Next Article in Journal
Significance of Autoantibodies to Ki/SL as Biomarkers for Systemic Lupus Erythematosus and Sicca Syndrome
Previous Article in Journal
Evaluating a Novel Treatment Adapting a Cognitive Behaviour Therapy Approach for Sexuality Problems after Traumatic Brain Injury: A Single Case Design with Nonconcurrent Multiple Baselines
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 11
Issue 12
10.3390/jcm11123528
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Current and Innovated Managements for Autoimmune Bullous Skin Disorders: An Overview

by
Kuan-Yu Chu
1,
Hsin-Su Yu
2,*,† and
Sebastian Yu
1,3,4,*,†
1
Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
2
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
3
Department of Dermatology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
4
Neuroscience Research Center, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
J. Clin. Med. 2022, 11(12), 3528; https://doi.org/10.3390/jcm11123528
Submission received: 16 May 2022 / Revised: 13 June 2022 / Accepted: 17 June 2022 / Published: 19 June 2022
(This article belongs to the Section Dermatology)
Browse Figures
Review Reports Versions Notes

Abstract

:
Autoimmune bullous skin disorders are a group of disorders characterized by the formation of numerous blisters and erosions on the skin and/or the mucosal membrane, arising from autoantibodies against the intercellular adhesion molecules and the structural proteins. They can be classified into intraepithelial or subepithelial autoimmune bullous dermatoses based on the location of the targeted antigens. These dermatoses are extremely debilitating and fatal in certain cases, depending on the degree of cutaneous and mucosal involvement. Effective treatments should be implemented promptly. Glucocorticoids serve as the first-line approach due to their rapid onset of therapeutic effects and remission of the acute phase. Nonetheless, long-term applications may lead to major adverse effects that outweigh the benefits. Hence, other adjuvant therapies are mandatory to minimize the potential harm and ameliorate the quality of life. Herein, we summarize the current therapeutic strategies and introduce promising therapies for intractable autoimmune bullous diseases.

1. Introduction

Autoimmune bullous skin disorders (AIBDs) are comprised of a constellation of potentially devastating diseases manifested by cutaneous and/or mucosal blisters, evolving eventually into erosions. These clinical features are generated through the binding of immunoglobulin G (IgG) and immunoglobulin A (IgA) against the cutaneous and mucosal adhesion molecules, resulting in detachment of the skin and mucosal layers [1,2]. These autoantigens can locate either on the epidermis or dermal–epidermal basement membrane zone (BMZ) which can thus be categorized into intraepithelial (Table 1) and subepithelial (Table 2) bullous disorders [2].
Direct immunofluorescence (DIF) microscopy of perilesional tissue remains the gold standard of diagnosis for AIBDs. Other assays such as histopathological and serological examinations (e.g., indirect immunofluorescence (IIF) on different substrates, salt-split human skin test, enzyme-linked immunosorbent assay (ELISA) and immunoblotting) further assist the confirmation and can even discern the types of the autoantigens [3,4].
For most AIBDs, the first-line intervention is glucocorticoids (GCs) in combination with immunosuppressive agents [23,24]. Nonetheless, prolonged administration of these conventional therapies brings about numerous adverse effects that overweigh the benefits. Novel approaches have been proposed to maintain therapeutic efficacy and minimize the harm simultaneously. In this review article, we introduce the standard (Table 3) and promising adjuvant therapies established for AIBDs, especially PV and BP.

2. Therapeutic Managements

2.1. Intraepithelial Autoimmune Bullous Skin Disorders

2.1.1. Pemphigus Vulgaris (PV)

First-Line Therapies

GCs remain the first-line therapy for PV. Potent topical and intralesional GCs are merely applied to milder cases with limited efficacy [25,26]. Based on the severity of the disease, a loading dose equivalent to 0.5 to 1.5 mg/kg/day of prednisolone is widely accepted. Dosage above 3 to 4 mg/kg/day is not recommended due to the subsequent side effects on the patient [27]. Short-term intravenous pulse therapy (intravenous methylprednisolone 1 g/day or dexamethasone 300 mg/day for 3 consecutive days with an interval of 3–4 weeks followed by 6–8 weeks [28]) can promptly reduce the prednisolone dose and hence cause fewer adverse effects [29,30]. Once through the acute phase, the doctor should taper down the dosage of GCs in order to avoid possible adverse effects such as hypertension, diabetes mellitus, lower resistance to infections, gastrointestinal irritation, osteoporosis, avascular necrosis, glaucoma, and cataracts.
Rituximab, a chimeric monoclonal antibody targeting against CD20 antigen on B-cells up to the pre-plasma cell stage, annihilates the autoreactive B-cells in the bloodstream expeditiously and the effects last for at least 6–12 months. It has been regarded as an effective first-line treatment for pemphigus since 2017 [31] and was approved by the U.S. Food and Drug Administration in June 2018 for the treatment of adults with moderate to severe PV. There are currently two strategies for its administration. One is the lymphoma protocol (weekly dosage of 375 mg/m2 for four consecutive weeks) and the other is the rheumatoid arthritis protocol (two doses of 1000 mg separated by 2 weeks; may be repeated 6 months later) [32,33,34,35]. Paracetamol and antihistamine are required before each infusion to prevent infusion reactions. In addition, premedication with methylprednisolone 100 mg intravenously is indicated particularly before the first dose of rituximab [36]. Early administration and use in combination with short-term GCs have shown higher efficacy and better therapeutic results. Infusion-related reactions, life-threatening infections, venous thromboembolism, and rarely progressive multifocal leukoencephalopathy are the possible adverse effects [37].
Additional first-line adjuvants including azathioprine (1 to 3 mg/kg/day, divided into two separate doses) and mycophenolate mofetil (MMF) (2 g/day)/mycophenolic acid (1440 mg/day) are administered in combination with GCs rather than as monotherapies due to their late onset. These immunomodulators act as GC-sparing agents with MMF demonstrating less myelosuppressive and hepatotoxic than azathioprine [38].

Second-Line Therapies

Cyclophosphamide (CYP), given either as 500 mg intravenous bolus or 2 mg/kg/day orally, and methotrexate (MTX) 10–20 mg/week, are assumed to be the second-line management in the European Dermatology Forum guidelines [39]. Aggressive hydration or Mesna post CYP is recommended in preventing the development of hemorrhagic cystitis [40]. As for MTX, the adverse effects are dose-dependent and can be mitigated by daily supplement of 1 to 5 mg of folic acid.
Dapsone at the dosage of 100 mg/day or up to ≤1.5 mg/kg/day is deemed as the second-line adjuvant treatment [39]. The significance of dapsone in managing PV is controversial. Screening of glucose-6-phosphate dehydrogenase status, complete blood count along with renal and liver functions is widely recommended before commencing dapsone treatment.
Intravenous immunoglobulin (IVIG) results in prompt degradation of serum autoantibodies [41]. In each cycle, IVIG is administered via slow infusion at a monthly dosage of 2 g/kg divided into 2 to 5 consecutive days [42]. Nausea, malaise, headache, and fever during infusion are several common, mild and self-limited adverse effects. Despite its effectiveness and safety, its expensiveness and low availability restrict its utilization [43,44].
Plasmapheresis non-selectively depletes the plasma proteins along with the pathogenic autoantibodies. Nonetheless, the following rebound phenomenon accelerates the production of the autoantibodies which exacerbates the clinical symptoms [45,46]. GCs and immunosuppressive agents should be given simultaneously to minimize the situation [47,48]. The concomitant complications are sepsis, fluid overload, hyper- or hypotension, hypogammaglobulinemia, hypoproteinemia, and depletion of clotting factors. Another ameliorated apheresis named immunoadsorption precisely removes the pathogenic immunoglobulins and preserves fibrinogens, albumins, and other coagulation factors, hence, with fewer adverse effects. Two cycles are performed monthly over 4 consecutive days (2.5-fold plasma volume/day) [49,50,51]. Both plasmapheresis and immunoadsorption are alternative approaches to managing refractory AIBDs that are ineffective or contraindicated to other therapeutic modalities.

