Journal of Dermatology 2014; 41: 471–486

doi: 10.1111/1346-8138.12486

REVIEW ARTICLE

Japanese guidelines for the management of pemphigus Committee for Guidelines for the Management of Pemphigus Disease Masayuki AMAGAI,1 Akiko TANIKAWA,1 Tomoko SHIMIZU,1 Takashi HASHIMOTO,2 Shigaku IKEDA,3 Michiko KUROSAWA,4 Hironori NIIZEKI,5 Yumi AOYAMA,6 Keiji IWATSUKI,6 Yasuo KITAJIMA7 1

Department of Dermatology, Keio University School of Medicine, Departments of 3Dermatology, and 4Epidemiology and Environmental Health, Juntendo University Faculty of Medicine, 5Department of Dermatology, National Center for Child Health and Development, Tokyo, 2Department of Dermatology, Kurume University School of Medicine, Kurume, 6Department of Dermatology, Okayama University Graduate School of Medicine, Okayama, and 7Kizawa Memorial Hospital, Gifu, Japan

ABSTRACT The Committee for Guidelines for the Management of Pemphigus was organized as one element of the Japanese Dermatological Association (JDA) and the Ministry of Health, Labour, and Welfare (MHLW) Research Project on Measures for Research Committee for Intractable Skin Disease. Pemphigus has been defined as a group of intractable autoimmune blistering diseases caused by anti-desmoglein 1 and/or anti-desmoglein 3 IgG autoantibodies by the MHLW. The diagnosis of this condition and the criteria for assessing its severity are based on suggestions from the MHLW Research Group. The clinical practice guidelines presented here are those that are currently recommended in Japan. However, symptoms and complications can vary widely among individual pemphigus patients, so not all therapies will be required to be in complete agreement with these guidelines.

Key words:

autoantibody, desmoglein, diagnosis, therapy.

INTRODUCTION Definitions Pemphigus is defined as a group of autoimmune blistering diseases that cause lesions in the skin and mucous membranes. From a histopathological perspective, the epidermis undergoes acantholysis, in which the cell–cell adhesion between adjacent keratinocytes are impaired, resulting in the formation of blisters. From an immunological perspective, pemphigus is characterized by the in vivo deposition of immunoglobulin (Ig)G on cell surfaces of keratinocytes in the epidermis, or of the detection of such autoantibodies in the circulation. The pemphigus antigen is desmoglein (Dsg), a cadherin-type cell–cell adhesion molecule found in desmosomes. Pemphigus can be broadly classified into three major forms: (i) pemphigus vulgaris; (ii) pemphigus foliaceus; and (iii) others. The other known forms include paraneoplastic pemphigus; pemphigus vegetans, which is a subtype of pemphigus vulgaris; pemphigus erythematosus or Senear–Usher syndrome, which is a subtype of pemphigus foliaceus; herpetiform pemphigus; and drug-induced pemphigus.

Epidemiology According to the Ministry of Health, Labor and Welfare (MHLW) Research Project on Measures for Intractable Diseases, applications for public financial aid for treatment were received from 3504 pemphigus patients in 2004 and 4085 pemphigus patients in 2007. The MHLW has a registration system of intractable diseases including pemphigus. We obtained the 2004 clinical database from the MHLW, which contained 2503 patients with pemphigus (input rate, 71%). The sex ratio of the patients (male : female) was 1:1.5, making the condition slightly more common in women. The disease most frequently afflicted patients in the 60–69-year age group. Disease onset of pemphigus was peak in those aged 50– 59 years. The most common disease type was pemphigus vulgaris (65%), followed by pemphigus foliaceus (23%), pemphigus erythematosus (6%), pemphigus vegetans (2%) and unknown disease type (4%). These conditions were classified as mild (74%), moderate (20.4%) or severe (5.0%), using Severity Criteria I from the MHLW Research Group for Rare Intractable Skin Diseases (Table 2). New applicants made up 10% of all applicants, and the ratio of relatively severe cases was higher among these new applicants (mild, 34.2%; moderate, 45.2%; severe, 20.6%) than among all patients.

Correspondence: Masayuki Amagai, M.D., Ph.D., Department of Dermatology, Keio University School of Medicine, 35 Schinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: [email protected] This is the secondary English version of the original Japanese manuscript for pemphigus guideline published in the Japanese Journal of Dermatology 120 (7); 1443–1460, 2010. Received 5 March 2014; accepted 7 March 2014.

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Pathophysiology The basic pathophysiology of blister formation in pemphigus is the inhibition of adhesive function of Dsg by IgG autoantibodies, which leads to the loss of cell–cell adhesion of keratinocytes with resultant blister formation. The pemphigus vulgaris antigen is Dsg3, and the pemphigus foliaceus antigen is Dsg1. Pemphigus vulgaris can be further classified as mucosal-dominant or mucocutaneous. Ordinarily, only anti-Dsg3 IgG antibodies are detected in mucosal-dominant pemphigus vulgaris, while both anti-Dsg3 and anti-Dsg1 IgG antibodies are detected in mucocutaneous pemphigus vulgaris. Only antiDsg1 IgG antibodies are detected in pemphigus foliaceus. The diversity of blister formation sites in pemphigus is explained by the Dsg compensation theory, which suggests that intercellular adhesion is compensated when two or more types of Dsg isoform are expressed in the same cell. Within the epidermis, Dsg3 is strongly expressed in the lower epidermis, and particularly in the basal and parabasal cell layers. Dsg1 is expressed in all layers of the epidermis, and particularly strongly expressed in the upper layers. However, within the oral mucosa or esophagus Dsg3 is strongly expressed in the whole epithelial layer and Dsg1 is weakly expressed in all layers except for the basal cell layer. In pemphigus foliaceus, where only anti-Dsg1 IgG antibody is found in the serum, in the skin, blisters are induced in the upper layer of the epidermis where there is no Dsg3-mediated compensation for the adhesive function. However, Dsg3 is strongly expressed in all layers of the mucosa, so Dsg3 compensates for the Dsg1 interference with the adhesion function. As a result, no apparent erosions develop in oral mucosa. In mucosal-dominant pemphigus vulgaris, where only anti-Dsg3 antibodies are found in the serum, Dsg1 is expressed in all layers of the epidermis. Thus, Dsg1 compensates for antibody-mediated inhibition of the Dsg3 adhesion function. Blisters do not form, or they form only locally in the skin. In oral mucosa, in contrast, Dsg1 is expressed in low levels and cannot compensate for the lost Dsg3 adhesion function, so erosions are formed. Similarly, in cases of mucocutaneous pemphigus vulgaris, the serum contains anti-Dsg1 antibody as well as anti-Dsg3 antibody, so function is inhibited both for Dsg3 and for Dsg1. In this condition, blisters and erosions can develop extensively in both the skin and the mucosa. Regarding the mechanisms of blister formation in pemphigus, at least two theories are well accepted. One is the direct inhibition of Dsg adhesion or steric hindrance by IgG autoantibodies. The other is the involvement of intracellular signal transduction induced by IgG binding to Dsg. Phosphorylation of Dsg or anchoring proteins causes Dsg internalization into the cells from the surface of the cell membranes, which leads to reduced levels of Dsg on the cell membrane. Paraneoplastic pemphigus is an autoimmune skin condition in which IgG autoantibodies to Dsg and plakin molecules are present. This disease is associated with a malignant or benign neoplasm (generally, a lymphoproliferative disorder) that is characterized by serious mucosal lesions, primarily erosive, and a variety of skin lesions. Characteristically, not only

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humoral immunity but also cellular immunity is involved in damage to the mucosal epithelium as well as to the skin.

