List of Abbreviations
ICD – International Classification of Diseases
IgG – immunoglobulin class G.
Terms and Definitions
Bullous pemphigoid is an autoimmune skin disease caused by the production of autoantibodies against hemidesmosome components (BP180 and BP230 antigens) and characterized by the formation of subepidermal blisters.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Bullous pemphigoid is an autoimmune skin disease caused by the production of autoantibodies against hemidesmosome components (BP180 and BP230 antigens) and characterized by the formation of subepidermal blisters.
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
The development of bullous pemphigoid is caused by the production of IgG autoantibodies against BP180 (type XVII collagen) and BP230 proteins, which are part of hemidesmosomes—structural components of the skin basement membrane.
The etiological factors contributing to the manifestation of bullous pemphigoid are not yet precisely known. It is hypothesized that one of the main factors is genetic predisposition. Certain class II HLA alleles (DQb1*0301, DQb1*0302, DRb1*04, DRb1*1101), which predominate in bullous pemphigoid, influence the restriction of the T-cell response to target antigens and may play a key role in the pathogenesis of the disease [1].
In most cases, the development of bullous pemphigoid is not associated with any triggering factor. In some patients with bullous pemphigoid, the appearance of rashes is triggered by medications, physical factors, or viral infections.
Medications that may be associated with the development of bullous pemphigoid include penicillamine**, beta-lactam antibacterial drugs (penicillins and other beta-lactams), captopril** and other ACE inhibitors; furosemide**, acetylsalicylic acid**, nonsteroidal anti-inflammatory and antirheumatic drugs, nifedipine**. Cases of bullous pemphigoid development have been reported following administration of influenza vaccine** and tetanus toxoid**. The development of bullous pemphigoid has also been described after exposure to physical factors—ultraviolet radiation, radiotherapy, thermal and electrical burns, and surgical procedures.
It is hypothesized that viral infections (hepatitis B and C viruses, cytomegalovirus, Epstein-Barr virus) may contribute to the development of bullous pemphigoid [2–4].
Bullous pemphigoid may have a paraneoplastic nature. Bullous pemphigoid is associated with lymphoproliferative disorders and certain tumors of organs such as the gastrointestinal tract, urinary bladder, and lungs [5–9].
1.3 Epidemiology of the Disease or Condition
According to Federal Statistical Surveillance data, the incidence of bullous pemphigoid in the Russian Federation in 2014 was 1.1 cases per 100,000 adult population (aged 18 years and older), and the prevalence was 2.6 cases per 100,000 adult population. It mainly affects elderly individuals. Among people aged 80 and older, the incidence of bullous pemphigoid reaches 15–33 cases per 100,000 of the corresponding population per year [10].
1.4 Features of Coding the Disease or Condition
Bullous pemphigoid – L12.0
1.5 Classification of the disease or condition
There is no universally accepted classification.
1.6 Clinical presentation of the disease or condition
Skin lesions in bullous pemphigoid can be localized or generalized. Eruptions are most frequently located on the extremities, abdomen, inguinal-femoral folds, and on the inner thighs. It is known that bullous pemphigoid has two periods of development: prodromal (non-bullous) and bullous. The non-bullous phase of pemphigoid typically manifests with non-specific symptoms and presents with severe pruritus accompanied by excoriations, eczematization, erythematous, papular, and/or urticarial rashes. True and false (evolutionary) polymorphism of the rash is possible. Pruritus and non-specific rashes may remain the sole sign of the disease for a long time (up to 5 years). Subsequently, when the specific clinical picture of bullous pemphigoid appears (bullous stage), its diagnosis is straightforward. The blisters have a tense, firm roof, a round or oval shape, and serous or sero-hemorrhagic contents; they are typically located on an erythematous background or on seemingly unchanged skin. Erosions formed at the site of the blisters, in the absence of secondary infection, rapidly epithelialize and are not prone to peripheral growth. Nikolsky's sign is negative. When pressure is applied to a blister, its diameter may increase due to subepithelial perifocal detachment – Asboe-Hansen sign is positive. Mucous membranes are affected in 10–25% of patients.
