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消化管アミロイドーシス

著者: 蔵原晃一 松山赤十字病院 胃腸センター(消化管内科)

著者: 池上幸治 松山赤十字病院 胃腸センター(消化管内科)

監修: 上村直実 国立国際医療研究センター 国府台病院

著者校正/監修レビュー済:2022/09/28
患者向け説明資料

概要・推奨   

  1. 消化管アミロイドーシスは増加傾向にあり、特に慢性関節リウマチによるAAアミロイドーシスと透析アミロイドーシスは頻度が高い(推奨度2)
  1. アミロイド型別に消化管病変の臨床病理学的特徴を理解することは診断と治療を進めるうえで重要である(推奨度2)
  1. アミロイドーシスは難治性進行性であり、根本治療ができなければ消化器症状に応じた対症療法が必要となる(推奨度2)
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  1. 透析アミロイドーシスは透析中に増加するß2MGが前駆蛋白となり発症し、血中ß2MG値、透析期間、患者年齢が発症の危険因子である。長期透析患者で特有な骨関節症状が出現したら本症を疑うことが重要である(推奨度1)
  1. 生体適合性のよい透析膜の選択や透析液の清浄化、血液透析濾過などの透析方法が発症予防に有効である。ß2MG吸着カラムは症状を緩和し進行を抑制する効果がある(推奨度2)
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。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※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、実際の保険適応の査定において保険適応及び保険適応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応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:
蔵原晃一 : 未申告[2022年]
池上幸治 : 未申告[2022年]
監修:上村直実 : 未申告[2022年]

改訂のポイント:
  1. 定期レビューを行い、2020年版 心アミロイドーシス診療ガイドラインの情報を補足し、また用語を一部変更した。

病態・疫学・診察

疾患情報(疫学・病態)  
ポイント:
  1. アミロイドーシスは異常なアミロイド線維蛋白が全身諸臓器に沈着して、種々の機能障害を生じる疾患群の総称である。消化管アミロイドーシスとは、消化管にアミロイドが沈着し、吸収不良やそれに伴う便通異常などの症状を呈した状態のことである。
 
主要な臨床病型:
  1. 厚生労働省特定疾患調査研究班では診療ガイドラインを作成し[1]、全身諸臓器にアミロイドが沈着する全身性と、特定臓器のみに沈着する限局性に大別し、さらにアミロイド前駆蛋白に対応する臨床病型に分類している。
 
アミロイドーシスの分類(厚生労働省特定疾患調査研究班新分類から改変)

全身諸臓器にアミロイドが沈着する全身性と、特定臓器のみに沈着する限局性に大別し、さらにアミロイド前駆蛋白に対応する臨床病型に分類している。

 
  1. 特に、①ALアミロイドーシス(AL型)、②AAアミロイドーシス(AA型)、③FAP:家族性アミロイドポリニューロパチー(ATTR型)、④透析アミロイドーシス(Aß2M型)――が主要な臨床病型である。
  1. 原因不明の原発性と骨髄腫に伴うアミロイドーシスはAL型であり、基礎疾患のある続発性の多くはAA型反応性アミロイドーシスである。消化管アミロイドーシスは増加傾向にある。
  1. 消化管へのアミロイド沈着は病型に応じた特徴があり[2]、さまざまな消化器症状を呈する。
 
  1. 消化管アミロイドーシスは増加傾向にあり、特に慢性関節リウマチによるAAアミロイドーシスと透析アミロイドーシスは頻度が高い(推奨度2O)
  1. まとめ:厚生労働省研究班の疫学研究により、全身性アミロイドーシスは年々増加傾向にあることが報告されている[1]
  1. 代表事例:1983年までの調査で死亡率は人口10万人当たり約0.1と推定されている。1991年の日本病理剖検輯報にて全身性アミロイドーシスの剖検数は302例で、剖検総数に対する比率は0.83%であった。内訳はAAアミロイドーシス113例(37%)、原発性ALアミロイドーシス85例(28%)、骨髄腫などに伴うALアミロイドーシス66例(22%)の順に多い[1]。1991年のわが国疫学調査による年間推定患者数では、原発性ALアミロイドーシス300人、骨髄腫などに伴うALアミロイドーシス200人、家族性アミロイドーシス140人、透析アミロイドーシス700人であった。AA型の基礎疾患として結核など感染症は減少し、最近では関節リウマチが90%以上を占めている。関節リウマチに対する治療の進歩により、生検にてアミロイドーシスを認める頻度は6~8%と減少傾向にはあるが[3]、2010年の統計で関節リウマチの全国罹患者数は70万人にも達している。
  1. 結論:以上よりアミロイドーシスは増加しており、特に関節リウマチによるAAアミロイドーシスと透析アミロイドーシスに注意が必要である。
  1. 追記:アミロイドーシスの疫学
 