Clinical symptoms and histopathological findings Pemphigus vulgaris. This is the most common form of pemphigus. The most characteristic clinical findings in pemphigus vulgaris are painful refractory erosions and ulcers in the oral mucosa. Initial symptoms generally involve the oral mucosa, and in severe cases can lead to insufficient food intake. In addition to the oral mucosa, this form of pemphigus can also affect the stratified squamous epithelium in areas such as the lips, pharynx, larynx, esophagus, eyelid conjunctiva and vagina. In approximately half of patients, the condition is not limited to the oral mucosa, but also involves the skin, with the development of flaccid bullae and erosions. The blisters rupture easily, and produce erosion of the overlying epidermis that is attached to the perimeter of the blister. Such erosions are often painful, and adjoining erosions tend to coalesce to form a large eroded surface. The most frequent sites for blistering are the head, axilla, inguinal area, upper back and buttocks, where pressure is applied, and this condition spreads readily. Even in areas that appear normal, if pressure is applied, the skin may be detached to reveal erosion (Nikolsky’s sign). Pemphigus vulgaris can be divided into two categories based on the clinical symptoms: (i) mucosal-dominant type in which mucosal lesions are the primary symptom, and skin blisters and erosions may be localized if present; and (ii) mucocutaneous cases in which there is widespread involvement of both the mucous membrane and the skin. Biopsy specimens should be obtained from new vesicles or margins of vesicles. The cell–cell adhesion of keratinocytes is lost, and the blister formation is seen between basal and parabasal layers as suprabasilar acantholysis. Within the vesicles, acantholytic cells can be seen. The attachment is damaged between the basal cells and their neighboring cells, but the connection to the basement membrane is retained, resulting in what is termed a “row of tombstones” appearance. Pemphigus foliaceus. Clinically, this condition is characterized by scaly crusted erosion, often on an erythematous base on the skin. The erythema is most commonly seen as small red spots, up to the size of a fingernail plate. Rarely, the erythema extends over a large local area and becomes erythroderma. Seborrheic regions such as the head, face, chest and back are most frequently affected. Pemphigus foliaceus almost never produces mucosal lesions in areas such as the oral cavity. Nikolsky’s sign can also be detected. The cell–cell adhesion of keratinocytes is lost, and blister formation can be noted in the upper layer of the epidermis, from the subcorneal layer to the granular layer. Blisters must be checked carefully, because the acantholytic cells are not numerous within the blisters, and can be easily missed. Paraneoplastic pemphigus. The most common clinical symptom of this condition is the presence of refractory lesions within the oral cavity. Paraneoplastic pemphigus is

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characterized by the presence of erosions and ulceration over an extensive mucosal area from the oral cavity to the pharynx, with erosions accompanied by bloody crust and crusting of the vermilion lips. Many patients may develop pseudomembranous conjunctivitis accompanied by lesions of the ocular mucous membrane, and eyelid adhesions can occur as a result of advanced lesions. Lesions also commonly form in the esophagus, nasal mucosa, vagina, labia and glans mucosa. A variety of skin lesions can develop, including erythema, flaccid bullae, tense bullae, erosions, erythema exudativum multiforme-like eruptions and lichen planus-like eruptions. The detection of erythema exudativum multiforme-like eruptions on the palm of the hand and/or sole of the foot is useful in identifying this condition, because palmoplantar lesions are not seen with pemphigus vulgaris. If the condition is chronic, there may be obvious lichenoid eruptions. The accompanying tumor is almost always from a lymphoproliferative disorder. Paraneoplastic pemphigus is only rarely accompanied by the common forms of solid tumor in the gastrointestinal tract lung or breast adenocarcinoma, squamous cell carcinoma, or basal cell carcinoma or squamous cell carcinoma in the skin. Note that the patient may also develop lesions typical of bronchiolitis obliterans, which can cause progressive damage to the respiratory organs; caution is advised. Histopathological findings are varied, reflecting the clinical symptoms. Findings at the site of skin lesions resemble a combination of pemphigus vulgaris, erythema multiforme exudativum and lichen planus-like findings. Suprabasal acantholysis can be seen in areas where blisters are present, accompanied by epidermal cell necrosis and lymphocytic infiltration within the epidermis. There also may be basal cell vacuolar degeneration and band-like dense lymphocytic infiltration into the upper dermis. Eosinophilic infiltration is rare. Pemphigus vegetans. Pemphigus vegetans is a subtype of pemphigus vulgaris that occurs in two types: (i) the Neumann type, in which proliferative changes of keratinocytes develop from blisters and erosive lesions; and (ii) the Hallopeau type, in which the proliferative changes come from pustular lesions in regions such as the intertriginous area. Just as with pemphigus vulgaris, pemphigus vegetans involves the anti-Dsg3 IgG autoantibody, and in some cases the anti-Dsg1 IgG antibody is also involved. Histologically, this condition is characterized by notable papillary proliferation in the skin and the formation of eosinophilic pustules along with the formation of suprabasal fissures. The Neumann type tends to be relatively aggressive and refractory. The prognosis is more favorable for the Hallopeau type, which may resolve spontaneously. Pemphigus erythematosus (Senear–Usher syndrome). Pemphigus erythematosus is a localized form of pemphigus foliaceus. This condition is characteristically accompanied by butterfly rash on the face. When Senear–Usher syndrome was first described, it was positioned between pemphigus and systemic lupus erythematosus, or was inferred to be a disease that was complicated by both of these conditions. However, subse-

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quently, patients with this condition were found to carry the IgG autoantibodies against cell surfaces of keratinocytes or Dsg1 that characterize the pemphigus family, clearly indicating that Senear–Usher syndrome shares the characteristics of pemphigus. Herpetiform pemphigus. Herpetiform pemphigus, a subtype of classical pemphigus, bears a clinical resemblance to dermatitis herpetiformis Duhring. Both conditions are characterized by pruritic erythema and blisters arranged in a ring shape, but patients are diagnosed with herpetiform pemphigus if immunofluorescence findings indicate the presence of IgG-class autoantibodies against the epidermal keratinocyte surface as in pemphigus. Under histopathological examination, herpetiform pemphigus shows no clear signs of acantholysis as seen in classical pemphigus. Instead, the predominant finding is eosinophilic spongiosis. Drug-induced pemphigus. This term designates pemphiguslike findings subsequent to a clear history of drug administration. A number of drugs are reported to be associated with this condition; most famously, D-penicillamine and captopril. In many cases, the symptoms are relieved after the discontinuation of drug administration.

Treatment Because pemphigus is an autoimmune disease, the most common treatment is the administration of oral steroids to inhibit antibody production, combined with the use of topical agents to prevent infection, protect the eroded areas and promote epithelialization. Other concomitant therapy can include the use of immunosuppressants, plasma exchange and the administration of high-dose i.v. Ig (IVIG). The goal of treatment is to be able to maintain remission with a minimal dose of oral steroid, namely, 0.2 mg/kg per day or 10 mg/day or less. To reach this goal, the initial treatment in the consolidation phase is very important. For specifics, please refer to treatment guidelines.