Emerging Options

Potential new therapeutics of PV are summarized in Figure 1.
Other anti-CD20 agents: Ofatumumab/Veltuzumab
Both ofatumumab and veltuzumab are purely humanized anti-CD20 monoclonal antibodies which reduce the possibility of immunological reactions caused by rituximab.
Ofatumumab, the first second-generation agent with high affinity, identifies the extracellular epitope of the CD20 molecule and possesses more potent complement-dependent cytotoxicity than rituximab [52]. Successful treatment following the chronic lymphocytic leukemia protocol (300 mg on day 1, 1000 mg on day 8 with eight concomitant cycles of monthly dosage of 1000 mg) was reported in a case report [53]. Two therapeutic trials in pemphigus were prematurely terminated due to financial issues [54].
Veltuzumab, a type I, second-generation medication with higher binding avidity compared to rituximab can be administered subcutaneously (two doses of 320 mg with an interval of 2 weeks [55]). It was granted Orphan-Drug Designation by the U.S. Food and Drug Administration in 2005 [54].
Chimeric autoantibody receptor T-cells (CAAR-T-cells)
CAAR-T-cells are derived from the patient’s autoantibodies engineered to recognize specific antigens located on the target tumor cells and were applied in numerous hematologic malignancies. Ellebrecht et al. manipulated CAAR-T-cells expressing Dsg3-CAAR to combat pathogenic B-cells in vitro [56]. The murine model also showed the Dsg3-CAAR-T-cells eliminate Dsg3-specific B-cells in vivo. A phase 1 trial aiming to establish the maximum tolerated dose of Dsg3-CAAR-T-cells in the mucosal-dominant PV patients is in progress.
Bruton tyrosine kinase inhibitors: Ibrutinib/Rilzabrutinib (PRN1008)
Bruton tyrosine kinase (BTK) modulates multiple downstream molecules and is in charge of the survival, proliferation and maturation of the B-cells [57,58]. Through binding with the antigens, Lyn and spleen tyrosine kinase (SYK) activate BTK which then phosphorylates phospholipase Cγ2 (PLCγ2) and initiates multiple inflammatory pathways such as the mitogen-associated protein kinase (MAPK), nuclear factor-κB (NF-κB) and nuclear factor of activated T-cells (NFAT) [59,60]. Ibrutinib was reported to be effective in cases of PNP associated with chronic lymphocytic leukemia [61,62] and mantle cell lymphoma [61,63]. Another oral regimen rilzabrutinib (400–600 mg twice daily for 12 weeks) illustrated an impressive outcome with > 50% of PV patients attaining control of the disease in a phase 2 BELIEVE study [61,64] and it is now undergoing a phase 3 clinical trial in 120 cases of PV and PF [65].
Anti-B-cell activating factor (BAFF) receptor monoclonal antibody: Ianalumab (VAY736)
BAFF belongs to the tumor necrosis factor (TNF) family which through binding to its receptor is in charge of the survival of the B-cells [66,67]. A higher serum level of BAFF was noticed in miscellaneous autoimmune diseases, namely rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, and systemic sclerosis [68,69,70]. A partial-blind, randomized, placebo-controlled phase 2 clinical trial of ianalumab, a novel and competent IgG1 monoclonal antibody of the BAFF receptor, was applied to 13 PV patients. The efficacy of the drug is not confirmed to date.
Neonatal Fc receptor (FcRn) antagonists: Efgartigimod (ARGX-113)/SYNT001
FcRn situated on the endothelial cells of the blood vessel is involved in the homeostasis of IgG and albumin. Once bound to the pathogenic IgGs, it prevents the immunoglobulins from degrading by the lysosomes, thus extending their half-lives [71]. Efgartigimod, an antagonist of FcRn, saturates the receptor, accelerating the degradation of the pathogenic autoantibodies. It demonstrated favorable effects in patients with myasthenia gravis [72] and primary immune thrombocytopenia [73]. Currently, one phase 2 trial in six pemphigus patients is ongoing [74]. Another phase 1/2B clinical trial with SYNT001 recruited eight pemphigus participants but was later terminated due to safety concerns.
Polyclonal regulatory T-cells (PolyTregs)
Regulatory T-cells (Tregs) play a significant role upstream in regulating the immune system. Schmidt et al. showed that induction of Tregs downregulates the activation of pathogenic Dsg3-specific T-helper (Th) 2 cells in one HLA-DRB1*04:02 PV transgenic mouse model [75]. Utilization of natural Tregs in lupus, cancer and organ transplantation individuals was proposed [76]. One phase 1 multicenter trial administering intravenous autologous PolyTregs in 12 PV or PF patients is being conducted.

2.1.2. Pemphigus Foliaceus (PF)

The principles in treating PF patients are, in general, identical to those for PV. Associated with lower morbidity and less recalcitrant than PV, the initial management of PF is usually less aggressive [77]. In some mild and localized cases, topical high-potency GCs can achieve satisfactory results.

2.1.3. Pemphigus Erythematosus (PE)

PE is a rare clinical variant of PF [1,78,79]. In mild cases, monotherapy with topical GCs is feasible. For widespread and persistent diseases, systemic prednisolone at the dosage between 0.5 and 1 mg/kg/day in addition to dapsone 100 to 200 mg/day are recommended as the first-line therapies.

2.1.4. IgA Pemphigus

Systemic GCs (0.5 to 1 mg/kg/day prednisolone) and dapsone (100 to 300 mg/day) remain the mainstay therapy for IgA pemphigus. Because HLA-B*13:01 is associated with dapsone hypersensitivity syndrome, genotyping of HLA-B*13:01 before dapsone administration is suggested [80]. In intractable cases, systemic retinoids such as isotretinoin [81] and acitretin [82] can be considered. Howell et al. have proposed a rapid therapeutic response when administering adalimumab (a monoclonal antibody to TNF-α) and MMF to these patients [83].

2.1.5. Paraneoplastic Pemphigus (PNP)

Conventional Treatments

Management of PNP is extremely challenging and onerous. Control of the underlying malignancy is the capital issue. Systemic prednisolone (0.5 to 1 mg/kg/day) is prescribed as the first-line treatment [84]. Rituximab, either with the lymphoma or rheumatoid arthritis protocol, is a practical therapeutic approach and has attained successful efficacy in non-Hodgkin lymphoma [85]. Other noteworthy methods include IVIG and immunoadsorption.

Emerging Options

Anti-CD52 agents: Alemtuzumab
CD52 is a membrane glycoprotein found on numerous immune cells, inclusive of mature lymphocytes [86]. Alemtuzumab, a humanized monoclonal antibody against CD52, causes prompt and long-term depletion of the CD52-bearing lymphocytes [87]. It may be suitable for adjunctive management in PNP cases refractory to other managements, notably in those with hematologic malignancies [88,89,90]. Alemtuzumab is given 30 mg three times per week for 12 weeks along with a daily dose of 40 mg prednisolone.

2.2. Subepithelial Autoimmune Bullous Skin Disorders

2.2.1. Bullous Pemphigoid (BP)

First-Line Therapies

In BP, stage-adjusted therapy is advocated [28]. According to the involved body surface area (BSA), patients are classified into mild (<10% BSA), moderate (10 to 30% BSA) and severe (>30% BSA) groups. In mild and moderate cases, topical super-potent GCs applied to the blisters, erosions and perilesional skin carry out remission. Studies prove that topical clobetasol propionate 40 g/day [91] or 10 to 30 g/day [92] demonstrates equivalent efficacy to systemic GCs and spares their displeasing adverse effects. Nonetheless, the treatment success depends prominently on the adherence and the ability of the patient and the caregiver to apply these topical creams to an extensive body surface area. For rapidly deteriorating and relapsing BPs, systemic GCs with initial doses between 0.5 and 0.75 mg/kg/day of prednisolone are suggested [93,94].
Currently, tetracycline antibiotics (e.g., doxycycline 200 mg/day) are the most widely endorsed for first-line adjuvant therapy. They can be utilized alone or in combination with nicotinamide (up to 2 g/day). Nonetheless, in the real world, relatively short-term effectiveness was reported in one Japanese investigation, revealing that 22 of 27 BP patients managed with doxycycline required second-line prednisolone treatment. [95] Alternative effective regimens such as azathioprine (2 to 2.5 mg/kg/day), MMF (2 g/day)/mycophenolic acid (1440 mg/day), dapsone (100 mg/day or up to 1.5 mg/kg/day), and MTX (10 to 20 mg/week) have been listed in various guidelines.

Second-Line Therapies

For severe and intractable cases, some of the available options include high-dose IVIG (2 g/kg per cycle with an interval of 4 to 6 weeks), immunoadsorption/plasmapheresis, and rituximab (either with the lymphoma or rheumatoid arthritis protocol) [28]. Furthermore, CYP given orally with a daily dosage of 2 mg/kg or intravenously with a monthly dose of 15 to 20 mg/kg can be considered.

Emerging Options

Potential new therapeutics of BP are summarized in Figure 2.
Anti-IgE monoclonal antibody: Omalizumab
Recent research has pronounced that the serum level of IgE-mediated autoantibodies directed against BP180 is correlated to the disease activity of BP [96]. Successful experience of omalizumab, a humanized monoclonal anti-IgE antibody, in BP cases has been broadly reported [97,98,99].
Anti-C5a receptor (C5aR) antibody: Avdoralimab
Complement activation, particularly the interaction between the C5a fragment and C5aR, results in mast cell degranulation and the subsequent blister formation in BP [100]. Avdoralimab, a monoclonal antibody against C5aR, is now being evaluated for its efficacy in 40 BP patients in a randomized multicenter phase 2 trial.
Interleukin-17A (IL-17A) and IL-23 antagonist: Ixekizumab/Ustekinumab/Tildrakizumab
Higher expression of IL-17 and IL-23 was detected in the serum and the lesional skin of BP patients [101]. Ixekizumab, ustekinumab, and tildrakizumab are all well-known biologics for psoriasis targeting IL-17A, IL-12/IL-23, and IL-23, respectively. As for the BP patients, ixekizumab and ustekinumab are recently undergoing an open-label phase 2 clinical trial, whereas tildrakizumab is in an early phase 1 trial. Further studies are mandatory to support their efficacy.
Inhibiting the eosinophil cytokines and chemokines: Dupilumab/Bertilimumab/Mepolizumab
The accumulation of eosinophils in the dermis and the subepidermal clefts is the histological hallmark of BP. With the presence of eosinophils, the elevation of both IL-5 and eotaxin is noted in the blister fluid by the ELISA [102]. Other studies revealed a predominance of Th2 cytokines, inclusive of IL-4, IL-5, and IL-13, in the skin of the BP patients [103,104]. These findings trigger the administration of numerous innovative agents in managing intractable BP cases.
Dupilumab, a monoclonal antibody against IL-4 and IL-13 approved in atopic dermatitis, achieved excellent clearance or satisfactory response in 92.3% of BP patients in a multicenter case series [105]. Bertilimumab is a humanized anti-eotaxin-1 monoclonal antibody. Nine out of eleven BP cases enrolled in a phase 2 clinical trial were prescribed with 10 mg/kg of intravenous bertilimumab on days 0, 14 and 28. Within the follow-up period of 13 weeks, 81% declination of the disease severity was reported without significant adverse effects [106]. Unfortunately, mepolizumab, an IL-5 antagonist sharing a similar mechanism as bertilimumab, failed to show significant differences in the clinical outcome in comparison with the placebo group in a double-blind phase 2 trial. Nonetheless, they still noted a prominent reduction in the serum eosinophil count in the experimental group [107].
C-C chemokine receptor 3 (CCR3) antagonist: AKST4290
AKST4290 is an oral antagonist of CCR3, a receptor for eotaxin. Blocking of the CCR3 was proven to cause depletion of eosinophils in animal models [108]. A double-blind, placebo-controlled phase 2 study for AKST4290 has been completed. The participants received AKST4290 at the dosage of 400 mg twice concurrently with mometasone furoate until the disease was under control. No results are available to date.

