Joanna N. Hooten, MD1; Russell P. Hall 3rd, MD1,2; Adela R. Cardones, MD1,2

1Department of Dermatology, Duke University School of Medicine, Durham, NC, USA
2Division of Dermatology, Department of Medicine, Duke University Medical Center, Durham VA Medical Center, Durham, NC, USA

ABSTRACT

Autoimmune blistering diseases are rare, but potentially debilitating cutaneous disorders characterized by varying degrees of mucosal and cutaneous bullae formation. Topical therapy is appropriate for mild and even some moderate disease activity, but systemic treatment can be considered for more extensive involvement. Corticosteroids remain the first-line systemic therapy for patients with moderate to severe bullous pemphigoid and pemphigus vulgaris. While the use of systemic steroids has dramatically reduced mortality from these two autoimmune blistering disorders, treatment is also associated with multiple side effects, especially when used long-term. Steroid sparing agents, therefore, are invaluable in inducing long-term remission while minimizing steroid associated side effects. Treatment must be tailored to the individual patient’s condition, and several other factors must be carefully considered in choosing appropriate therapy: 1) diagnosis, 2) severity of the condition and body site affected, 3) presence of comorbidities, and 4) ability to tolerate systemic therapy.

Key Words:
autoimmune blistering skin diseases, bullous pemphigoid, cicatricial pemphigoid, basement membrane zone, epidermolysis bullosa acquisita, pemphigus vulgaris

Introduction

Autoimmune blistering diseases (AIBD) are a heterogeneous group of chronic, acquired disorders characterized by blister formation within the epidermis, at the dermal-epidermal junction or at the basement membrane zone, and by the presence of autoantibodies directed against structural components of cellular adhesions molecules. AIBD are classified into different groups based on clinical and immunopathological criteria. Largescale, randomized studies on effective therapeutic strategies for AIBD are limited and treatment varies widely among providers. The patient population tends to be a heterogeneous mix of age, gender and comorbidities, and the mechanisms of injury to the skin are variable between blistering diseases. Management of these disorders, therefore, requires an understanding of the spectrum of available therapies. A complete discussion of the treatment of AIBD is beyond the scope of this review, however, we present some recommendations in approaching patients with pemphigus, pemphigoid, and epidermolysis bullosa acquisita (EBA). A brief description of the available medications and their roles in treating AIBD will be provided, but a thorough review of therapeutic and monitoring guidelines must be done before treatment is initiated.1

Approach to Patients with AIBD

Several factors need to be considered in treating a patient with an AIBD (Table 1). A complete history and thorough physical examination of the skin and mucous membranes must be performed. A skin biopsy, with direct and indirect immunofluorescence analysis, is important in arriving at the correct diagnosis and planning therapy. Determining titers of autoantibodies are not always necessary to confirm the diagnosis, but may be helpful in following the patient’s progress.2-4

First, an accurate diagnosis will help determine the likelihood of disease remission, potential for mucous membrane involvement, risk of scarring, and other long-term sequelae that may affect treatment plans. For example, bullous pemphigoid (BP) and EBA may demonstrate a similar clinical presentation, but have a different natural history. A clinician may plan to wean a BP patient off all medications in 9-12 months, whereas longer-term therapy is often needed in patients with EBA.

Second, severity and extent of disease has to be carefully evaluated. The extent of the disease can be variable in all types of AIBD. Additionally, the definition of mild, moderate and severe disease differs among experts. Some authors define limited disease as <10% body surface area, while others use the cut-off point of <10 new blisters per day to delineate between limited and severe disease.5,6 Nevertheless, even in the absence of new blisters and regardless of affected areas, the involvement of functional critical sites (e.g., hands and feet or mucosal surfaces) may require more aggressive therapy. Ocular disease, which can result in permanent scarring or blindness, warrants systemic treatment, in addition to subspecialty referral to ophthalmology.

Third, the presence of comorbidities may dictate the type and dosage of medication that can be used and must be accompanied by careful assessment. Diseases such as diabetes mellitus, hypertension, chronic infections (e.g., hepatitis or HIV), and previous or existent malignancies need to be considered. Patients who would otherwise be treated aggressively, but whose comorbidities preclude therapy with systemic corticosteroids (i.e., elderly patients or those with uncontrolled diabetes or hypertension) or more traditional steroid sparing agents, may instead have to be treated with topical, antibiotic or antiinflammatory medications.

