Treatment Guidance for Palmoplantar Pustulosis 2022

ABSTRACT

Palmoplantar pustulosis (PPP) is an inflammatory skin disease characterized by chronic and relapsing eruptions of multiple sterile pustules on the palms and soles, which subsequently crust and desquamate. In addition to pustules, vesicles and pustulo‐vesicles are often observed simultaneously. It is more prevalent among Japanese individuals, and the number of affected patients in Japan is estimated to be approximately 140,000 based on national health insurance claims data in Japan. Sterile osteitis occurs in 10%–30% of patients with PPP or a history of PPP, a condition referred to as pustulotic arthro‐osteitis. Because it has become evident that focal infections act as triggering factors in approximately 80% of both conditions, their therapeutic algorithms differ fundamentally from those for psoriasis. The aim of the Treatment Guidance for Palmoplantar Pustulosis 2022 was to clarify the clinical manifestations and histopathological findings supporting the diagnosis of PPP, and to explain treatment algorithms and recommendation grades based on differences in triggering factors and pathophysiology between PPP and psoriasis. Although the level of evidence is limited due to the ethical and practical difficulties in conducting rigorous double‐blinde clinical trials to evaluate the efficacy of focal infection treatment, the treatment recommendations were determined through expert consensus based on extensive clinical experience accumulated in Japan, together with relevant basic research findings.

1. Chapter I

1.1. Introduction

Palmoplantar pustulosis or pustulosis palmoplantaris (PPP) is a disease that forms lesions that are primarily sterile pustules in the palm and sole, and the number of patients with PPP in Japan is estimated to be about 140,000 based on the itemized statement of medical expenses collected by the Ministry of Health, Labour, and Welfare [1]. There are more female than male patients, and the peak age at onset is observed in middle age or later. In addition, patients show a characteristically high smoking rate. Although PPP is a relatively common disease, there have been few randomized controlled trials (RCTs) concerning its treatment and there are no treatment guidelines or comparable standards. PPP affects a more limited area of skin compared with its related disease psoriasis, but it impairs patients' quality of life (QOL) because lesions arise in locations visible to others and because skin atrophy may develop with prolongation of topical application of corticosteroid; furthermore, fissures are likely to occur due to body weight, causing pain. QOL is further impaired if the condition is accompanied by bone and joint symptoms (pustulotic arthro‐osteitis: PAO), which are characterized by pain in the anterior chest wall. The incidence of PAO is reported to be about 0.04% from the above data of the itemized statement of medical expenses [1], but it reaches 30% among PPP patients treated at university hospitals [2]. Although PAO most frequently affects areas including the sternum such as the sternoclavicular joint and sternocostal joints, it may also affect joints of the body axis (cervical spine, thoracic spine, lumbar spine, sacroiliac joints, hip joints), shoulder joints, and peripheral joints and may well be overlooked. Currently, since the diagnostic criteria for PAO have not been established, dissemination of knowledge is insufficient in not only the field of dermatology but also the fields of rheumatology and orthopedics, and making a definitive diagnosis may take time.

In view of such circumstances, the present Treatment Guidance for PPP was prepared to offer and share the latest information concerning the appropriate diagnosis and treatment of PPP and lifestyle guidance. It aims to contribute to improvement of patients' QOL by early diagnosis made possible by its use as a guide in the daily practice of physicians engaged in the diagnosis and treatment of PPP and PAO in Japan.

1.2. Position and Characteristics of the Treatment Guidance for PPP

This Treatment Guidance was drafted primarily by dermatologists, but cooperation was also requested from orthopedists and rheumatologists who examine and treat joint symptoms. A draft was prepared over several sessions and was released according to the procedure formulated by the Japanese Dermatological Association after obtaining approval from its board of directors.

The descriptions of medical actions mentioned in this Treatment Guidance are basically based on evidence‐based medicine (EBM), but as there have been few RCTs concerning treatment of PPP/PAO, the Guidance includes expert opinions based on the current situation and aims to offer provisional standards and treatment goals according to the current (December 2021) treatment principles for PPP/PAO. However, physicians in clinical situations must make decisions by conferring with patients and respecting their values and wishes.

1.3. Plans for Future Updates

The present Treatment Guidance for PPP was prepared at the strong request of clinicians due to the absence of domestic treatment guidelines for PPP and PAO. In the future, the results of basic and clinical research concerning PPP and PAO are expected to be reported, and many clinical trials of new treatments have been implemented. At present, treatments with a high evidence level based on RCTs are limited, and the necessity for future improvements of the Guidance is evident. After the present Treatment Guidance is put into effect, we intend to update it every 3–5 years also by reflecting clinicians' opinions.

1.4. Declaration of Conflicts of Interest

The members of the Drafting Committee of this Treatment Guidance have made self‐declaration of conflicts of interest (COI) based on the standards concerning COI at the institutions to which they belong (or the Japanese Association of Medical Sciences COI Management Guidelines^†). The cost of the preparation of this Treatment Guidance was borne by each committee member. Also, the committee members have received no compensation for their services including the preparation of the text of this Guidance and attendance at meetings. All decisions about recommendations were reviewed and revised by respecting the consensus of all members of the Drafting Committee as well as members in charge of each section.

Whether the members of the Treatment Guidance Drafting Committee or their relatives within the second degree of kinship have received any compensation in the form of the items mentioned below from companies involved in the diagnosis/treatment of PPP/PAO was declared. The target period was from January 1, 2018 until December 31, 2021. (1) Executive/advisor compensations, (2) Capital gain, (3) Patent royalties, (4) Lecture fees, (5) Manuscript fees, (6) Clinical research funding (consigned research funds, joint research funds, trial research funds), (7) Grant donations, (8) Honoraria for lectures, (9) Receipt of travel expenses/gifts. Corresponding companies/organizations: It was stipulated that if any of the committee members was involved in the development of a particular related drug or had COI, the member would be excluded from the assessment of the recommendation grade of the treatment concerned.

Tadashi Terui: (Maruho Co. Ltd. [Lecture fees, Grant donations], Janssen Pharmaceutical K.K. [Lecture fees], Eisai Co. Ltd. [Lecture fees, Grant donations], Taiho Pharmaceutical Co. Ltd. [Grant donations], Nippon Boehringer Ingelheim Co. Ltd. [Lecture fees], Sun Pharma Japan Ltd. [Grant donations], AbbVie GK. [Lecture fees, Grant donations]), Satomi Kobayashi: (Janssen Pharmaceutical K.K. [Lecture fees], Taiho Pharmaceutical Co. Ltd. [Lecture fees], Celgene Corporation [Lecture fees], Novartis Pharma K.K. [Lecture fees], Maruho Co. Ltd. [Lecture fees], Kyowa Kirin Co. Ltd. [Clinical research funding]), Toshiyuki Yamamoto: (Novartis Pharma K.K. [Lecture fees], Janssen Pharmaceutical K.K. [Lecture fees], AbbVie GK. [Lecture fees], Eisai Co. Ltd. [Lecture fees], Taiho Pharmaceutical Co. Ltd. [Lecture fees]), Yukari Okubo: (Kyowa Kirin Co. Ltd. [Lecture fees, Grant donations], Novartis Pharma K.K. [Lecture fees, Grant donations], Celgene Corporation [Lecture fees], AbbVie GK. [Lecture fees, Clinical research funding, Grant donations], Janssen Pharmaceutical K.K. [Lecture fees, Clinical research funding], Taiho Pharmaceutical Co. Ltd. [Lecture fees, Grant donations], Shiseido Company, Limited [Clinical research funding], Nihon Nohyaku Co. Ltd. [Clinical research funding], Mochida Healthcare Co. Ltd. [Clinical research funding], Sun Pharma Japan Ltd. [Clinical research funding, Grant donations], Pfizer Japan Inc. [Clinical research funding], Bristol‐Myers Squibb Company [Clinical research funding], Nippon Boehringer Ingelheim Co. Ltd. [Clinical research funding], Mediscience Planning Inc. [Clinical research funding], Otsuka Pharmaceutical Co. Ltd. [Clinical research funding], EPS Corporation [Clinical research funding], Cmic Co. Ltd. [Clinical research funding], Mebix Inc. [Clinical research funding], Pfizer R&D Japan G.K. [Clinical research funding], Parexel International Inc. [Clinical research funding], UCB Japan Co. Ltd. [Lecture fees, Clinical research funding], Eli Lilly Japan K.K. [Lecture fees, Clinical research funding], Eisai Co. Ltd. [Grant donations], Torii Pharmaceutical Co. Ltd. [Grant donations], Maruho Co. Ltd. [Lecture fees, Clinical research funding, Grant donations], Kaken Pharmaceutical Co. Ltd. [Grant donations], JIMRO Co. Ltd. [Grant donations], LEO Pharma K.K. [Grant donations, Clinical research funding], GlaxoSmithKline K.K. [Grant donations]), Masamoto Murakami: (AbbVie GK. [Lecture fees, Clinical research funding], Janssen Pharmaceutical K.K. [Lecture fees], Taiho Pharmaceutical Co. Ltd. [Lecture fees], Maruho Co. Ltd. [Lecture fees], Novartis Pharma K.K. [Lecture fees], Kyowa Kirin Co. Ltd. [Grant donations], Eli Lilly Japan K.K. [Grant donations], ARISTEA Therapeutic, USA [Clinical research funding]), Namiko Abe: (Shiseido Company, Limited [Clinical research funding], Nihon Nohyaku Co. Ltd. [Clinical research funding], Mochida Healthcare Co. Ltd. [Clinical research funding], Sun Pharma Japan Ltd. [Clinical research funding, Grant donations], Parexel International Inc. [Clinical research funding], UCB Japan Co. Ltd. [Clinical research funding], Eli Lilly Japan K.K. [Clinical research funding], Janssen Pharmaceutical K.K. [Clinical research funding], AbbVie GK. [Clinical research funding, Grant donations], Pfizer R&D Japan G.K. [Clinical research funding], Bristol‐Myers Squibb Company [Clinical research funding], Nippon Boehringer Ingelheim Co. Ltd. [Clinical research funding], Mediscience Planning Inc. [Clinical research funding], Otsuka Pharmaceutical Co. Ltd. [Clinical research funding], EPS Corporation [Clinical research funding], Cmic Co. Ltd. [Clinical research funding], Mebix Inc. [Clinical research funding], Maruho Co. Ltd. [Clinical research funding, Grant donations], Eisai Co. Ltd. [Grant donations], Torii Pharmaceutical Co. Ltd. [Grant donations], Taiho Pharmaceutical Co. Ltd. [Grant donations], Kyowa Kirin Co. Ltd. [Grant donations], Kaken Pharmaceutical Co. Ltd. [Grant donations], JIMRO Co. Ltd. [Grant donations], LEO Pharma K.K. [Clinical research funding, Grant donations], Novartis Pharma K.K. [Grant donations], GlaxoSmithKline K.K. [Grant donations]), Natsumi Ikumi: (Maruho Co. Ltd. [Lecture fees, Grant donations], Asahi Kasei Corporation [Lecture fees], Novartis Pharma K.K. [Lecture fees], AbbVie GK. [Lecture fees], Janssen Pharmaceutical K.K. [Lecture fees], Kyowa Kirin Co. Ltd. [Lecture fees], Taiho Pharmaceutical Co. Ltd. [Lecture fees], UCB Japan Co. Ltd. [Lecture fees], Sun Pharma Japan Ltd. [Grant donations], Eisai Co. Ltd. [Grant donations]), Madoka Ishii: (Maruho Co. Ltd. [Grant donations], Eisai Co. Ltd. [Grant donations], Taiho Pharmaceutical Co. Ltd. [Grant donations], Sun Pharma Japan Ltd. [Grant donations], AbbVie GK. [Grant donations]), Yoshinori Umezawa: (AbbVie GK. [Lecture fees], Eli Lilly Japan K.K. [Lecture fees], Maruho Co. Ltd. [Lecture fees], Janssen Pharmaceutical K.K. [Lecture fees], Kyowa Kirin Co. Ltd. [Lecture fees], Taiho Pharmaceutical Co. Ltd. [Lecture fees], UCB Japan Co. Ltd. [Lecture fees], Sun Pharma Japan Ltd. [Lecture fees]), Takuro Kanekura: (Maruho Co. Ltd. [Grant donations], Sun Pharma Japan Ltd. [Grant donations]), Mari Kishibe: (Taiho Pharmaceutical Co. Ltd. [Grant donations]), Ayano Kurumatani: (Maruho Co. Ltd. [Grant donations], Eisai Co. Ltd. [Grant donations], Sun Pharma Japan Ltd. [Grant donations]), Michiyoshi Kouno: (AbbVie GK. [Lecture fees], Taiho Pharmaceutical Co. Ltd. [Lecture fees], Nippon Boehringer Ingelheim Co. Ltd. [Clinical research funding]), Tadamichi Shimizu: (Janssen Pharmaceutical K.K. [Lecture fees], Tsumura & Co. Ltd. [Lecture fees], Maruho Co. Ltd. [Lecture fees]), Shigeyoshi Tsuji: (Asahi Kasei Pharma Corporation [Lecture fees], Astellas Pharma Inc. [Lecture fees], Amgen Astellas BioPharma K.K. [Lecture fees], AbbVie GK. [Lecture fees, Manuscript fees, Clinical research funding, Grant donations], Amgen Inc. [Lecture fees], Ayumi Pharmaceutical Corporation [Lecture fees], Eisai Co. Ltd. [Lecture fees], JIMRO Co. Ltd. [Lecture fees], Chugai Pharmaceutical Co. Ltd. [Lecture fees], JCHO Hoshigaoka Medical Center [Lecture fees], Nonprofit Corporation, Psoriasis Patients' Support Association in Tokyo [Lecture fees], Nippon Boehringer Ingelheim Co. Ltd. [Lecture fees], Japanese Red Cross Society Himeji Hospital [Lecture fees], Kyowa Kirin Co. Ltd. [Lecture fees, Manuscript fees], Gilead Sciences Inc. [Clinical research funding], Celgene Corporation [Lecture fees], Taiho Pharmaceutical Co. Ltd. [Lecture fees], Mitsubishi Tanabe Pharma Corporation [Lecture fees], Eli Lilly Japan K.K. [Lecture fees], Novartis Pharma K.K. [Lecture fees, Manuscript fees], Pfizer Japan Inc. [Lecture fees], Bristol‐Myers Squibb K.K. [Lecture fees], Janssen Pharmaceutical K.K. [Lecture fees, Manuscript fees], UCB Japan Co. Ltd. [Lecture fees, Clinical research funding], Maruho Co. Ltd. [Lecture fees, Manuscript fees], Daiichi Sankyo Company, Limited [Grant donations], Japan Agency for Medical Research and Development [Clinical research funding]), Eiko Toichi: (Janssen Pharmaceutical K.K. [Lecture fees], AbbVie GK. [Lecture fees], Taiho Pharmaceutical Co. Ltd. [Lecture fees]), Motoki Nakamura: (Ushio Inc. [Clinical research funding], Celgene Corporation [Clinical research funding], Inforward Inc. [Clinical research funding], Amgen Inc. [Clinical research funding], Janssen Pharmaceutical K.K. [Clinical research funding], Taiho Pharmaceutical Co. Ltd. [Grant donations], Torii Pharmaceutical Co. Ltd. [Grant donations], Maruho Co. Ltd. [Grant donations], Kyowa Kirin Co. Ltd. [Grant donations], LEO Pharma K.K. [Grant donations], Ono Pharmaceutical Co. Ltd. [Grant donations], Sun Pharma Japan Ltd. [Grant donations], AbbVie GK. [Grant donations], Mitsubishi Tanabe Pharma Corporation [Grant donations], Eisai Co. Ltd. [Grant donations], Novartis Pharma K.K. [Grant donations], Kaken Pharmaceutical Co. Ltd. [Grant donations], Mandom Corporation [Honoraria for lectures]), Emi Nishida: (Eli Lilly Japan K.K. [Lecture fees]), Koremasa Hayama: (AbbVie GK. [Lecture fees], Taiho Pharmaceutical Co. Ltd. [Lecture fees], Maruho Co. Ltd. [Grant donations], Eisai Co. Ltd. [Grant donations], Sun Pharma Japan Ltd. [Grant donations]), Daisuke Fujisawa: (Maruho Co. Ltd. [Grant donations], Sun Pharma Japan Ltd. [Grant donations], Eisai Co. Ltd. [Grant donations]), Hideki Fujita: (Novartis Pharma K.K. [Lecture fees], AbbVie GK. [Lecture fees], Taiho Pharmaceutical Co. Ltd. [Lecture fees], Maruho Co. Ltd. [Grant donations], Sun Pharma Japan Ltd. [Grant donations], Eisai Co. Ltd. [Grant donations]), Yuka Matsumoto: (Kuniyoshi Yoshizawa, Medical Corporation Yoshizawa Clinic [Executive/advisor compensations], Medical Corporation Shunkeibikai Mizutani Dermatology Clinic [Executive/advisor compensations]), Akimichi Morita: (Eisai Co. Ltd. [Lecture fees, Grant donations], AbbVie GK. [Lecture fees, Grant donations], Mitsubishi Tanabe Pharma Corporation [Lecture fees, Grant donations], Maruho Co. Ltd. [Lecture fees, Grant donations], Novartis Pharma K.K. [Lecture fees, Grant donations], Janssen Pharmaceutical K.K. [Lecture fees, Clinical research funding], Eli Lilly Japan K.K. [Lecture fees], UCB Japan Co. Ltd. [Lecture fees], Minophagen Pharmaceutical Co. Ltd. [Lecture fees], Amgen Inc. [Clinical research funding], Ushio Inc. [Clinical research funding], Celgene Corporation [Clinical research funding], Inforward Inc. [Clinical research funding], Taiho Pharmaceutical Co. Ltd. [Grant donations], Torii Pharmaceutical Co. Ltd. [Grant donations], Kyowa Kirin Co. Ltd. [Grant donations], LEO Pharma K.K. [Grant donations], Ono Pharmaceutical Co. Ltd. [Grant donations], Kaken Pharmaceutical Co. Ltd. [Grant donations], Mebix Inc. [Grant donations], Sun Pharma Japan Ltd. [Lecture fees, Grant donations]).

^† http://jams.med.or.jp/guideline/coi_guidelines.pdf.

1.5. Collection of Evidence

Already published papers were collected as evidence. In Western countries, PPP and palmoplantar pustular psoriasis are often considered synonymous, and both conditions are collectively referred to as PPP. Since palmoplantar pustular psoriasis does not form vesicles as described below, they are different disorders. Therefore, we did not include the literature that mentions palmoplantar pustular psoriasis as references. In addition, we checked whether palmoplantar pustular psoriasis was included even when the literature described the disorder as palmoplantar pustulosis.

Treatments that were not confirmed to be effective by an RCT but were considered to be effective were rated as B* or C1* if consensus was reached among the committee members after sufficient discussion.

1.6. List of the Evidence Levels and Recommendation Grades

1. Classification of evidence levels

   1. Systematic reviews/meta‐analyses
   2. One or more randomized controlled trials
   3. Non‐randomized controlled trials
   4. Analytical epidemiological studies (cohort studies and case–control studies)
   5. Descriptive studies (case reports and case series studies)
   6. Opinions of expert committees and individual experts
2. Classification of recommendation grades

   • A
     Implementation is strongly recommended
     (at least one level I or high‐quality level II piece of evidence indicating the efficacy)
   • B
     Implementation is recommended
     (at least one low‐quality level II, high‐quality level III, or very high‐quality level IV piece of evidence)
   • C1
     Consideration of implementation is supported, but there is no sufficient evidence
     (low‐quality level III–IV, multiple high‐quality level V, or level VI evidence recognized by the committee)
   • C2
     Not recommended because of the absence of evidence
   • D
     Recommended not to be performed
     (high‐quality evidence indicating inefficacy or harmfulness)

1.7. Disclaimer

The present Guidance does not hinder the contents of medical activities conducted based on individual patients' circumstances differing from those described in the present Guidance nor deny medical staff's experience. Furthermore, the present Guidance does not provide grounds for prosecuting physicians' actions if the contents described in the present Guidance are not conducted. The use of the present Guidance as materials for medical disputes or lawsuits deviates from its proper purpose.

Treatments reported in Japan or abroad are mentioned even if they are treatments that are not covered under the Japanese health insurance system (unapproved drugs). The idea that the drugs or treatments described in the present Guidance are available in clinical practice is incorrect. Likewise, concerning the usage of drugs for which contraindications, careful administration or the subjects to be treated are described in the package inserts, restrictions are not exempted with descriptions in the present guidance. Concerning individual drugs, it is important to take measures including obtaining the patients' informed consent based on the package inserts and the latest information.

2. Chapter II: Diagnosis and Severity of PPP

2.1. Definition and Diagnosis of PPP

2.1.1. Definition and Diagnosis

Primary items necessary for the definition and diagnosis of PPP were established, as shown in Table 1.

TABLE 1.

Definition and diagnosis of PPP.

Definition of palmoplantar pustulosis Palmoplantar pustulosis (PPP) is a disease that induces multiple new/old sterile pustules of the palm and sole or either site. In addition to pustules, vesicles are simultaneously observed in some cases. Repeated exacerbations and relief lead to a chronic course.

Primary items for diagnosis Multiple new/old sterile pustules of the palm and sole or either one. Repeated lesions show a chronic course. Psoriasis, contact dermatitis, pompholyx/dyshidrotic eczema, tinea manus/tinea pedis, eosinophilic pustular folliculitis, and mycosis fungoides can be ruled out.

Characteristic features for reference Repeated pustulation leads to the formation of a lesion with erythema and scales. Nail lesions or extra‐palmoplantar exanthema is sometimes observed. Osteoarticular symptoms, including pain of the anterior chest wall, are sometimes present (pustulotic arthro‐osteitis). Focal infection is present in many patients. This disease frequently develops in middle‐aged females, and the rate of smokers is high.

2.1.1.1. Definition

PPP* is a disease that induces multiple new/old sterile pustules** of the palm and sole or either site. In addition to pustules, vesicles*** are simultaneously observed in some cases. Repeated exacerbations and relief lead to a chronic course.

2.1.1.2. Primary Items Necessary for Diagnosis

1. Multiple new/old sterile pustules** of the palm and sole or either site are present.

2. Repeated exacerbations and relief lead to a chronic course****.

3. Psoriasis, contact dermatitis, pompholyx/dyshidrotic eczema, tinea manus/tinea pedis, eosinophilic pustular folliculitis, and mycosis fungoides can be ruled out.

2.1.1.3. Other Characteristics

1. Repeated formation of pustules leads to the development of erythemato‐squamous lesions. Nail lesions or extra‐palmoplantar exanthema is concomitantly observed in some cases.

2. Osteoarticular symptoms, including pain of the anterior chest wall, are sometimes observed. The condition is called PAO.

3. Many patients have focal infection*****.

4. This disease frequently develops in middle‐aged females, and the rate in smokers is high.

2.1.1.4. Explanations

*Types A and B of PPP: In Japan, PPP refers to “pustular bacterid of the hands and feet,” which was proposed by Andrews. It is classified as a type of pustulosis. However, in Europe and the United States, pustular psoriasis of extremities, which was reported by Barber, is often regarded as PPP. PPP (or PPPP) mentioned in European and American articles has often been used as the abbreviation for palmo‐plantar pustular psoriasis, and tends to be regarded as localized pustular psoriasis, that is, a type of “psoriasis” in addition to acrodermatitis continua of Hallopeau. Therefore, the former is sometimes termed Andrews' Type A, and the latter Barber's Type B [3].

**Pustules are classified into three types based on the tone: white, yellow, and brown pustules. Brown pustules (including crusts) result from preceding white or yellow pustules.

***During the course, vesicles are simultaneously observed in addition to pustules in some cases. In such cases, pustulo‐vesicles, which are vesicles containing small pustules, representing transitional lesions between vesicles and pustules, are sometimes observed [4, 5, 6].

****Sterile pustules of the hands and feet are transiently formed during acute tonsillitis in some cases, but they are regarded as bacterid and not as PPP.

*****Tonsillitis or sinusitis in the field of otorhinolaryngology; apical lesions or periodontitis in the field of dentistry.

2.1.2. Clinical Features

Sterile small pustules of the palm and sole, vesicles, pustulo‐vesicles, crusts, desquamation, and erythema with an unclear border are observed. These symptoms do not appear all together, and even pustules as the most important characteristic of PPP are not observed all the time. Therefore, if pustules cannot be confirmed on consultation, follow‐up must be continued as a tentatively diagnosed patient. When pustules are extremely small, it is sometimes difficult to differentiate vesicles from pustules macroscopically; they are confirmed by dermoscopy. The process of pustule formation is “vesicle → pustulo‐vesicle → pustule,” but all vesicles do not change into pustules. Pruritus is often noticed in the pre‐pustule stage. After pustule formation, pruritus is absent in many cases. The site of exanthema is unilateral in some cases, and either hands or feet alone are affected in other cases. Furthermore, pustules disappear during the course, changing into a desquamation‐predominant clinical type in some cases. At this point, it is impossible to differentiate the condition from psoriasis. Concerning palmar lesions, exanthema frequently tends to develop at the thenar, hypothenar area, and center of the palm. Concerning plantar lesions, the border (medial margin, lateral margin) between the sole and dorsum of the foot is frequently affected in addition to the sole and heel. In patients with PPP, Koebner's phenomenon is also observed. According to a study [7], exanthema involved the shoes‐stimulated sites of the feet, or PPP was induced at the disposable body warmer‐attached site of the sole (by Koebner's phenomenon). Furthermore, extra‐palmoplantar lesions, such as elbow, knee, underwear elastic string‐stimulated, and umbilical lesions, as described below, may also be regarded as Koebner's phenomena.

The rate of nail lesions in patients with PPP is approximately 30%, which is lower than that in patients with psoriasis [8]. Various findings such as thickening of the nail plate, yellow coloration, convex/concave irregularity of the nail plate, subungual hyperkeratosis, exfoliation of the nail plate, punctate excavation, subungual pustules, destruction of the nail plate, splinter hemorrhage, and dystrophy, are observed, resembling psoriasis. Lesions are classified into nail matrix and bed lesions. The former is represented by punctate excavation and whitish change of the nail plate, and the latter by subungual pustules and exfoliation of the nail plate. However, the two lesions are often mixed.

