今日の臨床サポート

成人スティル病

著者: 吉田佳弘 埼玉医科大学 リウマチ膠原病科

著者: 三村俊英 埼玉医科大学 リウマチ膠原病科

監修: 上阪等 千葉西総合病院 膠原病リウマチセンター

著者校正/監修レビュー済:2021/11/17
参考ガイドライン:
  1. 厚生労働科学研究費補助金難治性疾患等政策研究事業 自己免疫疾患に関する調査研究班:成人スチル病診療ガイドライン 2017年版

概要・推奨   

  1. 診断確定例にはステロイドにて治療を行うのが一般的である。国内外においてステロイドは約9割の症例で用いられている(推奨度2)。
  1. ステロイド効果不十分例には免疫抑制薬の併用が検討される。メトトレキサートやシクロスポリンAの有効性が報告されている(推奨度3)。
  1. 関節リウマチの治療に用いられる生物学的製剤が成人スティル病にも有効なケースが報告されている。その中で抗IL-6受容体抗体製剤のトシリズマブ(アクテムラ)は2019年5月に保険適用となった(推奨度3)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
吉田佳弘 : 未申告[2021年]
三村俊英 : 奨学(奨励)寄付など(中外製薬(株),武田薬品工業(株),旭化成(株))[2021年]
監修:上阪等 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、以下の点について加筆修正を行った。
  1. インターロイキン(IL)-6受容体の抗体製剤であるトシリズマブの有用性が示されてきたが、実際に保険適用となり実臨床で使用できるようになった。

病態・疫学・診察

疾患(疫学・病態)  
病態・疫学:
  1. 成人スティル病(または成人スチル病)とは、かつて報告者にちなんでスティル病と呼称された、小児の慢性炎症性疾患である全身型若年性特発性関節炎(sJIA)に類似した臨床症状が成人(16歳以上)に生じたものである。小児期にスティル病(現在のsJIA)を発症し成人に移行した例も成人スティル病に含めて扱われる。弛張熱、有熱時のサーモンピンク疹(<図表>)、多関節炎の3主徴に加え、肝障害やリンパ節腫脹、血清フェリチン値の著増などがみられ、成人における不明熱の鑑別疾患として重要である。一部の症例でマクロファージ活性化症候群または血球貪食症候群(合併症の項で後述)、DICなどを併発し重篤となることがある。
  1. 疫学的にはまれな疾患であり、有病率は約2/10万人程度とされる。年齢分布は16~35歳に6割の患者が分布するとされ、男女比は女性が男性の約2倍である。
  1. 病態に関してはいまだ不明であるが、ウイルスや細菌などの感染因子、HLA-DQ1やDR4など遺伝因子が発症に関与するとの報告がある。また単球・マクロファージの活性化やインターロイキン(IL)-1b、-6、-18やインターフェロン(IFN)-γ、腫瘍壊死因子(TNF)-αの著明な産生亢進も発症に関与していると考えられている。なおIL-18 増加は敗血症など他の炎症性疾患との鑑別に有効性も示される。ただ自己抗体の産生はなく自己免疫疾患というよりも、自然免疫系の制御異常による広義の自己炎症疾患と考えられる。 
  1. 成人スティル病は、指定難病であり、中等症以上の場合などは、申請し認定されると保険料の自己負担分の一部が公費負担として助成される。([平成27年1月施行])
  1.  難病法に基づく医療費助成制度 
 
  1. 成人スティル病患者における血中のIL-18濃度上昇が有意所見とされるようになってきた(推奨度3O)。
  1. 血清フェリチンの著増が参考所見とされるが、成人スティル病に特異的な検査所見はない。最近、成人スティル病患者の血中IL-18濃度が他疾患より有意に上昇していると報告されるようになった。
  1. 2001年に岡山大と東京女子医大のグループがそれぞれ別に成人スティル病患者の血中IL-18濃度が関節リウマチ患者などと比較し増加していることを報告している[1][2]。ただし、測定に関して保険適用はない。
 
