関節リウマチに続発するAAアミロイドーシスの現況と課題  [in Japanese] A review for recent advances in AA amyloid research and therapeutic approach to AA amyloidosis complicating rheumatoid arthritis  [in Japanese]

  関節リウマチ（RA）などの慢性炎症性疾患に続発するAAアミロイドーシスは，難溶性の線維性蛋白（アミロイド線維）が細胞外に沈着して様々な臓器の機能障害を引き起こす予後不良の病態である．近年，そのポリペプチド鎖の三次元構造を規定するfoldingの異常とアミロイド蛋白の難溶化・組織沈着の関連が明らかにされ，アミロイドーシスは“Conformation Disease”として認識されるようになった．またアミロイド蛋白の前駆体である血清アミロイドA蛋白（SAA）の遺伝子多型と疾患感受性，炎症性サイトカイン依存性のSAA産生メカニズムについても解明されつつある．臨床的にも血清SAA濃度と組織のアミロイド沈着の程度，さらには疾患の予後との関連性も明らかにされ，SAAの量的制御が重要な治療戦略の一つとなっている．これまで様々な治療が試みられてきたが，最も有効性が高いと考えられる治療法は，RA治療に広く用いられるようになった抗サイトカイン療法である．特にSAA発現に深く関与していると考えられるIL-6作用を効果的に阻止しえる抗IL-6受容体抗体を用いた治療はAAアミロイドーシスの画期的治療法となる可能性があり，注目に値する．

  AA amyloidosis is a life threatening clinical complication of chronic inflammatory diseases such as rheumatoid arthritis. It has been demonstrated biochemically that amyloidosis resulted from abnormal folding of proteins, which are deposited as insoluble fibrils in extracellular tissue, leading to the disruption of their normal function. In this regard, amyloidosis has been recognized as a conformation disorder. Interestingly, genetic polymorphisms of amyloid precursor protein (SAA) have been reported to associate with increased risk for AA amyloidosis. Also recent biochemical research revealed that SAA is synthesized under the influence of the proinflammatory cytokines, such as IL-6, TNF-α, IL-1. Additionally, it was suggested that amyloid deposits in extracellurar tissue could reflect to the serum level of SAA in the reversible fashion, leading to the hypothesis that the control of the SAA synthesis could be beneficial to the treatment of amyloidosis. In this context, anti-cytokine therapies may be most effective. Especially the inhibition of IL-6 is critical to suppression of SAA production, so treatment with a humanized monoclonal antibody against human IL-6 receptor may not only ameliorate RA disease activity but also pave the way for the treatment of AA amyloidosis.