Elderly patients tend to have age-related immune system impairment and comorbidities and therefore the recommendation to avoid immunosuppressive drugs is even more important in this group of patients.

It is also important to evaluate and take into account each patient's capacity and level of dependency in terms of activities of daily living, as well as their environment (e.g., do they live with their family or in a care home) and the support or help available. These aspects may determine the choice of treatment. For instance, topical treatments are difficult to apply for a person with reduced mobility or who does not have help. Scales such as the Karnofsky Performance Scale Index (originally developed for patients with cancer) can be used to evaluate the patient's general health and guide the assessment.

Furthermore, comorbidities and drug use (which are both common in elderly patients) should be carefully noted down in the initial clinical history, as should any changes that occur during the course of the disease, to avoid prescribing contraindicated drugs or causing unwanted drug interactions.

It should also be recalled that elderly patients may have impaired or altered cognitive functions. In such cases, it can be difficult to evaluate certain clinical aspects, such as pruritus or drug tolerance, and to give instructions about treatment. In our experience, it is important to adequately inform, support, and engage relatives or caretakers in the control of the disease.

Childhood BP typically has a better prognosis and a less aggressive course than adult BP.23 The use of toxic drugs and systemic corticosteroids should be minimized due to their adverse effects, particularly in terms of their potential interaction with growth and development. If systemic corticosteroids are to be used, data on height and percentiles should be recorded at the outset to control for changes during follow-up. In our practice, we have seen cases of aggressive, difficult-to-manage BP in children in whom immunosuppressants and systemic corticosteroids were needed to achieve control. In our opinion, management by a multidisciplinary team, including pediatricians, has many benefits. Systemic corticosteroids should not be withdrawn in a child without first performing an ACTH test to check that the adrenal glands are functioning correctly and protect against the risk of acute adrenal insufficiency.

It should also be noted that topical corticosteroids can cause complications due to systemic absorption (which is increased in children), particularly in the case of extensive or mucosal lesions.

Good skin hygiene with thorough daily cleansing of skin and mucous membranes is important in all patients with BP. We also recommend keeping an approximate count of lesions. The lesions should be cleansed before the application of the topical treatment. Blisters can be drained by piercing the base of the lesion with a sterile needle or blade. Application of an antiseptic solution, such as eosin 2% or chlorhexidine 0.5%, on erosive lesions reduces the risk of secondary infection. If such an infection does occur, topical antibiotics such as fusidic acid and mupirocin can be used. A course of systemic antibiotics must be started when deep cutaneous infection (cellulitis) is suspected.

Topical or systemic corticosteroids are generally the first line of treatment in BP. High-potency topical corticosteroids (Table 2) are particularly indicated in patients with mild or moderate symptoms. In such cases, additional treatment may not be necessary, thereby avoiding the risk of complications due to systemic agents. Very potent topical corticosteroids are also frequently used as adjuncts.

The effectiveness of topical corticosteroids as monotherapy has been reported in numerous case reports and small series. In a recent study of 96 patients with BP, topical corticosteroids alone (mean dose of 30 g/d of clobetasol propionate 0.05%) achieved disease control in 62% of patients.26 These drugs have also shown better efficacy and safety than systemic corticosteroids in a randomized study.22 The only disadvantage of this randomized study was that it used a rather unconventional treatment regimen, which consisted of 40g per day of clobetasol propionate applied to the entire surface of the body (including healthy skin). The regimen has received considerable criticism, as it is not easy to apply in older patients and it is not known either what quantity of corticosteroids is absorbed into the system. (We have seen patients on this regimen developing Cushing syndrome similar to that seen with systemic corticosteroids.) In a more recent study, the same group described similar efficacy but fewer side effects with lower doses of topical clobetasol.27 Another important consideration with topical corticosteroids is that many patients may not be able to apply the treatment without help. This would obviously make treatment adherence difficult and consequently result in considerably reduced effectiveness.

