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Background

Pemphigus vulgaris is the most common variant of pemphigus, accounting for 80% of cases. These patients may have a dramatic presentation with flaccid blisters on an erythematous base occurring on the trunk, groin, axilla, scalp, face, and points of pressure. Oral and mucosal lesions which may be the initial presentation are seen in 80-90% of cases. Affected mucosal surfaces include the esophagus, vulva, cervix, anus, larynx, and conjunctiva. There may be an early urticarial, non-blistering phase which may be difficult to diagnose both clinically and histologically.

The association with internal malignancies and other diseases has been well-studied. Associations have included Castleman's disease, myasthenia gravis, thymoma, scleroderma, Grave's disease, and oral herpes infection. The disease may be exacerbated or initiated by several agents, including minor trauma, ionizing radiation, burns, PUVA therapy, and pesticides. Offending drugs include rifampicin, norfloxacin, ampicillin, interleukin-2, penicillin, captopril, enalarpril, and drugs with thiol groups. A new variant, paraneoplastic pemphigus, has a unique set of serologic and histologic changes which should be excluded.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

PATHOGENESIS CHARACTERIZATION
AUTOIMMUNE DISORDER

Several circulating autoantibodies associated with the disease. The chief antibody is directed against desmoglein 3 (pemphigus vulgaris antigen). This protein is located on the desmosomes of keratinocytes. It binds to keratinocytes in the lower epidermis causing acantholysis. This desmosomal damage leads to complement activation.

Direct immunofluorescence (DIF) may identify intercellular IgG within the epidermis with lesser amounts of IgM, IgA, and C3. The serum also contains circulating antibodies in 80-90% of cases.

How does acantholysis occur in pemphigus vulgaris: a critical review.

Lanza A, Cirillo N, Femiano F, Gombos F.

Regional Center on Craniofacial Malformations, School of Medicine, II University of Naples, 80100 Naples, Italy.

J Cutan Pathol. 2006 Jun;33(6):401-12. Abstract quote  

Background: Pemphigus vulgaris is a life-threatening autoimmune blistering disease targeting skin and mucous membranes, characterized by disruption of keratinocytes' adhesion termed acantholysis. Today multiple classes of targets are considered to play a role in the genesis of the acantholysis; of these, the classical pemphigus antigens, desmosomal cadherins (desmoglein 1 and 3) are the best characterized and considered as the most important. Additional antigens include the novel epithelial acetylcholine receptors (alpha9 and pemphaxin).

Thus, acantholysis in pemphigus seems to result from a cooperative action of antibodies to different keratinocyte self-antigens, but the mechanisms by which epithelial cleft occurs are not yet clearly understood.

In fact, the binding of the autoantibodies to these targets generates a plethora of biological effects due, on one hand, to their direct interference with adhesive function and, on the other, to more complex events involving intracellular pathways that modify proteases activity or calcium metabolism, leading to loss of cell-cell adhesion.
CADHERIN  

Upregulation of P-cadherin expression in the lesional skin of pemphigus, Hailey-Hailey disease and Darierís disease

Megumi Hakuno, etal.

Journal of Cutaneous Pathology 2001; 28 (6): 277-281 Abstract quote

Background: Autoimmune blistering diseases, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), are known to be caused by binding of autoantibodies to the desmosomal cadherins, desmoglein 3 and desmoglein 1, respectively. Recently, mutations in the genes coding Ca2+ pumps leads to inherited blistering diseases, Hailey-Hailey disease (HHD) and Darierís disease (DD). Cadherins are a family of Ca2+-dependent cell adhesion molecules and P-cadherin is one of the major cadherins expressed in the epidermis. Although detailed mechanisms of acantholysis of these blistering diseases have not been fully clarified, abnormal expression of cadherins caused by altered Ca2+ concentration due to the binding of autoantibodies to cell surface or by mutations in Ca2+ pumps is suggested to be involved in mechanisms of acantholysis of these atuoimmune and inherited blistering diseases. The purpose of the present study was to determine whether altered P-cadherin expression is present in these diseases.

Method: Distribution patterns of P-cadherin in skin specimens from patients with PV (n=2), PF (n=2), HHD (n=4) and DD (n=3), were examined with confocal laser scanning microscopy using two anti-P-cadherin antibodies, 6A9 and NCC-CAD-299.

Results: In normal control skin, P-cadherin expression was restricted to the basal layer. In contrast, positive immunostaining of P-cadherin was observed not only in the basal cells, but also in the suprabasal cells in lesional skin of all the acantholytic diseases.

Conclusions: The present results clearly demonstrated that upregulation of P-cadherin expression occurs in the acantholysis in all the four blistering diseases PV, PF, HHD and DD. Upregulation of P-cadherin may be involved in the pathomechanism of both the autoimmune blistering diseases and the inherited blistering diseases.

CATENIN  

A possible role of catenin dyslocalization in pemphigus vulgaris pathogenesis

Lorenzo Lo Muzio1, Giuseppe Pannone2, Stefania Staibano2, Michele Davide Mignogna3, Corrado Rubini4, Eleonora Ruocco5, Gaetano De Rosa2 and James J. Sciubba6 1

Institute of Dental Sciences, University of Ancona, Ancona, Italy, 2 Department of Biomorphological and Functional Sciences Ė Pathology Unit, University of Naples Federico II, Naples, Italy, 3 Department of Dental Sciences, University of Naples Federico II, Naples, Italy, 4 Institute of Pathological Anatomy, University of Ancona, Ancona, Italy, 5 Institute of Dermatology, II University of Naples, Naples, Italy, 6 Otolaryngology Head and Neck Surgery, Division of Dental and Oral Medicine, Johns Hopkins Medical Center, Baltimore, Maryland, USA

Journal of Cutaneous Pathology 2001;28 (9), 460-469 Abstract quote

Background: Pemphigus vulgaris (PV) is an autoimmune blistering disease of the skin and mucosa due to the presence of autoantibodies against the components of desmosomes. To date, less is known about the expression levels of b- and g-catenins in blistering diseases. The objective of this study was to evaluate the role of b- and g-catenins in the pathogenesis of acantholysis in pemphigus vulgaris.

Methods: b- and g-catenin expression was evaluated by immunohistochemistry in 30 cases of PV at various stages of the disease and, as controls, in 18 specimens of the skin/oral mucosa of healthy patients.

Results: Healthy skin and normal oral mucosa showed a strong b- and g-catenin expression in basal and spinous layers with a prevalent cellular membrane distribution; the intensity of staining progressively decreased toward the superficial layers of epithelium. In PV patients, cytoplasmic expression of g-catenin was detected in 28/30 cases, and in 19/30 cases of PV for b-catenin. Moreover, a progressive displacement of the signal toward the nucleus was found in 14/30 cases for b-catenin, with dyslocalization toward the nucleus, particularly in areas with intense acantholysis, and in 22/30 cases of PV for g-catenin.

Conclusions: Abnormal distribution of g-catenin, consequent to PV IgG, may be considered a direct consequence of Dg3 dissociation from catenin. g-catenin likely plays a direct role in PV pathogenesis through its dyslocalization toward the nucleus or indirectly through the b-catenin dyslocalization toward the nucleus, which is thought to induce transcription of selected target genes, such as uPAR.

HUMAN HERPES VIRUS 8  
Higher prevalence of human herpesvirus 8 DNA sequence and specific IgG antibodies in patients with pemphigus in China.

Wang GQ, Xu H, Wang YK, Gao XH, Zhao Y, He C, Inoue N, Chen HD.

Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, China.

J Am Acad Dermatol. 2005 Mar;52(3 Pt 1):460-7. Abstract quote  

BACKGROUND: Environmental factors, including virus infection, may play a role in the onset and/or development of pemphigus. However, it is controversial whether human herpesvirus (HHV)-8 is involved in pathogenesis of pemphigus.

OBJECTIVE: The possible association of pemphigus with HHV-8 was investigated.

METHODS: A total of 36 lesional skin and 13 peripheral blood mononuclear cell specimens from 58 patients with pemphigus, and 18 normal skin and 230 peripheral blood mononuclear cell specimens from healthy individuals, were tested for HHV-8 DNA sequence by a nested polymerase chain reaction assay. In all, 29 sera from the patients and 109 sera from healthy individuals were tested for HHV-8-specific IgG antibodies by enzyme-linked immunosorbent assays using HHV-8-specific oligopeptides as antigens.