Prognosis Pemphigus vulgaris is generally more refractory than pemphigus foliaceus, and the prognosis is less favorable. Lesions in the oral mucosa tend to be particularly resistant to treatment. This is not necessarily the case, however, with pemphigus foliaceus that has progressed to erythroderma. The introduction of steroid therapy has considerably improved the prognosis, but complications from steroid-induced adverse drug reactions can be a problem.

PEMPHIGUS DIAGNOSTIC CRITERIA AND SEVERITY CRITERIA Pemphigus diagnostic criteria The diagnostic criteria that should be used are described below.

Pemphigus severity criteria In patients who are diagnosed with pemphigus based on the diagnostic criteria in Table 1, severity can be assessed from a

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score that is calculated using the following severity criteria. In addition to the earlier criteria (Severity Criteria I, shown in Table 2), current severity criteria also combine Severity Criteria IIa (complete version, Table 3) and IIb (simplified version, Table 4), which are based on the international Pemphigus Disease Area Index (PDAI).*

Table 1. Pemphigus diagnostic criteria

1. Clinical diagnosis parameters. (i) Multiple flaccid, easily ruptured bullae on the skin.

(ii) Progressive refractory erosions secondary to blisters, or scaly or crusted lesions.

PEMPHIGUS TREATMENT GUIDELINES General goal of treatment for pemphigus All efforts should be made toward early diagnosis, and the importance of initial treatment should be recognized. This condition requires treatment by board-certified dermatologists. The prognosis of pemphigus is often difficult to predict during the early stage of the disease. If initial treatment is inadequate, the condition can recur during steroid tapering, so it is extremely important to provide appropriate therapy during the early stage of the disease. In severe cases, it is necessary not only to ensure that blisters and erosions cease to develop during treatment, but also, following steroid tapering, to maintain remission with a low-dose steroid regimen (prednisolone [PSL] ≤0.2 mg/kg per day).

Treatment plan The treatment of pemphigus can be divided into initial therapy and maintenance therapy when developing the treatment plan (see Figure 1 for the treatment algorithm and Table 5 for a list of treatments). I Initial therapy (the treatment period until the disease state is controlled and tapering of the steroid dose is initiated. If the treatment is effective, this is generally achieved 2–4 weeks after the start of therapy)

Objective. In the early stage, the objective is to control the disease state through concentrated and thorough treatment. Specifically, this means that almost no new blisters are observed and that existing lesions show a tendency toward drying and epithelialization. When selecting the treatment method, it is important to consider that the effectiveness of initial treatment can affect the outcome, including potential recurrence after steroid tapering, and whether remission can be maintained with only low doses of steroid (PSL ≤0.2 mg/kg per day).

(iii) Non-infectious blisters or erosions on the visible mucosal areas, including the oral mucosa

(iv) Positive Nikolsky’s sign. 2. Histopathological diagnostic parameter Detection of intraepidermal blister formation due to loss cell–cell adhesion of keratinocytes (acantholysis). 3. Immunological diagnostic parameters.

(i) Demonstration of in vivo immunoglobulin (Ig)G (and sometimes complement) deposition on keratinocyte cell surfaces of the skin and mucosa, either in lesions or in apparently healthy skin by direct immunofluorescence. (ii) Detection of circulating IgG autoantibodies against keratinocyte membranes or intercellular spaces of the epidermis or anti-desmoglein IgG autoantibodies by indirect immunofluorescence or enzyme-linked immunoassay. [Assessment and diagnosis]

(a) Those cases that satisfy at least one of the parameters in (1), the parameter in (2), and at least one of the parameters in (3) are diagnosed as pemphigus. (b) Those cases that satisfy at least two of the parameters in (1) and also satisfy (i) and (ii) of the parameters in (3) are diagnosed as pemphigus

Evaluation of disease activity. During initial treatment, disease activity is evaluated primarily through clinical symptoms. Severity Criteria IIa and IIb (PDAI) assign numerical values to the

extent and severity of skin and mucosal eruptions, and provide excellent assessment of clinical severity during initial treatment. However, even if the treatment method is efficacious in inhibiting the lymphocytes that produce IgG autoantibodies, the halflife of IgG in the blood is ordinarily approximately 3 weeks, so time is required before IgG levels will be reduced. Thus, during initial treatment, 1 week should be the minimum unit for the evaluation of disease state through clinical symptoms. If no change is seen after 2–4 weeks of treatment, the next treatment method should be considered. It is important to avoid the unconsidered long-term continuation of oral steroids at that same dose level.

*The PDAI is calculated using the extent of skin and oral lesions as indicators. It is a sensitive indicator of changes in disease activity during the acute phase of the disease. In cases where international assessment is required, such as in clinical studies, the use of IIa (complete version) is advised. However, because of the large number of evaluation items and the complexity of IIa, a simplified version (IIb) is also provided. Effectiveness is being confirmed for these severity criteria, and methods for their assessment are continually being reviewed.

Selection criteria for treatment methods. Prednisolone is the therapy of first choice for initial treatment. For severe or moderate conditions, the standard dose is PSL 1.0 mg/kg per day. For mild conditions, cases have been reported in which 0.5 mg/kg per day is effective. If therapeutic effects are judged to be insufficient after 2 weeks of steroid monotherapy, consideration should promptly be given to the use of additional methods such as immunosuppressants, high-dose IVIG ther-

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Guidelines for the management of pemphigus

Table 2. Pemphigus severity criteria I (scores for findings from each parameter are totaled, and calculations are performed based on the assessment table) Pemphigus Autoantibody titer Parameter

Affected skin area*

Nikolsky’s phenomenon

No of new lesions per day

Indirect immunofluorescence

ELISA (index value)

Oral lesions†

Score Score Score Score Score

None 15%

None Only focal Positive Pronounced

None Occasionally‡ 1–4 blisters ≥5 blisters

Not detected 2 cm in diameter, 1 none > 6 cm 2 to 3 lesions and at least two > 2cm in diameter, 2 none > 6 cm 3 > 3 lesions, none > 6 cm 5 At least one > 6 cm in diameter At least one > 16 cm in diameter 10 or entire area

Nose Face Other than nose and ears Neck Chest Abdomen Back and Buttocks Arms

epithelialized area or pigmented area are not included

Hands Legs Feet Genitalia

2. Scalp Region Scalp

3. Mucous membrane Anatomical location Eyes Nose Buccal mucosa Hard palate Soft palate Upper gingiva Lower gingiva Tongue Floor of mouth Labial mucosa Posterior Pharynx Anogenital

Scores

Score

Scalp 0 1 2 3 4 10

Scores

Score (mucous membrane)

Erosions/Blisters or new erythema absent in one quadrant two quadrants three quadrants affects whole skull at least one lesion > 6 cm

Erosions/Blisters 0 1 2 5 10

absent 1 lesion 2 to 3 lesions more than 3 lesions or 2 lesions > 2 cm entire area

Total PDAI socre = A + B + C

IVIG therapy should be considered. If the patient is already receiving concomitant therapy, a change to another form of concomitant therapy should be considered.