Finally, the choice of medications may be restricted by side effects experienced by the patient. Potential side effects, which can be significant, include alterations in mental status, sleep disturbances, and gastrointestinal (GI) discomfort. The assessment of all adverse effects throughout therapy is critical to treatment success in AIBD. The clinician must exercise judgment in weighing the risks and benefits of initial therapy in an effort to maximize efficacy while minimizing systemic toxicity.

Mild to Moderate Disease

Topical Therapy

For pemphigus vulgaris (PV) patients with mild and even moderate cutaneous and oral mucosal7 involvement, BP or EBA, a high potency topical steroid such as clobetasol 0.05% ointment or gel applied 2-3 times daily is appropriate.5 Even in the setting of extensive disease, potent topical steroids remain an option if the patient is elderly or has numerous risk factors. Clobetasol 0.05% cream 40 g/day is at least as effective as oral prednisone in treating moderate to severe BP.8 Some degree of systemic absorption may contribute to the efficacy of topical steroids, however, the side effect profile is still acceptable.

Approach to Patients with AIBD
  1. Diagnosis
  2. Severity of the condition: extent of disease or site affected
  3. Comorbidities
  4. Ability to tolerate systemic therapy
Table 1. Factors in determining appropriate therapy

Antimicrobials

Antimicrobials decrease local inflammation, but have no effect on circulating autoantibodies.9 The combination of tetracycline 2 g PO daily plus nicotinamide 1.5 g PO is a reasonable alternative for the treatment of BP in patients who are not candidates for systemic steroid therapy. In a randomized trial of 18 patients comparing prednisone with tetracycline and nicotinamide, there was no statistically significant difference in response between the two groups. In addition, 83% of patients treated with tetracycline plus nicotinamide had some improvement and 42% experienced a complete response. At long-term follow-up, a small subset of patients in the tetracycline plus nicotinamide treatment group remained in remission with tapering of the medication.10 Several other small studies have also demonstrated variable improvement with this treatment combination.9,11

Colchicine

Colchicine is an anti-inflammatory drug with a mild side effect profile. High doses of colchicine have been effective in patients with classical and inflammatory EBA.12-14 The typical dosing ranges from 0.6 mg PO BID to TID. The most frequent side effects are GI complaints, particularly diarrhea, which can limit the utility of this therapy.

Moderate to Severe Disease

Systemic Corticosteroids

Much of the disease morbidity and mortality, particularly with PV and BP, has decreased with the introduction of corticosteroid therapy. Corticosteroids are the first-line systemic treatment for moderate to severe BP and PV and may have a role in treating the inflammatory subset of EBA, evidence is admittedly scant for the latter.2,15 There is no universal consensus on dosing and tapering systemic corticosteroids for AIBD. Some guidelines use weightbased dosing, whereas others recommend a starting dose of 40-60 mg PO daily.5,6 Patients with milder BP, PV and EBA can often be adequately managed with 0.5-0.75 mg/kg/day. However, in patients with severe disease (>10 new lesions per day), a starting dose between 0.75-1.0 mg/kg/day can be used.

Long-term use of corticosteroids is associated with multiple adverse effects including increased risk for infection, weight gain, high blood pressure, osteoporosis, fluid retention, elevated blood sugar, cognitive disturbances, cataracts, and glaucoma. Therefore, once the disease stabilizes, careful tapering of the medication is strongly recommended. We suggest re-evaluating the patient 1-2 weeks after initiating therapy. If the disease is stable, a slow tapering of prednisone may be initiated, decreasing the dose by 5-10 mg every month as tolerated. However, in patients who cannot tolerate long-term prednisone use (i.e., patients with labile blood sugar or blood pressure, significant agitation or neurologic side-effects) a more rapid tapering may be required, decreasing the dose by 5-10 mg each week. If the disease remains active, then a decision can be made to either increase the dose or initiate adjunctive therapy with steroid sparing agents. The American College of Rheumatology has established recommendations for monitoring steroid-induced osteoporosis in patients on longterm corticosteroids.16,17

Steroid Sparing Agents

In patients who cannot be tapered off steroids without inducing disease flares, steroid sparing agents are invaluable in achieving prolonged remission. Careful review of monitoring guidelines is essential before initiating therapy.1 Traditional immunosuppressive agents such as mycophenolate mofetil and azathioprine are more commonly used. However, with the advent of biologic therapy, treatment options such as intravenous immunoglobulin and rituximab are increasingly being employed earlier in the course of therapy.18-20