RESULTS: Prevalence of both HHV-8 DNA sequence (36.1% and 30.8% in lesional skin and in peripheral blood mononuclear cells, respectively) and HHV-8-specific IgG antibodies (34.5%) for patients with pemphigus was statistically higher than that of control subjects (<8% in both assays). There was no significant difference in HHV-8 prevalence among different types of pemphigus.

CONCLUSION: HHV-8 infection might be a contributing factor in the development of pemphigus.
PLAKOGLOBIN  


Strict correlation between uPAR and plakoglobin expression in pemphigus vulgaris.

Lo Muzio L, Pannone G, Staibano S, Mignogna MD, Rubini C, Farronato G, Ferrari F, Nocini PF, De Rosa G.

Institute of Dental Sciences, University of Ancona, Ancona, Department of Biomorphological and Functional Sciences, Pathology Unit and Department of Dental Sciences, University of Naples Federico II, Naples, Institute of Pathological Anatomy, University of Ancona, Ancona, Institute of Clinical Dentistry, University of Milano, Milano, and Division of Maxillo-facial Surgery, University of Verona, Verona, Italy.

J Cutan Pathol 2002 Oct;29(9):540-548 Abstract quote

BACKGROUND: Recent studies have reported nuclear delocalization of plakoglobin in acantholytic pemphigus vulgaris cells. The objective of this study was to evaluate the role of plakoglobin in the pathogenesis of acantholysis in pemphigus vulgaris (PV) and its relation with the urokinase-type plasminogen activator receptor (uPAR) expression.

MATERIALS AND METHODS: Plakoglobin and uPAR expressions were evaluated by immunohistochemistry in 22 cases of PV at various stages of the disease, and as controls in 18 specimens of skin/oral mucosa from healthy patients.

RESULTS: Healthy skin/normal oral mucosa showed strong plakoglobin expression in the basal and spinous layers with prevalent cellular membrane distribution; the intensity of staining progressively decreased toward the superficial layers of the epithelium. In PV patients, a progressive displacement of the plakoglobin signal toward the nucleus was found in 18/22 of the cases. Healthy skin/normal oral mucosa showed low uPAR expression with prevalent cellular membrane distribution. In the PV patients, strong uPAR expression was present in the acantholytic cells in 16/22 of the cases. There was direct correlation (p < 0.05) between the uPAR expression and nuclear plakoglobin.

CONCLUSIONS: The uPAR overexpression in acantholytic PV may be considered a direct consequence of plakoglobin abnormal distribution. Nuclear delocalization of plakoglobin, a direct consequence of plakoglobin-Dsg-3 dissociation induced by PV IgG, probably induces uPAR overexpression. This evidence suggests a central role for plakoglobin in PV pathogenesis because of its delocalization toward the nucleus, which is the probable cause of the uPAR gene expression.

IgA PEMPHIGUS  


Human desmocollin 1 (Dsc1) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus.

Hashimoto T, Kiyokawa C, Mori O, Miyasato M, Chidgey MA, Garrod DR, Kobayashi Y, Komori K, Ishii K, Amagai M, Nishikawa T.

Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan.

J Invest Dermatol 1997 Aug;109(2):127-31 Abstract quote

IgA pemphigus showing IgA anti-keratinocyte cell surface autoantibodies is divided into subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic IgA dermatosis (IEN) types.

We previously showed by immunoblotting that IgA from some IgA pemphigus patients reacted with bovine desmocollins (Dsc), but not human Dsc. To determine the antigen for IgA pemphigus, we focused on conformation-dependent epitopes of Dsc, because sera of patients with classical pemphigus recognize conformation-sensitive epitopes of desmogleins. We constructed mammalian expression vectors containing the entire coding sequences of human Dsc1, Dsc2, and Dsc3 and transiently transfected them into COS7 cells by lipofection. Immunofluorescence of COS7 cells transfected with single human Dscs showed that IgA antibodies of all six SPD-type IgA pemphigus cases reacted with the surface of cells expressing Dsc1, but not with cells expressing Dsc2 or Dsc3. In contrast, none of seven IEN-type IgA pemphigus cases reacted with cells transfected with any Dscs.

These results convincingly indicate that human Dsc1 is an autoantigen for SPD-type IgA pemphigus, suggesting the possibility of an important role for Dsc1 in the pathogenesis of this disease. This study shows that a Dsc can be an autoimmune target in human skin disease.


Identification of desmoglein 1 as autoantigen in a patient with intraepidermal neutrophilic IgA dermatosis type of IgA pemphigus.

Karpati S, Amagai M, Liu WL, Dmochowski M, Hashimoto T, Horvath A.

Department of Dermatology, Semmelweis Medical University, Budapest, Hungary.

Exp Dermatol 2000 Jun;9(3):224-8 Abstract quote

In a 51-year-old female patient with intraepidermal neutrophilic IgA dermatosis (IEN) type of IgA pemphigus, circulating IgA, but not IgG, autoantibodies were detected to bind to the cell surface of the whole epidermis, being much stronger in the upper epidermis.

In the patient's skin a heavy intraepidermal IgA staining was observed throughout the whole epidermis, accompanied by a weak IgG and a more prominent C3 staining. IgA from the patient's serum showed no reactivity either with epidermal proteins by immunoblot analysis, or with COS 7 cells transiently transfected with mammalian cell expression constructs containing full length human Dsc1, Dsc2 and Dsc3. Our patient's IgA specifically reacted with conformational epitopes of human desmoglein (Dsg) 1 but not Dsg 3, when studied in a previously established, here for IgA antibody detection modified enzyme-linked immunoabsorbent assay (ELISA) of baculovirus expression system. The immunoreactivity against keratinocyte cell surface was completely removed from the serum of the patient by pre-incubation with recombinant Dsg1 baculoprotein.

This finding indicates that the sera possess only IgA antibodies against the extracellular domain of Dsg1 baculoprotein, but no antibodies against components of keratinocyte cell surface other than Dsg1. This is the first case of IgA pemphigus where Dsg1 has been identified as the autoantigen.

 

DISEASE ASSOCIATIONS CHARACTERIZATION
PEMPHIGUS FOLIACEUS  

Shift in clinical features, histologic findings and antigen profiles from pemphigus vulgaris to pemphigus foliaceus--two case studies.

Kawana S, Hashimoto T, Nishikawa T, Nishiyama S.

Division of Dermatology, St. Luke's International Hospital, Tokyo, Japan

Dermatology 1994;189 Suppl 1:57-9 Abstract quote

We investigated antigen profiles of the sera from 2 cases of pemphigus vulgaris (PV) who subsequently developed pemphigus foliaceus (PF).

Immunoblotting was carried out using normal human epidermal extracts as the antigen source. The sera during PV reacted exclusively with the 130-kD PV antigen and the sera during PF exclusively with the 150-kD antigen.

Therefore, dermatologic, histologic and immunohistologic findings before and after this transition were clearly shown related to changes in serum reactivity with pemphigus antigens.

 

LABORATORY/
RADIOLOGIC
CHARACTERIZATION
LABORATORY
ELISA  


Diagnosis of pemphigus by ELISA: a critical evaluation of two ELISAs for the detection of antibodies to the major pemphigus antigens, desmoglein 1 and 3.

Harman KE, Gratian MJ, Seed PT, Bhogal BS, Challacombe SJ, Black MM.

St. John's Institute of Dermatology, King's Collrggr Hospita, London, UK.

Clin Exp Dermatol 2000 May;25(3):236-40 Abstract quote

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are characterized by autoantibodies to the desmosomal glycoproteins desmoglein 3 (Dsg 3) and Dsg 1 (Dsg 1), respectively.

In this study, two enzyme-linked immunosorbent assays (ELISA) which detect IgG autoantibodies to Dsg 1 and Dsg 3 have been evaluated. A total of 317 normal and disease controls, 82 patients with PV and 25 with PF were studied. The Dsg 3 ELISA was positive in all 34 patients with untreated PV and the Dsg 1 ELISA was positive in all 10 with untreated PF. When patients undergoing treatment were included, the sensitivities fell to 95% and 92%, respectively, but still compared favourably to the sensitivity of indirect immunofluorescence which was 79% in PV and 84% in PF. All PF sera were negative in the Dsg 3 ELISA and the specificity of both assays was 98% or greater. Large numbers of samples could be analysed simultaneously over a relatively short time period.

