Levels of evidence (I-IV) and grading of recommendations (A-E) are defined at the end of the "Major Recommendations" field.
Laboratory Diagnosis
A skin or mucosal biopsy should be taken for histology and direct immunofluorescence (DIF), the latter requiring perilesional, intact skin or clinically uninvolved skin. Suprabasal acantholysis and blister formation is highly suggestive of pemphigus vulgaris (PV) but the diagnosis should be confirmed by the characteristic deposition of immunoglobulin G (IgG) in the intercellular spaces of the epidermis. Indirect immunofluorescence (IIF) is less sensitive than DIF but may be helpful if a biopsy is difficult (e.g., children and uncooperative adults). Enzyme-linked immunosorbent assays (ELISA) are now available for direct measurement of desmoglein (Dsg)1 and Dsg 3 antibodies in serum. They offer advantages over IIF and may supersede this technique. Five millilitres of blood is sufficient for IIF and ELISA.
In patients with oral pemphigus, an intraoral biopsy is the optimum but IIF or DIF on a skin biopsy may suffice. One study showed that the sensitivity of DIF was 71% in oral biopsies compared with 61% in normal skin taken from 28 patients with oral PV. Another study reported that the sensitivity of DIF was 89% in oral biopsies compared with 85% for IIF.
Baseline Investigations
The following investigations are suggested prior to commencing treatment: biopsy (or IIF) as above, full blood count and differential, urea and electrolytes, liver function tests, glucose, antinuclear antibody (differential of pemphigus erythematosus), thiopurine methyltransferase (TPMT) levels (if azathioprine is to be used), chest x-ray, urinalysis, and blood pressure. Current guidelines on osteoporosis should be followed, so a bone density scan early in the course of treatment may be recommended.
General Principles of Management
The initial aim of treatment is to induce disease remission. This should be followed by a period of maintenance treatment using the minimum drug doses required for disease control in order to minimize their side-effects. Occasional blisters are acceptable and indicate that the patient is not being overtreated. The ultimate aim of management should be treatment withdrawal and a recent study reported complete remission rates of 38%, 50%, and 75% achieved 3, 5, and 10 years from diagnosis.
Most patients are treated with systemic corticosteroids (CS), which are effective. Adjuvant drugs are commonly used in combination with the aims of increasing efficacy and of having a steroid-sparing action, thereby allowing reduced maintenance CS doses and reduced CS side effects. Although mortality and complete remission rates have improved since the introduction of adjuvant drugs, this is in comparison with historical controls; a more recent study of PV patients treated with CS alone demonstrated outcomes comparable with studies using adjuvants. There are no prospective, controlled studies that conclusively demonstrate the benefits of adjuvant drugs in PV. Therefore, some respected authorities do not use adjuvant drugs unless there are contraindications or side-effects of CS, or if tapering the CS dose is associated with repeated relapses. However, most centres do use adjuvant drugs as standard practice. In general, adjuvant drugs are slower in onset than CS and are therefore rarely used alone to induce remission in PV.
Oral Corticosteroids (CS)
Systemic CS are the best established therapy for the management of PV (Strength of recommendation A, Quality of evidence II-iii).
Pulsed Intravenous Corticosteroids
Pulsed CS could be considered in severe or recalcitrant PV to induce remission, particularly if there has been no response to high oral doses (C, IV).
Adjuvant Drugs
Azathioprine
Azathioprine is a well-established choice as an adjuvant drug for the management of pemphigus (B, II-iii).
Oral Cyclophosphamide
Oral cyclophosphamide could be considered as an alternative to azathioprine (B, III).
Pulsed Intravenous Cyclophosphamide with Dexamethasone or Methylprednisolone
Pulsed CS cyclophosphamide therapy could be considered in severe or recalcitrant cases of PV. However, it may not be practical to administer repeated courses (B, II-iii).
Mycophenolate Mofetil
On the basis of current evidence, MMF could be considered in recalcitrant cases or when azathioprine and cyclophosphamide cannot be used (B, III).
Gold
Gold could be considered as an alternative to more established adjuvant drugs if they cannot be used (B/C, III).
Methotrexate
Methotrexate could be considered as an adjuvant drug if more established drugs cannot be used (C, III).
Ciclosporin
On the basis of current evidence, ciclosporin cannot be recommended as an adjuvant drug in PV (C, I).