病型:
  1. 成人スティル病の経過は、発熱などの全身症状が1回のエピソードのみで再発のない単周期全身型、全身症状の再発と寛解を繰り返す多周期全身型、関節炎が持続し慢性化する慢性関節炎型(全身症状が一過性かどうかで慢性関節炎・単周期全身型と多周期全身型とに分かれる)におおむね分類される。
  1. 以前は多周期全身型が多いとされたが、2011年のわが国の疫学調査では単周期全身型が4割を占め最多、慢性関節炎型は約2割5分であり、残りが多周期全身型である。
問診・診察のポイント  
問診:
  1. 抗菌薬加療に反応しない1週間以上持続する発熱(38~39℃台)患者、特に弛張熱(特徴としては、午前よりも午後・夕方に熱のピークがある)を示す場合に可能性を考慮する。
  1. 咽頭炎様症状で初発することもしばしばあり、風邪症状と間違われやすい。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: M Kawashima, M Yamamura, M Taniai, H Yamauchi, T Tanimoto, M Kurimoto, S Miyawaki, T Amano, T Takeuchi, H Makino
雑誌名: Arthritis Rheum. 2001 Mar;44(3):550-60. doi: 10.1002/1529-0131(200103)44:3<550::AID-ANR103>3.0.CO;2-5.
Abstract/Text OBJECTIVE: Interleukin-18 (IL-18) is a proinflammatory cytokine that is involved in immunologically mediated tissue damage, but its bioactivity is regulated in vivo by its soluble decoy receptor, IL-18 binding protein (IL-18BP). This study was undertaken to determine levels of IL-18 and IL-18 binding inhibition in the blood of patients with adult-onset Still's disease (ASD).
METHODS: Serum concentrations of IL-18 in ASD patients were compared by enzyme-linked immunosorbent assay (ELISA) with those in patients with other systemic rheumatic diseases and healthy controls. The biologically active mature protein of IL-18 was detected by Western blot analysis with anti-IL-18 antibody and its induction of interferon-gamma (IFNgamma) secretion from IL-18-responding human myelomonocytic KG-1 cells. The inhibitory activity on IL-18 binding to its receptor was determined by 125I-IL-18 binding inhibition assay using the Chinese hamster ovary cell line transfected with a murine IL-18 receptor (CHO-K1/mIL-18R).
RESULTS: Concentrations of serum IL-18 were extremely elevated in patients with active ASD compared with those in patients with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis/dermatomyositis, Sjogren's syndrome, or healthy individuals. Levels of IL-18 were found to correlate with serum ferritin values and disease severity in ASD. Western blot analysis revealed that serum samples from patients with active ASD contained an 18-kd polypeptide of IL-18, corresponding in size to the mature form. Accordingly, the samples were able to induce IFNgamma secretion from KG-1 cells, which was largely abolished by neutralizing anti-IL-18 antibody. However, the level of IL-18 bioactivity was more than 10-fold weaker than the concentration of IL-18 protein measured by ELISA. Serum samples from patients with active ASD showed an inhibitory effect on the binding of 125I-IL-18 to CHO-K1/mIL-18R cells, and this activity was associated with elevation of IL-18.
CONCLUSION: These data indicate that systemic overproduction of IL-18 may be closely related to the pathogenesis of ASD, despite the restriction on its inflammatory activity by IL-18 binding inhibitors such as IL-18BP. The disease activity appears to be determined on the basis of the relative levels of IL-18 and its specific inhibitors.