Practical examples of treatment protocol 1. Oral steroids (PSL 1.0 mg/kg per day) CQ1 If the patient does not respond to treatment within 2 weeks, one or a

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combination of the following treatment methods should be selected. (As of 2010, only plasma exchange and high-dose IVIG were covered by Japanese National Health Insurance.) 2. Oral steroids (PSL 1.0 mg/kg per day) + immunosuppressant (azathioprine 2.0 mg/kg per day) CQ2. 3. Oral steroid (PSL 1.0 mg/kg per day) + immunosuppressant (cyclosporin 3.0–5.0 mg/kg per day) CQ3.

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Guidelines for the management of pemphigus

Table 4. Pemphigus Severity Criteria IIb (Pemphigus Disease Area Index [PDAI] simplified version) 1. Skin Anatomical location Scalp

Scores

Score

0 absent 1 to 3 lesions and up to one > 2 cm in diameter, none > 6 cm 2 to 3 lesions and at least two > 2cm in diameter, 2 none > 6 cm 3 > 3 lesions, none > 6 cm 5 At least one > 6 cm in diameter At least one > 16 cm in diameter 10 or entire area

Face and Neck

1

Chest and Abdomen Back and Buttocks Arms and Hands Legs and Feet

2. Mucous membrane Anatomical location Buccal mucosa palate Upper gingiva Lower gingiva Tongue Anogenital

Erosions/Blisters or new erythema

Skin

epithelialized area or pigmented area are not included

Scores

Score (mucous membrane) 0 1 2 5 10

Erosions/ Blisters absent 1 lesion 2 to 3 lesions more than 3 lesions or 2 lesions > 2 cm entire area

Total PDAI socre = A + B

4. Oral steroid (PSL 1.0 mg/kg per day) + IVIG CQ4. A dose of 400 mg/kg per day is administrated for 5 successive days. This is the only treatment method that is not accompanied by general immunosuppression. 5. Oral steroids (PSL 1.0 mg/kg per day) + plasma exchange CQ5. In facilities that are able to provide plasma exchange, the implementation of this therapy should be aggressively considered, in order to make it possible to quickly decrease the steroid dose. In severe cases, too, this can be an effective treatment method. 6. Steroid pulse therapy (intravenous methylprednisolone 1.0 g/day for 3 days) CQ6 (during the 3 days of pulse therapy, the base treatment with oral PSL is not administrated). 7. Oral steroids (PSL 1.0 mg/kg per day) + immunosuppressant (cyclophosphamide 1.0 mg/kg per day) CQ7. 8. Oral steroids (PSL 0.5–1.0 mg/kg per day) + cyclophosphamide pulse therapy CQ8. Cyclophosphamide for injection, 500–750 mg/m² or 500–1000 mg (ordinarily 750 mg), is dissolved in 500 mL of fluid replacement preparation, and administrated over a 2-h period by drip infusion (≥1000 mL of fluid replacement following i.v. drip), once per month for 6 months. If needed, this can be followed

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9.

10. 11. 12.

13. 14.

by administration once every 3 months, to be concluded after a total of 1–2 years. Oral steroids (PSL 0.5–1.0 mg/kg per day) + plasma exchange + cyclophosphamide (p.o. administration of 2.0– 2.5 mg/kg per day or 100–125 mg/day, with simultaneous p.o. administration of 2–3 L of fluid replacement. If oral administration is not selected, then cyclophosphamide pulse therapy (see entry 8 above) should be performed) CQ9. Oral steroid (PSL 1.0 mg/kg per day) + immunosuppressant (mizoribine 1.0–3.0 mg/kg per day) CQ10. Oral steroid (PSL 1.0 mg/kg per day) + immunosuppressant (mycophenolate mofetil 40 mg/kg per day) CQ11. Oral steroid (PSL 0.4 mg to 1.0 mg/kg per day) + immunosuppressant (methotrexate 2.5–7.5 mg/week [maximum dose 12 mg/week, administrated over a period of 2 days) CQ12. Oral steroid (PSL 0.4 mg/kg per day) + dapsone (DDS 50– 100 mg/day) CQ13. Oral steroid (PSL 1.0 mg/kg per day) + anti-CD20 antibody therapy (rituximab 375 mg/m² once weekly [one cycle], repeated four times) CQ14.

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CLINICAL QUESTIONS (CQ) ON PEMPHIGUS GUIDELINES CQ1: Is the systemic administration of steroids effective? Degree of recommendation: A. Recommendation: Systemic steroid administration is effective, and is the standard treatment for pemphigus. Comments: Systemic steroid administration is considered to be the most standard treatment for pemphigus. In the past, the steroid dose was often determined based on experience at each specific medical institution. However, currently the standard recommended dose for severe to moderate pemphigus is to initiate treatment at 1 mg/kg per day, ordinarily 60 mg/day.1 In one study of pemphigus, 22 patients were randomly allocated to two groups of 11 patients each (the PSL 120 mg/day group and the PSL 60 mg/day group). Patients were followed for 5 years. Results showed that initially the disease state was more quickly controlled in the 120 mg/ day group, but that this group experienced no advantage in terms of rates of relapse and complications over the 60 mg/ day group. No long-term advantages were associated with the higher dose.2

CQ2: Is the concomitant use of oral steroids and azathioprine useful? Figure 1. Treatment algorithm for pemphigus.

CQ LIST CQ1: Is the systemic administration of steroids effective? CQ2: Is the concomitant use of oral steroids and azathioprine useful? CQ3: Is the concomitant use of oral steroids and cyclosporin useful? CQ4: Is IVIG therapy useful in refractory cases? CQ5: Is plasma exchange useful in the treatment of pemphigus? CQ6: Is steroid pulse therapy useful in the treatment of severe cases of pemphigus? CQ7: Is the concomitant use of oral steroids and cyclophosphamide useful? CQ8: Is cyclophosphamide pulse therapy useful? CQ9: Is the concomitant use of oral steroids, cyclophosphamide and plasma exchange useful in refractory cases? CQ10: Is the concomitant use of oral steroids and mizoribine useful? CQ11: Is the concomitant use of oral steroids and mycophenolate mofetil useful? CQ12: Is methotrexate useful in the treatment of pemphigus? CQ13: Is dapsone (diaminodiphenylsulfone; DDS) useful in the treatment of pemphigus? CQ14: Is rituximab (anti-CD20 antibody) useful in the treatment of refractory pemphigus?

