DMARDs

抗リウマチ薬

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/02/21 21:33:43」(JST)

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Methotrexate

Hydroxychloroquine

Auranofin, a gold salt

Disease-modifying antirheumatic drugs (DMARDs) is a category of otherwise unrelated drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to non-steroidal anti-inflammatory drug (which refers to agents that treat the inflammation but not the underlying cause) and steroids (which blunt the immune response but are insufficient to slow down the progression of the disease).

The term "antirheumatic" can be used in similar contexts, but without making a claim about an effect on the course.

Terminology

Although their use was first propagated in rheumatoid arthritis (hence their name) the term has come to pertain to many other diseases, such as Crohn's disease, lupus erythematosus (SLE), Sjogren's Syndrome, immune thrombocytopenic purpura (ITP), myasthenia gravis, sarcoidosis and various others. Many of these are autoimmune disorders, but others, such as ulcerative colitis, are probably not (there is no consensus on this).

The term was originally introduced to indicate a drug that reduced evidence of processes thought to underlie the disease, such as a raised erythrocyte sedimentation rate, reduced haemoglobin level, raised rheumatoid factor level and more recently, a raised C-reactive protein level. More recently, the term has been used to indicate a drug that reduces the rate of damage to bone and cartilage. DMARDs can be further subdivided into traditional small molecular mass drugs synthesised chemically and newer 'biological' agents produced through genetic engineering.

Some DMARDs (e.g. the Purine synthesis inhibitors) are mild chemotherapeutics but use a side-effect of chemotherapy - immunosuppression - as its main therapeutical benefit.

Members

Drug	Mechanism
abatacept	T-cell costimulatory signal inhibitor
adalimumab	TNF inhibitor
azathioprine	Purine synthesis inhibitor
chloroquine and hydroxychloroquine (antimalarials)	Suppression of IL-1 & TNF-alpha, induce apoptosis of inflammatory cells and decrease chemotaxis
ciclosporin (Cyclosporin A)	calcineurin inhibitor
D-penicillamine	Reducing numbers of T-lymphocytes etc.
etanercept	decoy TNF receptor
golimumab	TNF inhibitor
gold salts (sodium aurothiomalate, auranofin)	unknown
infliximab	TNF inhibitor
leflunomide	Pyrimidine synthesis inhibitor
methotrexate (MTX)	Purine metabolism inhibitor
minocycline	5-LO inhibitor
rituximab	chimeric monoclonal antibody against CD20 on B-cell surface
sulfasalazine (SSZ)	Suppression of IL-1 & TNF-alpha, induce apoptosis of inflammatory cells and increase chemotactic factors

Although these agents operate by different mechanisms, many of them can have similar impact upon the course of a condition.

Some of the drugs can be used in combination.

Alternatives

When treatment with DMARDs fails, cyclophosphamide or steroid pulse therapy is often used to stabilise uncontrolled autoimmune disease. Some severe autoimmune diseases are being treated with bone marrow transplants in clinical trials, usually after cyclophosphamide therapy has failed.Furthermore, should DMARDs fail, tocilizumab can be used for tumor necrosis factor(TNF) inhibitor treatments in NICE guidance.

Combinations of DMARDs are often used together, because each drug in the combination can be used in smaller dosages than if it were given alone, thus reducing the risk of side effects.

Many patients receive an NSAID and at least one DMARD, sometimes with low-dose oral glucocorticoids. If disease remission is observed, regular NSAIDs or glucocorticoid treatment may no longer be needed. DMARDs help control arthritis but do not cure the disease. For that reason, if remission or optimal control is achieved with a DMARD, it is often continued at a maintenance dosage. Discontinuing a DMARD may reactivate disease or cause a “rebound flare”, with no assurance that disease control will be reestablished upon resumption of the medication.

