Pemphigus vulgaris L10.0

Author: Prof. Dr. med. Peter Altmeyer

Co-Autors: Dr. med. Jeton Luzha, Hadrian Tran

All authors of this article

Last updated on: 13.03.2024

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History
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Wichmann, 1793; Hebra, 1860

Definition
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Chronic autoimmune disease associated with acantholytic blistering of the skin and/or mucous membranes, which may be severe and fatal without therapy. Pemphigus vulgaris is the most common variant of the pemphigus group.

Pemphigus vulgaris often progresses in two stages in an initially localized, later generalized form.

To be distinguished is:

  • the mucosal 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-s.u. DSG1 gene). Desmogleins are adhesion molecules from the cadherin family and are expressed on the surface of keratinocytes, among others. Other autoantibodies (around 50 target antigens have been described to date), which are formed in pemphigus vulgaris, are directed against desmocollin, plakoglobin, pemphaxin (annexin 9),E-cadherin, desmocollins and the cholinergic receptor of keratinocytes (see cell contacts below). Since the keratinizing epidermis expresses both Dsg 1 and Dsg 3, but the mucous membrane expresses almost only Dsg 3, immunoreactivity against Dsg 3 predominantly causes mucosal changes. In contrast, the integument is involved in the formation of antibodies against Dsg 1 and 3.

The binding of 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 after taking certain medications has been described for:

Drug-induced pemphigus vulgaris can also be induced after years of good tolerance to a drug.

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

Manifestation
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Depending on the population, there are different initial manifestations:

  • In European countries, the age of first manifestation is 50-60 years.
  • In non-European countries it is lower (30-50 years, average 43.4 years Daneeshpazhoo et al. 2012)
  • The disease is less common in childhood and late adulthood.

Localization
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In the localized stage: oral cavity (cheeks, palate, gingiva), nasal cavity (bloody cold), pharynx, genital mucosa, urethra, conjunctiva. Umbilical region, especially intertriginous areas (genital and perianal area) and periungual area may be affected.

In the generalized stage, disseminated clinical picture with symmetrical infestation of the trunk, capillitium, axillae, groin region, extremities.

Clinical features
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Pemphigus vulgaris usually manifests in two stages:

1. localized chronic erosive dermatitis and mucositis:

A chronic insidious onset, fluctuating between improvement and recurrence, is typical. Note: Blisters are often not seen at this localized stage; thus, the disease is usually not clinically evaluated as blistering.

Frequently (>50%!) first clinical manifestations in the oral cavity (erosive, painful stomatitis, fetor ex ore).

Skin involvement (>80%): localized pemphigus vulgaris is usually not clinically recognized as a blistering disease. It is diagnosed as pyoderma, weeping, and usually also as therapy-resistant pyoderma. Clinically, there are mostly large, crusted erosions on the trunk, cheeks, umbilical region, capillitium. Further manifestations are: red lips (clinically: erosive, crusty cheilitis), eyelids (clinically: weeping eczema), fingers (clinically: chronic, painful and therapy-resistant paronychia).

Further in decreasing frequency:

  • Nasal mucosa: refractory, bloody secreting rhinitis.
  • Pharynx: painful dysphagia (possibly combined with laryngitis: dysphagia, hoarseness).
  • Conjunctiva: erosive and therapy-resistant conjunctivitis (cave: corneal ulcer)
  • genital and anal mucosa: erosive vulvitis/balanitis and proctitis

In relevant oral mucosal infestation, weight loss is often an accompanying sign!.

2. generalized, chronic, erosive dermatitis and mucositis.

The generalized stage may occur suddenly. In this stage, in the absence of an inflammatory (local) preliminary stage, rapidly bursting clear, first tense, then flaccid, extremely fragile, rapidly bursting (the rupturability of the blister roof is the hallmark of intraepidermal pemphigus) large blisters occur, the bursting of which leave large areas of weeping erosion. These rapidly crust over.

Note: In pemphigus vulgaris, you have to look for blisters to find them!

Furthermore: Activity spurts lead to new erosion areas, while the old ones, already crusted, still persist. This results in a changeable clinical picture with large, weeping or encrusted erosions whose crumpled blister 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 extensive blisters, but extensive, crusted erosions with lobular blister margins. Sometimes, weeping crusts that are difficult to detach impose exclusively.

In the phase of generalization, skin and mucous membrane changes (see above) occur together. The formation of painful erosions is possible on all mucous membranes close to the skin. The rare manifestation in the esophageal region 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 result.

