Tetracycline mouthwash (250 mg in 5–10 mL of water) four times per day (5 min each)
Tacrolimus 0.03 % oral suspension, oral rinse for 5 min twice daily
Rotating between rinsing the mouth with hydrogen peroxide, elixir of dexamethasone and elixir of diphenhydramine separately
Clobetasol 0.05 % mouthwash with 100,000 IU/cc nystatin in aqueous solution for 5 min three times per day after meals
5 mL of cyclosporine 100 mg/mL swish for 5 min three times per day
Exogenous Factors That May Cause Blistering Disease
Exogenous factors have been reported to cause pemphigus. In 2003, Brenner reported three categories causing pemphigus as follows: (1) thiols (sulfhydryl group), (2) phenol (including topical phenol), (3) other (non-thiol and non-phenol). She reported that thiol-induced acantholysis has been noted in vitro by directly interfering with cell adhesion, whereas phenol-induced acantholysis may occur by keratoinocytes inducing IL-1alpha and TNF-alpha [55]. Phenol containing drugs reported to cause pemphigus include cephalosporins and rifampin as well as levodopa, heroin, phenobarbital, pentachlorophenol and aspirin [56].
One study interviewed 126 pemphigus patients and 173 healthy controls to identify potential risk factors in environmental exposures. Patients exposed to metal vapor (occupationally) and pesticides had an increased risk of pemphigus. This multi-site study found the highest risk for exposure to pesticides and related materials to be in patients from Bulgaria and Israel (as compared to Brazil, India, Italy, Spain and the United States) [57]. Theories for the mechanism of pemphigus due to pesticides include its pro-estrogenic effect [57] and allergic contact dermatitis [58].
Interestingly, it has also been observed that former smokers or current smokers had a lower risk for developing pemphigus than those who never smoked [57]. However, subsequent studies have found contrary results [59]. In 2008, a study of 10 smokers with pemphigus and 60 non-smokers with pemphigus found no baseline difference in the extent of pemphigus, but did find that after 1 year of treatment, smokers more frequently developed partial remission [60]. While a recent review on pemphigus associations suggests that smoking is not contraindicated in pemphigus [61], the authors do not advocate the use of tobacco since long term health risks far outweigh the possible benefits.
Food and Nutrition
While there are no specific studies that suggest foods to be an etiology of blistering lesions in the mouth, there are certain foods that have been suggested as being possible culprits in exacerbating disease or preventing lesions from healing. These include mango, cassava, mustard, coconut and areca nut [62]. While there has been some suggestion of an association between a higher intake of spices with pemphigus [63], it is important to note that spicy foods can be difficult to tolerate in patients with oral blistering disease and may potentially lead to more oral lesions.
Exacerbations of oral bullous disease have been reported in association with certain foods and trauma in the setting of oral lichen planus. Examples of triggers include tomatoes, spicy foods, and citrus as well as dental work and heavy alcohol and tobacco use [51]. These triggers likely have similar effects in ABDs with oral involvement, given the potential for mechanical trauma and irritation. Hence, physicians should emphasize at the initial visit the importance of ideally avoiding or minimizing certain foods, including citrus, spicy, cinnamon, and hard, crunchy foods.
In addition, BP patients with poor nutrition (measured by low albumin) have been associated with poorer outcome in the first year after hospitalization [64]. Hence, patients should be advised to eat chicken and fish, which would provide increased amounts of protein and be less traumatic for the oral cavity.
Dermatitis herpetiformis improves with dietary avoidance of gluten. It has also been suggested that a gluten-free diet can possibly help prevent the risk of lymphoma [65, 66]. Gluten is a protein that can be found in wheat, barley, rye and many processed foods and some medications. It is particularly important that patients pay attention to food labeling as some foods, such as oats (which are generally considered safe) may at times be processed with gluten (making them unsafe). Patients should additionally pay attention to prescription and over-the-counter medications and topical therapies (including lip balms, toothpastes, mouthwashes) [67]. Gluten can also be found in beer and whiskey. Many supermarkets have a separate section for gluten-free products. While gluten-free labeling is accurate in the United States about 95 % of the time [68], trace amounts of gluten may be found in several gluten-free labelled products [69]. Mulder et al. provides a helpful table of safe foods, which may be practical to give to patients [70]. Several additional resources are available online for patients including: The Gluten Intolerance Group (www.gluten.net), Academy of Nutrition and Dietetics (www.eatright.org), and National Foundation for Celiac Awareness (www.celiaccentral.org). Patients will need to maintain a well-balanced diet, while also avoiding gluten completely [71]. Of note, dermatitis herpetiformis can additionally flare with exposure to iodine, including radiocontrast material [72–74].
Poor oral hygiene has also been reported in gingival lichen planus [51]. Mucous membrane pemphigoid patients have been reported to have worse periodontal status compared to a control population in two studies [75, 76], but no statistically significant decrease in one small study [77]. Given the potential risk for periodontal disease, a detailed protocol for oral hygiene has been reported as helpful in a small study of 12 patients [78]. However, patients should be cautioned against elective dental procedures due to the risk of exacerbation from potential trauma. Anesthesiologists should also be made aware of potential traumatic lesions developing in the oral, pharyngeal, and laryngeal areas from intubations in ABD patients.