References

UpToDate Contents

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• 1. リウマチ性疾患における免疫抑制剤および疾患修飾剤の使用の概要 overview of the use of immunosuppressive and disease modifying drugs in the rheumatic diseases
• 2. 患者情報：疾患修飾抗リウマチ薬（DMARDs）（詳細） disease modifying antirheumatic drugs dmards beyond the basics
• 3. 成人における初回の抗リウマチ薬（DMARD）治療に抵抗性の活動性関節リウマチに対する治療 treatment of rheumatoid arthritis resistant to initial dmard therapy in adults
• 4. 成人における関節リウマチのマネージメントの一般的原則 general principles of management of rheumatoid arthritis in adults
• 5. 成人における中等度～重度の活動性関節リウマチの初期治療 initial treatment of moderately to severely active rheumatoid arthritis in adults

English Journal

• Mast cell mediators cause early allergic bronchoconstriction in guinea-pigs in vivo: a model of relevance to asthma.

• Riley JP, Fuchs B, Sjöberg L, Nilsson GP, Karlsson L, Dahlén SE, Rao NL, Adner M.SourceJanssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.
• Clinical science (London, England : 1979).Clin Sci (Lond).2013 Dec;125(11):533-42. doi: 10.1042/CS20130092.
• One feature of allergic asthma, the EAR (early allergic reaction), is not present in the commonly used mouse models. We therefore investigated the mediators involved in EAR in a guinea-pig in vivo model of allergic airway inflammation. Animals were sensitized using a single OVA (ovalbumin)/alum inje
• PMID 23799245

• The cost-effectiveness of TNF-inhibitors for the treatment of rheumatoid arthritis in Swedish clinical practice.

• Lekander I, Borgström F, Lysholm J, van Vollenhoven RF, Lindblad S, Geborek P, Kobelt G.SourceLIME/MMC, Karolinska Institute, Stockholm, Sweden, ingrid.lekander@ki.se.
• The European journal of health economics : HEPAC : health economics in prevention and care.Eur J Health Econ.2013 Dec;14(6):863-73. doi: 10.1007/s10198-012-0431-6. Epub 2012 Sep 19.
• OBJECTIVE: The objective was to estimate the cost-effectiveness of TNF-inhibitors for the treatment of rheumatoid arthritis in Swedish clinical practice, both as a first and second biological treatment, with or without the combination of conventional DMARDs. Further sub-group analysis of etanercept
• PMID 22990378

• Efficacy of biological agents in juvenile idiopathic arthritis: a systematic review using indirect comparisons.

• Otten MH, Anink J, Spronk S, van Suijlekom-Smit LW.SourceDepartment of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.
• Annals of the rheumatic diseases.Ann Rheum Dis.2013 Nov 1;72(11):1806-12. doi: 10.1136/annrheumdis-2012-201991. Epub 2012 Nov 21.
• OBJECTIVE: Over the past decade, the availability of biological agents for the treatment of juvenile idiopathic arthritis (JIA) has increased substantially. Because direct head-to-head trials comparing these agents are lacking, we indirectly compared their efficacy.METHODS: In a systematic review, a
• PMID 23172748

Japanese Journal

• 巨大な多発リウマチ結節を認めたコントロール不良の一例

• 栗之丸 直朗,峯 孝友,伊原 公一郎,河村 洋行,伊達 亮,梅原 渓太郎,生田 弘文
• 整形外科と災害外科 61(4), 811-814, 2012-09-25
• NAID 10031013923

• 関節リウマチの薬物療法(2)DMARDs (特集 関節リウマチに対する新しい治療戦略 : 新分類基準・ガイドラインに基づいて)

• 西村 慶太
• 整形・災害外科 55(10), 1203-1209, 2012-09
• NAID 40019427452

• Treatment discontinuation in patients with very early rheumatoid arthritis in sustained simplified disease activity index remission after synthetic disease-modifying anti-rheumatic drug administration

