Publications

2009

Raychaudhuri S, Thomson BP, Remmers EF, Eyre S et al . Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk. Nat Genet. 2009 Nov 8. [Epub ahead of print] PubMed PMID: 19898481. Abstract

Mahdi H, Fisher BA, Källberg H, Plant D et al. Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis. Nat Genet. 2009 Nov 8. [Epub ahead of print] PubMed PMID: 19898480. Abstract

Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet. 2009 Feb 21;373(9664):659-72. Epub 2009 Jan 20.

Bertsias GK, Nakou M, Choulaki C, Raptopoulou A, Papadimitraki E, Goulielmos G, Kritikos H, Sidiropoulos P, Tzardi M, Kardassis D, Mamalaki C, Boumpas DT. Genetic, immunologic, and immunohistochemical analysis of the programmed death 1/programmed death ligand 1 pathway in human systemic lupus erythematosus. Arthritis Rheum. 2009 Jan;60(1):207-18

van Kuijk AW, Wijbrandts CA, Vinkenoog M, Zheng TS, Reedquist KA, Tak PP; TWEAK and its receptor Fn14 in the synovium of patients with rheumatoid arthritis compared to psoriatic arthritis and its response to TNF blockade. Ann Rheum Dis. 2009 Jan 15. [Epub ahead of print]

Grevers LC, van Lent PL, Koenders MI, Walgreen B, Sloetjes AW, Nimmerjahn F,Sjef Verbeek J, van den Berg WB. Different amplifying mechanisms of interleukin-17 and interferon-gamma in Fcgamma receptor-mediated cartilage destruction in murine immune complex-mediated arthritis.Arthritis Rheum. 2009 Jan 29;60(2):396-407.

2008

van Lent PL, Grevers LC, Blom AB, Arntz OJ, van de Loo FA, van der Kraan P,Abdollahi-Roodsaz S, Srikrishna G, Freeze H, Sloetjes A, Nacken W, Vogl T, Roth J, van den Berg WB. Stimulation of chondrocyte-mediated cartilage destruction by S100A8 in experimental murine arthritis.Arthritis Rheum. 2008 Dec;58(12):3776-87.

van Lent PL, Grevers L, Blom AB, Sloetjes A, Mort JS, Vogl T, Nacken W, van den Berg WB, Roth J. Myeloid-related proteins S100A8/S100A9 regulate joint inflammation and cartilage destruction during antigen-induced arthritis. Ann Rheum Dis. 2008 Dec;67(12):1750-8

Sidiropoulos PI, Karvounaris SA, Boumpas DT. Metabolic syndrome in rheumatic diseases: epidemiology, pathophysiology, and clinical implications. Arthritis Res Ther. 2008;10(3):207.

Ospelt C, Brentano F, Rengel Y, Stanczyk J, Kolling C, Tak PP, Gay RE, Gay S, Kyburz D; Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: toll-like receptor expression in early and longstanding arthritis. Arthritis Rheum. 2008 Dec;58(12):3684-92.

Rihl M, Kellner H, Kellner W, Barthel C, Yu DT, Tak PP, Zeidler H, Baeten D; Identification of interleukin-7 as a candidate disease mediator in spondylarthritis. Arthritis Rheum. 2008 Nov;58(11):3430-5.

Wijbrandts CA, Remans PH, Klarenbeek PL, Wouters D, van den Bergh Weerman MA, Smeets TJ, Vervoordeldonk MJ, Baeten D, Tak PP; Analysis of apoptosis in peripheral blood and synovial tissue very early after initiation of infliximab treatment in rheumatoid arthritis patients. Arthritis Rheum. 2008 Nov;58(11):3330-9.