  1. アミロイド型別に消化管病変の臨床病理学的特徴を理解することは診断と治療を進めるうえで重要である(推奨度2O)
  1. まとめ:アミロイド蛋白に応じた特異的な沈着様式により、アミロイド型別に特徴的な消化管病変と臨床病理像が報告されている[2][4]
  1. 代表事例:AA型アミロイドは粘膜固有層と粘膜下層に顆粒状の沈着が特徴的で生検陽性率も高い。粘膜はびまん性に微細な顆粒状隆起が多発する。<図表>神経障害や平滑筋障害は軽く、腸管浮腫のため急性の偽性腸閉塞を生じても中心静脈栄養による腸管安静で軽快する場合が多い。AL型は粘膜筋板と粘膜下層から固有筋層へ塊状に沈着する。このため大小不同の皺襞肥厚と多発する軽度黄白色調の粘膜下腫瘤様隆起を形成する特徴がある(<図表>)。平滑筋障害による腸管の運動障害のため、悪心・嘔吐や偽性腸閉塞が出現しやすい。沈着が高度に限局するとアミロイド腫瘤(アミロイドーマ)となり腸管を閉塞する。血管壁の沈着により腸管に多発潰瘍や特異な粘膜内血腫を形成する例がある。<図表>2M型では粘膜固有層への沈着は乏しく、固有筋層へびまん性の沈着が出現する。このため腸管は拡張するが粘膜変化は乏しく生検陽性率は低い。血管周囲の沈着が高度となり、虚血性腸病変による出血、梗塞、穿孔を生じることがある。ATTR型では粘膜固有層や固有筋層への沈着は少ないが、高度の神経組織への沈着により消化管自律神経障害と運動障害が出現する。
  1. 結論:以上のようなアミロイド型別に消化管病変の臨床病理学的特徴を理解する必要がある。
  1. 追記:アミロイド型別消化管病変の臨床病理学的特徴
 
AA型アミロイドの特徴:
  1. AA型アミロイドは粘膜固有層と粘膜下層に顆粒状の沈着が特徴的で十二指腸粘膜からの生検陽性率も高い。なお、粘膜はびまん性に微細な顆粒状隆起が多発する。
  1. 神経障害や平滑筋障害は軽く、腸管浮腫のため急性の偽性腸閉塞を生じても中心静脈栄養による腸管安静で軽快する場合が多い。
 
AAアミロイドーシスの十二指腸内視鏡所見

AA型では粘膜固有層へのびまん性アミロイド沈着による粘膜の微細顆粒状所見が特徴である
a:通常観察像
b:色素散布像

出典

img1:  檜沢一興先生ご提供
 
 
 
AL型アミロイドの特徴:
  1. AL型は粘膜筋板と粘膜下層から固有筋層へ塊状に沈着する。このため大小不同の皺襞肥厚と多発する軽度黄白色調の粘膜下腫瘤様隆起を形成する特徴がある。平滑筋障害による腸管の運動障害のため、悪心・嘔吐や偽性腸閉塞が出現しやすい。沈着が高度に限局するとアミロイド腫瘤(アミロイドーマ)となり腸管を閉塞する。血管壁の沈着により腸管に多発潰瘍や特異な粘膜内血腫を形成する例がある。
 
