HistoryThis section has been translated automatically.
DefinitionThis section has been translated automatically.
Chronic autoimmune acantholytic disease associated with blistering of the skin and/or mucous membranes, which may be fatal without therapy. Most frequent variant of the pemphigus group. Pemphigus vulgaris often progresses in two stages, initially localized and later generalized.
A distinction is to be made between:
- the mucosal-dominant pemphigus vulgaris
- mucocutaneous pemphigus vulgaris.
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Occurrence/EpidemiologyThis section has been translated automatically.
Incidence: 0.1-0.5/100,000 population/year worldwide; clustered in Ashkenazi Jews.
Incidences in detail:
- Germany: 0.15/100,000
- Switzerland and Finland: 0.06-0.076/100,000
- 0.8-1.0: Greece, Romania, Iran
- Jewish population: 1,6-3,2/100.000
- Mortality: 5-10% global
EtiopathogenesisThis section has been translated automatically.
Pemphigus vulgaris is a type II allergic reaction (cytotoxic reaction) according to the classification of Coombs and Gell.
Formation of autoantibodies against desmoglein 3 (Dsg 3) or desmoglein 1 (Dsg 1). Desmogleins are adhesion molecules of the cadherin family and are expressed on the surface of keratinocytes, among others. Further autoantibodies (about 50 target antigens have been described so far), which are formed in pemphigus vulgaris, are directed against desmocollin, plakoglobin, pemphaxin (annexin 9),E-cadherin, desmocollins as well as the cholinergic receptor v. keratinocytes (see cell contacts below). Since the cornifying epidermis expresses both Dsg 1 and Dsg 3, but the mucosa expresses almost only Dsg 3, immunoreactivity against Dsg 3 causes predominantly mucosal changes. In contrast, the formation of antibodies against Dsg 1 and 3 involves the integument.
Thebinding of the autoantibodies in the tissue is associated with an inflammatory reaction, which is linked to autoinflammatory mechanisms such as inflammasome activation and leukocyte recruitment as well as an adaptive immune response of antigen-specific T cells.
Drug induction following ingestion of certain drugs has been described for, among others:
- captopril(ACE inhibitor)
- enalapril(ACE inhibitor)
- PUVA therapy
Drug-induced pemphigus vulgaris may occur even after years of good tolerance to a drug.
External provocation: triggering by burns, UV irradiation, X-ray irradiation is possible.
ManifestationThis section has been translated automatically.
Here, different initial manifestations occur depending on the population.
- In European countries the age of first manifestation is 50-60 years.
- In non-European countries it was lower (30-50 years, average 43.4 years Daneeshpazhoo et al. 2012)
- More rarely, the disease is found in childhood and old age.
LocalizationThis section has been translated automatically.
At the localized stage: oral cavity (cheeks, palate, gingiva), nasal cavity (bloody cold), pharynx, genital mucous membranes, urethra, conjunctiva. Navel region, especially intertriginous areas (genital and perianal area) and the periungual area can be affected.
In the generalised stage, a disseminated clinical picture with symmetrical infestation of the trunk, capillitium, axillae, groin region, extremities
Clinical featuresThis section has been translated automatically.
Pemphigus vulgaris usually manifests itself in two stages:
1. localized chronic erosive dermatitis and mucositis:
Typical is a chronic insidious onset, fluctuating between improvement and recurrence. Note: Bubbles are often not seen in this localized stage; therefore the disease is not clinically assessed as a blistering disease.
Often (> 50%!) first clinical manifestations in the oral cavity (erosive, painful stomatitis, foetus ex ore).
Skin infestation (>80%): the localized pemphigus vulgaris is usually not clinically recognized as a blistering disease. It is diagnosed as pyodermic, weeping pyoderma, which is usually resistant to therapy. Clinically impressive on the trunk, cheeks, umbilical region, capillitium, mostly extensive, encrusted erosions. Further manifestations are: red lips (clinical: erosive, crusty cheilitis), eyelids (clinical: weeping eczema), fingers (clinical: chronic, painful and therapy-resistant paronychia).