Vandooren B, Cantaert T, ter Borg M, Noordenbos T, Kuhlman R, Gerlag D, Bongartz T, Reedquist K, Tak PP, Baeten D; Tumor necrosis factor alpha drives cadherin 11 expression in rheumatoid inflammation. Arthritis Rheum. 2008 Oct;58(10):3051-62.
6. Vergunst CE, Gerlag DM, Lopatinskaya L, Klareskog L, Smith MD, van den Bosch F, Dinant HJ, Lee Y, Wyant T, Jacobson EW, Baeten D, Tak PP; Modulation of CCR2 in rheumatoid arthritis: a double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum. 2008 Jul;58(7):1931-9

Cantaert T, Kolln J, Timmer T, van der Pouw Kraan TC, Vandooren B, Thurlings RM, Cañete JD, Catrina AI, Out T, Verweij CL, Zhang Y, Tak PP, Baeten D; B lymphocyte autoimmunity in rheumatoid synovitis is independent of ectopic lymphoid neogenesis. J Immunol. 2008 Jul 1;181(1):785-94.

Thurlings RM, Wijbrandts CA, Mebius RE, Cantaert T, Dinant HJ, van der Pouw-Kraan TC, Verweij CL, Baeten D, Tak PP; Synovial lymphoid neogenesis does not define a specific clinical rheumatoid arthritis phenotype. Arthritis Rheum. 2008 Jun;58(6):1582-9.
9. Straub RH, Pongratz G, Cutolo M, Wijbrandts CA, Baeten D, Fleck M, Atzeni F, Grunke M, Kalden JR, Schölmerich J, Lorenz HM, Tak PP, Sarzi-Puttini P; Increased cortisol relative to adrenocorticotropic hormone predicts improvement during anti-tumor necrosis factor therapy in rheumatoid arthritis. Arthritis Rheum. 2008 Apr;58(4):976-84.

Baeten D, Kruithof E, Breban M, Tak PP; Spondylarthritis in the absence of B lymphocytes. Arthritis Rheum. 2008 Mar;58(3):730-3

Vandooren B, Cantaert T, Noordenbos T, Tak PP, Baeten D; The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation. Arthritis Rheum. 2008 Mar;58(3):718-29.

Wijbrandts CA, Dijkgraaf MG, Kraan MC, Vinkenoog M, Smeets TJ, Dinant H, Vos K, Lems WF, Wolbink GJ, Sijpkens D, Dijkmans BA, Tak PP; The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor alpha expression in the synovium. Ann Rheum Dis. 2008 Aug;67(8):1139-44. Epub 2007 Nov 29.

Thurlings RM, Vos K, Wijbrandts CA, Zwinderman AH, Gerlag DM, Tak PP; Synovial tissue response to rituximab: mechanism of action and identification of biomarkers of response. Ann Rheum Dis. 2008 Jul;67(7):917-25. Epub 2007 Oct 26.

van der Pouw Kraan TC, van Baarsen LG, Wijbrandts CA, Voskuyl AE, Rustenburg F, Baggen JM, Dijkmans BA, Tak PP, Verweij CL; Expression of a pathogen-response program in peripheral blood cells defines a subgroup of rheumatoid arthritis patients. Genes Immun. 2008 Jan;9(1):16-22. Epub 2007 Oct 11.

Cantaert T, Stone MA, ter Borg M, Mogg R, De Vries N, Wilson AG, Tak PP, Baeten D; A functional polymorphism of TIR-domain-containing adaptor protein is not associated with axial spondyloarthritis. Ann Rheum Dis. 2008 May;67(5):720-2. Epub 2007 Dec 11.

T. Cantaert et al, Exposure to nuclear antigens contributes to the induction of humoral autoimmunity during TNF blockade, Ann Rheum Dis, jul 2008, epub ahead of print

Vandooren B, Cantaert T, van Lierop MJ, Bos E, De Rycke L, Veys EM, De Keyser F, Bresnihan B, Luyten FP, Verdonk PC, Tak PP, Boots AH, Baeten D; Melanoma Inhibitory Activity, a biomarker related to chondrocyte anabolism, is reversibly suppressed by proinflammatory cytokines in rheumatoid arthritis. Ann Rheum Dis. 2008 Jul 16. [Epub ahead of print]

Polzer K, Baeten D, Soleiman A, Distler J, Gerlag DM, Tak PP, Schett G, Zwerina J. TNF blockade increases lymphangiogenesis in murine and human arthritic joints. Ann Rheum Dis. 2008 Jan 3; [Epub ahead of print]

Cantaert T et al, A functional polymorphism of TIR-domain-containing adaptor protein is not associated with axial spondyloarthritis. Ann Rheum Dis. 2008 May;67(5):720-2.

