteroids, systemic corticosteroids, or immunosuppressive agents [34]. In particular, the efficacy of dapsone as monotherapy was reviewed in a retrospective series of 36 patients with bullous pemphigoid. Among 15 patients treated with dapsone alone (50 to 200 mg per day), 20 percent appeared to respond to therapy, with 7 percent achieving complete remission [35]. Patients who were concomitantly treated with topical corticosteroids and dapsone (n = 19) seemed to have better outcomes; the rates of response and complete response were 63 and 47 percent, respectively.
●Adverse effects and monitoring – Examples of adverse effects include hemolytic anemia, methemoglobinemia, agranulocytosis, hypersensitivity, hepatotoxicity, and motor neuropathy. Severe hemolytic anemia may occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency during treatment with dapsone. We evaluate patients for G6PD deficiency prior to initiating dapsone therapy. Laboratory monitoring for hematologic toxicity is indicated for all patients, particularly early in the course of treatment. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)
Azathioprine
●Administration – Doses between 0.5 and 2.5 mg/kg per day are typically used [36].
Risk for toxicity among individuals influences the appropriate dosing of azathioprine, particularly in relation to TPMT and nucleoside diphosphate-linked moiety X motif 15 (NUDT15) gene polymorphisms associated with increased risk for toxicity. Although routine testing for these gene polymorphisms prior to treatment with azathioprine is advocated by some experts, factors such as varying prevalence of these polymorphisms among populations and the occurrence of myelosuppression in patients without these polymorphisms lead other experts to disagree. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15'.)
We typically perform genotyping for TPMT and NUDT15 polymorphisms prior to treatment and follow dosing recommendations outlined by the Clinical Pharmacogenetics Implementation Consortium guideline. If such testing is not feasible, we typically start with 0.5 mg/kg per day and monitor patients closely for hematologic toxicity.
Responses to treatment can occur within one month. (See 'Assessing response to therapy' above and 'Treatment tapering and cessation' above and 'Determining treatment failure' above.)
●Efficacy – Efficacy data for azathioprine are limited [36-39]. Although a randomized trial that compared azathioprine plus prednisolone with treatment with the same regimen of prednisolone given alone did not find that the addition of azathioprine increased the likelihood of achieving disease control [37], a separate randomized trial of 25 patients with bullous pemphigoid that allowed for adjustments in the dose of prednisone based upon the clinical response found support for a corticosteroid-sparing effect [38]. After three years, less prednisone had been taken by patients in the combination therapy group than in the group solely treated with prednisone (mean total dose of 6732 versus 3688 mg).
●Adverse effects and monitoring – A major side effect of azathioprine therapy is myelosuppression. Examples of other potential adverse effects include malignancy, gastrointestinal disorders, infections, and hypersensitivity. Laboratory monitoring for hematologic and hepatic adverse effects is needed. The adverse effects of azathioprine are reviewed separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects' and "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15'.)
Mycophenolate mofetil
●Administration – Typical doses for mycophenolate mofetil range from 1.5 to 2 g per day, with a maximum dose of 3 g per day. Achievement of disease control can occur within one month of treatment. (See 'Assessing response to therapy' above and 'Treatment tapering and cessation' above and 'Determining treatment failure' above.)
Serum levels of mycophenolate may vary widely among individuals given similar doses. The findings of a small, retrospective study suggest that obtaining a mycophenolic acid trough level may be helpful for patients who fail to respond to 2 g of mycophenolate mofetil per day [40].
●Efficacy – The only randomized trial of mycophenolate mofetil in bullous pemphigoid was an unblinded, randomized trial of 73 patients that compared treatment with methylprednisolone (0.5 mg/kg per day) plus mycophenolate mofetil (2 g per day) with methylprednisolone (0.5 mg/kg per day) plus azathioprine (2 mg/kg per day) [36]. The two regimens appeared similarly effective. All patients in both groups (with the exception of two patients who died and one patient who was lost to follow-up in the azathioprine group) achieved clinical remission. The differences between the mycophenolate mofetil and azathioprine groups in the mean number of days to remission (42±55 versus 24±19 days, respectively) and the mean cumulative doses of methylprednisolone (5754±9693 versus 4967±12,191 mg, respectively) were not statistically significant. However, mycophenolate mofetil was better tolerated.
Improvement in bullous pemphigoid during treatment with mycophenolate mofetil is also documented in case reports [41-45].
●Adverse effects and monitoring – Treatment with mycophenolate mofetil is often well tolerated; gastrointestinal distress is the most common side effect. An enteric-coated formulation of mycophenolate sodium has improved gastrointestinal tolerability and has appeared effective for bullous pemphigoid in several patients [46,47].
