via blogs.nejm.org
2011年5月10日火曜日
2011年5月8日日曜日
2011年5月7日土曜日
IL18 Polymorphism Is Associated with Behçet’s Disease But Not Lupus in Patients from Turkey
IL18 Polymorphism Is Associated with Behçet’s Disease But Not Lupus in Patients from Turkey
To the Editor:
Sánchez, et al have recently reported an association between a putative functional genetic variant in the promoter region of IL18 (rs360719) and systemic lupus erythematosus in Spanish patients 1. They found an increase in the relative expression of IL18 mRNA in individuals with the rs360719 lupus-risk allele 1. Interleukin 18 (IL-18) is a pleiotropic cytokine that can induce Th1 and Th2 responses in the presence and absence, respectively, of IL-12 2. Studies have described overproduction of IL-18 in several autoimmune and inflammatory diseases including Behçet’s disease (BD) and lupus 3, 4. Indeed, serum IL-18 levels in patients with lupus and BD correlate with disease activity 5, 6.
We attempted to replicate the results of Sánchez, et al in a set of Turkish patients with lupus. We examined if the same putative functional IL18 polymorphism is associated with BD in …
Address correspondence to Dr. A.H. Sawalha, 825 NE 13th Street, MS 24, Oklahoma City, OK 73104. E-mail: amr-sawalha@omrf.ouhsc.edu
via jrheum.org
LupusよりもBehcetでより自然免疫に近い側のサイトカインのPolymorphismが見つかるというのは自然な結果に思える…
Fish Oil, Arthritis and Resolvins
Does fish oil containing omega-3 fatty acids have any beneficial effect on arthritis pain? With all the other benefits being claimed for it, fish oil seems like it would help. But is there any scientific evidence? And is so, why does it confer these benefits?
One study, published in Feb 21, 2005 in Nutrition, found that taking fish oil omega-3 fatty acids “relieved several clinical parameters used in the present study. However, patients showed a more precocious and accentuated improvement when fish oil supplements were used in combination with olive oil.â€Â
The study tracked improvements in joint pain intensity, handgrip strength, duration of morning stiffness, ability to bend down to pick up clothing from the floor, and other clinical indicators after both 12 and 24 weeks, and compared them to a control group receiving a placebo.
Rheumatoid Arthritisand Omega 3
Another study, appearing in Oct 27, 2000 in the Journal of Rheumatology, looked at 50 rheumatoid arthritis subjects who were given fish oil supplements containing omega 3 fatty acids at 40 mg per kg body weight for 15 weeks.
The researchers, at the University of Newcastle in Australia, concluded that fish oil supplementation that delivers (n-3) fatty acids at a dose of 40 mg/kg body weight/day, with dietary (n-6) fatty acid intake & 10 g/day in the background diet, results in substantial cellular incorporation of (n-3) fatty acids and improvements in clinical status in patients with RA.
A similar study done in 1990 at Albany Medical College, looked at olive oil vs. low-dose fish oil vs. high-dose fish oil supplementation for 49 patients with active rheumatoid arthritis.
They found that 5 of 45 clinical measures were significantly improved from a baseline in the olive oil supplemented group, 8 of 45 measures improved in the low-dose fish oil group, and 21 of 45 in the high-dose fish oil group were improved during the 24 week study. The high dose supplementation was 54 mg of eicosapentaenoic acid, or EPA, per kg body weight and 36 mg/kg docosahexaenoic acid (DHA). This suggests that anyone taking fish oil for arthritis needs to take higher amounts than what is usually recommended, if they want to get any relief.
Anti-inflammatory Effects
There have been numerous other studies along the same lines, all showing some benefits. The improvements in symptoms are due to some kind of anti-inflammatory mechanism. We know that both omega-3 and omega-6 are converted in the body to molecules called prostaglandins, which have numerous beneficial effects, such as reducing inflammation, inhibition of blood clotting, and maintaining various regulatory states in the body.
A class of fatty compounds discovered in 2002, that our bodies make from eicosapentaenoic acid, called resolvins, may make clear how omega-3 gives its anti-inflammatory effects.