Tetracyclines/Nicotinamide
Tetracyclines with or without nicotinamide could be considered as adjuvant treatment, perhaps in milder cases of PV (C, IV).
Dapsone/Sulphonamides
Dapsone was reported to be beneficial as an adjuvant drug in four cases of PV. However, in two of these cases, it was started either with or shortly after prednisolone, and in two cases it was started after the long-standing prednisolone was increased to high doses. Therefore, it is difficult to be certain if dapsone had a significant role and there is little evidence to recommend the use of dapsone in PV (C, IV).
Chlorambucil
Chlorambucil could be considered as an adjuvant drug if more established options cannot be used but there are limited data to support its use (C, IV).
Intravenous Immunoglobulin (IVIG)
Repeated courses of intravenous immunoglobulin could be considered as an adjuvant, maintenance agent in patients with recalcitrant disease who have failed more conventional therapies. In view of reports of a rapid action in some cases, it could be used to help induce remission in patients with severe PV while slower-acting drugs take effect (B, III).
Plasma Exchange (PE)
Plasma exchange cannot be recommended as a routine treatment option in newly presenting patients with PV. However, it could be considered in difficult cases if combined with CS and immunosuppressant drugs (C, I).
Extracorporeal Photopheresis (ECP)
ECP could be considered in recalcitrant cases of PV where there has been failure to improve with more conventional therapy (B, III).
Topical Therapy
PV is largely managed with systemic therapy but adjuvant topical therapy may be of additional benefit, although there are no controlled studies to confirm this. Rarely, patients with mild disease, particularly if confined to the mucosal surfaces, can be managed on topical therapy alone.
For oral pemphigus, measures such as soft diets and soft toothbrushes help minimize local trauma. Topical analgesics or anaesthetics, for example benzydamine hydrochloride 0.15% (Difflam Oral Rinse®), are useful in alleviating oral pain, particularly prior to eating or tooth brushing. Oral hygiene is crucial. Otherwise PV may be complicated by dental decay; tooth brushing should be encouraged and antiseptic mouthwashes may be used, such as chlorhexidine gluconate 0.2% Corsodyl®), hexetidine 0.1% (Oraldene®), or 1:4 hydrogen peroxide solutions. Patients are susceptible to oral candidiasis, which should be treated. Topical CS therapy may help reduce the requirement for systemic agents. For multiple oral erosions, mouthwashes are most practical, for example, soluble betamethasone sodium phosphate 0.5 mg tablet dissolved in 10 mL water may be used up to four times daily, holding the solution in the mouth for about 5 minutes. Isolated oral erosions could be treated with application of triamcinolone acetonide 0.1% in adhesive paste (Adcortyl in Orabase®), 2.5 mg hydrocortisone lozenges or sprayed directly with an asthma aerosol inhaler, for example beclomethasone dipropionate 50-200 micrograms or budesonide 50-200 micrograms. Topical ciclosporin (100 mg/mL) in oral pemphigus has been described and may be of some benefit but is expensive.
Follow-up
Once remission is induced, there should follow a period of maintenance treatment using the minimum drug doses required for disease control and during which occasional blisters are acceptable. Drug doses should be slowly reduced and patients should remain under follow-up while they remain on therapy. Ultimately, treatment may be withdrawn if there has been prolonged clinical remission. This decision should largely be clinical but the chances of relapse are reduced if immunofluorescence studies are negative (e.g., the risk of relapse is 13-27% if DIF is negative, 44-100% if DIF is positive, 24% if IIF is negative, and 57% if IIF is positive). However, DIF can occasionally remain positive in patients who are in remission and off treatment.
Definitions:
Levels of Evidence
I: Evidence obtained from at least one properly designed, randomized controlled trial
II-I: Evidence obtained from well designed controlled trials without randomization
II-ii: Evidence obtained from well designed cohort or case-control analytic studies, preferably from more than one centre or research group
II-iii: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.
III: Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees
IV: Evidence inadequate owing to problems of methodology (e.g. sample size, or length or comprehensiveness of follow-up or conflicts of evidence).
Recommendation Grades
- There is good evidence to support the use of the procedure.
- There is fair evidence to support the use of the procedure.
- There is poor evidence to support the use of the procedure.
- There is fair evidence to support the rejection of the use of the procedure.
- There is good evidence to support the rejection of the use of the procedure