• KITA Junko,TAMAI Mami,ARIMA Kazuhiko,NAKASHIMA Yoshikazu,SUZUKI Takahisa,KAWASHIRI Shin-ya,IWAMOTO Naoki,OKADA Akitomo,KOGA Tomohiro,YAMASAKI Satoshi,NAKAMURA Hideki,ORIGUCHI Tomoki,IDA Hiroaki,AOYAGI Kiyoshi,UETANI Masataka,EGUCHI Katsumi,KAWAKAMI Atsushi
• Modern rheumatology 22(3), 346-352, 2012-06-01
• NAID 10030782090

Related Links

• DMARDs - 薬学用語解説 - 日本薬学会

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• Disease-modifying antirheumatic drugs (DMARDs)

Disease-modifying antirheumatic drugs (DMARDs) are a group of medications commonly used in patients with rheumatoid arthritis. They work to decrease pain and inflammation, to reduce or prevent joint damage, and to preserve the ...

Related Pictures

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★リンクテーブル★

リンク元	「100Cases 27」

「100Cases 27」

　　[★]

☆case27　関節痛

■症例

37歳　女性

主訴：関節痛

現病歴：数ヶ月、膝の痛みがだんだん強くなっていると感じていた。痛みは手や足の小関節に多く、朝歩くときに最もこわばる。痛みはジクロフェナクを飲むと和らぐ。そのほかの症状として疲労感を感じ、最近、体重が３ヶ月で４ｋｇ減っている。

喫煙歴：なし。

飲酒歴：機会飲酒

既往歴：なし

家族歴：既婚、子供は２人

服薬歴：ジクロフェナク

職業歴：legal sevretary

身体所見 examination

　顔貌　青白、臨床的な貧血を認める。近位指節間関節・中手指節関節　腫脹・effusionを伴う疼痛。中足趾節関節　圧痛。それ以外は正常。

検査　investigation

　血液検査

　　Hb低下

　　ESR上昇

　　尿素軽度上昇

　　クレアチニン軽度上昇

　　正常：白血球、MCV、血小板、ナトリウム、カリウム、グルコース、アルブミン

　尿検査

　　蛋白(-)、尿糖(-)、潜血(-)、

■問題

　本症例では診断とその根拠を考えるのは簡単なので、鑑別疾患をあげてその疾患に特徴的な症候を列挙しましょう。

■関節痛 DIF.283

　V Vascular

　　血友病 hemophilia　血友病性関節症(急性：疼痛、腫脹、熱感(SOR.241)

慢性：可動域の低下、変形、関節周囲筋萎縮(SOR.241))。家族歴

　　壊血病 scurvy　。生活環境。食事歴

　　無菌性骨壊死 aseptic bone necrosis (Osgood-Schlatter diseaseとか)

　I Inflammatory

　　感染性関節炎(細菌性関節炎(化膿性関節炎・淋菌性関節炎・結核性関節炎・嫌気性菌関節炎 )、真菌性関節炎、スピロヘータ関節炎(梅毒性関節炎・ライム関節炎)、マイコプラズマ関節炎、ウイルス性関節炎)

　N Neoplastic disorders

　　骨原性肉腫 osteogenic sarcoma

　　巨細胞腫 giant cell tumors

　D Degenerative disorders

　　degenerative joint disease

　　変形性関節症 osteoarthritis

　I Intoxication

　　痛風 gout (uric acid)

　　偽痛風 pseudogout (calcium pyrophosphate)

　　ループス症候群 lupus syndrome of hydralazine (Apresoline) and procainamide

　　gout syndrome of diuretics

　C Congenital and acquired malformations bring to mind the joint deformities of tabes dorsalis and syringomyelia and congenital dislocation of the hip. Alkaptonuria is also considered here.

