History of the establishment and revision of diagnostic criteria, severity index and therapeutic guidelines for pemphigus in Japan

Abstract

We summarize the process of establishing and revising the diagnostic criteria, severity index and therapeutic guidelines for pemphigus in Japan (including the results of a nationwide survey regarding these guidelines). We also summarize the content and present an evaluation of the utility of these guidelines. Due to the publication of these documents throughout the Japanese medical community, it appears that patients with pemphigus have recently begun to receive appropriate treatment, dramatically improving their quality of life and prognosis. Continuous examination of these criteria by means of follow-up studies of patients treated according to the guidelines is necessary to determine the long-term efficacy of treatment. To this end, it is hoped that these guidelines will be more extensively disseminated among the medical community.

Appendix: therapeutic guidelines for pemphigus (1993)

Selection of therapy

Diagnosis and evaluation of severity

• Diagnosis: use the diagnostic criteria. The subclass of pemphigus should be identified in each case.

• Severity: use the severity index to evaluate the patient's condition.

Details of therapy

For severe cases, start with systemic steroid (about 60 mg/day of prednisolone or an equivalent dose of another steroid) in conjunction with apheresis. The dose of steroid should be tapered if clinical improvement is achieved. If plasmapheresis cannot be done, or if 60 mg/day of prednisolone does not induce clinical improvement, consider using steroid pulse therapy as an alternative. Note that several laboratory examinations are required before pulse therapy is started in order to assess efficacy and safety of the therapy.

For moderate cases, start with systemic steroid (about 30 mg/day of prednisolone or an equivalent dose of another steroid) in conjunction with immunosuppressants. If systemic steroid or immunosuppressants cannot be used, for example due to side effects or allergic reactions, consider using apheresis as an alternative.

For mild cases, Start with systemic steroid (about 15 mg/day of prednisolone or an equivalent dose of another steroid). If needed, consider using immunosuppressants together with the steroid. If systemic steroid or immunosuppressants cannot be used, for example due to side effects or allergic reactions, consider using apheresis as an alternative.

For other cases:

• Apheresis is indicated for patients showing severe adverse effects from steroids.

• Evaluation of other kinds of immunosuppressants such as cyclosporine should be considered in future.

Parameters and critical points throughout therapy

• As parameters to assess the efficacy of therapy, use items listed in the severity index.

• As critical points in therapy, ascertain whether the proposed therapy is indicated in the patient's case before its implementation, with special attention to possible adverse side effects of each therapy, and with frequent monitoring to prevent adverse side effects before and after therapy is begun.

Details of therapy

Systemic therapy

Steroids

• 1. Obtain final diagnosis of pemphigus and subclassification using the diagnostic criteria.

• 2. Evaluate disease severity using the severity index and confirm appropriate initial dosage of steroid (see below).

• 3. Assess changes in disease severity using the severity index. As severity decreases, taper steroid dosage (see below).

• 4. If severity increases after tapering the steroid, add 5–10 mg prednisolone/day.

The following initial and maintenance dosages of steroid for pemphigus were obtained from a study of 202 pemphigus patients at 22 institutions belonging to the Rare and Intractable Skin Disease Research Committee of the MWHJ:

• Dosage for pemphigus vulgaris and pemphigus vegetans

  • Initial dosage 27–53 mg/day prednisolone (average 40 mg/day)

  • Maintenance dosage 3–19 mg/day prednisolone (average 11 mg/day)

• Dosage for pemphigus foliaceus and pemphigus erythematosus

  • Initial dosage 20–41 mg/day prednisolone (average 31 mg/day)

• Maintenance dosage 4–14 mg/day prednisolone (average 9 mg/day

Caution

The following cautionary points should be born in mind with the use of steroid therapy:

• 1. Clinical improvement will be achieved by steroid therapy. However, attention should be paid continuously during long-term therapy to the avoidance of unwanted side effects of steroids such as gastric ulcers, osteoporosis, diabetes mellitus, and oral candidiasis.

• 2. Laboratory examination for gastric ulcers, diabetes mellitus and infectious diseases should be done prior to therapy.

• 3. At the onset of any adverse side effects of steroid therapy, immediate tapering or discontinuation of the steroid is indicated and an alternative therapy should be used.

• 4. It is possible to reduce the initial and maintenance dosages of steroids by concomitant apheresis.

Immunosuppressants

The following immunosuppressants are frequently used:

• Azathioprine 50–100 mg/day

• Cyclophosphamide 50–100 mg/day

• Cyclosporine 3–5 mg/kg/day

The therapeutic regimen and efficacy of cyclosporine are as yet unclear, but there are favorable reports of its use. The effect of cyclosporine is thought to appear 3–10 days after administration.