PMID 11263769  Arthritis Rheum. 2001 Mar;44(3):550-60. doi: 10.1002/15・・・
著者: Y Kawaguchi, H Terajima, M Harigai, M Hara, N Kamatani
雑誌名: Arthritis Rheum. 2001 Jul;44(7):1716-7. doi: 10.1002/1529-0131(200107)44:7<1716::AID-ART298>3.0.CO;2-I.
Abstract/Text
PMID 11465725  Arthritis Rheum. 2001 Jul;44(7):1716-7. doi: 10.1002/15・・・
著者: Yu Funakubo Asanuma, Toshihide Mimura, Hiroto Tsuboi, Hisashi Noma, Fumihiko Miyoshi, Kazuhiko Yamamoto, Takayuki Sumida
雑誌名: Mod Rheumatol. 2015 May;25(3):393-400. doi: 10.3109/14397595.2014.974881. Epub 2014 Nov 10.
Abstract/Text OBJECTIVES: A nationwide survey was conducted to assess the number of patients, clinical aspects, treatment, and prognosis of adult Still's disease (ASD) in Japan.
METHODS: A primary questionnaire was sent to randomly selected medical institutions in order to estimate the number of patients. We sent a secondary questionnaire to the same institutions to characterize the clinical manifestations and treatment of ASD.
RESULTS: The estimated prevalence of ASD was 3.9 per 100,000. Analysis of 169 patients showed a mean age at onset of 46 years. The main clinical symptoms were fever, arthritis, and typical rash in agreement with previous surveys. Oral glucocorticoids were used to treat 96% of the patients, while methotrexate was used in 41% and biological agents were used in 16%. Lymphadenopathy and macrophage activation syndrome were significantly associated with increased risk of relapse (P < 0.05, each). Patients who achieved remission after tocilizumab therapy had significantly longer disease duration (6.2 years) than patients who did not (1.9 years) (p < 0.05).
CONCLUSIONS: The 2010-2011 nationwide survey of ASD identified important changes in treatment and improvement of prognosis compared with previous surveys.

PMID 25382730  Mod Rheumatol. 2015 May;25(3):393-400. doi: 10.3109/143・・・
著者: M Yamaguchi, A Ohta, T Tsunematsu, R Kasukawa, Y Mizushima, H Kashiwagi, S Kashiwazaki, K Tanimoto, Y Matsumoto, T Ota
雑誌名: J Rheumatol. 1992 Mar;19(3):424-30.
Abstract/Text We have attempted to design classification criteria for adult Still's disease by analyzing the data obtained through a multicenter survey of 90 Japanese patients with this disease and of 267 control patients. The proposed criteria consisted of fever, arthralgia, typical rash, and leukocytosis as major, and sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and the absence of rheumatoid factor and antinuclear antibody as minor criteria. Requiring 5 or more criteria including 2 or more major criteria yielded 96.2% sensitivity and 92.1% specificity. However, an exclusion process will be needed for an accurate classification, since this disease is relatively rare.

PMID 1578458  J Rheumatol. 1992 Mar;19(3):424-30.
著者: A Ohta, M Yamaguchi, T Tsunematsu, R Kasukawa, H Mizushima, H Kashiwagi, S Kashiwazaki, K Tanimoto, Y Matsumoto, M Akizuki
雑誌名: J Rheumatol. 1990 Aug;17(8):1058-63.
Abstract/Text A comprehensive survey of Japanese patients with adult Still's disease was made by questionnaire which was sent to major institutions with rheumatology units in Japan. Of 146 cases from 32 institutions, 90 were judged to be definitely diagnosed as adult Still's disease. The major clinical features in these 90 patients consisted of high fever, polyarthralgia, rash, increased erythrocyte sedimentation rate, negative autoantibodies, leukocytosis, liver dysfunction, and hyperferritinemia. The incidence of several features showed significant differences between these cases and previous nonJapanese cases.

PMID 2213780  J Rheumatol. 1990 Aug;17(8):1058-63.
著者: A Ohta, M Yamaguchi, H Kaneoka, T Nagayoshi, M Hiida
雑誌名: J Rheumatol. 1987 Dec;14(6):1139-46.
Abstract/Text To clarify the clinical pictures of adult Still's disease, 228 cases reported in the past 15 years since Bywaters' first description were reviewed. These included our 9 new cases and an additional 25 cases from the Japanese literature, none of which had been described in previous English reviews. Most of the patients with long followup showed frequent recurrences. About one third developed deforming arthritis with ankylosis. There were 6 deaths. Of interest was the remarkably elevated levels of serum ferritin and prostaglandin E1 in some patients.