2.2.2. Mucous Membrane Pemphigoid (MMP)

The therapeutic strategies depend on the afflicted mucosal areas, disease severity, and its progression. Mild to moderate oral MMP can be alleviated by topical GCs [109] and tacrolimus [110]. Severe cases or those with ocular involvement require systemic GCs, dapsone, or immunomodulators for disease control. IVIG, steroid/cyclophosphamide pulse therapy, plasmapheresis, and rituximab are reserved for recalcitrant patients [111].

2.2.3. Linear IgA Bullous Dermatosis

Dapsone contributes to prompt remission and qualifies as the first-line management in linear IgA bullous dermatosis [112]. Topical potent GCs can be applied to cutaneous lesions as the initial treatment. Systemic oral prednisolone 0.25 to 0.5 mg/kg/day should be considered for those who fail to improve from the topical GCs. Additional therapeutic options include sulfonamides, colchicine, and tetracycline/niacinamide.

2.2.4. Epidermolysis Bullosa Acquisita (EBA)

Conventional Treatments

Management of EBA is exceptionally arduous. High-dose systemic GCs ranging from 1 to 1.5 mg/kg/day remain the preferred regimen. Dapsone or colchicine can be applied together with GCs to accelerate remission. The administration of other adjuvant therapies such as immunosuppressive agents (e.g., cyclosporine, azathioprine, CYP, MTX, and MMF), IVIG, and rituximab is utilized in the refractory cases [113,114,115,116].

Emerging Options

Anti-CD25 monoclonal antibody: Daclizumab
The production of autoantibodies in EBA patients is highly associated with T-cells. CD25, a significant component of the IL-2 receptor, regulates the survival and activation of T-cells. Daclizumab, through blocking CD25, facilitates a rapid and continuous reduction in lymphocyte CD25 expression and was proven to be effective in one EBA patient [117].

2.2.5. Dermatitis Herpetiformis (DH)

A strict gluten-free diet takes a chief role in dealing with DH. Slow titration of dapsone is the most popular first-line therapy showing immediate clinical improvement. Pharmacotherapy with sulfa-based regimens (sulfapyridine, sulfasalazine and sulfamethoxypyridazine) is suitable for those who cannot tolerate prior treatments [118,119,120]. Topical GCs may soothe the pruritus; nevertheless, systemic GCs are not warranted in DH.

2.2.6. Laminin γ1 Pemphigoid

The therapeutic information is sparse due to its rarity. Topical GCs can be applied to those with milder symptoms. With higher disease severity, some of the popular selections include systemic GCs (starting from 0.5 mg/kg/day) in collaboration with dapsone (1–1.5 mg/kg/day), cyclosporine, or azathioprine [121,122]. Other documented managements include doxycycline, high-dose IVIG, colchicine, and ustekinumab [122].

3. Conclusions

AIBDs consist of a dozen of debilitating diseases that deserve our attention. In recent years, a growing number of investigations have provided us with some novel thoughts for confronting these diseases. In PV, clinical trials targeting autoreactive B-cells including anti-CD20 agents, CAAR-T-cells, BTK inhibitors, and anti-BAFF receptor antibodies are burgeoning fields of research. The same concern has been raised regarding FcRn antagonists and PolyTregs, both of which demonstrate the capabilities of suppressing pathogenic autoantibodies. On the other hand, in BP, the Th2 axis such as mast cells, eosinophils, and IgE is of paramount interest. Notably, biologics against the IL-17/IL-23 inflammatory pathway may be revolutionary choices for recalcitrant cases. In the future, these personalized approaches would usher in a brand new era in managing these diseases.

Author Contributions

K.-Y.C. and S.Y. drafted the manuscript. H.-S.Y. revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by grants from the Taiwan Ministry of Science and Technology (MOST-109-2628-B-037-013 and MOST-110-2628-B-037-007) to S.Y., and (MOST-110-2314-B-037-137) to H.-S.Y. and grants from Kaohsiung Medical University Hospital (KMUH108-8T03, KMUH109-9R67, and KMUH110-0R61) to S.Y. This study was supported partially by Kaohsiung Medical University Research Center Grants (KMU-TC109B03 and KMU-TC110B03).