The Dsg 1 and Dsg 3 ELISAs also provided objective, quantitative, reproducible data which allowed differentiation of PV from PF and in view of these advantages, they are likely to become a routine technique in diagnostic laboratories.


Detection of IgA autoantibodies to desmogleins by an enzyme-linked immunosorbent assay: the presence of new minor subtypes of IgA pemphigus.

Hashimoto T, Komai A, Futei Y, Nishikawa T, Amagai M.

Department of Dermatology, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka 830-0011, Japan

Arch Dermatol 2001 Jun;137(6):735-8 Abstract quote

OBJECTIVE: To examine the frequency of antidesmoglein 1 (Dsg1) and antidesmoglein 3 (Dsg3) IgA autoantibodies in IgA pemphigus.

DESIGN: We developed an enzyme-linked immunosorbent assay against recombinant Dsg1 and Dsg3 to detect IgA autoantibodies.

PATIENTS: Twenty-two patients with IgA pemphigus were studied. Among them, 10 patients had subcorneal pustular dermatosis type, 9 patients had intraepidermal neutrophilic IgA dermatosis type, and 3 patients had pemphigus foliaceus-like clinical features.

RESULTS: Of the 22 cases of IgA pemphigus, 3 cases were positive for anti-Dsg1 IgA antibodies and only 1 case was positive for anti-Dsg3 IgA antibodies. In those 4 cases, there were no IgA autoantibodies against other components of the keratinocyte cell surfaces because preincubation with the respective recombinant desmogleins removed the immunoreactivity on immunofluorescence. All 10 patients with subcorneal pustular dermatosis type IgA pemphigus were positive against desmocollin 1 expressed on COS-7 cells. No target antigen was detected in the other 8 cases.

CONCLUSIONS: Desmogleins were recognized by IgA antibodies of a few patients with IgA pemphigus. Considering that subcorneal pustular dermatosis type IgA pemphigus recognizes desmocollin 1, autoimmune targets of IgA pemphigus are more heterogeneous than previously considered.

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
General  
VARIANTS  
ATYPICAL  
Atypical pemphigus: discordance between clinicopathological findings and the antigenic profile in four cases.

Department of Dermatology, Hospital Clinic & Barcelona University School of Medicine, Barcelona, Spain.

 

J Cutan Pathol. 2006 Jul;33(7):502-7 Abstract quote

BACKGROUND: The diagnosis of pemphigus vulgaris and pemphigus foliaceus is usually based on clinical, histological, and immunofluorescence (IF) findings. In recent years, the antigenic profile of both diseases has been further defined by immunobiochemical techniques (ELISA, immunoblot, and immunoprecipitation).

METHODS: A retrospective study of 40 pemphigus patients was performed to determine the clinical, histological, and antigenic profile in patients with pemphigus followed at our Department. Charts review, clinical data, histological and IF findings, and antigenic analysis by ELISA were performed in all patients.

RESULTS: In most patients, there was a perfect correlation between the clinical and histological findings and their antigenic profile. In four patients (10%), clinicopathological features and antigenic findings were discordant.

CONCLUSIONS: The antigenic profiles in pemphigus do not always correlate with the clinical diagnosis. Therefore, clinical and histological features should be considered as the mainstay for the diagnosis of pemphigus.

CUTANEOUS ONLY  
Cutaneous type pemphigus vulgaris: a rare clinical phenotype of pemphigus.

Yoshida K, Takae Y, Saito H, Oka H, Tanikawa A, Amagai M, Nishikawa T.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

J Am Acad Dermatol. 2005 May;52(5):839-45. Abstract quote  

Pemphigus is an autoimmune blistering disease of the skin, mucous membranes, or both. There are two main categories of pemphigus: pemphigus foliaceus (PF) and pemphigus vulgaris (PV). PV is further subdivided into mucosal dominant and mucocutaneous types, according to the extent of cutaneous lesions. These classes of pemphigus have distinct histopathologic and serologic findings, with most cases falling into these subtypes.

We report 4 cases that clinically showed blisters and erosions in the skin only, without mucosal involvement. Histologic examination of cutaneous lesions demonstrated suprabasilar acantholysis, a typical finding for PV. These patients had predominant anti-desmoglein 1 (Dsg1) IgG autoantibodies as well as anti-Dsg3 IgG autoantibodies, as determined by enzyme-linked immunosorbent assay. The desmoglein compensation theory posits that this rare phenotype can be produced by pathogenically weak anti-Dsg3 IgG in the presence of potent anti-Dsg1 IgG autoantibodies.

Thus, cutaneous type PV without apparent mucosal involvement is observed as a rare clinical and histologic expression of pemphigus. This expression can be a transient phenotype that may develop from, or evolve into, other subtypes of pemphigus.
ENDEMIC TYPE  
Endemic Pemphigus Vulgaris

Rosicler Rocha-Alvarez, MD; Alex G. Ortega-Loayza, MD; Horacio Friedman, MD; Iphis Campbell, MD; Valeria Aoki, MD; Evandro A. Rivitti, MD; David Dasher, MD; Ning Li, PhD; Luis A. Diaz, MD; for the Cooperative Group on Fogo Selvagem Research

Department of Dermatology, Universidade Federal de Brasilia, Brasilia, Distrito Federal (Drs Rocha-Alvarez, Friedman, and Campbell), and Department of Dermatology, Universade de São Paulo, São Paulo (Drs Aoki and Rivitti), Brazil; and Department of Dermatology, University of North Carolina at Chapel Hill (Drs Ortega-Loayza, Dasher, Li, and Diaz).

 

Arch Dermatol. 2007;143:895-899. Abstract quote

Background  Investigators from Brasilia, Brazil, observed several patients with a mucocutaneous disease that resembles pemphigus vulgaris clinically and histologically but with epidemiological features of fogo selvagem. Our objective was to characterize antidesmoglein 3 and antidesmoglein 1 autoantibody profiles in these unique patients who reside in Goiânia and Brasilia, Brazil, known endemic regions of fogo selvagem.

Observations  We performed serological evaluation of 8 patients with a mucocutaneous disease clinically and histologically consistent with pemphigus vulgaris, as well as 27 healthy relatives of patients with fogo selvagem who reside in these endemic areas. Serum samples from all 8 patients bound desmoglein 3 by cold immunoprecipitation and from 6 patients by enzyme-linked immunosorbent assay, while serum samples from 4 patients bound desmoglein 1 by cold immunoprecipitation and by enzyme-linked immunosorbent assay. Antidesmoglein 3 autoantibodies were detected in 4 of 27 healthy donors by cold immunoprecipitation and by enzyme-linked immunosorbent assay, whereas antidesmoglein 1 autoantibodies were detected in 6 individuals by cold immunoprecipitation and in 3 individuals by enzyme-linked immunosorbent assay.

Conclusion  These findings provide serological evidence of a new endemic variant of pemphigus vulgaris.

FACE  


Pemphigus vulgaris localized to the nose and cheeks.

Baykal C, Azizlerli G, Thoma-Uszynski S, Hertl M.

Department of Dermatology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey; and the Department of Dermatology, University of Erlangen-Nurnberg, Germany.

 

J Am Acad Dermatol 2002 Dec;47(6):875-80 Abstract quote

Pemphigus vulgaris is an autoimmune blistering disease characterized by disseminated bullae and erosions of the mucosal surfaces and skin. Cases of pemphigus vulgaris with localized lesions on glabrous skin have been reported, and most of them have been attributed to the Koebner phenomenon. Lesions limited to the nose have mostly been described in pemphigus foliaceus, but the nose has also been the initial site of pemphigus vulgaris in a few patients.

We report 4 cases of localized pemphigus vulgaris: one case with lesions limited to the nose and cheeks and 3 cases with isolated lesions on the nose. Recurrent episodes in these patients also occurred on the nose. None of them showed mucosal involvement or dissemination during a follow-up period of 2 to 9 years. Three patients had autoantibodies against desmoglein-3 as detected by immunoblot. In the other patient, antibodies against desmoglein-3 were detected by enzyme-linked immunosorbent assay.

These localized lesions may represent a subgroup of pemphigus vulgaris or a period of limited activity during this chronic disease.