ALアミロイドーシスの十二指腸内視鏡所見

AL型では粘膜下層への塊状アミロイド沈着による多発粘膜下腫瘤様隆起と皺襞肥厚が特徴である
a:通常観察像
b:色素散布像

出典

img1:  檜沢一興先生ご提供
 
 
 
ALアミロイドーシスの大腸内視鏡所見

血管壁への高度沈着により消化管内に多発潰瘍や特異な粘膜内血腫を形成する例がある
a:横行結腸の多発潰瘍
b:潰瘍口側の粘膜下血腫

出典

img1:  檜沢一興先生ご提供
 
 
 
2M型の特徴:
  1. 2M型では粘膜固有層への沈着は乏しく、固有筋層へびまん性の沈着が出現する。このため腸管は拡張するが粘膜変化は乏しく生検陽性率は低い。血管周囲の沈着が高度となり、虚血性腸病変による出血、梗塞、穿孔を生じることがある。
 
ATTR型の特徴:
  1. ATTR型では粘膜固有層や固有筋層への沈着は少ないが、高度の神経組織への沈着により消化管自律神経障害と運動障害が出現する。また、生検でも粘膜下層までしっかり採取することで消化管病変の評価は可能である。
問診・診察のポイント  
  1. 患者の多彩な症候から本症を疑うことが診断の第一歩であり、問診と診察がきわめて重要である。

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文献 

Abstract/Text A clinicopathologic study was made of 16 patients with amyloidosis and with clinical signs of intestinal pseudo-obstruction. amyloid deposits in the small intestine were proved in all cases by endoscopic or intra-operative biopsies, and immunohistochemical study identified the chemical types of amyloid protein: amyloid A protein (AA) in 13 cases, light chain protein (AL) in two, and beta 2-microglobulin (AH) in one. Clinically, an acute self limiting obstructive condition was evident in 13 cases with AA, and 12 of them returned to normal bowel function after receiving total parenteral nutrition. Two cases with AL and one with AH presented chronic, intermittent, obstructive symptoms, and medical treatment, including total parenteral nutrition, was ineffective with no recovery of intestinal propulsion. Pathological examination of the necropsy specimens in seven cases showed considerable differences in the preferential sites of gastrointestinal deposits between the chemical types of amyloid; extensive infiltration and replacement of the muscularis propria by amyloid deposits throughout the gastrointestinal tract, especially the small intestine, were found in the AL and the AH cases, while amyloid deposits in the myenteric plexus without appreciable muscle infiltration were shown in the AA cases. These results show that intestinal pseudo-obstruction in patients with amyloidosis is caused by either myopathy or neuropathy, and that chemical types of amyloid may determine which of the two factors has the dominant affect on the bowel function.

PMID 8244111
Helen J Lachmann, Hugh J B Goodman, Janet A Gilbertson, J Ruth Gallimore, Caroline A Sabin, Julian D Gillmore, Philip N Hawkins
Natural history and outcome in systemic AA amyloidosis.
N Engl J Med. 2007 Jun 7;356(23):2361-71. doi: 10.1056/NEJMoa070265.
Abstract/Text BACKGROUND: Deposition of amyloid fibrils derived from circulating acute-phase reactant serum amyloid A protein (SAA) causes systemic AA amyloidosis, a serious complication of many chronic inflammatory disorders. Little is known about the natural history of AA amyloidosis or its response to treatment.
METHODS: We evaluated clinical features, organ function, and survival among 374 patients with AA amyloidosis who were followed for a median of 86 months. The SAA concentration was measured serially, and the amyloid burden was estimated with the use of whole-body serum amyloid P component scintigraphy. Therapy for inflammatory diseases was administered to suppress the production of SAA.
RESULTS: Median survival after diagnosis was 133 months; renal dysfunction was the predominant disease manifestation. Mortality, amyloid burden, and renal prognosis all significantly correlated with the SAA concentration during follow-up. The risk of death was 17.7 times as high among patients with SAA concentrations in the highest eighth, or octile, (>or=155 mg per liter) as among those with concentrations in the lowest octile (<4 mg per liter); and the risk of death was four times as high in the next-to-lowest octile (4 to 9 mg per liter). The median SAA concentration during follow-up was 6 mg per liter in patients in whom renal function improved and 28 mg per liter in those in whom it deteriorated (P<0.001). Amyloid deposits regressed in 60% of patients who had a median SAA concentration of less than 10 mg per liter, and survival among these patients was superior to survival among those in whom amyloid deposits did not regress (P=0.04).
CONCLUSIONS: The effects of renal dysfunction dominate the course of AA amyloidosis, which is associated with a relatively favorable outcome in patients with SAA concentrations that remain in the low-normal range (<4 mg per liter).