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Kneisel, A.; Hertl, M. Autoimmune bullous skin diseases. Part 1: Clinical manifestations. J. Dtsch. Dermatol. Ges. 2011, 9, 844–856. [Google Scholar] [CrossRef] [PubMed]
  2. Hertl, M.; Niedermeier, A.; Borradori, L. Autoimmune bullous skin disorders. Ther. Umschau. Rev. Ther. 2010, 67, 465–482. [Google Scholar] [CrossRef] [PubMed]
  3. Van Beek, N.; Zillikens, D.; Schmidt, E. Diagnosis of autoimmune bullous diseases. J. Dtsch. Dermatol. Ges. J. Ger. Soc. Dermatol. JDDG 2018, 16, 1077–1091. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Saschenbrecker, S.; Karl, I.; Komorowski, L.; Probst, C.; Dähnrich, C.; Fechner, K.; Stöcker, W.; Schlumberger, W. Serological Diagnosis of Autoimmune Bullous Skin Diseases. Front. Immunol. 2019, 10, 1974. [Google Scholar] [CrossRef]
  5. Baum, S.; Sakka, N.; Artsi, O.; Trau, H.; Barzilai, A. Diagnosis and classification of autoimmune blistering diseases. Autoimmun. Rev. 2014, 13, 482–489. [Google Scholar] [CrossRef]
  6. Schmidt, E.; Kasperkiewicz, M.; Joly, P. Pemphigus. Lancet 2019, 394, 882–894. [Google Scholar] [CrossRef]
  7. Amerian, M.L.; Ahmed, A.R. Pemphigus erythematosus. Senear-Usher syndrome. Int. J. Dermatol. 1985, 24, 16–25. [Google Scholar] [CrossRef]
  8. Düker, I.; Schaller, J.; Rose, C.; Zillikens, D.; Hashimoto, T.; Kunze, J. Subcorneal pustular dermatosis-type IgA pemphigus with autoantibodies to desmocollins 1, 2, and 3. Arch. Dermatol. 2009, 145, 1159–1162. [Google Scholar] [CrossRef]
  9. Solimani, F.; Maglie, R.; Pollmann, R.; Schmidt, T.; Schmidt, A.; Ishii, N.; Tackenberg, B.; Kirschbaum, A.; Didona, D.; Pickert, J.; et al. Thymoma-Associated Paraneoplastic Autoimmune Multiorgan Syndrome—From Pemphigus to Lichenoid Dermatitis. Front. Immunol. 2019, 10, 1413. [Google Scholar] [CrossRef]
  10. Anhalt, G.J. Paraneoplastic pemphigus. J. Investig. Dermatol. Symp. Proc. 2004, 9, 29–33. [Google Scholar] [CrossRef] [Green Version]
  11. Kaplan, I.; Hodak, E.; Ackerman, L.; Mimouni, D.; Anhalt, G.J.; Calderon, S. Neoplasms associated with paraneoplastic pemphigus: A review with emphasis on non-hematologic malignancy and oral mucosal manifestations. Oral Oncol. 2004, 40, 553–562. [Google Scholar] [CrossRef] [PubMed]
  12. Ohzono, A.; Sogame, R.; Li, X.; Teye, K.; Tsuchisaka, A.; Numata, S.; Koga, H.; Kawakami, T.; Tsuruta, D.; Ishii, N.; et al. Clinical and immunological findings in 104 cases of paraneoplastic pemphigus. Br. J. Dermatol. 2015, 173, 1447–1452. [Google Scholar] [CrossRef] [PubMed]
  13. Witte, M.; Zillikens, D.; Schmidt, E. Diagnosis of Autoimmune Blistering Diseases. Front. Med. 2018, 5, 296. [Google Scholar] [CrossRef] [PubMed]
  14. Schmidt, E.; della Torre, R.; Borradori, L. Clinical features and practical diagnosis of bullous pemphigoid. Dermatol. Clin. 2011, 29, 427–438, viii–ix. [Google Scholar] [CrossRef] [PubMed]
  15. Shetty, V.M.; Subramaniam, K.; Rao, R. Utility of immunofluorescence in dermatology. Indian Dermatol. Online J. 2017, 8, 1–8. [Google Scholar] [CrossRef]
  16. Chan, L.S.; Ahmed, A.R.; Anhalt, G.J.; Bernauer, W.; Cooper, K.D.; Elder, M.J.; Fine, J.D.; Foster, C.S.; Ghohestani, R.; Hashimoto, T.; et al. The first international consensus on mucous membrane pemphigoid: Definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch. Dermatol. 2002, 138, 370–379. [Google Scholar] [CrossRef]
  17. Thorne, J.E.; Anhalt, G.J.; Jabs, D.A. Mucous membrane pemphigoid and pseudopemphigoid. Ophthalmology 2004, 111, 45–52. [Google Scholar] [CrossRef]
  18. Ahmed, A.R.; Kurgis, B.S.; Rogers, R.S., 3rd. Cicatricial pemphigoid. J. Am. Acad. Dermatol. 1991, 24, 987–1001. [Google Scholar] [CrossRef]
  19. Genovese, G.; Venegoni, L.; Fanoni, D.; Muratori, S.; Berti, E.; Marzano, A.V. Linear IgA bullous dermatosis in adults and children: A clinical and immunopathological study of 38 patients. Orphanet J. Rare Dis. 2019, 14, 115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Roenigk, H.H., Jr.; Ryan, J.G.; Bergfeld, W.F. Epidermolysis bullosa acquisita. Report of three cases and review of all published cases. Arch. Dermatol. 1971, 103, 1–10. [Google Scholar] [CrossRef]
  21. Dainichi, T.; Kurono, S.; Ohyama, B.; Ishii, N.; Sanzen, N.; Hayashi, M.; Shimono, C.; Taniguchi, Y.; Koga, H.; Karashima, T.; et al. Anti-laminin gamma-1 pemphigoid. Proc. Natl. Acad. Sci USA 2009, 106, 2800–2805. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Kridin, K.; Ahmed, A.R. Anti-p200 Pemphigoid: A Systematic Review. Front. Immunol. 2019, 10, 2466. [Google Scholar] [CrossRef] [PubMed]
  23. Bishnoi, A.; De, D.; Handa, S.; Mahajan, R. Biologics in autoimmune bullous diseases: Current scenario. Indian J. Dermatol. Venereol. Leprol. 2021, 87, 611–620. [Google Scholar] [CrossRef] [PubMed]
  24. Di Lernia, V.; Casanova, D.M.; Goldust, M.; Ricci, C. Pemphigus Vulgaris and Bullous Pemphigoid: Update on Diagnosis and Treatment. Dermatol. Pract. Concept. 2020, 10, e2020050. [Google Scholar] [CrossRef]
  25. Dumas, V.; Roujeau, J.C.; Wolkenstein, P.; Revuz, J.; Cosnes, A. The treatment of mild pemphigus vulgaris and pemphigus foliaceus with a topical corticosteroid. Br. J. Dermatol. 1999, 140, 1127–1129. [Google Scholar] [CrossRef]
  26. Bystryn, J.C.; Steinman, N.M. The adjuvant therapy of pemphigus: An update. Arch. Dermatol. 1996, 132, 203–212. [Google Scholar] [CrossRef]
  27. Santi, C.G.; Gripp, A.C.; Roselino, A.M.; Mello, D.S.; Gordilho, J.O.; Marsillac, P.F.; Porro, A.M. Consensus on the treatment of autoimmune bullous dermatoses: Bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa acquisita—Brazilian Society of Dermatology. An. Bras. Dermatol. 2019, 94, 33–47. [Google Scholar] [CrossRef]
  28. Eming, R.; Sticherling, M.; Hofmann, S.C.; Hunzelmann, N.; Kern, J.S.; Kramer, H.; Pfeiffer, C.; Schuster, V.; Zillikens, D.; Goebeler, M.; et al. S2k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid. J. Dtsch. Dermatol. Ges. J. Ger. Soc. Dermatol. JDDG 2015, 13, 833–844. [Google Scholar] [CrossRef]
  29. Rao, P.N.; Lakshmi, T.S. Pulse therapy and its modifications in pemphigus: A six year study. Indian J. Dermatol. Venereol. Leprol. 2003, 69, 329–333. [Google Scholar] [PubMed]
  30. Chams-Davatchi, C.; Esmaili, N.; Daneshpazhooh, M.; Valikhani, M.; Balighi, K.; Hallaji, Z.; Barzegari, M.; Akhyani, M.; Ghodsi, S.Z.; Seirafi, H.; et al. Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris. J. Am. Acad. Dermatol. 2007, 57, 622–628. [Google Scholar] [CrossRef]
  31. Joly, P.; Maho-Vaillant, M.; Prost-Squarcioni, C.; Hebert, V.; Houivet, E.; Calbo, S.; Caillot, F.; Golinski, M.L.; Labeille, B.; Picard-Dahan, C.; et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): A prospective, multicentre, parallel-group, open-label randomised trial. Lancet 2017, 389, 2031–2040. [Google Scholar] [CrossRef]
  32. Huang, A.; Madan, R.K.; Levitt, J. Future therapies for pemphigus vulgaris: Rituximab and beyond. J. Am. Acad. Dermatol. 2016, 74, 746–753. [Google Scholar] [CrossRef]
  33. Cianchini, G.; Lupi, F.; Masini, C.; Corona, R.; Puddu, P.; De Pità, O. Therapy with rituximab for autoimmune pemphigus: Results from a single-center observational study on 42 cases with long-term follow-up. J. Am. Acad. Dermatol. 2012, 67, 617–622. [Google Scholar] [CrossRef] [PubMed]
  34. Heelan, K.; Al-Mohammedi, F.; Smith, M.J.; Knowles, S.; Lansang, P.; Walsh, S.; Shear, N.H. Durable Remission of Pemphigus With a Fixed-Dose Rituximab Protocol. JAMA Dermatol. 2014, 150, 703–708. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Kanwar, A.J.; Vinay, K.; Sawatkar, G.U.; Dogra, S.; Minz, R.W.; Shear, N.H.; Koga, H.; Ishii, N.; Hashimoto, T. Clinical and immunological outcomes of high- and low-dose rituximab treatments in patients with pemphigus: A randomized, comparative, observer-blinded study. Br. J. Dermatol. 2014, 170, 1341–1349. [Google Scholar] [CrossRef] [PubMed]
  36. Buch, M.H.; Smolen, J.S.; Betteridge, N.; Breedveld, F.C.; Burmester, G.; Dörner, T.; Ferraccioli, G.; Gottenberg, J.E.; Isaacs, J.; Kvien, T.K.; et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann. Rheum. Dis. 2011, 70, 909–920. [Google Scholar] [CrossRef] [PubMed]
  37. Wu, K.-J.; Wei, K.-C. Venous thromboembolism in a case with pemphigus vulgaris after infusion of rituximab plus systemic glucocorticoids and azathioprine: A possible adverse effect of rituximab? Derm. Sin. 2021, 39, 103–104. [Google Scholar] [CrossRef]
  38. Schiavo, A.L.; Puca, R.V.; Ruocco, V.; Ruocco, E. Adjuvant drugs in autoimmune bullous diseases, efficacy versus safety: Facts and controversies. Clin. Derm. 2010, 28, 337–343. [Google Scholar] [CrossRef]
