Bullous Pemphigoid: Title and subTitle BreakThe Latest in Diagnosis, Prognosis, and Therapy

When I was a dermatology resident in the mid-1980s, I became fascinated, some might say obsessed, with autoimmune blistering diseases. At that time, interest in and advances in the understanding of these diseases were on the rise. Since then, enormous leaps in our understanding of the pathophysiological features of these autoimmune blistering diseases have been made in large part because of the widespread application of sophisticated molecular biological techniques to ascertain the target antigens against which autoimmune responses are directed. Our appreciation of the full spectrum of bullous pemphigoid (BP), the most common of all the autoimmune blistering diseases, has grown as a function of advances in not only the basic science arena but also the clinical arena. In this editorial I focus my comments on key points relevant to caring for patients with BP, with the understanding that many of these clinical advances have been made possible by advances in basic science.

Bullous pemphigoid is most commonly seen in the elderly. The lesions of BP are tense blisters that occur on healthy skin or on an erythematous base. Blisters typically are found on the flexor surfaces of the arms and legs, axillae, groin, and abdomen. Oral lesions are seen in a minority of patients and the lesions are usually transient. Patients may also present with urticarial plaques that may evolve into blisters.¹ Several clinical variants have been described, including pemphigoid nodularis in which patients have overlapping features of prurigo nodularis and BP, dyshidrosiform pemphigoid in which patients have overlapping features of dyshidrotic eczema and BP, pemphigoid vegetans in which patients present with vegetating lesions, and erythrodermic BP in which patients present with an erythroderma either with or without typical lesions of BP.^{2 - 5} All of these subtypes, while clinically distinct, share immunopathologic features that allow them to be diagnosed as BP.

The histological features of BP include a subepidermal blister with an inflammatory infiltrate that often is rich with eosinophils but may also contain lymphocytes, histiocytes, or neutrophils. Since these histological findings are seen in several other related conditions, further diagnostic testing is essential. Direct immunofluorescence studies should be performed on healthy or erythematous nonbullous perilesional skin; these studies should reveal linear basement membrane zone deposits of IgG and C3, the third component of complement, in most patients. Similar direct immunofluorescence findings can also be observed in several other autoimmune blistering diseases, including epidermolysis bullosa acquisita, cicatricial pemphigoid, herpes gestationis, and bullous eruption of systemic lupus erythematosus. Therefore, indirect immunofluorescence studies performed using salt-split skin are necessary in the appropriate complete evaluation of these patients. For example, as reported in this issue, Vaillant and colleagues⁶ studied 231 patients who had a subepidermal blistering disease and IgG or C3 linearly deposited at the epidermal basement zone on direct immunofluorescence, and they found that 15% of this group had either epidermolysis bullosa acquisita or bullous systemic lupus erythematosus. Indirect immunofluorescence studies reveal that patients with BP and herpes gestationis have circulating IgG antibodies that typically bind to the epidermal side of salt-split skin as distinguished from patients with epidermolysis bullosa acquisita and bullous systemic lupus erythematosus who have circulating IgG antibodies that bind to the dermal side of salt-split skin.⁷ Most patients with cicatricial pemphigoid will have circulating IgG antibodies that bind to the epidermal side of salt-split skin, but some patients with cicatricial pemphigoid, such as those with the anti–laminin-5 variant, will have IgG antibodies that bind to the dermal side of salt-split skin.⁸ Unfortunately, I have found that many clinicians do not perform indirect immunofluorescence studies, even though these studies are helpful in distinguishing between these different diseases, thereby facilitating the choice of appropriate therapy. Since BP can often be sucessfully treated with systemic corticosteroids and epidermolysis bullosa acquisita may be resistant to systemic corticosteroids and often requires much more aggressive therapy, such as cyclosporine or extracorporeal photopheresis,^{9 - 10} obtaining the proper diagnosis at the onset of therapy is important. To assist in making the proper diagnosis, I suggest that serum samples for indirect immunofluorescence studies be obtained at the same time that biopsies for histological tests and direct immunofluorescence studies are performed. Because approximately 10% to 15% of patients may not have detectable circulating autoantibodies using salt-split skin indirect immunofluorescence studies, these patients should be evaluated using the salt-split skin direct immunofluorescence assay. This technique allows for the detection of in situ–bound immunoreactants in the skin and can also distinguish between BP, in which immunoreactants typically bind to the epidermal side of the split, and epidermolysis bullosa acquisita, in which the IgG binds to the dermal side of the split.¹¹ More sophisticated studies that aid in securing the diagnosis of BP include immunoblotting and immunoprecipitation, which demonstrate that most patients have circulating antibodies directed against 1 or both of the 230000 and 180000 molecular-weight BP antigens (known respectively as BPAG1 and BPAG2), and immune electron microscopy, which reveals immune deposits that localize to the hemidesmosome.^{12 - 14} Immunoblotting, immunoprecipitation, and immune electron microscopy are used primarily as research tools and only rarely in the routine examination of patients.