. Vandooren B et al, Absence of a classically activated macrophage cytokine signature in peripheral spondyloarthritis, including psoriatic arthritis Arthritis Rheum. (in press)

T. Cantaert et al, Anti-citrullinated protein antibodies define a distinct pathogenic subset of rheumatoid arthritis with preferential T lymphocyte involvement, submitted

T . Cantaert et al, Type 1 interferons do not influence humoral autoimmunity in rheumatoid arthritis, submitted

M I. Zervoua, Ds Mamoulakisb, C Panierakisb, D T. Boumpas, G N. Goulielmos. STAT4: A risk factor for type 1 diabetes? In press Hum Immunol (2008), doi: 10.1016/j. humimm.2008.07.004

M I. Zervoua, P Sidiropoulosb, E Petrakic, V Vazgiourakisc, E Krasoudakic, A Raptopouloub, H Kritikosb, E Choustoulakib, D T. Boumpas, G N. Goulielmosc. Association of a TRAF1 and a STAT4 gene polymorphism with increased risk for rheumatoid arthritis in a genetically homogeneous population. Human Immunology (2008) 69, 567–571

E Ammirati, A-C Vermi, D Cianflone, M Banfi, C Foglieni, C Godino, F Airoldi, L A. Ferri, C L. Gorman, A A. Manfredi, A Maseri, A P. Cope, C Monaco. Expansion of T-Cell Receptor dimeffector T Cells inAcute Coronary Syndromes Ammirati, Expansion of TCR dimT Cells in ACS. Accepted by Arteriosclerosis, Thrombosis and Vascular Biology (impact factor > 6), Sept 2008

Sheppard J, Kumar K, Buckley CD, Shaw KL, Raza K. 'I just thought it was normal aches and pains': a qualitative study of decision-making processes in patients with early rheumatoid arthritis. Rheumatology (Oxford). 2008 Aug 18. [Epub ahead of print]

Raza K, Mullazehi M, Salmon M, Buckley CD, Rönnelid J. Anti-collagen type II antibodies in patients with very early synovitis. Ann Rheum Dis. 2008 Sep;67(9):1354-5

Kinloch A, Lundberg K, Wait R, Wegner N, Lim NH, Zendman AJ, Saxne T, Malmström
V, Venables PJ. Synovial fluid is a site of citrullination of autoantigens in inflammatory
arthritis. Arthritis Rheum. 2008 Aug;58(8):2287-95

Hesselstrand R, Kassner A, Heinegård D, Saxne T. COMP: a candidate molecule in the pathogenesis of systemic sclerosis with a potential as a disease marker. Ann Rheum Dis. 2008 Sep;67(9):1242-8.

Khoury M, Escriou V, Courties G, Galy A, Yao R, Largeau C, Scherman D, Jorgensen C, Apparailly F. Efficient suppression of murine arthritis by combined anticytokine small interfering RNA lipoplexes. Arthritis Rheum. 2008 Aug;58(8):2356-67

Haworth O, Hardie DL, Burman A, Rainger GE, Eksteen B, Adams DH, Salmon M, Nash GB, Buckley CD. A role for the integrin {alpha}6{beta}1 in the differential distribution of CD4 and CD8 T-cell subsets within the rheumatoid synovium. Rheumatology (Oxford). 2008 Jul 17. [Epub ahead of print]

van Der Helm-van Mil AH, Detert J, Cessie SL, Filer A, Bastian H, Burmester GR, Huizinga TW, Raza K. Validation of a prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: Moving toward individualized treatment decision-making. Arthritis Rheum. 2008 Aug;58(8):2241-7.