However, in 20% of cases, the presentation of bullous pemphigoid is non-specific, and diagnosis relies on morphological and immunohistochemical research methods. The names of pemphigoid variants vary depending on its clinical picture. Thus, the presence of papules and vesicles tending to group with the formation of arcuate outlines and tense blisters on the skin of the back, extremities, and buttocks is considered as vesicular-bullous pemphigoid. The erythrodermic form of bullous pemphigoid occurs against the background of chronic dermatoses (e.g., psoriasis), where tense blisters are located across the entire skin surface, up to the scalp, against a background of erythroderma. The pruriginous form of bullous pemphigoid is represented by pruriginous elements located on the skin of the lower extremities and back. The localized form of bullous pemphigoid is characterized by a local (limited) arrangement of blisters on the skin with their spontaneous resolution and periodic appearance of tense blisters in the same place. In cases of paraneoplasia, the presentation of bullous pemphigoid may resemble the vulgaris form of autoimmune pemphigus, Stevens-Johnson syndrome, and Lyell's syndrome [11–13].
The severity of bullous pemphigoid is determined by the number of developing blister lesions. Bullous pemphigoid is defined as severe when more than 10 blisters appear per day for 3 consecutive days, and as mild when 10 or fewer blisters appear per day [14].
2. Diagnostics, medical indications and contraindications for diagnostic methods
Of diagnostic significance in bullous pemphigoid is obtaining anamnestic data and identifying characteristic blisters with a firm roof during physical examination, which persist for many hours or several days, as well as finding a cavity between the basal keratinocytes and the basement membrane with an absence of acantholytic cells upon pathomorphological examination of skin biopsy material from lesion sites. If necessary, the diagnosis is confirmed by detecting linear deposition of IgG along the basement membrane of the skin as a result of pathomorphological examination of skin biopsy material using immunofluorescence methods.
Criteria for establishing the diagnosis/condition:
The diagnosis of bullous pemphigoid is established based on:
1) anamnestic data,
2) physical examination – identification of blister eruptions, erosions at the site of former blisters
3) pathomorphological examination of skin biopsy material,
4) pathomorphological examination of skin biopsy material using immunofluorescence methods.
2.1 Complaints and Anamnesis
Patients complain of itchy rashes. The disease is characterized by a chronic relapsing course.
2.2 Physical Examination
The localization of rashes and their extent, the characteristics of blister roofs and crusts are assessed.
It is recommended that patients with bullous pemphigoid, if necessary, undergo differential diagnosis with acantholytic pemphigus and determine Nikolsky's sign [15, 16].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: Nikolsky's sign is determined for differential diagnosis with acantholytic pemphigus; in bullous pemphigoid, it is usually negative.
2.3 Laboratory Diagnostics
Laboratory tests are performed for the purpose of differential diagnosis of bullous pemphigoid with acantholytic pemphigus and to monitor the safety of ongoing systemic therapy.
It is recommended for patients with bullous pemphigoid receiving systemic corticosteroid therapy, #methotrexate** or #cyclophosphamide**, to undergo a complete blood count (CBC) with differential to monitor the safety of systemic therapy [15–20].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: Systemic corticosteroids are capable of causing leukocytosis, lymphopenia, and eosinopenia, which requires monitoring before prescribing systemic corticosteroid therapy and during its course.
It is recommended for patients with bullous pemphigoid receiving systemic corticosteroid therapy or #methotrexate** to undergo a general clinical blood chemistry panel to monitor the safety of systemic therapy [15–19].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: Systemic corticosteroids can cause hyperglycemia, hyperlipidemia, hypocalcemia, and hypokalemia, manifestations of a negative nitrogen balance as a result of protein catabolism, etc., which requires monitoring before prescribing systemic corticosteroid therapy and during its course.
It is recommended if necessary for differential diagnosis with acantholytic pemphigus, to perform cytologic examination for acantholytic cells from the floor of erosions of mucous membranes and/or skin in smear-imprints [16, 21, 22].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: The presence of acantholytic cells is not characteristic of bullous pemphigoid, which distinguishes it from acantholytic pemphigus.
It is recommended to perform a urinalysis in patients with bullous pemphigoid receiving therapy with systemic corticosteroids, #methotrexate**, and #cyclophosphamide** to monitor the safety of systemic therapy [15, 16, 19, 20]
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: Urinalysis is performed before the initiation of systemic corticosteroid therapy and during its course to determine the patient's condition and identify adverse events of the ongoing therapy. The study allows for the detection of an adverse event that may develop during systemic corticosteroid therapy – glucosuria. #Cyclophosphamide** has urotoxic effects. Due to its immunosuppressive action, #methotrexate** may contribute to the development of urinary tract infections.