Furthermore in decreasing frequency:
- Nasal mucosa: therapy-resistant, blood-secreting rhinitis
- Pharynx: painful difficulty swallowing (possibly combined with laryngitis: difficulty swallowing, hoarseness)
- Conjunctives: erosive and refractory conjunctivitis (cave: corneal ulcer)
- genital and anal mucosa: erosive vulvitis/balanitis and proctitis
Weight loss is often an accompanying sign in the case of relevant oral mucosa infections!
2. generalized, chronic, erosive dermatitis and mucositis
The generalized stage can occur suddenly. In this phase, without an inflammatory (local) preliminary stage, rapidly expanding clear, first tense, then flaccid, extremely fragile, rapidly bursting (the rupture of the bladder roof is the characteristic feature of the intraepidermal pemphigus bladder) large blisters occur, the bursting of which leaves large weeping erosion areas. These quickly become encrusted.
Remark: In pemphigus vulgaris, you have to look for bubbles to find them!
Furthermore: activity boosts lead to new erosion areas, while the old ones, already encrusted, still persist. This results in a changeable clinical picture with large, weeping or encrusted erosions whose crumpy bubble edges lie on the erosion surfaces like wet paper. They can be pushed off tangentially by light finger pressure (the diagnostically important Nikolski phenomenon is positive).
This resulted in the clinical leading symptoms of PV. These are not large-area blisters, but large-area, encrusted erosions with lobed blister edges. Sometimes only weeping, hard-to-remove crusts are impressive.
In the phase of generalisation, skin and mucous membrane changes (see above) occur together. The development of painful erosions is possible on all mucous membranes close to the skin. The rare manifestation in the area of the esophagus can become an emergency situation!
HistologyThis section has been translated automatically.
It is recommended to carefully remove a small intact bladder using a biopsy so that the bladder remains intact. If the removal of a complete bladder is not successful, a marginal biopsy is performed to detect the perilesional area of erosion (note: epidermis cannot float during preparation).
Tip: If the tissue appears very fragile, it is advisable to spread the biopsy on a small piece of firm, dry, absorbent paper and to place the paper with the specimen adhering to it in the 10% formalin solution. This fixes the material in its anatomically correct manner and is easier to prepare.
Further recommendation: It is not recommended to cut a bubble (histology and immunofluorescence), because the artifact when cutting often makes a histological evaluation significantly more difficult or impossible.
There are no preferences regarding the location of the tissue samples!
The histologist is asked to assess the bioptate by means of serial processing. HE diagnostics is sufficient.
In terms of results a superficial dermatitis with suprabasal, acantholytic continuity separation and blistering is found. In older blisters: neutrophil and eosinophil leucocytes. Electron microscopy: Desmolysis.
Direct ImmunofluorescenceThis section has been translated automatically.
The diagnosis of pemphigus vulgaris can be confirmed immunohistologically (this diagnosis is highly relevant!). A perilesional biopsy is important! The biopsy of a bladder can lead to a false positive (Ig and C3 are deposited non-specifically) or to a false negative result (Ig/C3 is degraded proteolytically, or the bladder roof does not appear at all for technical reasons). A preference for a certain body region is diagnostically not recommended.
The detection of IgG and mostly complement components (C3,C4,C1) in the intercellular space of the epidermis is diagnostic evidence.
Indirect immunofluorescenceThis section has been translated automatically.
Monkey esophagus is the most sensitive tissue for the detection of pemphigus antibody in serum. Sensitivities between 86% and 100% have been described.
Differential diagnosisThis section has been translated automatically.
Depending on the pattern of infestation, different clinical constellations and thus different DD.
In case of initial and initially exclusive infestation of the oral mucosa:
- Erosive Lichen planus: lack of serological evidence! Indirect: IF: Fibrinogen deposits and cytoid corpuscles. No IC-fluorescence
- Erythema exsudativum multiforme: Lack of serological evidence! Indirect: IF: negative in most cases. No IC fluorescence; in most cases the typical skin lesions of EEM are present.
- Stomatitis aphthosa: Adolescent age group or infants. Acute onset with severe general symptoms. IF: negative. DIF: no IC-fluorescence
In case of localized skin infestation:
- Chronic pyoderma
- Microbial eczema
- M. Hailey-Hailey
At the stage of generalisation:
- Microbial eczema
- Extended pyoderma
- Other blistering diseases
- M. Darier
- M. Grover
Complication(s)This section has been translated automatically.
