Bullous pemphigoid (BP) is the most common autoimmune blistering disease, appearing as large, tense blisters in the skin, usually preceded by urticarial plaques. In BP, circulating IgG (less commonly IgA and IgE) autoantibodies bind to adhesion proteins BP230 (also known as BPAG1-e and dystonin) and/or BP180 (also known as BPAG2 and type XVII collagen) in the skin’s basement membrane zone, creating a subepidermal split. The condition mainly affects people over the age of 70, and hence management needs to be tailored to the safest treatment in this population, who tend to have many comorbidities.

Management consists of general skin care measures as well as pharmacologic therapy and is aimed at attenuating autoantibody inflammation to promote healing, decrease morbidity, and improve quality of life.

First-line therapy, particularly in older patients, includes high-potency topical corticosteroids such as clobetasol 0.05 % cream applied over the whole body. When this is not feasible or practical, for example, in younger, healthier, working individuals, systemic glucocorticoid therapy is instituted. In patients without comorbidities, systemic glucocorticoid-sparing agents, such as mycophenolate or azathioprine, may be added. Recalcitrant BP may be treated with biologics.

55.2 Treatment

55.2.1 Approach to Therapy

Treatment options generally work to attenuate autoantibody production and the inflammatory activity triggered by antibodies that give rise to the blisters, urticaria, or pruritus. The goal of therapy should be to decrease blister formation and pruritus, promote healing of blisters and erosions, and improve quality of life using the minimum effective dose of medication [1].

Several factors influence the choice of therapy in BP. Individualization of treatment regimens should take into account that the disease occurs mostly in the elderly, a population likely to have existing comorbidities from other diseases and that is inherently more susceptible to drug side effects. A considerable proportion of BP patients is dependent on relatives or health workers for care. Ultimately, the choice of which agents to use is largely dependent on side effect profile and the patient’s comorbidities, cost and availability, or physician preference [1].

55.2.1.1 General Measures

As yet there is no consensus on the best care regimen for blistered skin. In our experience, rupturing a tense blister with a sterile needle at its lowest point to drain blister fluid speeds up healing and prevents lateral extension of the blister edges. Care should be taken not to de-roof the blister since it acts as a natural dressing and will assist in healing. A non-stick dressing may further be used to protect the blistered or eroded areas.

While localized BP may not carry significant morbidity, more extensive disease, concomitant use of systemic immunosuppressants, and the rare involvement of mucosal surfaces warrant careful attention to prevent further damage or superinfection. In general, BP should be managed by a dermatologist in conjunction with a physician or family practitioner. Ideally, patients would be kept out of hospital to reduce the chance of infection while immunosuppressed.

Referral to appropriate additional specialist(s) is important and is tailored to each patient’s circumstances. Ocular involvement such as itching, a burning sensation, or visual changes should prompt referral to an ophthalmologist to avoid long-term sequelae. Likewise, referral to a gastroenterologist or otolaryngologist is needed for esophageal, laryngeal, or pharyngeal involvement.

55.3 First-Line Therapy: Corticosteroids

55.3.1 Topical

Corticosteroids remain the cornerstone of therapy for BP. Topical steroids are often sufficient in localized disease. A multicenter randomized controlled trial (RCT) evidence from Joly and colleagues in 2002 demonstrated effectiveness of topical clobetasol propionate 0.05 % cream applied twice a day (40 g/day) in extensive BP (>10 new blisters per day). It was also superior to oral prednisone 1 mg/kg/day in extensive BP in terms of time to clinical improvement, complications, and 1-year survival rates. However, the difference between topical versus systemic treatment for moderate BP (defined as ≤10 new blisters per day) using the latter three parameters was not statistically significant [2]. Thus whenever practical, high-potency topical corticosteroids (specifically, clobetasol propionate ointment) should be used as first-line treatment, particularly in the elderly.

A milder, shorter regimen of topical steroids (10–30 g/day with 4-month taper) has been shown to be as effective as the standard (40 g/day with 12-month taper) protocol in moderate and severe BP, which further reduces side effects. The French Bullous Diseases Study Group also found that the milder regimen achieved faster control when compared with the standard 40 g/day regimen. Life-threatening adverse effects and mortality rate in patients with moderate BP (but not in extensive BP) were found to be less with the milder regimen as well [3–5].

There are practical difficulties, however, with instituting this desired treatment. The topical medication requires that a nurse or family member assists with popping of blisters and the twice-a-day application of the steroid over extensive areas of the body, usually the trunk and extremities. Some health systems, such as the French system, provide for nurses to visit patients’ homes and administer the topical steroids, improving compliance. Cost may be a hindrance when compared with oral corticosteroids. Other health systems subsidize the cost of high-potency topical steroids, others of low-potency topical steroids only, and still others do not cover any at all. For these practical reasons, patients are often given oral steroids, which are much cheaper than topical steroids and do not require time and nurses to administer, despite their much higher attendant risk of complications. Overall cost to the health system is likely to be higher with the systemic steroid treatment, due to the complications of steroids, but most health systems do not look at this when deciding whether to pay for large quantities of potent topical steroids and home nursing.