Johnsson L, Hansson MG, Eriksson S, Helgesson G. Patients' refusal to consent to storage and use of samples in Swedish biobanks: cross sectional study. BMJ. 2008 Jul 10;337:a345.

Hardy RS, Rabbitt EH, Filer A, Emery P, Hewison M, Stewart PM, Gittoes N, Buckley CD, Raza K, Cooper MS. Local and systemic glucocorticoid metabolism in inflammatory arthritis. Ann Rheum Dis. 2008 Apr 17

Parsonage G, Filer A, Bik M, Hardie D, Lax S, Howlett K, Church LD, Raza K, Wong SH, Trebilcock E, Scheel-Toellner D, Salmon M, Lord JM, Buckley CD. Prolonged, granulocyte-macrophage colony-stimulating factor-dependent, neutrophil survival following rheumatoid synovial fibroblast activation by IL-17 and TNFalpha. Arthritis Res Ther. 2008;10(2):R47

Khoury M, Escriou V, Courties G, Galy A, Yao R, Largeau C, Scherman D, Jorgensen C and F Apparailly. Combined anti-cytokine siRNA lipoplexes efficiently suppress arthritis. Arthritis Rheum. In press (2008).

Joanna Stanczyk, Deena M. Leslie Pedrioli, Fabia Brentano, Olga Sanchez-Pernaute et al. Altered Expression of MicroRNA in Synovial Fibroblasts and Synovial Tissue in Rheumatoid Arthritis. Arthritis Rheum, 2008 Apr; 58 (4), 1001-1009

Maalej A, Petit-Teixeira E, Chabchoub G, Hamad MB, Rebai A, Farid NR, Cornelis
F, Ayadi H. Lack of Association of VDR Gene Polymorphisms with Thyroid Autoimmune Disorders: Familial and Case/Control Studies. J Clin Immunol. 2008 Jan;28(1):21-5

Jacq L, Teixeira VH, Garnier S, Petit-Teixeira E, Cornélis F. The MMP2 rs243865-T allele is not a major genetic factor for rheumatoid arthritis in the French Caucasian population.
Int J Immunogenet. 2008 Jan 19;

2007

Karvounaris SA, Sidiropoulos PI, Papadakis JA, Spanakis EK, Bertsias GK,
Kritikos HD, Ganotakis ES, Boumpas DT. Metabolic syndrome is common among middle-to-older aged Mediterranean patients with rheumatoid arthritis and correlates with disease activity: a retrospective, cross-sectional, controlled, study.
Ann Rheum Dis. 2007 Jan;66(1):28-33.

V Vazgiourakis, P Sidiropoulos, G Bertsias, E Koutsounaki1, E Fragouli1, A Raptopoulou, H Kritikos, DT Boumpas and GN Goulielmos. Association of the nitric oxide synthase (eNOS) gene polymorphism with increased risk for both lupus glomerulonephritis and rheumatoid arthritis in a single genetically homogeneous population. Lupus (2007) 16, 867–874

Lars C. Huber, Joanna Stanczyk, Astrid Juüngel, and Steffen Gay. Epigenetics in Inflammatory Rheumatic Diseases. Arthritis Rheum, 2007 Nov;56 (11), 3523–3531

Lars C. Huber, Matthias Brock, Hossein Hemmatazad, Olivier T. Giger et al. Histone Deacetylase/Acetylase Activity in Total Synovial Tissue Derived From Rheumatoid Arthritis and Osteoarthritis Patients. Arthrits Rheum, 2007 Apr;56 (4), 1087-1093

Cantaert T, Stone MA, Terborg M, Mogg R, de Vries N, Wilson AG, Tak PP, Baeten
D. A functional polymorphism of TIR-domain-containing adaptor protein is not
associated with axial spondyloarthritis. Ann Rheum Dis. 2007 Dec 23; [Epub ahead of print]

Poulsom H, Charles P J. Antibodies to citrullinated vimentin are a specific and sensitive marker for the diagnosis of rheumatoid arthritis. Clinic Rev Allerg Immunol, DOI 10.1007/s12016-007-8016-3