The efficacy of systemic corticosteroids (Table 3) has been demonstrated in several studies and is supported by extensive clinical experience. Unless contraindicated, systemic corticosteroids are considered the treatment of choice in patients in whom topical treatment is insufficient or unfeasible. The most common agents used are prednisone and prednisolone.

The recommended dose ranges from 0.5 to 0.75mg/kg/d, as higher doses have not been seen to improve efficacy and are associated with a higher risk of adverse effects.28 When using doses within the above-mentioned ranges, it is important to administer proton pump inhibitors to prevent gastroduodenal peptic ulcers and also to prescribe calcium supplements, vitamin D, and bisphosphonates from the outset to prevent steroid-induced osteoporosis.

Systemic corticosteroids generally produce favorable outcomes within the first weeks of treatment, enabling subsequent dose tapering. Complete remission is often achieved within 6 to 10 months, after which time these agents can be completely withdrawn.21

In patients who respond only partially to corticosteroid therapy or who develop adverse effects, nonimmunosuppressive agents such as tetracyclines, erythromycin, nicotinamide, and sulfone can be used as adjuvant therapy, especially in patients with mild or moderate disease. Thanks to their anti-inflammatory properties, tetracyclines and nicotinamide (Table 4) are used in conditions like BP whose pathogenesis involves immune mechanisms. Furthermore, the fact that these agents do not cause major adverse effects makes them a good choice for older patients and children. Tetracyclines have been seen to inhibit chemotaxis of neutrophils and eosinophils and block the action of certain metalloproteases. They are frequently used in combination with nicotinamide, which acts on different parts of the inflammatory response.

Most of the data on the effectiveness of tetracyclines and nicotinamide originate from isolated cases. However, one randomized study of a small group of patients with BP found no significant differences in terms of response to tetracycline 2g/d combined with niacinamide 2g/d versus prednisone therapy alone (40-80g/d).29

The mechanism of action of sulfone (Table 5) has not been fully elucidated, but it appears to involve an anti-inflammatory component, as sulfone is capable of inhibiting neutrophil adherence to vascular endothelial cells, chemotaxis, lipoxygenase production, and the action of neutrophil and eosinophil myeloperoxidase. Its use in BP, either as monotherapy or adjuvant therapy, has not been investigated in randomized trials, but several retrospective studies have reported response rates of between 15% and 45%.30–33 One major drawback of sulfone is that therapeutic doses almost always cause anemia. Reductions in hemoglobin levels of 1 to 2g/dL are common and can sometimes be very poorly tolerated by elderly patients. (We have observed some cases of angina and heart failure in such cases.)

Immunosuppressive agents are indicated for patients with moderate or severe disease in whom high doses of corticosteroids fail to control the disease or in whom effective doses cannot be maintained due to adverse effects.

In our experience, methotrexate (MTX) (Table 6) is one of the first-line immunosuppressive treatments for BP. It is a folic acid antagonist that is used at low doses as a corticosteroid-sparing agent in numerous diseases. For dermatologists, it has the advantage of being a well-known drug with a very good safety profile that has been used widely in the treatment of psoriasis for decades.

MTX doses in BP are generally low, ranging from 2.5mg a week (in elderly patients with impaired renal function) to 10mg a week. Higher doses may be administered in some cases, but they should never exceed 15mg a week. It is very important to make clear to the patient (or to his/her carers, as elderly patients are often dependent and living in care) that MTX must be administered in a single weekly dose. There have been reports of cases (in patients with psoriasis) in which a shift to daily doses by health care personnel unfamiliar with MTX resulted in fatal toxic effects.

The effectiveness of MTX in BP is supported by evidence from numerous case reports and series in which it has been used in monotherapy as a systemic corticosteroid-sparing drug in patients with moderate to severe disease, or in association with topical corticosteroids in patients with less severe disease.34,35 In one prospective study involving 11 patients administered MTX and topical corticosteroids, all the patients responded rapidly.34 The authors recommended starting at a dose of 5mg/wk and increasing this by 2.5 mg every week (up to a maximum of 12.5mg/wk) until clinical remission is achieved.