  39. Hertl, M.; Jedlickova, H.; Karpati, S.; Marinovic, B.; Uzun, S.; Yayli, S.; Mimouni, D.; Borradori, L.; Feliciani, C.; Ioannides, D.; et al. Pemphigus. S2 Guideline for diagnosis and treatment—Guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). J. Eur. Acad. Dermatol. Venereol. JEADV 2015, 29, 405–414. [Google Scholar] [CrossRef]
  40. Meurer, M. Immunosuppressive therapy for autoimmune bullous diseases. Clin. Derm. 2012, 30, 78–83. [Google Scholar] [CrossRef]
  41. Li, N.; Zhao, M.; Hilario-Vargas, J.; Prisayanh, P.; Warren, S.; Diaz, L.A.; Roopenian, D.C.; Liu, Z. Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases. J. Clin. Investig. 2005, 115, 3440–3450. [Google Scholar] [CrossRef] [PubMed]
  42. Hoffmann, J.H.O.; Enk, A.H. High-Dose Intravenous Immunoglobulin in Skin Autoimmune Disease. Front. Immunol. 2019, 10, 1090. [Google Scholar] [CrossRef] [PubMed]
  43. Daoud, Y.J.; Amin, K.G. Comparison of cost of immune globulin intravenous therapy to conventional immunosuppressive therapy in treating patients with autoimmune mucocutaneous blistering diseases. Int. Immunopharmacol. 2006, 6, 600–606. [Google Scholar] [CrossRef]
  44. Keskin, D.B.; Stern, J.N.; Fridkis-Hareli, M.; Razzaque Ahmed, A. Cytokine profiles in pemphigus vulgaris patients treated with intravenous immunoglobulins as compared to conventional immunosuppressive therapy. Cytokine 2008, 41, 315–321. [Google Scholar] [CrossRef]
  45. Lever, W.F.; Schaumburg-Lever, G. Treatment of pemphigus vulgaris. Results obtained in 84 patients between 1961 and 1982. Arch. Dermatol. 1984, 120, 44–47. [Google Scholar] [CrossRef] [PubMed]
  46. Becker, B.A.; Gaspari, A.A. Pemphigus vulgaris and vegetans. Dermatol. Clin. 1993, 11, 429–452. [Google Scholar] [CrossRef]
  47. Ruocco, E.; Wolf, R.; Ruocco, V.; Brunetti, G.; Romano, F.; Lo Schiavo, A. Pemphigus: Associations and management guidelines: Facts and controversies. Clin. Derm. 2013, 31, 382–390. [Google Scholar] [CrossRef]
  48. Sinha, A.A.; Hoffman, M.B.; Janicke, E.C. Pemphigus vulgaris: Approach to treatment. Eur. J. Dermatol. EJD 2015, 25, 103–113. [Google Scholar] [CrossRef]
  49. Kasperkiewicz, M.; Shimanovich, I.; Meier, M.; Schumacher, N.; Westermann, L.; Kramer, J.; Zillikens, D.; Schmidt, E. Treatment of severe pemphigus with a combination of immunoadsorption, rituximab, pulsed dexamethasone and azathioprine/mycophenolate mofetil: A pilot study of 23 patients. Br. J. Dermatol. 2012, 166, 154–160. [Google Scholar] [CrossRef]
  50. Zillikens, D.; Derfler, K.; Eming, R.; Fierlbeck, G.; Goebeler, M.; Hertl, M.; Hofmann, S.C.; Karlhofer, F.; Kautz, O.; Nitschke, M.; et al. Recommendations for the use of immunoapheresis in the treatment of autoimmune bullous diseases. J. Dtsch. Dermatol. Ges. J. Ger. Soc. Dermatol. JDDG 2007, 5, 881–887. [Google Scholar] [CrossRef]
  51. Behzad, M.; Möbs, C.; Kneisel, A.; Möller, M.; Hoyer, J.; Hertl, M.; Eming, R. Combined treatment with immunoadsorption and rituximab leads to fast and prolonged clinical remission in difficult-to-treat pemphigus vulgaris. Br. J. Dermatol. 2012, 166, 844–852. [Google Scholar] [CrossRef] [PubMed]
  52. Robak, T.; Robak, E. New anti-CD20 monoclonal antibodies for the treatment of B-cell lymphoid malignancies. BioDrugs Clin. Immunother. Biopharm. Gene Ther. 2011, 25, 13–25. [Google Scholar] [CrossRef] [PubMed]
  53. Klufas, D.M.; Amerson, E.; Twu, O.; Clark, L.; Shinkai, K. Refractory pemphigus vulgaris successfully treated with ofatumumab. JAAD Case Rep. 2020, 6, 734–736. [Google Scholar] [CrossRef] [PubMed]
  54. Du, F.H.; Mills, E.A.; Mao-Draayer, Y. Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment. Auto-Immun. Highlights 2017, 8, 12. [Google Scholar] [CrossRef]
  55. Ellebrecht, C.T.; Choi, E.J.; Allman, D.M.; Tsai, D.E.; Wegener, W.A.; Goldenberg, D.M.; Payne, A.S. Subcutaneous veltuzumab, a humanized anti-CD20 antibody, in the treatment of refractory pemphigus vulgaris. JAMA Derm. 2014, 150, 1331–1335. [Google Scholar] [CrossRef] [Green Version]
  56. Ellebrecht, C.T.; Bhoj, V.G.; Nace, A.; Choi, E.J.; Mao, X.; Cho, M.J.; Di Zenzo, G.; Lanzavecchia, A.; Seykora, J.T.; Cotsarelis, G.; et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 2016, 353, 179–184. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Crofford, L.J.; Nyhoff, L.E.; Sheehan, J.H.; Kendall, P.L. The role of Bruton’s tyrosine kinase in autoimmunity and implications for therapy. Expert Rev. Clin. Immunol. 2016, 12, 763–773. [Google Scholar] [CrossRef] [Green Version]
  58. Corneth, O.B.J.; Klein Wolterink, R.G.J.; Hendriks, R.W. BTK Signaling in B Cell Differentiation and Autoimmunity. Curr. Top. Microbiol. Immunol. 2016, 393, 67–105. [Google Scholar] [CrossRef]
  59. Campbell, R.; Chong, G.; Hawkes, E.A. Novel Indications for Bruton’s Tyrosine Kinase Inhibitors, beyond Hematological Malignancies. J. Clin. Med. 2018, 7, 62. [Google Scholar] [CrossRef] [Green Version]
  60. Didona, D.; Maglie, R.; Eming, R.; Hertl, M. Pemphigus: Current and Future Therapeutic Strategies. Front. Immunol. 2019, 10, 1418. [Google Scholar] [CrossRef] [Green Version]
  61. Patsatsi, A.; Murrell, D.F. Bruton Tyrosine Kinase Inhibition and Its Role as an Emerging Treatment in Pemphigus. Front. Med. 2021, 8, 708071. [Google Scholar] [CrossRef] [PubMed]
  62. Lee, A.; Sandhu, S.; Imlay-Gillespie, L.; Mulligan, S.; Shumack, S. Successful use of Bruton’s kinase inhibitor, ibrutinib, to control paraneoplastic pemphigus in a patient with paraneoplastic autoimmune multiorgan syndrome and chronic lymphocytic leukaemia. Australas J. Derm. 2017, 58, e240–e242. [Google Scholar] [CrossRef] [PubMed]
  63. Vidal-Crespo, A.; Rodriguez, V.; Matas-Cespedes, A.; Lee, E.; Rivas-Delgado, A.; Giné, E.; Navarro, A.; Beà, S.; Campo, E.; López-Guillermo, A.; et al. The Bruton tyrosine kinase inhibitor CC-292 shows activity in mantle cell lymphoma and synergizes with lenalidomide and NIK inhibitors depending on nuclear factor-κB mutational status. Haematologica 2017, 102, e447–e451. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Murrell, D.F.; Patsatsi, A.; Stavropoulos, P.; Baum, S.; Zeeli, T.; Kern, J.S.; Roussaki-Schulze, A.V.; Sinclair, R.; Bassukas, I.D.; Thomas, D.; et al. Proof of concept for the clinical effects of oral rilzabrutinib, the first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: The phase II BELIEVE study. Br. J. Dermatol. 2021, 185, 745–755. [Google Scholar] [CrossRef] [PubMed]
  65. Izumi, K.; Bieber, K.; Ludwig, R.J. Current Clinical Trials in Pemphigus and Pemphigoid. Front. Immunol. 2019, 10, 978. [Google Scholar] [CrossRef]
  66. Mackay, F.; Browning, J.L. BAFF: A fundamental survival factor for B cells. Nat. Rev. Immunol. 2002, 2, 465–475. [Google Scholar] [CrossRef] [PubMed]
  67. Lesley, R.; Xu, Y.; Kalled, S.L.; Hess, D.M.; Schwab, S.R.; Shu, H.B.; Cyster, J.G. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 2004, 20, 441–453. [Google Scholar] [CrossRef] [Green Version]
  68. Matsushita, T.; Hasegawa, M.; Matsushita, Y.; Echigo, T.; Wayaku, T.; Horikawa, M.; Ogawa, F.; Takehara, K.; Sato, S. Elevated serum BAFF levels in patients with localized scleroderma in contrast to other organ-specific autoimmune diseases. Exp. Derm. 2007, 16, 87–93. [Google Scholar] [CrossRef] [Green Version]
  69. Groom, J.; Kalled, S.L.; Cutler, A.H.; Olson, C.; Woodcock, S.A.; Schneider, P.; Tschopp, J.; Cachero, T.G.; Batten, M.; Wheway, J.; et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren’s syndrome. J. Clin. Investig. 2002, 109, 59–68. [Google Scholar] [CrossRef]
  70. Cheema, G.S.; Roschke, V.; Hilbert, D.M.; Stohl, W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum. 2001, 44, 1313–1319. [Google Scholar] [CrossRef]
  71. Kuo, T.T.; Baker, K.; Yoshida, M.; Qiao, S.W.; Aveson, V.G.; Lencer, W.I.; Blumberg, R.S. Neonatal Fc receptor: From immunity to therapeutics. J. Clin. Immunol. 2010, 30, 777–789. [Google Scholar] [CrossRef] [Green Version]
  72. Howard, J.F., Jr.; Bril, V.; Burns, T.M.; Mantegazza, R.; Bilinska, M.; Szczudlik, A.; Beydoun, S.; Garrido, F.; Piehl, F.; Rottoli, M.; et al. Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis. Neurology 2019, 92, e2661–e2673. [Google Scholar] [CrossRef]
