By Lauren Hartman, DMSc, PA-C; Cynthia Faires Griffith, MPAS, PA-C; and Loderick A. Matthews, BS
Lauren Hartman, DMSc, PA-C, is a board-certified physician assistant specializing in general and cosmetic dermatology at Warmuth Institute of Dermatology in Elmer, New Jersey. She attended Thomas Jefferson University (formerly Philadelphia University) for both her undergraduate and graduate studies. She received her bachelor’s degree in Health Science and her Master’s in Physician Assistant Studies. Lauren also earned a Doctorate of Medical Science at the University of Lynchburg, an advanced practice clinical doctorate program for experienced physician assistants.
Cynthia Faires Griffith, MPAS, PA-C, is a Dermatology Physician Assistant at UT Southwestern Medical Center in Dallas, Texas, where she also earned her Masters of Physician Assistant Studies. Ms. Griffith is the co-founder of the UT Southwestern High-Risk Skin Cancer Transplant Clinic, a twice-monthly clinical initiative to serve patients who are immunosuppressed after solid organ or bone marrow transplant. She also practices general adult medical dermatology. She is Dermatology Grand Rounds Department Editor for the Journal of Dermatology for Physician Assistants (JDPA) and is a guest lecturer in the UT Southwestern PA program and a lecturer at local, regional, and national conferences. She is a member of the Texas Academy of Physician Assistants, the Society for Dermatology Physician Assistants, and the American Academy of Physician Assistants. She was awarded UT Southwestern’s PA of the Year in 2017. When not practicing, Ms. Griffith is an avid sailor, marathoner, and long-distance cyclist.
Loderick A. Matthews, BS, is a research associate in the Cutaneous Immunopathology Laboratory in the Department of Dermatology at the University of Texas Southwestern Medical Center in Dallas, Texas. Loderick frequently contributes fluorescent microscopy photographs to case studies presented by residents and faculty at the Department of Dermatology Grand Rounds. When Loderick is not in the lab, he is a runner, cyclist, and a working musician.
Disclosure: The authors have disclosed no potential conflicts of interest, financial or otherwise, relating to the content of this article.
Bullous pemphigoid, a rare autoimmune chronic skin disorder characterized by blistering, urticarial lesions (hives), and itching, is the most common among all pemphigoid diseases. BP has been growing in prevalence over the past two decades primarily due to an increasing elderly patient population and exposure to certain medication classes, such as dipeptidyl peptidase-IV (DDP-IV) inhibitors or “gliptins,” that are associated with bullous pemphigoid onset. Both of these factors contributing to a rise in potential BP cases underscores the need for health care providers in dermatology to be familiar with the clinical presentation, causes, diagnostic tools, and treatments for this condition. This article describes clinical manifestations, causes, diagnostic work-up, and treatment for BP, and includes an patient vignette to further illustrate disease presentation and management.
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1. Discuss the pathophysiology and clinical manifestation of bullous pemphigoid,
2. Identify risk factors of bullous pemphigoid.
3. Discuss bullous pemphigoid prevalence and prognosis.
4. Review diagnostic tools to employ when bullous pemphigoid is suspected.
5. Review treatment modalities available and considerations, such as patient lifestyle, list of medications, and severity of disease in choosing a treatment plan for a patient with bullous pemphigoid.