Copyright 2007 Massachusetts Medical Society.
PMID 17554117
S Tada, M Iida, T Yao, K Kawakubo, T Yao, M Okada, M Fujishima
Endoscopic features in amyloidosis of the small intestine: clinical and morphologic differences between chemical types of amyloid protein.
Gastrointest Endosc. 1994 Jan-Feb;40(1):45-50.
Abstract/Text Thirty patients with amyloidosis of the small intestine were studied to determine the correlations between the chemical types of amyloid protein and endoscopic, histologic, or clinical features. Endoscopic examinations of the jejunum revealed various findings such as a fine granular appearance, erosions and mucosal friability, thickening of the valvulae conniventes, and multiple polypoid protrusions in 23 cases. Immunohistochemical study of the biopsy specimens identified the following chemical types of amyloid protein: amyloid A protein (AA) in 20 cases, light chain protein (AL) in 8, beta 2-microglobulin (AH) in 1, and prealbumin (AF) in 1. The fine granular appearance was found significantly more often in the AA cases (p < 0.001), whereas multiple polypoid protrusions and thickening of the valvular conniventes were observed only in the AL cases (p < 0.001). Histologically, wide granular amyloid deposits in the propria mucosae were seen significantly more often in the AA cases (p < 0.01), whereas massive amyloid deposits in the muscularis mucosae, submucosa, and muscularis propria were the more dominant findings in the AL cases (p < 0.001). Clinically, a more frequent occurrence of diarrhea, malabsorption, and occult blood in stools was present in the AA cases, whereas mechanical obstruction and chronic intestinal pseudo-obstruction were evident only in the AL and the AH cases. These results suggest that clinicopathologic differences between the amyloid proteins exist in small intestinal amyloidosis and that endoscopic appearance relates to the specific accumulation pattern of each type of amyloid protein.

PMID 8163134
H Kobayashi, S Tada, T Fuchigami, Y Okuda, K Takasugi, T Matsumoto, M Iida, K Aoyagi, A Iwashita, Y Daimaru, M Fujishima
Secondary amyloidosis in patients with rheumatoid arthritis: diagnostic and prognostic value of gastroduodenal biopsy.
Br J Rheumatol. 1996 Jan;35(1):44-9.
Abstract/Text Upper gastrointestinal endoscopy was performed in patients with rheumatoid arthritis (RA) during the period 1989-1991, and biopsy specimens were obtained from the stomach and from the duodenum for examining amyloid deposits. Among 407 patients, gastrointestinal amyloidosis was confirmed in 54 (13.3%). Twenty-two patients were regarded as having slight amyloid deposits, while 32 patients were categorized as having marked amyloid deposits. The incidence of clinical manifestations suggestive of systemic amyloidosis was more frequent in the marked deposits group than in the slight deposits group (47% vs 14%, P<0.05). Among the patients who died of manifestations associated with amyloidosis, the survival period following endoscopy was shorter in the marked deposits group than in the slight deposits group. These findings suggest that gastroduodenal biopsies may be useful for diagnosing secondary amyloidosis and that the degree of amyloid deposits seems to be correlated with the clinical manifestations of RA.