In this issue, Vaillant and colleagues⁶ address the important issue of whether there is any specific group of clinical criteria that will allow one to reliably diagnose BP in the absence of the availability of more sophisticated testing. Using a group of 230 patients with a subepidermal blistering disease and IgG or C3 linearly deposited at the epidermal basement zone on direct immunofluorescence, Vaillant et al developed a set of 4 predictive items from a logistic/stepwise multivariate analysis that allowed them to diagnose BP with a positive predictive value of 95%. In this group of patients, the authors used immune electron microscopy as the criterion standard to distinguish BP from other autoimmune blistering diseases. Their 4 criteria included the absence of atrophic scars, the absence of head and neck involvement, the absence of mucosal involvement, and age older than 70 years. The authors found that if patients had 3 of these 4 criteria, a diagnosis of BP could be made with a sensitivity of 90% and a specificity of 83%. Although I am concerned that a specificity of 83% is not good enough for either clinical practice or therapeutic trials and my clinical experience does not support the observation that patients with BP tend not to have head and neck or oral involvement, the real question to be answered here is whether these findings will aid in the diagnosis of patients with autoimmune blistering diseases. Since these patients all have histological findings of a subepidermal blister along with direct immunofluorescence study findings revealing linear basement membrane zone deposits of IgG and/or C3, the question is whether measuring the 4 clinical criteria in this study is more reliable than performing tests such as indirect immunofluorescence on salt-split skin or more sophisticated tests such as immunoblotting, immunoprecipitation, immune electron microscopy, or the recently reported enzyme-linked immunosorbent assay technique¹⁵ to diagnose BP. Although we do not have sufficient information to answer this question, Vaillant and colleagues⁶ raise an important issue and hopefully future studies will allow us to answer this question. Currently, the evaluation of patients with suspected BP should continue to include histological studies and direct and indirect immunofluorescence studies performed on salt-split skin. In the absence of detectable circulating IgG antibodies using salt-split skin indirect immunofluorescence studies, then the salt-split direct immunofluorescence assay should be performed. In the occasional difficult-to-diagnose case, more sophisticated studies should be used to establish the diagnosis.

If left untreated, patients with BP typically have disease that will last from a few months to several years. They may have spontaneous remissions and exacerbations, and recurrent disease may be milder than the initial episode. One study attempted to identify whether there were any clinical features that could be predictive for the clinical course of BP. The authors evaluated numerous clinical and laboratory features of the disease but were unable to identify any criteria that would prospectively identify particular subgroups of patients with predictable outcomes.¹⁶ Two more recent studies looked specifically at the correlation of BP autoantigen profiles with disease prognosis. These studies demonstrated that patients who have circulating antibodies directed against BPAG2 have a poorer prognosis with an increased likelihood of dying in the first year of treatment,¹⁷ and they also tend to have more severe disease and require higher doses of corticosteroids.¹⁸ These findings strengthen growing evidence that autoantibodies directed against BPAG2, which have been shown in an animal model to reproduce the clinical, histological, and immunopathologic features of BP,¹⁹ play a critical role in the pathogenesis of the disease. The intriguing possibility is raised that when the enzyme-linked immunosorbent assay for BPAG2 becomes widely available as a laboratory tool, we will be able to determine if a given patient has BPAG2 antibodies and therefore might be at higher risk for more severe disease, thus allowing us to tailor our initial therapy more effectively.