HEAD AND NECK  

Laryngeal and nasal involvement in pemphigus vulgaris

Elizabeth K. Hale, etal.

J Am Acad Dermatol 2001;44:609-11. Abstract quote

Background: The presence of lesions of pemphigus vulgaris in the larynx and nasal cavity has been reported in individual case reports. However, the frequency with which these sites are involved is not known.

Objective: Our purpose was to investigate the incidence of laryngeal and nasal disease involvement in patients with pemphigus vulgaris.

Methods: This was a retrospective analysis conducted in a referral private practice in an academic department of dermatology. A total of 53 sequential patients with pemphigus vulgaris diagnosed by clinical, histologic, and immunofluorescence criteria were selected on the basis of having been treated by one of us (J. C. B.) during most of their illness. Patients' charts were reviewed for documentation of laryngeal and nasal symptoms, ear/nose/throat evaluation, and response to treatment.

Results: Twenty-six (49%) of the patients complained of laryngeal or nasal symptoms at some time during the course of their disease. Twenty-one patients had laryngeal symptoms and 12 had nasal symptoms. More than 80% of patients with laryngeal or nasal symptoms had evidence of pemphigus involvement based on ear/nose/throat examination or rapid response to increased doses of corticosteroids, and 2 patients had candidiasis confirmed by fungal culture.

Conclusion: These observations indicate that laryngeal and nasal symptoms are common in pemphigus vulgaris. In the majority of cases, this appears to be a result of involvement with the disease or with candidiasis.

MUCOSAL DOMINANT  
Mucosal dominant pemphigus vulgaris with anti-desmoplakin autoantibodies.

Mimouni D, Foedinger D, Kouba DJ, Orlow SJ, Rappersberger K, Sciubba JJ, Nikolskaia OV, Cohen BA, Anhalt GJ, Nousari CH.

Departments of Dermatology and Otolaryngology-Head and Neck Surgery of Johns Hopkins University; and the Departments of Dermatology at the University of Vienna; New York University; and the University of Pennsylvania USA.


J Am Acad Dermatol. 2004 Jul;51(1 Pt 1):62-7. Abstract quote  

BACKGROUND: Anti-desmoplakin (DP) antibodies are present in paraneoplastic pemphigus (PNP) as a component of a complex humoral autoimmune reaction characterized by antibodies against proteins of the plakin family, desmogleins, and an unidentified 170 kd protein. Anti-DP antibodies have also been rarely identified in other blistering diseases. The significance of anti-DP antibodies in the pathogenesis of bullous diseases is unclear.

OBSERVATION: We studied 3 patients with severe and chronic mucosal dominant pemphigus vulgaris (PV). In addition to anti-desmoglein 3 antibodies, these patients had anti-DP autoantibodies, demonstrable by immunofluorescence (IF), immunoprecipitation (IP), and indirect immunoelectromicroscopy (IIEM). This finding suggested these patients may have had PNP and not PV. However, antibodies against periplakin, envoplakin, bullous pemphigoid antigen 1 (BPAG 1), plectin, and 170 kd PNP antigen could not be detected using IP and immunoblotting. Extensive and repeated investigations for an underlying neoplasm throughout the follow-up period were consistently negative for all patients.

CONCLUSION: This study demonstrates that anti-DP antibodies without the presence of any other anti-plakin antibodies are not specific for PNP, and are present in some cases of PV. Cellular disadhesion induced by anti-desmoglein antibodies can trigger an epitope-spreading phenomenon with a secondary formation of autoantibodies against desmoplakins, intracellular desmosomal antigens.

The role of anti-DP antibodies in the pathogenesis of these PV patients is still unclear. The presence of anti-DP antibodies will produce a false positive serologic interpretation for the diagnosis of PNP especially if one uses only indirect IF on murine bladder, the most commonly employed screening test to identify PNP. More specific immunologic tests are required in this subset of patients with PV.
NIKOLSKIY SIGN  
The specificity and sensitivity of Nikolskiy sign in the diagnosis of pemphigus.

Uzun S, Durdu M.

Faculty of Medicine, Department of Dermatology, Cukurova University, Adana, Turkey.
J Am Acad Dermatol. 2006 Mar;54(3):411-5. Epub 2005 Dec 27. Abstract quote  

BACKGROUND: The Nikolskiy sign is a well-known mechanical symptom that can be helpful in the diagnosis of pemphigus. The reports about associations with other than pemphigus cause confusion concerning the diagnostic importance of the Nikolskiy sign in pemphigus.

OBJECTIVE: Our purpose was to examine the significance and usefulness of the Nikolskiy sign on the clinical diagnosis of pemphigus by determination of its sensitivity and specificity.

METHODS: Presence of the Nikolskiy sign with the modifications of "direct" and "marginal" on 123 consecutive patients with various cutaneous diseases presenting as intact blisters and/or erosions was sought.

RESULTS: A positive Nikolskiy sign was demonstrated in 24 (19.5%) of the 123 patients. Of the positive 24 patients, 18 had pemphigus, 4 had bullous pemphigoid, 1 had linear IgA dermatosis, and 1 had staphylococcal scalded skin syndrome. The sensitivity of "direct" Nikolskiy sign (38%) was less than that of the "marginal" form (69%), but the specificity of "direct" Nikolskiy sign (100%) was higher than that of the "marginal" form (94%) in the diagnosis of pemphigus.

LIMITATIONS: This study was primarily concerned with the diagnostic importance of the Nikolskiy sign in pemphigus. We did not focus on its prognostic value in pemphigus. The small size of the group of patients with pemphigus, which is related to low annual incidence of pemphigus in our region, is another limitation of this study.

CONCLUSIONS: The Nikolskiy sign offers a moderately sensitive but highly specific tool for the diagnosis of pemphigus.
OCULAR  
Ocular pemphigus.

Daoud YJ, Cervantes R, Foster CS, Ahmed AR.

Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

J Am Acad Dermatol. 2005 Oct;53(4):585-90. Abstract quote  

BACKGROUND: Ocular involvement in patients with pemphigus vulgaris (PV) has been rarely reported. We report ocular involvement in 11 patients with PV.

METHODS: Medical records of 11 biopsy-proven patients with PV treated during the period between 1990 and 2003 were reviewed and clinical information was analyzed.

RESULTS: Mean age at onset of PV was 52.3 years (range, 30-80 years). Ocular disease was preceded by involvement of the skin, other mucosae, or both in all patients. Ocular involvement was limited to the conjunctivae, the eyelids, or both. PV did not affect the visual acuity of any of the patients. Suprabasal acantholysis was observed on routine histologic examination of the conjunctiva and skin of the eyelid. Direct immunofluorescence of perilesional eyelid skin demonstrated deposition of IgG on epithelial cell surface. Mean duration of follow up was 48.9 months (range, 4-100 months). Recurrence of ocular disease occurred in 3 patients; recurrence at nonocular mucosae occurred in 4 patients. No sequelae were observed during detailed follow-up. Ocular pemphigus improved with systemic therapy. The mean remission period was 32 months (range, 0-92 months).

CONCLUSIONS: Ocular involvement in PV is rare. Involvement is limited to the conjunctiva, the eyelids, or both. PV does not appear to affect visual acuity. Patients have full recovery without sequelae.

 

HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL

The histopathology is distinctive with suprabasilar acantholysis extending down adnexal epithelium. There is preservation of the basal layer leading to a tombstone appearance of the keratinocytes. The blister is intraepidermal and may contain some acantholytic cells, eosinophils, and neutrophils.

The pathologist, however, may encounter difficulty diagnosing early cases which lack the characteristic acantholysis. In this urticarial, cell-poor stage, there may be eosinophilic spongiosis and even subepidermal clefting, raising the differential diagnosis of bullous pemphigoid. In these cases, DIF may be helpful.

Follicular acantholysis: a subtle clue to the early diagnosis of pemphigus vulgaris.

Mahalingam M.

From Quest Diagnostics Incorporated, Cambridge, Massachusetts.
Am J Dermatopathol. 2005 Jun;27(3):237-9. Abstract quote  

The histologic hallmark of fully established pemphigus vulgaris (PV), a chronic autoimmune disease of the skin and mucosa, is the presence of acantholysis induced at the suprabasal level.