PMID 8624622
Ole B Suhr, Styrbjörn Friman, Bo-Göran Ericzon
Early liver transplantation improves familial amyloidotic polyneuropathy patients' survival.
Amyloid. 2005 Dec;12(4):233-8. doi: 10.1080/13506120500363609.
Abstract/Text Since the first liver transplantation for familial amyloidotic polyneuropathy was performed in 1990, it has become an accepted treatment for this systemic amyloid disorder. Liver transplantation halts the production of the mutated amyloidogenic transthyretin, and thereby amyloid formation, and also progression of the majority of symptoms. Improvement in survival from onset of disease in transplanted patients compared to non-transplanted subjects has of yet not been demonstrated, partly because of the natural relatively slow progression of the disease with an expected median survival of 13 years. In this retrospective study we compared the early initial series (n=34) of transplantations, where severely malnourished patients were accepted, with a later series (n=27) of transplants, as well as a control group (n=19) consisting of non-transplanted patients. For transplanted patients with an modified body mass index (mBMI) above 600 an improved survival was noted compared with that of non-transplanted historical controls. So far no difference in survival between the early and late series has been found. Our previous recommendation of selection of patients primarily according to their nutritional status appears to be well justified, since it is now possible to demonstrate an increased survival for the transplanted group of patients with a preserved nutritional status (mBMI > 600) compared to the control group of non-transplanted patients.

PMID 16399648
Yoshio Shimojima, Hiroshi Morita, Sachio Kobayashi, Yo-ichi Takei, Shu-ichi Ikeda
Ten-year follow-up of peripheral nerve function in patients with familial amyloid polyneuropathy after liver transplantation.
J Neurol. 2008 Aug;255(8):1220-5. doi: 10.1007/s00415-008-0884-9. Epub 2008 May 20.
Abstract/Text BACKGROUND: The electrophysiological long-term effects of liver transplantation on peripheral nerve function in patients with familial amyloid polyneuropathy (FAP) have not been evaluated.
METHODS: Eight FAP patients with a proven ATTRVal30Met gene were observed for 10 years after liver transplantation. We performed repeated measurement of maximal motor nerve conduction velocity (MCV), distal latency, size of compound muscle action potential (CMAP) and maximal sensory nerve conduction velocity (SCV) in both the ulnar and tibial nerves. We also recorded the coefficients of variance in the R-R interval on the electrocardiogram (CV(R-R)).
RESULTS: Some autonomic symptoms subsided but motor and sensory symptoms 10 years after transplantation were either slightly improved or almost the same as before surgery in 7 of 8 patients. These 7 have returned to their previous social lives including their jobs. The MCV of the tibial nerve slightly improved, and other parameters of motor and sensory nerve function and CV(R-R) did not show any deterioration during the 10-year observation period.
CONCLUSIONS: Liver transplantation can halt the progression of peripheral neuropathy in FAP patients.

PMID 18484233
Tomohisa Fushimi, Yasuhumi Takahashi, Yuichiro Kashima, Kazuhiro Fukushima, Wataru Ishii, Kazuma Kaneko, Masahide Yazaki, Akinori Nakamura, Takahiko Tokuda, Masayuki Matsuda, Ryo Furuya, Shu-Ichi Ikeda
Severe protein losing enteropathy with intractable diarrhea due to systemic AA amyloidosis, successfully treated with corticosteroid and octreotide.
Amyloid. 2005 Mar;12(1):48-53. doi: 10.1080/13506120500032725.
Abstract/Text This report concerns two patients with severe protein losing enteropathy and refractory diarrhea due to AA amyloidosis who were successfully treated with corticosteroid and octreotide. In these patients, biopsied tissues from the gastrointestinal (GI) tract showed extensive deposition of AA amyloid, which was caused by rheumatoid arthritis in one case and was of unidentified etiology in the other. Both patients manifested severe diarrhea unresponsive to conventional treatment with hypoproteinemia, and protein leakage from the small intestine to the ascending colon was confirmed by 99mTc-diethylene triamine pentaacetic acid human serum albumin (HSA-D) scintigraphy. Soon after starting a long-acting somatostatin analogue, octreotide, with co-administration of oral prednisolone, their general status improved in parallel with a rapid decrease in the volume of watery diarrhea and an increase in serum levels of albumin and IgG. Also on 99mTc-HSA-D scintigraphy protein leakage from the GI tract was apparently decreased in both patients. Combination therapy with a somatostatin analogue and corticosteroid may be effective for protein losing enteropathy with intractable diarrhea ascribable to GI amyloidosis. Because of the lack of specific therapies in this serious clinical situation, the described therapy should actively be considered as a therapeutic option not only in AA amyloidosis, but also in other types of systemic amyloidosis.

