リウマチ

Yamaoka et al. A case of life-threatening refractory polychondritis successfully treated with combined intensive immunosuppressive therapy with methotrexate. Mod Rheumatol. 2007;17(2):144.

ステロイド 0.5-1mg/kgで病勢が抑えきれない場合はステロイドパルス療法を行う。気道病変を伴う難治例ではエンドキサンが用いられる（眼病変ではMTXが多い)。
この論文の、気道狭窄を伴う治療抵抗性症例（18才・女性・glottis声門, subglottis声門下部、主気管の病変で気切）では、ステロイドパルスの効果は一時的で、エンドキサンパルス（15mg/kg）を併用するもコントロールがつかず、メトトレキサート8mg追加したところでコントロールがついた。この論文では、眼症状や気道狭窄を伴うRPの免疫抑制薬の有効例10例の纏めや、TNF阻害薬やアナキンラの有効例の文献についても記載している（2例？3例？アナキンラ？）。ステントに関するコメントはない。

Cherkas LF et al. Heritability of Raynaud's phenomenon and vascular responsiveness to cold: a study of adult female twins. Arthritis Rheum (Arhtritis Care Res). 2007 Apr 15;57(3):524-8（イギリス）.

700組の一卵性双生児、726組の二卵性双生児にレイノー症状の問診を行い（リウマトイド因子や抗核抗体陽性者は除外）、10%,12%でレイノー症状が認められた。Casewise concordanceを求めたところ（*)、レイノー症状（重篤なレイノー）のCcは一卵性で37％（35％）、二卵性で20％（18％）であった。最尤法を用いた解析で遺伝要因heritablity estimateは55％、53％と計算されている。
129組の一卵性双生児、159組の二卵性双生児には寒冷刺激試験が行われた。皮膚温の低下度などは両群で差はないが、寒冷刺激反応の一致率は一卵性ペアの方が高く皮膚温のベースライン、低下、再上昇の遺伝性heritablity estimateは65%, 35%, 24%であった。

*Pairwise concordance is the relative number of twin pairs in whom an event has affected both twins, and it was calculated using the following formula.
concordant pairs/concordant pairs + discordant pairs

The casewise concordance rate reflects the probability that, if one twin experiences events, her twin will also have an event and was calculated with the following formula.
2 × concordant pairs/(2 × concordant pairs + discordant pairs
(Smith C. Concordance in twins: Methods and interpretation. Am J Hum Genet 1974;26:454-466)

文献的にはプライマリーレイノーの遺伝子座を第３染色体にマップしている報告がある(A&R 200,43,1641)。

http://www.nytimes.com/2007/04/27/us/27immune.html?ex=1335326400&en=8eddad2b13dd51bb&ei=5088&partner=rssnyt&emc=rss　のコピーペースト

A micro-RNA called miR-155（500以上あるmicro RNAのひとつでB cell に多い）のノックアウトマウス
・Allan Bradley and Martin Turner（英国）： ワクチンに対する応答不全：サイトカインやcell cell interactionも不全
・Rajewsky（ハーバード）：select antibody-making cells of the right specificity to attack invadersができなくなる

Scientists Identify 7 New Diabetes Genes（メモのコピーペースト）
By NICHOLAS WADE
Published: April 27, 2007
http://www.nytimes.com/2007/04/27/us/27diabetes.html?ex=1335326400&en=5168a558ebf7fde0&ei=5088&partner=rssnyt&emc=rss

◎Yesterday’s reports bring the number of well-attested genes involved in adult-onset, or Type 2 diabetes up to 10, from the 3 known previously.
->IGF2BP2, CDKAL1, CDKN2A/CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11

○Kari Stefansson of DeCode Genetics：
・TCF7L2(transcription factor 7-like 2 gene (TCF7L2; formerly TCF4)) was published in March 2006 in Nature Genetics.
・CDKAL1（Nat Genet. 2007 Apr 26）

○"Whole genome association technique"
“It has not been a terribly productive field until the last two or three months,” Dr. McCarthy said.But with improved technology and better understanding of the sources of error, the academic groups seem at last to have gotten their technique working.

○Mark McCarthy of the University of Oxford
・Science. 2007 Apr 26（We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8.）

○David Altshuler of the Broad Institute, Michael Boehnke of the University of Michigan
・Science. 2007 Apr 26（ variants near the genes IGF2BP2, CDKAL1, and CDKN2A/CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings to at least ten the number of T2D loci now confidently identified）
・Science. 2007 Apr 26（in a non-coding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 -- and replicate associations near HHEX and in SLC30A8 found by a recent whole genome association study. We identify and confirm association of a SNP in an intron of glucokinase regulatory protein with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues into the pathogenesis of common diseases.）

FDA Turns Down Merck Arthritis Drug
By THE ASSOCIATED PRESS
Published: April 28, 2007

The Food and Drug Administration has rejected Merck & Company’s bid to win approval for a successor to Vioxx（ロフェコキシブ）, the arthritis medication that Merck withdrew from the market more than two years ago, the company said yesterday.

The decision had been widely expected ever since a panel of F.D.A. advisers （FDA諮問委員会）　voted two weeks ago by 20 to 1 against approval of the drug, Arcoxia（etoricoxib、エトリコキシブ、MK-0663、5-chloro-2-(6-methylpyridin-3-yl)-3-(4-methylsulfonylphenyl) pyridine）, because of concerns that it could cause as many as 30,000 heart attacks a year if widely used.

Like Vioxx, whose name has become almost synonymous with drug safety problems, Arcoxia is among a class of anti-inflammatory drugs called cox-2 inhibitors. Such medications were developed in the hope that they would be less likely to cause stomach bleeding than ibuprofen and naproxen＊.

But while they did prove to safeguard the stomach, they have been linked to heart risks. Merck withdrew Vioxx in September 2004 after research showed that it doubled the risk of heart attacks and strokes.

Despite the safety concerns in the United States, Arcoxia is on sale in 63 other countries. It brought in revenue of $265 million last year.

＊MEDAL（Multinational Etoricoxib and Diclofenac Athritis Long-term）スタディは、46カ国の1380施設で行われた3件の臨床試験（EDGE、EDGE II、MEDAL）の総称で、変形性関節炎（OA）または関節リウマチ（RA）約3万5000人を対象に、COX-2阻害薬エトリコキシブと、非選択的NSAIDsジクロフェナクの、心血管イベント発生率を比較している。
EDGE trialの結果はJ Rheumatol. 2007 Feb;34(2):408-20）に報告されていて、7111例のOAを対象にetoricoxib 90 mg qd (n = 3593) またはdiclofenac sodium（ボルタレン） 50 mg tid (n = 3518)に割付け、約9ヶ月間フォロー。その結果、消化器症状は有意にエトリコキシブが優っていた。また、血栓リスクも両者で同様であった[1.25 vs 1.15 events per 100 PY]. しかし、高血圧関連の有害事象はエトリコキシブ群で多かった(2.3% vs 0.7%; p < 0.001)。
　MEDAL試験(約35,000例の関節炎患者（OA7割、RA3割）を対象にした)では、エトリコキシブ（Arcoxia、メルク、米国未発売）は従来のNSAIDと比べた場合、心血管イベントに問題はないと報告されていたが（Lancet;368:1771,2006）、結局米国では上市に至らなかった。