Hematologic, renal, and hepatic laboratory monitoring are indicated during treatment. The adverse effects of mycophenolate mofetil are reviewed in greater detail separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)
Methotrexate
●Administration – Methotrexate is typically administered at a dose of between 5 and 20 mg per week. Approaches to the initiation of treatment vary. We administer a low dose (eg, 7.5 mg per week) as initial therapy, and the drug is titrated upward (eg, weekly dose increased by 2.5 mg each month up to a maximum weekly dose of 20 mg) based upon patient tolerance and the response to therapy. Other clinicians begin with higher initial doses of methotrexate.
Achievement in disease control may occur within one month of reaching a therapeutic dose (eg, 15 mg per week). (See 'Assessing response to therapy' above and 'Treatment tapering and cessation' above and 'Determining treatment failure' above.)
Patients treated with methotrexate should also be given folic acid to reduce the risk for hematologic and common gastrointestinal side effects. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Folic acid supplementation'.)
●Efficacy – No randomized trials have evaluated the efficacy of methotrexate in bullous pemphigoid. However, case reports and uncontrolled studies suggest that methotrexate may be beneficial when used alone or in combination with topical or systemic corticosteroid [10,48-54].
A 2009 retrospective review of published reports with at least 5 patients identified 62 patients with bullous pemphigoid who were treated with methotrexate (5 to 25 mg per week), including 45 who received methotrexate without another systemic therapy [51]. Among the 45 patients who received only methotrexate and a topical corticosteroid, 93 percent responded well to treatment, and all 17 patients treated with methotrexate and systemic corticosteroids achieved disease control.
The results of a subsequent retrospective study suggest that monotherapy with methotrexate may also be effective [10].
●Adverse effects and monitoring – Additional potential side effects include hepatotoxicity and pulmonary fibrosis. The side effects of methotrexate are reviewed separately. Hematologic, hepatic, and renal monitoring are indicated during treatment. (See "Major side effects of low-dose methotrexate".)
REFRACTORY DISEASE — Biologic therapies are a treatment option for patients who fail to respond to topical corticosteroids, systemic corticosteroids, and corticosteroid-sparing agents. Although rituximab use for bullous pemphigoid has been reported most frequently, data are insufficient to determine the most effective biologic therapy.
Rituximab — Rituximab is a humanized chimeric monoclonal antibody that targets and destroys CD20+ B and pre-B cells. Case reports and small case series indicate that rituximab may be effective for bullous pemphigoid that is refractory to conventional therapies. A 2019 systematic review of the literature that assessed reports of patients treated with rituximab (doses ranging from 375 mg/m2 every one to four weeks to 500 mg weekly for two weeks) or omalizumab (doses ranging from 100 mg every two to four weeks to 525 mg every two weeks) found complete responses in 52 of 61 patients given rituximab (85 percent) and 16 of 19 patients given omalizumab (84 percent) [55]. Most patients had failed to respond to systemic corticosteroid therapy prior to biologic treatment. Reports of recurrence were less frequent in patients treated with rituximab than with omalizumab (29 versus 80 percent), with mean times to recurrence of 10 and 3 months, respectively.
Major side effects of rituximab are reviewed separately. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)
Dupilumab — Dupilumab is a human anti-interleukin (IL) receptor-alpha monoclonal antibody that inhibits signaling of IL-4 and IL-13, cytokines hypothesized to play an important role in the pathogenesis of bullous pemphigoid. In a multicenter case series of 13 patients with bullous pemphigoid treated with dupilumab (600 mg initially followed by 300 mg every other week up to weekly), 12 patients (92 percent) experienced improvement and desired to continue dupilumab, and 7 patients (58 percent) achieved disease clearance (absence of bullae and pruritus). Improvement occurred within one to five months [56]. Dupilumab has also been associated with improvement of bullous pemphigoid in case reports [57,58]. A randomized clinical trial is underway [59].
Omalizumab — Omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody, has been associated with improvement in bullous pemphigoid in case reports and case series [60-67]. The findings of a 2019 systematic review of the literature that assessed reports of rituximab and omalizumab use for bullous pemphigoid are reviewed above [55]. (See 'Rituximab' above.)
Intravenous immune globulin — Intravenous immune globulin (IVIG) is occasionally utilized for the treatment of bullous pemphigoid. A 2012 review of published reports identified 45 patients (including 43 adults and 2 infants) with bullous pemphigoid who were treated with IVIG with or without concomitant immunosuppressive therapy [68]. Most adults were treated with 2 g/kg per cycle, with cycles repeated every four weeks. Among the adult patients, 86 percent attained clinical improvement; improvement occurred within an average of three months.