  73. Newland, A.C.; Sánchez-González, B.; Rejtő, L.; Egyed, M.; Romanyuk, N.; Godar, M.; Verschueren, K.; Gandini, D.; Ulrichts, P.; Beauchamp, J.; et al. Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia. Am. J. Hematol. 2020, 95, 178–187. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Ulrichts, P.; Guglietta, A.; Dreier, T.; van Bragt, T.; Hanssens, V.; Hofman, E.; Vankerckhoven, B.; Verheesen, P.; Ongenae, N.; Lykhopiy, V.; et al. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J. Clin. Investig. 2018, 128, 4372–4386. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Schmidt, T.; Willenborg, S.; Hünig, T.; Deeg, C.A.; Sonderstrup, G.; Hertl, M.; Eming, R. Induction of T regulatory cells by the superagonistic anti-CD28 antibody D665 leads to decreased pathogenic IgG autoantibodies against desmoglein 3 in a HLA-transgenic mouse model of pemphigus vulgaris. Exp. Derm. 2016, 25, 293–298. [Google Scholar] [CrossRef] [PubMed]
  76. Zwang, N.A.; Leventhal, J.R. Cell Therapy in Kidney Transplantation: Focus on Regulatory T Cells. J. Am. Soc. Nephrol. 2017, 28, 1960–1972. [Google Scholar] [CrossRef] [PubMed]
  77. Wang, W.-E.; Wu, R.-W.; Chang, C.-H. An elderly female with pemphigus foliaceus possibly induced by losartan/hydrochlorothiazide. Derm. Sin. 2021, 39, 107–108. [Google Scholar] [CrossRef]
  78. Kasperkiewicz, M.; Ellebrecht, C.T.; Takahashi, H.; Yamagami, J.; Zillikens, D.; Payne, A.S.; Amagai, M. Pemphigus. Nat. Rev. Dis. Primers 2017, 3, 17026. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Hofmann, S.C.; Juratli, H.A.; Eming, R. Bullous autoimmune dermatoses. J. Dtsch. Dermatol. Ges. J. Ger. Soc. Dermatol. JDDG 2018, 16, 1339–1358. [Google Scholar] [CrossRef] [Green Version]
  80. Hong, H.; Chang, T.; Wu, C.; Chang, Y. Intraepidermal neutrophilic dermatosis-type immunoglobulin A pemphigus. Derm. Sin. 2021, 39, 47–48. [Google Scholar] [CrossRef]
  81. Gruss, C.; Zillikens, D.; Hashimoto, T.; Amagai, M.; Kroiss, M.; Vogt, T.; Landthaler, M.; Stolz, W. Rapid response of IgA pemphigus of subcorneal pustular dermatosis type to treatment with isotretinoin. J. Am. Acad. Dermatol. 2000, 43, 923–926. [Google Scholar] [CrossRef]
  82. Ruiz-Genao, D.P.; Hernández-Núñez, A.; Hashimoto, T.; Amagai, M.; Fernández-Herrera, J.; García-Díez, A. A case of IgA pemphigus successfully treated with acitretin. Br. J. Dermatol. 2002, 147, 1040–1042. [Google Scholar] [CrossRef] [PubMed]
  83. Howell, S.M.; Bessinger, G.T.; Altman, C.E.; Belnap, C.M. Rapid response of IgA pemphigus of the subcorneal pustular dermatosis subtype to treatment with adalimumab and mycophenolate mofetil. J. Am. Acad. Dermatol. 2005, 53, 541–543. [Google Scholar] [CrossRef] [PubMed]
  84. Sehgal, V.N.; Srivastava, G. Paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome. Int. J. Dermatol. 2009, 48, 162–169. [Google Scholar] [CrossRef] [PubMed]
  85. Heizmann, M.; Itin, P.; Wernli, M.; Borradori, L.; Bargetzi, M.J. Successful treatment of paraneoplastic pemphigus in follicular NHL with rituximab: Report of a case and review of treatment for paraneoplastic pemphigus in NHL and CLL. Am. J. Hematol. 2001, 66, 142–144. [Google Scholar] [CrossRef]
  86. Zhao, Y.; Su, H.; Shen, X.; Du, J.; Zhang, X.; Zhao, Y. The immunological function of CD52 and its targeting in organ transplantation. Inflamm. Res. 2017, 66, 571–578. [Google Scholar] [CrossRef] [PubMed]
  87. Ruck, T.; Bittner, S.; Wiendl, H.; Meuth, S.G. Alemtuzumab in Multiple Sclerosis: Mechanism of Action and Beyond. Int. J. Mol. Sci. 2015, 16, 16414–16439. [Google Scholar] [CrossRef]
  88. Paolino, G.; Didona, D.; Magliulo, G.; Iannella, G.; Didona, B.; Mercuri, S.R.; Moliterni, E.; Donati, M.; Ciofalo, A.; Granata, G.; et al. Paraneoplastic Pemphigus: Insight into the Autoimmune Pathogenesis, Clinical Features and Therapy. Int. J. Mol. Sci. 2017, 18, 2532. [Google Scholar] [CrossRef] [Green Version]
  89. Hohwy, T.; Bang, K.; Steiniche, T.; Peterslund, N.A.; d’Amore, F. Alemtuzumab-induced remission of both severe paraneoplastic pemphigus and leukaemic bone marrow infiltration in a case of treatment-resistant B-cell chronic lymphocytic leukaemia. Eur. J. Haematol. 2004, 73, 206–209. [Google Scholar] [CrossRef]
  90. Bech, R.; Baumgartner-Nielsen, J.; Peterslund, N.A.; Steiniche, T.; Deleuran, M.; d’Amore, F. Alemtuzumab is effective against severe chronic lymphocytic leukaemia-associated paraneoplastic pemphigus. Br. J. Dermatol. 2013, 169, 469–472. [Google Scholar] [CrossRef]
  91. Joly, P.; Roujeau, J.C.; Benichou, J.; Picard, C.; Dreno, B.; Delaporte, E.; Vaillant, L.; D’Incan, M.; Plantin, P.; Bedane, C.; et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N. Engl. J. Med. 2002, 346, 321–327. [Google Scholar] [CrossRef] [PubMed]
  92. Joly, P.; Roujeau, J.C.; Benichou, J.; Delaporte, E.; D’Incan, M.; Dreno, B.; Bedane, C.; Sparsa, A.; Gorin, I.; Picard, C.; et al. A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: A multicenter randomized study. J. Invest. Derm. 2009, 129, 1681–1687. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Kirtschig, G.; Middleton, P.; Bennett, C.; Murrell, D.F.; Wojnarowska, F.; Khumalo, N.P. Interventions for bullous pemphigoid. Cochrane Database Syst. Rev. 2010, 2010, Cd002292. [Google Scholar] [CrossRef] [PubMed]
  94. Daniel, B.S.; Borradori, L.; Hall, R.P., 3rd; Murrell, D.F. Evidence-based management of bullous pemphigoid. Dermatol. Clin. 2011, 29, 613–620. [Google Scholar] [CrossRef] [PubMed]
  95. Kimura, K.; Kawai, K. Doxycycline as an initial treatment of bullous pemphigoid in Japanese patients. J. Cutan. Immunol. Allergy 2020, 3, 80–85. [Google Scholar] [CrossRef]
  96. Van Beek, N.; Lüttmann, N.; Huebner, F.; Recke, A.; Karl, I.; Schulze, F.S.; Zillikens, D.; Schmidt, E. Correlation of Serum Levels of IgE Autoantibodies Against BP180 With Bullous Pemphigoid Disease Activity. JAMA Dermatol. 2017, 153, 30–38. [Google Scholar] [CrossRef]
  97. Yu, K.K.; Crew, A.B.; Messingham, K.A.; Fairley, J.A.; Woodley, D.T. Omalizumab therapy for bullous pemphigoid. J. Am. Acad. Dermatol. 2014, 71, 468–474. [Google Scholar] [CrossRef]
  98. Balakirski, G.; Alkhateeb, A.; Merk, H.F.; Leverkus, M.; Megahed, M. Successful treatment of bullous pemphigoid with omalizumab as corticosteroid-sparing agent: Report of two cases and review of literature. J. Eur. Acad. Dermatol. Venereol. JEADV 2016, 30, 1778–1782. [Google Scholar] [CrossRef]
  99. De, D.; Kaushik, A.; Handa, S.; Mahajan, R.; Schmidt, E. Omalizumab: An underutilized treatment option in bullous pemphigoid patients with co-morbidities. J. Eur. Acad. Dermatol. Venereol. JEADV 2021, 35, e469–e472. [Google Scholar] [CrossRef]
  100. Heimbach, L.; Li, Z.; Berkowitz, P.; Zhao, M.; Li, N.; Rubenstein, D.S.; Diaz, L.A.; Liu, Z. The C5a receptor on mast cells is critical for the autoimmune skin-blistering disease bullous pemphigoid. J. Biol. Chem. 2011, 286, 15003–15009. [Google Scholar] [CrossRef] [Green Version]
  101. Plée, J.; Le Jan, S.; Giustiniani, J.; Barbe, C.; Joly, P.; Bedane, C.; Vabres, P.; Truchetet, F.; Aubin, F.; Antonicelli, F.; et al. Integrating longitudinal serum IL-17 and IL-23 follow-up, along with autoantibodies variation, contributes to predict bullous pemphigoid outcome. Sci. Rep. 2015, 5, 18001. [Google Scholar] [CrossRef] [PubMed]
  102. Wakugawa, M.; Nakamura, K.; Hino, H.; Toyama, K.; Hattori, N.; Okochi, H.; Yamada, H.; Hirai, K.; Tamaki, K.; Furue, M. Elevated levels of eotaxin and interleukin-5 in blister fluid of bullous pemphigoid: Correlation with tissue eosinophilia. Br. J. Dermatol. 2000, 143, 112–116. [Google Scholar] [CrossRef] [PubMed]
  103. Rico, M.J.; Benning, C.; Weingart, E.S.; Streilein, R.D.; Hall, R.P., 3rd. Characterization of skin cytokines in bullous pemphigoid and pemphigus vulgaris. Br. J. Dermatol. 1999, 140, 1079–1086. [Google Scholar] [CrossRef] [PubMed]
  104. Fabbri, P.; Caproni, M.; Berti, S.; Bianchi, B.; Amato, L.; De Pità, O.; Frezzolini, A. The role of T lymphocytes and cytokines in the pathogenesis of pemphigoid gestationis. Br. J. Dermatol. 2003, 148, 1141–1148. [Google Scholar] [CrossRef] [PubMed]
  105. Abdat, R.; Waldman, R.A.; de Bedout, V.; Czernik, A.; McLeod, M.; King, B.; Gordon, S.; Ahmed, R.; Nichols, A.; Rothe, M.; et al. Dupilumab as a novel therapy for bullous pemphigoid: A multicenter case series. J. Am. Acad. Dermatol. 2020, 83, 46–52. [Google Scholar] [CrossRef] [PubMed]
  106. Maglie, R.; Hertl, M. Pharmacological advances in pemphigoid. Curr. Opin. Pharm. 2019, 46, 34–43. [Google Scholar] [CrossRef]
  107. Simon, D.; Yousefi, S.; Cazzaniga, S.; Bürgler, C.; Radonjic, S.; Houriet, C.; Heidemeyer, K.; Klötgen, H.W.; Kozlowski, E.; Borradori, L.; et al. Mepolizumab failed to affect bullous pemphigoid: A randomized, placebo-controlled, double-blind phase 2 pilot study. Allergy 2020, 75, 669–672. [Google Scholar] [CrossRef]