PMID 3325642  J Rheumatol. 1987 Dec;14(6):1139-46.
著者: B Fautrel, G Le Moël, B Saint-Marcoux, P Taupin, S Vignes, S Rozenberg, A C Koeger, O Meyer, L Guillevin, J C Piette, P Bourgeois
雑誌名: J Rheumatol. 2001 Feb;28(2):322-9.
Abstract/Text OBJECTIVE: To determine the usefulness of serum ferritin and glycosylated ferritin (GF) levels in diagnosing adult onset Still's disease (AOSD).
METHODS: We performed a retrospective multicenter study of 205 patients who had ferritin and GF assays in one hospital laboratory. Records of all patients were reviewed, and a standardized questionnaire used to extract all data available at the time of the assay. The clinicians' final diagnosis was also recorded. Patients were classified as having "certain AOSD" (based on Yamaguchi's criteria) or a control disease. The concordance of ferritin and GF levels with final diagnosis was evaluated.
RESULTS: In total 49 AOSD and 120 control patients were eligible. The mean ferritin value was significantly higher in the AOSD group (4,752 +/- 9,599 microg/l) than in the control group (1,571 +/- 3,807 microg/l), p = 0.029. GF was significantly lower in AOSD patients (15.9 +/- 11.9%) than in the control group (31.5 +/- 18.7%), p < 0.001. The combination of a GF level of < or = 20% with ferritin above the upper limit of normal yielded a sensitivity of 70.5% and specificity of 83.2%. The combination of a GF level < or = 20% with ferritin 5 times normal produced a sensitivity of 43.2% and specificity of 92.9%. This latter combination allowed an AOSD diagnosis to be ruled out for 6 of the 8 control patients who met Yamaguchi's positive criteria.
CONCLUSION: Ferritin and GF levels are powerful diagnostic markers of AOSD. They may be helpful in clinical practice for excluding differential diagnoses.

PMID 11246670  J Rheumatol. 2001 Feb;28(2):322-9.
著者: S S Desai, E Allen, A Deodhar
雑誌名: Rheumatology (Oxford). 2002 Feb;41(2):216-22.
Abstract/Text Adult-onset Still's disease (AOSD) is a multi-system inflammatory disorder characterized by high spiking fevers, evanescent salmon-coloured rash, arthralgias or arthritis, hepatosplenomegaly, lymphadenopathy and sore throat. There is no specific test or combination of tests that can establish the diagnosis of AOSD and patients may present with other systemic involvement including neurological manifestations in 7-12% of cases. We present a complex case of a patient with AOSD who developed the Miller-Fisher variant of Guillain-Barré syndrome. This immunological disorder of the nervous system has not been described in association with AOSD before. We also review the literature on other neurological manifestations in AOSD. AOSD mimics different disease processes and its multi-system manifestations may complicate the picture further.

PMID 11886973  Rheumatology (Oxford). 2002 Feb;41(2):216-22.
著者: A J Reginato, H R Schumacher, D G Baker, C R O'Connor, J Ferreiros
雑誌名: Semin Arthritis Rheum. 1987 Aug;17(1):39-57.
Abstract/Text
PMID 3306931  Semin Arthritis Rheum. 1987 Aug;17(1):39-57.
著者: P Bambery, R J Thomas, H S Malhotra, U Kaur, S R Bhusnurmath, S D Deodhar
雑誌名: Ann Rheum Dis. 1992 Apr;51(4):529-32.
Abstract/Text Over a 15 year period 18 patients (eight men, 10 women), 16-50 years old, were diagnosed as having adult onset Still's disease. Fever and arthralgia were always present but prominent lymphadenopathy was uncommon and the serosa were rarely affected. The typical rash of this disease was observed in nine patients. Several complications, including deforming arthritis, amyloidosis, granulomatous hepatitis, uveitis, scleritis, cutaneous vasculitis, and cardiomyopathy, were observed during follow up. Two patients were affected by a nosocomial infection during immunosuppressive treatment for uncontrolled disease. There were no characteristic features at necropsy. Ten patients had a monocyclic course that responded well to aspirin and indomethacin, whereas eight had a polycyclic pattern which invariably required treatment with corticosteroids. Serious complications developed exclusively in the latter group. This group of patients requires early, intensive disease modifying treatment.