Azathioprine
When used as adjunctive therapy, azathioprine enables a significant dosage reduction of prednisone in patients with moderate to severe BP.5,21 Azathioprine appears to be a superior steroid-sparing agent for PV when compared to cyclophosphamide and mycophenolate mofetil,22 although there is some evidence that cyclophosphamide may induce a quicker and more sustained remission.23 Genetics play a role in the efficacy and safety of azathioprine. The metabolism of azathioprine is dependent on xanthine oxidase and thiopurine methyltransferase (TMPT). Ten percent of the population is heterozygous with intermediate TPMT enzyme activity and 1/300 patients is homozygous or compound heterozygous with low enzyme activity.21,24 Although the effect on heterozygotes is still unclear, homozygotes are at risk of severe neutropenia.25 Other adverse effects include cytopenia, hepatitis, pancreatitis and infection. Allopurinol inhibits xanthine oxidase, potentiating the risk of myelosuppression. Azathioprine may also decrease the efficacy of warfarin, therefore, dose adjustments may be required. The recommended dose of azathioprine is 1-3 mg/kg daily.26 A lower dosage is recommended in the elderly or patients who have reduced TMPT levels.1 When TMPT levels are extremely low, azathioprine should not be used.

Mycophenolate Mofetil
Mycophenolate mofetil (MM) is effective both as combination therapy and monotherapy in PV and BP.27-32 In a randomized controlled trial comparing MM or placebo plus prednisone in the treatment of mild to moderate PV, the MM arm exhibited an improved time to and duration of response.33 A study comparing MM vs. azathioprine as adjuvant therapy to oral methylprednisolone demonstrated similar efficacy in both groups, but increased hepatotoxicity was observed in those who received azathioprine.34 Given its similar, if not superior, efficacy to azathioprine and better side effect profile, MM is becoming the first choice therapy for adjuvant treatment in BP and PV. The most common side effects are usually mild and include nausea, diarrhea, GI discomfort and malaise. However, hepatotoxicity, infections, leukopenia and anemia can occur.20 The usual dosing range is between 1-3 g/day.

Cyclophosphamide
Cyclophosphamide has a faster onset of action than azathioprine or MM, but is also associated with significant adverse effects. Therefore, its use is usually reserved for patients with refractory or rapidly progressive disease, individuals unable to tolerate first-line therapies, or those with ocular cicatricial pemphigoid. Combination therapy with cyclophosphamide and systemic corticosteroids is recommended in patients with severe mucous membrane disease, in order to decrease the potentially severe morbidities.7,35-37 Side effects are frequent and can be severe, and include nausea, vomiting, diarrhea, alopecia, and fatigue. More severe side effects are secondary to hematopoietic suppression leading to leukopenia, anemia and thrombocytopenia. An increased risk of transitional cell carcinoma and lymphomas is also concerning. One of the metabolites of cyclophosphamide, acrolein, can cause hemorrhagic cystitis in up to 40% of patients. Standard dosing of oral therapy is 2-2.5 mg/kg daily. Intravenous (IV) pulsed therapy is more frequently recommended in order to decrease the cumulative effect dose.

Cyclosporine
Several randomized controlled trials have failed to demonstrate a beneficial effect of oral cyclosporine either alone or as adjuvant therapy.38-41 Topical cyclosporine has been used for oral and ocular cicatricial pemphigoid.42,43 The most common adverse reactions to cyclosporine are renal dysfunction, hypertension, tremor, hirsutism, and gingival hyperplasia.

Methotrexate
Methotrexate (MTX) can be effective in treating BP and PV by decreasing disease activity and time to remission.44-49 The most common side effects of MTX are fatigue, nausea and vomiting. More severe adverse effects include pancytopenia and hepatotoxicity, which can be exacerbated by renal disease, chronic nonsteroidal anti-inflammatory drug (NSAID) use, hepatic disease (e.g., hepatitis, alcohol use, diabetes mellitus, and obesity), and lack of folic acid supplementation. Photosensitivity and radiation recall are also potential adverse effects, and hepatic fibrosis and cirrhosis can occur with long-term use. The issue of if and when to perform a liver biopsy is controversial, however, depending on individual risk factors, a liver ultrasound and/or biopsy should be considered after prolonged use. Some guidelines recommend liver biopsy after a cumulative dose of 4 g in the absence of risk factors for hepatic disease.50,51 Dosing is similar to that for rheumatoid arthritis, averaging 15 mg/week and 1 mg daily of folic acid.49