PPP frequently develops in the Japanese population. Its characteristics are: (1) the rate of female patients is high, (2) its incidence in smokers is high regardless of sex, (3) the appearance of articular symptoms of the anterior chest wall is not rare, (4) both cutaneous and articular symptoms are closely related with focal infections, and (5) coexistence with psoriasis is rarely, if ever, observed [9].

2.1.3. Histopathology

As initial lesions, unilocular vesicles form in the stratum spinosum around an intraepidermal sweat duct. When these vesicles become adjacent to the stratum corneum, neutrophils primarily accumulate in their sites, becoming pustulo‐vesicles. These are filled with neutrophils, forming unilocular pustules. Subsequently, the pustules collapse, becoming crusted [4, 10].

In 1998, a study reported the association between eccrine sweat glands and vesicles/pustules in patients with PPP for the first time [5]. In 2010, eccrine sweat gland‐derived antimicrobial peptides, hCAP‐18 and dermcidin, were identified in vesicles, suggesting that eccrine sweat glands were responsible for vesicle formation, and the histopathology of vesicle formation in the intraepidermal sweat ducts‐centered spots was studied [6]. Thus, it has been clarified that PPP‐related vesicles and pustules occur in eccrine sweat glands. Furthermore, it is often difficult to differentiate PPP from dyshidrotic eczema in some patients with PPP, such as mild‐status patients and those without typical pustules. Differentiation methods have been discussed [11, 12, 13]. When differentiating the two diseases, the usefulness of histopathology was again examined, and a differentiation method focusing on the presence or absence of intraepidermal spongiosis and presence or absence of pustulo‐vesicles or microabscess at the pustule margin was proposed [13]. At that time, it was recommended that histopathological findings of pustulo‐vesicles should be used as widely as possible to make a definitive diagnosis, because examination of biopsy samples of initial vesicles or complete pustules makes it difficult to obtain characteristic findings.

As a difference between PPP‐related vesicles and dyshidrotic‐eczema‐related vesicles, a large number of keratinocytes containing a large amount of hyaluronic acid are observed in the latter, whereas this phenomenon is absent in the former. It was confirmed that small round cells in PPP‐related vesicles were mononuclear cells, suggesting their usefulness for differentiating the two diseases [14]. Briefly, if biopsy of pustulo‐vesicles is difficult, vesicles rather than complete pustules should be biopsied to investigate the type of cells contained in vesicles: mononuclear cells or keratinocytes. The histopathologies of vesicles, pustulo‐vesicles, and pustules are described below.

2.1.3.1. Vesicles

In the epidermis, unilocular vesicles are formed, and a small number of mononuclear cells are observed in the vesicles. Spongiosis is absent around the vesicles. Furthermore, there is no neutrophil migration, which is a characteristic (Figure 1).

FIGURE 1.

Initial lesion of PPP (H–E staining). Unilocular vesicles are formed adjacent to the acrosyringium.

2.1.3.2. Pustulo‐Vesicles

Intraepidermal vesicles reach the stratum corneum, and neutrophils primarily accumulate in the reached area. In the inner area, mononuclear cells and neutrophils are observed (Figure 2a). Microabscesses have formed at the edge of the pustulo‐vesicles (Figure 2b, arrow), and there is no spongiosis at their periphery (Figure 2b,c).

FIGURE 2.

(a–c) Pustulo‐vesicle (H–E staining).

2.1.3.3. Pustules

Intraepidermal vesicles become pustules filled with mononuclear cells and neutrophils. There is no spongiosis in the peripheral epidermis (Figure 3a). At the edge of a pustule, microabscesses are present (Figure 3b, arrow), and neutrophil infiltration is noted at the pustular base (Figure 3c).

FIGURE 3.

(a–c) Pustular phase (H–E staining).

2.1.4. Dermoscopy

Typical cutaneous lesions of PPP are multiple sterile vesicles, measuring 1–5 mm in diameter, with pruritus at the center of the palm or thenar and at the arch of the foot, heel, and foot rim, followed by coexistence with small pustules. On dermoscopy, exanthema with small white pustules at the center of vesicles is observed in addition to vesicles and pustules. This is termed “pustulo‐vesicle.” As contrasted with histopathological findings, the finding represents accumulation of neutrophils in the stratum corneum when vesicles reach the stratum corneum [4, 13, 15]. The contents of pustules eventually become turbid and get crusted, leading to desquamation. Repeated inflammatory responses by coexistence of these exanthemas result in erythema, scales, thickening, crustae, and cracks.

Diseases to be differentiated from PPP include tinea, pompholyx, pustular psoriasis, and eosinophilic pustular folliculitis. In patients with these diseases, there are no pustulo‐vesicles; thus, pustulo‐vesicles are characteristic of PPP.

Thus, when PPP is suspected, the careful detection of pustulo‐vesicles by dermoscopy is useful for diagnosis (Figure 4).

FIGURE 4.

Dermoscopic finding. Pustule‐vesicles are observed.

2.1.5. Differential Diagnosis

There are many diseases that induce palmoplantar pustules, such as infectious and pustular diseases. Representative diseases are summarized in Table 2.

TABLE 2.

Diseases to be differentiated from PPP.

Name of disease		Test method	Differentiation point
Infectious disease	Timea pedis	KOH microscopy	Microscopic examination of scales surrounding vesicles to confirm fungi.
	Syphilis	Blood test	Papular syphilis may progress to pustular syphilis in some cases. Serological test for syphilis should be confirmed.
	Scabies	KOH microscopy	Vesicles can also be observed in scabies. Direct microscopy is performed to detect mites and eggs of S. scabiei .
Pustular disease	Pustular psoriasis	Dermoscopy	Only pustules are observed. Pustules and erythema involve the whole body in many cases.
		Skin biopsy
	Acrodermatitis continua	Dermoscopy	Pustules, erythema, and desquamation are primarily observed at fingertips.
		Skin biopsy
	Eosinophilic pustular folliculitis	Dermoscopy	Systemic pustules are observed in many cases. Eosinophilic pustules should be confirmed by pathological examination.
		Skin biopsy
Eczema allergic disease	Contact dermatitis	Inquiry	Exanthema appears only at an area of contact with an allergen.
	Dyshidrotic eczema	Dermoscopy	Multilocular vesicles are observed.
	Pompholyx
Tumorous disease	Mycosis fungoides	Skin biopsy	Histopathological findings, such as Pautrier's microabscess, are noted.
Others	Palmoplantar keratoderma	Skin biopsy	Histopathologically, marked hyperkeratosis, irregular epidermal thickening, and thickening of the granular layer are observed. There is no neutrophil accumulation.

PPP‐related pustules are sterile because PPP is not an infectious disease. Therefore, infectious diseases must be ruled out. If fungal infection is suspected, fungal testing with KOH should be conducted. For differentiation from impetigo, general bacterial culture should be performed. If secondary infection is suspected, antibiotics should be administered. After the infection subsides, additional examination should be performed. Skin biopsy is also useful for differentiating hyperkeratotic lesions. When biopsy is difficult, dermoscopy is useful. The detection of pustulo‐vesicles by dermoscopy is useful for differentiation.

It is often difficult to differentiate PPP from pompholyx. Recently, a study reported the differentiation of histopathological findings of the two diseases [13]. Histopathologically, pompholyx consists of lymphocyte infiltration in the epidermis, and spongiosis is observed. As to vesicles, there is a mixture of large and small spongiotic vesicles. On the other hand, PPP is characterized by non‐spongiotic vesicles and microabscesses at the upper margin of vesicles.

2.2. Gene and HLA

In Europe and the United States, PPP has been classified as a type of localized pustular psoriasis, but it was suggested that the condition should be regarded as differing from psoriasis vulgaris or pustular psoriasis at the IPC Roundtable meeting (London, 2005) [16]. In Japan, PPP has been regarded as differing from pustular psoriasis for the following reasons: this disease is complicated by PAO; and on human leukocyte antigen (HLA) investigation, there are no associations of PPP with HLA‐A1, B13, B17, B37, and Cw6, which are frequently detected in patients with psoriasis. Previously, a case of familial PPP was reported in which neither parent had an apparent history of this disease; yet all five siblings and one daughter of one of the siblings, six individuals in total, developed PPP. HLA typing was performed in patients with this familial PPP, and all but one shared the HLA‐A2, B46, Cw1, DR8, and DQ1 haplotype [17]. Furthermore, previous studies found that PPP was correlated with HLA‐B8 [18], HLA‐Bw52, DR4 [19], HLA‐DR9 [20], and HLA‐B27 [21].

In addition, several studies reported that IL‐36RN gene mutation was frequently detected in patients with pustular psoriasis, whereas it was not frequently detected in those with PPP [22, 23].

In 2017, autoinflammatory keratinization diseases (AiKD) were proposed as a disease entity associated with IL36RN and CARD14 gene mutations [24]. PPP may be included in AiKD. In particular, PPP with a CARD14 gene mutation is termed CARD14‐mediated psoriasis (CAMPS). In Japan, a patient with PAO‐complicated PPP with a CARD14 gene mutation [25] was also reported.

2.3. Extra‐Palmoplantar Lesions

Reddish‐brown erythema with desquamation or small pustules are sometimes observed on the dorsum of the foot, knee, lower legs, gluteal region, and elbow beyond the hands and feet in PPP patients. These are termed extra‐palmoplantar lesions [26]. In PPP patients, exanthema resembles psoriasis, but induration is slight, and there are no thick scales. The border is unclear. Accordingly, slight epidermal thickening with parakeratosis and slight inflammatory cell infiltration in the upper dermis are observed as histological findings. However, Munro's microabscesses are not observed. Extra‐palmoplantar lesions are primarily classified into chronic and acute types. In the latter, small pustules or erythema with scales appears and spreads over the trunk and extremities following focal infections, but they are transient, disappearing with subsidence of foci. In the former, erythema of the dorsum of the foot, elbow, and knee with desquamation is persistently observed. Without knowledge about extra‐palmoplantar lesions, PPP is misdiagnosed as psoriasis in many cases, but the concomitant development of psoriasis and PPP is rare in Japanese patients. As another pitfall, when patients initially complain of extra‐palmoplantar lesions only, it is difficult to make a diagnosis since these lesions are atypical for both psoriasis and nummular eczema; subsequent recognition of palmoplantar lesions may lead to a diagnosis of PPP.

The entity of extra‐palmoplantar lesions reflects that PPP is the primary disease, and that similar responses may also occur in extra‐palmoplantar areas. On the other hand, in other countries, extra‐palmoplantar lesions are regarded as psoriasis in many cases, and PPP of the palm and sole is regarded as palmoplantar pustular psoriasis. The same abbreviation, PPP (or PPPP), is used, which increases confusion. In Japan, where the incidence of PPP is high, a consensus on the above interpretation should be reached.

2.4. Osteoarticular Symptoms

2.4.1. PAO

In patients with PPP, osteoarticular symptoms are not rare. Especially in Japan, there are a large number of patients with PPP, and related osteoarticular disease is often observed. In Japan, Ishibashi et al. [27] reported that 14 of 132 patients with PPP had osteoarticular symptoms and were diagnosed as having Tietze syndrome (skeletal disease with symptoms in the Tietze region of the anterior chest wall), and suggested its association with focal infections in 10 of them. Furthermore, based on the results of a cooperative study by orthopedic surgeons and dermatologists, Sonozaki et al. [28] reported 12 patients with pain or swelling of the anterior chest wall among 128 patients with PPP; these symptoms are sometimes called Sonozaki syndrome. The incidence of PAO among PPP patients is reportedly 10%–30% at university hospitals in Japan [2, 29, 30, 31]. The most frequent sites are the sternum and clavicle. However, on bone scintigraphy, significant accumulations are also observed in areas other than the anterior chest wall, such as the vertebrae, sacroiliac joint, shoulder, knee, and peripheral joints [31]. Bone scintigraphy is useful for evaluating systemic joints (Figure 5), but magnetic resonance imaging (MRI) has recently been used from the viewpoint of radiation exposure (Figure 6). Fat‐suppressed T2‐weighted imaging shows a high‐signal‐intensity area. Furthermore, bone hypertrophy is sometimes detected on plain X‐ray (Figure 7).

FIGURE 5.

Bone scintigraphy (reproduced from reference [31]).

FIGURE 6.

Fat‐suppressed T2‐weighted MRI showing high signal intensity in the bilateral sternoclavicular articular regions.

FIGURE 7.

Plain radiograph showing marked thickening of the right clavicle (R) compared with the left (L).

Severe joint pain in the lumbogluteal and sternoclavicular regions is frequently observed together with palmoplantar eruptions following upper respiratory tract infections or tonsillitis. Treatment of the focal infection is initially prioritized. In particular, tonsillectomy is effective for ameliorating both cutaneous and articular symptoms in many cases. In the case of tonsillitis, tonsillar lymphocytes activated by Streptococcal infection may promote the appearance of cutaneous lymphocyte antigen (CLA), inducing inflammation or bone hypertrophy by chemokine‐/chemokine receptor‐mediated chemotaxis to topical osteoarticular areas [32].

A recent multicenter cooperative study conducted at four universities in Japan [32] showed that PAO was noted in 28.6% of patients with PPP. The male‐to‐female ratio in 165 patients with PAO was 1:3.7, and the mean age was 50.2 years. Extra‐palmoplantar exanthema was observed in 9.7%. The most frequent site of pain was the anterior chest wall (n = 134).

2.4.2. The Concept and Interpretation of SAPHO Syndrome

2.4.2.1. Perspective From Dermatologists

The interpretation of PAO and SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis) syndrome differs among countries and among different fields of study. In 1987, SAPHO syndrome was proposed by Chamot et al. The original article was written in French, but an English article was published the next year [33]. Skin symptoms of SAPHO syndrome include acne and pustulosis. Acne refers to severe cases (acne conglobata, acne fulminans, cystic acne). Among pustulosis, PPP is the representative manifestation, but hidradenitis suppurativa (acne inversa) is also included. When reviewing international articles on SAPHO syndrome, skin symptoms include psoriasis in some articles, and a broad interpretation is given. In other articles, skin symptom‐free conditions are included in SAPHO syndrome. On bone scintigraphy, a “bull‐head (horn) sign” in the sternum, which is considered characteristic of SAPHO syndrome, is similarly observed in PAO.

Etiologically, PAO is closely associated with focal infection, whereas SAPHO syndrome may be associated with infectious diseases, immunologic abnormalities, and a hereditary predisposition (HLA‐B27). In particular, Cutibacterium acnes may be involved in SAPHO syndrome. Several studies reported that C. acnes was detected on bone biopsy, but the detection rate differed among studies [34]. A recent study found that C. acnes stimulated interleukin (IL)‐1β, interferon‐gamma (IFN‐γ), and IL‐17 production; this may be associated with the pathogenesis of SAPHO syndrome. SAPHO syndrome has characteristics of an autoinflammatory syndrome, and frequently develops in young males. It tends to be used as a synonym of PAO particularly in other countries or other practice fields. For the diagnosis of SAPHO syndrome, all symptoms do not necessarily have to be present, and osteoarticular symptoms (especially bone hypertrophy) are markedly more severe in patients with SAPHO syndrome than in those with PAO. Specifically, there are various issues regarding the similarities and differences between SAPHO syndrome and PAO: (i) opinions differ among countries, (ii) opinions differ among different fields of study, (iii) opinions differ even among dermatologists in Japan where the incidence of PPP is high, and (iv) bone hypertrophy also is marked in some patients with PAO. If PAO is termed SAPHO syndrome, there would be a very large number of patients with SAPHO syndrome in Japan. Most patients diagnosed with SAPHO syndrome by physicians in fields other than dermatology in Japan are likely to actually have PAO. Furthermore, when the patients with PPP develop osteoarticular manifestations, the diagnosis is abruptly changed to SAPHO syndrome, which creates a problematic situation.

PPP resembles psoriasis in many features, but psoriasis should not be included in the skin symptoms of SAPHO syndrome. If articular symptoms of the anterior chest wall are observed in patients with psoriasis, they should be regarded as having psoriatic arthritis and not as having SAPHO syndrome. Since many Japanese dermatologists consider PPP as an independent entity different from psoriasis, it would be appropriate to take the stance that PAO differs from psoriatic arthritis or SAPHO syndrome. In Japanese patients with PPP, severe forms of acne are rarely observed; if a PPP patient develops concomitant severe acne or hidradenitis suppurativa, its condition is considered to be close to an autoinflammatory syndrome. At the time when the original article on SAPHO syndrome was published, there was no entity of autoinflammatory syndromes. The inclusion features of SAPHO syndrome proposed in the article at that time were relatively loose, therefore, many differential diagnoses of SAPHO syndrome are listed in a recent review, and PAO is also included [35]. Overseas, where the incidence of PPP is low, PAO tends to be equated with SAPHO syndrome, and rheumatology and orthopedic fields in Japan that adopt this perspective, the two diseases are likely to be regard as the same disease. However, a recent survey showed that at least most dermatologists belonging to university hospitals in Japan tended to distinguish PAO from SAPHO syndrome [36]. In Japanese patients, the incidence of classical SAPHO syndrome is extremely low [9].

2.4.2.2. Perspective From Orthopedic Surgeons/Rheumatologists

Among rheumatologists and orthopedic surgeons, there are various opinions on the differences between PAO and SAPHO syndrome [37, 38], raising important issues to be resolved.

The disease name “PAO” was first reported by Sonozaki et al. [39] in 1981. Since then, it had been quoted in many articles. However, the entity of “PAO” had internationally disappeared for a few years until it was reported by Hyodoh and Sugimoto [40] and Vaccaro et al. [41] in 2001.

This phenomenon (disappearance of PAO entity) started when a report was published by Chamot et al. [42] in France in 1987. They regarded 44 patients with severe acne in addition to osteoarticular lesions of the sternoclavicular costal bone, sacroiliac joint, or vertebrae and 28 skin‐lesion‐free patients with osteoarticular lesions as having “Syndrome Acne‐Pustulosis‐Hyper‐ostosis‐Osteitis: SAPHO syndrome” by a survey conducted by the French Society of Rheumatology. In 1988, Benhamou et al. [33] replaced the first character “S” of “SAPHO syndrome” to stand for “Synovitis,” and proposed a wide range of disease entities associated with chronic recurrent multifocal osteomyelitis (CRMO) and serum‐response‐negative spondyloarthritis. SAPHO syndrome was newly redefined as a syndrome meeting one of the following four criteria: (i) Osteoarticular lesions associated with severe acne, (ii) Osteoarticular lesions associated with PPP, (iii) Hyperostosis, (iv) Chronic recurrent multifocal osteomyelitis (CRMO).

In addition, concerning criteria (iii) and (iv), it was commented that the presence of concomitant skin lesions was unnecessary. As a wider range of disease entity than PAO was established, PAO was internationally replaced by SAPHO syndrome. In 1994, Kahn et al. [43] added cases in which there were osteoarticular changes related to pustulotic psoriasis or psoriasis vulgaris to the disease category of “SAPHO” syndrome.

Since then, continuous expansion of the conditions included in “SAPHO syndrome” has confused specialists, promoting discussion. As a point important for this discussion, it must be understood that “SAPHO syndrome” is not a new disease entity in which the etiology of disease was clarified but a disease group classified by collecting previously known diseases and drawing new boundaries. In other words, differences between SAPHO syndrome and PAO may be related to the following histories: PAO was difficult to report as an “independent disease” before the etiology of PAO, essentially, that of PPP, was clarified; and various diseases have been designated as SAPHO syndrome, including PAO, because of broad expansion of SAPHO syndrome category.

PAO is a disease entity corresponding to a “proper subset” of SAPHO syndrome, being a minimum‐unit disease entity. Concerning the pathogenesis of PPP as a disease foundation, many investigators, including Murakami et al. [6, 14], have investigated its pathogenesis. In November 2018, guselkumab, a human monoclonal antibody against IL‐23p19 subunits, for the treatment of PPP received approval for insurance coverage in Japan, which is very significant.

In the future, the pathogenesis of this disease should be further investigated with the accumulation of reports on “PAO” or “Sonozaki syndrome” [9, 32, 44, 45, 46], and a treatment regimen should be established. The position of PAO as a disease independent from SAPHO syndrome that is accepted internationally should be established.

2.5. Comorbidities

Comorbidities of PPP include (1) diseases or conditions triggering the onset and exacerbation of PPP and (2) diseases that are associated with PPP and may influence its treatment. As the former, focal infection and smoking are important. The treatments of focal infections and smoking cessation constitute the mainstay for PPP and PAO. The latter includes autoimmune thyroiditis, diabetes mellitus, and psychiatric diseases. These should be controlled to effectively promote PPP treatment. In addition, consideration should also be given to dyslipidemia, hypertension, IgA vasculitis, and paradoxical reactions related to the administration of tumor necrosis factor (TNF) inhibitors for PAO, which are known to occur concomitantly. The incidences of comorbidities differ among studies, but, essentially, PPP frequently develops in Japanese and Swedish persons, and there are differences in the morbidity rate. Cohort studies are limited to some countries in Asia or Europe in addition to these countries. The incidences of focal infection are particularly high in Japanese patients with PPP and PAO, whereas the prevalence of smoking is high regardless of ethnicity or country.

2.5.1. Diseases or Conditions That Trigger the Onset or Deterioration of PPP and PAO

2.5.1.1. Focal Infection

Focal infection refers to a clinical feature in which chronic inflammation causes reactive organic or functional disorder of remote organs in the presence of a localized infection focus, which is asymptomatic/mild or intermittently induces symptoms, in some area of the body. In many Japanese patients, asymptomatic foci, such as focal tonsil, odontogenic lesions, and chronic sinusitis, have been implicated as triggering or causal factors in the development of PPP and PAO. It is now well established that adequate treatment of focal infection results in the healing or relief of cutaneous symptoms early within a timeframe of 1–2 years [47, 48, 49, 50, 51, 52, 53, 54, 55, 56], and also helps in the relief of osteoarticular symptoms or pain reduction [47, 49, 57]. This type corresponds to pustular bacterid (Andrews) [58] among various types of localized pustular psoriasis, but it differs from pustular psoriasis in that clinical and pathological findings include a course in which small vesicles turn into pustules. It is sometimes termed “A type” based on the proposer's name, Andrews [3]. In Europe and the United States, PPP often refers to palmoplantar and extremity‐type of pustular psoriasis despite the same disease name [59, 60]. Plaque psoriasis or pustules of the extremities seem to be present [59, 60, 61], and primary pathological findings include spongiform pustules of Kogoj; focal infection is not involved [60]. In the European Rare and Severe Psoriasis Expert Network (ERASPEN), which was established to standardize classification in clinical studies, pustular psoriasis is classified into three types: generalized, palmoplantar, and acrodermatitis (Hallopeau) types. In addition, the respective types are classified into phenotypes based on the presence or absence of plaque psoriasis, considering background factors such as relevant genes and conditions [62].

Many studies noted focal infection in ≥ 80% of Japanese PPP patients [47, 48, 49, 50, 51, 53, 54, 55, 63]. Because triggering infectious foci in PPP are asymptomatic and latent, they go unrecognized. Moreover, cutaneous and osteoarticular manifestations of PPP induced by these foci show a chronic course; therefore, they cannot be detected through routine medical interviews or standard consultations in otolaryngology or dentistry [64, 65]. It must be considered that detection methods markedly influence the reported prevalence [63]. No biomarker of focal infection has been identified, and even 80 years after the concept proposed by Andrews, the only way to confirm a causal relationship remains to observe the clinical course in which symptoms that had been refractory for many years improve 1–2 years after treatment of focal infection [47, 50, 51, 63].

The most frequent triggering foci are odontogenic lesions and focal tonsil [47, 48, 49, 50, 51, 52, 53, 54, 55, 63], followed by sinusitis and nasopharyngitis [55, 63]. Odontogenic lesions are classified into three types: (i) apical lesions (apical periodontitis), (ii) moderate to severe periodontitis with alveolar bone resorption (marginal periodontitis), and (iii) periodontitis of the wisdom tooth. These are asymptomatic in most cases. In 70%–90% of Japanese patients with PPP, resolution or improvement of cutaneous symptoms is observed following treatment of odontogenic lesions [49, 53, 54, 55, 56, 63]. The efficacy of tonsillectomy has also been reported to be 60%–90% (≥ 80% in patients excluding current smokers) [47, 48, 49, 50, 51, 52, 63]. As a mechanism, disturbance of immune tolerance to the commensal bacteria, together with dysbiosis, has been proposed in PPP and PAO patients [66]. Focal tonsils are usually completely asymptomatic, but its association can be inferred from the clinical course in patients with deterioration of cutaneous or osteoarticular symptoms on upper respiratory tract infections. Chronic sinusitis is classified into two types: standard chronic sinusitis and dental sinusitis in which apical lesions of the upper teeth involve the maxillary sinus. The treatment of the latter is performed at a dental clinic, and others are treated in otolaryngology. Non‐responders to tonsillectomy may include continuous smokers and patients with nasopharyngitis as a primary focus.

2.5.1.2. Smoking

The smoking rate among patients with PPP ranges from 62% to 94.9% [59, 61, 64, 67, 68], being very high regardless of ethnicity. Clinically, cutaneous and osteoarticular symptoms often deteriorate with increased cigarette consumption; therefore, smoking is also presumed to be associated with the onset or deterioration of PPP and PAO. Smoking cessation alone rarely results in healing. On the other hand, smoking affects responsiveness to treatments [67], therefore, providing guidance for smoking cessation is important.