PMID 1586255  Ann Rheum Dis. 1992 Apr;51(4):529-32.
著者: J Pouchot, J S Sampalis, F Beaudet, S Carette, F Décary, M Salusinsky-Sternbach, R O Hill, A Gutkowski, M Harth, D Myhal
雑誌名: Medicine (Baltimore). 1991 Mar;70(2):118-36.
Abstract/Text Clinical and laboratory manifestations, disease course, outcome, and HLA associations were studied in an inception cohort of 62 subjects with adult Still's disease (ASD) from 5 Canadian universities. Twenty-eight patients (45%) were female and the median age at disease onset was 24 years. In general, the clinical features observed in our patients were identical to those in other published series. However, significantly higher frequencies of sore throat (92%), weight loss (76%), lymphadenopathy (74%), pleuritis (53%), pneumonitis (27%), and abdominal pain (48%) were noted in our patients compared to those in a recent literature review. Liver involvement with hepatomegaly (44%) or abnormal liver function tests (LFTs) (76%) was common and was responsible for the 2 deaths attributed to Still's disease in our series. Severe liver failure always occurred in conjunction with aspirin or NSAID therapy. Therefore, whether or not aspirin or other NSAIDs are used, we recommend close monitoring of LFTs in patients with ASD, especially early in the disease course. Laboratory manifestations were similar to those already reported. Leukocytosis (greater than or equal to 15,000/mm3) was present in 50 patients (81%), a normochromic, normocytic anemia (hemoglobin less than or equal to 10 g/dl) in 42 (68%), and an elevated ESR in all. The mean follow-up of the 62 patients was 70 months (range, 2-163). Twenty-one patients (34%) had a self-limited disease course, 15 (24%) an intermittent course, and 22 (36%) a chronic disease course. Four patients (6%) died, and 2 of these deaths were attributed to Still's disease. For those patients who experienced a recurrence of ASD, the flares were usually of shorter duration and milder in severity than the initial episode. No initiating factor for disease exacerbation was identified in our patients. Although 22 of 62 patients (36%) had a chronic disease course, 52 (90%) were in ARA Functional Class I, and only 4 and 2 patients were in ARA Functional Class II and III, respectively. Patients with Still's disease had higher scores than the controls on the Pain (P less than 0.01) and Physical Disability (P less than 0.05) subscales of Arthritis Impact Measurement Scales health status questionnaire. Joint radiographs performed at the follow-up evaluation disclosed typical carpometacarpal and intercarpal involvement in 16 of 39 patients. In our series, HLA-B17, B18, B35, and DR2 were significantly associated with ASD. Three significant predictors of an unfavorable outcome, either a chronic disease course or a longer time to clinical remission, were identified.(ABSTRACT TRUNCATED AT 400 WORDS)