The extensive erosions are an entry point for pathogens, which lead to secondary infections up to sepsis. Further danger of bronchopneumonia, cachexia.
During pregnancy: diaplacental transfer of IgG autoantibodies to the unborn → Occurrence of pemphigus in the newborn (Pemphigus neonatorum) → Healing of pemphigus in the newborn usually within weeks
General therapyThis section has been translated automatically.
Notice!Check intravenous accesses regularly (high risk of contamination), change daily if necessary! General guidelines for severe, large-area pemphigus vulgaris:
- Intensive care in appropriately equipped therapy units.
- Isolation of the patient.
- Aseptic protective clothing, mouth protection for medical and nursing staff.
- Wearing of gloves.
- Sufficient heat supply (exact temperature control).
- Sufficient moisture content of the room air.
- Use special bed for decubitus prophylaxis.
- Fluid balancing, if necessary bladder catheter.
- Documentation of the findings (expansion, severity on intensive care treatment sheets).
- Swabs of the wound surfaces every day (culture with resistance behaviour), danger of Pseudomonas colonisation.
- Storage on metal foil.
- Open blisters and remove the blister cover.
- In open and superinfected areas 1% sulfadiazine-silver cream (e.g. flammazine).
- Eye hygiene with disinfecting and astringent eye drops (e.g. Solan eye drops).
- Scheme with daily dosage: colloidal solution (1 ml/kg x affected KO), electrolyte solution (physiological saline solution 1 ml/kg x affected KO).
- When stabilized, transition to high-calorie liquid food (meritene), later diet with passed food; no spices, no fruit acids.
External therapyThis section has been translated automatically.
Symptomatic (non-steroidal) therapy, e.g. with mild antiseptics such as 0.5% clioquinol cream(e.g. R049, Linola-Sept). Alternatively 2% Clioquinol ointment. The blisters must be opened sterilely. Avoid secondary infections. In case of suspicion, immediately take a smear and antibiogram.
Eyes: Regular controls. Antiseptic eye drops like zinc sulphate eye drops R297.
Mucous membrane changes (mouth or genital mucous membrane):
- As "first step therapy" a local therapy with topical glucocorticoids, e.g. with 0.1% betamethasone mouth gel 031, is useful.
- Alternative: Good experience has also been made with clobetasol cream (e.g. Dermoxin cream on a gauze-wrapped mouth spatula and applied locally).
- Alternative: Aqueous prednisolone solution (Rp. Nystatin 100KUI/Lidocaine 0.1/ Prednisolone 0.1/ aqua purificata ad 100.0/ S: Mild, well-tolerated solution containing cortisone should be applied 1-2 times daily).
- Alternatively: Ciclosporin A-containing paste 046 or a 0,03% tacrolimus suspension.
- Alternative: 1% Pimecrolimus cream, which is better tolerated in the mucosal area than Ciclosporin and Tacrolimus (apply these externa with a soft toothbrush or on a spatula wrapped with gauze on the lesion and let it act as long as possible). Perform treatment 2-3 times a day.
- If the pain is severe, treatment with a gel containing lidocaine (e.g. Dynexan-Mundgel®) is recommended. The Krister solution according to NRF 7.14 (combination preparation with lidocaine, prednisolone and camomile extracts) is also suitable.
- Accompanying mouthwashes with dexpanthenol solution or Tormentillae astringents are recommended(R066 R255).
Internal therapyThis section has been translated automatically.
Notice. Pemphigus vulgaris often proves to be resistant to therapy!
The disease requires intensive immunosuppression with medication, which must be maintained over the long term (with staying power)! High-dose systemically applied glucocorticoids in combination with immunosuppressants ( azathioprine [e.g. Imurek]) or mycophenolate mofetil or cyclophosphamide (Endoxan) or ciclosporin A (Sandimmun) or more rarely methotrexate (MTX) (order according to survey results among clinical experts). Steroidal continuous therapy can be applied daily or alternately every 2nd day (evidence level IIA). The duration of "steroid-sparing" therapy with immunosuppressants (proven for azathioprine) is usually > 2 years, possibly lifelong. Close monitoring of laboratory values is essential! Watch out for opportunistic infections!