PMID 16076611
Sadahiro Amemori, Ryuichi Iwakiri, Hiroyoshi Endo, Akifumi Ootani, Shinichi Ogata, Takahiro Noda, Seiji Tsunada, Hiroyuki Sakata, Hisashi Matsunaga, Masanobu Mizuguchi, Yuji Ikeda, Kazuma Fujimoto
Oral dimethyl sulfoxide for systemic amyloid A amyloidosis complication in chronic inflammatory disease: a retrospective patient chart review.
J Gastroenterol. 2006 May;41(5):444-9. doi: 10.1007/s00535-006-1792-3.
Abstract/Text BACKGROUND: Amyloid A amyloidosis is an obstinate disease complication in chronic inflammatory disease, and there are few effective therapies. The objective of this study was to investigate the effect of oral dimethyl sulfoxide (DMSO) on amyloid A amyloidosis.
METHODS: Fifteen secondary amyloid A amyloidosis patients (4 men, 11 women; age, 23-70 years) were treated with DMSO between 1995 and 2003. DMSO was administered orally in all patients at a dose of 3-20 g/day. The clinical symptoms together with the renal and gastrointestinal functions were evaluated before and after treatment.
RESULTS: Among the 15 patients, amyloid A amyloidosis was a complication of rheumatoid arthritis (RA) in 10, of Crohn's disease in 4, and of Adult Still's disease in 1. Nine cases mainly involved the kidney, with renal dysfunction and proteinuria, five mainly involved the gastrointestinal tract, with protein-losing gastroenteropathy and intractable diarrhea, and one involved both gastrointestinal and renal amyloidosis. DMSO treatment was successful in 10 (66.7%) of the 15 patients (RA, 6/10; Crohn's disease, 4/4; Adult Still's disease, 0/1). Eight weeks of DMSO administration improved the renal function and proteinuria in five out of ten renal amyloidosis patients, but had no effect on those patients with severe and/or advanced renal dysfunction. With regard to gastrointestinal amyloidosis, gastrointestinal symptoms, including diarrhea and protein-losing gastroenteropathy, were improved in six patients. No serious side effects were encountered with the DMSO treatment.
CONCLUSIONS: Oral administration of DMSO is an effective treatment for amyloid A amyloidosis, especially for gastrointestinal involvement and the early stage of renal dysfunction.

PMID 16799886
F Locatelli, T Hannedouche, S Jacobson, G La Greca, A Loureiro, A Martin-Malo, M Papadimitriou, R Vanholder
The effect of membrane permeability on ESRD: design of a prospective randomised multicentre trial.
J Nephrol. 1999 Mar-Apr;12(2):85-8.
Abstract/Text The different permeability of high-flux and low-flux dialysis membranes results in different removal capacity, particularly for uremic toxins of middle and large molecular weight. High-flux dialysers have been evaluated in clinical and epidemiological studies for their effect on mortality, morbidity, dialysis-related amyloidosis, nutritional status, response to erythropoietin treatment, dialysis tolerance and the preservation of residual renal function. Many of these studies, however, lack a prospective design and randomised treatment allocation, or have too few patients and too short a follow-up. Therefore, this clinical trial was designed to prospectively investigate the long-term effect of membrane permeability on clinical outcome in a larger number of patients. The primary objective is to compare the effect of membrane permeability on mortality of patients on bicarbonate hemodialysis and treated with a minimum dialysis dose. Patients included in the study should have been on hemodialysis for no longer than one month and have serum albumin 4 g/dl or lower. Patients will be randomised to either the experimental or the control group. During the four-week run-in period the treatment parameters will be established in order to achieve the required dialysis dose. During the maintenance period of three to five years regular visits are scheduled to record clinical and laboratory parameters, to measure Kt/V and to adapt the treatment parameters. Altogether a minimum of 660 patients should be enrolled within a two-year recruitment period.