2.4 Instrumental Diagnostics
Not used.
2.5 Other Procedures
The diagnosis of bullous pemphigoid should be confirmed by the results of pathomorphological examination of skin biopsy material, and if necessary, by the results of pathomorphological examination of skin biopsy material using immunofluorescence methods.
It is recommended to perform pathomorphological examination of biopsy (surgical) material of the skin or mucous membrane from the area of a freshly formed (existing for no more than 24 hours) blister [21, 23].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: The examination reveals a subepidermal cavity with a superficial dermal infiltrate consisting of lymphocytes, histiocytes, and eosinophils. At the same time, histological examination does not always allow bullous pemphigoid to be distinguished from other diseases with subepidermal blister formation (dermatitis herpetiformis of Duhring, epidermolysis bullosa acquisita).
Material fixation is carried out in buffered 10% formalin. When taking a biopsy, it is advisable to capture a small blister in its entirety. If it is impossible to take an entire bullous lesion, 1/3 of the obtained biopsy specimen should be a blister fragment and 2/3 should be the adjacent skin/mucous membrane area [23].
It is recommended to perform a pathoanatomical examination of skin biopsy (surgical) material using immunofluorescence methods [21, 24].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: For the examination, a biopsy specimen is obtained from apparently unaffected skin of the patient or at a distance of about 1 cm from the lesions. Linear deposition of IgG and/or the C3 complement component is detected in the basement membrane zone. In cases of spontaneous separation of the epidermis from the dermis with the formation of a microscopic subepidermal blister, IgG/C3 fluorescence is detected at the sites of their binding to the target antigen (lamina lucida) forming the blister roof. This is an important differential feature distinguishing bullous pemphigoid from acquired epidermolysis bullosa, in which fixed IgG remains on the blister floor at the target antigen site (lamina densa) [21, 24].
Immunofluorescence examination does not always distinguish bullous pemphigoid from acquired epidermolysis bullosa.
After collection, the material must be wrapped in a sterile gauze pad soaked thoroughly with sodium chloride** solution and delivered to the laboratory within 2 hours for freezing and cryostat sectioning. Immunofluorescence examination of the patient's skin biopsy can be performed using either direct or indirect techniques [25, 26].
It is recommended, if differential diagnosis with acquired epidermolysis bullosa is necessary, to perform an additional pathoanatomical examination of skin biopsy (surgical) material using immunofluorescence methods, after preliminary cleavage by incubation in a 1M sodium chloride** solution for 24 hours [27].
Level of Recommendations CLevel of Evidence 3Level of Recommendation C (Level of Evidence – 3)
Comments: Pathoanatomical examination of skin biopsy (surgical) material using immunofluorescence methods with preliminary cleavage of the skin biopsy specimen by incubation in a 1M sodium chloride** solution for 24 hours allows the detection of IgG deposition in the upper part (blister roof) of the cavity (lamina lucida) formed in the dermo-epidermal junction zone of a patient with bullous pemphigoid, unlike acquired epidermolysis bullosa, in which IgG deposition is observed in the lower part (floor) of the cavity.
It is recommended that patients with bullous pemphigoid, if there are indications of adverse therapy events or an association between the development of bullous pemphigoid and a neoplasm, consult a general practitioner to monitor the safety of ongoing therapy or undergo screening to rule out oncological pathology of internal organs and systems [16, 28]
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: If adverse events of systemic corticosteroid therapy develop, a consultation with a general practitioner may be required for their management. In some cases, the development of bullous pemphigoid has been associated with lymphoproliferative disorders and neoplasms of the gastrointestinal tract, urinary bladder, and lungs [5–9].
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
Emerging blisters should be opened by puncture and drained, leaving the blister roof in place to accelerate epithelialization and reduce the risk of secondary infection [29, 30, 35].