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Degree of recommendation: B. Recommendation: The concomitant use of oral steroids and azathioprine is useful. The concomitant use of azathioprine may permit a reduction in steroid dose. Comments: When azathioprine is given concomitantly with an oral steroid, the azathioprine dose is ordinarily started at 100 mg/day, given in two partial doses. Ordinarily, 6 weeks or more are required before the effects of azathioprine are noted. In a single-center randomized study, 120 pemphigus vulgaris patients were allocated to PSL monotherapy (prednisolone 2 mg/kg per day, maximum dose 200 mg/day) or PSL + azathioprine concomitant therapy (azathioprine 2.5 mg/kg per day for 2 months and then reduced to 50 mg/day). Patients were followed for 1 year. Results showed that the concomitant use of azathioprine can enable reduction of the steroid dose, and that such use is effective.3 Treatment with corticosteroid + azathioprine was provided to 37 patients with severe pemphigus. Long-term follow up showed that remission was induced for 4–16 years in 29 of those patients. Of the 37 patients, there was only one death related to pemphigus therapy (pulmonary tuberculosis). The concomitant use of corticosteroid + azathioprine is considered to be extremely useful and highly safe for the treatment of patients with refractory pemphigus.4 In another study, 74 patients with early-stage pemphigus were treated with prednisolone 40 mg on alternate days + azathioprine 100 mg/day until the lesions were completely resolved, after which the steroid and immunosuppressant were tapered for a year. Patients were followed for 76 months, on average. At 53 months of treatment, remission had been achieved in 57 patients. For

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Table 5. List of pemphigus treatments*l Treatment 1) First choice Systemic steroid administration (usually prednisolone) 2) Second choice Concomitant use of prednisolone and other agent Azathioprine Cyclosporine Cyclophosphamide Mizoribine Mycophenorate mofetil*2 Methotrexate Dapsone methyl prednisolone pulse therapy High-dose IVIG*3 Plasmapheresis Anti-CD20 antibody (Rituximab) *2

Dose

Degree of recommnedation

CQ

Initial dose 1.0 mg/kg/day (usually 60 mg/day)

A

CQ1

2–4 mg/kg/day (usually100–150 mg/day) 3–5 mg/kg/day 1–3 mg/kg/day (usually 50–100 mg/day) 1–3 mg/kg/day 1–3 times/day 35–45 mg/kg/day (usually 2–3 g/day) 2.5–7.5 mg/wk (maximum dose 12 mg/wk, given over a 2-day period) 50–100 mg/day 500 mg to 1 g/day, over a period of 2–3 h by drip infusion, administered on 3 successive days 400 mg/kg/day administered on 5 successive days Rate of administration: Maintained at 2 mg/kg/min or less Usually 2–3 times/wk, double filtration/centrifugation 375 mg/m2, once/wk (1 cycle), repeated 4 times

B C1 C1 C2 C1 C1

CQ2 CQ3 CQ7 CQ10 CQ11 CQ12

C1 C1

CQ13 CQ6

B

CQ4

B C1

CQ5 CQ14

Evidence-based degree of recommendation: (A) Strongly recommended (B) Recommended (C1) May be implemented (C2) Limited evidence base; not actively recommended (D) Recommended not to implement.

30 of these patients, it was necessary to revise the protocol in order to achieve remission. This treatment method provides a high level of therapeutic effectiveness in patients with early-stage or stable-stage pemphigus of moderate severity, and is an excellent therapeutic regimen from the perspective of safety and improved quality of life.5

CQ3: Is the concomitant use of oral steroids and cyclosporin useful? Degree of recommendation: C1. Recommendation: The concomitant use of oral steroids and cyclosporin is useful. There have been cases in Japan in which the concomitant use of cyclosporin has been judged to be effective. However, questions have been raised overseas about the effectiveness of this treatment regimen. Comments: In one study where pemphigus patients were treated for 1 year with concomitant prednisolone (60– 80 mg/day) + cyclosporin (5 mg/kg per day) or with prednisolone monotherapy (120 mg/day, initial dose for both treatment regimens), statistical analysis showed no significant difference between the two treatment regimens with regard to therapeutic effectiveness, changes in antibody titer or the incidence of adverse drug reactions. However, the concomitant immunosuppressant group achieved remission within 25 days, sooner than the monotherapy group.6 In five pemphigus patients who received concomitant cyclosporin, case reports showed that, when relapse

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occurred, symptoms were eliminated in 35.5 days on average with this treatment, and that it was possible to decrease the steroid dose. The antibody titer converted to negative in three patients, and researchers concluded that this regimen was useful in the treatment of recurrent pemphigus.7 There also have been other reports of the effectiveness of concomitant cyclosporin.8,9 However, when 29 patients with pemphigus vulgaris and four patients with pemphigus foliaceus were randomly allocated to treatment with methylprednisolone monotherapy or prednisolone (1 mg/kg) + cyclosporin (5 mg/kg), follow-up tests showed no notable difference between the two groups on most points, including therapeutic effectiveness. Complications developed more frequently in the prednisolone + cyclosporin group, and it was concluded that concomitant therapy offered no advantages.10

CQ4: Is high-dose IVIG therapy useful in refractory cases? Degree of recommendation: B. Recommendation: High-dose IVIG therapy is useful in severe cases of pemphigus. Among the treatment regimens used for pemphigus, only this method has demonstrated effectiveness without generalized immunosuppression. It can be effective in pemphigus patients who show steroid resistance. Comments: A multicenter randomized double-blind study was conducted in Japan in 61 patients with pemphigus vulgaris or pemphigus foliaceus who had not responded to oral

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Table 6. Checklist for pemphigus treatment I. Before the start of treatment Strongly recommended

• Confirmation of pemphigus diagnosis (clinical symptoms, histopathological findings, direct • •

• • •

immunofluorescence and/or indirect immunofluorescence, tests for circulating antibodies using ELISA* Evaluation of disease severity using PDAI Urinalysis and hematology: Peripheral blood (including blood fractions), liver and kidney function, electrolytes, lipid levels. Presence or absence of antibodies for type B or type C hepatitis, diabetes mellitus-related findings (early morning blood glucose, hemoglobin A1c [HbA1c]), fever pattern, C-reactive protein [CRP] Chest X ray, bodyweight, blood pressure Evaluation of diabetes mellitus, hypertension, gastric ulcers, tuberculosis, and other prior illness or complications, and evaluation of status Evaluation of osteoporosis: Measurement of the bone metabolism marker NTX in the blood, bone density imaging 1–2-times/year (particularly in high-risk female patients middle-age and older)

Recommended

• Endoscopy: Evaluation of the presence or absence of lesions in the pharyngeal, laryngeal,

• • • • • •

and esophageal mucosa, with simultaneous evaluation of the presence or absence of gastric ulcers (if there is insufficient time to do these tests before the start of treatment, they should be conducted as soon as possible after the start of treatment) Tuberculin skin test or QFT:† To determine whether the patient has a history of tuberculosis. In particular, if there has been a history of tuberculosis or exposure to tuberculosis patient(s), prophylactic treatment with antituberculosis drugs should be considered Preparation of various cultures (e.g. from the pharynx, skin, urine, stool) Presence or absence of complications detected by methods such as ultrasound and computed tomography (e.g. thymoma, malignant tumor) Check for the presence or absence of ocular lesions (including glaucoma and cataracts) Immunoglobulin level (serum IgG, IgA, IgM) Evaluation of CD4/CD8

II After the start of treatment Strongly recommended

• Periodic tests of peripheral blood (including blood fractions), diabetes mellitus-related findings (fasting plasma glucose, HbA1c), liver and kidney function, electrolytes, lipid levels, fever pattern, CRP, IgG

• Evaluation of disease activity using PDAI • Periodic measurement of blood antibody titer using ELISA* (if possible, once every 1–2 weeks after the start of treatment and once every month after the condition has stabilized)

• From initial therapy to early-stage maintenance therapy (until the dose is reduced to prednisolone

• •

[PSL] 0.4 mg/kg per day or PSL 20 mg/day), periodic (e.g. once every 1–2 months) measurement of b-D-glucan and CMV antigenemia.‡ Particular caution is also advised in the event of pneumocystis pneumonia or other fungal infections (such as Aspergillus) From initial therapy to early-stage maintenance therapy (until the dose is reduced to PSL 0.4 mg/kg per day or PSL 20 mg/day), prophylactic administration of antibiotics is recommended to prevent infection (e.g. Baktar) Careful monitoring for steroid-induced adverse drug reactions (including steroid-induced mental and neurological disorders) is required