  108. Grimaldi, J.C.; Yu, N.X.; Grunig, G.; Seymour, B.W.; Cottrez, F.; Robinson, D.S.; Hosken, N.; Ferlin, W.G.; Wu, X.; Soto, H.; et al. Depletion of eosinophils in mice through the use of antibodies specific for C-C chemokine receptor 3 (CCR3). J. Leukoc. Biol. 1999, 65, 846–853. [Google Scholar] [CrossRef]
  109. Taylor, J.; McMillan, R.; Shephard, M.; Setterfield, J.; Ahmed, R.; Carrozzo, M.; Grando, S.; Mignogna, M.; Kuten-Shorrer, M.; Musbah, T.; et al. World Workshop on Oral Medicine VI: A systematic review of the treatment of mucous membrane pemphigoid. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2015, 120, 161–171.e120. [Google Scholar] [CrossRef]
  110. Lee, H.Y.; Blazek, C.; Beltraminelli, H.; Borradori, L. Oral mucous membrane pemphigoid: Complete response to topical tacrolimus. Acta Derm. Venereol. 2011, 91, 604–605. [Google Scholar] [CrossRef] [Green Version]
  111. Ujiie, H.; Iwata, H.; Yamagami, J.; Nakama, T.; Aoyama, Y.; Ikeda, S.; Ishii, N.; Iwatsuki, K.; Kurosawa, M.; Sawamura, D.; et al. Japanese guidelines for the management of pemphigoid (including epidermolysis bullosa acquisita). J. Derm. 2019, 46, 1102–1135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Alajlan, A.; Al-Khawajah, M.; Al-Sheikh, O.; Al-Saif, F.; Al-Rasheed, S.; Al-Hoqail, I.; Hamadah, I.R. Treatment of linear IgA bullous dermatosis of childhood with flucloxacillin. J. Am. Acad. Dermatol. 2006, 54, 652–656. [Google Scholar] [CrossRef] [PubMed]
  113. Gürcan, H.M.; Ahmed, A.R. Current concepts in the treatment of epidermolysis bullosa acquisita. Expert Opin. Pharm. 2011, 12, 1259–1268. [Google Scholar] [CrossRef]
  114. Sami, N. Mycophenolate mofetil (MMF) in the treatment of epidermolysis bullosa acquisita (EBA) long-term follow-up. JAAD Case Rep. 2015, 1, 321–323. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Caldwell, J.B.; Yancey, K.B.; Engler, R.J.; James, W.D. Epidermolysis bullosa acquisita: Efficacy of high-dose intravenous immunoglobulins. J. Am. Acad. Dermatol. 1994, 31, 827–828. [Google Scholar] [CrossRef]
  116. Sadler, E.; Schafleitner, B.; Lanschuetzer, C.; Laimer, M.; Pohla-Gubo, G.; Hametner, R.; Hintner, H.; Bauer, J.W. Treatment-resistant classical epidermolysis bullosa acquisita responding to rituximab. Br. J. Dermatol. 2007, 157, 417–419. [Google Scholar] [CrossRef]
  117. Egan, C.A.; Brown, M.; White, J.D.; Yancey, K.B. Treatment of epidermolysis bullosa acquisita with the humanized anti-Tac mAb daclizumab. Clin. Immunol. 2001, 101, 146–151. [Google Scholar] [CrossRef]
  118. Fry, L. Dermatitis herpetiformis: Problems, progress and prospects. Eur. J. Dermatol. EJD 2002, 12, 523–531. [Google Scholar]
  119. McFadden, J.P.; Leonard, J.N.; Powles, A.V.; Rutman, A.J.; Fry, L. Sulphamethoxypyridazine for dermatitis herpetiformis, linear IgA disease and cicatricial pemphigoid. Br. J. Dermatol. 1989, 121, 759–762. [Google Scholar] [CrossRef] [PubMed]
  120. Willsteed, E.; Lee, M.; Wong, L.C.; Cooper, A. Sulfasalazine and dermatitis herpetiformis. Australas J. Derm. 2005, 46, 101–103. [Google Scholar] [CrossRef]
  121. Wozniak, K.; Hashimoto, T.; Fukuda, S.; Ohyama, B.; Ishii, N.; Koga, H.; Dainichi, T.; Kowalewski, C. IgA Anti-p200 Pemphigoid. Arch. Dermatol. 2011, 147, 1306–1310. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Goletz, S.; Hashimoto, T.; Zillikens, D.; Schmidt, E. Anti-p200 pemphigoid. J. Am. Acad. Dermatol. 2014, 71, 185–191. [Google Scholar] [CrossRef] [PubMed]
Jcm 11 03528 g001 550
Figure 1. Mechanisms of the emerging therapies of pemphigus vulgaris. These therapies target anti-Dsg3 B-cells or autoantibodies. ① Ofatumumab and veltuzumab are new second generation monoclonal antibodies targeting CD20 on the surface of B-cells. ② Engineered CAAR-T-cell expressing the Dsg3 ectodomain recognizes and forms cytolytic synapse with the pathognomonic B-cells and subsequently annihilates them. ③ Ibrutinib and rilzabrutinib prohibit the proliferation of B-cells through blocking of the BTK. ④ Ianalumab inhibits the signal transduction of BAFF by binding to its receptor and contributes to depletion of B-cells. ⑤ Efgartigimod and SYNT001 occupy the binding sites of anti-Dsg3 antibodies to the FcRn and accelerate their clearance. ⑥ PolyTregs suppress the adaptive immune cells via inhibitory cytokines and terminate the differentiation of B-cells toward plasma cells. Abbreviations: Dsg3, desmoglein 3; CAAR-T-cell, chimeric autoantibody receptor T-cells; BTK, Bruton tyrosine kinase; BAFF, B-cell activating factor; BAFFR, B-cell activating factor receptor; FcRn, neonatal Fc receptor; PolyTregs, polyclonal regulatory T-cells.
Figure 1. Mechanisms of the emerging therapies of pemphigus vulgaris. These therapies target anti-Dsg3 B-cells or autoantibodies. ① Ofatumumab and veltuzumab are new second generation monoclonal antibodies targeting CD20 on the surface of B-cells. ② Engineered CAAR-T-cell expressing the Dsg3 ectodomain recognizes and forms cytolytic synapse with the pathognomonic B-cells and subsequently annihilates them. ③ Ibrutinib and rilzabrutinib prohibit the proliferation of B-cells through blocking of the BTK. ④ Ianalumab inhibits the signal transduction of BAFF by binding to its receptor and contributes to depletion of B-cells. ⑤ Efgartigimod and SYNT001 occupy the binding sites of anti-Dsg3 antibodies to the FcRn and accelerate their clearance. ⑥ PolyTregs suppress the adaptive immune cells via inhibitory cytokines and terminate the differentiation of B-cells toward plasma cells. Abbreviations: Dsg3, desmoglein 3; CAAR-T-cell, chimeric autoantibody receptor T-cells; BTK, Bruton tyrosine kinase; BAFF, B-cell activating factor; BAFFR, B-cell activating factor receptor; FcRn, neonatal Fc receptor; PolyTregs, polyclonal regulatory T-cells.
Jcm 11 03528 g001
Jcm 11 03528 g002 550
Figure 2. Mechanisms of the emerging therapies of bullous pemphigoid. ① Omalizumab prohibits the adherence of IgE antibodies to the basement membrane proteins BP180 and BP230. ② Avdoralimab blocks the subsequent binding of the C5aR on the mast cells to the complements and deters the process of degranulation. ③ In the upstream, dendritic cells release IL-4 and IL-23 which then activate Th2 and Th17 cells, respectively. Ustekinumab, tildrakizumab and ixekizumab are therefore applied to inhibit the cascade. ④ In the blisters, chemokines result in recruitment of multiple innate and adaptive cells of which eosinophils play the pivotal role. Dupilumab, mepolizumab, and bertilimumab targeting the downstream products of eosinophils (IL-4/IL-13, IL-5 and eotaxin) may reduce further blister formation. ⑤ AKST4290 interacts with the receptor of eotaxin CCR3 causing downregulation of the eosinophils. Abbreviations: IgE, immunoglobulin E; IgG, immunoglobulin G; C5aR, C5a receptor; IL, interleukin; Th, T-helper; CCR3, C-C chemokine receptor 3.
Figure 2. Mechanisms of the emerging therapies of bullous pemphigoid. ① Omalizumab prohibits the adherence of IgE antibodies to the basement membrane proteins BP180 and BP230. ② Avdoralimab blocks the subsequent binding of the C5aR on the mast cells to the complements and deters the process of degranulation. ③ In the upstream, dendritic cells release IL-4 and IL-23 which then activate Th2 and Th17 cells, respectively. Ustekinumab, tildrakizumab and ixekizumab are therefore applied to inhibit the cascade. ④ In the blisters, chemokines result in recruitment of multiple innate and adaptive cells of which eosinophils play the pivotal role. Dupilumab, mepolizumab, and bertilimumab targeting the downstream products of eosinophils (IL-4/IL-13, IL-5 and eotaxin) may reduce further blister formation. ⑤ AKST4290 interacts with the receptor of eotaxin CCR3 causing downregulation of the eosinophils. Abbreviations: IgE, immunoglobulin E; IgG, immunoglobulin G; C5aR, C5a receptor; IL, interleukin; Th, T-helper; CCR3, C-C chemokine receptor 3.
Jcm 11 03528 g002
Table
Table 1. Clinical characteristics, target autoantigens and diagnosis of the intraepithelial autoimmune bullous skin disorders (AIBDs).
Table 1. Clinical characteristics, target autoantigens and diagnosis of the intraepithelial autoimmune bullous skin disorders (AIBDs).
DiseasesClinical FeaturesAutoantigens [3]Diagnosis [3,4]
Pemphigus vulgaris (PV)
  • Flaccid blisters and painful erosions on skin with propensity to strained and intertriginous areas [5,6]
  • Extensive oral mucosal involvement precedes the skin lesions
Dsg1,3
  • H&E: Suprabasal acantholysis, tombstone pattern of the basal keratinocytes
  • DIF: Intercellular deposition of IgG/C3