Medical therapy for patients with bullous pemphigoid is based on the use of systemic corticosteroids [31, 32]. Topical therapy with very high potency corticosteroids (group IV) is also possible by applying clobetasol to the entire body surface except the face [32, 33]. However, topical therapy with very high potency corticosteroids (group IV) is preferred in cases where bullous pemphigoid manifests as a non-bullous inflammatory skin lesion or the localization of bullous eruptions is limited to a single anatomical region [32]. Systemic corticosteroid therapy can lead to adverse events requiring a dose reduction or discontinuation of the drug. To minimize adverse events that may occur during systemic corticosteroid therapy, #methotrexate** or #cyclophosphamide** may be prescribed for the treatment of patients with bullous pemphigoid when necessary [2, 16, 23, 34]. The administration of #methotrexate** or #cyclophosphamide** may also be required in case of insufficient efficacy of systemic corticosteroids.
3.1 Conservative Treatment
Are recommended for patients with bullous pemphigoid systemic corticosteroids or very high potency corticosteroids (group IV):
prednisolone** 0.5–0.75 mg/kg body weight orally [31, 35–37]
Level of Evidence CReliability of Evidence 5Level of Confidence C (Level of Evidence – 5)
Comments: According to available data, when prednisolone** is prescribed at a daily dose of less than 0.5 mg/kg body weight, treatment efficacy is often insufficient [38]. Increasing the dose of prednisolone** above 0.75 mg/kg of body weight does not lead to an increase in therapeutic efficacy [39]. Gradual reduction of the systemic corticosteroid dose begins 15–21 days after achieving a clinical response—cessation of new rashes and itching, onset of erosion epithelialization—and continues for 4–6 months down to a maintenance dose of 0.1 mg/kg/day (at least 2 tablets per day) [40]. In case of disease relapse, the systemic corticosteroid dose should be increased to the initial level [41].
or
clobetasol 0.05% topical cream for adults applied twice daily to the entire body surface [32, 33]
GCR BLOE 2Grade of Recommendation B (Level of Evidence – 2)
Comments: Clobetasol should not be applied to the facial skin. The daily consumption of clobetasol cream is 40 g of cream for 15 days, after which the dose is reduced: 20 g per day for 1 month, 10 g per day for 2 months, 10 g every other day for 4 months, 10 g twice a week for 4 months [32, 33, 40]
According to available data, disease control is achieved 7–15 days after the start of topical therapy with clobetasol [32]. Given the treatment duration, which reaches up to 1 year, when choosing clobetasol for the treatment of patients with bullous pemphigoid, the potential development of severe skin atrophy should be taken into account. Low patient compliance is possible. In patients with low compliance, the risk of relapse is 4 times higher than in patients with high compliance [42].
Are recommended for adult patients with bullous pemphigoid, if it is necessary to reduce the dose of systemic corticosteroids or discontinue them completely in order to minimize the adverse effects of systemic corticosteroid therapy, antimetabolites or alkylating agents:
#methotrexate** 2.5–17.5 mg once a week [34, 43, 47, 48]
LoR CGoE 4Level of Recommendation C (Level of Evidence – 4)
Comments: #Methotrexate** can be administered orally, subcutaneously, or intramuscularly. [47, 48]
or
#cyclophosphamide** orally 50 mg daily, in case of insufficient efficacy—100 mg daily [44].
EcoL CLoE 4Level of Evidence C (Level of Confidence of Evidence 4)
Comments: #Cyclophosphamide** is prescribed during treatment with systemic corticosteroids. Once disease control is achieved, the dose of systemic corticosteroids is gradually reduced until complete discontinuation [44]. Before starting therapy with #cyclophosphamide**, inflammation and infection of the urinary bladder and electrolyte imbalance must be ruled out. Treatment with #cyclophosphamide** may cause myelosuppression and significant suppression of the immune response. During #cyclophosphamide** therapy, a complete (clinical) blood count and microscopic examination of urine sediment must be performed. Careful hematological monitoring is required for all patients during treatment with #cyclophosphamide**. [19, 20]
3.2 Surgical Treatment
Not performed.
3.3 Other Treatment
Due to the fact that erosions form at the site of blisters in patients with bullous pemphigoid, which can become infected and develop secondary pyoderma, it is necessary to treat the surface of erosions with antiseptics and disinfectants to prevent infection and the development of pyoderma.
