Pemphigus vulgaris L10.0

Author: Prof. Dr. med. Peter Altmeyer

Co-Autors: Jeton Luzha, Hadrian Tran

All authors of this article

Last updated on: 22.02.2021

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History
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Wichmann, 1793; Hebra, 1860

Definition
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Chronic acantholytic autoimmune disease associated with blistering of the skin and/or mucous membranes, which can be fatal without therapy. Most frequent variant of the pemphigus group. Pemphigus vulgaris often has a two-stage course in an initially localized, later generalized form.

A distinction must be made:

  • the mucosally dominant pemphigus vulgaris
  • the mucocutaneous pemphigus vulgaris.

Occurrence/Epidemiology
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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

Etiopathogenesis
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According to the classification of Coombs and Gell, pemphigus vulgaris is a type II allergic reaction (cytotoxic reaction).

Formation of autoantibodies against desmoglein 3 (Dsg 3) or desmoglein 1 (Dsg 1). Desmogleins are adhesion molecules from the cadherin family and are expressed on the surface by 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, desmocollin as well as the cholinergic receptor of keratinocytes (see below cell contacts). Since the keratinizing epidermis expresses both Dsg 1 and Dsg 3, but the mucosa almost only Dsg 3, immunoreactivity against Dsg 3 causes predominantly mucosal changes. In contrast, the integument is involved in the formation of antibodies against Dsg 1 and 3.

The binding of the autoantibodies in the tissue is associated with an inflammatory reaction, which is linked by autoinflammatory mechanisms such as inflammasome activation and leukocyte recruitment as well as an adaptive immune response of antigen-specific T cells.

Medication triggering after taking certain drugs is described for:

Drug-induced pemphigus vulgaris can occur even after years of good tolerance of a drug.

External provocation: Triggering by burns, UV-radiation, X-ray radiation is possible.

Manifestation
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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.

Localization
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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 features
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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!

Special forms: Pemphigus herpetiformis, erythema-anulare-like pemphigus, intertrigo-like pemphigus, pemphigus vegetans.

Histology
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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 Immunofluorescence
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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 immunofluorescence
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Monkey esophagus is the most sensitive tissue for the detection of pemphigus antibody in serum. Sensitivities between 86% and 100% have been described.

Differential diagnosis
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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)
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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 therapy
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Exclusion of provoking factors, especially discontinuation of provoking drugs. Consistent textile light protection.

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 therapy
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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 therapy
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Remember! Pemphigus vulgaris often proves to be resistant to therapy!

The disease requires intensive immunosuppression with medication, which must be sustained over the long term (with a long breath)! High doses of systemically applied glucocorticoids in combination with immunosuppressive drugs ( azathioprine [e.g. Imurek]) or mycophenolate mofetil or cyclophosphamide (endoxane) or ciclosporin A (sandimmune) or, more rarely, methotrexate (MTX) (in order according to the results of a survey of clinical experts). Continuous steroidal therapy can be applied daily or alternately every 2nd day (level of evidence IIA). The duration of "steroid-sparing" therapy with immunosuppressive drugs (proven for azathioprine) is usually > 2 years, possibly for life. Close-meshed laboratory value controls are essential! Pay attention to opportunistic infections!

The following therapy recommendations are based on the level of evidence and the degree of recommendation, if available:

  • Glucocorticoids (A; II) in combination with azathioprine: Start 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 cushingdose should be aimed for (< 7-10 mg/day prednisone equivalent). Azathioprine dose should be left unchanged for the first months! In case of longer clinical freedom from symptoms (healing of old blisters, no further new blisters appearing) 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 resistance to therapy after several weeks of therapy (about 10% of cases), we recommend glucocorticoid pulse therapy: 1 g prednisone equivalent (e.g. Solu Decortin H) as a short infusion on 3 consecutive days, then decreasing dosage(750/500/250 mg/day). Leave azathioprine at the above dosage.
  • Cyclophosphamide (B; III): If resistance to therapy persists, replace azathioprine with cyclophosphamide (e.g. endoxane). Oral dose of cyclophosphamide: 1,0-2,0 mg/kg bw/day. Cyclophosphamide can also be applied as pulse therapy(500-1000 mg/ every 2-4 weeks).