While BP is the most common autoimmune blistering disease, with a reported incidence of approximately 10 cases per 1 million population, there have been relatively few studies of its prognosis. Previous studies have demonstrated that the mortality rate in patients with BP is relatively low, with a 1-year mortality rate of 19%,¹⁶ a 2-year mortality rate of 6%,²⁰ and 3-year mortality rates of 28% and 30%.^{21 - 22} Roujeau and colleagues²³ recently reported a 6-month mortality rate of 31%, with a 1-year mortality rate of 41% in a large group of patients with BP. In these patients, most of the mortality was due to an increased incidence of sepsis and cardiovascular disease. These mortality rates are alarmingly high for patients with BP and are not at all consistent with my personal experience in caring for patients with BP. Since these findings are so surprising, it is important to try to determine why these patients had such a high mortality rate. Roujeau and colleagues²³ suggest that the older age of these patients at disease onset is the major reason for the increased mortality, but this does not seem likely because the 217 patients described in this retrospective study had an average of 79 years, and the average age of all the other patients in the other 4 reported series was 75 years, which does not appear to be significantly different. Another possibility is that the patients who died had been treated differently than the patients who lived. Although we are given data about the initial dosage of prednisone in both groups of patients, it would be important to compare the prednisone dosages of the patients who died and those who lived at 3 months and at 6 months to determine if the increased mortality could be attributed to a requirement for the maintenance of higher dosages of prednisone. The importance of obtaining these data is highlighted by the fact that Roujeau et al²³ suggest that older patients with BP in poorer general health be treated with topical corticosteroids. The implication is that systemic corticosteroids lead to a higher risk of death in patients with BP, but unfortunately the data do not allow such a conclusion to be drawn.

Perhaps the most important factor that needs to be be addressed regarding that study is potential selection bias. This point is discussed by the authors, but I am concerned that since most of the patients had generalized disease and were seen in referral centers that there was a bias toward seeing the older, generally sicker patients with more extensive disease and that patients with less severe disease were not seen at these referral centers. This theory is underscored by the observation that each of the 3 hospitals in the study accrued approximately 10 new patients each year, which appears to be a relatively low number of patients diagnosed as having BP when compared with my observation of approximately 20 new patients diagnosed per year using immunofluorescence studies in an area where practitioners have several options regarding their choice of laboratory. Another possibility to be considered is that since the patients in that study²³ were mostly French, there are differences in survival of patients with BP from country to country. Indeed, this point may be relevant since 2 other French studies also found higher mortality rates: a 38% mortality rate at 1 year in one study²⁴ and a 31% mortality rate at 3 months in another study.²⁵ However, the recent study by Roujeau and colleagues²³ includes all the data previously reported in 1995 by Bernard et al.²⁴ Nevertheless, this data redundancy reveals that high mortality rates in French patients with BP have been documented in 2 separate studies, suggesting that there may be significant variations in the survival of patients with BP based on their ethnicity. Other information not included in this study that might be of prognostic value include the percentage of body surface involvement with BP and a better assessment of the patients' health status, which is more revealing than the overall general condition based on the patients' autonomy. Without significantly more information regarding comorbidities and given the selected sample, I believe that the findings of Roujeau and colleagues²³ cannot be extrapolated to all patients with BP. Future multicenter collaborative prognostic studies performed in a prospective fashion, which could be modeled after the ongoing study of the value of dapsone as a potential corticosteroid-sparing agent in the treatment of pemphigus vulgaris sponsored by the Medical Dermatology Society,²⁶ may allow us to better delineate important prognostic factors and death rates in patients with BP. I hope such future studies will also include information about how patients are doing after being diagnosed as having BP. Issues such as their level of functional impairment, what sequelae of medication toxicity they have experienced, and a comparison of their lives before and after being diagnosed as having BP would be addressed in this quality-of-life assessment.