Dapsone
Dapsone inhibits the chemotaxis of polymorphonuclear leukocytes and is an extremely effective drug in treating neutrophilic dermatoses.52-57 In many AIBD, dapsone is more successful as an adjunctive rather than single agent treatment. A 2009 meta-analysis of 170 BP patients demonstrated that 81% experienced clinical improvement with dapsone, but the best responses were observed in conjunction with steroids or other immunosuppressants.58 A randomized, double-blind, placebocontrolled crossover trial of dapsone vs. placebo favored dapsone over placebo as a steroid sparing agent in maintaining remission among patients with PV, but the results were not statistically significant.59

Dose-dependent hemolytic anemia and methemoglobinemia will occur to some degree in all patients. Cimetidine, 400 mg PO 3 times daily, can reduce dapsone-induced methemoglobinemia without affecting the clinical response.60 Dapsone may also cause agranulocytosis and hepatic function abnormalities. Distal motor neuropathy is a rare and reversible side effect, and monitoring by clinical examination and nerve-conduction studies must be done. The typical dose of dapsone ranges between 100-300 mg daily, although the effective dose varies significantly between individuals.61 In low-risk patients, treatment can be initiated at a dosage of 100 mg daily.

Intravenous Immunoglobulin (IVIg)
IVIg has been shown in numerous small studies to be beneficial in refractory PV, BP and EBA.62-81 A randomized, placebo-controlled, double-blind study demonstrated that pemphigus patients given a single cycle of high dose IVIg (400 mg/kg/day over 5 consecutive days) experienced a prolonged time to escape from the protocol compared to placebo.82 An earlier retrospective study found no response to IVIg in 9 of 11 patients with AIBD.83 Side effects are usually mild and self-limiting and include headache, back pain, chills, flushing, fever, hypertension, myalgia, nausea and vomiting. These may improve with decreased infusion rate or premedication with NSAIDs, antihistamines, or low-dose IV corticosteroids. Mild skin reactions including erythema, pain and phlebitis can occur at the infusion site. Potential severe side effects include anaphylaxis (particularly in IgA-deficient individuals), renal failure, aseptic meningitis, and infection. The typical dosing cycle is 2 g/kg divided into 2 or 3 equal doses, given on 3 consecutive days, repeated every 4 weeks.62

Rituximab
Rituximab has shown the most promise as therapy in PV, although it may also be beneficial in the treatment of BP and refractory EBA.84-89 A majority of patients treated with various protocols of rituximab achieved either complete or partial remission. Relapses are common, but can also be successfully treated with additional courses of rituximab.90 A group of 25 patients with mucous membrane pemphigoid (5 with mucous membrane dominant EBA) also responded well to rituximab.91 The data on rituximab use in BP is less robust due to the efficacy of steroids in this disease. In 11 patients with BP refractory to standard treatments, rituximab use resulted in either complete or partial remission.89,92-94 The most common adverse effects are mild and self-limiting and include fever, headache, nausea, chills, hypotension, and thrombocytopenia. Many of these symptoms are infusion related. Infections can also occur and may be life threatening, particularly in immunosuppressed patients. A potentially severe consequence is progressive multifocal encephalopathy (PMLE). The estimated rate of PMLE after rituximab therapy is 4.06 per 100,000 patients. To date, no cases have been reported in patients treated for AIBD.95,96 Nonetheless, clinicians and patients should be aware of the risk of this rare, but extremely serious, adverse event. Two dosing schedules exist for rituximab: the one traditionally used in lymphoma consists of weekly IV infusions of 375 mg/m2 for 4 weeks and the other more commonly used in rheumatoid arthritis is two 1 g infusions, administered 2 weeks apart. The latter has become increasingly used as the standard protocol for AIBD.

Conclusion

The treatment of AIBD varies greatly, but usually consists of topical or systemic steroids or combination therapy with steroid sparing agents or immunomodulators.97 For PV, BP and EBA, finding the optimal treatment can be very difficult and often requires several dose adjustments or trial of an alternative steroid-sparing agent before the disease is well-controlled. Supportive care is often necessary to reduce the risk of complications and improve quality of life. This often requires collaborative approaches to therapy with ophthalmology and/or otolaryngology, when severe mucous membrane disease is present. For PV, first-line therapy is systemic corticosteroids and first-line adjunctive therapy is usually azathioprine or MM. Rituximab has recently been gaining ground as a treatment for refractory cases. The treatment algorithm for BP is similar. However, because patients with BP tend to have more comorbidities, early transition to combination or steroid-sparing therapy may be necessary.

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