The following therapy recommendations include the level of evidence and the degree of recommendation, if available:
- For moderate to severe forms of pemphigus vulgaris and pemphigus folicacea, rituximab in combination with systemic glucocorticoids is recommended according to guidelines. Rituximab (MabThera, anti-CD20 AK. Therapy principle of B-cell depletion with drop in antibody level) Dosage: Rituximab: 375 mg/m2 KO on day 1 and 14(-21) i.v. Time to response of therapy about 7 weeks). Possibly repeat therapy regimen after 1 year.
A multicenter study showed complete remission in 86% of patients after a single infusion of rituximab (dose: 375 mg/m2 KO i.v.) after 3 months. Alternatively, rituximab as monotherapy can be used as a "low-dose" regimen (dose: 500mg each on day 1 and 14 i.v.).
- Glucocorticoids (A; II) in combination with immunosuppressants such as rituximab or azathioprine: starting with 2.0-4.0 mg/kg bw/day prednisone equivalent (e.g. Decortin H) and 1.5-2.5 mg/kg bw/day azathioprine (e.g. Imurek). As long-term therapy, treatment with glucocorticoid doses below the Cushing dose should be aimed for (< 7-10 mg/day prednisone equivalent). Leave the azathioprine dose unchanged for the first few months! With prolonged clinical freedom from symptoms (healing of old blisters, no further recurrence of blisters) reduction of azathioprine. Complete remissions under glucocorticoid/azathioprine combination in 28-53% of patients (mortality rate: 4-7%).
- It is recommended to adjust the dose of azathioprine to the individual activity of thiopurine methyltransferase (TPMT)! Patients with TPMT activity < 5U/ml should not receive azathioprine.
- Glucocorticoid pulse therapy (C; IV): In case of therapy resistance after several weeks of therapy (about 10% of cases), we recommend glucocorticoid pulse therapy while leaving the azathioprine dose unchanged: 1 g prednisone equivalent (e.g. Solu Decortin H) as a short infusion on each of 3 consecutive days, then descending dosage(750/500/250 mg/day ). Leave azathioprine at above dosage.
Cyclophosphamide (B; III): In case of further therapy resistance, azathioprine can be exchanged for cyclophosphamide (e.g. Endoxan). Oral cyclophosphamide dose: 1.0-2.0 mg/kg bw/day. Cyclophosphamide can also be administered as pulse therapy(500-1000 mg/every 2-4 weeks).
Reminder. When cyclophosphamide is used, bladder protection agents such as Mesna(e.g. Uromitexan) are essential!
- Alternative: As an alternative to the prednisolone/cyclophosphamide pulse therapy, dexamethasone can also be combined with cyclophosphamide (day 1: Fortecortin® mono 100 mg as a short infusion/cyclophosphamide 500 mg via perfusor over 2 hours, day 2: dexamethasone 100 mg i.v.; day 3: dexamethasone 100 mg i.v.). Repeat pulse regimen permanently after 4 weeks.
- Alternative: Ciclosporin A (C; I): Experience with systemically applied ciclosporin A has been positive. In case of therapy resistance, the immunosuppressive agent can be used in combination with a glucocorticoid, dosage: 5.0-7.5 mg/kg bw/day p.o..
- Alternative: Methotrexate (C; III): To be used as an alternative therapy (to AZ and cyclophosphamide) in combination with prednisolone. Dosage: 15 mg/week i.m. or i.v. Folic acid should be applied the following day (analogous dose to MTX).
- Alternative: Mycophenolate mofetil (A; IB): So far, case reports and a positive, randomized, placebo-controlled study (n = 94 patients!) are available. Use in contraindications or failure of other immunosuppressants justified. The combination of mycophenolate mofetil (2 g/day) and methylprednisolone (2 mg/kg bw) seems to achieve good clinical results according to a multicenter study.
- Alternative: IVIG (B; III): Good experience with high-dose i.v. immunoglobulin therapy (e.g. Intratect®). In studies mostly performed as monotherapy. Dosage: 2.0 g/kg bw distributed over 3 days, monthly therapy cycles. Caution! High therapy costs! Combinations with glucocorticoids are usually necessary. Alternative combination of Rituximab and IVIG: The combination therapy showed good clinical effects in a study in 9/11 patients after a total of 6 Rituximab infusions.