With initial and initially exclusive infestation of the oral mucosa:

  • Erosive lichen planus: Lack of serologic evidence! Indirect: IF: Fibrinogen deposits and cytoid corpuscles. No IC fluorescence
  • Erythema exsudativum multiforme: Lack of serologic evidence! Indirect: IF: negative in most cases. No IC fluorescence; the typical skin changes of EEM are usually present.
  • Stomatitis aphthosa: Young age group or infants. Acute onset with severe general symptoms. IF: negative. DIF: no IC fluorescence

With localized skin infestation:

  • Chronic pyoderma
  • Microbial eczema
  • M. Hailey-Hailey

In the stage of generalization:

  • Microbial eczema
  • Extensive pyoderma
  • Subcorneal pustulosis (Sneddon-Wilkinson)
  • 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. Open the blisters sterilely. Avoid secondary infections. If secondary infection is suspected, swab and antibiogram immediately.

Eyes: Regular checks. Antiseptic eye drops such as zinc sulfate eye drops R297.

Mucosal lesions (oral or genital mucosa):

  • Local therapy with topical glucocorticoids, e.g. with 0.1% betamethasone mouth gel 031, is useful as a "first step" therapy.
  • Alternative: Good experience also exists with clobetasol cream (e.g. Dermoxin cream applied to a gauze-wrapped mouth spatula and applied locally).
  • Alternatively: Aqueous prednisolone solution (Rp.: Nystatin 100KUI/Lidocaine 0.1/Prednisolone 0.1/ aqua purificata ad 100.0/ S: Apply mild well tolerated cortisone containing solution 1-2x daily).
  • Alternative: 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 externals to the lesion with a soft toothbrush or on a gauze-wrapped spatula and leave on 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®) or a spray containing lidocaine (e.g. Sulagil Spray®) is recommended. The Krister solution according to NRF 7.14 (combination preparation with lidocaine, prednisolone and chamomile extracts) is also suitable.
  • After the meal, accompanying antiseptic mouth rinse with e.g. Octenisept mouth rinse solution or Betaisodona mouth rinse and subsequently caring Dexpanthenol solution or Tormentillae astringent(R066 R255).

Internal therapy
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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 mostly > 2 years, possibly lifelong. Close monitoring of laboratory values is essential! Pay attention to opportunistic infections!

The following therapy recommendations include the level of evidence and the degree of recommendation, if available:

  • For moderate to severe fromen of pemphigus vulgaris as well as pemphigus folicacea, rituximab in combination with systemic glucocorticoids is recommended according to guidelines. Rituximab (MabThera, anti-CD20 AK. Therapeutic 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 after a single infusion of rituximab (dose: 375 mg/m2 KO i.v.) in 86% of pat. after 3 months. Alternatively, rituximab can be used as monotherapy 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 azathioprine dose unchanged in the first 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): If therapy resistance continues, azathioprine may be substituted for cyclophosphamide (e.g., Endoxan). Oral cyclophosphamide dose: 1.0-2.0 mg/kg bw/day. Cyclophosphamide can also be applied as pulse therapy(500-1000 mg/every 2-4 weeks)

    .Note! When cyclophosphamide is used, bladder protection agents such as Mesna (e.g. Uromitexan) are essential!

  • Alternative: As an alternative to 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 hrs, 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): To date, case reports and a positive, randomized, placebo-controlled study (n = 94 pat.!) are available. Use warranted in contraindications or failure of other immunosuppressants. 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.
  • Alternatively and steroid sparingly, rituximab can be used . Opportunistic side effects (HSV, COVID, cytomegalovirus infections) of ahcluding a higher risk for pneumococcal infections (penumococcal vaccination is recommended) should be considered (Chen DM et al 2020; Frampton JE 2020).
  • 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: 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 immunoadsorption): Initially as adjunctive therapy with cycles 14 days apart in cases of therapy resistance to other procedures. The goal 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 treatment modality only when any other immunosuppressive therapy appears contraindicated. Recent studies seem to show high efficacy in terms of rapid clinical remission, but without permanent cure. Small studies have shown success with combination therapy immunoadsorption (3 times) followed by stabilizing therapy with rituximab (see below).

Recurrence and/or resistance to the previously listed therapy regimens: 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/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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Step therapy for severe pemphigus vulgaris

Stage

Therapy regime

Stage I

Glucocorticoids in combination with azathioprine: start with prednisone equivalent 2.0-4.0 mg/kg bw/day and azathioprine 1.5-2.0 mg/kg bw/day.

Stage II

Glucocorticoid pulse therapy: prednisone equivalent 1 g as a short infusion on 3 consecutive days. Leave azathioprine dose unchanged. 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).

Why is rituximab not listed here?

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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