PMID 2005777  Medicine (Baltimore). 1991 Mar;70(2):118-36.
著者: J Cabane, A Michon, J M Ziza, P Bourgeois, O Blétry, P Godeau, M F Kahn
雑誌名: Ann Rheum Dis. 1990 May;49(5):283-5.
Abstract/Text Still's disease is a clinical entity of unknown origin, which can appear before 15 years of age (juvenile onset Still's disease) or later (adult onset Still's disease). There are few reported data about the long term prognosis of Still's disease and no study compares the long term evolution of adult onset and juvenile onset Still's disease. Eighteen patients fulfilling the American Rheumatism Association criteria for Still's disease were followed up for more than 10 years. Ten (group 1) had juvenile onset Still's disease and eight (group 2) adult onset Still's disease. A comparison of the groups showed no significant differences in the initial systemic manifestations of Still's disease, or in the joint lesions. Both groups had severe sequelae, which appeared between six and 10 years after the initial flare up of Still's disease. Nine patients had articular damage and nine had only arthritis without apparent x ray abnormalities. Nine patients had bilateral hip destruction in less than four years. Of these nine, seven required 13 total hip replacements before the age of 45. In the whole group of 18 patients bilateral involvement of the following joints was also seen: carpus (seven patients), knee (four), tarsus (four), ankle (three); three patients had ankylosis of the cervical spine. The occurrence of amyloidosis (three cases, two deaths) was restricted to group 2. This was the only difference between the groups, as the treatments were identical. It is concluded that the articular prognosis of Still's disease is poor, be it adult onset or juvenile onset, with severe joint destruction in half of the patients.

PMID 2344206  Ann Rheum Dis. 1990 May;49(5):283-5.
著者: B Godeau, C Leport, C Perronne, D Salmon-Ceron, J L Vilde, M F Kahn
雑誌名: Ann Rheum Dis. 1991 Dec;50(12):968.
Abstract/Text
PMID 1768176  Ann Rheum Dis. 1991 Dec;50(12):968.
著者: C Masson, X Le Loët, F Lioté, P Renou, J J Dubost, M C Boissier, L Brithmer, C Brégeon, M Audran
雑誌名: Rev Rhum Engl Ed. 1995 Dec;62(11):758-65.
Abstract/Text DESIGN: a multicenter study conducted in France identified 65 cases of adult Still's disease. Follow-up exceeded one year in 52 cases.
OBJECTIVES: were as follows: 1) to describe treatments used; 2) to analyze disease course patterns; 3) to study joint alterations; 4) to determine whether any characteristics present within the first six months of onset were of prognostic significance.
RESULTS: aspirin was ineffective. Indomethacin ensured satisfactory control in eight patients. Corticosteroid therapy was required in 88% of cases. Among patients followed up for more than one year, half developed radiologic joint alterations; 23% had monocyclic systemic disease, 38.5% had polycyclic systemic disease and 38.5% had chronic articular disease. More than half of the patients (58%) had more than one systemic flare. Polyarthritis at onset and involvement of the proximal limb joints were significantly predictive of chronic articular disease, whereas isolated arthralgia was predictive of monocyclic or polycyclic systemic disease. Oligoarthritis was not predictive of the outcome.
CONCLUSION: the knowledge that polyarthritis or proximal limb joint involvement within six months of onset is predictive of chronic joint disease may have important therapeutic implications.

PMID 8869217  Rev Rhum Engl Ed. 1995 Dec;62(11):758-65.
著者: B Fautrel, J Sibilia, X Mariette, B Combe, Club Rhumatismes et Inflammation
雑誌名: Ann Rheum Dis. 2005 Feb;64(2):262-6. doi: 10.1136/ard.2004.024026. Epub 2004 Jun 7.
Abstract/Text BACKGROUND: Consensus is lacking on treatment for corticosteroid resistant adult onset Still's disease (ASD).
OBJECTIVE: To assess anti-TNFalpha efficacy and tolerance in refractory ASD.
METHODS: All departments of rheumatology and internal medicine in France were contacted by mail to identify cases of refractory ASD for which anti-TNFalpha had been used. Medical information was collected using a standardised questionnaire.
RESULTS: Of 20 patients with mean age 40.7 years (range 18-74) at treatment start and mean disease duration 8.5 years (range 2-21), the clinical expression of ASD was predominantly systemic in five patients and polyarticular in 15. Response to corticosteroids and methotrexate had been considered inadequate in all patients. Infliximab was used to treat 15 patients, and etanercept used for 10; five had received both drugs consecutively. Steroids were concurrently used in 18 patients and an immunosuppressant in 17. At a mean (SD) follow up of 13 (14) months, complete remission had occurred in five cases (of 25 treatment sequences): one receiving etanercept and four infliximab. Partial response was observed in 16 cases (seven etanercept and nine infliximab). Treatment failed in four cases (two with each anti-TNFalpha). At the last visit, anti-TNFalpha therapy was discontinued in 17 cases, 11 times because of lack (or loss) of efficacy, four times because of a side effect, and twice for other reasons.
CONCLUSION: Anti-TNFalpha therapy may be helpful for some patients with refractory ASD. However, most patients achieve only partial remission. Additional information is thus needed to evaluate more precisely the risk-benefit ratio of this treatment.