2.5.1.3. Constipation, Diarrhea, and Irritable Bowel Syndrome

The incidence of concomitant celiac disease in Swedish patients is reportedly 18% [61]. In Japanese patients, diarrhea, constipation, and irritable bowel syndrome are also sometimes observed. Rarely, PPP is complicated by ulcerative colitis or Crohn's disease [63]. An improvement in the intestinal environment reduces cutaneous or osteoarticular symptoms in some patients. Mucosa‐associated lymphoid tissue (MALT) includes the tonsil/oral mucosa/thyroid gland/digestive tract [66, 69]. Intestinal dysbiosis and induction of intestinal inflammation against it may also be associated with PPP or PAO.

2.5.1.4. Dental Metal Allergy

Previous studies reported the involvement of dental metal allergy in PPP. However, in fact, odontogenic lesions are simultaneously treated on metal removal in most cases, and the difficulty of evaluating the effects of dental metal removal alone has been pointed out. Recently, a study has indicated that metal removal alone relieved PPP in only a small percentage of patients [70]. It is of note that a metal patch test‐positive reaction cannot be regarded as the etiology of PPP. Dental metal removal should not be performed based on the results of patch test alone.

2.5.2. Comorbidities Affecting Treatment Response and Systemic Prognosis in PPP

2.5.2.1. Autoimmune Thyroiditis

Types of autoimmune thyroiditis accompanying PPP include Graves' disease and Hashimoto's thyroiditis. Its incidence in Swedish and German patients is reportedly 12% [61] and at least 8.2% [60], respectively. In Japan, its incidence is 4%–5% [63], which is not high. However, this disorder may influence the state of PPP or treatment responsiveness. Therefore, early detection and adequate treatment are necessary.

2.5.2.2. Diabetes Mellitus

The incidence of concomitant diabetes mellitus in Swedish females with PPP is high at 28% [61], whereas that in Japanese or German patients is approximately 10% [60, 71, 72]. However, the treatment of uncontrolled diabetes mellitus reduces PPP symptoms in some patients, as demonstrated for autoimmune thyroiditis, and there may be an association. Adequate treatment should be administered in cooperation with internal medicine physicians.

2.5.2.3. Dyslipidemia

The incidence of concomitant dyslipidemia in Japanese patients reportedly ranges from 4.4% [73] to 22.7% [72]. In other countries, it ranges from 18.0% [61] to 49.3% [60]; it varies among studies. The incidence of hypertension is also similar [61, 73]. However, from the viewpoint that PPP is a disease related to psoriasis, and its influence on arteriosclerosis and ischemic disease warrants further investigation especially in patients with chronically persistent osteoarthritis.

2.5.2.4. Depression and Mental Stress

In Japanese patients, the incidence of concomitant psychiatric diseases, such as depression, is 4.4% [73], but mental stress often influences the onset or state of PPP. According to a study, symptom deterioration related to mental stress was noted in 56.4% of German patients [60]. Among Swedish patients, psychiatric comorbidities were observed in 18% of patients, including depression in 13% [61], and in 32.8% or higher of German patients [71], respectively.

2.5.2.5. Allergic Disease

It has been reported that allergic rhinitis was observed in 15.1% of German patients, asthma in 11.6%, and atopic dermatitis in 7.0% [60]. Among Japanese PPP patients, asthma was noted in 1.5%–7% [69, 71]. A substantial proportion of these cases with concomitant asthma were adult‐onset. Given that IL‐17 levels are elevated in both conditions [74, 75], therefore, the association of asthma with PPP cannot be ruled out although the detailed mechanism remains to be clarified.

2.5.2.6. IgA Vasculitis

During the course of PPP, IgA vasculitis occurs in some patients, and it is of note that urinary protein is frequently detected; careful attention should be paid to the coexistence of IgA nephropathy [76]. IgA vasculitis is also related to focal infection, such as tonsillar infection.

2.6. Evaluation of the Severity of PPP and Osteoarticular Symptoms

2.6.1. PPPASI

Based on the Psoriasis Area and Severity Index (PASI), the Palmoplantar Pustulosis Area Severity Index (PPPASI) was devised in reference to the PASI scoring for psoriasis vulgaris [53, 77]. Objective scoring can be performed by evaluating symptoms of the palm and sole. Initially, the area of skin lesions and clinical symptoms (pustules, erythema, desquamation/scales) are evaluated (Figure 8). This score facilitates objective assessment of the patient's condition; therefore, this tool is useful for evaluating the treatment response. However, there is a limitation in that extra‐palmoplantar lesions cannot be evaluated.

FIGURE 8.

Calculation of the PPPASI (Palmoplantar Pustulosis Area Severity Index). Each score is calculated as follows, and added up: Right palm area score × (erythema + vesicle/pustule + desquamation/scales score) × 0.2; Left palm area score × (erythema + vesicle/pustule + desquamation/scales score) × 0.2; Right sole area score × (erythema + vesicle/pustule + desquamation/scales score) × 0.3; Left sole area score × (erythema + vesicle/pustule + desquamation/scales score) × 0.3. (Reference: Approximate number of vesicles/pustules: 0, none; 1, < 10; 2, < 50; 3, < 100; 4, ≥ 100).

2.6.2. PPSI

The Palmo‐Plantar Severity Index (PPSI) is used to evaluate the severity of PPP lesions and treatment response [78, 79, 80]. The PPSI score ranges from 0 to 12.

In this evaluation, the severest site of the palm or sole is evaluated. In subsequent evaluations, the same site is examined. In the lesion to be evaluated, erythema, pustules/vesicles, and desquamation/scales are separately evaluated using a scale of 0–4 without considering the area score.

No lesion: 0 points, Mild: 1 point, Moderate: 2 points, Severe: 3 points, Severest: 4 points.

E: Erythema, P: Sum of pustules and vesicles*, D: Desquamation/scales.

PPSI = E + P + D

*The number of pustules and vesicles as a guide is similar to that for the PPPASI.

In PPSI scoring, the severest site is evaluated as a single point; this index is simpler than the PPPASI, and is useful for evaluating the efficacy of therapeutic drugs in clinical studies. However, the PPSI score is not always correlated with QOL since all of the lesions are not evaluated.

2.6.3. Evaluation of the Severity of Nail Lesions Related to PPP

Nail lesions are observed in 28.1%–85.5% of patients with psoriasis [81, 82, 83]. They are also noted in 31.1% of patients with PPP [8]. In the former, these lesions are often evaluated using the Nail Psoriasis Severity Index (NAPSI) [84]. Each finger/toe nail plate is divided into four in the horizontal and vertical directions, and the sum of the highest score among four area for the nail bed lesion of each nail plate and that among four area for the nail matrix lesion is calculated. Nail bed lesions (onycholysis, splinter hemorrhage, oil drop, subungual hyperkeratosis) and nail matrix lesions (nail pitting, leukonychia, red lunula, nail destruction) are evaluated using five grades (0–4), and the following scores are calculated:

2.6.3.1. NAPSI Formula

NAPSI score (0–160) = Nail bed lesion score (0–4) × Number of nail plates (0–20) + Nail matrix lesion score (0–4) × Number of nail plates (0–20).

Nail bed lesion: Onycholysis, splinter hemorrhage, oil drop, subungual hyperkeratosis; Nail matrix lesion: Nail pitting, leukonychia, red lunula, nail destruction.

The simplified NAPSI, in which the nail plate with the most marked symptoms is evaluated among nail plates of the hands and feet, was also proposed.

2.6.3.2. Simplified NAPSI Formula

Simplified NAPSI score (0–32) = Nail bed lesion (onycholysis [0–4] + splinter hemorrhage [0–4] + oil drop [0–4] + subungual hyperkeratosis [0–4]) + Nail matrix lesion (nail pitting [0–4] + leukonychia [0–4] + red lunula [0–4] + nail destruction [0–4]).

In patients with PPP, nail lesions resembling nail psoriasis are observed, but there are also nail lesions characteristic of PPP such as thickening of the nail [8]. Using the NAPSI, it is impossible to evaluate nail lesions commonly observed in patients with PPP, which is a limitation. In the future, preparation of a tool that facilitates the accurate assessment of nail lesions related to PPP must be reviewed.

2.6.4. Evaluation of the Severity of PAO

To date, no method for evaluating the severity of the disease activity of PAO has been established. This may be because no adequate method to evaluate anterior chest pain, that is, front‐axial pain, which frequently develops in patients with PAO, has been established.

In a phase III double‐blind comparative study of guselkumab (Tremfya) for PPP (PPP3001 study) in Japan, the EQ‐5D index score (5‐dimension quality‐of‐life scale) was used for QOL assessment, and the EQ‐5D pain/discomfort dimension score and visual analog scale (VAS) were used as health parameters [85]. The change in the EQ‐5D index score from baseline at Week 52 was 0.20 (SD ±0.17) in PPP patients with PAO in the guselkumab group, being similar to that (0.15 [SD ±0.17]) in those without PAO. However, the change in the percentage of patients with middle to high pain/discomfort dimension scores at Week 16 in the PAO group was 73.3% (33/45 patients), showing an improvement in comparison with that in the placebo group (47.4%, 9/19 patients). It was found that the percentage of patients in whom pain/discomfort was absent or extremely mild at Week 52 was 87.5% (35/40 patients), showing continuous effects. Furthermore, the percentage of patients in whom pain/discomfort was absent or extremely mild at Week 52 was 94.4% (17/18 patients) even in the group in which the placebo was switched to guselkumab at Week 16. In the study, analysis was performed by dividing the EQ‐5D pain/discomfort dimension scores into: absent or extremely mild (1–2) and moderate to severe (3–5).

As an attempt to evaluate the severity of disease activity, severity assessment was reviewed using the “modified ASDAS‐CRP,” in which the “parasternal area” was added to the 1st question of the ASDAS‐CRP: “How was neck, back, or low back pain?” in 90 patients with PAO in Japan. The reason why the assessment of the site of parasternal pain appearing in ≥ 90% of patients with PAO was added to the question of the body axis, such as the neck, back, and low back, is derived from the finding that the parasternal area is included in the extent of the body axis. The definition of the extent of the body axis is shown in Figure 9. As a result, “no disease activity,” which corresponds to remission, accounted for 50% of all patients, “low disease activity” accounted for 21.8%, and “high disease activity” accounted for 21.7%. “Very high disease activity” accounted for 6.5% [87]. In the future, the adequate method of evaluating the severity (disease activity parameter) should be established.

FIGURE 9.

Definition of front‐axial and back‐axial areas [86]. The axial region is defined as the area encompassing regions 1–7, shown in the figure. Regions 1–5 are referred to the back‐axial region, while regions 6 and 7 are referred to as the front‐axial region; together, these constitute the axial region. PAO and SAPHO syndrome often involve region 7, which comprises the sternum and the sternoclavicular joints, sternocostal joints, and manubriosternal joint.

3. Chapter III: Clinical Statistics of Palmoplantar Pustulosis and QOL

3.1. Epidemiology

3.1.1. Epidemiology of PPP

Kubota et al. [1] conducted a large‐scale epidemiological survey on PPP using the receipt information database from the Ministry of Health, Labour, and Welfare involving ≥ 90% of the total population. The observation period was from April 2010 to March 2011. The number of PPP patients was 136,224. The morbidity rate was 0.12%, being higher than that in Europe and the United States (0.01 [88] and 0.05% [89], respectively). The patients consisted of 47,248 males and 88,976 females. The male‐to‐female ratio was approximately 1:2; PPP was more frequent in females. The mean age at the time of onset was 55.5 years, and this disease was frequent in middle‐aged females. Patients who consulted a hospital/clinic in the summer accounted for 40.7% (July), and those who consulted it in the winter accounted for 30.7% (April). Concerning the contents of treatment, topical steroid therapy was performed in 109,692 patients (80.5%), followed by therapy with topical vitamin D3 in 42,903 patients (31.5%), phototherapy in 10,408 patients (7.6%), oral etretinate therapy in 1950 patients (1.4%), oral cyclosporine therapy in 251 patients (0.2%), oral methotrexate therapy in 174 patients (0.1%), infliximab therapy in 197 patients (0.1%), adalimumab therapy in 64 patients (0.05%), and no treatment in 21,209 patients (15.6%).

In addition, there are some single‐center epidemiological survey reports of 100 patients [28, 64, 67, 68, 90, 91, 92]. The median duration of disease was 2 [67] and 8 [92] years. The rates of smokers were approximately 40 [64], 49% [68], 62% [67], and 76% [92]. Nail lesions were observed in approximately 11% [68], 22% [91], and 31% [67]. Osteoarticular symptoms were noted in approximately 9% [28], 15% [64], 17% [68], 35% [92], and 45% [67]. As focal infection, tonsillitis was observed in approximately 5% [68], 30% [67], and 31% [90], caries in approximately 5% [64], 6% [68], and 49% [67], tonsillar hypertrophy in 58% [67], and sinusitis in approximately 2% [64] and 5% [67]. On the other hand, as to international reports, a study in Korea examined the characteristics of nails in 116 patients with PPP, and reported that patients with ≥ 1 nail symptoms accounted for 58.7%, with a mean age of 51.5 years and a male‐to‐female ratio of 1:1.4 [93]. In Germany, a study of 172 patients with PPP found that the mean age was 41.6 years, and that the male‐to‐female ratio was 1:3.9 [60]. In Austria, a study investigated 102 patients with PPP, and reported that the mean age was 42 years, with a maleto‐female ratio of 1:5.8 [94]. In Europe, an epidemiological survey of 203 patients with PPP in England and 193 with PPP in North Europe showed that the mean age was 48 and 45 years, respectively, and that the male‐to‐female ratio was 1:3.7 and 1:5, respectively [95].

Miyazaki et al. [96] analyzed the actual state of PPP treatment based on a receipt database of 5162 Japanese patients between 2011 and 2017 (6 years), and reported that biologics had been used in 18 patients (0.4%). On the other hand, Andersen et al. [97] investigated the actual state of PPP treatment using the insurance databases between 2015 and 2016 in various countries, and reported that biologics had been used in 264 (18.4%) of 1435 patients with PPP in the United States, in 64 (8.5%) of 751 patients with PPP in Denmark, and in 45 (2.5%) of 1832 patients with PPP in Germany.

Fujishiro et al. [67] statistically examined 111 patients with PPP during the past 3 years, and reported that nail lesions, a history of metal allergy, and onset at < 50 years of age were more frequent in those with osteoarticular symptoms than in those without osteoarticular symptoms. Furthermore, they found that treatment responses in the group with nail lesions and the group with a history of metal allergy were weaker. In addition, they reported that the treatment response was weaker in the current smoking continuation group than in the smoking‐history‐free group, and that the treatment response was weaker in patients who developed PPP at ≥ 40 years of age than in those who developed it at < 40 years of age. Thus, there have only been a few large‐scale epidemiological surveys on PPP, and a large‐scale epidemiological survey should be further conducted in Japan, where the morbidity rate is higher than in Europe and the United States.

3.1.2. Epidemiology of PAO

In Japan, PPP is a common disease, and arthro‐osteitis with sternoclavicular arthritis or spondylitis is observed in 10%–30% of patients. This is termed PAO [39]. However, internationally, PAO has been reported as a symptom of SAPHO syndrome, and the international literature cannot be utilized as is. SAPHO syndrome was proposed by Chamot et al. [42]; 85 patients with synovitis, acne, pustulosis, hyperostosis, and osteitis, particularly and clinically characterized by sternoclavicular arthritis and hyperostosis were regarded as having SAPHO syndrome. PPP‐related SAPHO syndrome was noted in 44 patients, showing the highest percentage. However, the 85 patients included 13 with severe acne‐related SAPHO syndrome and 28 without cutaneous lesions. Thereafter, the definition of SAPHO syndrome became controversial because symptoms of chronic recurrent multifocal osteomyelitis (CRMO), which primarily develops in children, resembled those of SAPHO syndrome. Chamot et al. extended this entity and recommended that all diseases with hyperostosis of the body axis (inclusion criteria) in the absence of infection or intervertebral disk degeneration (exclusion criteria) should be included in SAPHO syndrome [33]. As a result, currently, SAPHO syndrome is recognized as an umbrella disease that covers 50 different disease names [98]. As important points, the clinical characteristics of PPP differ between Japanese and European/American patients, and localized pustular psoriasis with palmoplantar pustules is termed PPP in Europe and the United States. When osteitis is present in European/American patients with pustular psoriasis, they are regarded as having SAPHO syndrome. On the other hand, when osteitis is observed in Japanese patients with PPP, there is a disease name of PAO, and it is not necessary to regard the condition as SAPHO syndrome; the use of the name “PAO” facilitates the understanding of the following points: the pathogenesis of this disorder is similar to that of PPP, and the same treatment algorithm is used. However, also in Japan, this disorder has been reported in two ways: PAO and SAPHO syndrome. To discuss epidemiology, PAO or descriptions of PAO must be extracted from various references, and aggregated.

Concerning the incidence of PAO as a percentage of patients with SAPHO syndrome, 29 (70.7%) of 47 patients with cutaneous lesions had PAO according to a single‐center cohort study of 67 Japanese patients who consulted the Department of Orthopedics [99], followed by severe acne and psoriasis in four patients each (9.8%). However, most patients diagnosed with cutaneous lesions by dermatologists in Japan actually have PPP‐related PAO. According to a single‐center cohort study of 164 Chinese patients with SAPHO syndrome [100], PPP was observed in 143 (92.3%) of 155 patients with cutaneous lesions, and 108 patients (69.7%) were definitively diagnosed with PAO due to the presence of PPP alone as cutaneous lesions. In Asian areas, PAO accounts for a large portion of patients with SAPHO syndrome. According to single‐center cohort studies of European/American patients [101, 102], PAO also accounted for the highest percentage, but the percentage was 55%–65%, being slightly lower. Severe acne accounted for 25%, and psoriasis vulgaris for 10%–30%; the rates of these disorders were higher. Thus, there are marked race differences in skin diseases in patients with SAPHO syndrome.

The incidence of concomitant PAO in patients with PPP differs among institutions: Sonozaki et al., 9.8% [39]; Akiyama et al., 14.9% [64]; Hashimoto et al., 16.5% [68]; Hradil et al., 22% [103]; Yamamoto et al., 28.6% [2]; Yayama et al., 30.4% [104]; Kase et al., 34.8% [92]; Jurik et al., 36% [105]; and Fujishiro et al., 45% [67]. It may range from approximately 10%–30%. The morbidity rate of PPP in Japan is reportedly 0.12% according to a study that used the Ministry of Health, Labour, and Welfare receipt database by Kubota et al. [1] (April 2010–March 2011). The morbidity rate of PAO is estimated to be 0.03%–0.04%. The peak age at the time of onset of PAO is 30–49 years [39, 100]. Concerning sex, this disorder frequently develops in females, and females account for 63%–65% [2, 28]. Internationally, 4%–18% of patients are positive for HLA‐B27, but there are few HLA‐B27‐positive Japanese patients. In addition, a study investigated the association of HLA‐B61 [1].

Patients who develop arthro‐osteitis within 2 years before and after the onset of PPP account for ≥ 70% [39, 68, 103]. The rate of patients who initially develop cutaneous lesions is similar to that of patients who initially develop arthro‐osteitis. In some patients, arthro‐osteitis occurs ≥ 10 years before the onset of PPP [39]. The axil joints are frequently affected. In particular, anterior chest wall lesions are observed in 65%–90% of patients [2, 39, 99, 100, 101, 102]. Among these lesions, the sternoclavicular joint is the most frequently affected, followed by the sternocostal joint of the 1st costal bone and sternal joints [39]. Hyperostosis is noted, and protrusion of the anterior chest wall, which is characteristic of PAO, as well as the “bull's head” sign on bone scintigraphy and fat‐suppressed MRI, is observed. Spondylitis is noted in 30%–40% of patients [39, 99, 102]. In Europe and the United States, the thoracic vertebrae are the most frequently affected in patients with SAPHO syndrome, followed by the lumbar and cervical vertebrae [101, 102]. In Chinese patients, the lumbar vertebrae are the most frequently affected, followed by the thoracic and cervical vertebrae [100]. Multiple skip lesions are observed, differing from ankylosing spondylitis. The incidence of sacroiliac arthritis ranges from 13% to 52%, and unilateral arthritis is frequent [98]. Peripheral arthritis is observed in 30%–40% of patients, and peripheral proximal joints, such as the acromial joint, are frequently affected, leading to osteitis, arthritis, and enthesitis involving the knees, hands, and feet [39, 99, 103]. Yamamoto et al. [2] investigated the site of pain in 167 patients with PAO, and reported that anterior chest wall, peripheral joint, vertebral, and sacroiliac joint pain was noted in 81%, 15.2%, 18.8%, and 4.8% of these patients, respectively.

PAO often induces acute, extremely severe pain, limiting the range of motion and markedly reducing QOL. As ossification or bone ankylosis progresses slowly, the prognosis has been considered to be favorable [39, 106]. However, cases in which the condition leads to vertebral ankylosis or fracture in a few years are not rare [107]; we cannot conclude that the prognosis is favorable. In Japanese patients, focal infection related to focal tonsil, odontogenic lesions, or sinusitis is important as the cause of onset, as demonstrated for PPP. Antimicrobial drugs are effective [108, 109], and adequate treatment of the focal infection, such as tonsillectomy and dental treatment, reduces pain in many patients [32, 110, 111, 112]. However, patients with recurrence have also been reported [113, 114].

3.2. PPP/PAO Patients' QOL

PPP is a representative chronic inflammatory skin disease. During the course, cycles of remission/exacerbation are repeated, making treatment difficult in many patients. This markedly reduces patients' quality of life (QOL) according to domestic and international reports [60, 94, 95, 115]. Briefly, the palm with a lesion is always seen by other people, and pain of the sole sometimes occurs on walking; pain or pruritus of the skin, nail lesions, and arthralgia are observed, affecting patients' QOL.

In a questionnaire survey on QOL of 64 Japanese patients with PPP (2005–2007) [115], the mean PPPASI score was 10.2, and patients with pruritus accounted for 50.9%. Those with articular symptoms accounted for 43.5%. On assessment with a skin‐disease‐specific QOL scale, Skindex‐16, items for emotion were particularly affected. A PPP patients' mental health survey with GHQ‐28 showed that approximately 48% of the patients had some neurosis‐like symptoms, and that 25.4% had a depressive tendency [115]. As demonstrated for psoriasis, the severity of cutaneous lesions was not always correlated with QOL, especially mental health. Furthermore, patients who reported satisfaction with treatment as “satisfied” or “slightly satisfied” accounted for only 60%, and the mean time required for topical drug application per day was 14.6 min. It was reported that the number of patients feeling stressful increased when the time exceeded 30 min.

The disease entity of PPP is not always consistent between Japan and Europe/the United States. However, in Europe, three articles on patients whose conditions resemble the entity of PPP in Japan have been published. According to a cross‐sectional study of 102 patients with PPP (2003–2013) in Austria [94], pain was observed in 46.2% of the patients, and pruritus in 51.9%. In addition, pain during walking was noted in 25%. The mean PPPASI score was 8.9, and the mean score of the DLQI (Dermatology Life Quality Index), which is a skin‐disease‐specific QOL scale, was 7. Of these patients, the severity was moderate in 24.7% and severe in 27.3%. There was a positive correlation between the severity of skin lesions and DLQI score. According to a cross‐sectional study of 172 patients with PPP in Germany (2011–2014) [60], the mean PPPASI score was 12.6, and the mean DLQI score was 12.2. Approximately 50% of the patients showed a moderate or marked reduction in QOL. The DLQI score was significantly higher in patients with a PPPASI score of > 10 than in those with a PPPASI score of ≤ 10; QOL was reduced. There was a positive correlation between the severity of cutaneous lesions and DLQI score. Furthermore, two cohort studies of 203 patients with PPP in the United Kingdom (2016–2019) and 193 with PPP in North Europe (2016–2020) were reported [95]. In the cohort study in the United Kingdom, the mean PPPASI score was 8.2 and the mean DLQI score was 10. There was a negative correlation between the PPPASI score and age at the time of onset. The PPPASI score was significantly higher in young patients, females, and smokers, reflecting that the cutaneous lesions of these subgroups of patients are severe. The cohort study in North Europe also showed a similar tendency. In addition, in the former study, the DLQI score was significantly higher in females and smokers, and there was a reduction in QOL. There was a positive correlation between the severity of cutaneous lesions and DLQI score.

Few studies have evaluated patients' QOL before and after treatment. In a phase III clinical study of guselkumab in Japanese patients with PPP [80], the mean PPPASI score at baseline in 54 patients treated at 100 mg was 27.5, and the mean DLQI score was 9.3. The mean EQ‐5D (EuroQoL 5 dimension) index score, as a scale of comprehensive health status, was 0.7. Sixteen weeks after the start of administration, the mean PPPASI score was 12.4 and the mean DLQI score was 4.3. The mean EQ‐5D index score was 0.8, suggesting a significant improvement in QOL. Briefly, the results showed that guselkumab was effective for PPP, improving patients' QOL.

Few studies have evaluated QOL in patients with PAO. In a study in Japan, cyclosporine was administered to seven patients with refractory PAO for 8 weeks, and QOL was assessed using a scale of comprehensive health status, SF‐8, before and after treatment. As a result, there was a significant improvement in QOL, and it was correlated with the pain score [116], suggesting that cyclosporine is effective for PAO, improving QOL. Furthermore, a phase III clinical study of guselkumab in Japanese patients with PPP analyzed 66 PAO‐complicated patients with osteoarticular symptoms [85], and found that the mean PPPASI score at baseline was 27.24 and the mean DLQI score was 10.6. In addition, the mean EQ‐5D index score improved from 0.64 at baseline to 0.84 fifty‐two weeks after the start of administration. Analysis of non‐PAO‐complicated patients also revealed an improvement in the mean EQ‐5D index score from 0.75 to 0.93, suggesting an improvement in QOL. The EQ‐5D “pain/discomfort” score 52 weeks after the start of administration was improved regardless of the presence or absence of PAO as a complication, suggesting that guselkumab improves PAO‐complicated patients' QOL.

Overall, patients with PPP and PAO experience a reduced QOL; therefore, therapeutic decisions should consider not only skin disease severity but also patient‐reported QOL and treatment satisfaction.

4. Chapter IV: Pathogenesis of Palmoplantar Pustulosis

4.1. Pathophysiology

4.1.1. Cutaneous Lesions

In Europe and the United States, PPP had been classified as a type of localized pustular psoriasis, but an opinion that this condition should be regarded as different from psoriasis vulgaris or pustular psoriasis was expressed at the IPC Roundtable meeting (London, 2005) [16]. In Japan, PPP has been regarded as a condition differing from pustular psoriasis for the following reasons: (1) this disease is complicated by PAO; and (2) investigation of human leukocyte antigen (HLA) revealed no associations with HLA‐A1, B13, B17, or B37, which are frequently detected in patients with psoriasis. A recent study showed that intraepidermal vesicles before pustule formation in patients with PPP were associated with eccrine sweat glands, providing a strong reason why this disease frequently involves the palm and sole. However, its fundamental pathogenesis remains to be clarified [6, 117].

A phase II RCT of PPP treatment with complete human anti‐IL‐8 antibody was conducted in Europe in 2008, and its efficacy was reported [118]. The pathogenesis of vesicles remains to be clarified, but changes in the topical concentration gradients of complements (C3, C5a) and IL‐8 at the lesion site were reported as a mechanism by which neutrophils migrate into vesicles [119]. Th17‐associated mRNA microarray analysis for keratinocytes around pustulo‐vesicles collected from PPP lesional tissue showed increases in IL‐8, IL‐17C, IL‐22, and IL‐23p19 expression (Figure 10) [74]. However, there were also increases in IFN‐γ and IL‐10 expression, suggesting that multiple factors in addition to Th17, which is associated with the pathogenesis of psoriasis, are associated with the pathogenesis of PPP, or that the timing of sampling corresponded to the pustule phase, reflecting the complete pustulo‐vesicle‐related state of keratinocytes. In addition to IL‐8, overexpression of IL‐36γ in the PPP lesional tissue, at the periphery of intraepidermal sweat glands, and in the peripustular tissue was immunohistologically confirmed, but there was no IL‐36Ra expression [120].

FIGURE 10.

mRNA microarray analysis in PPP lesional skin [74].

Prior to this trial, the presence of hCAP‐18/LL‐37 and dermcidin, antimicrobial peptides contained in eccrine sweat, was confirmed in PPP vesicles [6]. Stimulating the two‐dimensionally and three‐dimensionally cultured epidermis with LL37 at a concentration confirmed in the vesicle contents increased inflammatory cytokine (IL‐8, IL‐17C, IL‐1α, IL‐1β) mRNA expressions. In addition, the results of an experiment on stimulation with the posttreatment vesicle contents after adsorbing/removing hCAP‐18/LL37, which is present in the vesicle contents, using an antibody column with anti‐LL37 antibody showed that intrinsic hCAP‐18/LL37 was closely associated with IL‐8 mRNA induction [121]. In the presence of proteinase‐3 or elastase, hCAP‐18 becomes active in the form of LL37. In sweat, RK‐31, KS‐30, and KR‐20 fragments are physiologically synthesized as post‐secretory processing, but it was shown that these exhibited antimicrobial activities similar to or more potent than that of LL37 [122]. However, in skin with rosacea, the hCAP18 fragment produced by abnormal increases in KLK5/7 exhibits inflammation‐promoting actions, contributing to the formation of a morbid state [123]. In PPP vesicles, a new processing form of hCAP‐18 was also found (TLN‐58), and it was shown to more potently induce IL‐8 expression at the mRNA and protein levels [124].

As described above, IL‐36 [125] is associated with the pathogenesis of pustulation in patients with PPP. However, an active form of hCAP‐18, LL37, was reported to induce IL‐36γ expression against epidermal keratinocytes [126]. As the presence of antimicrobial peptides, hCAP‐18/LL‐37 and dermcidin, was confirmed in PPP vesicles, the involvement of IL‐36γ in the pathogenesis of PPP is strongly suggested. In addition, non‐active IL‐36 (IL‐36α, IL‐36β, IL‐36γ) became active IL‐36 in the presence of neutrophil‐derived cathepsin G, elastase, and proteinase‐3, showing a 500‐fold increase in biological activity [125]. From the results of these previous articles, a hypothesized mechanism of the pathogenesis of pustules in PPP patients that involves the conversion of vesicles to pustules is shown in Figure 11.

FIGURE 11.

Proposed mechanism of pustule formation in PPP (adapted from reference [3]).

In addition, according to previous pathogenesis‐related reports, it was found that somatostatin receptor [127], chromogranin/synaptophysin [128], and Langerhans cell/IL‐17‐positive cell [129] expressions at the lesion site differed, suggesting that they may play some roles in the sweat glands at the PPP lesion site.

4.1.2. Focal Tonsil

In patients with PPP, tonsillar lymphocytes induce an excessive immune response or become activated as a result of impaired immune tolerance to oral commensal bacteria, such as α‐hemolytic streptococcus, subsequently infiltrate the palmoplantar skin via a homing mechanism [130]. In addition, autoantibodies against antigens shared between tonsillar tissue or α‐hemolytic streptococci and palmoplantar skin may be produced, forming a pathogenic focus.

As background factors, elevated titers of anti‐α‐hemolytic streptococcus antibody have been detected in both tonsillar lymphocyte‐cultured supernatant and serum from patients with PPP, and stimulation with α‐hemolytic streptococci increased the production of inflammatory cytokines, such as TNF‐α and IFN‐γ, by tonsillar lymphocytes [131]. In tonsillar T cells from PPP patients, the expression level of cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4), a molecule involved in T‐cell suppression, is reduced. Simultaneously, overexpression of Smad7, which inhibits the intracellular signal transmission of transforming growth factor‐β (TGF‐β) produced by regulatory T cells, has been observed [132]. These findings suggest that T cells are more readily activated in patients with PPP. Tonsillar T cells from PPP patients have been shown to have a high affinity for the palmoplantar skin. At lesional sites, infiltration of cutaneous lymphocyte antigen (CLA)‐positive and chemokine receptor 6 (CCR6)‐positive T cells has been observed; moreover high expression levels of CLA and CCR6 have also been detected in tonsillar and peripheral blood T cells [133, 134]. Furthermore, CD4‐positive T cells from the tonsillar and peripheral blood of PPP patients exhibit high expression levels of β1 integrin [132]. β1 integrin is a cofactor for T‐cell activation, and promotes T‐cell chemotaxis to the site of skin inflammation. At lesional sites of PPP, expression levels of vascular cell adhesion molecule‐1 (VCAM‐1), a ligand of β1 integrin, are significantly increased [132]. An in vitro study showed that stimulation with α‐hemolytic streptococcus increased the number of CLA‐positive and CCR6‐positive T cells, and unregulated β1 integrin expression in patient‐derived tonsillar CD4‐positive T cells. Thus, the number of T cells with affinity for palmoplantar skin is increased in the patient's tonsil, but this phenomenon may be associated with stimulation by indigenous bacteria (Figure 12). In addition to PPP, diseases associated with tonsillar focal infection include IgA nephropathy, IgA vasculitis, and sternocostoclavicular hyperostosis. In the tonsils of patients with IgA nephropathy, immune tolerance against Haemophilus parainfluenzae is impaired, inducing excessive immune responses to bacterial cell components or bacteria‐derived DNA in the context of a hereditary predisposition and producing galactose‐deficient IgA1 (Gd‐IgA1) [135]. Gd‐IgA1 forms an immune complex with anti‐Gd‐IgA1 IgG or IgA antibodies, or with soluble FcαRI, which subsequently deposit in the renal mesangial region and induce nephritis [136]. Various pathogens such as Group A Streptococcus, H. parainfluenzae , and Helicobacter pylori , may be associated with the onset of IgA vasculitis. Nephropathy related to IgA vasculitis occurs via a mechanism similar to that of IgA nephropathy, but vasculitis may be induced by binding of IgA1 to vascular endothelial cell antigen [135].

FIGURE 12.

Immunopathogenic mechanism of PPP associated with tonsillar focal infection.

As a proposed mechanism of palmoplantar lesion formation, antigen mimicry between the tonsillar crypt epithelium and palmoplantar skin has also been reported. Furthermore, transplantation of tonsillar lymphocytes from PPP patients to SCID mice increased serum anti‐keratin antibody titers and induced PPP‐like exanthema [137]. Indeed, in patients with PPP, the numbers of tonsillar and peripheral blood IgG keratin‐specific homing cells, as well as the serum anti‐keratin antibody or keratin‐specific IgG antibody titers, are significantly increased; however, these parameters decreases after tonsillectomy [138, 139]. Recently, an interesting study examining the influence of smoking on the condition of PPP was published [136]. Activation of IL‐36 is known to be associated with neutrophil‐mediated skin inflammation, such as pustular psoriasis. In that study, IL‐36 production was significantly increased following exposure of tonsillar epithelial cells from patients with PPP to tobacco extract. Moreover, concomitant stimulation with IL‐17A synergistically increased IL‐36γ production. These findings suggest that immune responses of tonsillar epithelial cells are associated with the pathogenesis of PPP and may be modulate by smoking. Mucosa‐associated lymphoid tissue (MALT), which is responsible for mucosal immunity, is classified into nasopharynx‐associated lymphoid tissue (NALT) of the respiratory system, bronchus‐associated lymphoid tissue (BALT), and gut‐associated lymphoid tissue (GALT) of the digestive system. However, in PPP, it has been proposed that the disease may originate from a mucosal immune disorder of NALT, with primarily involvement of the tonsil.

4.1.3. Odontogenic Lesions

Recently, the association of PPP with odontogenic focal infection, such as periodontal disease and apical lesions, in addition to tonsillar focal infection has been reported [32]. In clinical research in patients with PPP, odontogenic lesions were observed in ≥ 80%, and dental treatment relieved cutaneous symptoms in ≥ 60% [53, 54, 55]. To elucidate the mechanism associated with the onset of PPP, the oral flora (microbiome) of patients with PPP is being analyzed.

Kouno et al. [140] analyzed the variable region of the 16S gene in the oral bacteria obtained in saliva obtained from 12 patients with PPP and 10 healthy adults using next‐generation sequencing, and compared its distribution between the two groups using UniFrac analysis, in which a difference in the structure between bacterial floras is expressed as a distance, and principal coordinate analysis (PCoA) with a calculated‐value‐based distance matrix. PCoA analysis revealed that the patient and control groups showed different distributions. UniFrac distance analysis found that the distance between the two groups' microbiota was significantly long, and oral dysbiosis was observed in the patients with PPP (Figure 13). In addition, when comparing seven patients with PAO with five articular‐symptom‐free patients with PPP, PCoA analysis showed that distributions differed between the two groups of patients. UniFrac distance analysis also found that the distance between the two groups' bacterial floras was significantly long, suggesting that the oral microbiome in PAO patients differs from that in articular‐symptom‐free patients with PPP. Similarly, the patients were divided into two groups based on the presence or absence of periodontal disease (present: 6 patients, absent: 6 patients) and the presence or absence of smoking (9 smokers, 3 nonsmokers), and the results of UniFrac distance analysis were studied. It showed that the patients in the periodontal disease and smoking groups had different microbiota.

FIGURE 13.

Comparison of the oral microbiome between patients with PPP and healthy controls (reproduced from reference [141]). (a) PCoA plot shows distinct clustering of patients with PPP (pts, open circles) and healthy controls (HCs, closed circles). (b) UniFrac distance analysis demonstrates that the distances between healthy controls and patients with PPP (HCs‐pts) are greater than those within healthy controls (HCs‐HCs) or within patients (pts‐pts), indicating that the oral microbiome composition differs between the two groups.

The species composition comprising the oral flora in PPP patients was compared with the species composition in the healthy controls. In the patients with PPP, a decrease in the number of proteobacteria, an increase in the number of Prevotella, and a decrease in the number of Haemophilus compared with those in the healthy controls were noted, suggesting that these changes in species composition are observed in patients with PAO, but not in articular‐symptom‐free patients with PPP. Smoking is a risk factor for periodontal disease [142], and it was reported that the number of Firmicutes was increased in the oral microbiome of smokers [141]. Even among the patients with PPP, there was an increase in the number of Firmicutes in the smoking group, suggesting that changes in the oral microbiome, as a background factor, are associated with the finding that periodontal disease and smoking are PPP‐exacerbating factors.

In patients with PPP, an increase in the IL‐17 level in blood and at the lesion site is observed [74]. An increase in the IL‐17 level is also noted in patients with periodontal disease [143]. A study found that Prevotella induced IL‐17‐associated cytokines, contributing to inflammation of the oral mucosa [144]. An increase in the number of Prevotella is observed in patients with PPP, and it is particularly closely associated with periodontal disease and smoking, suggesting that periodontal disease and smoking are associated with the onset of PPP via IL‐17‐associated cytokines.

An increase in the number of Prevotella and a decrease in the number of Haemophilus, which were observed in PAO patients, were also observed in patients with rheumatoid arthritis [145]. These common changes in species composition may be associated with arthritis. An increase in the number of Prevotella was also observed in the oral microbiome of patients with inflammatory bowel disease, and the number of Prevotella was correlated with the patient saliva level of IL‐1β [146]. Furthermore, an increase in the number of Prevotella and a decrease in the number of Haemophilus are also observed in the tonsillar crypt of patients with IgA vasculitis [147]. These results suggest that there is a common tendency for changes in the oral microbiome in patients with inflammatory diseases in which focal infection is involved.

4.2. Relationship Between Focal Infection and PPP

Several studies found an association of PPP with focal infection, such as tonsillar and odontogenic lesions, and focal treatment may be effective in relieving PPP or achieving the disappearance of cutaneous symptoms [58, 63, 148]. The pathogenesis of focal infection involves an autoimmune/autoinflammatory mechanism in the nasopharyngeal and oral mucosae, but not infection [66]. According to a single‐center survey of 513 patients with PPP by Kobayashi [63], focal infection was present in approximately 80% of the patients with PPP, and the rate of clinical resolution in PPP following focal infection treatment was approximately 80% of cases. As many patients had multiple overlapping focal infections, investigation and treatment of odontogenic lesions/sinusitis/bowel symptoms, which are detectable, were initially performed; as a result, odontogenic lesions and sinusitis were observed in 66.1% and 6.2% of the patients, respectively. Because tonsillar focal infection treatment, such as tonsillectomy, was applied specifically to refractory or insufficiently responsive cases in this cohort study, tonsillar focal infection accounted for 40% of the entire cohort cases [63]. At the same time, with respect to the frequency at which focal tonsil is involved, Takahara et al. [57] performed tonsillectomy in 138 patients with PPP who did not respond to conservative treatment regardless of the presence or absence of symptoms of tonsillitis, and found that the response rate for skin lesions 12 and 24 months after surgery were 71% and 95%, respectively, suggesting the efficacy of this procedure. In 78% of patients with PAO, pain had disappeared 12 months after surgery [57], suggesting that focal tonsil is closely associated with the pathogeneses of PPP and PAO. In particular, the response rates in the nonsmoking or smoking‐cessation groups were high [57]. Similarly, a subgroup analysis in which the efficacy of tonsillectomy was investigated by dividing the subjects into the smoking and nonsmoking groups showed that an improvement or better was achieved in 50% of the patients in the smoking group and in 83.3% in the nonsmoking group; the percentage was higher in the nonsmoking group, although there was no significant difference. Healing was achieved only in the nonsmoking group [52]; smoking cessation may improve the effects of tonsillectomy. Concerning the effects of periodontal treatment of odontogenic lesions, the response rate for PPP during the 4‐month to 3‐year posttreatment follow‐up (mean: 8.7 months) was approximately 80% [54]. The response rate for treatment of focal infection at an adequate timing of evaluation 1 to 2 years after focal treatment seems to be approximately 80%.

In a single‐center case study of 469 patients with PPP conducted by Akiyama et al. [64], focal tonsil was detected in only 173 patients (27.1%) on a provocation test of the tonsil or blood test, and the odontogenic lesion detection rate in the absence of X‐ray in all patients remained at 4.7%. Fujishiro et al. [67] performed a single‐center retrospective study, and reported that focal infection was present in 65 (58.6%) of 111 patients with PPP: dental foci in 38 patients (47%), tonsillitis in 21 (30%), sinusitis in 5 (4.5%), and mandibular osteomyelitis in 1. Additionally, they reported that tonsillar hypertrophy was observed in 18 (58.1%) of 31 patients, and 10 (55.6%) of the 18 patients were positive for ≥ 1 item on a provocation test of the tonsil. However, it has been demonstrated that the efficacy of tonsillectomy was not correlated with the presence or absence of tonsillar hypertrophy, the results of a provocation test of the tonsil, or PPP symptom deterioration at the time of upper respiratory inflammation [57, 66, 149]. It must be considered that most infection foci in patients with PPP are asymptomatic. Recently, Takahara et al. [57] reported that tonsillectomy was more effective in patients achieving smoking cessation and in PAO‐complicated patients.

4.3. Relationship With Cigarette Smoking

4.3.1. Cigarettes/AhR and Immunity

Previous studies suggested a strong association between PPP and smoking. According to a report in 1995, heavy smokers accounted for 75% of patients with this disease [64]. A recent study also showed that smoking was associated with both the onset of PPP and its subsequent severity, especially in females [136]. Furthermore, smoking cessation significantly reduced symptoms [150]. As a mechanism, aryl hydrocarbon receptors (AhRs) may be involved. Polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke bind to AhR, regulating the transcription of various genes by intranuclear transfer. Induction of inflammation, immunosuppression, pigment production, and skin cancer development are known as its actions on the skin. AhR induces differentiation into Th17 cells by Stat1 control [151], contributing to the onset and deterioration of PPP. In patients with PPP, Th17 cells [152], which are present in peripheral blood at a larger number than in healthy adults, accumulate in skin lesions, causing inflammatory responses. The formation of Th17 cells is induced by smoking, and their count increases in the patient's peripheral blood [153]. Furthermore, IL‐17A produced by Th17 cells increases IL‐36γ expression in tonsillar epithelial cells [150]. A neutrophil chemotactic factor, IL‐8, is also induced by cigarette smoke‐activated AhR by the production of reactive oxygen species, deteriorating PPP [154]. AhR interacts with NF‐kB [155], promoting induction of inflammatory cytokines and increasing and prolonging inflammation. On the other hand, ultraviolet B (UVB) irradiation, which is routinely performed as PPP treatment, is also known to activate AhR [156]. The therapeutic effects of UVB therapy may be associated with an AhR ligand‐specific activity and Th17/Treg cell balance.

4.3.2. Skin Acetylcholine Receptor (AChR) and Nicotine

In Japan and other countries, an association between PPP and habitual smoking has been reported. In Japan, a 20‐year study conducted between 1975 and 1994 investigated smoking prevalence among patients with PPP (203 males, 266 females) and healthy controls. Heavy smokers (≥ 20 cigarettes/day) accounted for 74.7% of male patients with PPP, compared with 37.2% in the healthy male group, and 32.9% of female patients with PPP, compared with 9.8% in the healthy female group; these proportions were significantly higher in the patients with PPP [54]. In a subsequent survey, smokers accounted for 84.6% of male and 72.0% of female patients with PPP, suggesting an increased prevalence of smoking among female patients [157]. A retrospective study of 229 patients with PPP showed that 85.5% had a history of smoking. Especially these population was markedly higher among females, reaching 93.8% [68]. Internationally, it had also reported that 95% of patients with PPP were smoker at the time of disease onset [5]. A prospective survey comparing nine patients with PPP who successfully achieved smoking cessation with eight patients who continued smoking demonstrated significant improvements in cutaneous symptoms and patient‐reported disease after 3 months in the smoking cessation group [150]. In addition, treatment responses in the smoking continuation group were significantly less pronounced than those observed in the never‐smoking group and in patients with a history of smoking who achieve smoking cessation [67]. Although the number of patients was small, these findings suggest that smoking influences disease activity and treatment response in PPP.

As a mechanism linking smoking to the onset or exacerbation of PPP, a nicotinic acetylcholine receptor (nAChR)‐mediated cholinergic signal pathway has been suggested. nAChRs are abundantly expressed in neural cells, immune cells, the epidermis, and eccrine sweat glands and ducts; notably eccrine sweat glands are densely distributed in the palms and soles [158, 159]. In the epidermis, several subtypes of nAChR, such as α7, α9, α3β2, and α3β4, are expressed, and the pattern of subtype expression varies according to the degree of keratinocyte differentiation [158]. For example, α7nAChR is expressed in the superficial layer of the epidermis, and α3AChR is expressed in the subepidermal layer, contributing to the differentiation and proliferation of the epidermis, respectively [158]. In addition, α7nAChR influences innate immune responses in the epidermis [158]. Acetylcholine, which induces sweating, and nicotine, a principal ingredient of tobacco, act as agonists of nAChRs; therefore, cholinergic signaling pathways have been suggested to be associated with the pathogenesis of PPP, which involves the palms and soles and is exacerbated by smoking. A study examined nAChR expression in the palmoplantar skin of patients with PPP, healthy smokers, and healthy nonsmokers using immunostaining. In the healthy subjects, among the AChR subtypes examined, α3nAChR and α7nAChR were detected on the surface of the epidermal granular layer as well as in the intraepidermal sweat ducts and eccrine sweat ducts/glands. In contrast, the patients with PPP exhibited increased α7nAChR expression in the intraepidermal sweat ducts and peripheral epidermal cells [159]. Alteration in α7nAChR expression may be involved in the differentiation of epidermal keratinocytes or innate immune responses. Furthermore, anti‐nAChR autoantibodies have been detected in patients with PPP. In a study examining the serum of 45 patients with PPP and 23 with chronic hand eczema, 42% of the PPP patients were positive for anti‐nAChR antibodies, whereas none of patients with hand eczema showed antibody positivity. Immunofluorescence staining with anti‐nAChR antibodies demonstrated positivity for the vascular endothelium of the papillary dermis, whereas the sweat glands were positive in smokers. These findings suggest that smoking may be associated with the induction of autoimmune disorders [160]. In addition, the expression of acetylcholine synthesizing enzyme choline acetyltransferase, was markedly increased pustule granulocytes from PPP patients, whereas the expression levels of acetylcholine‐degrading enzyme acetylcholinesterase was decreased in mast cells from smokers [161]. These findings suggest that an imbalance between acetylcholine synthesis and degradation may influence inflammatory responses.

4.4. Relationship With Metal Allergy

Several case reports have suggested that metal allergy may be associated with the onset of PPP [162, 163, 164, 165, 166, 167, 168, 169], but few studies have examined the mechanism by which metal allergy induces PPP in detail. Nakamura et al. [169] investigated the concentrations of LTB4 in the contents of sterile pustules at the site of cutaneous symptoms and serum before and after a patch test in seven patients who showed a positive reaction to either of nickel, platinum, palladium, tin, cobalt, or iron on the patch test under a diagnosis of PPP. As a result, there were increases in the pustule content and serum concentration of LTB4 after the patch test in all patients. Symptom deterioration was confirmed in all patients 48 h after the patch test. In two patients, removal of dental metals reduced the symptoms, suggesting that metal allergy induces pustulation related to PPP [169]. Watanabe et al. [170] administered a leukotriene antagonist, oral montelukast, to patients with PPP who showed positive reactions to chrome, cobalt, and nickel on a metal patch test, complaining of arthralgia, and reported that a nearly recovered condition was achieved 4 months after the start of administration.

On the other hand, Masui et al. [70] examined the effects of metal removal in 257 patients with PPP who underwent a metal patch test, and found that there was no significant difference in the effects between the group in which a dental metal allergen to which a positive reaction was confirmed on the patch test was removed from the oral cavity and the group in which it was not removed. They commented that, when evaluating the effects of dental metal removal, the possibility that patients responded to odontogenic lesion treatment, such as periodontal disease treatment, that was conducted in parallel with metal removal should be considered. However, in nickel‐positive patients on the patch test, the efficacy of removal of nickel‐containing dental metals and restricted consumption of nickel‐containing foods was suggested.

5. Chapter V: Treatment Algorithm of Palmoplantar Pustulosis

PPP treatment is classified into three categories: (1) lifestyle guidance, (2) removal of deteriorating factors that may become a trigger of onset, and (3) topical and systemic therapies as symptomatic therapy.

In approximately 80% of patients with PPP, focal infection or smoking was associated with its onset. These deteriorating factors should be investigated. If there are deteriorating factors, treatment to remove them should be prioritized, because healing can be expected within 1–2 years after the completion of focal treatment in patients achieving smoking cessation and effective focus removal [57, 171]. Therefore, local therapy (topical application therapy, phototherapy) and systemic therapy (oral therapy, biologics, granulocytapheresis) are positioned as symptomatic therapy (Figure 14).

FIGURE 14.

Overview of the treatment of PPP/PAO (adapted from reference [172]). The yellow boxes also indicate cases with osteoarticular involvement.

5.1. Inquiry/Blood Collection/Odontogenic Lesion Investigation to Be Performed on Initial Consultation [172]

With respect to factors that may become a trigger of onset, the following items should be investigated (Figure 15).

1. Inquiry: Family history, presence or absence of articular symptoms.

   Smoking, a history of tonsillitis, previous dental treatment, presence or absence of sinusitis, presence or absence of constipation or diarrhea.

2. Hematology: Presence or absence of concomitant diseases such as diabetes mellitus, autoimmune thyroiditis, and dyslipidemia.

3. Dental consultation: Investigation of odontogenic lesions, understanding of the treatment course and future prospects in patients receiving dental treatment.

   Based on the results, the following should be conducted if necessary.

4. Diagnosis of PAO and differential diagnosis: Plain X‐ray, MRI fat‐suppressed images, cooperation with rheumatologists/orthopedic surgeons regarding differential diagnosis and therapeutic strategies.

5. Consultation for the diagnosis and treatment of sinusitis.

6. Consultation for the treatment of bowel symptoms.

7. Consultation for detailed examination and treatment of diabetes mellitus and autoimmune thyroiditis.

FIGURE 15.

Examinations and multidisciplinary collaboration in PPP.

5.2. Removal of Triggering/Deteriorating Factors Should Be Prioritized [63]

1. Guidance for smoking cessation.

2. If an odontogenic lesion is detected, the physician should request a dentist to perform treatment.

3. In patients in whom focal tonsil is strongly suspected based on the clinical course, those with multiple pustules in the absence of other triggering factors, and those in whom osteoarthritis activity persists, tonsillectomy should be considered [173]. In such cases, a dermatologist should determine whether tonsillectomy is indicated, considering its risks and benefits.

4. If sinusitis is present, the physician should request an otorhinolaryngologist to perform treatment. If odontogenic sinusitis is present, the physician should request a dentist to perform treatment.

Most odontogenic lesions in patients with PPP are asymptomatic, and such asymptomatic lesions are usually not treated. Therefore, it is important to explain to patients and dentists that even asymptomatic odontogenic lesions may become a trigger of PPP/PAO onset or an etiological factor for a severe condition or protraction, and that dental treatment is necessary. Based on the severity of PPP and PAO, the necessity and methods of dental treatment are discussed with dentists and patients, and dental treatment is subsequently requested.

The tonsillar tissue consists of several lymphatic tissues (Waldeyer's ring: pharyngeal tonsil, tubal tonsil, palatine tonsil, lingual tonsil). For tonsillectomy, only the palatine tonsil is removed. If smoking is continued after palatine tonsillectomy, compensatory activation of the other tonsillar tissues may lead to post‐tonsillectomy recurrence of symptoms. As a rule, palatine tonsillectomy should be considered only for patients achieving smoking cessation. In patients with odontogenic lesions or sinusitis, this procedure should also be considered when there is no relief of symptoms of PPP or PAO even after the completion of treatment for these disorders.

5.3. Symptomatic Therapy During and After Focal Treatment [174]

During focal treatment, stimulation of the infectious focus may induce flares, which can lead to the expansion or deterioration of PPP and PAO in some cases. Even in cases without symptom deterioration, local therapies, such as topical therapy and phototherapy, or oral therapy should be concomitantly performed for management of symptom, as a few months or longer are required for focal treatment. If an evident focus remains, systemic therapy that exhibits systemic immunosuppressive effects should be avoided as much as possible. When administration is necessary, the administration period should be shortened. Caution is needed to ensure that the prompt completion of focal treatment is not hindered (Figure 16).

1. Topical therapy: topical steroids, topical vitamin D3 analogs, moisturizers, topical keratolytic agents.

2. Phototherapy: narrow‐band (NB)‐UVB, excimer light, PUVA (topical psoralen plus UVA), UVA1.

3. Systemic therapy (immunosuppression‐free or adjunctive therapy for focal treatment):

FIGURE 16.

Treatment algorithm and recommendation grades for PPP.

For skin symptoms—bacteriostatic antibiotics for focal infections, Chinese herbal medicines, etretinate (the administration period should be shortened in patients with PAO), high‐dose biotin*, granulocytapheresis.

For osteoarticular symptoms—nonsteroidal anti‐inflammatory drugs (NSAIDs), bacteriostatic antibiotics for focal infections, Chinese herbal medicines, high‐dose biotin* (pain relief only), colchicine*, bisphosphonates* (avoided on tooth extraction in some cases), granulocytapheresis.

• 4Immunosuppressive systemic therapy:

For skin symptoms—cyclosporine*, apremilast, guselkumab.

For osteoarticular symptoms—cyclosporine*, apremilast*, guselkumab*, TNF inhibitors*, oral corticosteroids (short period), methotrexate*, salazosulfapyridine*.

*Not covered by the Japanese health insurance system.

Even after the completion of focal infection treatment, it takes several months for immunologically activated focus to begin to decrease, and 1–2 years are required for subsequent improvement of cutaneous and osteoarticular symptoms. Therefore, non‐immunosuppressive agents should be prioritized for 6 months after focal treatment, and when signs of clinical improvement are observed after 6 months, patients should be subsequently followed for an additional 6 months. It should be noted that the efficacy and safety of guselkumab for skin symptoms [80] were demonstrated in clinical trials were based on the data from treatment‐refractory patients who remained unresponsive even after at least 6‐months following focal infection treatment, according to the inclusion criteria of the clinical trials. An improvement in PAO symptoms tends to appear earlier than an improvement in skin symptoms. On the other hand, aggressive treatment for relieving symptoms is necessary when severe skin or osteoarticular symptoms markedly impair the patient's QOL after completion of focal treatment. When severe pain is present in the acute inflammation phase of PAO, hospital admission may be considered to maintain local rest, and intravenous or oral antibiotics targeting inflammation of residual infectious foci, short‐term corticosteroids, and/or granulocytapheresis would be included as treatment options. If these are ineffective, the indication of immunosuppressive drugs including biologics can be considered, with careful attention to possible adverse reactions related to the focal infection. After the completion of focal treatment, the administration of TNF inhibitors for refractory severe PAO may induce multiple pustules over the entire body in addition to the palm and sole. Furthermore, patients with pharyngeal pain or lymph node swelling have been reported [175, 176].

5.4. The Importance of Collaborative Care for Chronic PAO With Structural Damage

In patients with a vertebral compression fracture or microfracture of the long bone periosteum related to inflammation or inflammatory osteoporosis in the presence of spondylitis or osteomyelitis of long bones, surgical fixation is required. Patients with hip arthritis complicated by femoral head necrosis or hip osteoarthritis may require joint replacement surgery. Furthermore, in cases with bone ankylosis, the treatment and management are required for persistent limitations in range of motion, fracture risk, and chronic pain, even after resolution of inflammation. It is important to promote the assessment and treatment of inflammatory osteoporosis, adequate rehabilitation, and guidance for daily living in cooperation with specialists in orthopedic surgery, rheumatology, and rehabilitation.

6. Chapter VI: Grade of Recommendation for Each Treatment and Explanations (Table 3)

TABLE 3.

Clinical question (CQ).

Category		CQ	CQ summary	Grade of recommendation	Evidence level
FAQ in clinical practice		CQ1‐1	Does PPP regress spontaneously?	Not established	V
		CQ1‐2	Should the vesicle/pustule contents be drained?	C2	V
		CQ1‐3	Are there any laboratory parameters useful for diagnosis?	C1	VI
		CQ1‐4	Is dermoscopy useful for diagnosis?	B*	V
		CQ1‐5	Why are skin lesions localized in the palm/sole?	Not established	V
		CQ1‐6	Can PAO be cured?	Not established	V
		CQ1‐7	Should smoking cessation be recommended to reduce cutaneous lesions?	B*	Not described
		CQ1‐8	Should smoking cessation be recommended to reduce arthralgia?	B*	Not described
		CQ1‐9	Is a provocation test of the tonsil useful?	C2	V
		CQ1‐10	Is screening of comorbidities, including diabetes mellitus and autoimmune thyroid disease, necessary?	C1	V
Treatment for exanthema	Focal infection treatment	CQ2‐1‐1	Is odontogenic focal infection treatment useful?	B*	V
		CQ2‐1‐2	Is tonsillectomy useful?	B*	V
		CQ2‐1‐3	Are there tonsillar characteristics from which the efficacy of tonsillectomy can be predicted?	C2	V
	Topical Medications	CQ2‐2‐1	Are topical steroids useful?	B	I–V
		CQ2‐2‐2	Are topical vitamin D3 analogs useful?	B	II–V
	Phototherapy	CQ2‐3‐1	Is PUVA useful?	C1	I–V
		CQ2‐3‐2	Is NB‐UVB useful?	C1	II–V
		CQ2‐3‐3	Is excimer light useful?	C1	III–V
	Oral administration	CQ2‐4‐1	Are retinoids useful?	C1	II–V
		CQ2‐4‐2	Are oral corticosteroids useful?	D	IV
		CQ2‐4‐3	Is cyclosporine useful?	B	II
		CQ2‐4‐4	Are phosphodiesterase 4 (PDE4) inhibitors useful?	C1	III–V
		CQ2‐4‐5	Is methotrexate (MTX) useful	C1	V–VI
		CQ2‐4‐6	Is biotin useful?	C1	IV–V
		CQ2‐4‐7	Are Chinese herbal medicines useful?	C1: Jumihaidokuto, Orengedokuto, Unseiin	IV–V
				C2: Keishibukuryogan
		CQ2‐4‐8	Are other oral drugs useful?: Antibiotics (minomycin, macrolide), colchicine, diaphenylsulfone (DDS)	C1: Antibiotics, colchicine	IV–V
				C2: DDS
	Biologics	CQ2‐5‐1	Are IL‐23p19 & p40 inhibitors useful?	B: Guselkumab	II–V
				C1: Ustekinumab
		CQ2‐5‐2	Are TNF inhibitors useful?	C2	II–V
		CQ2‐5‐3	Are IL‐17 inhibitors useful?	C2: Secukinumab	II–V
		CQ2‐6	Is dental metal removal useful?	C1: Metal removal	IV
		CQ2‐7	Is granulocytapheresis useful?	C1	V
Treatment for osteoarticular symptoms	Focal infection treatment	CQ3‐1‐1	Is odontogenic lesion treatment useful?	B*	IV–V
		CQ3‐1‐2	Is tonsillectomy useful?	B*	V
	Oral administration	CQ3‐2‐1	Are NSAIDs useful?	C1	VI
		CQ3‐2‐2	Are oral corticosteroids useful?	C1	VI
		CQ3‐2‐3	Are retinoids useful?	C2	V
		CQ3‐2‐4	Is cyclosporine useful?	C1	V
		CQ3‐2‐5	Are PDE4 inhibitors useful?	C1	V
		CQ3‐2‐6	Is MTX useful?	C1	II–VI
		CQ3‐2‐7	Is azulfidine useful?	C1	Not described
		CQ3‐2‐8	Is biotin useful?	C1	II–VI
		CQ3‐2‐9	Are bisphosphonate useful?	C1	Not described
	Biologics	CQ3‐3‐1	Are IL‐23p19 & p40 inhibitors useful?	C1: Guselkumab	V
				C1: Ustekinumab
		CQ3‐3‐2	Are TNF inhibitors useful?	C1	V
		CQ3‐3‐3	Are IL‐17 inhibitors useful?	C1	V
		CQ3‐4	Is granulocytapheresis useful?	C1	V

*Expert consensus opinions.

6.1. Questions Frequently Asked in Clinical Practice (FAQ)

6.1.1. CQ1‐1: Does PPP Regress Spontaneously?

Recommendation comment: There is no evidence for the spontaneous disappearance of PPP.

Grade of recommendation: Not established, Evidence level: V.

Explanation: The mean interval until healing is reportedly 3–7 years [177], but this was presented at an expert's opinion level. Currently, there is no scientific evidence. Furthermore, no study has confirmed the spontaneous disappearance of PPP in the absence of therapeutic intervention.

6.1.2. CQ1‐2: Should the Vesicle/Pustule Contents Be Drained?

Recommendation comment: There is no evidence that drain of the vesicle/pustule contents makes the subsequent course better.

Grade of recommendation: C2, Evidence level: V.

Explanation: It is known that pustulation promptly occurs after vesicle formation, inducing erythema, marked scales, and abnormal desquamation [6, 178]. However, no study has compared patients who did or did not undergo early vesicle/pustule content drained. Currently, there is little evidence that this procedure is effective.

6.1.3. CQ1‐3: Are There Any Laboratory Parameters Useful for Diagnosis?

Recommendation comment: There is no blood test parameters that is routinely investigated, but measurement of the leukocyte count, serum anti‐streptolysin O antibody (ASO) level, and serum anti‐streptokinase antibody (ASK) level may be sometimes helpful in inferring the presence of focal infection. Additionally, testing for comorbidities should be conducted at appropriate times.

Grade of recommendation: C1, Evidence level: VI.

Explanation: To date, there has been no sufficient evidence for a routine blood test that can be used to diagnose PPP. The leukocyte count, ASO level, and ASK level may be sometimes be helpful in inferring the presence of focal infection. Additionally, diabetes mellitus or thyroid dysfunction is present in some cases [179], and blood tests should be performed at appropriate times.

6.1.4. CQ1‐4: Is Dermoscopy Useful for Diagnosis?

Recommendation comment: Dermoscopy is a noninvasive test, and is useful for the diagnosis of PPP.

Grade of recommendation: B*, Evidence level: V.

Explanation: When examining PPP skin lesions by dermoscopy, vesicles containing small pustules in center are observed in addition to small vesicles and pustules [4]. This is termed “pustulo‐vesicle,” which is a finding characteristic of PPP. Furthermore, a case series study showed that the detection rate of pustules on dermoscopy was significantly higher than that on visual inspection [180].

6.1.5. CQ1‐5: Why Are Skin Lesions Localized in the Palm and Sole?

Recommendation comment: Currently, the strongest hypothesis is that an extremely large number of eccrine sweat glands are distributed in the palm and sole in comparison with other areas, contributing to localization.

Grade of recommendation: Not established, Evidence level: V.

Explanation: An association between eccrine sweat glands and the pathogenesis of PPP has been suggested [5]. In PPP‐related vesicles or pustulo‐vesicles, the presence of antimicrobial peptides contained in eccrine sweat, hCAP‐LL‐37 and dermcidin, was confirmed. In addition, intraepidermal sweat duct cells that may have dilated were histologically/immunohistologically observed around vesicles/pustulo‐vesicles [6]. To date, few pathological studies have reported the reason why lesions are localized in the palm/sole; this remains hypothetical.

6.1.6. CQ1‐6: Can PAO Be Cured?

Recommendation comment: In patients with sternoclavicular arthritis as the most frequent type of PAO, pain sometimes disappears, leading to clinical remission. However, in many cases, the presence or absence of remission on imaging is not confirmed. Furthermore, there are no data on long‐term follow‐up, and spontaneous remission of PAO may not be achieved, differing from skin symptoms of PPP. PAO progresses year by year, leading to irreversible osteoarticular destruction; therefore, adequate therapeutic intervention by drug therapy should be performed after early investigation/treatment of focal infection and guidance for smoking cessation.

Grade of recommendation: Not established, Evidence level: V.

Explanation: Sonozaki et al. [39] reported that PAO rarely caused functional disorder, differing from rheumatoid arthritis, and that the prognosis was favorable. With respect to the clinical course of SAPHO syndrome, Colina et al. [181] found that there were three patterns: (i) patients with disappearance after only a single episode, (ii) those with repeated remission and recurrence, and (iii) those requiring the continuation of treatment due to a chronic course with short remission periods. On the other hand, Fritz et al. [107] conducted a prospective cohort study of a 15‐year follow‐up of clinical, laboratory, imaging, and pathological findings in 12 patients with SAPHO syndrome, including one patient with PAO, and reported that changes on imaging slowly progressed while recurrence and remission were clinically repeated, and that inflammation ended when complete ankylosis occurred by ≥ 10 years. They evaluated the severity of imaging findings using the following staging system: Stage I: Costoclavicular ligament calcification (ossification) without bone destruction and sclerosis at the site of adhesion, Stage II: Ossification of the sternocostoclavicular joint, clavicle, manubrium, costal bone, and costal cartilage, and Stage III: Complete ankylosis of these bones. They noted stage progression in 5 of the 12 patients, and serial gradual progression on imaging was observed in Stage II patients. They also reported that spondylitis concomitantly developed during the course in patients with PAO, leading to bone ankylosis resembling ankylosing spondylitis. In all patients, irreversible organic changes of the bone/joint/ligament remained. The clinical courses of the patients presented by Fritz et al. [107] correspond to the (ii) and (iii) patterns described by Colina et al. [181], suggesting that recovery from inflammation‐related bone erosion or ankylosis cannot be achieved. Furthermore, a cohort study of Chinese patients with SAPHO syndrome, including 143 patients with PAO [100], revealed that the discontinuation of drug administration resulted in recurrence; there is a possibility that drug therapy cannot be discontinued.

In patients with sternoclavicular arthritis as the most frequent type of PAO in clinical practice, pain sometimes disappears, showing clinical remission. This clinical course may correspond to the (i) or (ii) pattern described by Colina et al. [181] However, in many cases, the presence or absence of remission on imaging remained unconfirmed. Furthermore, patients in whom back‐axial lesions, such as spondylitis and sacroiliac arthritis, appear and progress over a ≥ 10‐year course, leading to ankylosis, as observed in the prospective cohort study conducted by Fritz et al. [107], are not rare. In Japanese patients with long‐term progression, factors associated with the onset or deterioration of PPP, such as odontogenic lesions, chronic sinusitis, and smoking, are often detected.

Thus, healing or clinical remission can be achieved especially in some patients with sternoclavicular arthritis. However, patients who undergo repeated cycles of remission and recurrence over a long period of time, resulting in spondylitis, are not rare. Osteoarthritis causes irreversible bone/joint destruction, such as ankylosis, differing from recurrence symptoms; therefore, early investigation/treatment of infection foci and guidance for smoking cessation are necessary. Adequate therapeutic intervention by drug therapy should be conducted if necessary.

6.1.7. CQ1‐7: Should Smoking Cessation Be Recommended to Reduce Cutaneous Lesions?

Recommendation comment: There has only been one prospective observational study on smoking cessation in smokers with PPP, but marked symptom relief was observed a few months after smoking cessation. Theoretically, smoking cessation may be effective for the following reasons: epidemiological surveys have shown the association between smoking and PPP; and a pathway mediated by the nicotine receptor or aryl hydrocarbon receptor (AhR) is associated with the onset of PPP. Furthermore, the continuation of smoking made it difficult to obtain better therapeutic effects. To improve therapeutic effects, smoking cessation should be recommended.

Grade of recommendation: B*, Evidence level: Not described.

Explanation: In patients with PPP, the rate of smokers is high at 70%–90% [5, 64, 68, 92]. According to a cohort study, the odds ratio for the association of smokers with pustular lesions in patients with psoriasis was 10.5 [182]. In current smokers, the age‐adjusted risk for PPP was 74‐fold that in individuals with no history of smoking [161]. There has only been one prospective observational study on smoking cessation in smokers with PPP. Although it was a small‐scale study, marked decreases in the number of new pustules and the score that takes into account erythema, scales and disease extent were observed a few months after smoking cessation [150].

Nicotine receptor α7 subunit expression is marked at the lesion site. In particular, it is increased in the intraepidermal sweat ducts/glands [159]. The neutrophil or mast cell levels of choline acetyltransferase at the lesion site are increased, and a study found that smoking increased these levels [183]. Several studies showed that PPP‐related inflammation primarily involved the intraepidermal sweat ducts, and that IL‐17 and neutrophils were induced at vesicle sites, forming pustules [6, 129].

On the other hand, polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke bind to AhR, regulating gene transcription by intranuclear transfer. AhR is present in T cells such as Th17 and regulatory T cells. In patients with PPP, the number of Th17 cells in peripheral blood is larger than in healthy adults [152]. A study showed that the induction of Th17 cells was promoted by a cigarette smoke extract, and that they were derived from CD4‐positive T cells [153]. It is becoming increasingly clear that a nicotine receptor‐ or AhR‐mediated pathway is involved in the onset of PPP, and the association between smoking and PPP development is clear in consideration of the results of epidemiological surveys. In addition, it was shown that the continuation of smoking reduces treatment efficacy; therefore, smoking cessation should be recommended [57, 67].

6.1.8. CQ1‐8: Should Smoking Cessation Be Recommended to Reduce Arthralgia?

Recommendation comment: Smoking cessation is recommended as treatment for osteoarticular symptoms. There is no sufficient evidence for the effectiveness of smoking cessation in reducing osteoarticular symptoms. However, given its association with PPP and the harmfulness of smoking, smoking cessation should be considered as a first‐line therapeutic intervention.

For smoking cessation, medical intervention (i.e., referral to an outpatient smoking cessation clinic) should be reviewed if necessary, considering its influence, such as nicotine dependency.

Grade of recommendation: B*, Evidence level: Not described.

Explanation: No randomized controlled trial for evaluating the therapeutic effects of smoking cessation has been conducted.

There are only two reports on the therapeutic effects of smoking cessation in PPP patients: a case control study involving the comprehensive assessment of cutaneous and osteoarticular symptoms in a small number of patients [67] and a prospective study involving the assessment of skin symptoms in a small number of patients, with no assessment of osteoarticular symptoms [150]. Therefore, there is little evidence for the efficacy of smoking cessation for this disease. However, the rate of smokers in patients with PPP is high [5, 64, 67, 68, 92]. In females, the age‐adjusted odds ratio for PPP in the smoking history group in comparison with nonsmokers is reportedly 36.5 [61]; there may be a strong correlation between PPP and smoking. Furthermore, the incidence of adverse events related to smoking is considered to be high [184]. Although there is little evidence, there may be no adverse event related to smoking cessation; therefore, it should be initially reviewed. However, the influence of smoking, such as nicotine dependency, may make it difficult to execute smoking cessation; therefore, medical intervention (i.e., referral to an outpatient smoking cessation clinic) is required in some cases [184].

6.1.9. CQ1‐9: Is a Provocation Test of the Tonsil Useful?

Recommendation comment: It is difficult to predict the efficacy of tonsillectomy before surgery by a provocation test of the tonsil; it cannot be recommended. When performing this test, its results should be used only as a reference.

Grade of recommendation: C2, Evidence level: V.

Explanation: As a treatment procedure for PPP, tonsillectomy is considered to be effective. As methods to predict the efficacy of tonsillectomy before surgery, the tonsillar provocation test, the tonsillar elimination test, tonsillar clinical findings, the relationship between tonsillitis and PPP/PAO symptoms, and laboratory findings have been investigated, but diagnostic criteria have not been established.

For the tonsillar provocation and elimination tests, there are several procedures. Procedures of the former include tonsillar massage, the ultrashort wave provocation method, hyaluronidase method, and low‐frequency provocation method. Procedures of the latter include the crypt lavage method, tonsillar aspiration method, and Impletol test. Evaluation parameters include body temperature, erythrocyte sedimentation rate, leukocyte count, complements, urine, C‐reactive protein (CRP), arteriosclerosis obliterans (ASO), and clinical findings (exanthema in the presence of PPP) that are compared before and after testing.

With respect to the relationship between the result of the tonsillar provocation test and the effect of tonsillectomy, only case series studies have been published, and there has been no RCT.

Nosaka proposed the efficacy of a provocation test of the tonsil [185]. Since then, this test has been performed in Japan. However, many subsequent studies noted its limitations and problems. A multicenter survey conducted by the Committee for the Standardization of Diagnostic Criteria for Tonsillar Focal Infections of the Japan Society of Tonsil Problem [65, 186] included 1090 patients with focal infection, including 349 with PPP, and showed that the positive predictive value of a provocation test of the tonsil was high, whereas its negative predictive value was extremely low, as previously reported; the diagnostic predictive value was reported to be low. Furthermore, it was reported that there were no differences in the body temperature, leukocyte count, erythrocyte sedimentation rate, urine findings, and ASO‐ and CRP‐positive rates on the tonsillar provocation test between patients and healthy adults [65]. A study examined new evaluation parameters to improve the accuracy of the tonsillar provocation test, and reported that thermography of the palm and sole (22 patients with PPP) was effective [187]. However, there have been no further studies on this method, and this method is not generally used. It is unclear whether the use of other evaluation parameters for the tonsillar provocation test may improve its predictive value.

Thus, the diagnostic predictive value of the tonsillar provocation test using the current evaluation parameters (body temperature, leukocyte count, erythrocyte sedimentation rate, urine findings, ASO, CRP, exacerbation of exanthema) for predicting the efficacy of tonsillectomy is low, and this test cannot be recommended. As the positive predictive value is high, the test results should be used as a reference.

6.1.10. CQ1‐10: Is Screening for Comorbidities, Including Diabetes Mellitus and Autoimmune Thyroid Disease, Necessary?

Recommendation comment: Thyroid disease or diabetes mellitus screening should be considered in patients with PPP.

Grade of recommendation: C1, Evidence level: V.

Explanation: According to a patient survey in 2017 [188] that was conducted by the Ministry of Health, Labour, and Welfare, the total number of patients with thyroid disease (estimation with respect to diseases) was 389 000, and there were 73 000 males and 316 000 females. Patients with thyrotoxicosis (Graves' disease in most patients) consisted of 35 000 males and 97 000 females. Those with thyroiditis consisted of 8000 males and 57 000 females. Furthermore, according to this survey, the total number of patients with diabetes mellitus (estimation with respect to diseases) was 3 284 000.

On the other hand, several studies in Europe and the United States found that the incidence of autoimmune thyroiditis in patients with PPP was approximately 10% [189], 12% [61], 14% [5], and 24% [190], respectively, being relatively high. In Japan, a study reported that thyroid abnormalities were noted in 7 (3%) of 194 patients with PPP [90], and another study showed that Graves’ disease was present in 1 (3%) of 29 patients [191]. However, there has been no large‐scale epidemiological survey report; currently, there is little evidence to strongly recommend thyroid screening for all patients. According to a study, antithyroglobulin antibodies were detected in approximately 10% of healthy adults [192]. For screening, the presence or absence of abnormal thyroid hormone levels should always be confirmed.

In Japan, impaired glucose tolerance was observed in 8 (20%) of 41 patients with PPP [193]. Other studies showed that diabetes mellitus was present in 17 (8%) of 229 patients [68] and in 13 (7%) of 194 patients [90]. In Europe and the United States, diabetes mellitus was observed in 17 (28%) of 60 patients [61]. There has been no large‐scale survey report; currently, there is little evidence to strongly recommend diabetes mellitus screening for all patients. However, such screening may also be considered based on the above studies.

Hirano and Okubo [72] analyzed the incidences of complications based on the receipt data from 6978 patients with PPP, and reported that hyperlipidemia, hypertension, diabetes mellitus, thyroid disorder, heart disease, cerebrovascular disease, alopecia areata, and vitiligo were observed in 1586 (22.7%), 1241 (17.8%), 895 (12.8%), 389 (5.6%), 315 (4.5%), 292 (4.2%), 109 (1.6%), and 43 (0.6%) of these patients, respectively. Other studies noted hypertension in 13 (6.7%) of 194 patients [90], in 13 (6.3%) of 206 patients [68], and in 25 (18.4%) of 136 patients [73], hyperlipidemia in 4 (1.9%) of 206 patients [68] and in 6 (4.4%) of 136 patients [73], heart disease in 18 (30%) of 60 patients [61] and in 2 (1.5%) of 136 patients [73], vitiligo in 3 (5%) of 59 patients [5], and alopecia areata in 2 (3%) of 59 patients [5] and in 1 (0.5%) of 194 patients [90].

6.2. Treatment for Skin Symptoms

6.2.1. Treatment of Focal Infection

6.2.1.1. CQ2‐1‐1: Is Odontogenic Focal Infection Treatment Useful?

Recommendation comment: In Japanese patients, odontogenic focal infection is the most frequent trigger of the onset of PPP. Additionally, the high efficacy of treatment, involving healing, has been reported, and dental treatment should be performed in consideration of disease severity related to skin symptoms and invasiveness of the dental treatment.

Grade of recommendation: B*, Evidence level: V.

Explanation: As background studies, only single‐center cohort or clinical studies have been conducted, but pustular bacterid (Andrews) triggered by focal infection is frequently observed in Japanese patients with PPP [58]. It was reported that odontogenic lesion treatment led to the disappearance or relief of cutaneous symptoms from several institutions [53, 54, 56, 194, 195]. Odontogenic lesions as a trigger of PPP onset include apical periodontitis, moderate or severe marginal periodontitis, and wisdom tooth periodontitis. In several institutions, clinical studies on the concomitant incidence of odontogenic lesions and efficacy of odontogenic lesion treatment have been performed. Odontogenic lesions are observed in 47%–96.7% of patients with PPP [53, 54, 63, 64, 67, 195], and the response rate to odontogenic lesion treatment ranges from 64.5% to 80.0% [53, 56], being markedly high. Differences in the incidence of odontogenic lesions among institutions may be related to methods of detecting asymptomatic odontogenic lesions. Asymptomatic apical lesions, which are usually not an indication for treatment in Japan, can be detected on orthopantomography as radiolucent areas resulting from jawbone resolution; however, it has been pointed out that dentists often respond that there are no dental lesions requiring treatment [63]. When lesions cannot be detected by orthopantomography, close‐up intraoral dental radiography or dental cone‐beam computed tomography (CBCT) is required in some cases.

In the presence of apical periodontitis, oral bacteria reaching the root apex by pulpitis progression aggregate, forming a biofilm. In the presence of marginal periodontitis, periodontal bacteria induce destruction of the gingiva or alveolar bone, forming a periodontal pocket, and biofilm‐forming plaques in the pocket [63, 195]. The two conditions correspond to a state of dysbiosis, and destruction of immune tolerance to dysbiosis and induction of autoinflammation are speculated, as described for focal tonsil. For odontogenic lesion treatment, tooth extraction is sometimes required depending on the supporting tissue or tooth states in addition to root canal treatment and apicoectomy. However, when only treatments for skin symptoms are provided without the treatment of focal infection, it may take a longer period of time—often 7–13 years or longer—until healing, whereas focal infection treatment results in healing or a nearly recovered condition within a short period of 1–2 years, improving the QOL of patients. The treatment of focal infection has the additional advantage of avoiding chronically continuous drug therapy. Therefore, it is important to obtain informed consent in consideration of the severity of skin symptoms, maintenance of masticatory function, and patient burden. In addition, focal infection treatment may inhibit the onset of PAO. If neither investigation nor treatment of odontogenic lesions is performed, the long‐term disadvantages for patients are immeasurable.

6.2.1.2. CQ2‐1‐2: Is Tonsillectomy Useful?

Recommendation comment: For non‐responders to conservative treatment, tonsillectomy is proposed as a treatment option.

Grade of recommendation: B*, Evidence level: V.

Explanation: Several epidemiological studies examined the efficacy of tonsillectomy in improving the severity of skin symptoms in patients with PPP [48, 51, 52, 54, 57, 67, 68, 92, 148, 157, 173, 196, 197, 198, 199, 200, 201, 202]. In studies that described criteria for performing palatine tonsillectomy, the procedure was undertaken in patients with refractory PPP in whom conservative treatment failed to result in complete resolution of skin lesions. Treatment efficacy was evaluated using various methods, including macroscopic observation by physicians [48, 52, 67, 68, 92, 196, 197, 198], PPPASI [57, 148, 173], a self‐scoring method by patients themselves [51], and a questionnaire survey of physicians [51]. Thus, despite differences among studies in patient selection criteria of and evaluation methods, the response rate of skin lesions after tonsillectomy was consistently high, with approximately 80% of the patients (60.8%–89%) being evaluated as having “effective or better” or “≥ 50% improvement.” When compared with the non‐tonsillectomy group, the improvement rate was significantly higher in the tonsillectomy group [173, 196, 199, 201]. The efficacy of tonsillectomy was slightly higher in patients with a shorter interval between disease onset and surgery; however, the procedure remained effective even in patients with a long disease duration [198]. Significant improvement in skin lesions was observed as early as 1 month after surgery, with disappearance of exanthema achieved in many patients by 1 year postoperatively [57, 148]. The recrudescence rate is low, and even when recrudescence occurs, a return to the pre‐tonsillectomy state or further deterioration is rare [48, 148]. Because improvement rates after tonsillectomy were significantly higher in nonsmoking and smoking cessation groups, smoking cessation before and after surgery is recommended [57, 157]. Tonsillectomy has been reported to be more effective in patients with a history of tonsillitis and in those who tested positive on tonsil provocation test; however, macroscopic findings, such as tonsillar hypertrophy or findings suggestive of focal infection, such as deterioration of skin lesions after upper respiratory infection, were not correlated with the efficacy of tonsillectomy [57]. Furthermore, false‐negative results are frequently observed in tonsillar provocation tests; therefore, these test results are not reliably predict treatment efficacy [57]. Tonsillectomy is effective for PPP; however, it should be considered a treatment option for PPP to be selected in collaboration with otorhinolaryngologists, with careful consideration of surgical invasiveness and possible complications such as postoperative hemorrhage.

6.2.1.3. CQ2‐1‐3: Are There Tonsillar Characteristics From Which the Efficacy of Tonsillectomy Can Be Predicted?

Recommendation comment: There is no tonsillar characteristic from which the efficacy of tonsillectomy can be predicted.

Grade of recommendation: C2, Evidence level: V.

Explanation: Tonsillectomy is performed under general anesthesia, and patients may be highly stressed. Many dermatologists and otorhinolaryngologists explain that it cannot be predicted whether skin lesions or arthralgia will improve after the tonsil is removed. This is correct, but, if the efficacy could be predicted to some degree in advance, it would be useful for patients. However, actually, there seems to be no evidence for topical findings characteristic of focal tonsil that can predict its efficacy [173].

6.2.2. Topical Medications

6.2.2.1. CQ2‐2‐1: Are Topical Steroids Useful?

Recommendation comment: Topical steroid therapy for PPP may be effective due to its potent anti‐inflammatory effects. There have been two RCTs; evidence is not sufficient, but this treatment is recommended as symptomatic therapy.

Grade of recommendation: B, Evidence level: I–V.

Explanation: With respect to the effects of topical steroids on PPP, an RCT where patients used the occlusive dressing technique (ODT) or simple application [203] showed the superiority of ODT. Another RCT compared topical steroid monotherapy with combination therapy consisting of topical steroid and a vitamin D₃ analog, and demonstrated the higher efficacy of the latter [78]. There have been two RCTs, and evidence may not be sufficient. However, several case series studies [204, 205, 206, 207, 208] showed an efficacy rate of ≥ 60%, and topical steroid therapy is routinely performed as a first‐choice treatment [209, 210]. Steroids exhibit potent anti‐inflammatory effects through upregulation of IκB‐α, an inhibitor of inflammation‐related NF‐κB, and through direct binding to AP‐1, leading to suppression of its transcriptional activity [211]. In addition, steroids inhibit the production of inflammatory cytokines [212], and exhibit inhibitory actions on epidermal cell proliferation [213]. They may contribute to correction of dyskeratosis and inhibition of pustulation in patients with PPP. In the palm and sole, the thick stratum corneum hampers permeation of topical steroid through the skin; therefore, very strong or stronger topical steroids must be used. Due to topical use, systemic adverse reactions may be limited [204, 214], but attention must be paid to topical adverse reactions such as skin atrophy and thinning. Concerning ODT, topical adverse reactions and infection must be considered, but short‐term or intermittent ODT for obtaining anti‐inflammatory effects in the initial phase or at the time of exacerbation is useful. Furthermore, there are merits: effects may be obtained even when low‐potency topical steroids are used, and the dose of the steroid can be reduced [215].

6.2.2.2. CQ2‐2‐2: Are Topical Vitamin D₃ Analogs Useful?

Recommendation comment: Vitamin D₃ analogs for topical use are recommended. They may be used in combination therapy with topical steroids or in topical monotherapy.

Grade of recommendation: B, Evidence level: II–V.

Explanation: Concerning the efficacy of topical vitamin D₃ analogs for PPP, several RCTs [78, 216] and case studies [217, 218, 219] demonstrated their usefulness. As the mechanism of action of vitamin D₃ analogs, they may inhibit pustulation by suppressing the production of IL‐6 and IL‐8, which induce neutrophil chemotaxis [220]. It was confirmed that the effects of maxacalcitol on pustules/small vesicles were particularly potent [216]. Furthermore, because of high expression of IL‐17 in serum and lesional skin from PPP patients, its association with the pathogenesis of PPP has been suggested [74], and the mechanism of action of topical vitamin D₃ via suppression of IL‐17 production has also been speculated [221]. The response rate for pustules/small vesicles after combination therapy with topical steroids and vitamin D₃ analogs was significantly higher than that with monotherapy using topical steroids, suggesting that combination therapy relieves desquamation/scales in the early phase [78]. In the presence of superantigens, the anti‐inflammatory actions of steroids are reduced [222], but vitamin D₃ analogs complement the effects [223]. Combination therapy with topical steroids as initial therapy and a subsequent switch to monotherapy with topical vitamin D₃ analogs at the time of relief may be advantageous [218].

Adverse reactions to topical vitamin D₃ include irritative symptoms in the applied skin as well as hypercalcemia in patients with renal hypofunction, and must be considered.

Among topical vitamin D₃ analogs, only maxacalcitol and low‐dose tacalcitol for PPP treatment are covered by health insurance in Japan.

6.2.3. Phototherapy

6.2.3.1. CQ2‐3‐1: Is PUVA Useful?

Recommendation comment: PUVA therapy for PPP may be considered, but there is no sufficient evidence for its effectiveness. Concerning retinoid plus PUVA (Re‐PUVA) therapy, there has been a systematic review. However, with respect to the dose of retinoids, the type of retinoids that are available differs between Japan and other countries, and sufficient examination is necessary. Concerning PUVA therapy, neither the optimal number of treatment sessions nor the optimal irradiation dose has been determined.

Grade of recommendation: C1, Evidence level: I–V.

Explanation: Adverse reactions to long‐term PUVA therapy reportedly depend on the total UVA irradiation dose and total number of treatment sessions in patients with psoriasis. However, there have been no such reports in patients with PPP; the irradiation dose and number of treatment sessions must be examined. Most studies on PUVA therapy for PPP were conducted before the introduction of other phototherapies, such as narrow‐band UVB (NB‐UVB) and excimer light, and no comparative study has been carried out. Therefore, a highly effective method with a low incidence of adverse reactions must be examined in the future.

PUVA therapy was initiated in the 1970s and was established as ultraviolet therapy approximately 30 years later. There are three methods: oral (systemic), local (topical), and bath‐PUVA methods. In addition, some studies reported the efficacy of a combination of retinoids and PUVA therapy, termed Re‐PUVA therapy [224, 225, 226]. A systematic review of PUVA therapy for PPP [227] compared a placebo/retinoid with PUVA and supported the effects of systemic retinoids (response rate: 44%, 95% CI: 28–59) and oral PUVA (response rate: 44%, 95% CI: 26–62) alone. However, it was concluded that combination therapy with PUVA and retinoids was more advantageous than monotherapy. Concerning oral PUVA therapy, Murray et al. [228] performed unilateral UVA irradiation 4 times a week (total: 30 times) at an initial dose of 0.5 J/cm² to a maximum dose of 2 J/cm² in 22 patients and reported that the irradiated area became clear in 12 patients and that an improvement and slight improvement were achieved in five patients each. No patient showed “no change” or “deterioration.” In the non‐irradiated area, an improvement was achieved in 13 patients, there was no change in 6, and exacerbation was noted in 32, indicating a significant difference between the irradiated and non‐irradiated areas (p < 0.001). Furthermore, topical PUVA therapy was similarly performed. Complete cure was achieved in seven patients, an improvement in two, and a slight improvement in six. No patient showed “no change” or “deterioration.” However, as adverse reactions, burns were observed in one patient treated with oral PUVA therapy and in four treated with topical PUVA therapy.

Concerning topical PUVA therapy, Mizuno et al. [229] performed topical PUVA therapy in four patients with PPP in 1976, and demonstrated its efficacy. This was the first report. Subsequently, Layton et al. [230] compared topical PUVA with a placebo at 44 sites in 27 patients, but there was no difference in response rate (68% and 66%, respectively). Furthermore, Lassus et al. [231] conducted oral, topical, and trioxsalen bath therapies as methods of PUVA for 12 weeks, and reported that the response rate for oral PUVA was 0%, whereas that for topical PUVA was 8%. Concerning Re‐PUVA therapy, Lawrence et al. [226] randomly assigned 17 patients with PPP to receive PUVA‐etretinate (1 mg/kg) or PUVA‐placebo therapies, and performed PUVA three times a week for a maximum of 18 weeks and monotherapy with a placebo or etretinate every day for 2 weeks. In all 10 patients in the PUVA‐etretinate group, disappearance was achieved, but there was no improvement in four patients in the PUVA‐placebo group (p = 0.03). In the PUVA‐etretinate‐treated patients, the number of PUVA treatment sessions (13.1 ± 2.9 times; mean ± SE) and treatment period (30.3 ± 7.1 days) were significantly smaller/shorter than in the PUVA‐placebo group (23.2 ± 4.2 times, 59.2 ± 11.5 days, respectively, p ≤ 0.05). In addition, the cumulative UVA dose until disappearance in the PUVA‐etretinate group (53.9 ± 18.5 J/cm²) was lower than that in the PUVA‐placebo group (113.1 ± 33.4 J/cm²), but there was no significant difference. Rosen et al. [224] randomly assigned 30 patients with PPP to receive a placebo (n = 14) or etretinate (n = 23); 2 weeks later, 12 patients in the placebo group and 18 in the etretinate group underwent PUVA therapy on the unilateral hand or foot, and used the other hand or foot as untreated controls. In 14 of 18 patients’ hands and feet, combination therapy led to disappearance, compared with 3 of 18 patients treated with etretinate and 3 of 12 treated by PUVA therapy. Matsunami et al. [225] divided 20 patients with PPP into two groups: etretinate and etretinate‐free groups (n = 10 each). They performed local PUVA on the right hand and foot in the latter group, and regarded the left hand and foot as a control. In the former group, they conducted Re‐PUVA on the left hand and foot, and regarded the right hand and foot as a control. Local PUVA was performed once a week; 0.3% 8‐MOP was applied for 2 h using the ODT, and UVA irradiation was started at 1.0 J/cm². The radiation dose was increased to a maximum of 9.0 J/cm² by increments of 1.0 J/cm². Etretinate at 1.0 mg/kg was orally administered every day for 4 weeks, and, subsequently, the dose was decreased to 0.5 mg/kg. Complete disappearance was achieved in Week 12 at 10 sites treated by Re‐PUVA therapy, at 2 of 10 sites treated with etretinate alone, and at 1 site treated by PUVA therapy. In the control group, there was no disappearance. Based on these results, they reported that Re‐PUVA therapy was the most effective. With respect to bath‐PUVA therapy, there have been two case reports on local bath‐PUVA therapy in Japan [232, 233].

This treatment is covered by the Japanese health insurance system as long‐wavelength ultraviolet therapy (150 points per day).

6.2.3.2. CQ2‐3‐2: Is NB‐UVB Useful?

Recommendation comment: For patients with PPP, NB‐UVB may be considered, but there is no sufficient evidence of its effectiveness.

Grade of recommendation: C1, Evidence level: II–V.

Explanation: PPP patients treated with NB‐UVB have been reported, but an RCT showed a significant improvement related to UVA1 treatment.

The greater portion of NB‐UVB consists of narrow‐wavelength‐width ultraviolet distributed at approximately 311–313 nm. In April 2008, in Japan, it became possible to calculate 340 insurance points per day (covered by health insurance as of February 2021) for medium‐wavelength ultraviolet therapy limited to a range of 308–313 nm even in patients with PPP. However, regarding reports on NB‐UVB therapy in Japan, a review of four case reports was published, before excimer light became commercially available [234], followed by one case report [235], and a comparative study with UVA1 [236]. In March 2021, treatment with UVA1 irradiators also became covered by health insurance in Japan. Sixty‐four patients with PPP were divided into the UVA1‐irradiated and NB‐UVB‐irradiated groups, and irradiation was performed three times a week for a total of 30 times. Concerning evaluation, the PPPASI was used, and there was no difference in the pre‐PPPASI scores between the two groups. In the UVA1‐irradiated group, the values before irradiation and after the 30th session of irradiation were 7.538 ± 2.906 and 1.556 ± 1.265, respectively. In the NB‐UVB‐irradiated group, the values were 6.919 ± 1.893 and 2.569 ± 1.796, respectively. In each group, there was a significant improvement after treatment (p < 0.05). The PPPASI improvement rate was significantly higher in the UVA1‐irradiated group (p < 0.05) [236].

NB‐UVB therapy is covered by the Japanese health insurance system; it is possible to calculate 340 insurance points per day as medium‐wavelength ultraviolet therapy.

6.2.3.3. CQ2‐3‐3: Is Excimer Light Useful?

Recommendation comment: Excimer light irradiation may be considered as one of the treatment options.

Grade of recommendation: C1, Evidence level: III–V.

Explanation: Excimer light irradiation for PPP may be recommended, but the irradiator and irradiation protocol that were used differed among studies; it is difficult to evaluate the results by integrating various studies. Furthermore, the number of subjects was ≤ 100; there have only been small‐scale studies, and no strict RCT has been conducted. However, in addition to the treatment response, there was a significant increase in the regulatory T cell (Treg) count in peripheral blood after excimer light treatment in comparison with the pretreatment value, suggesting immunological actions.

Excimer light/laser is a device for phototherapy, with an action wavelength of 308 nm. As described for NB‐UVB therapy, 340 insurance points per day can be calculated as medium‐wavelength ultraviolet therapy limited to a range of 308–313 nm in Japan.

Aubin et al. [237] performed excimer light irradiation every week in 17 patients with PPP, and reported that the response rate after irradiation at 11.8 MED (mean: 318.2 ± 28.4 mJ/cm²) at a mean frequency of 5.3 times during the irradiation period (5–10 weeks) was 79%. Furthermore, Takahara et al. [238] performed irradiation once a week for a total of 16 times in 8 patients with PPP, and evaluated the results of treatment using the PPPASI. Before irradiation, the mean score was 10.8, but the mean scores after 8, 12, and 16 weeks were 6.5 (p < 0.05), 4.6 (p < 0.01), and 4.2 (p < 0.01), respectively, showing significant improvements. In addition, there were significant increases in the lesional skin or peripheral blood Th17 cell ratios in the patients with PPP; they suggested that a decrease in the regulatory T cell (Treg) count was associated with the pathogenesis of PPP. Fumimori et al. [239] performed excimer light irradiation twice a week in 34 patients with PPP, and reported that the PPPASI scores before and after irradiation were 8.49 ± 5.82 and 4.24 ± 2.85, respectively, and that patients scoring 1 or 2 (response rate: ≤ 50%) accounted for 44.1% on assessment with a PPPASI improvement rating‐scoring system (< 25% of the initial PPPASI score: 1, 25.1%–50%: 2, 50.1%–75%: 3, ≥ 75.1%: 4).

Furuhashi et al. [240] reported that the peripheral blood Th17 cell ratio was high in patients with PPP, whereas the Treg ratio was low. In addition, they analyzed peripheral blood mononuclear cells in patients before and after excimer light treatment by flow cytometry, and found no change in the Th17 cell ratio, whereas there was a significant increase in the Treg count. Simultaneously, they conducted PPP assessment using the PPPASI in 20 patients with PPP, and reported that the mean scores before and after phototherapy were 19.5 ± 8.1 and 10.8 ± 9.8, respectively, with a mean irradiation frequency of 26.9 ± 5.9 times and a mean total irradiation dose of 2.1 ± 0.9 J/cm².

6.2.4. Oral Administration

6.2.4.1. CQ2‐4‐1: Are Retinoids Useful?

Recommendation comment: The usefulness of retinoids for PPP treatment was confirmed using a double‐blind, placebo‐controlled method in which a control group was established. This study found mucosal symptoms as adverse reactions to short‐term administration. Long‐term adverse reactions are reportedly associated with the dose and treatment period. In children, adverse reactions include developmental disorders (early closure of the epiphysis), hyperostosis, ectopic ligament calcification, liver dysfunction, and vision disorders. After providing sufficient explanation of the risks and benefits to patients, retinoid treatment must be performed with informed consent.

Grade of recommendation: C1, Evidence level: II–V.

Explanation: Foged et al. conducted an RCT in 50 patients with PPP and randomized them into two groups: a group orally treated with etretinate at 1 mg/kg every day for 8 weeks and a placebo group. Marked to moderate effects were observed in 18 of 20 patients in the etretinate group, but in only 6 of 21 patients in the placebo group (p < 0.001). Etretinate was markedly more effective for individual symptoms and pustules than the placebo. In the etretinate group, slight adverse reactions in the mucosa occurred in all patients. After 4 weeks, three patients dropped out for reasons unrelated to treatment. Four patients in the placebo group dropped out of this trial due to insufficient effects, and two in the etretinate group dropped out due to adverse reactions. The author concluded that etretinate had efficacy comparable to those of other systemic therapies [241].

Furthermore, Lassus and Geiger [242] assigned 60 patients with PPP (18 males, 42 females) to receive etretinate or another vitamin A derivative, acitretin, and conducted the study using a double‐blind method. For the first 4 weeks, acitretin or etretinate at 30 mg/day was orally administered and the dose used was based on a previous study on psoriasis. In the subsequent 8 weeks, the oral dose was adjusted depending on clinical improvements and tolerance in each patient, and each drug was orally administered after meals once a day. At the completion of the 12‐week treatment period, the mean number of pustules (±SEM) had decreased from 57.8 (±8.6) to 3.9 (±1.6) in the acitretin group and from 57.1 (±14.1) to 5.7 (±2.7) in the etretinate group. In the two groups, there were similar improvements in the erythema‐, infiltration‐, and scale‐related areas. As adverse reactions to hypervitaminosis A, cheilitis, oral/cutaneous/nasal/eye dryness, conjunctivitis, desquamation, alopecia, pruritus, and nail fragility were observed, but the frequency and severity of these adverse reactions were similar between the two groups. The mean number of 10‐mg capsules per day was comparable in the two groups: 2.82 (range: 1.23–4.67) in the acitretin group and 2.77 (range: 1.60–4.82) in the etretinate group. It was concluded that there were no significant differences in the efficacy and safety of acitretin and etretinate in patients with PPP [242]. However, in Japan, etretinate is covered by health insurance, while acitretin is not available. A consensus on the dose of etretinate has not been reached, but previous case reports showed that PPP control was possible at a maintenance dose of 10–20 mg/day [243, 244, 245, 246].

With respect to adverse reactions to etretinate, many studies examined the use of this drug in patients with psoriasis, and reported that adverse reactions were associated with the dose and treatment period. Frequent adverse reactions to retinoids include desquamation, cheilitis, oral dryness, liver dysfunction, hyperlipidemia, pruritus of the skin, bone abnormalities (hyperostosis, early closure of the epiphysis), ectopic ligament calcification, renal dysfunction, and vision disorder; caution is needed [247]. A study found no associations between the onset of hyperostosis or ectopic calcification and treatment period of etretinate [248]. However, there is an opinion that adverse reactions may occur at a total dosage of 30 g as a guide [249]. Treatment must be performed with informed consent after providing sufficient explanation of the risks and benefits of etretinate to patients.

6.2.4.2. CQ2‐4‐2: Are Oral Corticosteroids Useful?

Recommendation comment: In PPP patients with skin symptoms alone, there are problems regarding the efficacy and safety of oral corticosteroids, and the oral administration of corticosteroids should generally be avoided.

Grade of recommendation: D, Evidence level: IV.

Explanation: The effect of oral corticosteroids is temporary. Dose‐reduction or discontinuation frequently leads to symptom recurrence; therefore, long‐term oral administration would be required. Based on accumulated experience, systemic adverse reactions become problematic in some cases, and sudden discontinuation often results in exacerbation of pustules. Therefore, there are instructive descriptions in textbooks [177, 250], and no double‐blind placebo‐controlled trial has been conducted. As their risks are greater than their benefits, oral corticosteroids should be avoided.

6.2.4.3. CQ2‐4‐3: Is Cyclosporine Useful?

Recommendation comment: For PPP treatment, cyclosporine (CyA) is recommended as one of the treatment options. However, various adverse reactions, such as increased blood pressure and nephropathy, must be considered. Furthermore, PPP is a chronic disease, as was suggested for psoriasis; therefore, there is a possibility that CyA may be used for a long period. However, the administration period of CyA should be restricted to 1 to 2 years in accordance with guidelines for the management of psoriasis from the viewpoint of preventing adverse reactions [251, 252].

Grade of recommendation: B, Evidence level: II.

Explanation: Two double‐blind RCTs demonstrated the efficacy of CyA for PPP. Reitamo et al. [253] administered CyA at 2.5 mg/kg (to be divided and taken twice a day) or a placebo to 40 patients with PPP for 4 weeks, and reported that the response rates in the CyA and placebo groups were 89% and 21%, respectively, being significantly higher in the CyA group. Furthermore, in their study, placebo administration at 1.25 mg/kg (to be divided and taken twice a day) was continued using a non‐blind method in 15 patients in the placebo group, and it was effective in 60%. Erkko et al. [254] administered CyA (1.0 mg/kg, twice a day) or a placebo to 58 patients for 4 weeks, and found that 48% of the patients responded, with the response rate being significantly higher in the CyA group. In addition, they examined the optimal dose at which the drug is effective for PPP by increasing the dose by 1.0 mg/kg in non‐responders (CyA and placebo groups), and reported that the optimal dose of CyA was 1.2–1.7 mg/kg/day. In the two studies, not Neoral, a microemulsion type, but Sandimmun was used.

While only a limited number of studies have demonstrated the efficacy of CyA for PPP, these studies are RCTs as described above. Furthermore, in patients with PPP, its efficacy was confirmed at a dose lower than that used in patients with psoriasis. Therefore, when administering CyA to patients with PPP, starting administration at a dose of approximately 1.0 mg/kg/day and gradually increasing the dose may be adequate.

For reference, CyA for PPP treatment is not covered by the Japanese health insurance system.

6.2.4.4. CQ2‐4‐4: Are Phosphodiesterase 4 (PDE4) Inhibitors Useful?

Recommendation comment: While PDE4 inhibitors for PPP treatment are currently not covered by the Japanese health insurance system currently, apremilast may be considered as a therapeutic option in cases that are difficult to manage (apremilast subsequently received approval for insurance coverage after publication of the Treatment Guidance for Palmoplantar Pustulosis 2022 in Japanese).

Grade of recommendation: C1, Evidence level: III–V.

Explanation: A PDE4 inhibitor (apremilast) is a small molecule inhibitor that increases the intracellular level of cAMP by inhibiting PDE4 in inflammatory cells, leading to reduced production of inflammatory cytokines and increased production of anti‐inflammatory cytokines. It is used for the treatment of psoriasis vulgaris, psoriatic arthritis, and oral ulcers related to Behcet's disease. Patients with PPP have increased levels of inflammatory cytokines such as IL‐23, IL‐17, and TNF in the serum and in skin lesions [74]. Based on the anticipated efficacy of PDE4 inhibitors in PPP, a randomized, double‐blind, placebo‐controlled phase II trial (CC10004‐PPP‐001 trial) was conducted in Japan, and a significantly greater proportion of patients achieved PPPASI‐50 at week 16, as a primary endpoint, in the apremilast group than in the placebo group (p = 0.0003) [255]. Concerning safety, there was no new adverse event. A phase III trial of apremilast is currently being carried out. According to case series [256, 257] and case reports [258, 259, 260, 261] of patients receiving apremilast, there were significant improvements in the PPPASI and QOL. In one patient, a PDE4 inhibitor was also effective for PAO [259].

6.2.4.5. CQ2‐4‐5: Is Methotrexate (MTX) Useful?

Recommendation comment: Methotrexate (MTX) for the treatment of PPP is not covered by health insurance in Japan. MTX may be considered as a therapeutic option in case that are difficult to manage, however, there is no sufficient evidence for its effectiveness.

Grade of recommendation: C1, Evidence level: V–VI.

Explanation: Methotrexate (MTX) has been used to treat rheumatoid arthritis, psoriasis vulgaris [262], and PPP [263] for many years. MTX is a folic acid metabolism antagonist, and adverse reactions, such as bone marrow suppression, liver dysfunction, alopecia, and interstitial pneumonia, are known. As described in the clinical practice guidelines for rheumatoid arthritis treatment with MTX, it is necessary to perform liver function/hepatitis B virus screening tests (HBs antigen, HBs antibodies, HBc antibodies) and hepatitis C virus testing before the use of this drug and evaluate risk factors for liver dysfunction [264]. Both males and females receiving this drug must avoid pregnancy for 3 months after the completion of oral administration. Furthermore, this drug should not be administered to hemodialysis patients. Considering these points, informed consent should be obtained from patients before use.

Concerning the administration method, the frequency of administration is once a week to twice a week, and the initial dose is 2.5–5.0 mg/week. Depending on the symptoms, the frequency of administration can be increased to three times a week, and the dose can be gradually increased to 7.5–16 mg/week. Regular anemia/liver function/interstitial pneumonia screening tests are necessary. Management methods at the onset of liver dysfunction in clinical practice guidelines for psoriasis treatment with MTX differ among various countries. In the United States, liver biopsy is considered when the cumulative oral dose is 3.5–4.0 g in patients with a low risk of hepatopathy [265]. However, in guidelines for the management of rheumatoid arthritis in Japan, it is described that dose‐reduction or discontinuation, as well as consultation by a gastroenterologist, is necessary when the AST/ALT levels increase ≥ 3‐fold the upper limit of the reference range in non‐hepatitis‐virus‐infected patients [264]. Similar management is also necessary in patients with PPP.

MTX has also been used for the treatment of psoriasis vulgaris [262] and PPP [263]. In Japan, MTX was approved for patients with psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, or psoriatic erythroderma who do not respond to conventional treatment in March 2019. However, MTX for the treatment of PPP is not covered by health insurance. Internationally, no RCT for evaluating the treatment response has been conducted. According to case reports of a single patient and a case series study of seven patients, an improvement was achieved even at a low dose, 2.5 mg/week, in some patients [266], and skin symptoms improved in approximately 60% of patients orally treated with MTX [267]. On the other hand, a study found that improvement was achieved in only 1 of 13 patients [263]; the results of evaluation are not consistent. However, in other countries, the dose of MTX is high at 15–25 mg/week, and the risks of liver dysfunction and interstitial pneumonia may increase. In treatment guidelines in France, MTX treatment is recommended as 3rd‐line therapy for skin lesions [268].

Thus, the benefits of MTX should be investigated in a high‐evidence‐level clinical study in the future. However, MTX treatment is selected as first‐line therapy in many countries [269]. In clinical practice, MTX administration may be considered in difficult‐to‐treat cases. However, in Japan, MTX for the treatment of PPP is not covered by health insurance.

6.2.4.6. CQ2‐4‐6: Is Biotin Useful?

Recommendation comment: After investigation and treatment manage of focal infection and other triggering factors associated with the pathogenesis of PPP, high‐dose biotin is sometimes effective as adjuvant therapy.

Grade of recommendation: C1, Evidence level: IV–V.

Explanation: The effects of biotin have been investigated by a study group at Tohoku University over many years. This group measured the serum concentration of biotin, and found that its concentration in patients with PPP (215 ± 108 ng/dL, n = 19) was lower than that in healthy adults (580 ± 150 ng/dL, n = 30). In 30 patients with PPP, biotin at 9 mg/day was orally administered, and intramuscular injection of biotin at 2 mg was additionally performed 2–3 times a week in non‐responders. As a result, healing of skin symptoms or a nearly recovered condition was achieved in four patients 2–22 months to 1 year and 10 months after the start of administration, a complete response in seven, and a partial response in six; beneficial effects were observed in 56.7% of the patients [270]. However, they also found a reduction in the biotin level in patients with psoriasis (219 ± 132 ng/dL, n = 25); this cannot be regarded as a disease‐specific phenomenon. Subsequently, another study reported no difference in the serum biotin level between patients with PPP (0.219 ± 0.050 ng/mL, n = 19) and a control group (0.205 ± 0.042 ng/mL, n = 47), and there was also no difference in serum biotinidase activity between the two groups [271]. In that study, biotin at 10 mg/day was orally administered to 27 patients with PPP while continuing topical steroids. The serum level of biotin at 1 and 6 months had increased approximately 100‐fold. Concerning the effects on skin symptoms, there was no complete response in any patient, and a partial response was achieved in 16 patients; effects were obtained in 59.3% of the patients, but there were no immediate effects in most patients [271]. Since then, research has not progressed, and there has been no analysis of a large number of patients. However, in a recent study, biotin at 4–6 mg/day was orally administered to 30 patients with PPP, and its efficacy for skin symptoms was evaluated using the PPPASI response rate 3 and 6 months after the start of administration. A ≥ 70% improvement in the PPPASI was achieved in 24 patients (80%) [272]. The subjects of this study included patients receiving a combination of a topical medicine, PUVA, and an antimicrobial drug, those under caries treatment, and those treated by tonsillectomy. Furthermore, 20 of 24 responders were smokers, and smoking cessation was achieved in 14. The treatment response was not related to biotin alone [272]. According to case reports, monotherapy with biotin was ineffective, and other treatments were combined in many patients. This suggests that a sufficient level of efficacy may not be obtained if there is no treatment of triggering factors such as focal infection and smoking.

Concerning safety, biotin is a water‐soluble vitamin, and no adverse reactions resulting from excessive dosing have been reported in adults. One study noted excessive dosing‐related teratogenicity in mice on Day 16 of pregnancy [273], whereas another study found no abnormality in 8‐week‐old pregnant rats [274], and this was not regarded as data suggestive of the teratogenicity of biotin by the Food Safety Commission of Japan, Ministry of Health, Labour, and Welfare (2014), considering the frequency of spontaneous development [274]. However, an experimental study in rats has reported that administration of high‐dose biotin before and after embryo implantation led to growth retardation of the fetus and placenta, and embryonic resorption [274]. Currently, there is no sufficient information on the safety of biotin, and high‐dose biotin administration is not recommended for pregnant women or patients who wish to become pregnant.

Biotin is an imidazole derivative that is widely found in foods. In humans, it is a water‐soluble vitamin (vitamin H) that belongs to the vitamin B group produced by the intestinal bacteria. Biotin may catalyze carboxylation reactions as a coenzyme for pyruvate carboxylase and acetyl‐CoA carboxylase, and directly act on the metabolic pathway, such as the synthesis of polyunsaturated fatty acids, production of prostaglandin and leukotriene, and glucose utilization by glucose‐responsive insulin secretion‐enhancing actions [275]. Its indirect actions remain to be clarified, but recent studies showed that LPS stimulation‐related TNF‐α production was increased in mouse‐derived macrophages cultured under biotin deficiency [276], that TNF‐α, IL‐1α, IL‐23, and IL‐12/23 p40 production was increased in response to LPS stimulation in human peripheral blood‐derived dendritic cells cultured under biotin deficiency, and that it was suppressed by the addition of biotin [277]. Another study reported that biotin was necessary for maintaining the small intestinal mucosal structure [278]. In addition, stimulation of peripheral blood CD4⁺T cells from healthy adults with anti‐CD3/CD28 antibodies under biotin deficiency promoted differentiation into Th1/Th17, decreasing the Treg count. In mice fed a biotin‐deficient diet for 16 weeks, an increase in the intestinal mucosa infiltration of neutrophils and CD4⁺T cells, increased IFN‐γ, TNF, and IL‐17 production mediated by activation of mammalian target of rapamycin (mTOR) in inguinal lymph node CD4⁺T cells, and a decrease in the Treg count were observed [279], suggesting that biotin deficiency increases the production of inflammatory cytokines, suppressing differentiation into Treg. However, a consensus on the decrease in the biotin level in patients with PPP has not been reached among institutions, and skin symptoms related to biotin deficiency differ from those of PPP; few studies have examined how biotin is associated with the improvement in exanthema in patients with PPP. Currently, this is a matter of speculation. Biotin at 2 mg/day for the treatment of dermatitis is covered by the Japanese health insurance system, however, the reported efficacy has been based on evaluations using high‐dose therapy (4.5–9 mg/day) (subsequently, it was reported that high‐dose biotin causes interference in biotin‐based laboratory assays, necessitating informed consent regarding this potential risk).

6.2.4.7. CQ2‐4‐7: Are Chinese Herbal Medicines Useful?

Recommendation comment: Under circumstances in which other treatments are ineffective or cannot be performed, the administration of Jumihaidokuto, Orengedokuto, or Unseiin is recommended as a treatment option for PPP. Keishibukuryogan may be administered, but is not recommended.

Grade of recommendation: C1 (Jumihaidokuto, Orengedokuto, Unseiin), C2 (Keishibukuryogan), Evidence level: IV–V.

Explanation: In the treatment of PPP, various prescriptions of Chinese herbal medicines such as Jumihaidokuto, Orengedokuto, Unseiin, and Keishibukuryogan, have been used. Many clinical studies on the efficacy of Kampo therapy for PPP consisted of before and after comparative studies and case series studies. No RCT has been conducted. To treat erythema in patients with PPP, Orengedokuto has been used as a heat‐clearing agent. To treat scaly plaque, Unseiin, which exhibits heat‐clearing, moisturizing actions, and Keishibukuryogan as a blood‐flow‐improving drug, have been used. To treat pustules, Jumihaidokuto has been used [280].

The administration of Jumihaidokuto for 4–8 weeks led to improvements in pustules and hyperkeratosis in 7 of 10 patients, and PPPASI score significantly decreased from 8.34 ± 9.00 to 5.46 ± 7.02 (p = 0.01) [281]. Furthermore, a study found that Jumihaidokuto administration to 38 patients for 12 weeks was slightly effective or better for skin lesions in 50% of the patients, and that it was effective or better for symptoms in 74% [282]. Another study reported that Orengedokuto administration for 4–8 weeks was effective or better in 69%; patients with a ruddy face comprised the greater portion [283]. In addition, combination therapy with Orengedokuto and minocycline was performed in 24 patients, and, subsequently, it was switched to monotherapy with Orengedokuto, resulting a partial response or better was achieved in 22 of these patients [284]. Concerning Unseiin, the response rate after 4‐week administration to 97 patients was 59.8%, and that after 8‐week administration was 69.8%, suggesting that a longer administration period increases the response rate [285]. Concerning Keishibukuryogan, there have only been reports on its use in combination therapy with other Kampo drugs, such as Unseiin or Jumihaidokuto [286, 287, 288]. However, considering the low incidence of adverse reactions, the above Kampo (Chinese medicine) extract may also be a treatment option when the condition is refractory to other treatments or other treatments cannot be performed. Although no Chinese herbal medicine is covered by the Japanese health insurance system for PPP, however, Jumihaidokuto has an indication for purulent skin disease.

Thus, under circumstances in which other treatments are ineffective or cannot be performed, the administration of Jumihaidokuto, Orengedokuto, or Unseiin is recommended as a treatment option for PPP. Keishibukuryogan may be administered, but is not recommended.

6.2.4.8. CQ2‐4‐8: Are Other Oral Drugs Useful?: Antibiotics (Minomycin, Macrolide), Colchicine, Diaphenylsulfone (DDS)

Recommendation comment: Antibiotics can be effective. However, recurrence of symptoms following discontinuation is a clinical concern. Colchicine should be considered when other treatments are ineffective or cannot be administrated. There is no sufficient evidence regarding DDS, and it cannot be recommended.

Grade of recommendation: C1 (antibiotics), C1 (colchicine), C2 (DDS), Evidence level: IV–V.

Explanation: Antibiotics: A case series report showed the efficacy of cefcapene pivoxil [110]. In a study, potassium iodide was additionally administered to PPP patients who did not respond to tetracyclines, and marked and partial responses were achieved in 5 and 4 of 13 patients, respectively, suggesting the usefulness of combination therapy with potassium iodide [289]. Some case series reports found that macrolide antibiotics were effective for SAPHO syndrome [109, 290, 291]. As these drugs exhibit anti‐inflammatory effects in addition to antimicrobial actions on foci, administration may be considered. However, their effects are temporary in many cases, and definitive treatments of the underlying focal infections should be prioritized.

Colchicine: Previous studies reported the efficacy of colchicine on PPP [209, 292, 293, 294]. However, no RCT has been conducted and there is no sufficient evidence for its effectiveness. Colchicine should be considered when other treatments are ineffective or cannot be administrated.

DDS: There has been no report even at the case report level. It cannot be recommended.

Notably, these drugs for PPP treatment are not covered by the Japanese health insurance system.

6.2.5. Biologics

6.2.5.1. CQ2‐5‐1: Are IL‐23p19 and p40 Inhibitors Useful?

Recommendation comment: The administration of guselkumab is recommended for patients with PPP in whom the effects of conventional treatment are insufficient. Ustekinumab administration for PPP may be considered, but its efficacy has not been established (risankizumab subsequently received approval for insurance coverage after publication of the Treatment Guidance for Palmoplantar Pustulosis 2022 in Japanese).

Grade of recommendation: B (guselkumab), C1 (ustekinumab), Evidence level: II–V.

Explanation: An anti‐IL‐23‐p19‐subunit human monoclonal antibody, guselkumab, became covered by the Japanese health insurance system in May 2018 for patients with psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, or psoriatic erythroderma in whom the effects of conventional treatment are insufficient. In November 2018, guselkumab was additionally approved for patients with PPP in whom the effects of conventional treatment are insufficient based on the results of a phase III trial of Japanese patients with PPP [80]. According to the approved dosage regimen, a single dose of 100 mg of guselkumab is subcutaneously administered at Week 0, at Week 4, and, subsequently, every 8 weeks thereafter. An outline of a phase II RCT of guselkumab in Japanese patients with PPP [79], which was conducted by Terui et al., and a phase III clinical trial in Japan [80] is presented. Forty‐nine patients were randomized to receive guselkumab at 200 mg or a placebo subcutaneously at Weeks 0 and 4 (guselkumab group: 25 patients, placebo group: 24 patients), and the results were evaluated using the total PPSI (palmoplantar pustulosis severity index) score until Week 24. There was a significant difference in the changes in the PPSI score from baseline between the guselkumab and placebo groups.

In a phase III clinical trial of Japanese patients with PPP, 159 patients were randomized to one of three groups (100‐mg group: 54 patients, 200‐mg group: 52 patients, placebo group: 53 patients). In the active treatment groups, guselkumab was administered at Weeks 0 and 4 and, subsequently, every 8 weeks thereafter. In the placebo group, the patients were re‐randomized at Week 16 to receive guselkumab at either 100 mg or 200 mg, and changes in the PPPASI score were evaluated until Week 52. Both guselkumab groups demonstrated significant improvement, and there was a significant difference in the extent of change in the total PPPASI score at Week 16 from baseline between the guselkumab and placebo groups. In the 100 mg group, PPPASI‐50 response rates at Weeks 16 and 52 were 57.4% and 83.3%, respectively. In the 200 mg group, PPPASI‐50 response rates at Weeks 16 and 52 were 36.5% and 84.6%, respectively. The PPPASI‐50 response rate exceeded 80% at Week 52, but it was only 50% at Week 16; therefore, it should be noted that a certain period of time is required until the appearance of effects of guselkumab in some cases. In both the 100 and 200 mg groups, the efficacy was maintained 6 months after the completion of administration, that is, at Week 84 [295].

Ustekinumab is a recombinant human IgG1 monoclonal antibody against p40, a subunit common between IL‐12 and IL‐23. Concerning the effects of ustekinumab on PPP, an RCT was conducted [296] (13 patients with PPP), and the PPPASI‐50 response rates at Week 16 in the 45 mg ustekinumab (n = 5) and placebo (n = 8) groups were 20% and 37.5%, respectively. There was no significant difference in the improvement rate of PPP. At the case series study report and case report level, some studies found that all patients were responders [297, 298], whereas two studies reported a partial response (5 of 11 patients [299], 1 of 3 patients [300]).

6.2.5.2. CQ2‐5‐2: Are TNF Inhibitors Useful?

Recommendation comment: Concerning the use of TNF inhibitors for skin symptoms of PPP, there is no evidence for their efficacy.

Grade of recommendation: C2, Evidence level: II–V.

Explanation: TNF inhibitors include infliximab as a chimera‐type monoclonal antibody, adalimumab as a human monoclonal antibody, and etanercept as a human soluble TNF receptor‐Fc fusion protein. These TNF inhibitors are approved for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, inflammatory bowel disease, Behcet's disease, and the acute phase of Kawasaki disease by the Japanese health insurance system. In the field of dermatology, infliximab and adalimumab were approved in 2010. Concerning their effects on pustular psoriasis, no RCT has been conducted, and case reports have primarily been published. However, reports on patients treated with TNF inhibitors have accumulated [301, 302, 303, 304].

With respect to the effects of TNF inhibitors on PPP skin lesions, an RCT of etanercept was conducted [305]. However, concerning infliximab and adalimumab, only case series studies and case reports have basically been published. An RCT of etanercept (n = 15) demonstrated a significant improvement in the PPPASI score for PPP skin lesions in the etanercept group at Week 24 in comparison with the placebo group [305]. There has been no RCT of infliximab or adalimumab, and a case series study of adalimumab using PGA (Physician's Global Assessment) until Week 12 (n = 11) reported ≥ 50% improvement in five patients [306]. In reports cases of infliximab use in patients with PPP, most administrations were for concomitant osteoarticular symptoms. For PPP skin lesions, international reports presented one responder and one non‐responder [307, 308], and a report in Japan presented one responder, indicating their efficacy is not consistent [309].

A review of paradoxical reactions occurring during TNF inhibitor therapy in patients with rheumatoid arthritis, ankylosing spondylitis, or psoriasis showed that various types of skin lesions were observed, and that PPP‐like eruptions were the most frequent, followed by psoriasis‐like eruption and generalized pustular psoriasis‐like eruption [176, 310, 311]. Furthermore, PPP‐like eruption after TNF inhibitor administration for psoriasis was reported [312], and the infliximab or adalimumab administration‐related deterioration of PPP skin symptoms occurred [176, 313]. Therefore, when exacerbation of skin symptoms or new psoriasis‐like eruptions occur during the administration of TNF inhibitors, the possibility of paradoxical reactions must always be considered.

In Japan, infliximab is approved for the treatment of psoriasis vulgaris, pustular psoriasis, psoriatic arthritis, and psoriatic erythroderma, and adalimumab is approved for the treatment of psoriasis vulgaris and psoriatic arthritis by health insurance. However, etanercept for the treatment of dermatological diseases is not covered by health insurance. These three agents for the treatment of PPP have not been approved for insurance coverage.

6.2.5.3. CQ2‐5‐3: Are IL‐17 Inhibitors Useful?

Recommendation comment: Concerning the use of secukinumab for skin symptoms in patients with PPP, there is no evidence for its efficacy (brodalumab subsequently received approval for insurance coverage after publication of the Treatment Guidance for Palmoplantar Pustulosis 2022 in Japanese).

Grade of recommendation: C2 (secukinumab), Evidence level: II–V.

Explanation: There are three IL‐17 inhibitors: secukinumab as a human anti‐IL‐17A monoclonal antibody, ixekizumab as a human anti‐IL‐17A monoclonal antibody, and brodalumab as a human anti‐IL‐17 receptor A monoclonal antibody. In 2015, secukinumab was approved for patients with psoriasis vulgaris or psoriatic arthritis. In addition, an indication for pustular psoriasis was added in the same year. In 2016, ixekizumab and brodalumab were approved for patients with psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, or psoriatic erythroderma. Open‐label studies of the three drugs showed their efficacy for generalized pustular psoriasis and long‐term safety [314, 315, 316]. These drugs for PPP treatment are not covered by the Japanese health insurance system.

Several studies found that IL‐17A expression in PPP lesions was increased compared with that in healthy individualsl [74, 296]. Concerning secukinumab, an international phase III trial (2PRECISE trial) in patients with PPP was conducted [317]. The results were compared among the 300‐mg (n = 79), 150‐mg (n = 80), and placebo (n = 78) groups. The PPPASI‐75 response rate at 16 weeks in the 300‐mg group was 26.6%, but there was no significant difference in comparison with the placebo group (14.1%). It was reported that PPPASI‐75 was achieved in 41.8% of the patients at 52 weeks, however, the subjects included patients with plaque type psoriasis accounting for 43%–47.5% in the secukinumab group and it may be adequate to regard the results as reference values. Two case series study reports have been published. One describes that an improvement in skin symptoms was achieved in 2 of 3 patients, and the other describes that it was achieved in all four patients [300, 318].

To date, no RCT of ixekizumab or brodalumab has been conducted. Concerning brodalumab, there have been several reports of the case studies [319, 320], but these may have involved patients with palmoplantar psoriasis, but not PPP of our disease entity. Therefore, they were not included in responders. Only one patient with PPP was reported as a responder to ixekizumab [321].

Recently, paradoxical reactions related to IL‐17 inhibitors have been reported in Japan and other countries. All patients had psoriasis. Although these were case reports, the secukinumab‐related deterioration of psoriasis‐like eruptions [322], pustular psoriasis [323], ixekizumab‐related eczema‐like eruptions [324], PPP‐like eruptions [325], new onset of palmoplantar psoriasis [326] PPP eruption or pyoderma gangrenosum related to a switch from secukinumab to brodalumab [327] have been reported. The mechanism remains to be clarified.

Concerning IL‐17 inhibitors, there is no sufficient evidence for their effectiveness in PPP treatment, and these drugs should be carefully used after considering their risks and benefits and only when other drugs are ineffective.

6.2.6. Dental Metals

6.2.6.1. CQ2‐6: Is Dental Metal Removal Useful?

Recommendation comment: If there is no improvement despite tonsillectomy or treatment for odontogenic lesions including periodontal disease, removal of dental metals or restriction of metals to be orally ingested during meals may be reviewed. However, dental metal removal leads to financial or physical burdens to patients, and dietary restrictions may reduce their QOL. Therefore, attention must be paid so that this procedure is not unnecessarily performed. This procedure should be considered after conducting tests such as the patch and metal (metal‐containing diet) load tests.

Grade of recommendation: C1 (metal removal), Evidence level: IV.

Explanation: Most of the findings that removal of dental metals or restricted metal intake during meals is effective for PPP are based on case reports and descriptive studies of a few patients [162, 163, 164, 165, 166, 167, 168, 169]. On the other hand, several studies found its association with odontogenic lesions represented by periodontal disease [53, 55, 58, 70, 328]. Considering the possibility that PPP patients may have responded to dental treatment, such as periodontal disease treatment, conducted in addition to dental metal removal, the effects of dental metal removal must be evaluated.

A study on the effects of metal removal was conducted in 257 patients with PPP in whom the metal patch test confirmed a dental metal allergy. It found no significant difference in its effects between the two groups, in which the metal allergen was removed from the oral cavity, and in which it was not removed. However, concerning patients who were positive for nickel allergy on the patch test, the efficacy of removing nickel‐containing dental metals or restricting nickel‐containing food consumption was suggested [70].

6.2.7. Granulocytapheresis

6.2.7.1. CQ2‐7: Is Granulocytapheresis Useful?

Recommendation comment: As a safe treatment with a low incidence of adverse reactions, granulocytapheresis may be considered, but there is no sufficient evidence for its effectiveness.

Grade of recommendation: C1, Evidence level: V.

Explanation: Granulocytapheresis (GMA) is extracorporeal circulation therapy in which neutrophils, monocytes, and macrophages, which cause inflammation, are selectively adsorbed/removed, and their cell functions are regulated. Concerning the efficacy and safety of GMA therapy for pustular psoriasis, a multicenter, cooperative, open‐label, single‐arm study was conducted, and its efficacy and safety were confirmed [328].

With respect to the efficacy and safety of GMA therapy for PPP, there have only been case reports and reports/reviews on case series studies, and no RCT has been conducted [329, 330, 331].

Due to the limited number of patients and the therapeutic features of extracorporeal circulation therapy, it is difficult to perform a double‐blind placebo‐controlled study; therefore, we have to rely on accumulated case reports. Based on multicenter cooperative studies, case reports, and case series studies, no serious adverse reaction has been reported. Furthermore, a study found a mechanism by which activated morbid granulocytes are selectively adsorbed/removed [332], and this therapy may be useful, considering the mechanism of action.

6.3. Treatment for Osteoarticular Symptoms

6.3.1. Focal Infection Treatment

6.3.1.1. CQ3‐1‐1: Is Odontogenic Lesion Treatment Useful?

Recommendation comment: In Japanese patients, odontogenic focal infection is the most frequent trigger of the onset of PPP. The high efficacy of odontogenic lesion treatment has been reported, and treatment should be performed if odontogenic lesions are observed.

Grade of recommendation: B*, Evidence level: IV–V.

Explanation: As described for PPP, the efficacy of odontogenic lesion treatment for PAO was also reported [113]. Among three patients with PAO, an antibiotics was administered to one patient to treat apical lesions, and tooth extraction was performed in the other two patients. As a result, all patients showed healing or marked relief of PPP lesions. In two patients, cure of PAO was achieved, suggesting that odontogenic lesion treatment is effective also for PAO. Furthermore, apical lesion tooth extraction led to the cure of palmoplantar lesions, nail lesions, and sternoclavicular arthritis/osteitis with complete resolution of MRI abnormalities [333]. There has been no cohort case series study on PAO, but odontogenic lesions are the most frequently observed as infection foci of PPP. According to experts' opinions, investigation and treatment of odontogenic lesions should be initially performed [174]. It is ethically difficult to conduct a double‐blind study to evaluate the progression of osteitis and bone damage in the absence of odontogenic lesion treatment over a long period of time. Furthermore, although inflammatory markers like CRP and erythrocyte sedimentation rate are commonly monitored, their fluctuations do not necessarily correlate with disease severity in many patients. Currently, assessment of treatment efficacy remains limited to pain VAS and radiological findings, such as MRI including fat suppression. An international prospective cohort study on the course of SAPHO syndrome in patients with PAO found that osteoarticular symptoms progressed, inducing irreversible changes, such as bone ankylosis [107]. To date, no other long‐term effective treatments have been established. Failure to investigate and treat odontogenic lesions, which can provide definitive cure in addition to symptom relief, results in a persistent disadvantage for patients with PAO. In patients with advanced PAO, even pain relief alone markedly contributes to their QOL.

Odontogenic lesions include apical periodontitis, marginal periodontitis, and wisdom tooth periodontitis, and these dysbiosis conditions are presumed to trigger [140]. For the treatment of apical periodontitis, root canal treatment or apicectomy, and tooth extraction are required in some cases. However, odontogenic lesions are asymptomatic, and such lesions are usually not treated. Currently, there are no treatment guidelines on dental treatment for patients with PPP or PAO. Therefore, when deciding treatment based on the severity of PAO, it is important to discuss with patients the degree of QOL disturbance and the risk of future progression, and to obtain informed consent. In 2018, a biologics was approved for the treatment of PPP that does not respond to conventional treatments, and its efficacy for PAO is also expected. However, neither the efficacy nor safety of biologics or immunosuppressive drugs administered in the presence of an untreated infection focus has been confirmed. Initially, priority should be placed on investigation and treatment of odontogenic lesions, which can trigger the onset of PPP and PAO [334].

6.3.1.2. CQ3‐1‐2: Is Tonsillectomy Useful?

Recommendation comment: Tonsillectomy may lead to the relief or disappearance of pain related to osteoarticular lesions, and it can be recommended as a treatment option.

Grade of recommendation: B*, Evidence level: V.

Explanation: According to a questionnaire survey of physicians, ≥ 40% of responders reported that tonsillectomy was effective for PAO (improvement rating: ≥ 50%), with an efficacy comparable to that observed for cutaneous lesions [335]. In a single‐center retrospective study of 31 patients with PAO, tonsillectomy was performed in patients who were positive for tonsillar provocation test and non‐responders to oral NSAIDs; the improvements in osteoarticular lesions were observed in eight patients (25.8%), although the effect was less pronounced than on cutaneous lesions [336]. Among 79 patients with PPP complicated by sternocostoclavicular hyperostosis, tonsillectomy reduced pain in 80.9% of cases, suggesting a potentially beneficial effects [337]. In a study of 12 patients with PPP complicated by sacroiliac arthritis and gait disorder, tonsillectomy was performed in six patients who showed insufficient response to other treatment modalities; all six patients subsequently achieved relief or recovery to a state that allowed amblation [338]. Another study evaluating PAO‐related arthralgia using the pain severity score demonstrated a significant reduction in scores as early as 1 month after surgery, with a pain disappearance rate of 78% at 1 year after tonsillectomy [57]. On the other hand, another study reported that among six patients with PPP who experienced articular symptoms before tonsillectomy, the improvement was observed in only one patient, whereas no changes was noted in the remaining five patients [92]. Although tonsillectomy appears to be less effective for osteoarticular manifestations than for cutaneous lesions, it should nevertheless be considered to have therapeutic potential. Future studies should clarify the characteristics of responders and evaluate recurrence rates. Currently, tonsillectomy may be considered as a treatment option for PAO in collaboration with otorhinolaryngologists, with careful consideration of surgical invasiveness and possible complications such as postoperative hemorrhage.

6.3.2. Oral Administration

6.3.2.1. CQ3‐2‐1: Are NSAIDs Useful?

Recommendation comment: After investigating and treating the focal infection, NSAIDs can be used as adjunctive treatment to alleviate pain.

Grade of recommendation: C1, Evidence level: VI.

Explanation: In clinical practice, NSAIDs are initially used to control PAO‐related arthralgia in many cases. However, there is no evidence for their efficacy for PAO. There are no data of comparison with a placebo, and these drugs are currently used based on physicians' experience. Although it is often prescribed as a first‐line treatment, its effectiveness is frequently limited, and it should be used with the understanding that it is generally insufficient to adequately control pain when used as monotherapy.

6.3.2.2. CQ3‐2‐2: Are Oral Corticosteroids Useful?

Recommendation comment: Only to relieve osteoarticular symptoms at the time of acute exacerbation, short‐term oral administration of corticosteroids may be considered. To prevent systemic adverse reactions, prednisolone should be limited to 10–20 mg/day for 1–2 weeks, and administration should be promptly discontinued if no rapid clinical response is observed.

Grade of recommendation: C1, Evidence level: VI.

Explanation: In patients with PAO, SAPHO syndrome, or sternocostoclavicular hyperostosis who show an insufficient response to NSAIDs, the oral corticosteroids at the dose of 10–20 mg/day or intra‐articular injection or local injections around entheses of triamcinolone have been performed [101, 181]. The effects of oral administration are not consistent [103, 339], whereas systemic adverse reactions related to long‐term administration, such as diabetes mellitus, are problematic; therefore, corticosteroids are administered for only a short period of about 2 weeks, based on physician's experience in their use for other types of inflammatory arthritis. Intra‐articular injection of triamcinolone is sometimes used to control severe pain in the acute phase. To prevent systemic adverse reactions, its use is typically restricted to one or two administrations. Since a single 20 mg triamcinolone injection did not result in significant improvements in the CRP level, erythrocyte sedimentation rate, or MRI radiological findings [340], its use is limited to the control of acute symptoms. No double‐blind placebo‐controlled trial has been conducted.

6.3.2.3. CQ3‐2‐3: Are Retinoids Useful?

Recommendation comment: There is no robust evidence for the efficacy of retinoids for PAO.

Grade of recommendation: C2, Evidence level: V.

Explanation: According to a report, treatment with etanercept and acitretin was effective for PAO [341], but this is at the case report level. Currently, there is no scientific evidence for their efficacy.

6.3.2.4. CQ3‐2‐4: Is Cyclosporine Useful?

Recommendation comment: Concerning osteoarticular symptoms related to PPP, currently, there is no sufficient evidence for the efficacy of cyclosporine. Therefore, the use of CyA may be considered for refractory case. However, it should not be used as a first‐line therapy.

Grade of recommendation: C1, Evidence level: V.

Explanation: CyA is an effective treatment for skin symptoms related to PPP. On the other hand, there have only been a few studies on CyA for the treatment of articular symptoms related to PPP [41, 116, 342, 343]. Hayama et al. [116] examined cyclosporine administration in 7 PPP patients with PAO. The mean dose of CyA was 2.48 mg/kg, and pain significantly decreased at Week 2 in all patients. Complete pain resolution was achieved in 6 of the 7 patients. Furthermore, they found a significant improvement in the QOL on assessment with SF‐8. CyA for PPP treatment is not covered by the Japanese health insurance system, but administration/monitoring methods have been established for psoriasis treatment. Therefore, CyA administration may be attempted as a treatment in refractory cases with PPP. However, concomitant use of NSAIDs and CyA increases the risk of renal dysfunction, and careful monitoring for nephrotoxicity is required.

6.3.2.5. CQ3‐2‐5: Are PDE4 Inhibitors Useful?

Recommendation comment: PDE4 inhibitors may be used if the condition cannot be controlled with other treatments.

Grade of recommendation: C1, Evidence level: V.

Explanation: Currently, PDE4 inhibitors are not covered by health insurance in Japan. However, a PDE4 inhibitor (apremilast) is used in patients with psoriasis/psoriatic arthritis, and this drug may also be effective for PAO. Although the number of patients was small, some case reports and case series studies have been published in Japan [344, 345]. Internationally, apremilast was effective in patients in whom treatment was difficult despite the use of several biologics, although this was a report on a patient with SAPHO syndrome [259]. According to a review of five patients treated with the same administration protocol established for psoriasis, a complete response was achieved in two patients, a partial response in one, and a slight partial response in one, and deterioration was noted in one patient [345]. However, the observation period was short, and the duration of efficacy is unclear. A comparative study with a placebo must be performed in the future.

6.3.2.6. CQ3‐2‐6: Is MTX Useful?

Recommendation comment: Methotrexate (MTX) is commonly used to control arthralgia in patients with rheumatoid arthritis, and psoriatic arthritis. In patients with PPP, monotherapy or combination therapy with other therapies may be considered in those with severe arthralgia in whom treatment is difficult.

Grade of recommendation: C1, Evidence level: II–VI.

Explanation: MTX is a folic acid metabolism antagonist, and adverse reactions such as bone marrow suppression, liver dysfunction, alopecia, and interstitial pneumonia, are known, as described in the outline section of CQ2‐4‐5. Both males and females receiving this drug must avoid pregnancy for 3 months after the completion of oral administration. Furthermore, MTX should not be administered to hemodialysis patients. In addition, in Japan, MTX for the treatment of PPP and PAO is not covered by the Japanese health insurance system. Therefore, it should be used after obtaining informed consent from patients.

MTX is administered once or twice weekly, and folic acid for the prevention of anemia and liver dysfunction is provided after 48 h. The initial dose is 2.5–5.0 mg/week. Depending on symptoms, the dose can be gradually increased to 7.5 to 16 mg/week. Periodic monitoring for anemia/liver function/interstitial pneumonia are necessary. If liver dysfunction occurs, the dose should be reduced or administration should be discontinued, and consultation with specialist in gastroenterology should be sought.

MTX is a disease‐modifying anti‐rheumatic drug (DMARD), and is reportedly effective for psoriatic arthritis [346]. In patients with PAO, axial lesions, such as sternoclavicular and sacroiliac lesions, are frequent rather than peripheral osteoarticular lesions [347]; the condition is not completely similar to psoriatic arthritis. Although PAO is common in Japan [27, 30], SAPHO syndrome associated with acne has frequently been reported, internationally. No RCT on the efficacy of MTX has been conducted, but there have been case reports and case series studies. Based on these, arthralgia before and after MTX treatment was examined in 1–10 patients, but a consensus has not been reached: some studies showed the efficacy of MTX [348, 349], whereas others reported its ineffectiveness [350]. In treatment guidelines in France, MTX treatment is recommended as second‐line therapy for patients with arthralgia [268].

There have also been reports on the therapeutic efficacy with MTX and other DMARDs was effective [351], as well as those with MTX in combination with bisphosphonates [352].

Thus, there has been no high‐evidence‐level report, but MTX is routinely used for arthralgia control, and monotherapy or combination therapy with other drugs may be considered in refractory cases in PPP with arthralgia. However, MTX for PAO treatment is not covered by the Japanese health insurance system.

6.3.2.7. CQ3‐2‐7: Is Azulfidine Useful?

Recommendation comment: There is no clear evidence demonstrating sufficient efficacy to recommend Azulfidine.

Grade of recommendation: C1.

Explanation: A retrospective study of SAPHO syndrome reported the use of sulfasalazine [101], but no study has presented sufficient evidence. In Japan, a case series study reported the use of sulfasalazine in patients with PAO who were treated by rheumatologists [353]. However, in Japan, azulfidine for PAO treatment is not covered by the Japanese health insurance system.

6.3.2.8. CQ3‐2‐8: Is Biotin Useful?

Recommendation comment: After investigating and treating other factors such as focal infection, high‐dose administration of biotin is sometimes effective in relieving pain related to osteoarthritis.

Grade of recommendation: C1, Evidence level: II–VI.

Explanation: The number of reports on the efficacy of biotin is limited, but biotin was reported to relieve PAO‐related pain. In a single‐center study, oral administration at 4–9 mg/day or additional intramuscular injection led to resolution of pain related to sternoclavicular arthritis or an improvement in bone erosion on plain X‐ray [270]. A clinical study of 30 patients with PPP investigated auxiliary effects [272]. However, non‐responders [354, 355] and patients with progression of bone lesions despite pain relief [356] were reported indicating that biotin therapy does not constitute a fundamental treatment for PAO. Therefore, after investigating and treating other triggers of onset such as focal infection, biotin should be administered as adjuvant therapy only for relieving pain. The mechanism of action by which biotin relieves pain remains to be clarified. It is rather inconsistent from the viewpoint of increasing the production of prostaglandin as a coenzyme for carboxylation reactions, whereas in vitro studies showed the inhibitory effects of biotin on LPS stimulation‐related cytokine production which may be associated with focal infection with oral bacteria [277, 278]. As biotin is a water‐soluble vitamin, there is no accumulation even after high‐dose administration, but its teratogenicity in pregnant mice [273] and inhibition of placental growth in rats [274] were reported. For patients who wish to become pregnant, biotin cannot be recommended. In patients other than pregnant women, oral administration at 4–9 mg/day or intramuscular/subcutaneous injection at 1–2 mg may be considered as adjuvant therapy for relieving pain to avoid the prolonged use of NSAIDs, antibiotics for infectious foci, or DMARDs—the latter of which are not covered by Japan's national health insurance.

6.3.2.9. CQ3‐2‐9: Are Bisphosphonate Useful?

Recommendation comment: Bisphosphonates can be considered in parallel with investigation and treatment of triggers of onset of PPP such as focal infection.

Grade of recommendation: C1.

Explanation: Amita et al. [357] performed drip infusion of a second‐generation bisphosphonate, pamidronate, in 10 patients with SAPHO syndrome who did not respond to NSAIDs, DMARDs, or infliximab. A complete response was achieved in nine patients. All 10 patients had PPP. Acne was present in nine patients, and enteritis or inflammatory bowel disease in three. They found that bisphosphonate was effective even in the one patient with skin symptoms related to PPP alone. Colina et al. [358] reported that 11 of 14 patients with SAPHO syndrome had PAO, and that pretreatment with NSAIDs, DMARDs, and prednisolone was ineffective in these patients. After drip infusion of pamidronate, a significant improvement in the pain VAS score and a decrease in the CRP level were observed in 10 patients. Recently, Zwawnepoel and Vlam [359] reported that a bisphosphonate was effective in most of the 21 patients with SAPHO syndrome. In Japan, accumulating case reports have documented clinical improvement in various PAO manifestations, including sternoclavicular arthritis [355], spondylitis [360], and non‐purulent osteomyelitis of the long bone [361], with oral alendronate. No cohort study or RCT has been conducted. Bisphosphonate is a pyrophosphate derivative that has the P‐C‐P structure. It has a high affinity for bone tissue, and it is retained in bones for a long period of time, inhibiting bone remodeling by primarily suppressing bone resorption by osteoclasts, which are derived from monocyte–macrophage lineage cells. In vitro studies suggested that bisphosphonates relieve acute phase inflammation by inhibiting the production of inflammatory cytokines such as IL‐1β, TNF‐α, and IL‐6 by monocytes [357, 358]. In addition, osteitis and post‐osteitis osteoporosis may be reduced by the inhibitory effects on bone remodeling [362]. In most Japanese patients with PAO, smoking and focal infection are involved as triggers of onset of PAO. As an adverse reaction to bisphosphonate, bisphosphonate‐associated necrosis of the jaw is known [363]. When reviewing administration, attention should be paid to establishing a schedule for tooth extraction or promoting an improvement in the oral environment in cooperation with dentists. If there is no effect in approximately 3 months, this therapy should be switched to other treatments. Even when pain is relieved, an improvement on radiological imaging should be confirmed by MRI with fat‐suppressed sequences.

In Japan, bisphosphonates for osteoarticular symptoms related to PPP are not covered by health insurance. However, patients in whom chronic osteitis results in inflammatory osteoporosis are not rare, and this disorder concomitant with bone ankylosis increases the risk of fracture; therefore, the development of inflammatory osteoporosis should be considered, and it is necessary to take the indication of bisphosphonates into consideration from this viewpoint.

6.3.3. Biologics

6.3.3.1. CQ3‐3‐1: Are IL‐23p19 and p40 Inhibitors Useful?

Recommendation comment: An IL‐23p19 inhibitor, guselkumab, was additionally approved for patients with PPP who do not respond to conventional treatment in November 2018. Its indication for patients with PAO has not been approved, and evidence is being accumulated. Although evidence is not yet sufficient, a study found an improvement in the QOL in PPP patients with PAO, and another study reported that guselkumab was effective in relieving pain related to sternoclavicular arthritis in patients with PAO. No treatments for PAO are currently covered by the Japanese health insurance system.

Grade of recommendation: C1 (guselkumab), C1 (ustekinumab), Evidence level: V.

Explanation: In a phase III trial of guselkumab in Japanese patients with PPP [85], 66 patients with PAO were randomized to one of three groups (100‐mg group: n = 21, 200‐mg group: n = 24, placebo group: n = 21) and were instructed to evaluate the “pain/discomfort” domain in a QOL scale, EQ‐5D [364] (EuroQoL 5 dimension), using five grades (1: no pain/discomfort, 2: mild, 3: moderate, 4: severe, and 5: extremely severe). The number of patients reporting moderate or grater pain declined from 14 to 6 in the 100‐mg group and from 18 to 6 in the 200‐mg group by Week 16, whereas only a slight reduction was observed in the placebo group, from 14 to 12. However, it was concluded that evaluation is difficult due to the lack of objective outcome measures. In a study on guselkumab, relief of pain was noted 28 weeks after the start of administration in 3 of 5 guselkumab‐treated patients with PAO [365]. However, regarding radiological improvement, although inflammation of the sternoclavicular joint improved, signal enhancement in other sites was observed, indicating that long‐term follow‐up is required. Responders to a single dose of guselkumab for long‐lasting pain of the vertebral joints other than the sternocostoclavicular joint were also reported [366].

An IL‐23p40 inhibitor, ustekinumab, became covered by health insurance for psoriasis vulgaris and psoriatic arthritis in the field of dermatology prior to other fields in 2011 in Japan. In the guidelines for the management of psoriatic arthritis prepared by the GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis) [367] in 2016 and EULAR (European League Against Rheumatism) in 2019 [368], ustekinumab is positioned at the grade of recommendation similar to TNF inhibitors for conditions other than axial arthritis. There have been one case series study and one case report on articular symptoms related to SAPHO syndrome, and one responder and three non‐responders were presented [369, 370]. In patients with PAO, the use of ustekinumab or guselkumab may be considered, but there is no evidence for the efficacy of ustekinumab for PAO. It may be adequate to consider its use only in patients who are refractory to other treatments.

6.3.3.2. CQ3‐3‐2: Are TNF Inhibitors Useful?

Recommendation comment: There have been several case reports on the efficacy of TNF inhibitors for PAO, but the evidence is not sufficient. The influence of TNF inhibitors for PPP skin symptoms is not consistent, and the possibility of deterioration or onset of eruption due to paradoxical reaction must be discussed with patients before use, and informed consent and careful monitoring should be obtained.

Grade of recommendation: C1, Evidence level: V.

Explanation: No RCT has examined the efficacy of TNF inhibitors for PAO, and there have only been case reports. Of five case reports, four were published from Japan [307, 309, 371, 372]. Infliximab was administered to five patients, and adalimumab to two patients (bioswitch from infliximab). It was reported that these two drugs relieved articular symptoms. Outside Japan, cases demonstrating the efficacy of TNF inhibitors for articular symptoms of SAPHO syndrome were reported [373], and 3 of the 5 patients had symptoms consistent with PAO. Infliximab was effective in one patient and adalimumab was effective in one patient.

TNF inhibitors, infliximab and adalimumab, became covered by health insurance for the treatment of psoriasis vulgaris and psoriatic arthritis in 2010 in Japan. RCTs demonstrated their efficacy for psoriatic arthritis [374, 375]. In the guidelines for the management of psoriatic arthritis prepared by the GRAPPA in 2016 [367] and EULARin 2019 [368], these inhibitors are positioned as drugs to be considered as first‐line therapy when the effects of DMARDs are insufficient. However, in Japan, most cases of PPP are of the A type, which is associated with focal infection and characterized by the appearance of small vesicles as initial lesions. Therefore, PPP should be regarded as a disease entity distinct psoriasis, and psoriatic arthritis and PAO should likewise be considered separate conditions. There have been Japanese patients with PAO who responded to TNF inhibitors, whereas generalized pustules due to paradoxical reactions may occur at the time of administration [175, 376], indicating sufficient informed consent and careful management are necessary.

6.3.3.3. CQ3‐3‐3: Are IL‐17 Inhibitors Useful?

Recommendation comment: IL‐17 inhibitors may be considered for PPP‐related osteoarticular symptoms, but sufficient evidence to support their use remains limited.

Grade of recommendation: C1, Evidence level: V.

Explanation: No IL‐17 inhibitor is covered by the Japanese health insurance system for PAO. In a case series study of SAPHO syndrome patients treated with secukinumab, the condition may have been consistent with PAO in two patients, and secukinumab was ineffective for osteoarticular symptoms in all three patients [370]. Another study showed improvement of radiological findings in all four patient [318]. However, currently, evidence is limited to the results of case series studies, and the effects are not consistent, therefore, IL‐17 inhibitors should be carefully used only in patients who are refractory to other treatments, considering their risks and benefits. These are not covered by the Japanese health insurance system.

6.3.4. Granulocytapheresis

6.3.4.1. CQ3‐4: Is Granulocytapheresis Useful?

Recommendation comment: In patients with PAO, granulocytapheresis may be considered as a safe treatment with a low incidence of adverse reactions, but there is no sufficient evidence of its effectiveness.

Grade of recommendation: C1, Evidence level: V.

Explanation: As described in the outline section of CQ2‐7, granulocytapheresis (GMA) is extracorporeal circulation therapy that selectively adsorbs and removes neutrophils, monocytes and macrophages which are involved in the pathogenesis of inflammation, and regulates their cell functions; therefore, it is expected to have therapeutic effects on osteoarticular symptoms as well. Most reports on psoriatic arthritis are case studies [330, 332, 377, 378]. For reasons similar to those in PPP, it is difficult to conduct an RCT, and we have to rely on accumulated case reports. In this context, a multicenter, cooperative, open‐label, single‐arm study on GMA therapy for psoriatic arthritis was conducted in 2014 to 2015, and its efficacy and safety were confirmed [379]. No serious adverse reaction has been reported from the multicenter cooperative study or case studies. Considering the mechanism of action of GMA as described for skin lesions, GMA may also be beneficial for PAO.

Previously reported patients who underwent GMA included 16 patients with PAO. Osteoarticular symptoms were evaluated using the visual analog scale (VAS) of the severity of pain, number of affected joints, and range of motion. The VAS score decreased to ≤ 20% in 4 patients, to ≤ 50% in 10 patients, and to ≤ 90% in 2 patients; effects were obtained in all patients. Furthermore, no serious adverse reaction has been reported. GMA therapy for PAO treatment is not covered by the Japanese health insurance system.

Conflicts of Interest

Hideki Fujita, Toshiyuki Yamamoto, and Mari Kishibe are Editorial Board members of The Journal of Dermatology, and coauthors of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication.

Japanese Dermatological Association Palmoplantar Pustulosis Treatment Guidance Drafting Committee , Terui T., Kobayashi S., Yamamoto T., et al., “Treatment Guidance for Palmoplantar Pustulosis 2022,” The Journal of Dermatology 53, no. 7 (2026): 1–57, 10.1111/1346-8138.70246.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during this study.