PMID 10378663
Giovanni Palladini, Vittorio Perfetti, Laura Obici, Riccardo Caccialanza, Alessandra Semino, Fausto Adami, Giobatta Cavallero, Roberto Rustichelli, Giovambattista Virga, Giampaolo Merlini
Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation.
Blood. 2004 Apr 15;103(8):2936-8. doi: 10.1182/blood-2003-08-2788. Epub 2003 Dec 18.
Abstract/Text The most efficient therapeutic approach for immunoglobulin light chain amyloidosis (AL) is autologous stem cell transplantation (ASCT); however, the toxicity of ASCT limits its feasibility to a minority of patients. Patients ineligible for ASCT are usually treated with standard oral melphalan and prednisone, but the response rate to this regimen is unsatisfactory, and time to response is long. High-dose dexamethasone provides a rapid response time in patients with AL. We evaluated the combination of oral melphalan and high-dose dexamethasone (M-Dex) in 46 patients with AL ineligible for ASCT. Thirty-one (67%) achieved a hematologic response and 15 (33%) a complete remission. In 22 (48%) of the responsive patients functional improvement of the organs involved was observed. Five patients (11%) experienced severe adverse events, 3 required hospitalization, and no treatment-related deaths were observed. M-Dex represents a feasible and effective therapeutic option for patients with advanced AL who are ineligible for ASCT.

PMID 15070667
Arnaud Jaccard, Philippe Moreau, Veronique Leblond, Xavier Leleu, Lotfi Benboubker, Olivier Hermine, Christian Recher, Bouchra Asli, Bruno Lioure, Bruno Royer, Fabrice Jardin, Frank Bridoux, Bernard Grosbois, Jérome Jaubert, Jean-Charles Piette, Pierre Ronco, Fabrice Quet, Michel Cogne, Jean-Paul Fermand, Myélome Autogreffe (MAG) and Intergroupe Francophone du Myélome (IFM) Intergroup
High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis.
N Engl J Med. 2007 Sep 13;357(11):1083-93. doi: 10.1056/NEJMoa070484.
Abstract/Text BACKGROUND: High-dose chemotherapy followed by autologous hematopoietic stem-cell transplantation has been reported to provide higher response rates and better overall survival than standard chemotherapy in immunoglobulin-light-chain (AL) amyloidosis, but these two strategies have not been compared in a randomized study.
METHODS: We conducted a randomized trial comparing high-dose intravenous melphalan followed by autologous hematopoietic stem-cell rescue with standard-dose melphalan plus high-dose dexamethasone in patients with AL amyloidosis. Patients (age range, 18 to 70 years) with newly diagnosed AL amyloidosis were randomly assigned to receive intravenous high-dose melphalan plus autologous stem cells or oral melphalan plus oral high-dose dexamethasone.
RESULTS: Fifty patients were enrolled in each group. The results were analyzed on an intention-to-treat basis, with overall survival as the primary end point. After a median follow-up of 3 years, the estimated median overall survival was 22.2 months in the group assigned to receive high-dose melphalan and 56.9 months in the group assigned to receive melphalan plus high-dose dexamethasone (P=0.04). Among patients with high-risk disease, overall survival was similar in the two groups. Among patients with low-risk disease, there was a nonsignificant difference between the two groups in overall survival at 3 years (58% in the group assigned to receive high-dose melphalan vs. 80% in the group assigned to receive melphalan plus high-dose dexamethasone; P=0.13).
CONCLUSIONS: The outcome of treatment of AL amyloidosis with high-dose melphalan plus autologous stem-cell rescue was not superior to the outcome with standard-dose melphalan plus dexamethasone. (ClinicalTrials.gov number, NCT00344526 [ClinicalTrials.gov].).