Bullous pemphigoid (BP) is a rare autoimmune chronic skin disorder characterized by blistering, urticarial lesions (hives), and itching. BP is the most common among all pemphigoid diseases with a reported incidence of 10 cases per million population (pmp) per year in the United States (US).1,2 BP, traditionally considered a disease of the elderly, mainly affects the patient population over the age of 60, however, it can appear earlier in life, including during infancy and childhood. Although classified as a rare condition, BP has been growing in prevalence over the past two decades, underscoring the need for health care providers to be aware and well equipped to care for these patients.3
PATHOPHYSIOLOGY & CLINICAL PRESENTATION
BP results from the autoimmune response to two proteins within the dermal-epidermal junction—BP180 and/or BP230 within the hemidesmosomes. Hemidesmosomes hold basal keratinocyte cells to the dermis. As a result, tense blisters form as the epidermal skin cells separate from the dermis. Prior to development of the blisters, itching can be present.4
In some patients, itching and urticaria can be the prodrome before the blisters; in other patients, pruritus can be the only presenting symptom with blisters never developing, making it a challenge to properly diagnose on visual examination alone. BP can be localized to one body surface area, typically the lower legs/feet, or generalized, and typical locations for BP reported in the literature are the trunk and extremities. Though the disease primarily affects the skin, 10 to 40 percent of patients experience mucous membrane involvement in the oral, ocular, and genital areas.5,6
An 82-year-old man was referred to dermatology outpatient clinic for nonhealing wounds on the lower legs. The patient had a medical history of chronic kidney disease stage 3, hypertension, gout, type 2 diabetes mellitus (T2DM), depression, and vitamin D deficiency. He also had a history of skin shearing trauma as a result of repeated falls on the left lower leg for the past three years. He has had home health/wound care for the past three years, treating wounds on his lower legs with Xeroform® and Hydrofera Blue® dressings. He also regularly wrapped compression bandages on the lower legs as part of the wound care routine but, two weeks prior to presentation at dermatology, “took a break” from using the compression bandages. Since making this change in his routine, he noticed the appearance of new blisters filled with clear fluid located under the skin on the left lower leg and left tibial tuberosity, which were all areas of previous trauma. He reported no history of blisters on the feet, right leg, arms, or scalp. The patient denied experiencing itching, malodorous drainage, or pain and did not have a history of similar blistering.
The patient’s list of current medications included dulaglutide, hydralazine, insulin, levothyroxine, and losartan. Physical examination revealed erosions on the left tibial tuberosity with some erosions on an erythematous base. Of note, these erosions did not appear undermined. Figure 1 shows the patient’s left lower leg and left tibial tuberosity with chronic erosions and ulcers with granulation tissue. Unrelated to the leg erosions, the patient had an abrasion on the right vertex of the scalp and left arm from involvement in a car accident four days before his appointment.
A punch biopsy for histopathology was taken from the edge of the erosion on the left leg. (Figure 2). A shave biopsy for histopathology was performed to remove a 4×5 mm bulla on an erythematous base; the entire bulla was shave biopsied (Figure 3). Normal appearing skin within 1 cm of the bulla was punch biopsied for direct immunofluorescence. The patient’s serum (blood) was taken for indirect immunofluorescence for autoantibodies against skin and enzyme-linked immunosorbent assays (ELISA). The histopathology from the punch biopsy of the erosion and the shave biopsy of the bulla showed a sub-epidermal vesicle with an inflammatory infiltrate of eosinophils, neutrophils, and lymphocytes. Type IV collagen was on the floor of the blister.
The perilesional skin punch biopsied for direct immunofluorescence revealed Immunoglobulin G (IgG), third component of complement (C3), and fibrin in the epidermal basement membrane (Figure 4). The patient’s serum tested for indirect immunofluorescence was positive for autoantibodies against the epidermal side of 1 M NaCl split skin at a titer of ≥40 (Figure 5). The patient’s serum was then tested for IgG autoantibodies against baculovirus-derived BP180 and BP230 by ELISA. The patient was negative for IgG autoantibodies against both BP180 and BP230.
The patient’s clinical picture and biopsy and direct and indirect immunofluorescence are compatible with the diagnosis of bullous pemphigoid (BP).
This patient was prescribed topical clobetasol to use on the left knee. He used this not on the open skin but on intact skin. As he had traumatic skin erosions from falls, the knee was covered with wound dressing with Vaseline then nonstick pad and then coban wrap. Care was taken to not shear off the tops of the blisters that developed with his dressing changes. The bullae healed with a little milia formation within three weeks of this treatment (Figure 6). Since then, the patient was started on doxycycline and nicotinamide. He did not develop any new bullae. He did not tolerate the doxycycline due to gastrointestinal upset, so this was held. At the time of publication, the patient continued to have no new bullae.
