Treating Immunobullous Diseases: An Update

Sandrine Reynaert; Martin M. Black

Disclosures

Dermatology Nursing. 2004;16(1) 

Autoimmune bullous diseases are often associated with significant morbidity and some can even cause mortality, if left untreated. Multiple therapies are now available to treat these blistering conditions. However, few have been evaluated objectively.

Immunobullous diseases vary in clinical presentation and have different histopathologic and immunologic features (see Table 1 ). Immunofluorescence (IMF) can demonstrate the presence of antibodies bound in the skin or antibodies circulating in the serum by showing specific green fluorescence under the fluorescent microscope. IMF can depict different patterns, specific for certain types of immunobullous diseases (see Table 1 ).

Figure 1a.

Bullous pemphigoid

Figure 1b.

Bullous pemphigoid: Immunofluorescence

Figure 2a.

Pemphigus vulgaris: Mouth

Figure 2b.

Pemphigus foliaceous

Figure 2c.

Pemphigus: Immunofluorescence

Figure 3a.

Dermatitis herpetiformis: Buttocks

Figure 3b.

Dermatitis herpetiformis

Figure 3c.

Dermatitis herpetiformis: Immunofluorescence

Figure 4a.

Linear IgA disease

Figure 4b.

Linear IgA disease: Immunofluorescence

Epidermolysis bullosa acquisita

Epidermolysis bullosa acquisita: Immunofluorescence

The treatment of immunobullous diseases consists of three phases: control, consolidation, and maintenance. In the control phase intense therapy is given to suppress disease activity until no new lesions appear. The duration of this phase is weeks. Subsequently, the patients reach the consolidation phase during which drugs and doses are maintained until complete clearance of lesions. Finally, medications can be gradually tapered in the maintenance phase, aiming for the lowest dose that prevents new lesions from appearing (Bystryn, 2002).

The drugs used for treating immunobullous disorders can be classified into rapid and slow acting (see Table 2 ), topical and systemic (see Table 3 ), or immunosuppressant/immunomodulatory and anti-inflammatory (see Table 4 ).

Steroids

The mainstay of treatment of immunobullous diseases are steroids. Generally, high-dose steroids (prednisolone, prednisone, methylprednisolone, dexamethasone), oral or IV, are effective in obtaining rapid disease control. However, high-dose and prolonged treatment with steroids often causes significant side effects. Screening and risk assessment of possible side effects (diabetes, glaucoma, osteoporosis, blood pressure, history of GI bleeding) are required prior to and during treatment. It is recommended to give concomitant calcium supplements and anti-acid drugs (proton pump inhibitors) throughout therapy. A recent study (Femiano, Gombos, & Scully, 2002) of patients with pemphigus vulgaris showed IV pulse combined with low-dose oral steroid therapy to be more effective and associated with less severe side effects than oral high- dose steroid therapy.

To reduce the side effects of systemic steroids, French researchers compared the efficacy and side-effect profile of topical steroids compared to systemic steroids in the treatment of moderate to severe bullous pemphigoid (Joly et al., 2002). Topical steroids were more effective than oral therapy and were associated with far less severe complications. However, a recent report warns of steroid-induced skin atrophy and striae after trying this regime in a patient (Hull, McKenna, & Zone, 2003).

Intravenous Immunoglobulins

Recently, intravenous immunoglobulins (IVIG) have proven beneficial in achieving rapid disease control in patients with immunobullous diseases (Ahmed & Colon, 2001; Ahmed, 2001: Ahmed & Sami, 2002; Giourgiotou et al., 2002; Leverkus et al., 2002; Sami, Qureshi, & Ahmed, 2002). This therapeutic agent consists of IgG immunoglobulins which are collected from a pool of thousands of blood donors (virus free); therefore, providing a wide range of immunologically different IgG immunoglobulins. Theoretically, they bind and neutralize the pathogenic auto-antibodies. This product is given to the patient through an IV line, each cycle lasting 3 to 5 days, at a dose of 1 to 2 g/kg per cycle. However, several cycles are usually required. Cost and availability of this agent limits its use. IVIGcosts £3,000 (approximately $5,500 U.S.) for a 5-day course based on a patient of 70 kg. IVIG is generally used in resistant and severe bullous diseases in addition to immunosuppressive therapy or as monotherapy in patients with contraindications for immunosuppressive drugs.

Plasmapheresis

Plasmapheresis (Egan, Meadows, & Zone, 2002; Furue et al., 1986; Turner, Sutton, & Sauder, 2000), and more recently immuno-adsorption (Matic, Bosch, & Ramlow, 2001; Ogata, Yasuda, Matsushita, & Kodama, 1999; Schneider, 1998) are extracorporeal treatments which act rapidly on disease activity by lowering the load of the causative auto-antibodies in the patient's circulation. In immuno-adsorption, the immunoglobulins are selectively removed from the patient's plasma by adsorbing the antibodies to the matrix in a column of the immuno-adsorption apparatus after which the "cleansed" plasma is returned to the patient. Higher efficacy and less side effects of immuno-adsorption over plasmapheresis are claimed. In one German study (Schmidt et al., 2003), immuno-adsorption was effective and safe in treating resistant and severe pemphigus. However, more studies are needed to support these data.