This case report of acantholysis restricted to the follicular epithelium as a subtle histologic manifestation of the disease, draws attention to the pitfalls encountered in the histologic diagnosis of early cases of pemphigus vulgaris.
VARIANTS  
IgA PEMPHIGUS  


Intercellular IgA dermatosis.

Ongenae KC, Temmerman LJ, Vermander F, Naeyaert JM.

Department of Dermatology, University Hospital, Gent, Belgium.

Eur J Dermatol 1999 Mar;9(2):85-94 Abstract quote

We report three cases of intercellular IgA dermatosis (IAD) and review the literature. IAD is a spectrum of vesiculobullous or vesiculopustular diseases mediated by intercellular IgA deposition.

The clinical picture may vary from a vesiculopustular eruption with centrifugal evolution mainly involving the trunk and extremities, to the typical picture of classic pemphigus variants (foliaceus, vegetans). Histologically, infiltrating polymorphonuclear cells (mainly neutrophils) are observed in the epidermis with formation of pustules and bullae at various levels. However cases with typical histological features of pemphigus (variants) are described. Direct immunofluorescence on perilesonal skin typically displays intercellular IgA deposition at different levels or throughout the epidermis and indirect immunofluorescence often detects low levels of circulating antibodies. The disease has been repeatedly reported in association with monoclonal IgA gammopathy. Most cases respond to dapsone. In some cases IgA is directed against known pemphigus antigens whereas their targets in other cases are newly discovered antigens (105 kD, 115 kD, 120 kD).

We observe a heterogeneity within the clinical, histological and immunological characteristics of the disease. Many reported cases feature various combinations of these characteristics. We therefore consider IAD as a disease spectrum with IgA pemphigus (clinical and histological pemphigus) at one end and intercellular IgA vesiculopustular dermatosis at the other end.


Intercellular IgA dermatosis (IgA pemphigus)--two cases illustrating the clinical heterogeneity of this disorder.

Harman KE, Holmes G, Bhogal BS, McFadden J, Black MM.

St John's Institute of Dermatology, St Thomas' Hospital, King's College, London, UK.

Clin Exp Dermatol 1999 Nov;24(6):464-6 Abstract quote

IgA pemphigus is rare but may be underdiagnosed. We describe two cases, a 50-year-old female with a pustular eruption resembling subcorneal pustular dermatosis and a 55-year-old male with a pruritic vesiculopustular eruption simulating dermatitis herpetiformis. They illustrate the clinical heterogeneity of IgA pemphigus which is likely to reflect differences in autoantigens, analogous to pemphigus vulgaris and pemphigus foliaceus.

There is now evidence that IgA pemphigus encompasses at least two subgroups: a subcorneal pustular dermatosis (SPD)-type, (see case 1) characterized by subcorneal pustules and autoantibodies to desmocollin 1; and intra-epidermal neutrophilic dermatosis (IEN)-type cases (see case 2) which show intra-epidermal pustules and in whom the autoantigen may be desmoglein 3, the pemphigus vulgaris antigen.


Subcorneal pustular dermatosis type of IgA pemphigus: demonstration of autoantibodies to desmocollin-1 and clinical review.

Yasuda H, Kobayashi H, Hashimoto T, Itoh K, Yamane M, Nakamura J.

Department of Dermatology, Sapporo Social Insurance General Hospital, 2-1, 2-Jo, 6-Chome, Atsubetsu Chuo, Atsubetsu, Sapporo 004-8618, Japan.

Br J Dermatol 2000 Jul;143(1):144-8 Abstract quote

We describe a 40-year-old Japanese man with a 3-year history of vesiculopustular lesions resembling subcorneal pustular dermatosis.

Histopathology showed subcorneal pustules containing a few acantholytic cells, and direct immunofluorescence disclosed IgA deposition in the intercellular space of the upper epidermis. Circulating IgA autoantibodies of very low titre were also demonstrated by indirect immunofluorescence. A novel cDNA transfection technique clearly detected IgA autoantibodies reactive with human desmocollin-1. Combined therapy with dapsone and etretinate improved the skin lesions.

We review the clinical features of 49 patients in the literature who presented with vesiculopustular lesions and intraepidermal IgA deposition.


IgA pemphigus: a case report and its characteristic clinical features compared with subcorneal pustular dermatosis.

Niimi Y, Kawana S, Kusunoki T.

Department of Dermatology, Nippon Medical School, and Kusunoki Dermatology Clinic, Tokyo, Japan.

J Am Acad Dermatol 2000 Sep;43(3):546-9 Abstract quote

We report a case of IgA pemphigus. A 35-year-old woman had vesiculopustular eruptions on her scalp, trunk, and extremities.

Histologic examination showed a subcorneal pustule containing numerous neutrophils without acantholysis. Direct immunofluorescence revealed IgA deposits in the intercellular space throughout the epidermis, more intense in superficial layers and less intense in lower layers. The titer of circulating IgA antibodies was 1:160 in normal human skin as a substrate. Skin lesions responded to dapsone. The IgA autoantibody from this patient did not react with desmogleins or desmocollins when immunoblotting, enzyme-linked immunosorbent assay, or complement DNA transfection was used.

We consider the characteristic clinical features that favor the diagnosis of IgA pemphigus rather than classic subcorneal pustular dermatosis as follows: (1) the lesions involve the scalp and/or face, and (2) the distribution of the lesions is more widespread.


Subcorneal pustular dermatosis-type IgA pemphigus induced by thiol drugs.

Kishimoto K, Iwatsuki K, Akiba H, Motoki Y, Kaneko F.

Department of Dermatology, Fukushima Medical University School of Medicine, 1-Hikarigaoka, Fukushima 960-1295, Japan.

Eur J Dermatol 2001 Jan-Feb;11(1):41-4 Abstract quote

We report a case of subcorneal pustular dermatosis (SPD)-type IgA pemphigus arising in a 49 year-old woman with rheumatoid arthritis who had been treated with chrysotherapy. Scaly erythemic plaques containing vesicles and pustules occurred on her chest and abdomen during the course of anti-rheumatic treatments using prednisolone at 11 mg/day and thiol compounds (bucillamine and gold sodium thiomalate).

Histological investigations revealed subcorneal pustules containing many neutrophils and a few acantholytic cells, and intercellular IgA deposits at the upper epidermis of the eruptions without any other immunoglobulins and complement component C3. Circulating IgA antibodies directed against intercellular spaces of the epidermis were found by prolonged incubation of normal skin specimens in medium containing 20% patient's serum in an explant culture, although standard indirect immunofluorescence for IgA antibodies was negative.

The eruptions were treated successfully with prednisolone, 30 mg/day, dapsone, 50 mg/day, and discontinuance of the thiol compound. In addition to the coexistent rheumatoid arthritis, both thiol compounds might have been responsible for the development of the eruptions.

PEMPHIGUS HERPETIFORMIS  


Pemphigus herpetiformis with IgA and IgG antibodies to desmoglein 1 and IgG antibodies to desmocollin 3.

Kozlowska A, Hashimoto T, Jarzabek-Chorzelska M, Amagai A, Nagata Y, Strasz Z, Jablonska S.

Department of Dermatology, Warsaw School of Medicine, Warsaw; Kurume University School of Medicine, Fukuoka; and Keio University School of Medicine, Tokyo.

 

J Am Acad Dermatol 2003 Jan;48(1):117-22 Abstract quote

We describe a case with clinical and histologic features of pemphigus herpetiformis associated with IgG and IgA anti-keratinocyte cell surface antibodies to desmoglein 1 (Dsg1) and exclusively IgG antibodies to desmocollin 3 (Dsc3).

The clinical presentation was somewhat similar to IgA pemphigus; the main difference was the prevailing association with IgG antibodies to Dsg1. The presence of IgA anti-Dsg1 antibodies was confirmed by IgA enzyme-linked immunosorbent assay and IgG anti-Dsc3 antibodies were detected by a novel enzyme-linked immunosorbent assay with the use of baculovirus expressing recombinant Dscs for IgG and IgA. The reactivity of IgG antibodies with Dsc3 was confirmed by COS-7 cell cDNA transfection method using cDNA of human Dsc1 to Dsc3.

We discuss the differentiation of pemphigus herpetiformis, associated with both IgG and IgA antibodies, from IgA pemphigus, particularly in regard to the autoimmune reaction with Dsgs and Dscs.