Ultraviolet Light
Ultraviolet light has been reported to exacerbate multiple ABDs [79–88]. Cases have been reported to both UVB [80, 81, 86, 87] as well as UVA [85, 87, 88]. BP has also been reported to occur after exposure to red light of photodynamic therapy (peak 636 nm) [89] used to treat biopsy-proven Bowen’s disease on the lower legs. In addition, low level laser therapy (including the 980 nm diode laser) has been reported as a treatment in mucous membrane pemphigoid [90–92].
It is important to remind all patients with ABDs to use sun protection to help prevent a photo-exacerbation of their disease. Sunscreens with an SPF of at least 30 and ideally containing physical blockers such as zinc oxide and titanium dioxide should be strongly encouraged. Clothing with UPF (ultraviolet protective factor) should be emphasized as part of the treatment since photo-protection could prevent both relapse of the disease along with preventing potential skin cancers from prolonged immune suppression.
Infection Control
Patients with ABDs have experienced decreased mortality from the disease itself with the introduction of steroid-sparing systemic agents. Unfortunately, these treatments also increase the risk for opportunistic infections. These infections are often a major cause of morbidity in ABDs, either secondary to the breakdown of the skin barrier or immune suppression [93].
A prospective study of 172 patients with newly-diagnosed pemphigus found that 14 patients developed opportunistic infections after a mean of 4 months following their diagnosis (while on systemic treatments for pemphigus). The risk of developing an opportunistic infection within the first year of diagnosis of pemphigus was found to be 9.3 %, with increased risk in older patients and possibly diabetic patients [94]. Infections reported in bullous patients include bacterial, viral and fungal sources. Reported bacterial infections include Staphylococcus aureus (including methicillin-resistant cases) and Streptococcus A [95], as well as Nocardia, Cytomegalovirus, Legionella and Listeria [94]. Nocardia has been reported in both pemphigus vulgaris [81, 96, 97] and BP [98]. Studies have found sepsis to be one of the highest causes of mortality in both pemphigus [99] and BP [100].
Given the risk of opportunistic infections while on chronic immunosuppressives, three studies have examined the role of routine prophylaxis for pneumocystis pneumonia. Overall, less than 2 % of their examined cases developed pneumocystis pneumonia, and study sizes range from 198 to 334 patients [101–103]. As such, it is recommended that physicians consider pneumocystis prophylaxis in high risk patients and to have a high suspicion in patients developing pulmonary symptoms while on immunosuppressive agents.
Viral or herpetic lesions can mimic immunobullous disease, especially in patients on immunosuppressive therapy. Viral infections include recurrent oral herpes simplex [104], genital herpes simplex [105], severe herpetic gingivostomatitis [106], generalized herpes simplex [107] and varicella zoster [108], and can be potentially fatal [109, 110]. One study suggests ABD patients may have occult herpes simplex colonization [111]. Viral-specific studies should be performed of any recalcitrant blisters.
Scabies can mimic pruritus in ABD, and if not diagnosed can mistakenly be treated with increased immunosuppression [112]. In addition, some new patients may initially be misdiagnosed with ABD when they actually have bullous scabies [113–117].
A variety of fungal infections have also been reported. One case reported a flare of local BP associated with concomitant dermatophyte infection (identified on culture and potassium hydroxide preparation) [118]. Rare reported infections in ABD patients include Cryptococcal cellulitis [119], primary cutaneous Blastomycosis [120] and various presentations of Nocardia [94, 96–98, 121].
Patients may often observe increased pain in mucosal areas of involvement including the oral cavity, esophagus, and genital area. This can often be secondary to the presence of Candida infection, which can present from the usage of corticosteroids and systemic immunosuppressants. Patients should be examined if they report an exacerbation, as increasing systemic medications may lead to progression of mucosal Candidiasis.
Prevention of infections is a key factor in the overall clinical outcome. Patients should be encouraged not to “pop” or drain blisters since this could provide a route for infection. Fluid filled blisters can be soaked up to three times per day with an aluminum acetate solution which has both anti-infectious and astringent properties. In the United States, a common available brand is Domboros.
There are other over-the-counter antibacterial products which can also be used for topical hygiene and can help clear and possibly prevent infections. Topical therapies with antibacterial properties include the following: benzoyl-peroxide soap or creamy wash (mostly gram positive coverage), acetic acid (vinegar) diluted with water in solution (gram negative coverage) as well as hydrogen peroxide solution (diluted 1:4) with antiseptic mouthwash, and chlorhexidine (coverage against both gram positive and negative bacteria). While iodine solutions also have anti-septic properties, these would not be preferred due to potential local irritant reactions and risk of exacerbating dermatitis herpetiformis.
Since most patients will be on long term immune suppression, screening for certain infections (including tuberculosis and hepatitis serologies) is crucial at the initial visit. If any of the screening tests are found to be positive, infectious disease and hepatology should be consulted before proceeding with systemic treatment.