  • IIF: Intercellular deposition of IgG
  • ELISA: Anti-Dsg3 and/or anti-Dsg1 antibodies
Pemphigus foliaceus (PF)
  • Flaccid blisters and erosions affect exclusively the cornified skin and spared the mucosal regions
  • Usually in a seborrheic distribution
Dsg1
  • H&E: Acantholysis and spongiosis within the stratum granulosum
  • DIF: Intercellular deposition of IgG/C3
  • IIF: Intercellular deposition of IgG
  • ELISA: Anti-Dsg1 antibodies
Pemphigus erythematosus (PE)Blisters on the erythematous plaques at the nose, nasolabial folds and malar regions [7]Dsg1
  • H&E: The same as PF
  • DIF: Intercellular and shaggy basement membrane deposition of IgG/C3
  • IIF: Intercellular deposition of IgG
  • ELISA: Anti-Dsg1 antibodies
  • Positive serum antinuclear antibody
IgA pemphigusVesiculopustular lesions on the erythematous plaques in an annular morphology at the trunk and proximal extremities [8]Dsc1,2,3 & Dsg1,3
  • H&E: Prominent intraepidermal neutrophilic infiltrates
  • DIF: Intercellular deposition of IgA/C3
  • IIF: Intercellular deposition of IgA
  • ELISA: Anti-Dsc1,2,3 and anti-Dsg1,3 IgA antibodies
Paraneoplastic pemphigus (PNP)
  • Blisters, erosions or lichenoid lesions on the skin
  • Extensive and intractable stomatitis
  • Related to thymoma [9] and hematological malignancies [10,11,12]
Envoplakin,
periplakin,
BP230, Dsg1,3,
desmoplakins,
epiplakin, α-2-
macroglobulin-
like antigen-1,
and plectin
  • H&E: Overt interface/lichenoid infiltrates with dyskeratotic cells, foci suprabasal acantholysis
  • DIF: Intercellular and basement membrane deposition of IgG and/or C3
  • IIF: Intercellular deposition of IgG (monkey esophagus and monkey/rat bladder [13]) 1
  • ELISA: Common anti-Dsg3 and anti-envoplakin antibodies
Abbreviations: H&E, hematoxylin and eosin stain. DIF/IIF, direct/indirect immunofluorescence. ELISA, enzyme-linked immunosorbent assay. IgA/IgG, immunoglobulin A/G. Dsg, desmoglein. Dsc, desmocollin. 1 IIF is commonly performed on monkey esophagus. The urothelium of monkey and rat bladder serve as excellent substrates for detecting anti-plakin autoantibodies to distinguish PNP from other pemphigus diseases.
Table
Table 2. Clinical characteristics, target autoantigens and diagnosis of the subepithelial autoimmune bullous skin disorders (AIBDs).
Table 2. Clinical characteristics, target autoantigens and diagnosis of the subepithelial autoimmune bullous skin disorders (AIBDs).
DiseasesClinical FeaturesAutoantigens [3]Diagnosis [3,4]
Bullous pemphigoid (BP)
  • Tense blisters, erosions, and urticarial erythema on the trunk and flexural sites with preceding severe pruritus
  • Uncommon mucosal involvement (10–20%) [14]
BP180, BP230
  • H&E: Subepidermal blisters with eosinophils and eosinophilic spongiosis
  • DIF: Linear deposition of IgG and/or C3 on the BMZ
  • IIF: Linear deposition of IgG on the BMZ; antibodies on the blister roof (salt-split skin [15]) 1
  • ELISA: Anti-BP180/Anti-BP230 antibodies
Mucous membrane
pemphigoid (MMP)		Blistering occur predominantly on the oral cavity and conjunctiva which frequently healed with scarring [16,17,18]BP180, BP230, laminin 332, α6β4 integrin
  • H&E: Similar to BP but with fewer eosinophils
  • DIF: Linear deposition of IgG, IgA and/or C3 on the BMZ
  • IIF: Linear deposition of IgG on the BMZ; antibodies on the blister roof and/or floor (salt-split skin)
  • ELISA: Anti-BP180/Anti-BP230 and/or anti-laminin 332 antibodies
Linear IgA bullous
dermatosis
  • Tense blisters located on the skin with involvement of the oral cavity (50%)
  • String-of-pearls sign seen especially in the pediatric groups [19]
BP180 (LAD-1), type VII collagen
  • H&E: Subepidermal blisters with neutrophilic infiltrates
  • DIF: Linear deposition of IgA on the BMZ
  • IIF: Linear deposition of IgA on the BMZ; antibodies on the blister roof (salt-split skin)
  • ELISA: Anti-BP180/Anti-LAD-1 IgA antibodies
Epidermolysis bullosa
acquisita (EBA)
  • Tense bullae localized at the extensor aspects of the skin
  • Nail dystrophy and esophageal stenosis may take place [20]
Type VII collagen
  • H&E: Subepidermal blisters with mixed infiltrates
  • DIF: Linear deposition of IgG (less often IgM and IgA) and/or C3 on the BMZ
  • IIF: Linear deposition of IgG on the BMZ; antibodies on the blister floor (salt-split skin)
  • ELISA: Anti-type VII collagen antibodies
Dermatitis herpetiformis
(DH)
  • Symmetrically distributed eruption of prurigo and tense vesicles on the skin
  • Associated with celiac disease, a gluten-sensitive enteropathy
Epidermal/Tissue transglutaminase, endomysium, deamidated gliadin
  • H&E: Subepidermal blisters with papillary neutrophilic microabscess and scattered eosinophils
  • DIF: Granular deposits of IgA on the dermal papillae
  • IIF: Deposition of anti-endomysium IgA
  • ELISA: Anti-epidermal/tissue transglutaminase antibodies, anti-deamidated gliadin IgA/IgG autoantibodies
Laminin γ1 pemphigoid
  • Tense bullae with urticarial erythema similar to BP [21,22]
  • Some may associated with development of scars/milia (15.7%) [22]
p200 protein, laminin γ1
  • H&E: Subepidermal blisters with neutrophils and eosinophils infiltrates; some with papillary microabscess
  • DIF: Linear deposition of IgG and/or C3 on the BMZ
  • IIF: Linear deposition of IgG on the BMZ; antibodies on the blister floor (salt-split skin)
  • ELISA: Anti-p200/Anti-laminin γ1 antibodies
Abbreviations: H&E, hematoxylin and eosin stain. DIF/IIF, direct/indirect immunofluorescence. ELISA, enzyme-linked immunosorbent assay. IgA/IgG, immunoglobulin A/G. BMZ, basement membrane zone. LAD-1, the linear IgA bullous dermatosis autoantigen. 1 IIF is commonly performed on monkey esophagus. Salt-split skin test separating the skin from the level above lamina lucida by immersing the specimen in 1 M sodium chloride solution elucidates the location of autoantibodies in subepidermal AIBDs.
Table
Table 3. First-line therapeutic approaches to autoimmune bullous skin disorders (AIBDs).
Table 3. First-line therapeutic approaches to autoimmune bullous skin disorders (AIBDs).
DiseaseFirst-Line Treatment
Intraepithelial AIBDs
Pemphigus vulgarisHigh dose systemic glucocorticoids (0.5 to 1.5 mg/kg/day prednisolone) and rituximab (either the lymphoma (weekly dosage of 375 mg/m2 for four consecutive weeks) or the rheumatoid arthritis (2 doses of 1000 mg separated by 2 weeks; may be repeated 6 months later) protocol)
First-line adjuvants: Azathioprine (1 to 3 mg/kg/day), MMF (2 g/day) or mycophenolic acid (1440 mg/day)
Pemphigus foliaceusThe same as PV but usually with lower dosage
Pemphigus erythematosusSystemic glucocorticoids (0.5 to 1 mg/kg/day prednisolone) and dapsone (100 to 200 mg/day)
IgA pemphigusSystemic glucocorticoids (0.5 to 1 mg/kg/day prednisolone) and dapsone (100 to 300 mg/day)
Paraneoplastic pemphigusControl of the underlying malignancy, systemic prednisolone (0.5 to 1 mg/kg/day) and rituximab (either the lymphoma (weekly dosage of 375 mg/m2 for four consecutive weeks) or the rheumatoid arthritis (2 doses of 1000 mg separated by 2 weeks; may be repeated 6 months later) protocol)
Subepithelial AIBDs
Bullous pemphigoidSystemic glucocorticoids (0.5 to 0.75 mg/kg/day of prednisolone) or high potency topical glucocorticoids, and tetracyclines ± niacinamide
Mucous membrane pemphigoidSystemic glucocorticoids (0.25 to 0.5 mg/kg/day prednisolone) and dapsone (50 to 200 mg/day)
Linear IgA bullous dermatosisTopical high potency glucocorticoids and dapsone (~2 mg/kg/day for children; 100 to 200 mg/day for adults)
Epidermolysis bullosa acquisitaHigh dose systemic glucocorticoids (1 to 1.5 mg/kg/day), dapsone (25 to 100 mg/day) and colchicine (0.6 to 1.2 mg/day)
Dermatitis herpetiformisGluten-free diet and dapsone (50 to 150 mg/day)
Abbreviations: IgA, immunoglobulin A. MMF, mycophenolate mofetil.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Chu, K.-Y.; Yu, H.-S.; Yu, S. Current and Innovated Managements for Autoimmune Bullous Skin Disorders: An Overview. J. Clin. Med. 2022, 11, 3528. https://doi.org/10.3390/jcm11123528

AMA Style

Chu K-Y, Yu H-S, Yu S. Current and Innovated Managements for Autoimmune Bullous Skin Disorders: An Overview. Journal of Clinical Medicine. 2022; 11(12):3528. https://doi.org/10.3390/jcm11123528

Chicago/Turabian Style

Chu, Kuan-Yu, Hsin-Su Yu, and Sebastian Yu. 2022. "Current and Innovated Managements for Autoimmune Bullous Skin Disorders: An Overview" Journal of Clinical Medicine 11, no. 12: 3528. https://doi.org/10.3390/jcm11123528

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop