Modern Rheumatology

ISSN: 1439-7595 (Print) 1439-7609 (Online) Journal homepage: http://www.tandfonline.com/loi/imor20

Evidence-based clinical practice guideline for adult

Still’s disease

Toshihide Mimura, Yuya Kondo, Akihide Ohta, Masahiro Iwamoto, Akiko

Ota, Nami Okamoto, Yasushi Kawaguchi, Hajime Kono, Yoshinari Takasaki,
Shuji Takei, Norihiro Nishimoto, Manabu Fujimoto, Yu Funakubo Asanuma,
Akio Mimori, Naoko Okiyama, Shunta Kaneko, Hiroyuki Takahashi, Masahiro
Yokosawa & Takayuki Sumida

To cite this article: Toshihide Mimura, Yuya Kondo, Akihide Ohta, Masahiro Iwamoto,
Akiko Ota, Nami Okamoto, Yasushi Kawaguchi, Hajime Kono, Yoshinari Takasaki, Shuji
Takei, Norihiro Nishimoto, Manabu Fujimoto, Yu Funakubo Asanuma, Akio Mimori, Naoko
Okiyama, Shunta Kaneko, Hiroyuki Takahashi, Masahiro Yokosawa & Takayuki Sumida (2018):
Evidence-based clinical practice guideline for adult Still’s disease, Modern Rheumatology, DOI:
10.1080/14397595.2018.1465633

To link to this article: https://doi.org/10.1080/14397595.2018.1465633

Accepted author version posted online: 13

Apr 2018.

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MORH-D-18-00087 Received: 22-Feb-2018; Accepted: 3-Apr-2018

Review Article

Evidence-based clinical practice guideline for adult Still’s disease

1, 2 3 4,* 5 6 7
Toshihide Mimura , Yuya Kondo , Akihide Ohta , Masahiro Iwamoto , Akiko Ota , Nami Okamoto , Yasushi
8 9 10 11 12 13
Kawaguchi , Hajime Kono , Yoshinari Takasaki , Shuji Takei , Norihiro Nishimoto , Manabu Fujimoto , Yu
1 14 13 3 3
Funakubo Asanuma , Akio Mimori , Naoko Okiyama , Shunta Kaneko , Hiroyuki Takahashi , Masahiro
3 3
Yokosawa , and Takayuki Sumida

t
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1 2
Department of Rheumatology and Applied Immunology, Center for Intractable Diseases, Saitama Medical

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University, Saitama, Japan
3

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Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
4
Faculty of Medicine, Saga University, Saga, Japan
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5
Division of Rheumatology/Clinical Immunology, Department of Internal Medicine, Jichi Medical University,

Tochigi, Japan
M

6
Division of Public Health, Department of Social Medicine, Faculty of Medicine, Saitama Medical University,

Saitama, Japan
ed

7
Department of Pediatrics, Osaka Medical College, Osaka, Japan
8
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan
pt

9
Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
10
Department of Rheumatology, Juntendo University Koshigaya Hospital, Saitama, Japan
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11
Faculty of Medicine, School of Health Sciences, Kagoshima University, Kagoshima, Japan
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12
Department of Molecular Regulation for Intractable Disease, Institute of Medical Science, Tokyo Medical

University, Tokyo, Japan

13
Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
14
Department of Rheumatology, Iwate Prefectural Central Hospital, Iwate, Japan
*
Present affiliation: Kohokai Group Medical Corporation
Correspondence to: Toshihide Mimura,

Department of Rheumatology and Applied Immunology, Saitama Medical University

e-mail: toshim@saitama-med.ac.jp

Abstract

Objectives: Using an expert- and data-driven methodology, we have constructed the first clinical practice

guidelines (CPG) for adult Still’s disease (ASD) after complete systematic review (SR) of the literature based

upon the Medical Information Network Distribution Service (Minds) procedure.

Methods: The CPG committee for ASD organized by the Research Team for Autoimmune Diseases, the

Research Program for Intractable Disease of the Japanese Ministry of Health, Labour, and Welfare has

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developed CPG for ASD 2017, according to the procedure proposed by Minds. The CPG development process

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includes 1) clarification of the purpose of CPG, 2) organization of the steering committee, 3) organization of the

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CPG committee and secretariat, 4) defining the scope [setting of clinical questions (CQs)], 5) SR, 6) development

of recommendations, 7) drafting the CPG, 8) external evaluation and public comments, and 9) release. Because

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we wanted to construct CPG for ASD to encompass both adult-onset Still’s disease (AOSD) and adult patients

with systemic juvenile idiopathic arthritis (sJIA), we also included SR data from sJIA in this study.
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Results: Twenty-six CQs were selected and roughly divided into the following items: 1) clinical findings (CQs 1–
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4), 2) laboratory findings (CQs 5–8), 3) complications (CQs 9–13), 4) treatment with oral medicine (CQs 14–19),

5) treatment with biological reagents (CQs 20–23), and 6) treatments for sJIA (CQs 25–26). Recommendations
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and the strength of the recommendations for these CQs were decided by a modified Delphi method.

Conclusion: We have developed the first published CPG for ASD including AOSD and sJIA, which includes 26
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CQs and recommendations. This guideline will help rheumatologists, non-specialized physicians, other

healthcare providers, medical and health-related students, and patients and their family members to understand
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and treat ASD.

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Key Words: diagnosis, management, treatment, arthritis, recommendation

Introduction

Adult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disorder that was first reported in 1971 [1],

approximately 74 years after the initial description of its childhood counterpart [2], systemic juvenile idiopathic

arthritis (sJIA). AOSD is characterized by a daily high spiking fever, evanescent rash, arthritis, sore throat,

lymphadenopathy, splenomegaly, leukocytosis with predominant neutrophils, liver dysfunction, and elevated

inflammatory markers and serum ferritin [3, 4]. It is generally accepted that AOSD and sJIA are the same disease

entity but occur in different age groups, although they show some differences in prevalence and clinical profiles [5,

6].

The pathogenesis of AOSD remains obscure; however, recent progress in molecular genetics,

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especially in the field of innate immunity and autoinflammatory disorders, has mainly contributed to a better

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understanding of its pathophysiology [5, 7]. AOSD is considered a multifactorial disease in which an individual

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with susceptible polygenes develops sustained autoinflammatory conditions in response to multiple

environmental factors. According to different pathogenic mechanisms, AOSD is heterogeneous in terms of clinical

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features, disease course, severity, and prognosis. In this context, AOSD can be divided into multiple clinical

subtypes and was recently classified into systemic and articular (rheumatic) subtypes according to clinical
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characteristics, including responsiveness to anti-cytokine treatment [5, 7].
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Because AOSD is rare, clinical research has been limited to case reports and small retrospective

series. As to the treatment, large cohort studies or randomized controlled trials (RCTs) are few, and the treatment
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decision in each case has generally been made empirically, mostly based upon the reported data of these small

retrospective case series studies. In addition, a recent nationwide epidemiologic survey in Japan revealed that
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many AOSD patients had been primarily treated by non-specialists or non-experts in rheumatology. Moreover,

due to frequent occurrences of disease flare, most patients had to be transferred to another hospital with
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rheumatologists in the middle of the therapy [8]. Therefore, development of evidence-based clinical practice

guidelines (CPG) for AOSD has long been expected.

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In the present study, using an expert- and data-driven methodology, we have constructed the first CPG

for adult Still’s disease (ASD) after performing a complete systematic review (SR) of relevant literature based

upon the Medical Information Network Distribution Service (Minds) procedure. Because we wanted to construct

guidelines for ASD that encompassed both patients with AOSD and adult patients with sJIA, we also included SR

data from sJIA in this study.

Methods

CPG development process

The CPG committee for ASD organized by the Research Team for Autoimmune Diseases, the Research

Program for Intractable Disease of the Japanese Ministry of Health, Labour, and Welfare (MHLW) (principal

investigator: Takayuki Sumida) has developed CPG for ASD 2017, according to the procedure proposed by

Minds [9]. The CPG development process includes 1) clarification of the purpose of CPG, 2) organization of the

steering committee, 3) organization of the CPG committee and secretariat, 4) defining the scope [setting of

clinical questions (CQs)], 5) SR, 6) development of recommendations, 7) drafting the CPG, 8) external evaluation

and public comments, and 9) release (Figure 1).

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Clarification of the purpose of CPG

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The CPG was developed to support decision-making in clinical practice about clinical symptoms and treatment of

ASD patients, which included AOSD and transitional adult cases of sJIA. Thus, this CPG targeted all health care

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professionals who could be involved in the clinical practice of ASD, such as family physicians, rheumatologists,

dermatologists, pediatricians, and health professionals other than physicians. The purpose of the CPG is to
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improve the diagnosis, evaluation of disease activity, and treatment of ASD.
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Organization of the CPG committee and secretariat

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The steering committee was composed of six multidisciplinary researchers (four rheumatologists, one

dermatologist, and one public health scholar) of the Research Team for Autoimmune Diseases, the Research
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Program for Intractable Disease of the MHLW. An additional nine collaborators (seven rheumatologists and two

pediatricians) joined the steering committee members described above to organize the CPG committee (15
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members total).
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Defining the scope (setting of CQs)

The CPG committee set 26 CQs targeting three important clinical issues (diagnosis, complications, and treatment

of ASD) using the PICO (P: patients, problem, or population, I: interventions, C: comparisons, controls, or

comparators, and O: outcomes) format (Tables 1 and 2). The relationship between the clinical practice algorithm

for ASD and each CQ is shown in Figure 2.

SR

Another four collaborators from institutions to which each CPG committee member belonged joined the 13 CPG

committee members to form the SR team. The independence of SR was guaranteed because the 15 CPG

committee members reviewed evidence for other CQs that they had not worked on while setting the CQs. A

literature search was performed by The Japan Medical Library Association using medical databases including

National Guideline Clearinghouse, National Institute for Health Care Excellence (NICE) Evidence Search, Minds

guideline center, Cochrane Database of Systematic Reviews, PubMed, The Cochrane Library, and Igaku Chuo

Zasshi of the Japan Medical Abstracts Society, based on English or Japanese keywords listed from each PICO

formatted CQ. The literature search initially focused on articles published between 2000 and 2015. However,

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because searched literature was judged to be insufficient for SR by the SR team, a second literature search was

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performed for several CQs on articles published between 1980 and 2015. SR team members performed the first

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and second literature searches, evaluated and integrated evidence, and formed SR reports. The strength of

evidence for each outcome was evaluated according to the methods proposed by Minds [5], i.e., A (strong), B

(moderate), C (weak), and D (very weak).

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Development of recommendations
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CPG committee members decided the overall evidence level for each CQ, i.e., A (strong), B (moderate), C

(weak), and D (very weak), by integrating the body of evidence for each outcome based on SR reports and
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evidence evaluation sheets produced by SR team members. Strength of evidence, balance between benefit and

harm, diversity of patients’ sense of value, and economical viewpoints were considered in developing the
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recommendations. Recommendations and the strength of the recommendations (strong or weak) were decided

by the 15 CPG committee members using a modified Delphi method with 70% agreement (11/15 members)
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required for a consensus. Revision of recommendations that failed to achieve consensus was permitted for up to

4 rounds. The course of development of recommendations including advantages and limitations of adopted
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studies, summary of SR, application in the MHLW policy, and the final decision was described as explanations in

the CPG.