RISK FACTORS & RELAPSE
Known risk factors of BP include genetic predisposition, age, adverse responses to medication, infections, and physical and viral agents.1 Researchers have pointed to two main factors contributing to increased BP prevalence worldwide: 1) a growing elderly population with several comorbidities, such as type 2 diabetes mellitus (T2DM), cardiovascular diseases, and neurogenerative diseases and 2) environmental influences, such as UV radiation, traumas, and increased exposure to drugs that may potentially trigger the disease.3 Age is a significant risk factor. Mean age of BP diagnosis ranges from 65 to 80 years with incidence exponentially increasing after age 70. Patients 90 and older have a 300-fold higher relative risk than those 60 or younger.3,5,6,7
Drug-induced BP cases have also been reported with certain medications triggering onset of disease.5 Drug types and examples associated with BP emergence include the following:
• Dipeptidyl peptidase-IV (DDP-IV) inhibitors or “gliptins” (e.g., vildagliptin and linagliptin) used to treat type 2 diabetes mellitus [T2DM])
• Diuretics (e.g., furosemide, spironolactone)
• Antipsychotics (e.g., phenothiazines with aliphatic side chain)
• Cancer immunotherapies (e.g., pembrolizumab, nivolumab, and durvalumab, all “checkpoint inhibitors” that target the programmed cell death protein-1 [PD-1] and the programmed death ligand-1 [PD-L1]
BP is a chronic, relapsing skin disorder that may be fatal, particularly in elderly, immunosuppressed patients who are at greater risk of succumbing to related side effects from dementia, infection, and sepsis, which have all been shown to be significant contributors to death in patients with BP.8 Though patients can experience remission of disease with treatment, the relapse rate is high. Wang et al9 conducted a systematic review to investigate relapse and risk factors for relapse in patients with BP reported in the literature. In their study, relapse, also referred to as a “flare,” was defined using the following criteria: the appearance of at least three new lesions in one month (including blisters, urticarial plaques or eczematous lesions) or no less than one large (>10 cm in diameter) urticarial plaque or eczematous lesion that does not heal within one week, or the extension of original lesions or daily pruritus in patients within disease control. They concluded that the one-year relapse rate in patients with was more than 50 percent (range: 27.87-53%) after disease remission with the majority of relapse episodes occurring within six months during remission.9
DIAGNOSIS & TREATMENT
Although there are no widely accepted guidelines on diagnosis and management of BP, dermatology associations around the globe have put forth proposed criteria. There are currently multiple diagnostic tools for care providers who suspect BP, and diagnosis relies on careful examination of medical history, including a list of current and previous medications, clinical presentation, and histopathology. Four significant clinical predictors proposed by the French Bullous Study Group and adopted by other BP researchers include the following: 1) absence of atrophic scars, 2) absence of head and neck involvement, 3) absence of mucosal involvement, and 4) age greater than 70 years.10 The authors showed that, if three of these four characteristics were present in a patient, a diagnosis of BP could be made with a sensitivity of 90 percent and a specificity of 83 percent.
Biopsy for histopathology should be taken from an intact bulla (using shave or punch technique) or punch biopsy from the edge of an erosion. Tissues samples are then placed in formalin and the pathologist examines the level of the skin that is separating to cause the blister formation; in the case of BP, this will be a subepidermal blister. Histology also elucidates the cell types present in the skin including lymphocytes, neutrophils, and eosinophils.
A biopsy of perilesional skin, meaning normal appearing skin that is within 1 cm of the blister, can be sampled with punch biopsy and placed in Michel’s media for direct immunofluorescence testing. This testing looks for autoantibodies and other immunoreactants in skin to identify the type and where they are deposited within the skin. The patient’s skin is cross sectioned and examined for in situ deposits of IgG, IgA, IgM, C3, and fibrinogen. Deposits of IgG or C3 in the basement membrane zone, or more specifically on the epidermal side of the blister, supports the diagnoses of bullous pemphigoid. Other blistering disease can present with different deposits in different locations. For example, IgA in the dermal papillae is characteristic of dermatitis herpetiformis.
Further tests that can be done to gain additional evidence for a diagnosis of BP is indirect immunofluorescence testing (IDIF) and enzyme-linked immunosorbent assays (ELISA). IDIF can be used to see if the patient’s blood carries autoantibodies, specifically IgG, that localizes to the epidermal side of 1 M NaCl split skin, which could suggest that the IgG autoantibodies are binding to the hemidesmosomes (180 and 230) and causing the blistering. To further illuminate the target of the binding of the patient’s autoantibodies, the serum is tested by ELISA. In ELISA, the patient’s serum is diluted in a buffer, incubated in a well of a plate that is coated with the antigen of interest, BP180 or BP230 in this case, washed extensively and an enzyme conjugated antihuman IgG antibody is applied and incubated. After further washing, the enzyme substrate is added to the plate and if the patient’s autoantibodies have bound the antigen, a color change is observed. This color change is read by a plate reader that measures the absorbance of transmitted light and produces a readout that can be quantified against the standards provided by the kit manufacturer. It’s important to note that, when testing for BP, clinicians should look at the full clinical picture, not just a single test, which can potentially come out negative even though the diagnosis is in fact BP.
The goal of treatment for patients with bullous pemphigoid is to maintain complete resolution of existing lesions as well as prevent new flare-ups.11 The current standard of care includes the use of systemic glucocorticoids (e.g., prednisone or prednisolone) and potent topical corticosteroids (e.g., clobetasol propionate). A study by Grantham et al compared the effects of oral doxycycline and oral prednisolone in treating BP.12 This study ultimately found that prednisolone is not superior to doxycycline for treatment based on a six-week short term trial on blisters and life-threatening events for patients. Doxycycline has also been proven to be a safer long-term option, showing a decreased number of deaths caused by BP at a significantly greater rate compared with oral prednisolone.12
Combination treatments have also been described. For instance, using oral corticosteroids prior to use of doxycycline with doxycycline then used for additional maintenance has been shown to produce better control of the disease process. Ultimately, published literature supports the use of both modalities, with the final decision belonging to the medical provider who can determine the best treatment option for each patient on a case-by-case basis. Other medications have however led to some resolution of symptoms for BP. These include intravenous immunoglobulin therapy, which is beneficial for patients that are resistant to corticosteroids, as well as the monoclonal antibody drug rituxan, both of which have been studied for potential usage in improving this disease process.
Kremer et al discuss how bullous pemphigoid is often associated with morbidity and can affect an individual’s overall quality of life.3 Although systemic glucocorticoids are considered the hallmark medication for this condition, the long-term side effects associated with corticosteroid use (e.g., weight gain, hypertension, osteonecrosis, osteoporosis, insulin resistance, myopathy, cataracts, and glaucoma) are important to monitor. It is also vital that clinicians explore the use of other therapies, including rituximab and omalizumab, given that the safety profiles of these medications are considered superior to immunosuppressive agents such as azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, and cyclophosphamide. Rituximab is used to treat B-Lymphocyte related malignancies and was approved by the food and drug administration (FDA) in June of 2018 for treating pemphigus. The complete response rate for patients with rituximab was 85 percent.3
Omalizumab is used to treat chronic urticaria and has been shown to be beneficial in treating pemphigoid due to the role the drug plays in the release of Ig-E mediated histamine.3 The complete response rate for patients with omalizumab was 84 percent. The recurrence rate for bullous pemphigoid was significantly lower with rituximab at 29 percent than omalizumab at 80 percent. The mean time to recurrence for rituximab was 10.2 months versus 3.4 months for omalizumab. Overall, rituximab established a lower recurrence rate and longer duration between recurrences.3 Miyamoto et al5 discusses various treatment modalities centered on enabling cutaneous healing while also gaining control of pruritus. A Cochrane systemic review published in 2010 analyzed ten randomized clinical trials based on the treatment modalities for BP. First-line recommendations include high-potency topical steroids such as clobetasol cream for mild-to-moderate severity and a systemic steroid such as prednisone for moderate-to-severe severity. The second-line treatments for mild-to-moderate disease include doxycycline and dapsone. For moderate-to-severe disease states, methotrexate, azathioprine, and mycophenolate mofetil are recommended. For severe cases intravenous immunoglobulin, rituximab and omalizumab are recommended. The aforementioned studies addressed overall improvement with topical corticosteroids, doxycycline, prednisone, rituximab, and omalizumab.5 Combination therapies can improve the quality of life for a patient without impairing the comorbidities.
Immunosuppressive medications such as azathioprine, mycophenolate mofetil, and methotrexate can also be used as viable treatment options. Biologics ultimately selectively surpass the auto-antibody formation which prevents the inflammatory cascade, leading to a positive therapeutic outlook for patients. Reports have shown that methotrexate has a strong efficacy long term when analyzing the clinical remission of the disease process. The medications are particularly chosen based on their side effect profiles.
Ultimately, the evidence suggests the use of various modalities in treating this condition, thus treatment plans are often tailored to an individual patient’s lifestyle, health, and preferences. For instance, if the disease is localized to an area, topical treatment with high-potency topical steroids like clobetasol would be a good option. If the patient has extensive disease covering more body surface area, other treatments like antibiotics, specifically doxycycline in combination with nicotinamide, also known as niacinamide or vitamin B3, can be utilized to slow the formation of additional bullae. Oral steroids are a mainstay of therapy if topical therapy is not feasible given body surface involvement; however, this can be detrimental to patient’s bone and cardiovascular health when used long term, so steroid-sparing agents like azathioprine, mycophenolate, or rituximab are also used in refractory BP to arrest development of bullae.
BP is a chronic, relapsing skin disorder that may be fatal, particularly in elderly, immunosuppressed patients who are at greater risk of succumbing to related side effects from dementia, infection, and sepsis, which have all been shown to be significant contributors to death in patients with BP.8 Though patients can experience remission of disease with treatment, the relapse rate is high. Diagnosis can be confirmed by looking at the full clinical picture comprising review of patient profile and medical history, visual examination, and histology. The goal of treatment for patients with bullous pemphigoid is to maintain complete resolution of existing lesions as well as prevent new flare-ups. Evidence suggests the use of various modalities in treating this condition, thus treatment plans are often tailored to an individual patient’s lifestyle, health, and preferences. With prevalence of BP on the rise globally, so too are the chances that dermatology providers will encounter a patient with BP. Becoming familiar with the manifestations, causes, diagnostic tools, and treatments discussed in a growing body of literature will ultimately facilitate better care for this condition.
1. Lo Schiavo A, Ruocco E, Brancaccio G, et al. Bullous pemphigoid: etiology, pathogenesis, and inducing factors: facts and controversies. Clin Dermatol;31(4):391-399.
2. Lee J, Seiffert-Sinha K, Attwood K, Sinha AA. A retrospective study of patient-reported data of bullous pemphigoid and mucous membrane pemphigoid from a US-based registry. Front Immunol. 2019;10:2219
3. Kridin K, Ludwig RJ. The Growing Incidence of Bullous Pemphigoid: Overview and Potential Explanations. Front Med (Lausanne). 2018;5:220. Published 2018 Aug 20. doi:10.3389/fmed.2018.00220
4. Kasperkiewicz M, Zillikens D. The pathophysiology of bullous pemphigoid. Clin Rev Allergy Immunol. 2007 Oct;33(1-2):67-77. doi: 10.1007/s12016-007-0030-y. PMID: 18094948.Miyamoto
5. Miyamoto D, Santi CG, Aoki V, Maruta CW. Bullous pemphigoid. An Bras Dermatol. 2019;94(2):133-146.
6. T he International Pemphigus & Pemphigoid Foundation. Pemphigoid: Information for Patients. https://www.pemphigus.org/pemphigoid/. Accessed July 7, 2021
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8. Barrick BJ, Lohse CM, Lehman JS. Specific causes of death in patients with bullous pemphigoid as measured by death certificate data: a retrospective cohort study. Int J Dermatol. 2015;54(1):56-61. doi:10.1111/ijd.12243
9. Wang Y, Mao X, Wang Y, Zeng Y, Liu Y, Jin H, Li L. Relapse of bullous pemphigoid: an update on this stubborn clinical problem. Ann Med. 2018 May;50(3):234-239. doi: 10.1080/07853890.2018.1443346. Epub 2018 Feb
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10. Vaillant L, Bernard P, Joly P, Prost C, Labeille B, Bedane C, Arbeille B, Thomine E, Bertrand P, Lok C, Roujeau JC. Evaluation of clinical criteria for diagnosis of bullous pemphigoid. French Bullous Study Group. Arch Dermatol. 1998 Sep;134(9):1075-80. doi: 10.1001/archderm.134.9.1075. PMID: 9762017.
11. Yamagami J. Recent Advances In The Understanding And Treatment Of Pemphigus And Pemphigoid. F1000Research. 2018;7. doi: 10.12688/f1000research.14474.1.
12. Grantham HJ, Stocken DD, Reynolds NJ. Doxycycline: A First-line Treatment For Bullous Pemphigoid? Lancet. 2017;389(10079):1586-1588. doi: 10.1016/S0140-6736(17)30549-4.
13. Kremer N, Snast I, Cohen ES, et al. Rituximab and omalizumab for the treatment of bullous pemphigoid: A systematic review of the literature. Am. J. Clin. Dermatol. 2019;20(2):209-216. doi: 10.1007/s40257-018-0401-6.