Recommended parameters

• • • • •

Periodic chest X rays, depending on the severity of the case Gargling with an antifungal agent to prevent the development of Candida within the oral cavity Periodic preparation of various cultures as needed (e.g. skin, urine, stool) Investigation of the possible use of antiviral agents, based on the results of CMV‡ tests Patients who have mucosal lesions should receive instruction from a dentist about good oral hygiene and tooth-brushing techniques, so that the oral cavity can be kept clean

PDAI, Pemphigus Disease Area Index. *If the enzyme-linked immunoassay (ELISA) index value is ≥120, the ELISA enzyme reaction reaches a plateau, and actual changes may not be reflected in the ELISA findings. In that event, it is necessary to establish an optimal dilution (usually 100-fold dilution) and to determine the true index value. †QFT: QuantiFERON (QFT)-2G. ‡CMV (cytomegalovirus): This test is performed by polymerase chain reaction assay or CMV antigenemia assay, in which the early antigens in leukocyte nuclei are stained with monoclonal antibody.

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PSL 20 mg/day or above. Patients were assigned to the 5day treatment group (IVIG 400 or 200 mg/kg per day) or the control group. Results showed that time to escape from the protocol was significantly longer in the IVIG 400 mg/kg per day group than in the control group, and the dose–response study showed statistically significant differences among the three groups.11 This clinical study confirmed the effectiveness of a single cycle of high-dose IVIG therapy (400 mg/kg per day for 5 days) in patients with steroid-resistant pemphigus. Results from separate clinical research in eight cases of refractory pemphigus showed that high-dose IVIG was effective in all eight patients, enabling steroid dose reduction and induction of remission with almost no adverse drug reactions.12

CQ5: Is plasma exchange useful in the treatment of pemphigus? Degree of recommendation: B. Recommendation: Clinically, it is known that the combined use of plasma exchange with oral steroids can not only improve clinical symptoms and serum antibody titer, but can also make it possible to reduce the steroid dose. The treatment method is distinctive, so no double-blind studies have been performed, but numerous clinical reports are available. Treatment methods include: (1) centrifugation; (2) double filtration plasmapheresis (DFPP); and (3) immunoadsorption. Currently, DFPP is the most widely used. 1. The centrifugation method involves the transfer of large volumes of blood and plasma at one time, which places a considerable burden on the circulatory system. In addition, the centrifuge bag is difficult to obtain, and the procedure requires the use of fresh frozen plasma, which is associated with a potential risk of infection. The immunoadsorption method did not demonstrate effectiveness in Japanese clinical trials (unpubl. data). 2. The DFPP method. The following two types of DFPP are most commonly used in Japan: (i) plasma separator (Asahi Kasei Medical Plasmaflo OP-05W [membrane material polyethylene, membrane surface area 0.5 m2, internal diameter 330 lm, membrane thickness 50 lm, pore size 0.3 lm, filling volume of blood side 55 mL, filling volume of plasma side 75 mL; and Kawasumi Laboratories Plasmacure PE-05 (same as OP-05W); and (ii) plasma fractionation (Asahi Kasei Medical Cascadeflo EC-20W [membrane material EVAL, membrane surface area 2.0 m², internal diameter 175 lm, membrane thickness 40 lm, pore size 0.01 lm, filling volume of plasma side 150 mL, filling volume of filtrate side 110 mL]; and Kawasumi Laboratories Inc., Evaflux 2A20 [same as EC-20W]. 3. Immunoadsorption (apheresis equipment: Asahi Kasei Medical, Plasauto iQ21 and Kawasumi Laboratories Inc., KM-8900EX). Comments: A comparative research was conducted in 40 patients who were treated with prednisolone monotherapy (18 patients) or prednisolone + 10 large-volume plasma

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exchanges (centrifugation method, 4 weeks, 22 patients). All patients were started on an initial prednisolone dose of 0.5 mg/kg per day, and this dose was increased each week if necessary. Results showed that remission was induced in 32 patients. There was no difference between the two groups with regard to total steroid dose or change in pemphigus antibody titer. Treatment was ineffective in four patients in each group. In addition, four patients in the plasma exchange group died of septicemia. Low-dose steroid therapy with concomitant plasma exchange is thus not recommended.13 However, the efficacy and safety of DFPP have been reported in numerous cases.14–17 DFPP has also been reported to cause decreased factor XIII; caution is advised.18

CQ6: Is steroid pulse therapy useful in the treatment of severe cases of pemphigus? Degree of recommendation: C1. Recommendation: Steroid pulse therapy provides extremely rapid effects to suppress the disease activity in severe cases of pemphigus. Comments: Twelve pemphigus vulgaris patients with severe mucosal symptoms were treated with steroid pulse therapy for 3–5 days at a maximum dose of 1000 mg/day. All patients showed a tendency toward relief of clinical symptoms after 1 week of treatment. This pulse therapy was administrated in a 3-week cycle. Remission was induced after 2–3 cycles.19 There has been an additional clinical report of the administration of pulse therapy (8–10 mg/kg per day) in eight patients, with rapid improvement seen in the clinical symptoms of all eight patients. Oral immunosuppressant was administrated as usual. Relapse occurred in four cases, and was treated with repeated pulse therapy. Remission was induced in three out of these four cases. No severe adverse drug reactions were observed.20 In contrast, findings from multicenter randomized research on the use of dexamethasone in pulse therapy raised questions about the need for the addition of dexamethasone pulse therapy in typical pemphigus treatment.21

CQ7: Is the concomitant use of oral steroids and cyclophosphamide useful? Degree of recommendation: C1. Recommendation: A combination of oral steroid and cyclophosphamide should be tried in patients who are resistant to treatment with immunosuppressants such as azathioprine and cyclosporin, but careful monitoring for adverse drug reactions is required. Comments: Research in 54 pemphigus patients showed that the concomitant use of cyclophosphamide enabled a decrease in the steroid dose.3 In clinical research in 11 patients, cyclophosphamide exhibited effectiveness even at the low dose of 50 mg/day.22 A comparative study was also conducted of 28 patients with mucosal-dominant pemphigus, allocated into three groups (prednisone 40 mg monotherapy, prednisone 40 mg + cyclophosphamide 100 mg and prednisone 40 mg + cyclosporin 5 mg/kg).