Drafting the CPG

A draft of the CPG comprising six chapters—organization, development process, scope, recommendations,

activities after release, and appendix (collected evidence data)—was created.

External evaluation and public comments

External evaluation and public comments on the draft of CPG were collected from the Japan College of

Rheumatology (JCR) and Pediatric Rheumatology Association of Japan (PRAJ). The CPG was revised

according to these evaluations, and the final version of CPG was approved by the CPG committee, JCR, and

PRAJ.

Release

‘CPG for ASD 2017’ was reported by the Research Team for Autoimmune Diseases, the Research Program for

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Intractable Disease of the MHLW in 2017 and published as a book on November 2017 in Japan [10]. This

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guideline was slightly modified from the original Japanese CPG for publication.

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CQs and recommendations

CQ 1: Is there a fever type characteristic of ASD?

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Recommendation 1: It is suggested that a spiking fever of 39°C or higher once or twice a day is
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characteristic (strength of recommendation: weak).

[Summary of evidence] This recommendation was examined based on three case series studies [11-13]. There
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was no study comparing ASD fever type with those of other pyrogenic diseases. A spiking fever of 39°C or higher

once or twice a day is characteristic of ASD.

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[Development of recommendation] Regarding fever types, there are only case series reports, and no study

included comparison with a control group, such as patients with other pyrogenic diseases. Although the evidence
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level is low, it was proposed as an experts’ opinion.

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CQ 2: Are there cutaneous symptoms characteristic of ASD?

Recommendation 2: There are two recommendations.

1) An evanescent, salmon-pink, flat erythematous rash appearing with fever and persistent erythema are

cutaneous symptoms characteristic of ASD. It is suggested that the presence of these skin rashes

increases the diagnostic sensitivity (strength of recommendation: weak).

2) It is suggested to perform skin biopsy since persistent erythema is a characteristic pathological

finding of epidermal keratinocyte necrosis (strength of recommendation: weak).

[Summary of evidence] These recommendations were examined based on three case-control studies [14-16]

and two case series reports [17, 18]. In the three case-control studies [14-16], it was suggested that the presence

of skin eruption increases the diagnostic sensitivity and diagnostic specificity when using pyrogenic diseases

other than ASD as a control (strength of evidence: D). In particular, it is suggested that an evanescent rash typical

of ASD is a highly specific finding (strength of evidence: D). Regarding the types of skin rash, two case series

reports described that, as with transient erythema, persistent erythema is observed at high frequencies (64–78%)

in the face, neck, trunk, and extensor of the extremities during the course of ASD. Histopathologically, transient

erythema shows inflammatory cell infiltration around superficial vessels, whereas persistent erythema shows

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necrotic foci of epithelial keratinocytes with surrounding inflammatory cell infiltrates [17, 18]. Consequently,

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although the strength of evidence is very weak, the presence of skin eruption may increase the diagnostic

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sensitivity and specificity of ASD.

[Development of recommendation] Three case-control studies suggested that the presence of skin eruption

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increase the diagnostic specificity when compared with pyrogenic diseases other than ASD. In particular, it was

suggested that a typical evanescent rash was a highly specific finding.

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In addition, two case series studies described that persistent erythema was found in high frequencies
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(64–78%) in the face, neck, trunk, and extensor of the extremities during the course of ASD. Histopathologically, it

is reported that transient erythema shows inflammatory cell infiltration around superficial vessels, and persistent
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erythema shows keratinocyte necrosis with surrounding inflammatory cell infiltration. Although the strength of

evidence is very weak, it is possible that skin biopsy from evanescent erythematous rash and persistent
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erythema may increase the diagnostic sensitivity and specificity of ASD.

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CQ 3: Is there a clinical feature of joint symptoms in ASD patients?

Recommendation 3: It is suggested that polyarthritis is common in knees, hands, and ankles, often
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leading to bone erosion and bone fusion/bone ankylosis in carpal and wrist joints (strength of

recommendation: weak).

[Summary of evidence] This recommendation was examined based on 12 case series studies [3, 8, 13, 19-28],

3 case-control studies with JIA [29-31], and 1 case-control study with unknown fever patients [16], and 1

case-control study with infectious disease, collagen disease, and unknown fever [4]. These studies were

observational studies. Joint symptoms are one of the three major symptoms of ASD, which is recognized in 83–
100% and 51–94% of ASD patients with joint pain and arthritis, respectively. Joint symptoms tend to worsen with

fever (spike fever) [19]. In addition, symptoms are strong early in the onset of ASD. Many patients have

polyarthritis, which often occurs in knees, hands, and ankles. Approximately one-third of ASD patients have the

chronic arthritic type, and a duration of joint symptoms of >6 months has been associated with the clinical course

of chronic arthritic type [20]. Arthritis and bone erosion at diagnosis are strong predictors of the shift to the chronic

arthritis type [21]. In the diagnosis of ASD, only one report, by Yamaguchi et al., estimated the sensitivity and

specificity of only joint symptoms [4]. According to this study, the positive frequency (sensitivity) of joint symptoms

was 100% in ASD patients. In the diagnosis of ASD, the sensitivity and specificity of joint symptoms lasting 2

weeks or more were calculated as 90% and 50%, respectively. Although joint symptoms are considered a major

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symptom in ASD and may be useful for diagnosis, they are not specific for ASD. Therefore, it is necessary to rule

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out other diseases that cause joint symptoms (strength of evidence: C). Abnormal X-ray observations of joints

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were recognized in 14–40% of ASD patients in the 1990s [1, 5, 6], which was reduced to 14–20% in the 2000s [3,

4, 9]. In addition, bone destruction is common in carpal and wrist joints. Although the prognosis of joint function of

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ASD patients is relatively good, bone erosion in carpal and wrist joints, joint narrowing, joint fracture, and bone

ankylosis may occur [8, 19, 22-28]. In the report from the 1990s, ankylosis occurred as frequently as 15–25% but
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decreased in the 2000s to 1.6–7.1%, which may be influenced by early diagnosis and treatment of ASD.
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According to Colina and colleagues, the increase in bone destruction scores (bone erosion and joint space

narrowing) in ASD patients is related to serum ferritin levels (P<0.001) and Disease Activity Score 28 values
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(P<0.001) [20]. However, since there is only one report, the evidence level is very weak.

[Development of recommendation] SR identified 12 case series studies, 3 case-control studies with JIA, and 1
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case-control study with unknown fever patients, and 1 case-control study with infectious disease, collagen

disease, and unknown fever. In these observational studies, arthritis and arthralgia were frequently observed in
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ASD patients. Characteristics of joint symptoms are that it is common in knees, hands, and ankles and many

patients have polyarthritis. Bone erosion, joint narrowing, and joint fusion/bone ankylosis in carpal and wrist joints
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may occur. However, these findings are based on an accumulation of clinical symptoms from joint research,

suggesting that the evidence level of clinical features of joint symptoms is weak.
CQ 4: Are there clinical features specific for sJIA?

Recommendation 4: It is suggested that important clinical symptoms of sJIA at diagnosis are fever (98–

100%), skin rash (67.9–100%), and arthritis (88–100%). In addition, arthritis tends to be more frequent in

knee and ankle joints, and some patients are complicated with macrophage activation syndrome (MAS)

(strength of recommendation: weak).

[Summary of evidence] This recommendation was examined based on four observational studies (4 case

accumulation studies [32-35]) and one cohort study [36]. In this SR, we did not identify clinical features that

increased the sensitivity and specificity of sJIA because the studies did not include a control group. Moreover, no

clear evidence of bone destruction could be identified. In sJIA, fever was observed at the time of onset in 98–

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100% of cases and skin rash was confirmed in 67.9–100% of cases [32-35]. In these studies, no statistical

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analysis was conducted to compare the systemic type with other disease types among JIA patients; however, the

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frequency of fever and skin rash in the systemic type was higher than those in other disease types [32]. In

addition, arthritis was observed at onset in 88–100% of cases, suggesting that there were cases in which arthritis

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was not necessarily present at onset. Regarding the characteristics of affected joints, the frequency of affected

knee joints was the highest in all studies, followed by ankle joint, wrist joint, elbow joint, and proximal
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interphalangeal (PIP) joint. From these results, it is impossible to examine the sensitivity and specificity of specific
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findings; however, the existence of fever, skin rash, and arthritis mainly of knee and ankle joints may be

characteristic clinical symptoms of sJIA.

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[Development of recommendation] There is no article with high evidence level on clinical symptoms of sJIA.

Four case accumulation studies and one cohort study were identified by SR. In these studies, common clinical
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symptoms were presented as described above. Clinical characteristics of fever, skin rash, and arthritis are not

specific to sJIA because these symptoms also may occur in other diseases. Thus, the strength of the
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recommendation is weak.
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CQ 5: Which laboratory items are useful for diagnosing and excluding ASD?

Recommendation 5: It is suggested that an increased serum C-reactive protein (CRP) level, increased

erythrocyte sedimentation rate (ESR), leukocytosis (≥ ratio (≥80%),

increased serum ferritin level (≥5 times above the upper reference value), elevated serum liver enzyme

level, and increased serum interleukin (IL)-18 level are distinctive laboratory findings for ASD (strength

of recommendation: weak).
[Summary of evidence] This recommendation was examined based on 12 case-control studies and 7 case

series studies for sensitivity and specificity of laboratory markers of ASD [8, 17, 20, 21, 37-51]. Serum CRP [8, 20,

21, 41, 43, 44, 51], ESR [8, 20, 21, 43], leukocytosis [8, 17, 20, 21, 47, 51], increased neutrophil ratio [8, 17, 21,

47, 51], increased serum ferritin level [17, 42, 47, 51], glycosylated ferritin [21, 47, 51], elevated liver enzyme [8,

20, 21, 43, 47, 51], and increased serum IL-18 level [38, 40, 49, 50] have relatively high sensitivity and specificity

for diagnosing and excluding ASD (strength of evidence: D).

[Development of recommendation] SR suggested that an elevated serum CRP level, increased ESR,

leukocytosis (≥10,000/µl), increased neutrophil ratio (≥80%), increased serum ferritin level (≥5 times above the

upper reference value), elevated serum liver enzyme level, and increased serum IL-18 level are useful laboratory

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markers for ASD. However, no RCT was conducted, and there were a relatively small number of case-control

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and case series studies and various biases. The CPG committee noted the issue that the MHLW does not cover

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the cost for measuring serum IL-18, although serum IL-18 has a high value for diagnosing ASD.

CQ 6: Which laboratory items are useful to assess disease activity of ASD?

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Recommendation 6: It is suggested that disease activity of ASD is comprehensively assessed with
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blood examination data such as CRP, ESR, ferritin, white blood cell (WBC) count, neutrophil count, and
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hepatic enzymes. In addition, serum IL-18 level is used for reference to estimate the activity and severity

of ASD (strength of recommendation: weak).

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[Summary of evidence] Because this recommendation was examined based on case series studies with small

numbers of ASD patients and case reports [20, 38, 40, 46, 49, 50, 52-72], the evidence level is judged to be very
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low. Although analysis of the evidence was difficult because proper assessment of disease activity of ASD has

not been established, most case series studies showed that CRP [62, 64, 65, 71, 72], ESR [64, 70, 72], ferritin [46,
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62, 64-69, 71, 72], WBC count [64, 70, 71], neutrophil count [67, 70], and hepatic enzymes [71] improved in

parallel with the amelioration of clinical symptoms of ASD (strength of evidence: D). Moreover, it was reported that
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disease activity is associated with some cytokines and inflammatory markers such as IL-18 [20, 38, 49, 50, 53, 54,

59-61], IL- -6 [54, 59, 63], soluble CD25 [60, 61], soluble intracellular adhesion molecule (ICAM-1) [58],

hemoxygenase-1 [46], and calprotectin [40, 55], among which serum IL-18 level is suggested to be correlated

with disease activity of ASD and an indicator of refractory cases [49] (strength of evidence: D).

[Development of recommendation] SR suggested that evidence on blood examination data, cytokines, and

inflammatory markers such as IL-18 in assessing disease activity of ASD is weak. However, the difficulty in
measuring cytokines and inflammatory markers in daily clinical practice is a future problem in this

recommendation. Thus, the CPG committee decided the recommendation that disease activity of ASD is

comprehensively assessed by blood examination data, and IL-18 is used as a reference to estimate disease

activity and severity of ASD.

CQ 7: Is lymph node biopsy useful when observing a swollen lymph node in ASD?

Recommendation 7: It is suggested that lymph node biopsy is useful for excluding malignant lymphoma

or infectious lymphadenitis (strength of recommendation: weak).

[Summary of evidence] This recommendation was examined based on three case series studies [73-75] and

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four case reports [76-78] for lymph node biopsy in swollen lymph nodes of ASD. Lymph node histopathology is

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generally reactive hyperplasia (lymphadenitis), of which specificity is low. However, lymph node biopsy has the

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ability to rule out malignant lymphoma or infectious lymphadenitis (strength of evidence: D).

[Development of recommendation] SR suggested that histopathology in swollen lymph node biopsy of ASD is

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reactive hyperplasia (lymphadenitis) at heterogeneous levels but this finding is nonspecific. The CPG committee

decided the recommendation that lymph node biopsy has significance to exclude malignant lymphoma or
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infectious lymphadenitis.
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CQ 8: Which laboratory items are characteristic for sJIA patients?

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Recommendation 8: It is suggested that elevated serum ferritin, soluble CD25, and IL-18 levels are a

characteristic laboratory finding in sJIA patients (strength of recommendation: weak).

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[Summary of evidence] Because this recommendation was examined based only on case series studies of

sJIA patients [31, 34, 79-93], the evidence level is judged to be very low. Some reports showed that elevation of
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WBC count, neutrophil count, platelet count, CRP, ESR, or serum ferritin contributes to increased sensitivity in the

diagnosis of sJIA (strength of evidence: D). It was also reported that >500 ng/ml of serum ferritin [80], >7,500
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ng/ml of soluble CD25 [86], or >1,600 ng/ml of IL-18 [83] contributes to increased specificity in the diagnosis of

sJIA (strength of evidence: D).

[Development of recommendation] SR suggested that several laboratory findings contribute to increased

sensitivity or specificity in the diagnosis of sJIA. However, it was not possible to determine cut-off values, since a

meta-analysis could not be performed because of discordance in control subjects, and the normal value for each

parameter differs according to age. Moreover, parameters contributing to increased sensitivity are considered to
be non-specific to inflammatory disorders. Thus, the CPG committee decided the recommendation that elevated

serum ferritin, soluble CD25, and IL-18 levels are characteristic laboratory findings in sJIA, with a focus on their

contribution to the specificity of the diagnosis. Although IL-18 is suggested to be valuable for the diagnosis of sJIA,

the difficulty in measuring IL-18 in daily clinical practice is a future problem in this recommendation.

CQ 9: What organ dysfunctions are associated with ASD?

Recommendation 9: It is suggested to consider liver damage, pericarditis, pleuritis, interstitial

pneumonia, gastrointestinal disorder, and renal disorder as organ dysfunctions associated with ASD

(strength of recommendation: strong).

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[Summary of evidence] This recommendation was examined based on three case-control studies [53, 94, 95]

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and nine case series studies [26, 43, 96-102]. Regarding organ dysfunction complicated with ASD, hepatic

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enlargement, elevated levels of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/alkaline

phosphatase (ALP), pericarditis, pleuritis, interstitial pneumonia, diarrhea/vomiting/abdominal pain, and renal

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disorder were documented. Although there were large differences in occurrence rates among reports, the most

frequent complication was liver damage [26, 43, 53, 95-102]. The studies documented that hepatomegaly
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occurred in 10–30%, AST/ALT in 50–80%, and ALP increase in 48–65% of patients [43, 100]. The complication
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rates of each organ were as follows: pericarditis 10–20% [26, 43, 95, 97, 98, 101, 102], pleuritis 6–18% [26, 43,

95, 97, 101, 102], interstitial pneumonia 0–9% [26, 95, 101, 102], gastrointestinal disorders around 20%, and
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renal disorder 9–25% [99, 101]. As described above, there is a large gap among studies and the evidence level is

very weak (strength of evidence: D). Although no study investigated the treatment strategy of ASD in terms of
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concomitant organ dysfunction, patients with MAS who showed higher liver injury had a tendency to be treated

with additional treatments such as steroid pulse therapy or intravenous immunoglobulin (IVIG) [94]. Conversely,
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the response rate to glucocorticoid was not associated with the presence of liver damage, pericarditis, or pleuritis

[101]. Therefore, the evidence level is very weak (strength of evidence: D). In addition, one study indicated that
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poor prognosis was associated with pleuritis and interstitial pneumonia, but not with liver damage [97]. However,

the evidence level is very weak (strength of evidence: D).

[Development of recommendation] The outcomes of this CQ were defined as diagnosis, treatment strategy,

and its influence on the prognosis of ASD. SR indicated that the major organ dysfunctions complicated with ASD

include liver damage, pericarditis, pleuritis, interstitial pneumonia, gastrointestinal disorders, and renal disorders.

The evidence is very weak, partly due to differences in the methods used to diagnose organ disorders,
differences in frequency of organ dysfunction, and relatively small number of case series studies. Regarding the

treatment and prognosis of ASD by the presence of organ dysfunction, there was inconsistency among studies.

Notably, MAS, which frequently accompanies liver damage, was reported to be associated with stronger

therapies. One case series study indicated that pleuritis and interstitial pneumonia, but not liver damage,

significantly correlate with poor prognosis.

CQ 10: What are the characteristics of MAS associated with ASD?

Recommendation 10: It is suggested that the characteristics of MAS associated with ASD are

pancytopenia, splenomegaly, and increased serum ferritin and triglyceride levels (strength of

t
recommendation: strong).

ip
[Summary of evidence] This recommendation was examined based on six observational studies including five

cr
retrospective case-control studies [53, 94, 103-105] and one case series study [106]. The diagnosis of MAS in

ASD was based on the diagnostic criteria of hemophagocytic lymphohistiocytosis (HLH)-2004 of Henter et al

us
[107] or the 2009 proposed HLH diagnostic criteria [106, 108]. The frequency of MAS in ASD was reported as

12–21% in these studies [53, 94, 104, 105]. Two case-control studies identified splenomegaly and lymph node
an
swelling as significantly more frequent clinical features in ASD with MAS compared with the ASD control group
M

(p<0.001) [104], but these findings were not confirmed in other studies. Although splenomegaly and lymph node

swelling can be diagnostic reference items, their specificities are considered to be low (strength of evidence: D).
ed

Pancytopenia (WBC count <3,400/µl, hemoglobin <10.0 g/dl, and number of platelets <100,000/µl) was reported

to significantly occur in ASD with MAS in two case-control studies (p<0.001) [94, 104]. In another case-control
pt

study, anemia or decreased WBC count was identified in ASD with MAS [105]. However, in one study, the

number of WBC in ASD with MAS did not differ from control ASD patients. In conclusion, cytopenia is considered
ce

to be a useful finding for diagnosis of MAS in ASD (strength of evidence: D).

Serum ferritin level was also found to be significantly higher in patients with ASD complicated with MAS
Ac

than those without in three case-control studies [53, 94, 104]. Severe hyperferritinemia is considered a useful

marker for diagnosis of MAS in ASD (strength of evidence: D). Triglyceride level was also significantly higher in

patients with ASD complicated with MAS in the two studies and may be considered a useful marker for diagnosis

(p<0.02) (strength of evidence: D) [94, 104].

Bone marrow aspiration/biopsy for the diagnosis of MAS has also been suggested. One case-control

study showed the frequency of hemophagocytosis in bone marrow was 38.9% in ASD with MAS compared with
0% in the control ASD group without clinical features of MAS [94]. This study indicated that the sensitivity of bone

marrow aspiration/biopsy was low in diagnosis and suggested comprehensive diagnosis of MAS based on

clinical features and non-invasive tests (strength of evidence: D).

Regarding treatment, one case-control study showed that ASD patients with MAS more often received

additional treatments including steroid pulse therapy or IVIG than those without [53]. Other studies indicated that

MAS in ASD was treated with high-dose glucocorticoids, IVIG, methotrexate, azathioprine, non-steroidal

anti-inflammatory drugs (NSAIDs) or anti- TNF antibodies [94, 104, 105]. At present,

there is no standardized treatment for ASD with MAS, and it seems that ordinary treatment of ASD is employed

(strength of evidence: D).

t
Regarding the deterioration of prognosis due to complication with MAS, one case-control study

ip
indicated a higher rate of recurrence in the ASD with MAS group (13 of 21 cases, 61.9%) than the control ASD

cr
group (16 of 88 cases, 18.2%) [94]. However, the death rate was not significantly higher in the ASD with MAS

group (2 of 21 cases, 9.5%) than the control group (3 of 88 cases, 3.4%) [94]. In addition, other studies did not

us
show a clearly increased number of deaths in the MAS complicated group [104, 105]. In summary, MAS in ASD

may be related to a higher rate of recurrence but not higher mortality rate (strength of evidence: D).
an
[Development of recommendation] The outcomes of this CQ were defined as the diagnosis, treatment
M

strategy, pain accompanying examination, and deterioration of prognosis. Although the number of

reports on the frequency of MAS in ASD is low, and diagnostic criteria for MAS were not unified among
ed

reports, SR revealed the frequency of MAS in ASD is estimated to be approximately 10–20% (strength

of evidence: D). SR also identified the clinical and laboratory features of MAS in ASD as splenomegaly,
pt

pancytopenia, abnormally elevated ferritin levels (≥5,000 ng/ml), and hypertriglyceridemia. The

treatment for MAS is not standardized; however, empiric therapies include steroid pulse therapy,
ce

immunosuppressive medications, IVIG, anti-TNF therapy, or plasma exchange (strength of evidence:

D). The use of anti-IL-6R antibody for MAS in ASD is controversial. Prospective studies are needed to
Ac

develop proper treatment for ASD with MAS. Although bone marrow aspiration/biopsy can contribute to

the definitive diagnosis of MAS, the examination is painful. Clinical features with non-invasive tests are

reliable enough to diagnose MAS, and the usefulness of bone marrow aspiration/biopsy is limited when

considering its invasiveness (strength of evidence: D).

CQ 11: What are the clinical features of drug allergy in ASD?

Recommendation 11: It is suggested that ASD does not have specific drug allergy features, although the

frequency of drug allergy in ASD might be higher than that in rheumatoid arthritis (RA) (strength of

recommendation: weak).

[Summary of evidence] This recommendation was examined based on one observational case-control study

[109]. It is suggested that patients with ASD have significantly more frequent severe side effects with

sulfasalazine treatment than patients with RA (strength of evidence: D). There was no paper indicating a change

in treatment or prognosis attributed to drug allergy in ASD. According to the above results, it is suggested that the

frequency of drug allergy is higher in ASD.

t
[Development of recommendation] The outcomes of this CQ were defined as the diagnosis of drug allergy,

ip
treatment strategy of ASD, and deterioration of the prognosis of ASD. In a case-control study on the side effects

cr
of sulfasalazine, adverse reactions appeared more frequently in ASD than in RA (60% vs 15%) [1]. It is possible

that adverse reactions to medication are more frequent in ASD. Clinicians might need to consider the possibility of

us
drug allergy or side effects when an unexpected change in the clinical picture is seen shortly after the

administration of new medication. However, the relationship between treatment strategy or prognosis and drug
an
allergy in ASD is unclear as all medication responsible for drug allergy in ASD was discontinued in the study.
M

CQ 12: What are the organ dysfunctions and clinical features of sJIA patients?
ed

Recommendation 12: It is recommended to consider that liver damage and serositis are often observed

in sJIA. It is also recommended to consider MAS as a potentially severe complication (strength of

pt

recommendation: strong).

[Summary of evidence] This recommendation was examined based on four review articles [33, 110-112]. The
ce

main clinical features of sJIA include rheumatoid papules, intermittent fever, lymphadenopathy,

hepatosplenomegaly, and serositis. MAS was identified as an important complication that may be related to the
Ac

prognosis of sJIA [33, 110-112].

[Development of recommendation] The outcomes of this CQ were defined as the diagnosis of the

complication, treatment strategy, pain related to the examination, and its influence on the prognosis of sJIA. SR

showed that the main clinical picture of sJIA is rash, intermittent fever, lymph node swelling, hepatosplenomegaly,

and serositis. MAS and amyloidosis were identified as important complications (strength of evidence: C). No

controlled study was found regarding treatment, and case studies indicated that patients were mainly treated with
glucocorticoid and NSAIDs. Administration of a biologic agent (anti-IL-6) was reported to be effective for

intractable cases (strength of evidence: C). Few studies referred to pain due to the examination or

change/discontinuation of treatment due to organ dysfunction (strength of evidence: D). Regarding worsening of

the prognosis due to organ dysfunction, MAS was identified to be a serious complication, which might be related

to a worse prognosis of sJIA (strength of evidence: C). Based on the above findings, liver injury and serositis are

frequently seen as organ dysfunctions in sJIA, and organ dysfunction accompanying MAS is considered a

serious complication.

CQ 13: What are useful findings for early diagnosis of MAS complicating sJIA?

t
Recommendation 13: It is suggested that MAS in sJIA accompanies high fever, liver injury, cytopenia,

ip
and elevated ferritin, IL-18, soluble CD25, and CD163 levels in the early phase. It is suggested to utilize a

cr
preliminary MAS guideline that includes these findings (strength of recommendation: weak).

[Summary of evidence] The frequency of MAS in sJIA is around 10%, but it is subclinically observed in 30–40%

us
of sJIA [113, 114]. A recent international multicenter survey identified triggers of MAS in sJIA as follows: disease

activity (52%), infection (34%), and medication (4%). Moreover, 22% of sJIA patients develop MAS at the onset of
an
sJIA [80, 115]. SR also identified the clinical features of MAS, which include fever, hepatomegaly, splenomegaly,
M

lymph node swelling, arthritis, and central nerve symptoms. Characteristic laboratory abnormalities comprise

thrombocytopenia and elevated liver enzyme, ferritin, triglyceride, and D-dimer levels at the time of MAS [80,
ed

113-117]. It is also noted that elevated IL-18, soluble CD25 (soluble IL-2 receptor), and CD163 levels are

characteristic of MAS [113, 114, 116].

pt

[Development of recommendation] The outcomes of this CQ were defined as the diagnosis of MAS, treatment

strategy, pain related to the examination, and its influence on the prognosis of sJIA. SR identified the frequency,
ce

triggers, characteristic clinical features, and characteristic laboratory findings of MAS complicating sJIA. Based on

the results of an international multicenter survey, classification criteria for MAS complicating sJIA by the European
Ac

League Against Rheumatism (EULAR), the American College of Rheumatology (ACR) and the Paediatric

Rheumatology International Trials Organization (PRINTO) were announced in 2016, which have a sensitivity of

73% and specificity of 99% [118]. In addition, it is noted that elevated IL-18, soluble CD25 (soluble IL-2 receptor),

and CD163 levels are characteristic for MAS complicating sJIA. Although this paper was not published when SR

was conducted, the CPG committee agreed to include it in the summary of evidence. The multicenter survey

included Japanese cases and the evidence level seemed to be relatively high (strength of evidence: B). SR
identified few control studies regarding treatments; however, a standardized treatment was not recognized. MAS

is often treated with glucocorticoid, steroid pulse therapy, cyclosporine, or IVIG. Biologic agents and etoposide are

also used, albeit less frequently. In order to standardize treatment, future prospective studies should be

conducted for the treatment of MAS complicating sJIA. As bone marrow aspiration/biopsy is accompanied by

pain, we investigated whether this examination is needed to diagnose MAS in sJIA. Although bone marrow

aspiration/biopsy can contribute to the definitive diagnosis of MAS, the sensitivity of hemophagocytosis in bone

marrow is around 60%. In addition, the presence of hemophagocytosis was not related to the clinical features of

MAS. In conclusion, it is considered that the usefulness of bone marrow examination is insufficient considering its

invasiveness (strength of evidence: D). Regarding the change in prognosis due to MAS, one-third of patients with

t
MAS complicated with sJIA required hospitalization in the intensive care unit and the mortality rate was 8%, which

ip
may indicate that MAS worsens the prognosis of sJIA (strength of evidence: C) [115]. The overall summary of

cr
evidence level was considered as C (weak) because of the small number of studies contributing to SR. In

addition, one study with a large number of MAS patients (n=362) had a limitation of the control group, which

included sJIA without MAS and systemic infection [80].

us
an
CQ 14: Are NSAIDs effective for ASD?
M

Recommendation 14: It is suggested that the administration of NSAIDs might relieve clinical symptoms

in mild ASD cases (strength of recommendation: weak).

ed

[Summary of evidence] This recommendation was examined based on seven case series studies [24, 25, 29,

101, 119-121] and two case reports [122, 123]. The seven case series studies reported that the efficacy ratio of
pt

NSAIDs for cases with ASD is between 0 and 13.6%, indicating that the efficacy of NSAIDs might be low to

improve ASD symptoms or pathology, although no reports compared ASD cases that received NSAIDs and
ce

untreated cases [24, 25, 29, 101, 119-121] (strength of evidence: D). in addition, there are no reports regarding

the inhibitory effect of NSAIDs on relapse of ASD. Case reports showed NSAIDs induced gastrointestinal
Ac

dysfunction [122] or allergic reaction [123] in ASD cases, although there are no reports that compared ASD cases

that received NSAIDs and untreated cases (strength of evidence: D). Accordingly, these results suggested that

the efficacy of NSAIDs to improve ASD symptoms and pathology might be low, although the evidence level is

weak.

[Development of recommendation] SR suggested that NSAIDs have low efficacy to improve ASD symptoms

or pathology in observational case series studies, although NSAIDs might be effective to relieve symptoms such
as low-grade fever, arthralgia, and arthritis in ASD patients and prediagnosed ASD patients. Gastrointestinal

dysfunction and allergic reaction were reported as NSAID-induced adverse events. Collectively, the CPG

committee decided the recommendation based on the possibility of NSAIDs to relieve clinical symptoms in mild

ASD patients.

CQ 15: Are systemic glucocorticoids effective for ASD?

Recommendation 15: It is recommended that systemic glucocorticoids ameliorate clinical symptoms

and manifestations in ASD (strength of recommendation: strong).

[Summary of evidence] This recommendation was examined based on ten case series studies [24, 25, 28, 43,

t
97, 101, 120, 124-126]. Systemic glucocorticoids significantly ameliorated clinical symptoms and manifestations

ip
compared with untreated or NSAID-treated ASD patients (strength of evidence: C). One case series study

cr
showed systemic glucocorticoid therapy was more effective for disease control than no therapy or NSAID

treatment [odds ratio (OR)=0.32, 95% confidence interval (CI): 0.113–0.923] [124]. Glucocorticoid therapy tended

us
to reduce the relapse rate of ASD (strength of evidence: D); however, most reports of glucocorticoid use for the

treatment of ASD involved combination therapy with disease-modifying antirheumatic drugs (DMARDs) or
an
biologic agents, and the influence of concomitant drugs was not taken into account. Adverse effects of
M

glucocorticoids such as increased infection, glucocorticoid-induced osteoporosis, and aseptic necrosis of the

femur head tended to increase slightly; however, it is hard to grasp the overall situation because most case series
ed

studies did not mention outcomes. Consequently, systemic glucocorticoid therapy significantly improved clinical

symptoms and manifestations compared with no therapy or NSAID treatment, although the evidence level is
pt

weak.

[Development of recommendation] SR was performed targeting ten case series studies to investigate the
ce

efficacy and safety of systemic glucocorticoids compared with no therapy or NSAIDs treatment in ASD patients.

The outcomes of this CQ were improvement of clinical symptoms and manifestations, relapse prevention,
Ac

increase in infection, glucocorticoid-induced osteoporosis, hypertension, glucose intolerance, dyslipidemia, and

aseptic necrosis of the femur head. Systemic glucocorticoids ameliorated clinical symptoms and manifestations

in patients with ASD compared with no therapy or NSAID treatment (strength of evidence: C). Systemic

glucocorticoids tended to prevent relapse; however, many cases were treated with glucocorticoid in combination

with DMARDs or biologics. The effect of concomitant medications has not yet been taken into account. Systemic

glucocorticoids cannot prevent structural joint damage, despite controlling systemic symptoms and arthritis in
some ASD cases with chronic arthritis. Adverse effects of glucocorticoids such as increase in infection,

glucocorticoid-induced osteoporosis, and aseptic necrosis of the femur head tended to increase slightly; however,

it is hard to grasp the overall situation because most case series studies did not mention adverse effects due to

glucocorticoids. These results suggest that systemic glucocorticoids significantly ameliorate clinical symptoms

and manifestations compared with no therapy or NSAID treatment, although the evidence level is weak.

CQ 16: Are high-dose intravenous pulse glucocorticoids effective for ASD?

Recommendation 16: It is recommended that high-dose intravenous pulse glucocorticoids ameliorate

clinical symptoms and manifestations in ASD patients with severe organ damage (strength of

t
recommendation: strong).

ip
[Summary of evidence] This recommendation was examined based on three case series studies [104, 127,

cr
128]. Pulse glucocorticoid therapy improved clinical symptoms and manifestations of ASD, although the results

were not obtained by head-to-head trials with systemic glucocorticoid-treated patients (strength of evidence: D).

us2
The dose of methylprednisolone differed among studies (e.g., 700 mg/m , 2–3 mg/kg, or not listed). Pulse

glucocorticoid therapy tended to reduce the relapse rate of ASD (strength of evidence: D); however, most patients
an
receiving pulse glucocorticoid therapy were treated with combination therapy including DMARDs or biologic
M

agents, and the influence of concomitant drugs was not taken into account. One case series study investigated

glucose intolerance as an adverse effect of glucocorticoids in ASD patients. Patients treated with systemic
ed

glucocorticoids including glucocorticoid pulse therapy did not have an increased risk of glucose intolerance

compared with patients receiving low- to moderate-dose glucocorticoids (42.9% vs 33.3%) [127] (strength of
pt

evidence: D). The risk of glucocorticoid adverse effects such as infection, glucocorticoid-induced osteoporosis,

hypertension, and aseptic necrosis of the femur head has not been investigated in ASD patients treated with
ce

pulse glucocorticoid therapy. These results suggest that pulse glucocorticoid therapy is highly effective at

improving clinical symptoms and manifestations in ASD patients. However, the evidence level is weak due to the
Ac

lack of studies that compared ASD patients treated with pulse glucocorticoid therapy to those receiving systemic

glucocorticoids.

[Development of recommendation] SR was performed on three case series studies to investigate the efficacy

and safety of pulse glucocorticoid therapy compared with systemic glucocorticoids in ASD patients. The

outcomes of this CQ were improvement of clinical symptoms and manifestations, relapse prevention, increase in

infection, glucocorticoid-induced osteoporosis, hypertension, glucose intolerance, dyslipidemia, and aseptic

necrosis of the femur head. Pulse glucocorticoid therapy improved clinical symptoms and manifestations of ASD,

although the results were not obtained by head-to-head trials with systemic glucocorticoid-treated patients

(strength of evidence: D). Case series studies and case reports showed pulse glucocorticoid therapy ameliorated

clinical symptoms and manifestations in ASD patients with severe organ damage. Pulse glucocorticoid therapy

tended to reduce the relapse rate of ASD (strength of evidence: D); however, most patients receiving pulse

glucocorticoid therapy were treated with combination therapy including DMARDs or biologic agents, and the

influence of concomitant drugs was not taken into account. One case series study showed that glucose

intolerance as an adverse effect of pulse glucocorticoid therapy was not significantly increased compared with

systemic glucocorticoid therapy (strength of evidence: D). An increased risk of glucocorticoid adverse effects such

t
as infection, glucocorticoid-induced osteoporosis, hypertension, and aseptic necrosis of the femur head has not

ip
been reported. Nevertheless, clinicians must pay attention to glucocorticoid adverse effects in patients treated

cr
with pulse glucocorticoid therapy, similar to systemic glucocorticoids, referencing the safety reports of

glucocorticoids in rheumatic diseases other than ASD. These results suggest that pulse glucocorticoid therapy is

us
effective to ameliorate clinical symptoms and manifestations in ASD patients with severe organ damage as long

as the benefits and risks are considered. However, the evidence level is weak. Although one of the SR references
an
mentioned a therapeutic dose for methylprednisolone of 2–3 mg/kg, the dose seems to be too low for high-dose
M

intravenous pulse glucocorticoid therapy in the current standard treatment.

ed

CQ 17: Is methotrexate (MTX) effective for ASD?

Recommendation 17: Concomitant use of MTX is recommended for the management of clinical
pt

symptoms and manifestations, and the glucocorticoid sparing effect in glucocorticoid-resistant

refractory ASD (strength of recommendation: strong).

ce

[Summary of evidence] This recommendation was examined based on three case series studies [64, 70, 129]

to investigate the usefulness of concomitant use of MTX compared with glucocorticoid monotherapy in ASD
Ac

patients. Concomitant use of MTX achieved remission in 50–70% of ASD patients among glucocorticoid-resistant

active patients. Although the glucocorticoid sparing effect of MTX was reported, an inhibitory effect on relapse has

not been identified. Adverse reactions of MTX, including gastrointestinal damage, liver toxicity, and drug-induced

interstitial pneumonia (one patient), were reported [64]. Clinicians should pay attention to adverse events

following MTX administration in ASD patients, as described in RA patients. We could not evaluate the increase in

infection or decrease in liver function. Since there have been no reports that compared MTX-treated and control
cases, the evidence level is low (strength of evidence: D). These results suggest that concomitant use of MTX is

recommended for the management of clinical symptoms and manifestations, and the glucocorticoid sparing

effect in refractory ASD, although there is insufficient evidence.

[Development of recommendation] SR was performed targeting three case series studies to investigate the

efficacy and safety of concomitant use of MTX compared with glucocorticoid monotherapy in ASD patients. The

outcomes of this CQ were improvement of clinical symptoms and manifestations, relapse prevention,

glucocorticoid sparing effect, increase in infection, cytopenia, liver damage, gastrointestinal damage,

drug-induced interstitial pneumonia, and drug adherence. MTX was administered to active and

glucocorticoid-resistant ASD patients in all three studies. Concomitant use of MTX improved clinical symptoms

t
and manifestations in 50–70% of ASD patients among glucocorticoid-resistant ASD patients who did not achieve

ip
control of their disease activity. Although a glucocorticoid sparing effect of MTX was reported, an inhibitory effect

cr
on relapse has not been identified. Adverse reactions of MTX, including gastrointestinal damage, liver toxicity, and

drug-induced interstitial pneumonia (one patient), were reported. Clinicians should pay attention to adverse

us
events following MTX administration in ASD patients, as described in RA patients. We could not evaluate

increase in infection or decrease in liver damage. Since there have been no reports with head-to-head trials
an
between MTX and control cases, the evidence level is low (strength of evidence: D).
M

These results suggest that concomitant use of MTX is useful for the management of clinical symptoms

and manifestations and glucocorticoid sparing effect in glucocorticoid-resistant refractory ASD, although there is
ed

insufficient evidence. However, clinicians should pay attention to adverse events following MTX administration in

ASD patients, as described in RA. The use of MTX should be carefully considered because MTX treatment for
pt

ASD is not approved by the MHLW. Informed consent for MTX treatment should be obtained from patients and/or

their families after thorough consideration of the benefits and risks.

ce

CQ 18: Is cyclosporine effective for ASD?

Ac

Recommendation 18: It is suggested that concomitant use of cyclosporine is one treatment option to

control symptoms in ASD patients who do not adequately respond to glucocorticoids and/or MTX or

when MTX is contraindicated (strength of recommendation: weak).

[Summary of evidence] This recommendation was examined based on three case series studies [120, 130,

131]. Concomitant use of cyclosporine improved clinical symptoms in 81–89% of ASD patients who did not

respond to high-dose glucocorticoid [120, 130, 131]. However, data to support the above finding are unavailable
because improvement of manifestations, relapse prevention, glucocorticoid sparing effect, safety, and drug

adherence have not been evaluated in ASD patients who received cyclosporine. Renal toxicity or gastrointestinal

damage was not mentioned in the safety reports. Since there is a lack of randomized trials to compare

concomitant use of cyclosporine and glucocorticoid monotherapy, the evidence level is low (strength of evidence:

D). These results suggest that concomitant use of cyclosporine may be effective to improve symptoms in ASD

patients whose disease is not controlled by glucocorticoids or MTX; however, the safety of the drug has not been

sufficiently investigated in ASD.

[Development of recommendation] SR was performed on three case series studies to investigate the efficacy

and safety of concomitant use of cyclosporine compared with glucocorticoid monotherapy in ASD patients. The

t
outcomes of this CQ were improvement of clinical symptoms and manifestations, relapse prevention,

ip
glucocorticoid sparing effect, increase in infection, renal damage, gastrointestinal damage, drug allergy, and drug

cr
adherence. Concomitant use of cyclosporine improved clinical symptoms in 81–89% of ASD patients who did not

respond to high-dose glucocorticoid. Improvement of manifestations, relapse prevention, glucocorticoid sparing

us
effect, safety, and drug adherence have not been evaluated in ASD patients who received cyclosporine. Since

there is a lack of randomized trials to compare concomitant use of cyclosporine and glucocorticoid monotherapy,
an
the evidence level is low (strength of evidence: D). These results suggest that concomitant use of cyclosporine is
M

effective to control symptoms in ASD patients when MTX is contraindicated or when glucocorticoid and MTX are

ineffective. Clinicians should pay attention to adverse effects of cyclosporine, as in other rheumatic diseases.
ed

Cyclosporine treatment should be carefully considered because cyclosporine use for ASD is not approved by the

MHLW. Informed consent for cyclosporine treatment should be obtained from ASD patients and/or their families
pt

after thorough consideration of the benefits and risks.

ce

CQ 19: Are DMARDs effective for arthritis in ASD?

Recommendation 19: It is suggested that concomitant use of DMARDs controls arthritis in ASD patients
Ac

when MTX is contraindicated or when they do not adequately respond to glucocorticoids and/or MTX,

after thorough consideration of the benefits and risks (strength of recommendation: weak).

[Summary of evidence] This recommendation was examined based on eight case series studies [28, 29, 109,

121, 130, 132-134]. RCTs comparing patients that received concomitant use of DMARDs and control cases with

glucocorticoid monotherapy have not been carried out. Three case series studies suggested that concomitant

use of DMARDs improves arthritis equal to or greater than glucocorticoid monotherapy in ASD patients; however,
there was no head-to-head comparison between DMARDs and glucocorticoid monotherapy [29, 121, 130]

(strength of evidence: C). Since preventive effect against relapse, glucocorticoid sparing effect, and drug

adherence of DMARDs have not been investigated in ASD, the efficacy of DMARDs for these items is unknown

(strength of evidence: D). These results suggest that concomitant use of DMARDs may be useful for arthritis in

ASD patients, although the evidence level is low.

[Development of recommendation] SR was performed on eight case series studies to investigate the efficacy

and safety of concomitant use of DMARDs compared with glucocorticoid monotherapy in ASD patients. The

outcomes of this CQ were improvement of arthritis, relapse prevention, glucocorticoid sparing effect, drug allergy,

and drug adherence. Three case series studies suggested that concomitant use of DMARDs except MTX

t
improves arthritis equal to or greater than glucocorticoid monotherapy in ASD patients. RCTs comparing

ip
concomitant use of DMARDs and glucocorticoid monotherapy have not been carried out (strength of evidence:

cr
C). Preventive effect against relapse, glucocorticoid sparing effect, and drug adherence of DMARDs have not

been investigated in ASD. These results suggest that concomitant use of DMARDs is effective for arthritis in ASD;

us
however, the evidence level is very low. Clinicians should consider the additional use of DMARDs in ASD patients

when MTX is contraindicated or when they do not adequately respond to glucocorticoids and/or MTX. Clinicians
an
need to decide the use of DMARDs carefully because DMARDs treatment for ASD is not approved by the MHLW.
M

Informed consent for DMARDs should be obtained from ASD patients and/or their families after thorough

consideration of the benefits and risks.

ed

CQ 20: Are TNF inhibitors useful for ASD?

pt

Recommendation 20: It is suggested that TNF inhibitors are one of the useful therapeutic options for

treatment-resistant ASD (strength of recommendation: weak).

ce

[Summary of evidence] Improvement of systemic symptoms, joint symptoms, and inflammatory findings of

ASD by administration of TNF inhibitors has been reported in case accumulation and cohort studies, although no
Ac

study has compared placebo and TNF inhibitor groups [8, 135-141] (strength of evidence: C). Since there is no

report on the suppressive effect of TNF inhibitors on recurrence of ASD, it is unknown whether TNF inhibitors

have this effect. However, a glucocorticoid sparing effect has been shown [136, 139] (strength of evidence: C).

Although treatment with TNF inhibitors has been reported to have sustained efficacy up to 28 months [8], the TNF

inhibitor-administered group had a lower continuation rate compared with the IL-6 inhibitor-administered group in

one case accumulation study [136] (strength of evidence: D). In addition, there are no specific safety profiles of
TNF inhibitors for ASD compared with those for RA or other rheumatic diseases.

[Development of recommendations] Based on the summary of evidence above, we weakly recommend that

TNF inhibitors are one of the useful therapeutic options for treatment-resistant ASD because TNF inhibitors are

not accepted for use against ASD by the MHLW and studies have not compared the use of TNF inhibitors with

other standard drugs in ASD.

CQ 21: Is IL-6 inhibitor useful for ASD?

Recommendation 21: It is suggested that IL-6 inhibitor is a useful therapeutic agent for

treatment-resistant ASD (strength of recommendation: weak).

t
[Summary of evidence] This recommendation was examined based on seven case accumulation studies [136,

ip
142-147]. Although there were no studies that compared the treatment group with placebo, it was suggested that

cr
IL-6 inhibitor is effective for improving symptoms and disease condition of ASD as well as tapering glucocorticoid

[136, 142-147] (strength of evidence: C). In one case accumulation study, the recurrence rate decreased after

us
IL-6 inhibitor treatment as compared with before the start of such treatment [142]. In addition, no report showed

adverse events related to IL-6 inhibitor treatment, such as infection, induction of MAS, and drug allergy. The
an
continuation rate was examined in one case accumulation study. The continuation rate in the
M

tocilizumab-administered group (90.9%) at the final examination was higher than that of the

etanercept-administered group (25%) and infliximab-administration group (11.1%) (follow-up period: 0.2–15.4
ed

years) [136]. However, no report examined the increase in medical expense burden.

[Development of recommendations] We conducted SR on seven case accumulation studies for this CQ as

pt

described above. Taken together, IL-6 inhibitor is effective for improvement of symptoms and the disease

condition of ASD. In addition, IL-6 inhibitor showed a glucocorticoid sparing effect and suppressed ASD
ce

recurrence. However, the evidence level is not high and IL-6 treatment for ASD is not currently approved by the

MHLW. Initially, there was no agreement among committee members concerning the decision of the
Ac

recommendation level of IL-6 inhibitor in ASD treatment. There were some positive opinions about the superiority

of IL-6 inhibitor to TNF inhibitors or other biological agents and about the presumption that AOSD may be similar

to sJIA, for which the MHLW has approved the use of tocilizumab. However, the recommendation level was

finally decided as “weak” because the CPG committee members agreed that the recommendation is not based

on comparison or presumption but the present evidence level. Through discussion on this matter, every member

agreed there is a high possibility that evidence showing the effectiveness of IL-6 inhibitors will accumulate in the
future, which may strengthen the recommendation level. Thus, we would like to emphasize that IL-6 inhibitors for

ASD therapy will be considered as one of the drugs strongly recommended for corticosteroid-refractory or

-dependent conditions.

CQ 22: Are IL-1 inhibitors useful for ASD?

Recommendation 22: It is suggested that IL-1 inhibitors are useful therapeutic agents for

treatment-resistant ASD (strength of recommendation: weak).

[Summary of evidence] This recommendation was examined based on one RCT [148], seven case

accumulation studies [21, 25, 149-152], and seven books [153-159]. In the RCT and case accumulation studies,

t
the IL-1 inhibitor-administration group showed improvement of symptoms and pathological conditions compared

ip
with the non-biologic DMARDs-administration group [21, 25, 148-152], and IL-1 inhibitor effectively reduced the

cr
glucocorticoid dose [25, 148-152] (strength of evidence: C). Although there are a few cases in which ASD

recurred after IL-1 inhibitor administration was stopped or reduced in patients achieving and maintaining

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remission of ASD, the effectiveness and treatment continuity (about 1 year, up to 4 years) was confirmed in

almost all cases, suggesting that IL-1 inhibitor has a suppressive effect on recurrence of ASD [21, 25, 148-159]
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(strength of evidence: D). Furthermore, although the frequencies of injection site reactions and skin rash as
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adverse events are relatively high [149, 150], there are only a few reports showing infection and MAS by

administration of IL-1 inhibitor (strength of evidence: D). There was no report on drug allergy (strength of
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evidence: D).

[Development of recommendations] There are currently no indications for the use of IL-1 inhibitors for ASD or
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other rheumatic diseases such as RA by the MHLW. In addition, there is also no evidence for the use of IL-1

inhibitors for Japanese patients with ASD. Taken together with the evidence summary above, the CPG
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committee members agreed that IL-1 inhibitor is weakly recommended as a therapeutic against refractory ASD.
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CQ 23: Are any biological reagents useful for ASD besides TNF, IL-6, and IL-1 inhibitors?

Recommendation 23: Apart from TNF, IL-6, and IL-1 inhibitors, it is suggested that abatacept and

rituximab are alternative biological reagents for ASD (strength of recommendation: weak).

[Summary of evidence] This recommendation was examined based on four case reports. The effectiveness of

abatacept [160, 161] and rituximab [162, 163] was reported; however, no research compared these treatments

with placebo. The efficacy of abatacept and rituximab for the symptoms and pathology of ASD was suggested
[160-163] (strength of evidence: D). In addition, the effect of weight loss due to corticosteroid use was also shown

[160-163] (strength of evidence: D). The inhibitory effect of both drugs against recurrence of ASD is unknown.

Increases in infectious diseases, induction of MAS, drug allergy, and drug continuity rate have not been reported.

Although the evidence level is very weak, abatacept and rituximab improved the symptoms and pathology of

ASD, suggesting the possibility of a steroid weight reduction effect.

[Development of recommendations] Although the level of evidence was very weak, it is suggested that

abatacept and rituximab improve the symptoms and disease conditions of ASD and have a steroid sparing effect.

Based on the summary of evidence above, the CPG committee recommends that abatacept and rituximab are

useful biological reagents for ASD apart from TNF, IL-6, or IL-1 inhibitors. Since both abatacept and rituximab for

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ASD are not approved by the MHLW, informed consent must be obtained from patients and/or their families after

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careful consideration of the benefits and risks.

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CQ 24: Is methylprednisolone (mPSL) pulse therapy effective for sJIA?

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Recommendation 24: It is suggested that mPSL pulse therapy might be effective, especially in sJIA

patients refractory to conventional therapy or patients in the early phase of the disease (strength of
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recommendation: weak).
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[Summary of evidence] This recommendation was examined based on one case series study [164] and one

prospective case-control study [165] screened from the 2011 and 2013 ACR recommendations for JIA [166, 167].
ed

The case series study indicated that mPSL pulse therapy was effective in improving clinical and biological

parameters of inflammation. In the case-control study, mPSL pulse therapy induced a prompt decrease in CRP
pt

levels compared with daily oral glucocorticoid treatment [164]. In the case series study, hypertension was

observed in 13.3% of patients treated with mPSL pulse therapy. Conversely, no patients with hypertension or
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impaired glucose tolerance were observed at 6 and 12 months after initiating mPSL pulse therapy in the

case-control study. Compared with patients treated with daily oral glucocorticoid at 6 months, body mass index
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(BMI) was similar and Cushingoid symptoms including obesity were decreased in patients treated with mPSL

pulse therapy due to the lower accumulated dose of glucocorticoid [165]. However, in both studies, no beneficial

effect on disease relapse, infection, dyslipidemia, and period of hospitalization was observed. According to these

results, it is suggested that mPSL pulse therapy might be safe and useful for sJIA patients, especially in the early

phase of disease or for those who are refractory to conventional therapy.

[Development of recommendation] SR was performed on one case series study and one case-control study.
Both studies suggested that mPSL pulse therapy was effective in improving symptoms and pathologies of sJIA.

Especially, the case-control study indicated that mPSL pulse therapy was effective in improving symptoms and

severe pathological condition resistant to conventional therapy and induced prompt CRP decrease compared

with daily oral glucocorticoid treatment. As to the safety of mPSL pulse therapy, the case-control study indicated

that the risk for inducing hypertension, impaired glucose tolerance, and obesity was low and BMI was similar

compared with daily oral glucocorticoid treatment in the medium- to long-term use, though transient hypertension

was observed in the case series study. However, no evidence was obtained in these studies regarding increased

risk of infection, osteoporosis, dyslipidemia, and shorted hospitalization by mPSL pulse therapy.

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CQ 25: Are there any useful immunosuppressants for sJIA?

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Recommendation 25: There are two suggestions. For sJIA patients refractory to conventional therapy, it

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is suggested that:

1) concomitant use of cyclosporine is useful to improve arthritis, fever, and inflammatory condition,

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especially MAS, and has a glucocorticoid dose sparing effect (strength of recommendation: weak),

2) concomitant use of MTX is not useful to improve arthritic condition or systemic symptoms, and MTX
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has no glucocorticoid dose sparing effect (strength of recommendation: weak).
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[Summary of evidence] These recommendations were examined based on two RCTs for MTX [90, 168] and

five case series studies for cyclosporine [169-173]. Concomitant use of MTX was not effective for sJIA in
ed

improving arthritic or systemic symptoms or CRP and ESR values [90, 168], and MTX has no glucocorticoid dose

sparing effect [90] (strength of evidence: D). No evidence was obtained in this SR as to the preventive effect of
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MTX on disease flare, complication of infection, development of MAS, and progression of joint damage. The case

series studies suggested that cyclosporine was effective in improving joint symptoms, fever, inflammatory
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condition such as MAS [169-173], and had a glucocorticoid dose sparing effect [170]. Especially, cyclosporine

was reported to induce prompt improvement in MAS condition [172]. No evidence was obtained in this SR
Ac

regarding the preventive effect of cyclosporine on disease relapse, complication of infection, development of

MAS, and progression of joint damage. Considering these results, it is suggested that cyclosporine might be

effective in improving symptoms and inflammatory conditions in sJIA (strength of evidence: D).

[Development of recommendation] Immunosuppressants are concomitantly used with glucocorticoid therapy

in sJIA patients resistant to conventional therapy. Therefore, SR was performed on two RCTs targeted on MTX

and five case series studies targeted on cyclosporine. The RCTs suggested that MTX was not effective to
improve systemic symptoms and CRP and ESR values, and no evidence was observed as to the preventive

effect on disease relapse, development of MAS, and progression of joint damage. Accordingly, a beneficial effect

of MTX on sJIA was not observed. SR on the five case series studies suggested that cyclosporine was effective

for joint symptoms, fever, and especially MAS condition. In addition, the SR suggested that cyclosporine had a

glucocorticoid dose sparing effect. However, no clear evidence was observed as to a preventive effect for

cyclosporine on disease flare, infection, and development of MAS. Considering these results, cyclosporine may

be useful for the treatment of sJIA, especially patients who develop MAS or are refractory to steroid therapy.

CQ 26: Are there any effective biologics for sJIA?

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Recommendation 26: There are two suggestions.

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1) It is recommended that tocilizumab and canakinumab are useful for the improvement of symptoms

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and disease state and they have an effect of reducing the glucocorticoid dose and improving growth in

sJIA that shows resistance to conventional therapy (strength of recommendation: strong).

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2) It is suggested that etanercept and abatacept are proposed as one of the treatment options for the

disease state of active arthritis without systemic symptoms in sJIA that shows resistance to
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conventional therapy (strength of recommendation: weak).
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[Summary of evidence] These recommendations were examined based on seven studies on tocilizumab (3

RCTs, 1 quasi-RCT, and 3 cohort studies) [174-180], seven studies on anakinra (1 RCT and 6 case series
ed

studies) [152, 181-186], two studies on canakinumab (1 RCT and 1 case series study) [187, 188], one quasi-RCT

on rilonacept [189], two case series studies on TNF inhibitors [190, 191], and two studies on abatacept (1 RCT
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and 1 case series study) [192, 193]. These articles focused on sJIA patients who were resistant to conventional

treatments.
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1) Tocilizumab, anakinra, and canakinumab had a significant improvement effect on symptoms and disease

states compared with placebo. Tocilizumab also showed a significant improvement effect (relative risk (RR)=3.93,
Ac

95%CI: 2.42–6.40, P<0.00005) on meta-analysis (strength of evidence: A) [174, 175]. The effect of tocilizumab

on improvement of disease states, glucocorticoid reduction effect, growth improvement effect, and improvement

of joint function was also confirmed (strength of evidence: B) [174, 175]. The effect of canakinumab on

improvement effect of disease states, glucocorticoid reduction effect, and recurrence reduction effect was also

confirmed (strength of evidence: B) [187, 188]. However, it has not been observed whether tocilizumab and

canakinumab would increase or reduce MAS, drug-free remission, medical expenses, or dosage of concomitant
immunosuppressant (strength of evidence: D) [174-180, 187, 188]. Anakinra showed effectiveness for disease

state improvement (strength of evidence: B) [181] and MAS (strength of evidence: C) [185, 186], and rilonacept

showed improvement in disease state (strength of evidence: B) [189]. TNF inhibitors were ineffective for systemic

symptoms such as fever (strength of evidence: C) [191], and there is no report on abatacept administered for

systemic symptoms (strength of evidence: D). However, a meta-analysis on tocilizumab showed a significant

increase in infection compared with placebo (RR=2.25, 95%CI: 1.48–3.41, P<0.0001) [174, 175] (strength of

evidence: C). In summary, it is considered that tocilizumab and canakinumab are useful for improvement of

symptoms, disease state, glucocorticoid reduction effect, and growth improvement effect in the treatment of sJIA

patients who show resistance to conventional therapy (strength of evidence: B). However, attention should be

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paid to the occurrence of infectious diseases (strength of evidence: C).

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2) In the case series study, in which patients started with etanercept treatment and switched to infliximab or

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adalimumab, TNF inhibitors were effective in the improvement of symptom and disease state, especially in cases

without systemic symptoms [190] (strength of evidence: C). In another case series study on etanercept, the

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glucocorticoid reduction effect was observed [191] (strength of evidence: C). It has not been observed whether

these drugs would increase or reduce recurrence, MAS, drug-free remission, medical expenses, joint disorder, or
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dosage of concomitant immunosuppressant (strength of evidence: D) [190, 191]. In the study that evaluated
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abatacept use for patients with arthritis without systemic symptoms, abatacept was effective for improvement of

symptoms and disease states, though there was no comparison with the placebo group (strength of evidence: C)
ed

[192, 193]. In the study evaluating recurrence, the recurrence rate of arthritis was significantly lower in the

abatacept group compared with the placebo group [192] (strength of evidence: C). However, it has not been
pt

determined whether abatacept would increase or reduce MAS, drug-free remission, medical expenses, or

dosage of concomitant immunosuppressant (strength of evidence: D). In summary, in the treatment of sJIA in
ce

which arthritis is prolonged without systemic symptoms and exhibits resistance to conventional therapy, TNF

inhibitors (such as etanercept) and abatacept may be one of the treatment options (strength of evidence: C).
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[Development of recommendation] In sJIA, there is a subtype in which only arthritis is prolonged without

systemic symptoms. Because literature about systemic inflammatory disease states and arthritis disease states

was available, we made recommendations for both. In children whose growth disorder due to glucocorticoid use

is a major problem, the glucocorticoid reduction effect is equivalent to improvement effect of symptoms and

disease state. In terms of TNF inhibitors, there is no literature evaluating infliximab and adalimumab under the

same conditions as etanercept, and evidence of the previous two biologics is thus considered limited. The CPG
committee decided the above recommendations from the viewpoint of evidence for sJIA and adaptation in Japan

(including drugs used in clinical trials). SR suggested that anti-IL-1 and anti-IL-6 preparations were effective for

the disease states of systemic inflammation, and anti-TNF and anti-CTLA-4Ig preparations might improve arthritis

disease states without systemic symptoms.

SR suggested that tocilizumab might increase infection. However, it is not possible to conclude that

only tocilizumab is a significant risk factor for infection because similar meta-analyses were not conducted for the

other drugs and the effects of concomitant drugs were not examined.

Discussion

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The first version of the CPG for ASD has been developed. Although several review papers or expert opinions on

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treatment with the management of AOSD have been published [1-12], our literature search did not identify any

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clinical guidelines or recommendations.

Because ASD has been treated by not only specialists but also non-specialist medical doctors and

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their treatments may not be standardized, this guideline is designed to inform all doctors caring for ASD patients

about evidence-based clinical information for the disease. It also aims to educate other medical staff, medical or
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health-related students, patients and their families, and related personnel about ASD. Thus, it may be the most
M

evidence-based textbook for learners about the clinical features, biomarkers, necessary clinical examinations,

and medical management of AOSD

ed

For this purpose, 26 CQs were selected and roughly divided into the following items: 1) clinical findings

(CQs 1–4), 2) laboratory findings (CQs 5–8), 3) complications (CQs 9–13), 4) treatment with oral medicine (CQs
pt

14–19), 5) treatment with biological reagents (CQs 20–23), and 6) treatments for sJIA (CQs 24–26).

As a strongly recommended item, it is important to know that organ complications in ASD include liver
ce

disorder, pericarditis, pleuritis, interstitial pneumonia, gastrointestinal disorder, and kidney disorder in the disease

course. It is also important to recognize that pancytopenia, splenomegaly, and increased serum ferritin and
Ac

triglyceride levels are characteristic features of MAS associated with ASD. Regarding glucocorticoid treatment,

there are two strong recommendations: 1) systemic glucocorticoid administration for the purpose of improving

clinical symptoms and disease conditions of ASD and 2) high-dose intravenous pulse glucocorticoid therapy

aimed at improving clinical symptoms and disease conditions of ASD patients with severe organ lesions.

Interestingly, for treatment with immunosuppressants, only MTX is strongly recommended for improvement of

clinical symptoms and disease conditions in steroid-refractory ASD and for the steroid sparing effect, while
cyclosporine is weakly recommended for ASD. It is also strongly recommended that tocilizumab and

canakinumab are useful for the improvement of symptoms and disease states, and they have an effect of

reducing glucocorticoid dose and improving growth in sJIA patients who show resistance to conventional therapy.

Although the recommendation level is weak because of the weak evidence level, it is assumed that biological

reagents, such as tocilizumab and canakinumab, will also be an important therapeutic option for AOSD in the

near future [21, 25].

However, this CPG has some limitations. In particular, there are 19 weak recommendations for the

CQs. AOSD is rare, and we estimate that approximately 4,760 individuals (estimated prevalence: 3.7/100,000

population) are affected in Japan [8]. Moreover, it is difficult to develop clinical studies on new drugs for rare

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diseases; thus, an exhaustive literature search found only a few global reports about the disease with high quality

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evidence. Therefore, we could make only a few strong recommendations among the 26 CQs.

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Because SR was based on global evidence, we should note that some contents included in this CPG

are not compatible with MHLW policy. In addition, descriptions of intentions and perspectives of the patients and

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verification of the CPG compliance status at clinical sites will be issues for future revision.

In conclusion, we have developed the first published CPG for ASD, which comprises 26 CQs and
an
recommendations. This guideline is very useful to understand ASD, especially its clinical features, biomarkers,
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necessary clinical examinations, and medical management, for all doctors treating ASD patients as well as other

medical staff, medical or health-related students, patients, their families, and related personnel.
ed

Conflict of interest
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TM has received research grants from Astellas Pharma, UCB Japan, Mitsubishi Tanabe, and Takeda.

MI has received patent royalties from Chugai Pharmaceutical Co.

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YT has received honoraria from Chugai Pharmaceutical Co., Mitsubishi Tanabe and Bristol-Myers Squibb;

research grants from Mitsubishi Tanabe, Astellas Pharma, Chugai Pharmaceutical Co., Ayumi, Takeda, Eisai,
Ac

and MSD.