Are recommended for adult patients with bullous pemphigoid who have erosions, antiseptics and disinfectants for treating erosive surfaces and preventing the development of pyoderma:
Boric acid + Resorcinol + Phenol + Fuchsin solution for topical application applied to erosions [45, 46]
Level of Recommendations CLevel of Evidence 4Level of Recommendations C (Level of Evidence – 4)
Comments: The solution is applied topically using a cotton swab to the affected skin areas 2–4 times a day. There are no age restrictions for the use of the Boric acid + Resorcinol + Phenol + Fuchsin topical solution.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
Rehabilitation measures for patients with bullous pemphigoid are determined by comorbid conditions.
5. Prevention and Dispensary Observation
There are no prevention methods.
6. Organization of Medical Care
Medical care for patients with bullous pemphigoid can be provided on an outpatient basis, in a day hospital, or in an inpatient setting.
Primary specialized health care is provided by a dermatologist, or in their absence, by a general practitioner or pediatrician.
Specialized medical care is provided by dermatologists in inpatient settings.
Indications for hospital admission to a medical organization:
1) Appearance of new blisters;
2) Lack of response to outpatient therapy.
Indications for patient discharge from a medical organization
1) Stabilization of the condition (no new rashes).
7. Additional Information
Patients with bullous pemphigoid are most often elderly individuals with concomitant comorbidities, which must be taken into account when planning therapy.
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Grade of Recommendation | Level of evidence | ||
|---|---|---|---|---|---|
1. | A detailed complete (clinical) blood count was performed for patients with bullous pemphigoid receiving systemic therapy. | 5 | C | ||
2. | A general medical biochemical blood test was performed for patients with bullous pemphigoid receiving systemic therapy. | 5 | C | ||
3. | A general urinalysis was performed for patients with bullous pemphigoid receiving systemic therapy. | 5 | C | ||
4. | Pathological examination of skin biopsy (surgical) material and/or pathological examination of skin biopsy (surgical) material using immunofluorescence methods was performed. | 5 | C | ||
5. | Systemic corticosteroid therapy and/or #methotrexate** and/or #cyclophosphamide** or high-potency topical corticosteroid therapy (Group IV) was administered. | 4 | C | ||
References
Show references
Büdinger L., Borradori L., Yee C. et al. Identification and characterization of autoreactive T cell responses to bullous pemphigoid antigen 2 in patients and healthy controls. J Clin Invest. 1998; 102 (12): 2082–2089. doi: 10.1172/JCI3335
Kirtschig G., Middleton P., Bennett C. et al. Interventions for bullous pemphigoid. Cochrane Database Syst Rev. 2010 Oct 6; 2010 (10): CD002292. doi: 10.1002/14651858.CD002292.pub3
Parker S.R., Dyson S., Brisman S. et al. Mortality of bullous pemphigoid: an evaluation of 223 patients and comparison with the mortality in the general population in the United States. J Am Acad Dermatol. 2008; 59 (4): 582–588. doi: 10.1016/j.jaad.2008.07.022
Schmidt E, Zillikens D. Pemphigoid diseases. Lancet. 2013; 381 (9863): 320–332. doi: 10.1016/S0140-6736(12)61140-4
Gül U., Kiliç A., Demirel O. et al. Bullous pemphigoid associated with breast carcinoma. Eur J Dermatol. 2006; 16 (5): 581–582. PMID: 17101485
Iranzo P., López I., Robles M.T. et al. Bullous pemphigoid associated with mantle cell lymphoma. Arch Dermatol. 2004; 140 (12): 1496–1499. doi: 10.1001/archderm.140.12.1496
Mabrouk D., Gürcan H.M., Keskin D.B. et al. Association between cancer and immunosuppressive therapy--analysis of selected studies in pemphigus and pemphigoid. Ann Pharmacother. 2010; 44 (11): 1770–1776. doi: 10.1345/aph.1P309
Teplyuk N.P., Kotelnikova L.A., Grabovskaya O.V., et al. Lever's paraneoplastic bullous pemphigoid in ovarian cancer and stage IIa left breast cancer. Russian Journal of Skin and Venereal Diseases. 2013; 4: 10–14.
Teplyuk N.P., Altaeva A.A., Belousova T.A., et al. Lever's bullous pemphigoid as a paraneoplastic process. Russian Journal of Skin and Venereal Diseases. 2012; 4: 5–10.