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Results showed no significant difference in time to remission induction or relapse rate, and a higher incidence of adverse drug reactions was observed in the concomitant use groups.23

results indicate that plasma exchange concomitantly with high-dose steroid + immunosuppressant can lower the blood antibody titer more rapidly than typical treatment, leading to the conclusion that this therapy can be useful in refractory cases of pemphigus.27

CQ8: Is cyclophosphamide pulse therapy useful? Degree of recommendation: C1. Recommendation: In cases of pemphigus that are resistant to a variety of therapies, cyclophosphamide pulse therapy may be effective. Comments: Research was conducted in 22 pemphigus patients, using MA therapy (methylprednisolone 2 mg/kg per day + azathioprine 2–2.5 mg/kg per day) in 11 patients and DC pulse therapy (dexamethasone 100 mg/day for 3 consecutive days + cyclophosphamide 500 mg on day one) in 11 patients, and effectiveness and adverse drug reactions were compared. In evaluation conducted at 24 months, DC therapy resulted in five patients in remission and six patients in progressive disease, and MA therapy resulted in nine patients in remission and one patient in progressive disease. The incidence of relapse and adverse drug reactions were clearly higher with MA therapy.24 In separate clinical research in 26 pemphigus patients, once monthly cyclophosphamide (15 mg/kg) with concomitant daily prednisolone 60 mg (PSL dose decreased depending on clinical symptoms), marked improvement was noted in all patients 1 month after the start of treatment. Relapse, primarily mucosal, occurred after 3 weeks to 8 months in nine patients. Cyclophosphamide pulse therapy + prednisolone can be effective in the treatment of refractory pemphigus, but the necessity of close monitoring for adverse drug reactions is strongly emphasized.25 Clinical research in 50 patients in India has shown the effectiveness of dexamethasone–cyclophosphamide pulse therapy.26

CQ9: Is the concomitant use of oral steroids, cyclophosphamide and plasma exchange useful in refractory cases? Degree of recommendation: C1. Recommendation: This therapy is useful in patients who are resistant to various forms of therapy with oral steroids in combination with cyclophosphamide and plasma exchange. The removal of IgG by plasma exchange can be followed by a rebound effect that is associated with B-cell activation, and cyclophosphamide can be effective against that activation. However, after administration, patients should undergo periodic testing for adverse drug reactions. Comments: Patients were allocated to two groups. The 11 patients in group A were treated with plasma exchange + corticosteroids + immunosuppressive drugs (on average, a patient underwent 5–12 courses of plasma exchange at intervals of 10–24 days). The 11 patients in group B were treated with corticosteroids + immunosuppressive drugs. Laboratory tests were conducted to investigate changes in blood antibody titer. After 3 weeks, antibody titers in group A were reduced 83% from baseline at the time of admission, in comparison to an 18% reduction in group B. These

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Additional research was conducted in seven pemphigus patients whose condition was resistant to typical treatment or who had developed serious complications. Patients were assigned to one of three groups for plasma exchange: three patients in the low-volume group (400 mL exchange followed by 200 mL of 5% albumin supplementation once weekly for 9 weeks), three patients in the high-volume group (1200 mL plasma exchange followed by 5% albumin 400 mL and physiological saline solution 500 mL supplementation once weekly for 6 weeks), and one patient in the ultra-high-volume group (4000 mL plasma exchange with equivolume donor plasma exchange, followed by 2500 mL plasma exchange once monthly + cyclophosphamide 200–300 mg/day). After plasma exchange, there was considerable dispersion among patients with regard to the extent of reduction in antibody titer. However, the results were reported to indicate effectiveness following both low-volume and high-volume plasma exchange, and improvement in symptoms was seen 1 month after treatment, on average. Adverse drug reactions were mild and few. Lowvolume plasma exchange is well-suited for use in patients who want to decrease their usual therapy, and high-volume plasma exchange is considered to be useful in patients who are resistant to usual therapy. Particularly rapid improvement, both in clinical symptoms and in laboratory test values, was seen after the first plasma exchange in the patient treated with a combination of ultra-high-volume plasma exchange + cyclophosphamide; blood antibody titer decreased from 1280 to 160. Reportedly, 3 months after the start of treatment it was possible to transition this patient to typical therapy.28 In other research, Debprah et al. used cyclophosphamide 2.0–2.5 mg/kg per day + oral prednisone 1.0 mg/kg per day (doses of both cyclophosphamide and prednisone based on ideal bodyweight rather than actual bodyweight) to treat 23 pemphigus patients in whom clinical remission could not be induced by other treatment methods (20 pemphigus vulgaris patients and three pemphigus foliaceus patients). Those patients who had lesions on at least 40% of the body surface area received concomitant plasma exchange therapy 4–6 times during the first 2 weeks of treatment. Following a mean duration of treatment of 17 months and a mean observation period of 27 months, complete remission was achieved in 19 out of 23 patients. The condition was relieved in one patient in the pemphigus foliaceus group, and treatment was ineffective in three patients in the pemphigus vulgaris group. The mean time to the induction of remission was 8.5 months. Adverse drug reactions were hematuria in five patients and infection in six patients. One patient developed bladder transitional epithelial cell carcinoma 15 years after the discontinuation of cyclophosphamide administration. No deaths attributed to oral cyclophosphamide administration have been reported.29

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CQ10: Is the concomitant use of oral steroids and mizoribine useful? Degree of recommendation: C2. Recommendation: The combined use of oral steroid and mizoribine has been reported to be useful,30 but further investigation is needed in a larger number of patients.

CQ11: Is the concomitant use of oral steroids and mycophenolate mofetil useful? Degree of recommendation: C1. Recommendation: Concomitant therapy with mycophenolate mofetil can be useful in cases of refractory pemphigus that are resistant to steroid monotherapy or to combined therapy with other immunosuppressants. Comments: In multicenter cooperative research in 40 pemphigus patients (33 cases of pemphigus vulgaris and seven cases of pemphigus foliaceus), patients were assigned to two groups: oral methylprednisolone + azathioprine (18 patients) or oral methylprednisolone + mycophenolate mofetil (21 patients). Results showed the same levels of clinical effectiveness and safety for both azathioprine and mycophenolate mofetil, with both regimens providing excellent control of the disease state.31 In multicenter clinical research, 51 pemphigus patients were treated with prednisolone monotherapy or prednisolone in combination with mycophenolate mofetil. The use of mycophenolate mofetil made it possible to decrease the steroid dose, but the effect was not as strong as that seen with azathioprine.3 Separately, clinical research in 17 patients with refractory pemphigus resulted in decreased steroid dose and induction of remission without adverse drug reactions in 12 cases.32 Additional research in 42 patients resulted in complete or partial remission in 32 cases, indicating the effectiveness of this drug.33 According to a very recent report of pemphigus therapy in 31 patients, mycophenolate mofetil was useful in reducing steroid dose. Those authors concluded that mycophenolate mofetil should be the immunosuppressant of first choice for concomitant use with steroids except in patients with extensive lesions and patients who have high blood antibody titers.34

CQ12: Is methotrexate useful in the treatment of pemphigus? Degree of recommendation: C1. Recommendation: Low to moderate doses of methotrexate can be useful in reducing steroid dose. Comments: Low-dose methotrexate was administrated concomitantly with oral steroid in nine relapsing pemphigus patients. Methotrexate was given once weekly (2.5 mg every 12 h for a total of three times). The dose was increased every 2 weeks if needed, depending on symptoms, to a maximum of 17.5 mg/week. After symptoms were relieved, the steroid dose was decreased by 50% every 2 weeks. The nine patients were treated a total of 13 times. The mean methotrexate dose was 12.2 mg/week. In six out of nine of these patients (67%), steroid administration did not continue beyond 6 months. There were no instances of relapse during

© 2014 Japanese Dermatological Association

the period of oral methotrexate administration, and it was possible to control the disease state (prior to the administration of methotrexate, it had not been possible to reduce the steroid dose below 20 mg/day). In comparison, when 40 other pemphigus patients were treated concomitantly with another immunosuppressant, steroid discontinuation within any 6-month period was reported to be feasible in only 5– 7% of patients. This leads to the conclusion that concomitant therapy with methotrexate can be useful in the treatment of cases that have been otherwise resistant to steroid tapering and in the treatment of relapsed cases. Adverse drug reactions were few and mild (one case of nausea and one case of elevated transaminase enzymes). Mean time to relapse after methotrexate discontinuation was 23 days.35