Azathioprine

Among the slowly acting adjuvant therapies, azathioprine is a useful and safe steroid-sparing agent, provided triphosphate-methyltransferase (TPMT) assay is performed prior to treatment. TPMT is an enzyme that converts azathioprine into its inactive metabolites. If this enzyme is lacking or present in a much lower concentration, the patient will be at high risk for bone marrow suppression and thus anemia, thrombocytopenia, and leukopenia. Therefore, it is recommended TPMT levels be analyzed before starting treatment with azathioprine. However, other side effects of this drug (such as abnormal liver function tests) are not reflected by this enzyme level (Glied & Rico, 1999; Tan, Lear, Gawkrodger, & English, 1997).

Cyclosporine

Cyclosporine was not of additional benefit as a steroid-sparing agent in two controlled studies in patients with pemphigus and pemphigoid (Ioannides, Chrysomallis, & Bystryn, 2000). Furthermore, more side effects were found in patients treated with adjuvant cyclosporine and all these side effects were due to cyclosporine (Ioannides et al., 2000).

Methotrexate

Recent studies have shown low-dose methotrexate (up to 15 mg weekly), as monotherapy or adjunctive therapy, to be efficacious in bullous disorders, mainly bullous pemphigoid (Böhm, Beissert, Schwarz, Metze, & Luger, 1997a; Dereure, Bessis, Guillot, & Guilhou, 2002; Heilborn et al., 1999; Paul, Jorizzo, Fleischer, & White, 1994; Smith & Bystryn, 1999).

Mycophenolate Mofetil

Mycophenolate mofetil, first used in psoriasis, has more recently been introduced in the treatment of immunobullous diseases, usually in combination with steroids. Mycophenolate mofetil is an immunosuppressant that specifically targets lymphocyte proliferation and antibody production; hence, its beneficial effect in antibody-producing autoimmune blistering diseases. Usually mycophenolate is given at a dose of 2 grams daily. Recent studies have demonstrated a good response and few side effects in several autoimmune blistering conditions (Böhm et al., 1997b; Chams-Davatch et al., 2002; Enk & Knop, 1997 & 1999; Grundmann-Kollmann et al., 1999a & b; Katz, Marks, & Helm, 2000; Megahed, Schmiedeberg, Becker, & Ruzicka, 2001; Nousari, Sragovich, Kimyai-Asadi, Orlinsky, & Anhalt, 1999; Nousari, Griffin, & Anhalt, 1998; Nousari & Anhalt, 1999; Schattenkirchner, Eming, Hunzelmann, Krieg, & Smola, 1999; Trebing, 2001).

Cyclophosphamide

Several regimens with cyclophosphamide have been described in the treatment of immunobullous disorders. Cyclophosphamide is a potent cytotoxic agent which can cause severe cytopenia and hemorrhagic cystitis (bladder inflammation).

Oral low-dose cyclophosphamide is usually used as a steroid-sparing agent. Second, cyclophosphamide IV (500 mg daily for 1 day) plus low-dose oral (50 mg daily) has been combined with IV pulse dexamethasone (100 mg daily for 3 days) to achieve rapid disease control. IV pulse cyclophosphamide (500 mg daily) has also been suggested as adjunctive therapy after plasmapheresis to prevent "rebound" (marked increase of antibodies compensating for the antibodies depleted by plasmapheresis) (Turner et al., 2000). More recently, high-dose immunoablative cyclophosphamide without stem cell rescue was effective in two patients with resistant pemphigus. However, considering the serious side effects of this high-dose regimen, it should be reserved for patients who are resistant to other treatments (Cohen, Cohen, & Kerdel, 2002; Hayag, Cohen, & Kerdel, 2000; Nousari, Brodsky, Jones, Grever, & Anhalt, 1999). More studies are needed to outline the risk of side effects versus the benefits of this therapy regime.

Anti-Inflammatory Agents

Anti-inflammatory agents, such as dapsone, gold, and tetracyclines, are also being used to treat certain immunobullous disorders. However, these agents are generally used in patients with mild to moderate disease, with the exception of dermatitis herpetiformis and linear IgA disease, where dapsone is still first-line treatment. Dapsone can be started after glucose-6-P-dehydrogenase screening. Low levels are associated with a high risk of methemoglobinemia. When using tetracyclines, some authors have reported minocycline- induced pigmentation in patients with pemphigus and pemphigoid, with an incidence that appears to be much higher than in acne and rheumatoid arthritis (Ozog, Gogstetter, Scott, & Gaspari, 2000).

Rituximab

Finally, rituximab, a monoclonal anti-CD20 antibody (CD20 is a protein on the surface of lymphocytes), has been reported to be effective in treating resistant pemphigus foliaceous and vulgaris. It is hypothesized that this agent depletes B-lymphocytes (antibody-producing cells) and rapidly removes desmoglein antibodies (antibodies causing pemphigus) from the circulation. This agent, which targets a cell-specific protein, may represent a promising novel therapeutic option for refractory immunobullous diseases (Borradori et al., 2001; Goebeler, Herzog, Brocker, & Zillikens, 2003; Herrmann, Hunzelmann, & Engert, 2003; Mrowietz, 2002; Salopek, Logsetty, & Tredget, 2002).

These different therapies have enabled health care professionals to reduce mortality and morbidity of immunobullous diseases markedly.

Severity of disease, variable response to treatment potential side effects of therapies, must be evaluated for each individual patient. Hence, treatment of immunobullous diseases needs to be "tailored" to each patient, based on previous studies. Therefore, more studies comparing different treatment regimens are needed to optimize future management of immunobullous diseases.

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