Lo Schiavo A., Ruocco E., Brancaccio G. et al. Bullous pemphigoid: etiology, pathogenesis, and inducing factors: facts and controversies. Clin Dermatol. 2013; 31 (4): 391–399. doi: 10.1016/j.clindermatol.2013.01.006
Laffitte E. Bullous pemphigoid: clinical features, diagnostic markers and immunopathogenic mechanisms / Laffitte E., Borradori L. // In book: Autoimmune diseases of the skin; ed. Michel Hertl. – Springer Wien NewYork. – 2005. – p.71–93.
Castanet J., Lacour J.P., Ortonne J.P. Formes cliniques atypiques des pemphigoïdes bulleuses [Atypical clinical forms of bullous pemphigoid]. Ann Dermatol Venereol. 1990; 117 (1): 73–82. French. PMID: 2181909
Nguyen V.T., Ndoye A., Bassler K.D. et al. Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of paraneoplastic pemphigus. Arch Dermatol. 2001; 137 (2): 193–206. PMID: 11176692.
Joly P., Roujeau J.C., Benichou J. 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): 1681–1687. doi: 10.1038/jid.2008.412
Order of the Ministry of Health of the Russian Federation No. 1484n dated December 24, 2012, "On approval of the standard of primary health care for bullous pemphigoid."
Fitzpatrick's Dermatology in General Medicine. Eighth Edition. Lowell A. Goldsmith, Stephen I. Katz, Barbara A. Gilchrest. ISBN 978-0-07-166904-7. McGraw-Hill Companies, 2012.
Stanbury R.M., Graham E.M. Systemic corticosteroid therapy – side effects and their management. Br J Ophthalmol. 1998; 82 (6): 704–708. doi: 10.1136/bjo.82.6.704
Dodiuk-Gad R.P., Ish-Shalom S., Shear N.H. Systemic glucocorticoids: important issues and practical guidelines for the dermatologist. Int J Dermatol. 2015; 54 (6): 723–729. doi: 10.1111/ijd.12642
Wolverton S.E. Monitoring for adverse effects from systemic drugs used in dermatology. J Am Acad Dermatol. 1992; 26 (5 Pt 1): 661–679. doi: 10.1016/0190-9622(92)70092-t
Dutz J.P., Ho V.C. Immunosuppressive agents in dermatology. An update. Dermatol Clin. 1998; 16 (2): 235–251. doi: 10.1016/s0733-8635(05)70006-1
Hadi S.M., Barnetson R.S., Gawkrodger D.J. et al. Clinical, histological and immunological studies in 50 patients with bullous pemphigoid. Dermatologica. 1988; 176 (1): 6–17. doi: 10.1159/000248663
Tkachenko S.B., Teplyuk N.P., Minnibaev M.T., et al. Modern methods of differential diagnosis of pemphigus vulgaris (autoimmune) and bullous pemphigoid. Russian Journal of Skin and Venereal Diseases. 2015; 18 (3): 17–22.
Cozzani E., Marzano A.V., Caproni M. et al. Bullous pemphigoid: Italian guidelines adapted from the EDF/EADV guidelines. G Ital Dermatol Venereol. 2018; 153 (3): 305–315. doi: 10.23736/S0392-0488.18.06006-6
Beletskaya L.V. Labeled antibodies in normal and pathological morphology (atlas) / Beletskaya L.V., Makhneva N.V. – Moscow: MNPI, 2000, – 111 p.
Makhneva N.V. Immunopathological aspects of autoimmune bullous dermatoses / Makhneva N.V., Beletskaya L.V. – Palmarium Academic Publishing, 2012, - 408 p.
Sárdy M., Kostaki D., Varga R. et al. Comparative study of direct and indirect immunofluorescence and of bullous pemphigoid 180 and 230 enzyme-linked immunosorbent assays for diagnosis of bullous pemphigoid. J Am Acad Dermatol. 2013; 69 (5): 748–753. doi: 10.1016/j.jaad.2013.07.009
Yang B., Wang C., Chen S. et al. Accuracy of indirect immunofluorescence on sodium chloride-split skin in the differential diagnosis of bullous pemphigoid and epidermolysis bullosa acquisita. Indian J Dermatol Venereol Leprol. 2011; 77 (6): 677–682. doi: 10.4103/0378-6323.86479
Ariunaa M., Khandsuren B., Batbaatar G., Tsogtstaykhan S. Differential diagnostic criteria for bullous pemphigoid. Siberian Medical Journal. 2011; 106 (7): 129–132.