- Alternative: Plasmapheresis (C; I) (or immunadsorption): In case of therapy resistance to other methods, initially as an add-on therapy with cycles every 14 days. The aim of treatment is prompt antibody reduction in serum. However, a study with 19 patients showed no benefit in treated patients compared to a control group. Indicated as a therapeutic modality only when any other immunosuppressive therapy appears contraindicated. Recent studies seem to show a high efficacy with regard to a rapid clinical remission, but without a permanent cure. In small studies, success has been achieved with the combination therapy of immunoadsorption (3 times) followed by stabilizing therapy with rituximab (see below).
Recurrence and/or resistance to the previously listed therapy regimes: In case of pronounced recurrence of skin or mucosal changes, high immunosuppression is again necessary initially (glucocorticoid pulse therapy)! In case of minor recurrences (few erosions), do not necessarily increase immunosuppressive therapy: First try local glucocorticoid therapy, potent glucocorticoids such as 0.1% mometasone (e.g. Ecural® ointment).
Progression/forecastThis section has been translated automatically.
Different course. Without therapy death mostly in 1 to 3 years. Physical decay due to aggravation of food intake.
Persistent high levels of desmoglein1 have (in contrast to desmoglein3 levels) a positive predictive value for skin recurrence.
TablesThis section has been translated automatically.
Stepwise therapy for severe pemphigus vulgaris
Glucocorticoids in combination with azathioprine: Entry with prednisone equivalent 2.0-4.0 mg/kg bw/day and azathioprine 1.5-2.0 mg/kg bw/day.
Glucocorticoid pulse therapy: Prednisone equivalent 1 g as a short infusion on 3 consecutive days. Leave azathioprine dose. If necessary, simultaneous plasmapheresis (cycles at 14-day intervals).
Cyclophosphamide (instead of azathioprine) 1.0-2.0 mg/kg bw/day (also as pulse therapy; 500-1000 mg/month).
Ciclosporin in combination with glucocorticoids (5,0-7,5 mg/kg bw/day p.o.)
Immunoglobulins in high doses i.v. in combination with immunosuppressive therapy (glucocorticoids or methotrexate)
Diet/life habitsThis section has been translated automatically.
Note(s)This section has been translated automatically.
Patients with thymoma are associated with pemphigus vulgaris in 30% (!).
Documentation of the spread of the disease can be done by clinical records using the Autoimmune Skin Disorder Intensity Score (ABSIS) and the Pemphigus Disease Area Index (PDAI) (Boulard 2016)
LiteratureThis section has been translated automatically.
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- Altmeyer P et al (1999) High-dose intravenous immunoglobulin (IVIG) therapy for refractory ANCA-negative necrotizing vasculitis. Dermatologist 50: 853-858
- Anhalt GJ et al (1990) Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. New Eng J Med 323: 1729-1735
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- Boulard C et al.(2016) Calculation of cut-off values based on the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and Pemphigus Disease Area Index (PDAI) pemphigus scoring systems for defining moderate, significant and extensive types of pemphigus. Br J Dermatol 175:142-149.
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- Schmidt E et al (2015) S2k guideline on the diagnosis of pemphigus vulgaris/foliaceus and bullous pemphigoid. JDDG 13: 713-726
- Turner MS et al (2000) The use of plasmapheresis and immunosuppression in the treatment of pemphigus vulgaris. J Am Acad Dermatol 43: 1058-1064
- Vecchietti G (2003) Topical tacrolimus for relapsing erosive stomatitis in paraneoplastic pemphigus. Br J Dermatol 148: 833-834
- Wichmann JE (1793) Pemphigus. In: Wichmann JE (ed) Ideen zur Diagnostik, vol 1, Verlag der Helwing'schen Hof-Buchhandlung, Hannover, pp 103-230.
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- vulgaris. Immunol Allergy Clin North Am 32:233-243
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Incoming links (46)Acantholysis; Autoimmune dermatoses, bullous; Balanitis symptomatica; Cadherine; Cd classification; Ciclosporin a; Clioquinol cream 0.5-2% (o/w); Conjunctivitis; Conjunctivitis in pemphigus; Daclizumab; ... Show all
Outgoing links (55)Ace inhibitors; Adhesion molecules; Antiseptic; Autoantibodies; Azathioprine; Cadherine; Carcinoma of the skin (overview); Cell contacts; Cephalosporins; Chamomile; ... Show all
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