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
Prognostic Factors  
Survival Mortality ranges up to 5-15% and is usually due to infectious complications secondary to the steroid treatment.
Treatment The mainstay of treatment is corticosteroids. In difficult cases, gold has also been used. Plasmapheresis may be helpful in reducing the circulating antibodies.
IgA PEMPHIGUS  


Effect of colchicine in the subcorneal pustular dermatosis type of IgA pemphigus.

Hodak E, Lapidoth M, David M.

Department of Dermatology, Rabin Medical Center, Beilinson Campus, Petah Tiqva, Israel.

J Am Acad Dermatol 1999 Jan;40(1):91-4 Abstract quote

BACKGROUND: IgA pemphigus of the subcorneal pustular dermatosis (SPD) type is characterized by subcorneal acantholysis and by an abundance of neutrophils, making colchicine a reasonable pharmacologic option for treatment.

OBJECTIVE: We attempted to determine the efficacy of colchicine in the treatment of SPD-type IgA pemphigus.

METHODS: Two patients with SPD-type IgA pemphigus were treated with colchicine 1.5 mg/day as monotherapy.

RESULTS: A sustained clinical response was achieved within 2 to 3 weeks of therapy. Relapses were noted each time colchicine was stopped.

CONCLUSION: Colchicine should be considered in the treatment of SPD-type IgA pemphigus.


Rapid response of IgA pemphigus of subcorneal pustular dermatosis type to treatment with isotretinoin.

Gruss C, Zillikens D, Hashimoto T, Amagai M, Kroiss M, Vogt T, Landthaler M, Stolz W.

Department of Dermatology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93042 Regensburg, Germany.

J Am Acad Dermatol 2000 Nov;43(5 Pt 2):923-6 Abstract quote

Diagnosing IgA pemphigus and distinguishing between its 2 subtypes, intraepidermal neutrophilic IgA dermatosis type and subcorneal pustular dermatosis type, is important because treatment of IgA pemphigus has to be different from treatment of other blistering autoimmune dermatoses.

We present a patient with subcorneal pustular dermatosis type of IgA pemphigus who rapidly responded to systemic treatment with isotretinoin. Specific diagnosis was established by detecting IgA serum activity to desmocollin 1 by indirect immunofluorescence microscopy on unfixed COS7 cells transfected with desmocollin 1. No IgA or IgG serum reactivity was found to recombinant forms of desmogleins 1 and 3 by an antigen-specific enzyme-linked immunosorbent assay. The disease was not effectively controlled by conventional therapeutic regimens. Systemic treatment with isotretinoin 20 mg daily led to complete clearance of skin lesions within 3 weeks.

Assaying IgA serum reactivity to desmocollin 1, desmoglein 1, and desmoglein 3 as a valuable method for establishing the diagnosis and differentiating the 2 subtypes of IgA pemphigus. Isotretinoin was an effective drug in the treatment of subcorneal pustular dermatosis type of IgA pemphigus in this patient.

Aggressive immunosuppressive therapy for a refractory case of IgA pemphigus.

Sibley Hash K, Rencic A, Hernandez MI, Hashimoto T, Nousari HC.

Division of Immunodermatology, Department of of Dermatology, Johns Hopkins Medical Institutions, 720 Rutland Ave, Room 771, Baltimore, MD 21205.

Arch Dermatol 2002 Jun;138(6):744-6
CONVENTIONAL PEMPHIGUS  
CHOLINERGIC AGONISTS  

Pemphigus vulgaris acantholysis ameliorated by cholinergic agonists.

Nguyen VT, Arredondo J, Chernyavsky AI, Pittelkow MR, Kitajima Y, Grando SA.

Departments of Dermatology, University of California Davis, Sacramento, Mayo Clinic, Rochester, Minn, and Gifu University, Gifu City, Japan.


Arch Dermatol. 2004 Mar;140(3):327-34. Abstract quote  


BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune, IgG autoantibody-mediated disease of skin and mucosa leading to progressive blistering and nonhealing erosions. Patients develop autoantibodies to adhesion molecules mediating intercellular adhesion and to keratinocyte cholinergic receptors regulating cell adhesion.

OBSERVATIONS: To determine whether a cholinergic agonist can abolish PV IgG-induced acantholysis, litter mates of neonatal athymic nude mice were injected with PV IgG together with carbachol (0.04 micro g/g body weight). None of these mice developed skin lesions. Through in vitro experiments, we measured the expression of adhesion molecules in monolayers of normal human keratinocytes incubated overnight in the presence of 0.25mM carbachol using semiquantitative Western blot and immunofluorescence. Carbachol caused an elevation of the relative amount of E-cadherin in keratinocytes (P<.05) without changing that of plakoglobin (P>.05). The phosphorylation level of E-cadherin and plakoglobin was increased by PV IgG, whereas this effect of PV IgG was attenuated in the presence of 0.5mM carbachol. Pyridostigmine bromide, an acetylcholinesterase inhibitor, produced effects similar to those of carbachol, which helps explain its clinical efficacy in a patient with active PV that was resistant to treatment with systemic glucocorticosteroids. Treatment with pyridostigmine bromide (360 mg/d) in a patient with PV allowed to keep his disease under control at a lower dose of prednisone than that used before starting pyridostigmine bromide treatment.

Conclusion Elucidation of the cholinergic control of keratinocyte adhesion merits further consideration because of a potential for the development of novel antiacantholytic therapies using cholinergic drugs.
CYCLOPHOSPHAMIDE  


Oral cyclophosphamide for treatment of pemphigus vulgaris and foliaceus.

Cummins DL, Mimouni D, Anhalt GJ, Nousari CH.

Department of Dermatology, Johns Hopkins University, School of Medicine, Baltimore, MS 21205, USA.


J Am Acad Dermatol. 2003 Aug;49(2):276-80 Abstract quote

BACKGROUND: Cyclophosphamide is an alkylating adjuvant used in refractory cases of pemphigus.

OBJECTIVE: We sought to evaluate the effectiveness and safety of oral cyclophosphamide in the treatment of patients with pemphigus vulgaris (PV) and pemphigus foliaceus (PF) with refractory disease.

PATIENTS: We studied 23 patients with pemphigus (20 with PV; 3 with PF) who failed to achieve clinical remissions with the use of prednisone and antimetabolites.

RESULTS: Complete remission was achieved in 17 patients with PV and 2 with PF. A total of 3 patients with PV failed therapy. A partial remission was achieved in 1 patient with PF. The treatment was administered for a median duration of 17 months with a follow-up period of 27 months. The median time to complete remission was 8.5 months. A total of 9 patients who were severely affected received concomitant plasma exchange. Adverse reactions included 5 cases of hematuria, 6 nonlife-threatening infections, and the development of transitional cell carcinoma of the bladder 15 years after discontinuation of cyclophosphamide in 1 patient. No death was associated with cyclophosphamide treatment.

CONCLUSION: Oral cyclophosphamide is an effective adjuvant in the treatment of severe and refractory PV and PF, but requires close monitoring.

DAPSONE  
Multicenter Randomized, Double-blind, Placebo-Controlled, Clinical Trial of Dapsone as a Glucocorticoid-Sparing Agent in Maintenance-Phase Pemphigus Vulgaris

Victoria P. Werth, MD; David Fivenson, MD; Amit G. Pandya, MD; Diana Chen, MD; M. Joyce Rico, MD; Joerg Albrecht, MD; David Jacobus, MD

 

Arch Dermatol. 2008;144(1):25-32. Abstract quote

Objective  To determine the efficacy of dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris (PV).

Design  A randomized, double-blind, placebo-controlled study with a crossover arm for those who failed treatment.

Setting  A US multicenter outpatient study.

Patients  A total of 19 subjects enrolled among 5 centers, 9 randomized to receive dapsone and 10 to receive placebo. Inclusion criteria were biopsy and direct immunofluorescence-proven PV controlled with glucocorticoids and/or cytotoxic agents, disease in maintenance phase, and aged 18 to 80 years. Physicians had tried at least 2 tapers of glucocorticoids unsuccessfully and had 30 days of stable steroid dosage. Treatment for any patient unable to taper glucocorticoids by more than 25% within 4 months was declared a failure, and the patient was allowed to switch to the opposite medication while maintaining the double-blind.