The therapeutic management of patients with BP is dictated by the degree of involvement and the rate of disease progression. Almost all therapeutic regimens are based on clinical experience, and there are few controlled clinical trials in the treatment of BP. Generally, patients with localized disease may be treated with potent topical corticosteroids. Systemic corticosteroids have always been the major form of therapy for most patients diagnosed as having BP. Despite the absence of controlled studies demonstrating the efficacy of systemic corticosteroids over placebo or topical corticosteroids, a vast body of clinical experience supports the efficacy of systemic corticosteroids in the treatment of patients with BP. The study by Roujeau and colleagues,²³ while failing to demonstrate any statistically significant (P=.80) evidence to support the notion that systemic corticosteroid treatment places patients at a higher risk of dying, goes on to suggest that elderly infirm patients with BP be treated with topical corticosteroids to avoid the increased risk of infection that systemic corticosteroid treatment imparts. The authors cannot have it both ways. Since their study does not demonstrate that patients treated with systemic corticosteroids have a higher mortality rate, it is not reasonable for them to suggest that elderly infirm patients be treated with topical corticosteroids to avoid the increase of death due to infection. The only conclusion that can be drawn from this study is that there was a high mortality rate in this group of elderly French patients with BP. The authors have not presented any convincing data to prove that treatment with systemic corticosteroids played any role in this increased mortality, and I do not believe that the results of this study should cause dermatologists to stop prescribing systemic corticosteroids for patients with BP.

I treat patients with BP who have mild generalized disease with low-dose prednisone, and those whose disease is more significant are usually treated with moderate-dose prednisone. Patients with contraindications to systemic corticosteroid therapy may be treated with dapsone (particularly those patients who have a neutrophil-predominant infiltrate),²⁷ a combination of tetracycline and nicotinamide,²⁸ or immunosuppressive drugs such as azathioprine.^{21 ,29} Younger patients with BP who have contraindications to systemic corticosteroids are often treated with tetracycline and nicotinamide. I reserve azathioprine for older patients with more significant disease because of the probable increased risk of malignant neoplasms in patients receiving azathioprine.³⁰ Patients taking azathioprine alone generally respond within 3 to 6 months of treatment, often allowing discontinuation of therapy at that time. Subsequent disease flares often respond well to the reinstitution of azathioprine therapy. Unfortunately, there is no monitoring system that allows one to predict when the azathioprine therapy can be discontinued without concern for disease relapse. Patients with BP who have significant disease are often successfully treated with moderate-dose prednisone along with azathioprine. As the disease comes under control, prednisone therapy is tapered to every other day and then discontinued. Treatment with azathioprine alone is continued for another 3 to 6 months, and then when the disease is quiescent, the azathioprine therapy is discontinued. Cyclophosphamide therapy also is used in the treatment of elderly patients with BP as a corticosteroid-sparing agent, along with systemic corticosteroids.³¹ However, because of a more severe toxicity profile than azathioprine, cyclophosphamide therapy is reserved for use in only those patients who have extensive disease and who have not responded to or have not been able to tolerate azathioprine therapy.³⁰