PMID 15184196  Ann Rheum Dis. 2005 Feb;64(2):262-6. doi: 10.1136/ard.2・・・
著者: Yuko Kaneko, Hideto Kameda, Kei Ikeda, Tomonoti Ishii, Kosaku Murakami, Hyota Takamatsu, Yoshiya Tanaka, Takayuki Abe, Tsutomu Takeuchi
雑誌名: Ann Rheum Dis. 2018 Dec;77(12):1720-1729. doi: 10.1136/annrheumdis-2018-213920. Epub 2018 Oct 2.
Abstract/Text OBJECTIVE: To evaluate the efficacy and safety of tocilizumab, an interleukin-6 receptor antibody, in patients with adult-onset Still's disease.
METHODS: In this double-blind, randomised, placebo-controlled phase III trial, 27 patients with adult-onset Still's disease refractory to glucocorticoids were randomised to tocilizumab at a dose of 8 mg/kg or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients received open-label tocilizumab for 40 weeks subsequently. The primary outcome was American College of Rheumatology (ACR) 50 response at week 4. The secondary outcomes included ACR 20/50/70, systemic feature score, glucocorticoid dose and adverse events at each point.
RESULTS: In the full analysis set, ACR50 response at week 4 was achieved in 61.5% (95% CI 31.6 to 86.1) in the tocilizumab group and 30.8% (95% CI 9.1 to 61.4) in the placebo group (p=0.24). The least squares means for change in systemic feature score at week 12 were -4.1 in the tocilizumab group and -2.3 in the placebo group (p=0.003). The dose of glucocorticoids at week 12 decreased by 46.2% in the tocilizumab group and 21.0% in the placebo group (p=0.017). At week 52, the rates of ACR20, ACR50 and ACR70 were 84.6%, 84.6% and 61.5%, respectively, in both groups. Serious adverse events in all participants who received one dose of tocilizumab were infections, aseptic necrosis in the hips, exacerbation of adult-onset Still's disease, drug eruption and anaphylactic shock.
CONCLUSION: The study suggests that tocilizumab is effective in adult-onset Still's disease, although the primary endpoint was not met and solid conclusion was not drawn.

© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.
PMID 30279267  Ann Rheum Dis. 2018 Dec;77(12):1720-1729. doi: 10.1136/・・・
著者: Rie Suematsu, Akihide Ohta, Emi Matsuura, Hiroki Takahashi, Takao Fujii, Takahiko Horiuchi, Seiji Minota, Yoshiaki Ishigatsubo, Toshiyuki Ota, Shuji Takei, Sachiko Soejima, Hisako Inoue, Syuichi Koarada, Yoshifumi Tada, Kohei Nagasawa
雑誌名: Mod Rheumatol. 2012 Sep;22(5):712-9. doi: 10.1007/s10165-011-0569-6. Epub 2011 Dec 9.
Abstract/Text OBJECTIVE: The efficacy of biologics in treating adult Still's disease (ASD) is suggested, but the information is still lacking and the validation is insufficient. To determine the efficacy of several biologic agents in refractory ASD in Japan, a multicenter survey was performed.
METHOD: Clinical data on 16 ASD patients who had been treated with at least 1 of the biological agents (total 24 occasions) were collected retrospectively.
RESULTS: Infliximab was used in 9 cases, etanercept in 4, and tocilizumab in 11. Half of the patients that had been treated initially with infliximab or etanercept were changed to another biologics. Tocilizumab was effective in cases switched from another 2 drugs. Tocilizumab showed efficacy in treating both systemic and arthritic symptoms and showed apparent steroid-sparing effect and the highest continuation rate.
CONCLUSION: Tocilizumab may be a promising biologic agent in refractory ASD.