　A Autoimmune indicates

　　関節リウマチ RA

　　血清病 serum sickness

　　全身性エリテマトーデス lupus erythematosus

　　リウマチ熱 rheumatic fever

　　ライター症候群 Reiter syndrome

　　潰瘍性大腸炎 ulcerative colitis

　　クローン病=限局性回腸炎 regional ileitis

　　乾癬性関節炎 psoriatic arthritis

　　リウマチ性多発筋痛症 polymyalgia rheumatica

　T Trauma

　E Endcrine

　　先端肥大症 acromegaly

　　閉経 menopause

　　糖尿病 diabetes mellitus

■関節炎の分類

・炎症部位の数

　単関節炎：痛風、偽痛風、離断性骨軟骨炎、血行性の化膿性関節炎のほとんど

　多関節炎：リウマチ性疾患、ウイルス性疾患、白血病での関節症状、易感染性宿主における血行性の化膿性関節炎

■関節リウマチ

　診断基準

　関節症状

　　朝のこわばり、疼痛、腫脹、関節の動揺、関節可動域制限、変形(手指、足趾、膝関節)。(SOR.211)

　　手指の近位指節間関節(PIP関節)、中手指節関節(MP関節)。遠位指節間関節(DIP関節)に初発することは稀。(SOR.211)

　　左右対称性に生じることが多い。手関節、足趾、膝関節に初発する。(SOR.211)

　関節外症状

　　全身症状：発熱

　　皮膚症状：リウマトイド結節(肘の伸側、後頭部、手指)

　　眼症状：上胸膜炎(10日の経過で治癒)、強膜炎(予後不良)。稀に角膜穿孔

　　血液障害：(高頻度)貧血、白血球減少(Felty病。DMARDs投与中の場合は薬剤性の骨髄抑制を考慮)

　　アミロイドーシス：ネフローゼや下痢を来した症例で疑う。アミロイド蛋白はAA

　　腎障害：稀。アミロイドーシスの続発症か薬剤性を考慮。

　　呼吸器症状：間質性肺炎の合併多い。下肺野に好発。通常無症状。メトトレキセートなどの使用により薬剤性の急性間質性肺炎を生じることがある。

　　心・血管障害：リンパ管炎による難治性の浮腫。

　　神経症状：環軸関節亜脱臼により項部痛や脊髄症上が出現しうる。

　　骨粗鬆症

　　腱鞘滑膜炎：手指、手関節、足関節

■両側性多関節炎の鑑別疾患

　OA：遠位指節間関節を冒すのが特徴的で、近位指節間関節、中手指節関節を冒しうる。

　RA：

　SLE：軽度、症状の程度が変動する非びらん性の関節炎

　gout：単関節炎からはじまる。

　血清陰性関節炎：強直性脊椎炎、感染、ライター病：中～大関節に非対称性の関節炎。仙腸関節と遠位指節間関節にも関節炎

　急性ウイルス性関節炎：風疹。

■KEY POINTS

・RAでは遠位指節間関節は冒されない傾向がある。

・RAの全身症状は関節症状に先行することがある。

・RAの活動性と貧血及びESRは相関している。

・NSAIDsは腎機能に悪影響を与えることがある。

■initial plan

　Dx 1. 単純X線写真

　　　　・亜脱臼、関節周囲の骨萎縮(傍関節性骨骨粗鬆症,juxta-articular osteoporosis)、関節裂隙の狭小化、関節辺縁のびらん(bony erosion)

　　　　　・初期のRAで第5趾に骨びらんが一般的に見られる。

　　　　・血液検査

　　　　　・RF、抗DNA抗体

　Tx 1. 鎮痛薬

　　　　・NSAIDs：鎮痛とこわばりの軽減

　　 2. DMARDs(メトトレキセート、レフルノミド、金製剤、ペニシラミン)

　　　　・NSAIDsで症状が治まらない場合に考慮

　　 3. 抗TNF抗体

　　　　・重症のRAで効果がある場合がある。

■参考文献

SOR　標準整形外科学 第10版 医学書院

DIF　Differential Diagnosis in Primary Care Fourth Edition版 Lippincott Williams & Wilkins