Although further studies are necessary to determine the optimal regimen and indications for IVIG, factors that have been proposed to contribute to favorable responses include multiple treatment cycles [68,69], coadministration of an immunosuppressant [70], and shorter durations of disease prior to the initiation of therapy [71].
The beneficial effects of IVIG on bullous pemphigoid are supported by evidence that serum levels of bullous pemphigoid antigen 180 (BP180) and bullous pemphigoid antigen 230 (BP230) antibodies decline in response to treatment. In an uncontrolled study of 10 patients with bullous pemphigoid, treatment with IVIG was associated with the induction of both serologic and clinical remissions in all patients [72]. (See 'Assessing response to therapy' above.)
The adverse effects of IVIG are reviewed separately. The high cost of IVIG limits the use of this therapy. (See "Intravenous immune globulin: Adverse effects".)
OTHER THERAPIES — Limited data or safety concerns preclude routine use of various other therapies. Although benefit of oral Janus kinase (JAK) inhibitors for bullous pemphigoid has been suggested in case reports and a case series, data are insufficient to confirm efficacy and safety in this population [73-76].
Examples of other medications that have appeared to be of benefit for bullous pemphigoid in a small number of patients include erythromycin in children [77,78], topical tacrolimus [79,80], cyclosporine [81,82], chlorambucil [83,84], cyclophosphamide [85,86], and leflunomide [87]. A few case reports document beneficial effects of immunoadsorption in patients with refractory bullous pemphigoid [88,89]. Data conflict on the efficacy of plasmapheresis (plasma exchange) [37,90].
Trials involving other biologic and nonbiologic therapies, such as benralizumab, efgartigimod, and the investigational drug bertilimumab, are underway.
PROGNOSIS — The clinical course of bullous pemphigoid is variable. In general, bullous pemphigoid follows a chronic, relapsing course [15,91-93]. Long-term remission may occur after months to years. In an early report that preceded the use of systemic corticosteroids, 8 of 30 patients entered remission after 3 to 38 months of active disease. Drug-induced bullous pemphigoid most often has a limited course following cessation of the inciting dug (see 'Identification of drug-induced disease' above):
●Risk of relapse – High titers of bullous pemphigoid antigen 180 (BP180) antibodies at the time of cessation of therapy may portend an increased likelihood for disease relapse. In a prospective study of 114 patients with bullous pemphigoid, a high enzyme-linked immunosorbent assay (ELISA) anti-BP180-NC16A titer at the time of cessation of oral or topical corticosteroid therapy was an independent predictor of disease relapse within one year [15]. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Enzyme-linked immunosorbent assay'.)
In addition to high titers of BP180 antibodies at the time of cessation of therapy [15], other factors may portend an increased risk for relapse. A one-year, prospective, multicenter, observational study of 120 patients with newly diagnosed bullous pemphigoid found that extensive disease at baseline (hazard ratio [HR] 2.37, 95% CI 1.2-4.8) and associated dementia (HR 2.09, 95% CI 1.0-4.2) were independent risk factors for disease relapse within the first year of treatment [13]. In addition, the change in bullous pemphigoid antibody levels after the start of treatment appeared to correlate with risk for relapse. The mean decrease in BP180 antibody levels during the first 60 days of treatment was smaller among patients who relapsed than among patients who remained in remission (-10.0 versus -45.2 percent). A similar but lesser effect was observed for bullous pemphigoid antigen 230 (BP230) antibodies.
●Risk of death – Bullous pemphigoid is a potentially fatal disease. Estimates for one-year overall mortality of patients with bullous pemphigoid have ranged from 11 to 48 percent, with most studies finding increased rates of mortality compared with subjects without bullous pemphigoid [94-98]. Examples include:
•A French, prospective, cohort study of 312 patients with bullous pemphigoid found an overall one-year mortality rate of 38 percent [95]. The risk for death was more than six times greater for patients with bullous pemphigoid than for age- and sex-matched subjects in the general population.
•A Swiss study that evaluated the course of bullous pemphigoid in 115 patients found probabilities of death one, two, and three years after diagnosis of 21, 28, and 39 percent, respectively. The mortality rate for patients with bullous pemphigoid was approximately three times greater than for age- and sex-matched subjects in the general population [94]. The increase in likelihood for death was most pronounced among patients less than 70 years in age.