Main Outcome Measure  The ability of patients to taper to 7.5 mg/d or less within 1 year of reaching the maximum dosage of the study drug.

Results  Of the 9 patients receiving dapsone, 5 were successfully treated, 3 failed treatment, and 1 dropped out of the study. Of the 10 patients receiving placebo, 3 were successfully treated, and 7 failed treatment. This primary end point favored the dapsone-treated group but was not statistically significant (P = .37). Four patients who failed treatment while receiving placebo were switched to treatment with dapsone. Of these, 3 were successfully treated after switching to dapsone treatment, and 1 failed treatment. We found that, overall, 8 of 11 patients (73%) receiving dapsone vs 3 of 10 (30%) receiving placebo reached the primary outcome of a prednisone dosage of 7.5 mg/d or less.

Conclusion  This trial demonstrates a trend to efficacy of dapsone as a steroid-sparing drug in maintenance-phase PV.

Dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris.

Heaphy MR, Albrecht J, Werth VP.

Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.
Arch Dermatol. 2005 Jun;141(6):699-702. Abstract quote  

OBJECTIVE: To determine the effect of dapsone on glucocorticoid-dependent patients with active or maintenance-phase pemphigus vulgaris.

DESIGN: Retrospective study of consecutive patients treated with dapsone.

SETTING: University of Pennsylvania, Philadelphia (a tertiary referral hospital).Patients We observed 9 consecutive adult patients with pemphigus vulgaris being treated with immunosuppressants who were unable to taper prednisone use without abrupt worsening of their disease.Interventions Dapsone treatment added to prednisone and other immunosuppressive therapy.Main Outcome Measure Steroid dosage.

RESULTS: All patients were unable to taper their steroid dose during the 3 months prior to the initiation of dapsone therapy or had active disease that was not well controlled by prednisone prior to dapsone treatment. With the exception of 1 patient with uncontrolled disease, all 9 patients were able to taper their steroid dose below the adrenal replacement level during dapsone treatment. Maintenance-phase patients taking 15 mg/d or more of prednisone (n = 5) experienced a mean +/- SEM drop of 67% +/- 7.1% in prednisone dose by 4 months of maximal dapsone treatment and an 84% +/- 3.5% drop in prednisone dose after 8 months of dapsone treatment.

CONCLUSIONS: These retrospective study findings suggest that dapsone reduces steroid dependence in patients with pemphigus vulgaris, provided they are in the maintenance phase of their disease. These data support the need for a prospective, randomized trial to confirm these findings.
GOLD  

Treatment of pemphigus with gold.

Pandya AG, Dyke C.

Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, USA.

Arch Dermatol 1998 Sep;134(9):1104-7 Abstract quote

BACKGROUND: Although gold has been reported to be useful in treating pemphigus vulgaris, its use has waned in recent years because of concerns regarding efficacy and toxicity.

OBJECTIVE: To review 26 patients with pemphigus who were treated with intramuscular gold over a 10-year period.

RESULTS: Gold was effective in 62% of patients as a primary treatment for pemphigus or as a steroid-sparing agent. An average of 3 months of therapy was required before the daily prednisone dosage could be halved. Four patients were free of disease and stopped receiving all therapy at the conclusion of the study. Toxic effects due to gold therapy developed in 42% of patients and all adverse effects resolved with its cessation.

CONCLUSIONS: While toxic effects limit the use of gold in many patients with pemphigus, it may be effective in treating a large percentage of patients who otherwise are unable to reduce their steroid requirement. Because of its delayed onset of action, patients treated with gold usually require systemic steroids when therapy is initiated. Controlled, prospective trials are needed to further evaluate the efficacy of gold and its potential steroid-sparing effects.

IMMUNOGLOBULIN  

Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment

A. Razzaque Ahmed, MD

Boston, Massachusetts

J Am Acad Dermatol 2001;45:679-90 Abstract quote

Background: Severe pemphigus vulgaris (PV) is conventionally treated with high-dose oral prednisone, usually in combination with an immunosuppressive agent (ISA). Some patients experience significant side effects, which are sometimes fatal, from prolonged immunosuppression.

Objective: Intravenous immunoglobulin (IVIg) was administered to 21 patients with severe cutaneous and mucosal PV who had not responded to the prolonged use of oral prednisone and multiple ISAs.

Methods: A preliminary dose-determination study tested 7 additional volunteers to ascertain the optimal IVIg dose of 2 g/kg per cycle. Parameters to assess clinical outcome were recorded before and after IVIg therapy. Variables tested were highest dose, total dose, and duration of prednisone and ISAs, their side effects, frequency of recurrence and relapse, duration of IVIg therapy, clinical response, induction and duration of remission, number of hospitalizations, total days of hospital stay, and quality of life.

Results: Use of IVIg monotherapy resulted in effective control of disease and produced a sustained remission in the 21 patients. The patients became free of lesions and remained so after finishing IVIg therapy. IVIg had a steroid-sparing effect and produced a high quality of life. Serious side effects from the use of IVIg were not observed. IVIg needs to be gradually withdrawn after achievement of clinical control.

Conclusion: In patients with PV who do not respond to conventional immunosuppressants, IVIg appears to be an effective treatment alternative. Its early use is of significant benefit in patients who may experience life-threatening complications from immunosuppression. IVIg is effective as monotherapy.


Treatment of pemphigus with intravenous immunoglobulin.

Bystryn JC, Jiao D, Natow S.

Ronald O. Perelman Department of Dermatology, New York University School of Medicine.

J Am Acad Dermatol 2002 Sep;47(3):358-63 Abstract quote

BACKGROUND: Intravenous immunoglobulin (IVIg) has recently been advocated as a treatment for pemphigus, but the results of published studies are in conflict. This study was conducted to re-examine the effectiveness of IVIg for the immediate control of active disease and to study the mechanisms of its action.

METHODS: Six patients with active pemphigus vulgaris unresponsive to conventional therapy with high doses of corticosteroids were treated with IVIg (400 mg/kg per day for 5 days) and concurrently given cyclophosphamide (100-150 mg/d). The primary end points were healing of skin lesions and changes in the level of intercellular antibodies and steroid dose.

RESULTS: New lesions ceased to form within 1 week of initiating IVIg therapy, and within 2 weeks the extent of existing skin lesions was reduced by 80% or more in all but one patient. Within 3 weeks, steroid doses were reduced by an average of 41%. The improvement was more rapid than that in patients previously treated with similar doses of steroids and cytotoxic agents at the same institution. Clinical improvement was associated with a rapid decline in pemphigus antibodies whose levels decreased by 72% within 1 week of initiation of IVIg therapy. The rapidity and extent of this decline were similar to those achieved with intensive plasmapheresis. The decline was not due to blocking the synthesis or the immunologic activity of intercellular antibodies by IVIg, suggesting that it resulted from increased immunoglobulin catabolism.

CONCLUSIONS: These results indicate that IVIg can effectively and rapidly control active pemphigus unresponsive to conventional therapy and suggest that the mechanism of its action is decreasing serum levels of intercellular antibodies.


Corticosteroid-sparing effect of intravenous immunoglobulin therapy in patients with pemphigus vulgaris.

Sami N, Qureshi A, Ruocco E, Ahmed AR.

Department of Oral Medicine, Harvard School of Dental Medicine, 188 Longwood Ave, Boston, MA 02115.

Arch Dermatol 2002 Sep;138(9):1158-62 Abstract quote

BACKGROUND: Pemphigus vulgaris (PV) is a rare, potentially fatal autoimmune mucocutaneous blistering disease. The prolonged use of systemic corticosteroids, though clinically effective in high doses, can result in multiple debilitating adverse effects. Immunosuppressive agents, used as adjuvants and as corticosteroid-sparing agents, are not effective in all patients and are contraindicated in some. Therefore, alternative treatment modalities are needed to provide effective control of PV in such patients.

OBJECTIVE: To demonstrate the corticosteroid-sparing effect of intravenous immunoglobulin (IVIg) therapy in patients with moderate to severe PV.

DESIGN: A retrospective analysis in a cohort of 15 patients with moderate to severe PV who were treated with IVIg therapy. All 15 patients were corticosteroid dependent, and the use of other systemic conventional immunosuppressive agents was contraindicated. The patients were followed up over a mean period of 6.2 years.