Vaccinations are an extremely important modality for the prevention of infection. It is recommended that patients continue with their vaccination schedules and vaccines, unless contraindicated. Live vaccines are contraindicated in patients on immunosuppression. These contraindicated live vaccines include zoster, live influenza, measles, mumps and rubella [93, 122].
Antihistamines
Antihistamines are used commonly to control pruritus in many dermatological disorders. Many of the ABDs can have intense pruritus during the initial onset or during a relapse of the disease. While these can be acutely controlled in most instances with topical and systemic steroids, some patients may require the addition of an antihistamine as an adjuvant anti-pruritic agent. Since there are no studies evaluating the role and efficacy of anti-histamines in controlling pruritus in ABDs, both first and second generation anti-histamines may be considered as anti-pruritic agents in the appropriate patient. Antihistamines are generally avoided in pregnancy due to the risk of teratogenicity in the first trimester. However, specific first and second generation antihistamines, classified by the FDA as Category B, can sometimes be considered as adjuvant anti-pruritic treatments for pemphigoid gestationis since this presents later in pregnancy. These can include chlorpheniramine, dexchlorpheniramine, loratidine, and cetirizine, pending prior consultation with and approval by the patient’s obstetrician [123].
Conclusions
In this chapter, the authors have tried to emphasize non-systemic measures which can help improve outcomes. A variety of topical and local treatment options have proven to be beneficial in mild as well as moderate and severe ABDs as an adjuvant. The regimen will often be determined by many clinical and non-clinical factors and must be individualized by the treating physician. Clinicians should constantly remind patients to minimize the risk of infection, excessive sun exposure, and trauma, including direct contact from the water of high-pressure showers. Appropriate nutritional recommendations should also be emphasized since compliance can be difficult. Patients should be constantly encouraged and reminded that while these measures may not provide a “cure,” such precautions may help reduce the dosage and duration of their systemic treatments.
References
2.
Taghipour K, Mohd Mustapa MF, Highet AS, Venning VA, Kirtschig G. The approach of dermatologists in the UK to the treatment of bullous pemphigoid: results of a national survey. Clin Exp Dermatol. 2013;38(3):311–3.PubMed
3.
Westerhof W. Treatment of bullous pemphigoid with topical clobetasol propionate. J Am Acad Dermatol. 1989;20(3):458–61.PubMed
4.
Joly P, Roujeau J-C, Benichou J, Picard C, Dreno B, Delaporte E, et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med. 2002;346(5):321–7.PubMed
5.
Gelfand JM, Werth VP. Treatment of bullous pemphigoid with topical corticosteroids: review of a randomized controlled trial. Arch Dermatol. 2002;138(9):1236–7.PubMed
6.
Korman NJ. Oral and topical corticosteroids in bullous pemphigoid. N Engl J Med. 2002;347(2):143–5; author reply 143–5.PubMed
7.
Spigel GT. Oral and topical corticosteroids in bullous pemphigoid. N Engl J Med. 2002;347(2):143–5; author reply 143–5.PubMed
8.
Joly P, Roujeau J-C, Benichou J, Delaporte E, D’Incan M, Dreno B, et al. A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study. J Invest Dermatol. 2009;129(7):1681–7.PubMed
9.
Stockman A, Beele H, Vanderhaeghen Y, Naeyaert JM. Topical class I corticosteroids in 10 patients with bullous pemphigoid: correlation of the outcome with the severity degree of the disease and review of the literature. J Eur Acad Dermatol Venereol JEADV. 2004;18(2):164–8.PubMed
10.
Terra JB, Potze WJB, Jonkman MF. Whole body application of a potent topical corticosteroid for bullous pemphigoid. J Eur Acad Dermatol Venereol JEADV. 2014;28(6):712–8.PubMed
11.
Claudy A. Evaluation of the safety and efficacy of a potent topical cortico-steroid in the treatment of bullous pemphigoid. Clin Dermatol. 2001;19(6):778–80.PubMed
12.
Zimmermann R, Faure M, Claudy A. Prospective study of treatment of bullous pemphigoid by a class I topical corticosteroid. Ann Dermatol Venereol. 1999;126(1):13–6.PubMed
13.
Paquet P, Richelle M, Lapiere CM. Bullous pemphigoid treated by topical corticosteroids. Acta Derm Venereol. 1991;71(6):534–5.PubMed
14.
Muramatsu T, Iida T, Shirai T. Pemphigoid and pemphigus foliaceus successfully treated with topical corticosteroids. J Dermatol. 1996;23(10):683–8.PubMed
15.
Bingham LG, Noble JW, Davis MDP. Wet dressings used with topical corticosteroids for pruritic dermatoses: a retrospective study. J Am Acad Dermatol. 2009;60(5):792–800.PubMed
16.
Fichel F, Barbe C, Joly P, Bedane C, Vabres P, Truchetet F, et al. Clinical and immunologic factors associated with bullous pemphigoid relapse during the first year of treatment: a multicenter, prospective study. JAMA Dermatol. 2014;150(1):25–33.PubMed
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