ST has received honoraria from Chugai Pharmaceutical Co.

NN has received patent royalties from Chugai Pharmaceutical Co.; honoraria from Chugai Pharmaceutical Co.

and Mitsubishi Tanabe; research grants from Chugai Pharmaceutical Co.; and a consulting fee from Chugai

Pharmaceutical Co.
MF has received research grants from Astellas Pharma, Novartis, Japan Blood Products Organization,

Mitsubishi-Tanabe, Pfizer, Ono Pharma, Shionogi, Bristrol-Myyers Squibb, Maruho, Torii Phama, and Kyowa

Hakko Kirin.

TS has received honoraria from Astellas Pharma, Chugai Pharmaceutical Co., and Mitsubishi Tanabe; research

grants from Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Mitsubishi Tanabe, and Ono.

The other authors have no conflicts of interest.

Authors’ contributions

All authors contributed to the design of the study, data collection, and participated in the writing of the manuscript.

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All authors agree to accept equal responsibility for the accuracy of the contents of this paper.

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Acknowledgement

This work was supported by Health and Labour Sciences Research Grants for research on intractable diseases

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(The Research Team for Autoimmune Diseases) from the Ministry of Health, Labour, and Welfare of Japan.
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Table 1. Setting of clinical questions using PICO format (Illustration of CQs 1 and 14)

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P I/C O
CQ Dise Patholog Benefit/ Import Pros or
Sex Age I C List Content

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ase y Harm ance cons
Body
Increase in
temperature
O1 sensitivity of Benefit 7 Yes
an
Fever type diagnosis
(continuous
fever, remittent Increase in
CQ 1
fever, O2 specificity of Benefit 7 Yes
Is there a fever Not Not
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intermittent diagnosis
type assig assig ASD Fever None
characteristic of ned ned fever, undulant Suffering
O3 Harm 3 No
ASD? fever, cyclic from fever
fever)
ed

Duration
Prodromal
symptom
pt

Improvement
Fever O1 Benefit 5 Yes
of symptoms
Improvement
ce

Arthritis O2 Benefit 4 Yes

of pathology
CQ 14
Arthropat Inhibition of
Are non-steroidal Not Not Non-steroidal O3 Benefit 4 Yes
hy Plac relapse
anti-inflammatory assig assig ASD anti-inflammato
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Systemic ebo Gastrointesti

drugs effective ned ned ry drug O4 Harm 4 Yes
inflammat nal toxicity
for ASD?
ion O5 Renal toxicity Harm 4 Yes
Organ
dysfunctio O6 Drug allergy Harm 6 Yes
n

PICO, P: patients, problem, or population, I: interventions, C: comparisons, controls, or comparators, O:

outcomes; CQ, clinical question; ASD, adult Still’s disease

Table 2. Summary of clinical questions and recommendations
Number CQ
Is there a fever type
1 Weak
characteristic of ASD?
Are there cutaneous symptoms
2 diagnostic sensitivity.
characteristic of ASD?
Is there a clinical feature of joint
3 Weak
symptoms in ASD patients?
Are there clinical features
4 Weak
specific for sJIA?
Which laboratory items are
5 useful for diagnosing and
excluding ASD?
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Which laboratory items are
6 useful to assess disease activity
of ASD?
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Is lymph node biopsy useful
7 when observing a swollen lymph
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node swollen in ASD?
Which laboratory items are
8 soluble CD25, and IL-18 levels are
characteristic for sJIA patients?
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What organ dysfunctions are
9 Strong
associated with ASD?
What are the characteristics of
10
MAS associated with ASD?
What are the clinical features of
11
drug allergy in ASD?
12 What are the organ dysfunctions
Strength of
Recommendation
recommendation
It is proposed that a spiking fever of 39°C or
higher once or twice a day is characteristic.
An evanescent, salmon-pink, flat
erythematous rash appearing with fever and
persistent erythema are cutaneous symptoms
Weak
characteristic of ASD. It is proposed that the
presence of these skin rashes increases the
It is proposed to perform skin biopsy since
persistent erythema has a characteristic
Weak
pathological finding of epidermal keratinocyte
necrosis.
It is suggested that polyarthritis is common in
knees, hands, and ankles, often leading to
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bone erosion and bone fusion/bone ankylosis
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in carpal and wrist joints.
It is suggested that important clinical
symptoms at diagnosis are fever (98–100%),
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skin rash (67.9–100%), and arthritis (88–
100%), and arthritis tends to be more frequent
in knee and ankle joints. In addition, some
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cases are complicated with MAS.
It is suggested that an increased serum CRP
level, increased ESR, leukocytosis
an
(> ratio
(>80%), increased serum ferritin level (>5
Weak
times above the upper reference value),
elevated serum liver enzyme level, and
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increased serum IL-18 level are distinctive
laboratory findings for ASD.
It is suggested that disease activity of ASD is
comprehensively assessed by blood
examination data such as CRP, ESR, ferritin,
white blood cell count, neutrophil count, and Weak
hepatic enzyme, and the serum IL-18 level is
used for reference to estimate the activity and
severity of ASD.
It is suggested that lymph node biopsy is
useful for excluding malignant lymphoma or Weak
infectious lymphadenitis.
It is suggested that elevated serum ferritin,
Weak
characteristic laboratory findings in sJIA.
It is recommended to consider liver damage,
pericarditis, pleuritis, interstitial pneumonia,
gastrointestinal disorder, and renal disorder as
organ dysfunctions associated with ASD.
It is recommended that the characteristics of
MAS associated with ASD are pancytopenia,
Strong
splenomegaly, and increased serum ferritin
and triglyceride levels.
It is suggested that ASD does not have a
specific feature in drug allergy, although the
Weak
frequency of drug allergy in ASD might be
higher than that in rheumatoid arthritis.
It is recommended to consider that liver Strong
 and clinical features of sJIA
patients?
What are the useful findings for
13 early diagnosis of MAS
complicating sJIA?
14 Are NSAIDs effective for ASD?
Are systemic glucocorticoids
15
effective for ASD?
Are high-dose intravenous pulse
16 glucocorticoids effective for
ASD?
damage and serositis are often observed in
sJIA. It is also recommended to consider MAS
as a potentially severe complication of sJIA.
It is suggested that MAS in sJIA accompanies
high fever, liver injury, cytopenia, and elevated
ferritin, IL-18, soluble CD25, and CD163 levels
Weak
from the early phase of disease. It is
suggested to utilize a preliminary MAS
guideline which includes these findings.
It is suggested that administration of NSAIDs
might relieve clinical symptoms in mild ASD Weak
cases.
It is recommended that systemic
glucocorticoids ameliorate clinical symptoms Strong
and manifestations of ASD.
It is recommended that high-dose intravenous
pulse glucocorticoids ameliorate clinical
Strong
symptoms and manifestations of ASD patients

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with severe organ damage.

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It is recommended to concomitantly use MTX
for the management of clinical symptoms and
17 Is MTX effective for ASD? manifestations, which has a glucocorticoid Strong

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sparing effect in glucocorticoid-resistant
refractory ASD.
It is suggested that concomitant use of

18
Is cyclosporine effective for
ASD?
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cyclosporine is one of the treatment options to
control symptoms in ASD patients who do not
adequately respond to glucocorticoids and/or
Weak
an
MTX or when MTX is contraindicated.
It is suggested that concomitant use of
DMARDs controls arthritis in ASD patients
Are DMARDs effective for when MTX is contraindicated or in patients
19 Weak
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arthritis in ASD? who do not adequately respond to

glucocorticoids and/or MTX, after thorough
consideration of the benefits and risks.
It is suggested that TNF inhibitors are one of
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Are TNF inhibitors useful for

20 the useful therapeutic options for Weak
ASD?
treatment-resistant ASD.
It is suggested that IL-6 inhibitor is a useful
21 Is IL-6 inhibitor useful for ASD? Weak
therapeutic agent for treatment-resistant ASD.
pt

It is suggested that IL-1 inhibitors are useful

Are IL-1 inhibitors useful for
22 therapeutic agents for treatment-resistant Weak
ASD?
ASD.
ce

Are any biological reagents Apart from TNF, IL-6, and IL-1 inhibitors, it is
23 useful for ASD besides TNF, suggested that abatacept and rituximab are Weak
IL-6, and IL-1 inhibitors? alternative biological reagents for ASD.
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It is suggested that mPSL pulse therapy might

Is mPSL pulse therapy effective be effective, especially in sJIA patients
24 Weak
for sJIA? refractory to conventional therapy or in
patients in the early phase of disease.
For sJIA patients refractory to conventional
therapy, it is suggested that concomitant use
Are there any useful of cyclosporine is useful to improve arthritis,
25 Weak
immunosuppressants for sJIA? fever, and inflammatory condition, especially
in MAS, and has a glucocorticoid dose
sparing effect.
 For sJIA patients refractory to conventional
therapy, it is suggested that concomitant use
of MTX is not useful to improve arthritic Weak
condition or systemic symptoms, and has a
glucocorticoid dose sparing effect.
It is recommended that tocilizumab and
canakinumab are useful for the improvement
of symptoms and disease states, and they
Strong
have an effect of reducing the glucocorticoid
and improving the growth in sJIA cases that
Are there any effective biologics
26 show resistance to conventional therapy.
for sJIA?
It is suggested that etanercept and abatacept
are proposed as one of the treatment options
for the disease state of active arthritis without Weak
systemic symptoms in sJIA patients who show
resistance to conventional therapy.
CQ, clinical question; ASD, adult Still’s disease; sJIA, systemic juvenile idiopathic arthritis; MAS, macrophage

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activation syndrome; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL, interleukin; NSAIDs,

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non-steroidal anti-inflammatory drugs; MTX, methotrexate; DMARDs, disease-modifying antirheumatic drugs;
TNF, tumor necrosis factor; mPSL, methylprednisolone

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Figure Legends

Figure 1. Clinical practice guideline development process us

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CPG, clinical practice guideline; CQs, clinical questions

Figure 2. Relationship between clinical practice algorithm for ASD and each CQ
CQ, clinical question; ASD, adult Still’s disease
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ed
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ce
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 Figure1
Clarification of the purpose of CPG

Organization of the steering committee

Organization of the CPG committee and secretariat

Making of scope (setting of CQs)

Systematic review

Development of recommendation

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Making of the draft of CPG

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External evaluation and public comments

Release

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Popularization/Introduction/Evaluation
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Revision
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ed
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ce
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 Figure2

Adult case Child case

Suspected case

Clinical symptoms: CQ1-CQ3 Clinical symptoms: CQ4

Laboratory findings: CQ5-CQ7 Laboratory findings: CQ8

Diagnosis

Characteristics of complications: Characteristics of complications:

CQ9-CQ11 CQ12-CQ13

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Assessment of
complications

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Non-biological drugs: CQ14-CQ19 Treatment of pediatric case:
Biological drugs: CQ20-CQ24

us CQ25-27
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Treatment
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ed
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