PMID 22160845  Mod Rheumatol. 2012 Sep;22(5):712-9. doi: 10.1007/s1016・・・
著者: B Fautrel, C Borget, S Rozenberg, O Meyer, X Le Loët, C Masson, A C Koeger, M F Kahn, P Bourgeois
雑誌名: J Rheumatol. 1999 Feb;26(2):373-8.
Abstract/Text OBJECTIVE: Adult Still's disease (ASD) is a rare chronic polyarthritis, usually treated with corticosteroid therapy. Because some patients become dependent on high dose prednisone or are refractory to that treatment, and because adverse events are frequent with corticosteroid, we evaluated the efficacy of low dose methotrexate (MTX) as a second-line drug.
METHODS: We retrospectively studied 26 patients with ASD treated with low dose MTX because their disease was either resistant to or dependent on corticosteroids.
RESULTS: The group included 13 women and 13 men, with a mean age of 32.6 years at onset of ASD. Mean disease duration at the beginning of MTX treatment was 59.9 mo (range 7 to 444). Evaluation took place at the maximum followup, which averaged 48.9 mo (range 8 to 136). The mean dose of MTX was 11.5+/-3.6 mg/week (range 7.5 to 17.5). Twenty-three patients responded to MTX; 18 had complete remission. No difference was seen between patients with or without extraarticular manifestations. Leukocyte and neutrophil counts and erythrocyte sedimentation rate were significantly reduced (p = 0.0001). Daily prednisone intake decreased by 69% (21.5 mg) (p = 0.0001). Eleven patients were able to stop taking corticosteroids. One patient with AA amyloidosis renal failure died of neutropenia: this was the only serious adverse event.
CONCLUSION: MTX is an effective second-line treatment of ASD that does not respond to prednisone. It allows significant reduction of corticosteroid doses, which is beneficial to these patients, who have frequent and numerous corticosteroid related adverse events.

PMID 9972972  J Rheumatol. 1999 Feb;26(2):373-8.
著者: Mio Mitamura, Yoshifumi Tada, Syuichi Koarada, Hisako Inoue, Rie Suematsu, Akihide Ohta, Kohei Nagasawa
雑誌名: Mod Rheumatol. 2009;19(1):57-63. doi: 10.1007/s10165-008-0126-0. Epub 2008 Oct 7.
Abstract/Text For over 10 years there have been no clinical studies about adult-onset Still's disease (AOSD) in Japan. We aimed to investigate recent clinical features and treatment of AOSD and to evaluate the efficacy of cyclosporin A (CyA) in the treatment of AOSD. The data from 34 patients with AOSD who were admitted to our hospital between 1994 and 2007 were analyzed retrospectively. Of several immunosuppressive agents, the efficacy of CyA given to seven patients was precisely evaluated. Clinical features observed in this study did not differ from those in our previous study, and serum ferritin levels were elevated in all the patients. Among immunosuppressive agents CyA, used concomitantly with corticosteroids (CS) for seven patients with severe AOSD, proved to be very effective. The disease was led to remission promptly by CyA in six patients, and all the patients except one experienced no recurrence. These results suggest that CyA can be one of the potent candidates to be used next to CS for patients with AOSD that is resistant to CS.

PMID 18839270  Mod Rheumatol. 2009;19(1):57-63. doi: 10.1007/s10165-00・・・

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