- See the study: Resolvins : A Family of Bioactive Products of Omega-3 Fatty Acid Transformation Circuits Initiated by Aspirin Treatment that Counter Proinflammation Signals
Resolvins have been shown to reduce cellular inflammation by inhibiting the production and transportation of inflammatory cells and chemicals to the sites of inflammation. They are produced by the COX-2 pathway especially in the presence of aspirin. This suggests that diet supplementation with fish oil may work better when combined with low aspirin doses.
Of course, more evidence is needed, but as far as a replacement for Vioxx, fish oil and omega-3 could be a serious contender.
Related Studies
1. Kremer JM, Lawrence DA, Jubiz W, DiGiacomo R, Rynes R, Bartholomew LE, et al. Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clinical and immunologic effects. Arthritis Rheum 1990;33:810-20.
2. Cleland LG, French JK, Betts WH, Murphy GA, Elliott MJ. Clinical and biochemical effects of dietary fish oil supplements in rheumatoid arthritis. J Rheumatol 1988;15:1471-5.
3. Volker D, Fitzgerald P, Major G, Garg M. Efficacy of fish oil concentrate in the treatment of rheumatoid arthritis. J Rheumatol 2000;27:2343-6.
4. Lau CS, Morley KD, Belch JJ. Effects of fish oil supplementation on non-steroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritis-a double-blind placebo controlled study. Br J Rheumatol 1993;32:982-9.
5. James MJ, Cleland LG. Dietary n-3 fatty acids and therapy for rheumatoid arthritis. Semin Arthritis Rheum 1997;27:85-97.
6. Vargova V, Vesely R, Sasinka M, Torok C. Will administration of omega-3 unsaturated fatty acids reduce the use of nonsteroidal antirheumatic agents in children with chronic juvenile arthritis? [Slovak] Cas Lek Cesk 1998;137:651-3.
7. Harris WS. N-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr 1997;65:1645S-54S.
8. Clària, J., and C.N. Serhan. 1995. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc. Natl. Acad. Sci. USA. 92:94759479
9. Calder, P. C (2006). n-3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am. J. Clin. Nutr. 83: S1505-1519S
10. Arita, M., Bianchini, F., Aliberti, J., Sher, A., Chiang, N., Hong, S., Yang, R., Petasis, N. A., Serhan, C. N. (2005). Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J. Exp. Med. 201: 713-722
Image: Kirlian photography image suggesting inflammatory conditions such as rheumatoid arthritis, or conditions affecting the ulnar nerve. Wellcome Images Creative Commons Attribution.
via fountia.com
Resolvinは今後注意深く見守っていきたいところ。
ナントカの寛解導入！とか、おおきな治療には不向きだけれど、患者さんのQOLを上昇させられる場面がどこかにありそう…
新規RA治療： TNF阻害薬を超えて？
Current Opinion in Rheumatology
New Therapies in the Management of Rheumatoid Arthritis
Maya H. Buch; Paul Emery言及されている「新規治療」
・既存治療のNew Formulation
Abatacept SC, Tocilizumab SC
・新規TNFi
Certolizumab, Golimumab
・B-cell depletion（萩野註：うまい訳が見つからない）
Ocrelizumab：安全性の懸念からポシャった
Ofatumumab：rituximab and ocrelizumabがCD20のlarge loopを認識するのに対して、ofatumumabはCD20分子の膜近位部ループをepitopeとして認識する。
Veltuzumab：その他の抗CD20抗体（Complementarity determining resion付き）
Epratuzumab：抗CD22抗体
・B-cell pathwayを標的としたもの
BLys（B-lymphocyte stimulator）
APRIL（A PRoliferation-Inducing Ligand：TNFファミリー）
その他：TNF-receptor related receptors TACI, BCMA, BAFFR
Atacicept TACIとBAFF/APRILの結合部位阻害 効果いまひとつ
・IL-6 pathway
Tocilizumab：TAMARA study, ACT-SURE study
新規抗IL-6R抗体：REGN88/SAR153191（SC投与）
抗IL-6抗体：ALD518
・抗IL-17
Secukinumab (AIN457)
・抗Treg
BT-061, a humanized agonistic mAb that selectively activates Tregs（萩野註：なにをepitopeにしているのかは記載なし？）
・抗G-CSF/GM-CSF
Now under investigation（萩野註：ACR2010で見かけたような）
・Tyrosine Kinase Inhibitors
JAKi: IL-2, IL-4, IL-9, IL-15 and IL-21 inhibitor
SyKi: Its activation is important in TNF-induced cytokine and matrix met alloproteinases (MMP) production from RA fibroblast-like synoviocytes
P38 Mitogen-activated Protein Kinase Inhibitors
・Mitogen-activated protein kinasesには3つのmajor familiesあり
MAPKS-extracellular signal-regulated kinase (ERK),
c-JUN N-terminal kinase (JNK),
p38 MAPK.