SETTING: Ambulatory tertiary medical care facility of a university-affiliated hospital.

INTERVENTION: All 15 patients received an IVIg dose of 1 to 2 mg/kg per cycle.

MAIN OUTCOME MEASURES: The following information was documented in each of the 15 patients before and after the initiation of IVIg therapy: total dosage and total duration of prednisone therapy and number of relapses. Also, the highest dosage and adverse effects of prednisone therapy, as well as the total duration of observation, were recorded.

RESULTS: All 15 patients had a satisfactory clinical response to IVIg therapy. The use of systemic prednisone was gradually discontinued over a mean period of 4.3 months. A statistically significant difference was noted in the total dose of prednisone (P =.004), total duration of prednisone therapy (P =.003), and number of relapses (P<.001) before and after the initiation of IVIg therapy.

CONCLUSIONS: Intravenous immunoglobulin therapy has a demonstrable corticosteroid-sparing effect. It is a safe and effective alternative treatment modality in patients with PV who are dependent on systemic corticosteroids or who develop significant adverse effects as a result of their use.

MYCOPHENOLATE MOFETIL  


Treatment of pemphigus vulgaris and pemphigus foliaceus with mycophenolate mofetil.

Mimouni D, Anhalt GJ, Cummins DL, Kouba DJ, Thorne JE, Nousari HC.

Department of Dermatology, Johns Hopkins University, School of Medicine, Baltimore, Md.

Arch Dermatol. 2003 Jun;139(6):739-42. Abstract quote

BACKGROUND: Mycophenolate mofetil is increasingly being used as a corticosteroid-sparing agent in immunosuppressive regimens.

OBJECTIVE: To elucidate the effectiveness of mycophenolate as adjuvant therapy in the treatment of both pemphigus vulgaris and pemphigus foliaceus.

DESIGN: Historical prospective study.

SETTING: University hospital.Patients The study included 42 consecutive patients with pemphigus (31 with pemphigus vulgaris and 11 with pemphigus foliaceus) who had relapses during prednisone taper or had clinically significant adverse effects from previous drug therapy.

RESULTS: Remission was achieved in 22 (71%) and 5 (45%) of patients with pemphgus vulgaris and pemphigus foliaceus, respectively. Partial remission was achieved in 1 (3%) and 4 (36%), respectively. The median time to achieve complete remission was 9 months (range, 1-13 months). The treatment was administered for a median of 22 months, and the median follow-up period was 22 months. Seventy-seven percent of patients had no adverse effect. Two patients had side effects severe enough to necessitate discontinuation of treatment, one because of symptomatic but reversible neutropenia and the other because of nausea.

Conclusion Mycophenolate is an effective and safe adjuvant in the treatment of both pemphigus vulgaris and pemphigus foliaceus.

RITUXIMAB (ANTI-CD20)  
Treatment of Severe Pemphigus With Rituximab

Report of 12 Cases and a Review of the Literature

Giuseppe Cianchini, MD; Rosamaria Corona, DSc, MD; Alessandra Frezzolini, BSc; Marina Ruffelli, BSc; Biagio Didona, MD; Pietro Puddu, MD

 

Arch Dermatol. 2007;143:1033-1038. Abstract quote

Background  Treatment of pemphigus vulgaris can be challenging. Systemic steroids associated with other immunosuppressant agents are the mainstay of therapy and have dramatically reduced morbidity and mortality from pemphigus vulgaris. In some patients, however, these agents are not able to control the disease or have severe adverse effects. Rituximab (MabThera; Roche, Basel, Switzerland), a chimeric monoclonal anti-CD20 antibody, induces depletion of B cells in vivo and has shown efficacy in patients with refractory antibody-mediated autoimmune disorders. We report 10 cases of pemphigus vulgaris and 2 cases of pemphigus foliaceous treated with rituximab—to our knowledge the largest series of patients so far—and review the existing literature on the topic.

Observation  The 12 patients were selected for treatment with the anti-CD20 antibody. Rituximab was administered intravenously at a dosage of 375 mg/m2 once weekly for 4 weeks. The treatment was well tolerated, and all 12 patients showed a good clinical response during an 18-month follow-up period, along with a consensual decline of the serum antidesmoglein titers. No infectious complications were observed.

Conclusions  Rituximab is able to induce a prolonged clinical remission in patients with both pemphigus vulgaris and pemphigus foliaceous after a single course of 4 treatments. The preliminary experiences worldwide make rituximab a promising therapeutic option for patients with autoimmune diseases. The high costs and the limited knowledge of long-term adverse effects, however, limit its use to selected patients with treatment-resistant or life-threatening disease.


Treatment of refractory Pemphigus vulgaris with rituximab (anti-CD20 monoclonal antibody).

Dupuy A, Viguier M, Bedane C, Cordoliani F, Blaise S, Aucouturier F, Bonnetblanc JM, Morel P, Dubertret L, Bachelez H.

Institut de Recherche sur la Peau, Institut National de la Sante et de la Recherche Medicale Unite 532, and Service de Dermatologie 2, Laboratoire d'Immunologie, Hopital Saint-Louis Assistance Publique-Hopitaux de Paris, France.
Arch Dermatol. 2004 Jan;140(1):91-6 Abstract quote.  


BACKGROUND: Pemphigus vulgaris (PV) is a severe antibody-mediated autoimmune blistering disease. Because some patients with PV do not enter into remission, despite the use of high-dose corticosteroid therapy and immunosuppressive adjuvant treatments, new effective and safer agents are warranted to treat refractory PV. Rituximab, a monoclonal anti-CD20 antibody, induces depletion of B cells in vivo and has shown efficacy in patients with refractory antibody-mediated autoimmune disorders. We describe herein 3 patients treated with rituximab for severe PV.

OBSERVATIONS: Three patients with refractory PV were treated with rituximab, resulting in a clinical response in all patients, which was complete in 2 patients. A decline in titers of circulating antiepidermis autoantibodies paralleled disease activity, while circulating B cells remained undetectable for 6 to 10 months. Two patients experienced bacterial infection in the weeks following the rituximab course. A clinical relapse occurred in 2 patients, at 6 and 10 months. A second course of rituximab controlled the disease in one of them.

CONCLUSION: These patients' response suggests that rituximab may be a valuable treatment for refractory PV and warrants further studies to evaluate the risk-benefit ratio in patients with PV showing resistance to classic therapy.

Anti-CD20 chimeric monoclonal antibody (rituximab) for the treatment of recalcitrant, life-threatening pemphigus vulgaris with implications in the pathogenesis of the disorder.

Salopek TG, Logsetty S, Tredget EE.

Division of Dermatology & Cutaneous Sciences, and the Firefighter's Burn Treatment Unit & Department of Surgery, University of Alberta.

J Am Acad Dermatol 2002 Nov;47(5):785-8 Abstract quote

Rituximab, a chimeric monoclonal antibody directed against CD20 of B cells, has been reported to be effective in the treatment of B-cell lymphomas and malignant and nonmalignant plasma cell-dependent diseases.

We describe a 30-year-old woman with refractory pemphigus vulgaris who experienced a partial remission after treatment with rituximab.

STEROIDS  

The steroid-sparing effect of long-term plasmapheresis in pemphigus: an update.

Sondergaard K, Carstens J, Zachariae H.

Department of Rheumatology, Aarhus University Hospital, Denmark.

Ther Apher 1997 May;1(2):155-8 Abstract quote

Glucocorticoids and immunosuppressive agents can induce remission in most pemphigus patients, but mortality remains at 5 to 15% as a result of side effects.

We reviewed the adjunctive effect of long-term plasmapheresis in 8 pemphigus patients. Four cases had been resistant to conventional therapy. One or 2 large-volume plasmapheresis treatments were given monthly over 5 to 141 months. All patients, were in clinical remission within 2 months. Relapses seldom occurred: the patients stayed in remission 90% (40-94) (median, ranges) of the period. In all cases the daily dose of glucocorticoid was reduced. The prednisone level could be decreased from 38 (15-80) mg/day to 7.5 (2.5-35) mg/day (p = 0.002). The overall level of other immunosuppressive agents remained unchanged, except in 1 patient for whom cyclosporine was introduced.

This indicates that long-term plasmapheresis could have a steroid-sparing effect and clinical efficacy in pemphigus.

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