Young-Min S, Cawston T, Marshall N, Coady D, Christgau S, Saxne T, Robins S,
Griffiths I. Biomarkers predict radiographic progression in early rheumatoid arthritis and
perform well compared with traditional markers. Arthritis Rheum. 2007 Oct;56(10):3236-47

Svenson M, Geborek P, Saxne T, Bendtzen K. Monitoring patients treated with anti-TNF-alpha biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies.
Rheumatology (Oxford). 2007 Dec;46(12):1828-34

Hesselstrand R, Kassner A, Heinegard D, Saxne T. COMP a candidate molecule in the pathogenesis of systemic sclerosis with a potential as a disease marker.
Ann Rheum Dis. 2007 Dec 7

Mathsson L, Mullazehi M, Wick MC, Sjöberg O, van Vollenhoven R, Klareskog L, Rönnelid J. Antibodies against citrullinated vimentin in rheumatoid arthritis: Higher sensitivity and extended prognostic value concerning future radiographic progression as compared with antibodies against cyclic citrullinated peptides. Arthritis Rheum. 2007 Dec 28;58(1):36-45

Cohen IR, Klareskog L. Antiinflammatory therapy for rheumatoid arthritis? Arthritis Rheum. 2007 Dec 28;58(1):2-4

Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: A comprehensive review. Pharmacol Ther. 2007 Oct 26; [Epub ahead of print]

Kurreeman, F. A., L. Padyukov, R. B. Marques, S. J. Schrodi, M. Seddighzadeh, G. Stoeken-Rijsbergen, van der Helm-van Mil AH, C. F. Allaart, W. Verduyn, J. Houwing-Duistermaat, L. Alfredsson, A. B. Begovich, L. Klareskog, T. W. Huizinga, and R. E. Toes. 2007. A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis. PLoS.Med. 4:e278

Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PI, Le JM, Lee HS, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, Kastner DL, Gregersen PK. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007 Sep 6;357(10):977-86.

Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B, Liew A, Khalili H, Chandrasekaran A, Davies LR, Li W, Tan AK, Bonnard C, Ong RT, Thalamuthu A, Pettersson S, Liu C, Tian C, Chen WV, Carulli JP, Beckman EM, Altshuler D, Alfredsson L, Criswell LA, Amos CI, Seldin MF, Kastner DL, Klareskog L, Gregersen PK. TRAF1-C5 as a Risk Locus for Rheumatoid Arthritis -- A Genomewide Study. N Engl J Med. 2007 Sep 5;

Kallberg H, Padyukov L, Plenge RM, Ronnelid J, Gregersen PK, van der Helm-van Mil AH, Toes RE, Huizinga TW, Klareskog L, Alfredsson L; Epidemiological Investigation of Rheumatoid Arthritis study group. Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am J Hum Genet. 2007 May;80(5):867-75. Epub 2007 Apr 2.

Olofsson P, Nerstedt A, Hultqvist M, Nilsson EC, Andersson S, Bergelin A, Holmdahl R. Arthritis suppression by NADPH activation operates through an interferon-beta pathway. BMC Biol. 2007 May 9; 5:19 .

Huber LC, Jüngel A, Distler JHW, Moritz F, Gay RE, Michel BA, Pisetsky DS, Gay S, Distler O. The role of membrane lipids in the induction of macrophage apoptosis by microparticles, Apoptosis 12:363-374, 2007

Kooloos, W. M., D. J. de Jong, T. W. Huizinga, and H. J. Guchelaar. 2007. Potential role of pharmacogenetics in anti-TNF treatment of rheumatoid arthritis and Crohn's disease. Drug Discov.Today 12:125-131.
Ref ID: 24

Hoberg M, Rudert M, Pap T, Klein G, Gay S, Aicher WK. Attachment to laminin-111 facilitates transforming growth factor beta-induced expression of matrix metalloproteinase-3 in synovial fibroblasts. Ann Rheum Dis 66:446-51, 2007

Huber LC, Brock M, Hemmatazad H, Giger O, Moritz F, Trenkmann M, Distler JHW, Gay RE, Kolling C, Moch H, Michel BA, Gay S, Distler O, Jungel A. Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. Arthr Rheum 56:1087-93, 2007