CQ13: Is dapson (diaminodiphenylsulfone: DDS) useful in the treatment of pemphigus? Degree of recommendation: C1. Recommendation: In cases where it is difficult to decrease the steroid dose during maintenance therapy, concomitant use of DDS may be effective. Comments: A multicenter randomized double-blind study was conducted in 19 pemphigus patients who were receiving maintenance therapy for pemphigus (patients in whom steroid tapering had been attempted unsuccessfully at least twice, and patients who had been treated with the same steroid dose for ≥30 days). The DDS group that remained in maintenance therapy contained, at the end, eight patients whose PSL dose had been successfully tapered to 7.5 mg/ day. This goal was achieved in only three patients in the control group. Although final statistical analysis in this clinical research indicated no significant difference between the two groups, the DDS group showed a tendency toward greater potential for steroid tapering than the control group.36

CQ14: Is rituximab (anti-CD20 antibody) useful in the treatment of refractory pemphigus? Degree of recommendation: C1. Recommendation: Rituximab (anti-CD20 antibody) is useful in serious cases of pemphigus that are resistant to treatment modalities such as conventional steroid and immunosuppressant therapies. However, serious adverse drug reactions that resulted in deaths have been reported, so it is important to monitor patients particularly carefully for adverse drug reactions during the administration of rituximab. Comments: According to a report on five refractory pemphigus patients who were treated with rituximab 375 mg/m² once weekly for 4 weeks, all five patients showed improvement in clinical symptoms during the 3-year monitoring period, and it was possible to decrease the immunosuppressant dose or discontinue immunosuppressant administration entirely. B cells were effectively inhibited for 6–12 months, and in one case for 3 years.37 In separate clinical research, the same protocol was used to treat an additional five pemphigus patients. Complete or partial remission was achieved in three of those five patients;

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treatment was ineffective in the remaining two patients. Effectiveness was noted in 2–8 months, and symptomatic improvement was observed for 13–18 months. Complications of infection developed in two patients (communityacquired pneumonia in one case and cytomegalovirus infection in one case).38 In additional clinical research, when 11 pemphigus patients were treated with two courses of treatment using rituximab 375 mg/m² once weekly for 3 weeks + Ig 400 mg/kg per day for 5 days once monthly, after which the same dose of rituximab + the same dose of Ig was continued for a total of 4 months. Nine of these patients responded rapidly to this treatment. The mean duration of remission was 31.1 months. In all cases, it was possible to reduce the dose both of steroid and of immunosuppressant prior to the completion of rituximab therapy.39 Separately, research was conducted on the effects of a single cycle of rituximab therapy in 21 patients with refractory pemphigus. Patients were treated with rituximab 375 mg/m² once weekly for 4 weeks. Observation for 3 months after the discontinuation of treatment showed complete remission in 18 patients. Relapse was noted in nine patients (after a mean period of 18 months). During the 34-month observation period, 18 patients experienced remission, and in eight of those patients it was possible to discontinue steroid administration. Adverse drug reactions consisted of one case of pyelonephritis (occurring 12 months after administration) and one death from septicemia (18 months after administration). In both cases, there was pronounced B-cell suppression, but serum IgG was within the normal range. The administration of a single cycle of rituximab can be effective in the treatment of refractory pemphigus, but because this treatment regimen has been associated with serious adverse drug reactions, investigators concluded that it should only be used in extremely refractory cases.40 The method of administration should be rituximab 375 mg/m² once weekly, repeated four times (one course of treatment). The effectiveness of administration of two courses of this treatment in 6 months has also been reported.41

STANDARDS FOR THE DETERMINATION OF EVIDENCE LEVEL AND DEGREE OF RECOMMENDATION The following standards, from skin cancer treatment guidelines edited by the Japanese Dermatological Association, were used for the classification of evidence level and degree of recommendation as used in this document.

STANDARDS FOR THE CLASSIFICATION OF EVIDENCE LEVEL AND DEGREE OF RECOMMENDATION A: Classification of evidence level. I: Systematic review and/or meta-analysis. II: One or more randomized comparative studies.

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III: Non-randomized comparative study. IV: Analytical epidemiology study (cohort research and case-control studies). V: Descriptive study (case reports and case series studies). VI: Opinions of expert committee and individual specialists (1). B: Degree of recommendation classification (2) a: Strongly recommended for implementation b: Recommended for implementation (Efficacy shown by one or more evidence-based reports: low-quality Level II, high-quality Level III, or very high-quality Level IV. There is evidence for the basis of classifying the evidence level and the degree of recommendation.) C1: Implementation can be considered, but evidence is insufficient (low-quality III to IV, high-quality multiple V, or commission-approved VI). C2: No evidence (3); not actively recommended (no evidence of effectiveness, or evidence available of ineffectiveness). D: Recommended not to implement (high-quality evidence of ineffectiveness or harmfulness). Notes: 1. Data from basic research and theories derived from such data are placed at this level. 2. Some of the “degree of recommendation” statements in these Guidelines are not in complete agreement with the above. Internationally, the standardization of evaluation criteria for the pemphigus disease state has only begun. These “degree of recommendation” grades were established after indicating the evidence levels, and were based on a consensus among the committee members after reviewing the practicality of such grades. This was done with consideration for the fact that in some cases the evidence is insufficient or the evidence from overseas is not directly applicable in Japan. 3. “Evidence” refers to knowledge from clinical trials and epidemiological research.

SPONSORS AND CONFLICTS OF INTEREST The costs of formulating these guidelines were covered by a Health and Labor Sciences Research Grant from the Japanese Ministry of Health, Labor and Welfare. In cases where any of the committee members named above were involved with the development of a related specific drug or treatment method, those committee members did not contribute directly to the decision regarding the degree of recommendation for that treatment. None of the committee members had any other conflicts of interest that should be revealed in relation to the formulation of these guidelines.

DISCLAIMERS 1. These clinical practice guidelines are intended to provide an objective assessment of the current level of medical

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treatment, from the viewpoint of dermatologists and clinicians. We do not require that the treatment selected for individual patients must agree with the content of these guidelines. These guidelines are not intended to limit the physician’s discretion or to regulate therapeutic decisions. The use of these guidelines as materials in medical malpractice claims or lawsuits is a gross deviation from the intended objective, and is not countenanced by this committee. 2. Treatment methods and medications that are not approved by the Japanese health insurance system but for which there is medical evidence in Japan and overseas have been covered in these guidelines, and the degree of recommendation for those drugs and treatment methods has been added. Portions of these guidelines also discuss methods of use that are not included in the Japanese package insert for that drug. This is because the guidelines are descriptions based on medical evidence, rather than being a manual for medical services under National Health Insurance. It is incorrect to assume that the treatment methods and medications that are described in these guidelines can be freely incorporated and used in the context of ordinary medical practice. In all cases, application to and approval by the institutions involved will be required for each treatment approach, and it will be necessary to obtain informed consent from the patient or the patient’s family.

CONFLICT OF INTEREST:

None.

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