While uncontrolled studies have demonstrated the utility of both azathioprine and cyclophosphamide therapy in the treatment of patients with BP, a recent controlled study failed to demonstrate an increased benefit of treatment with azathioprine and corticosteroids together when compared with corticosteroids alone.³² Since the patients in this study did not have their thiopurine methyltransferase (TPMT) levels evaluated, it has been suggested that most of these patients (approximately 89% according to previous studies)³³ may have received inadequate doses of azathioprine. Thiopurine methyltransferase is an enzyme that metabolizes azathioprine, and genetic polymorphisms in this enzyme control whether the patient develops bone marrow toxic effects (most commonly leukopenia but rarely pancytopenia) or fails to respond to the drug. The measurement of TPMT allows for a more rational method than empirical dosing in determining the appropriate dosage of azathioprine to be used. A recent study of 28 patients treated with azathioprine who had their TPMT levels measured demonstrates the utility of this approach.³⁴ Leukopenia was observed in 3 patients who had either intermediate TPMT levels and were treated with midrange doses of azathioprine or who had slightly higher TPMT levels and were treated with very high doses of azathioprine. Poor clinical response was seen in 10 patients who had very high TPMT levels but were treated with low doses of azathioprine.³⁴ Based on these preliminary studies, the following rough guidelines for azathioprine regimens were suggested. Patients who are homozygous for the low TPMT allele (TPMT level, <5.0 U/mL of red blood cells) should not receive azathioprine because they have a high likelihood of developing pancytopenia. Patients who are heterozygous for the TPMT low allele (TPMT level, 5.0-13.7 U/mL of red blood cells) should receive approximately 0.5 mg/kg of azathioprine. Patients who are homozygous for the TPMT high allele (TPMT level, 13.7-19.0 U/mL of red blood cells) should receive approximately 1.5 mg/kg of azathioprine, and patients with TPMT levels above 19.0 U/mL of red blood cells should receive approximately 2.5 mg/kg of azathioprine.³⁴ Although larger studies will be necessary to rigorously ascertain the validity of these guidelines, I have followed these recommendations in the treatment of more than 40 patients taking azathioprine and have found these guidelines to be helpful. Since I began using TPMT testing, I have found that patients seem to respond better to azathioprine therapy with somewhat more rapid clearing, often allowing a more rapid tapering of corticosteroids, perhaps because I am able to use higher doses of azathioprine when I discover that a patient has a high TPMT level. It is encouraging that TPMT testing can be of value not only in predicting which patients should be receiving azathioprine, but also in assisting in the development of dosing guidelines. Thiopurine methyltransferase testing may prove to be even more useful in the treatment of patients taking azathioprine than is glucose-6-phosphate dehydrogenase testing in patients receiving dapsone, but further study will be necessary to confirm its value. In the controlled trial of azathioprine and corticosteroids compared with corticosteroids alone by Guillaume and colleagues,³² the apparent failure to demonstrate a good therapeutic response to azathioprine therapy may be at least partially explained by the underdosing of patients with high TPMT levels.³⁵ Given this observation, it is reasonable to conclude that the value of azathioprine as an adjuvant to systemic corticosteroid therapy in the treatment of BP has not yet been adequately assessed. Therefore, I continue to use azathioprine therapy in the treatment of patients with BP.

Other treatments that have been used as corticosteroid-sparing agents in patients with moderate-to-severe disease with varying degrees of success include cyclosporine, chlorambucil, and methotrexate.^{22 ,36 - 37} Mycophenolate mofetil is a newly developed immunosuppressive drug that is a derivative of mycophenolic acid; the drug was used several years ago in the treatment of psoriasis and has increased bioavailability and decreased toxicity. Mycophenolate mofetil recently has been used with some success as a corticosteroid-sparing agent in the treatment of BP.³⁸ Options to be considered in patients with the most severe progressive disease that is uncontrollable include pulse corticosteroids, plasmapheresis, intravenous immunoglobulins, and intravenous pulse cyclophosphamide.^{39 - 42}

Herein is an up-to-date look at BP that hopefully will aid the clinician in the treatment of these patients. Further studies will be necessary to determine whether the latest reports on the diagnosis and prognosis of BP^{6 ,23} are relevant in our day-to-day treatment of these patients. Future basic science advances may allow us to use innovative approaches for the treatment of BP, such as antigen-specific plasmapheresis, that has been suggested for the treatment of pitalicigus vulgaris.⁴³

Accepted for publication June 7, 1998.

Reprints: Neil J. Korman, PhD, MD, Department of Dermatology, University Hospitals of Cleveland, 11100 Euclid Ave, Cleveland, OH 44106-5028.