More powerful immunosuppressive drugs such as azathioprine (AZA), mycophenolate, and cyclophosphamide are indicated for severe or refractory cases of BP.

AZA (Table 7) is an imidazolyl derivative of 6-mercaptopurine with anti-inflammatory and immunosuppressive properties. It is administered orally or intravenously. To date, no significant differences in response have been observed in BP between patients treated with AZA as an adjunct agent and patients treated with systemic corticosteroids alone.36,37 There is, however, extensive experience with the use of AZA as a corticosteroid-sparing drug, and in our setting it is the most common drug used for this purpose.

The therapeutic effect is normally achieved within 6 to 10 weeks of commencement of treatment. It is important to measure TPMT enzyme levels before prescribing AZA. TPMT metabolizes this drug and therefore knowledge of its activity helps to prevent hematologic toxicity through dose adjustments, although it does not provide information on hepatic toxicity. TPMT activity depends on 3 mutant alleles of the TPMT gene—TPMT*2, TPMT*3A, and TPMT*3C—which are involved in 95% of cases of low or moderate enzyme activity. The presence of these 3 alleles is predictive of phenotype. Heterozygous patients (with 1 wild-type allele and 1 mutant allele) will have moderate TPMT activity, while homozygous patients (with 2 mutant alleles) will have complete TPMT deficiency (this is the case of approximately 1 in every 300 members of the general population). TPMT activity can be measured by 2 methods: determination of the intraerythrocytic activity of the enzyme (a less accurate method) or allele identification by polymerase chain reaction.

Mycophenolate (Table 8) inhibits the synthesis of DNA nucleotides. Two different drugs are used in clinical practice: mycophenolate mofetil (MPM) and enteric-coated mycophenolate sodium (EC-MPS). MPM is a prodrug of mycophenolic acid that has been used since 1997 for the prophylaxis of kidney transplant rejection. According to its summary of product characteristics, it is now also indicated for liver and heart transplantation. EC-MPS was designed to reduce the gastrointestinal intolerance frequently seen with MPM. The enteric coating delays the release of the active substance, preventing contact with the acid medium of the stomach. EC-MPS is currently licensed by the US Food and Drug Administration (FDA) for use in kidney transplantation.

Few studies to date have analyzed the use of MPM (or EC-MPS) in the treatment of BP. It is generally used in a similar fashion to AZA, i.e., as a corticosteroid-sparing agent, although it has also produced favorable results when used as monotherapy.38 It is as effective as AZA and has a better safety profile, but it is considerably more expensive. In a recent study of patients with BP, corticosteroids combined with MPM showed similar efficacy to corticosteroids combined with AZA.39

The toxicity of cyclophosphamide (Table 9), particularly its effects on fertility, myelosuppression, and increased risk of malignancy, is an important limitation to its use in patients in whom other drugs are contraindicated or ineffective. Cyclophosphamide is one of the most potent suppressors of cell-mediated and humoral immunity, but it is also one of the most effective drugs of its kind. It is an alkylating agent, administered orally or intravenously, that is metabolized by cytochrome P450. Although no randomized trials have investigated its value in BP, several case reports and small series have reported on its use as an adjuvant, corticosteroid-sparing agent. The results have shown that it is a potent drug but that it is considerably more toxic than other immunosuppressants.40,41 In our experience, cyclophosphamide can be a very good second-line option when used at low doses (50-100mg/d), particularly in elderly patients in whom long-term side effects are perhaps not the overriding concern.18

New nonimmunosuppressive treatments, with different mechanisms of action, have emerged in recent years. Examples are IVIG therapy and rituximab, which have been used as third-line alternatives, particularly in cases of severe or refractory BP (Fig. 8).

Figure 8.

Treatment algorithm for bullous pemphigoid (BP). MTX indicates methotrexate; MPM, mycophenolate mofetil; CPH, cyclophosphamide; IVIG, intravenous immunoglobulin therapy; RTX, rituximab.