For unknown reasons, the mortality rates reported in Europe (19 to 48 percent) [93-95,99-104] have generally been higher than those reported in the United States (11 to 23 percent) [94,105]. One retrospective, cohort study in the United States failed to find an increase in mortality compared with the general population [92].
The reasons for an increase in death among patients with bullous pemphigoid may be multifactorial. Complications secondary to therapeutic agents are likely a contributing factor. In the Swiss study, the most common causes for death were heart disease, infection, and neurologic disease [94].
PATIENT SUPPORT — The International Pemphigus and Pemphigoid Foundation is a resource that provides patients and clinicians with information about bullous pemphigoid.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bullous pemphigoid".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topic (see "Patient education: Bullous pemphigoid (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Disease overview – Bullous pemphigoid is an uncommon, potentially fatal, autoimmune blistering disease that most commonly affects older adults (picture 1A-D). (See "Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid" and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)
●Approach to management – The management of bullous pemphigoid involves assessment for drug-induced disease and signs of ocular or internal involvement, as well as careful selection of immunomodulatory treatments that attenuate autoantibody production and antibody-mediated inflammation. Much of the morbidity and mortality related to bullous pemphigoid results from the combined effect of patient comorbidities and adverse effects of treatment, rather than from direct effects of the disease. (See 'Treatment goals' above and 'Pretreatment assessment' above and 'Approach to management' above.)
●Preferred initial treatments – Topical corticosteroids, oral corticosteroids, and doxycycline are the mainstays of initial treatment based upon data that support efficacy of these interventions. Selection among these treatments is influenced by the feasibility of treatment, risk for adverse effects, efficacy, and patient preference. (See 'Overview of therapeutic approach' above.)
Although topical corticosteroid monotherapy is effective and generally well tolerated, treatment requires application of topical corticosteroids to extensive areas of skin daily, which can be challenging for some patients (see 'Selection of initial treatment' above):
•Patients who can tolerate topical therapy – For patients with extensive bullous pemphigoid (eg, widespread skin involvement or development of many new bullae per day) who are willing and able to perform topical therapy and who prefer topical treatment, we recommend treatment with a high-potency topical corticosteroid, such as clobetasol 0.05% cream, rather than oral prednisone (Grade 1A). (See 'Topical corticosteroids' above.)
•Patients who cannot tolerate topical therapy – For patients who prefer to avoid extensive, daily application of topical corticosteroids or are unable to perform or receive such treatment, an oral agent should be used as the primary initial treatment (see 'Selection of initial treatment' above):
-Mild disease – For patients with milder presentations of bullous pemphigoid (eg, localized bullous pemphigoid or development of only a few new bullae per day) who desire oral treatment, we suggest doxycycline rather than oral prednisone as initial treatment (Grade 2B). Doxycycline may be less likely to induce rapid remission compared with oral prednisone but has a more favorable side effect profile. We typically combine doxycycline therapy with application of a high-potency topical corticosteroid to active lesions. (See 'Tetracyclines' above.)
-Extensive disease – For patients with extensive bullous pemphigoid (eg, widespread skin involvement or development of many new bullae per day) who desire oral treatment, we suggest oral prednisone as initial treatment rather than doxycycline (Grade 2B). Initial treatment with doxycycline is an acceptable alternative for patients who are unlikely to tolerate systemic corticosteroid therapy or who prefer to avoid the risks of oral corticosteroid therapy. We typically combine doxycycline therapy with application of a high-potency topical corticosteroid to active lesions. (See 'Systemic corticosteroids' above and 'Tetracyclines' above.)
Limited data suggest that methotrexate may also be effective as primary treatment. (See 'Methotrexate' above.)
●Role of corticosteroid-sparing therapies – Because bullous pemphigoid often persists for years, corticosteroid-sparing therapies, such as tetracyclines, dapsone, mycophenolate mofetil, azathioprine, and methotrexate, are often prescribed to facilitate tapering of oral corticosteroids. However, high-quality data to confirm the value of corticosteroid-sparing agents in bullous pemphigoid are lacking. (See 'Corticosteroid-sparing therapy' above.)
●Refractory disease – Biologic therapy may be useful for the management of patients who fail standard therapy. (See 'Refractory disease' above.)
●Prognosis – The clinical course of bullous pemphigoid is variable. Remission may occur after months or years. Certain characteristics, such as a high titer of bullous pemphigoid antigen 180 (BP180) antibodies at the time of treatment cessation, may be associated with increased risk for relapse. Bullous pemphigoid is a potentially fatal disease. (See 'Prognosis' above.)
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