High-potency topical steroids are generally applied twice daily for 2–4 weeks at a time, with rest periods of one to a few weeks in between. When evidence of inflammation, new blisters, and pruritus have ceased for at least 2 weeks and 80 % of erosions have healed, the topical medication is then slowly tapered over 4 months or longer as tolerated [6]. Prolonged use (>3 months) of topical corticosteroids is generally not recommended because of local (striae, atrophy, or folliculitis) and systemic side effects. Considerable systemic absorption can lead to suppression of the hypothalamic-pituitary-adrenal (HPA) axis [7, 8].

55.3.2 Systemic

Systemic corticosteroids such as prednisone at 0.5–1 mg/kg/day are still widely used in clinical practice for extensive disease as initial therapy and should be used when use of topical corticosteroids is not feasible/affordable and when there is mucosal involvement that precludes use of topical agents (see above). A multicenter randomized study performed in France found that no additional benefit could be gained from starting prednisolone doses higher than 0.75 mg/kg/day. In this study, there was no significant difference in blister resolution in 50 patients using 0.75 mg/kg/day and 1.25 mg/kg/day [5, 9].

The type of steroid seems irrelevant, because another French multicenter study found no significant difference in treatment effectiveness between biologically equivalent doses of methylprednisolone and prednisolone [10].

While systemic corticosteroids are generally well tolerated, they have potentially serious acute and long-term side effects [4]. Chronic (>3 months) use of systemic steroids warrants monitoring of electrolytes, glucose, triglycerides, cholesterol, weight, fevers, skeletal or abdominal pain, bone mineral density, and eyes to prevent steroid-induced complications such as elevated blood glucose, hyperlipidemia, cataract, and glaucoma [4].

Glucocorticoid-induced osteopenia is most pronounced in the first 3–6 months of use, and prednisone dose (or equivalent) as low as 2.5–7.5 mg/day has been associated with an increased risk of fractures [11]. It is therefore imperative to prevent or minimize glucocorticoid-induced bone loss especially since the disease primarily involves a population that carries an inherent risk for fractures.

55.4 Second-Line Therapy: Adjuvant/Steroid-Sparing Agents

There are very few RCTs on the use of these adjuvant agents for BP, and there is only limited evidence for their use [5]; hence, they should be avoided in elderly patients with comorbidities. Corticosteroids are used as first-line treatment especially for widespread or severe disease to bring the disease under rapid control (days). Steroid-sparing immunosuppressive agents such as azathioprine, mycophenolate mofetil, mycophenolate sodium, or methotrexate are usually used when treatment with corticosteroids is ineffective or contraindicated. Unlike corticosteroids, they may take 4–6 weeks to show benefit [12] and, if being used to reduce overall corticosteroids, should be commenced before tapering oral corticosteroids. However, although the aim of these adjuvant agents is to reduce cumulative steroid dose until corticosteroids can be completely withdrawn, they are not without the potential for harm.

55.4.1 Immunosuppressive Agents

There have been less than a dozen small RCTs examining effectiveness of immunosuppressive agents in BP, and to date, none have shown superiority to steroids along in controlling BP [5]. Hence, the use of these agents, whose effectiveness has not been convincingly demonstrated, should be avoided in elderly patients or patients with comorbidities.

55.4.1.1 Azathioprine

Among the steroid-sparing agents used for BP, azathioprine is the best established. Yet convincing evidence from well-designed randomized controlled trials is lacking. It belongs to a class of purine analogues that has been used in organ transplantation and autoimmune disease, typically given at doses between 0.5 and 2.5 mg/kg/ day.

Myelosuppression is a major side effect of azathioprine, and thiopurine methyltransferase (TPMT) levels should be determined prior to administration of the drug to determine the appropriate starting dose.

55.4.1.2 Mycophenolate

Mycophenolate mofetil is the prodrug of mycophenolic acid that inhibits DNA synthesis by reversibly inhibiting inosine monophosphate dehydrogenase (IMPDH). IMPDH is an enzyme that catalyzes the rate-limiting step in guanine de novo biosynthesis that is vital to T and B cell proliferation and differentiation [13]. It is used at doses of 35–45 mg/kg/day, usually 1.5–3 mg/day.

The few randomized trials and case reports addressing pemphigus and pemphigoid treatment have reported a comparable efficacy of mycophenolate mofetil to other immunosuppressants [14]. Beissert et al. found no significant difference between azathioprine (2 mg/kg/day, n = 38) and mycophenolate mofetil (2 g/day, n = 35) when used with methylprednisolone (0.5 mg/kg/day) in terms of achieving disease remission in patients with BP in an unblended randomized study [15].

While azathioprine is associated with more hepatic side effects than mycophenolate mofetil, azathioprine may be more practical to use because it is cheaper, has a more rapid onset of action, and has better steroid-sparing effect. However, the use of enteric-coated mycophenolate sodium (EC-MPS) is associated with better gastrointestinal tolerability than mycophenolate mofetil [16–18] and is usually given at a dose of 720 mg once or twice per day. A patient that fails to respond clinically or develops toxicity to the drug at standard doses should be promptly checked for serum levels of mycophenolate, which may vary among individuals receiving similar doses [19].

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Tags: Blistering Diseases

Jun 3, 2017 | Posted by admin in Dermatology | Comments Off

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Management of Bullous Pemphigoid

55. Management of Bullous Pemphigoid

55.1 Introduction