(0.12MB).

The immunoglobulins used in IVIG therapy (Table 10) are obtained from the plasma of numerous donors. Approximately 90% of the immunoglobulins present in each formula are IgG and the remainder are IgE and IgM. The mechanism of action involved is complex and not yet fully understood. IVIG therapy has been associated with a clear, rapid decrease in levels of pathogenic antibodies in several autoimmune diseases. This decrease has also been demonstrated in animal models42 and anti-basement membrane antibodies in BP.

While BP is not among the FDA-approved indications for IVIG therapy, there have been numerous reports of it being used successfully to treat this disorder. Most of the patients, including 15 from a prospective study,43 had refractory BP that failed to respond to other treatments but responded adequately to IVIG therapy. The addition of immunosuppressive drugs has been seen to reduce the rebound effect seen following the rapid reduction of pathogenic antibodies induced by IVIG therapy.

IVIG therapy is expensive, fast-acting, and nonimmunosuppressive, and must be administered in an inpatient or day-hospital setting. Because of its cost, it would only be indicated for patients who do not respond to or who develop adverse effects to second-line treatments, or for patients in whom a rapid response is required and immunosuppression is no longer an option.

Rituximab (RTX) (Table 11) is a humanized chimeric monoclonal antibody that selectively targets CD20 cells. These include pre-B cells and mature B cells, but not stem or plasma cells. The drug was initially developed to control lymphoproliferative B-cell disorders, but in recent years, used either alone or in combination with IVIG therapy, it has proven to be effective at controlling an increasing number of autoimmune diseases that do not respond to other treatments.

The effects of RTX take approximately a month to appear and are maintained for 9 to 12 months (the time it takes for B cells to recover). It has proven effective in autoimmune blistering disorders with higher morbidity and mortality than BP, such as pemphigus vulgaris and pemphigus foliaceous. Consideration of rituximab in refractory cases of BP is warranted considering the involvement of B cells in the pathophysiology of this disease. However, experience with its use in this setting is still limited to isolated cases and no randomized trials have investigated factors such as dose regimens, monitoring, etc.

In a recent retrospective study in which 5 patients with BP who had not responded to several drugs were treated with RTX, 3 of the patients showed complete response and a fourth showed partial response. The other patient, who had heart disease, died unexpectedly several days after starting treatment.44

RTX must be administered in an inpatient or day-hospital setting. Its toxicity and associated mortality are not negligible, particularly in relation to the risk of serious opportunistic or other infections. It should therefore only be considered in patients with severe disease who do not respond to conventional treatments.45

Therapeutic plasma exchange is a costly technique that is not available in most hospitals. It is therefore not widely used in our setting, even for autoimmune blistering disorders with higher morbidity than BP. The technique involves substituting a considerable volume of the patient's blood (2-5L) with replacement plasma.

Two randomized studies have compared the effects of plasma exchange combined with systemic corticosteroids versus corticosteroids alone36 or in combination with AZA.46 No significant differences were observed between plasma exchange and AZA as adjuncts, although in one of the studies46 a reduction was observed in the dose of corticosteroids in the plasma exchange group.

Therapeutic plasma exchange increases the risk of thrombosis, infections, and electrolyte abnormalities. Furthermore, it requires the use of an arteriovenous fistula, which carries an addition risk of adverse effects. It is generally administered in association with systemic corticosteroids or immunosuppressive drugs, which help to reduce the rebound effect produced by the activation of autoreactive lymphocytes following the exchange.

Plasma exchange is thus an exceptional treatment that is rarely used in BP. It should be reserved for patients with acute, severe disease who have high levels of circulating antibodies and contraindications for other treatments.

The authors declare that no tests were carried out in humans or animals for the purpose of this study.

The authors declare that they have followed their hospital's protocol on the publication of data concerning patients and that all patients included in the study have received sufficient information and have given their written informed consent to participate in the study.

The authors declare that no private patient data appear in this article.