    Remember!

    When using cyclophosphamide, bladder protection products 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 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 pattern permanently after 4 weeks.
  • Alternative: Ciclosporin A (C; I): The experience with systemically applied Ciclosporin A has been positive. In case of resistance to therapy, 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 alternative therapy (to AZ and cyclophosphamide) in combination with prednisolone. Dosage: 15 mg/week i.m. or i.v. The following day folic acid has to be applied (analogue dose to MTX).
  • Alternative: Mycophenolate mofetil (A; IB): So far, case reports and a positive, randomized, placebo-controlled study (n = 94 Pat.!) are available. The use is justified in case of contraindications or failure of other immunosuppressive drugs. 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 over 3 days, monthly therapy cycles. Cave! High therapy costs! Combinations with glucocorticoids are usually necessary.
  • Alternative: Plasmapheresis (C; I) (or immunoadsorption): In case of resistance to other procedures, initial as additional therapy with cycles in intervals of 14 days. The aim of the treatment is the prompt reduction of antibodies in serum. However, a study with 19 patients showed no benefit in treated patients compared to a control group. Indicated as a therapy modality only if any other immunosuppressive therapy appears contraindicated. Recent studies seem to show high efficacy in terms of rapid clinical remission, but without permanent cure. In small studies, success was achieved with the combination therapy immunoadsorption (3 times) and subsequent stabilizing therapy with rituximab (see below).

Recurrence and/or resistance to the previously mentioned therapy regimes: In case of a pronounced recurrence of the skin or mucous membrane changes, high immunosuppression is necessary initially (glucocorticoid pulse therapy)! In the case of fewer recurrences (few erosions), immunosuppressive therapy does not necessarily increase: Initially, try local glucocorticoid therapy, potent glucocorticoids such as 0.1% mometasone (e.g. Ecural ointment).

  • Alternative: Rituximab (MabThera): Casuistic contributions exist on the use of rituximab (anti-CD20 AK) for therapy resistance.

    Remember!

    Rituximab seems to be a serious "second line" therapy (therapeutic principle of B-cell depletion with a drop in antibody levels) for severe, therapy-resistant pemphigus vulgaris. Dosage: Rituximab: 375 mg/m2 KO on day 1 and 14 i.v. time to respond to therapy about 7 weeks). Possible repetition of the therapy regime after 1 year.
  • Alternative: A multicenter study showed after a single infusion of rituximab (dose: 375 mg/m2 KO i.v.) in 86% of patients a complete remission after 3 months.
  • Alternative: Rituximab as monotherapy can also be used as a low-dose regime (dose: 500mg on day 1 and 14 i.v.).
  • Alternative combination of rituximab and IVIG: In a study in 9/11 patients, the combination therapy showed good clinical effects after a total of 6 rituximab infusions.

Progression/forecast
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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.

Tables
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Stepwise therapy for severe pemphigus vulgaris

Level

Therapy regime

Stage I

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.

Step II

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).

Stage III

Cyclophosphamide (instead of azathioprine) 1.0-2.0 mg/kg bw/day (also as pulse therapy; 500-1000 mg/month).

Alternatively: Ciclosporin.

Stage IV

Ciclosporin in combination with glucocorticoids (5,0-7,5 mg/kg bw/day p.o.)

Experimental

Immunoglobulins in high doses i.v. in combination with immunosuppressive therapy (glucocorticoids or methotrexate)

Diet/life habits
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In case of mucous membrane changes in the oral area, ensure a balanced and sufficient diet (vitamins, minerals), if necessary a diet plan.

Note(s)
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Associations with myasthenia gravis, thymomas, lupus erythematosus, lymphomas and carcinomas are present in varying percentages.

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)

Literature
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