Le Roux-Villet C., Prost-Squarcioni C., Oro S. et al. Rôle infirmier dans la prise en charge de la pemphigoïde bulleuse [Role of the nurse in care of bullous pemphigoid]. Rev Infirm. 2010; (160): 38–40. French. PMID: 20461987
Venning V.A., Taghipour K., Mohd Mustapa M.F. et al. British Association of Dermatologists" guidelines for the management of bullous pemphigoid 2012. Br J Dermatol. 2012; 167 (6): 1200–1214. doi: 10.1111/bjd.12072
Kubin M.E., Hellberg L., Palatsi R. Glucocorticoids: The mode of action in bullous pemphigoid. Exp Dermatol. 2017; 26 (12): 1253–1260. doi: 10.1111/exd.13408
Bernard P, Antonicelli F. Bullous pemphigoid: A review of its diagnosis, associations and treatment. Am J Clin Dermatol. 2017; 18 (4): 513–528. doi: 10.1007/s40257-017-0264-2
Joly P., Roujeau J.C., Benichou J. et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med. 2002; 346 (5): 321–327. doi: 10.1056/NEJMoa011592
Kjellman P, Eriksson H, Berg P. A retrospective analysis of patients with bullous pemphigoid treated with methotrexate. Arch Dermatol. 2008; 144 (5): 612–616. doi: 10.1001/archderm.144.5.612
Fuertes de Vega I., Iranzo-Fernández P., Mascaró-Galy J.M. Bullous pemphigoid: clinical practice guidelines. Actas Dermosifiliogr. 2014; 105 (4): 328–346. doi: 10.1016/j.ad.2012.10.022
Göbel M., Eming R. Therapie des bullösen Pemphigoids [Management of bullous pemphigoid]. Hautarzt. 2019; 70 (4): 236–242. German. doi: 10.1007/s00105-019-4390-z
Hébert V., Bastos S., Drenovska K. et al. International multicentre observational study to assess the efficacy and safety of a 0·5 mg kg-1 per day starting dose of oral corticosteroids to treat bullous pemphigoid. Br J Dermatol. 2021; 185 (6): 1232–1239. doi: 10.1111/bjd.20593
Borradori L., Van Beek N., Feliciani C. et al. Updated S2 K guidelines for the management of bullous pemphigoid initiated by the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol. 2022; 36 (10): 1689–1704. doi: 10.1111/jdv.18220
Morel P, Guillaume JC. Traitement de la pemphigïde bulleuse par la prednisone seule: 0,75 mg/kg/j contre 1,25 mg/kg/j. Etude randomisée multicentrique [Treatment of bullous pemphigoid with prednisolone only: 0.75 mg/kg/day versus 1.25 mg/kg/day. A multicenter randomized study]. Ann Dermatol Venereol. 1984; 111 (10): 925–928. French. PMID: 6395773.
Feliciani C., Joly P., Jonkman M.F. et al. Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology. Br J Dermatol. 2015; 172 (4): 867–877. doi: 10.1111/bjd.13717.
Murrell D.F., Marinovic B., Caux F. et al. Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international panel of experts. J Am Acad Dermatol. 2015; 72 (1): 168–174. doi: 10.1016/j.jaad.2014.08.024
Sobocinski V., Duvert-Lehembre S., Bubenheim M. et al. Assessment of adherence to topical corticosteroids in patients with bullous pemphigoid. Br J Dermatol. 2016; 174 (4): 919–921. doi: 10.1111/bjd.14285
Heilborn J.D., Ståhle-Bäckdahl M., Albertioni F. et al. Low-dose oral pulse methotrexate as monotherapy in elderly patients with bullous pemphigoid. J Am Acad Dermatol. 1999; 40 (5 Pt 1): 741–749. doi: 10.1016/s0190-9622(99)70156-8
Gual A., Iranzo P., Mascaró J.M. Jr. Treatment of bullous pemphigoid with low-dose oral cyclophosphamide: a case series of 20 patients. J Eur Acad Dermatol Venereol. 2014; 28 (6): 814–818. doi: 10.1111/jdv.12155
Efanova E.N., Rusak Yu.E., Vasilyeva E.A., Elmanbetova A.A. Lever's bullous pemphigoid in the setting of concurrent somatic pathology. Lechaschy Vrach. 2018; 10: 84–86.