Copyright 2007 Massachusetts Medical Society.
PMID 17855669
Jacques-Eric Gottenberg, Florence Merle-Vincent, Fabrice Bentaberry, Yannick Allanore, Francis Berenbaum, Bruno Fautrel, Bernard Combe, Antoine Durbach, Jean Sibilia, Maxime Dougados, Xavier Mariette
Anti-tumor necrosis factor alpha therapy in fifteen patients with AA amyloidosis secondary to inflammatory arthritides: a followup report of tolerability and efficacy.
Arthritis Rheum. 2003 Jul;48(7):2019-24. doi: 10.1002/art.11163.
Abstract/Text OBJECTIVE: Because anti-tumor necrosis factor alpha (anti-TNF) has emerged as a highly effective treatment for numerous inflammatory arthritides, which are a common cause of AA amyloidosis, we retrospectively evaluated the safety and efficacy of anti-TNF in a nationwide study.
METHODS: The rheumatology departments of all French teaching hospitals were contacted by mail to obtain the files of patients with histologically proven secondary AA amyloidosis and renal involvement who were treated with anti-TNF. Efficacy was assessed as a sustained decrease in 24-hour proteinuria and a stable/improved glomerular filtration rate (GFR).
RESULTS: Among the 15 patients studied, the 24-hour proteinuria was 4.5 +/- 3.6 gm (mean +/- SD), creatininemia was 178.4 +/- 74.9 micromoles/liter, and GFR was 46 +/- 23 ml/minute before starting anti-TNF. Ten patients received infliximab, 4 received etanercept, and 1 received both types of treatment. The mean followup was 10.4 months. No severe adverse events were recorded; one episode of herpes zoster in the first branch of the trigeminal nerve occurred after one infusion of infliximab. Amyloidosis progressed in 7 patients and was stabilized in 5 patients. Three patients (receiving infliximab alone, infliximab plus methotrexate [MTX], or etanercept plus MTX) experienced rapid, dramatic, and sustained decreases in proteinuria (>or=80%), with the GFR increasing 15-78%.
CONCLUSION: Anti-TNF was well-tolerated and safe in the 15 patients with AA amyloidosis and renal involvement. The pathogenic role of TNF in AA amyloidosis, the sustained proteinuria decrease in 3 patients, and the stabilization of renal parameters in 5 other patients make anti-TNF a promising candidate to treat AA amyloidosis secondary to inflammatory arthritides.

PMID 12847696
S Nishida, K Hagihara, Y Shima, M Kawai, Y Kuwahara, J Arimitsu, T Hirano, M Narazaki, A Ogata, K Yoshizaki, I Kawase, T Kishimoto, T Tanaka
Rapid improvement of AA amyloidosis with humanised anti-interleukin 6 receptor antibody treatment.
Ann Rheum Dis. 2009 Jul;68(7):1235-6. doi: 10.1136/ard.2008.099267.
Abstract/Text
PMID 19525413
Takeshi Kuroda, Naohito Tanabe, Hiroe Sato, Jyunya Ajiro, Yoko Wada, Syuichi Murakami, Hisashi Hasegawa, Minoru Sakatsume, Masaaki Nakano, Fumitake Gejyo
Outcome of patients with reactive amyloidosis associated with rheumatoid arthritis in dialysis treatment.
Rheumatol Int. 2006 Oct;26(12):1147-53. doi: 10.1007/s00296-006-0204-6. Epub 2006 Sep 5.
Abstract/Text The aim was to analyze the clinical outcome of a group of 51 patients diagnosed with systemic amyloidosis associated with rheumatoid arthritis who received hemodialysis (HD) as renal replacement therapy. We monitored the clinical course of the disease and factors that could influence survival. Determination of the onset of the underlying disorder was made retrospectively by reviewing the patient's chart when a diagnosis of amyloid was confirmed. During a 96.9 person-year follow-up, 42 patients died. Survival of these 51 patients from the initiation of HD at 251 days was 50%. Poor prognosis in amyloid patients was mainly due to a large number of sudden deaths immediately following HD therapy. Out of 51 patients 21 needed unplanned initiation of HD. The unplanned initiation was significantly associated with poor survival. Seventy-five percentile of creatinine clearance (Ccr) was 9.7 ml/min, and 75% of these patients who initiated HD had highly impaired renal functional states. These data indicated that amyloidotic patients with HD showed a high mortality rate; therefore, planned initiation of HD was highly recommended to improve the patient's survival. Particular attention was given to the Ccr levels, because the levels of serum creatinine may not be a useful marker for some patients with amyloidosis.

PMID 16953393

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