Dapsone

Dapsone (diaminodiphenylsulfone) is very effective for dermatitis herpetiformis. In general, dapsone is not very effective for pemphigus, but is used to enable tapering of steroid dosages. Dapsone is reported to be effective for herpetiform pemphigus. Doses in the range 25–75 mg/day are recommended.

Caution

With the use of dapsone therapy the possibility of bone marrow suppression, liver dysfunction and dapsone syndrome should be born in mind.

Gold therapy

The doses used in pemphigus are one-half to one-third those used in rheumatoid arthritis. The effect is not pronounced, but a small number of patients have been reported to respond to this therapy. Oral administration (as auranofin) requires a longer time to produce the desired effects as compared to injection (as sodium aurothiomalate). It has also been reported that orally administered gold is less effective than injected gold. Oral gold is thought to be useful for maintenance therapy. The recommended doses are as follows:

• Sodium aurothiomalate (injection): 10–25 mg once every 1–2 weeks

• Auranofin (tablets): 6 mg/day

Caution

The following cautionary points should be born in mind with the use of gold therapy:

• 1. Adverse effects such as renal failure, allergic skin reactions, bone marrow suppression, and interstitial pneumonitis have been reported. Laboratory examinations at regular intervals are necessary.

• 2. A common adverse side effect of auranofin is gastrointestinal distress.

Apheresis

There are several methods of apheresis used for pemphigus. Double-filtration apheresis (DFPP) is currently the most widely accepted method. In the initial apheresis method using bag centrifugation, normal human fresh frozen plasma (FFP) was necessary. In DFPP, FFP is not necessary, hence the possible adverse side effects of FFP, such as anaphylactic shock, allergic reaction, hepatitis and hypoproteinemia, are not observed. Apheresis is indicated (and covered by insurance) in Japan for the treatment of several diseases including pemphigus and bullous pemphigoid. Candidates for apheresis therapy are patients diagnosed with pemphigus and pemphigoid by means clinical, histopathological and immunohistochemical examinations, and who are not able to tolerate high dosages of steroids due to complications or adverse side effects. Apheresis can be performed twice a week for up to 6 months. The number of apheresis sessions is varied depending on the course of the disease and the laboratory data in each patient.

Apheresis is indicated for the treatment of pemphigus in the following groups of patients:

• 1. Patients in whom steroids and immunosuppressants cannot be used

• 2. Patients in whom various therapies do not produce the desired effect

• 3. Patients with a severe clinical presentation and a high titer of circulating pemphigus antibodies

Caution

Care is needed to prevent infection at the site of penetration, as blisters and erosions may readily occur.

Steroid pulse therapy

Typically, 1 g/day of methylprednisolone is intravenously administered over the course of more than 1 h. The initial cycle consists of three consecutive days of administration. If the desired effect is not achieved, another cycle can be considered. Steroid pulse therapy is usually done in order to induce early remission, to reduce regular steroid intake in patients with a severe clinical presentation, or in patients who are expected to need long-term high doses of steroids.

Laboratory examinations are important to prevent acute adverse side effects of pulse therapy such as, among others, anaphylactic shock, acute cardiac failure, and perforation of digestive organs. Intensive investigations are important to determine whether this therapy is indicated for a particular patient.

Other therapies

A proteinase inhibitor usually used for the treatment of pancreatitis (camostat mesilate, 600 mg/day orally) has been reported to be effective, and will allow a reduction in the dosage of steroid.

Topical therapy

Therapy of cutaneous lesions

To prevent secondary infection and to reduce focal pain, antibiotic or antipyretic ointment can be applied to blisters and erosions. Adhesive bandages cannot be applied directly to the diseased skin. The most popular ointments used are betamethasone plus gentamicin ointment, chloramphenicol plus fradiomycin plus prednisolone ointment, gentamicin ointment and tetracycline ointment. These ointments can be used together with Vaseline and a solvase ointment. Some mild cases of pemphigus are controllable by oral antihistamine and steroid ointment. However, systemic steroid treatment is necessary in most cases.

Therapy for mucosal lesions

The aim of therapy for cutaneous lesions is prevention of secondary infection and reduction of pain. The patient should be advised to gargle frequently with iodine solution or azulene solution, and for oral candidiasis with amphotericin B solution. Steroid ointments such as triamcinolone acetonide are recommended for mucosal lesions.