・このうち、p38 MAPK、特にp38αisoform (その他-β, -δ, and -γ isoformsがある) が主にサイトカイン産生・制御に関わっている
"Four recent trials have been reported, with disappointing results"感想：新規抗リウマチ薬（生物学的製剤・低分子製剤）は、TNFiの達成した数々のベンチマークを達成することを期待されているが、上記薬剤ではわずかにJAKi, SyKiで少し期待できるかも？といった程度か。
重症RAに対して投与したとき、MTX併用下でACR20-50-70を60%-40%-20%で達成する薬剤、というのがTNFi, IL-6RAに共通した特徴。JAKiは単剤でもう少し行っているように見えるが、ACR2010ではカナダのKeystoneは「大した差ではない。もしかするとそのあたりにceilingがあるのかもしれない」とコメントしていた。
New Therapies in the Management of Rheumatoid Arthritis
Maya H. Buch; Paul Emery言及されている「新規治療」
・既存治療のNew Formulation
Abatacept SC, Tocilizumab SC
・新規TNFi
Certolizumab, Golimumab
・B-cell depletion（萩野註：うまい訳が見つからない）
Ocrelizumab：安全性の懸念からポシャった
Ofatumumab：rituximab and ocrelizumabがCD20のlarge loopを認識するのに対して、ofatumumabはCD20分子の膜近位部ループをepitopeとして認識する。
Veltuzumab：その他の抗CD20抗体（Complementarity determining resion付き）
Epratuzumab：抗CD22抗体
・B-cell pathwayを標的としたもの
BLys（B-lymphocyte stimulator）
APRIL（A PRoliferation-Inducing Ligand：TNFファミリー）
その他：TNF-receptor related receptors TACI, BCMA, BAFFR
Atacicept TACIとBAFF/APRILの結合部位阻害 効果いまひとつ
・IL-6 pathway
Tocilizumab：TAMARA study, ACT-SURE study
新規抗IL-6R抗体：REGN88/SAR153191（SC投与）
抗IL-6抗体：ALD518
・抗IL-17
Secukinumab (AIN457)
・抗Treg
BT-061, a humanized agonistic mAb that selectively activates Tregs（萩野註：なにをepitopeにしているのかは記載なし？）
・抗G-CSF/GM-CSF
Now under investigation（萩野註：ACR2010で見かけたような）
・Tyrosine Kinase Inhibitors
JAKi: IL-2, IL-4, IL-9, IL-15 and IL-21 inhibitor
SyKi: Its activation is important in TNF-induced cytokine and matrix met alloproteinases (MMP) production from RA fibroblast-like synoviocytes
P38 Mitogen-activated Protein Kinase Inhibitors
・Mitogen-activated protein kinasesには3つのmajor familiesあり
MAPKS-extracellular signal-regulated kinase (ERK),
c-JUN N-terminal kinase (JNK),
p38 MAPK.
・このうち、p38 MAPK、特にp38αisoform (その他-β, -δ, and -γ isoformsがある) が主にサイトカイン産生・制御に関わっている
"Four recent trials have been reported, with disappointing results"感想：新規抗リウマチ薬（生物学的製剤・低分子製剤）は、TNFiの達成した数々のベンチマークを達成することを期待されているが、上記薬剤ではわずかにJAKi, SyKiで少し期待できるかも？といった程度か。
重症RAに対して投与したとき、MTX併用下でACR20-50-70を60%-40%-20%で達成する薬剤、というのがTNFi, IL-6RAに共通した特徴。JAKiは単剤でもう少し行っているように見えるが、ACR2010ではカナダのKeystoneは「大した差ではない。もしかするとそのあたりにceilingがあるのかもしれない」とコメントしていた。
登録:
投稿 (Atom)