Chistyakova I.A., Isaeva D.R. Lever's bullous pemphigoid, features of diagnosis and therapy. Vestnik Dermatologii i Venerologii. 2008; 4: 67–72.
Tikhonovskaya I.V., Katina M.A. Subepidermal bullous dermatoses. Part II. Bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita // Vestnik VSMU. – 2019. – Vol. 18. – No. 3. – P. 7-15.
A. Du‐Thanh, S. Merlet, H. Maillard, P. Bernard, P. Joly, E. Estève, M.A. Richard, C. Pauwels, S. Ingen‐Housz‐Oro, B. Guillot, O. Dereure, Combined treatment with low‐dose methotrexate and initial short‐term superpotent topical steroids in bullous pemphigoid: an open, multicentre, retrospective study, British Journal of Dermatology, Volume 165, Issue 6, 1 December 2011, Pages 1337–1343, https://doi.org/10.1111/j.1365-2133.2011.10531.x
Appendix A1. Working Group Composition
Kubanov Alexey Alekseevich – Academician of the RAS, Doctor of Medical Sciences, Professor, Director of the State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, President of the Russian Society of Dermatovenereologists and Cosmetologists.
Lyudmila F. Znamenskaya – MD, Leading Researcher at the Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, member of the Russian Society of Dermatovenereologists and Cosmetologists.
Karamova Arfenya Eduardovna – Candidate of Medical Sciences, Head of the Department of Dermatology at the State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, member of the Russian Society of Dermatovenerologists and Cosmetologists.
Nataliya V. Makhneva – MD, Head of the Scientific and Organizational Department, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, member of the Russian Society of Dermatovenereologists and Cosmetologists.
Mariya A. Nefedova – Junior Researcher at the Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, member of the Russian Society of Dermatovenereologists and Cosmetologists.
Teplyuk Nataliya Pavlovna – Doctor of Medical Sciences, Professor at the Department of Skin and Venereal Diseases, I.M. Sechenov First Moscow State Medical University, member of the Russian Society of Dermatovenerologists and Cosmetologists.
Vadim V. Chikin – MD, Senior Researcher at the Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, member of the Russian Society of Dermatovenereologists and Cosmetologists.
Conflict of Interest: The authors declare no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
1. Medical specialists: dermatovenereologists.
2. Residents and trainees of continuing professional education courses in the specified specialty.
Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | There is only a rationale for the mechanism of action or expert opinion |
Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)
LoE | Definitions |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | There is only a rationale for the mechanism of action of the intervention (preclinical studies) or expert opinion |
Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of evidence of proper quality; all considered efficacy criteria [outcomes] are unimportant, all studies have low methodological quality, and their conclusions regarding outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines.
The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
These clinical guidelines were developed taking into account the following regulatory legal documents:
Order of the Russian Ministry of Health No. 924n dated November 15, 2012, "On approval of the Procedure for the provision of medical care to the population in the profile 'dermatovenereology'."
Appendix B. Physician Action Algorithms
Appendix C. Patient Information
If treatment of concomitant diseases requires penicillamine**, beta-lactam antibacterial drugs (penicillins and other beta-lactam antibacterial drugs), captopril** and other ACE inhibitors, furosemide**, acetylsalicylic acid**, nonsteroidal anti-inflammatory and antirheumatic drugs, or nifedipine**, it should be considered that the onset of bullous pemphigoid rashes may be associated with their administration.
When taking systemic corticosteroids, regular monitoring of blood pressure, complete (clinical) blood count, and general medical biochemical blood test (blood glucose levels, water-electrolyte balance) is necessary. It should be kept in mind that prednisolone** and other systemic corticosteroids may reduce resistance to infection; therefore, hypothermia should be avoided.
Treatment with #methotrexate** and #cyclophosphamide** must be carried out under medical supervision.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Special assessment scales, indices, and questionnaires specific to bullous pemphigoid are not used in the examination of patients with bullous pemphigoid.