Meinecke I, Cinski A, Baier A, Peters MA, Dankbar B, Willie A, Drynda A, Mendoza H, Gay RE, Hay RT, Ink B, Gay S, Pap T. Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. Proc Natl Acad Sci USA 104:5073-8, 2007

Jacq L, Garnier S, Dieude P, Michou L, Pierlot C, Migliorini P, Balsa A, Westhovens R, Barrera P, Alves H, Vaz C, Fernandes M, Pascual-Salcedo D, Bombardieri S, Dequeker J, Radstake TR, Van Riel P, van de Putte L, Lopes-Vaz A, Glikmans E, Barbet S, Lasbleiz S, Lemaire I, Quillet P, Hilliquin P, Teixeira VH, Petit-Teixeira E, Mbarek H, Prum B, Bardin T, Cornelis F; the European Consortium on Rheumatoid Arthritis Families. The ITGAV rs3738919-C allele is associated with rheumatoid arthritis in the European Caucasian population: a family-based study. Arthritis Res Ther. 2007 Jul 3;9(4):R63

Hansson MG. For the safety and benefit of current and future patients. Pathobiology. 2007;74(4):198-205.

Van der Helm –van Mil et al. A rule to predict disease outcome in patients with recent-onset undifferentiated arthritis to guide individual treatment decisions, Arthritis Rheum . 2007 Feb;56(2):433-40

van der Pouw Kraan TC et al. Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: Assignment of a type I interferon signature in a subpopulation of patients. Ann Rheum Dis . 2007 Jan 12; (partner 22 and 6)

T. C.G. Timmer et al. Identification of the IL-7 signaling pathway in rheumatoid arthritis synovial tissues with lymphoid neogenesis, Arthritis Rheum in press. (partner 22 and 6

Canete JD et al. Ectopic lymphoid neogenesis in psoriatic arthritis., Ann Rheum Dis. 2007 Jan 12; (partner 6)

Cantaert T et al. Citrullinated proteins in rheumatoid arthritis: crucial...but not sufficient! Arthritis Rheum . 2006 Nov;54(11):3381-9. (partner 6)

De Rycke L et al. Pathogenesis of spondyloarthritis: insights from synovial membrane studies. Curr Rheumatol Rep . 2006 Aug;8(4):275-82. (partner 6)

Bongartz et al. Citrullination in extra-articular manifestations of rheumatoid arthritis. Rheumatology ( Oxford ). 2007 Jan;46(1):70-5. (partner 6)

Bessis, N., D. Lemeiter, L. Laroche, C. Fournier, T. Huizinga, H. Brok, H. B. 't, and M. C. Boissier. 2007. Engraftment of cutaneous fibroblasts within synovial membrane in a nonhuman primate: short-term results. Joint Bone Spine 74:48-51. Ref ID: 27

Kruithof E, et al; OMERACT Special Interest Group on Synovial Analysis in Clinical Trials. Identification of synovial biomarkers of response to experimental treatment in early-phase clinical trials in spondyloarthritis. Arthritis Rheum. 2006 Jun;54(6):1795- 804. (partner 5 and 6)

Wijbrandts CA, Dijkgraaf MG, Kraan MC, Vinkenoog M, Smeets TJ, Dinant H, Vos
K, Lems WF, Wolbink GJ, Sijpkens DE, Dijkmans BA, Tak P. The clinical response to infliximab in rheumatoid arthritis is in part dependent on pre-treatment TNF{alpha} expression in the synovium. Ann Rheum Dis. 2007 Nov 29; (partner 6)

Grundtman C, Salomonsson S, Dorph C, Bruton J, Andersson U, Lundberg IE. Immunolocalization of interleukin-1 receptors in the sarcolemma and nuclei of skeletal muscle in patients with idiopathic inflammatory myopathies. Arthritis Rheum . 2007 56:674-87.

Krystufkova O, Wallerskog T, Helmers SB, Malmstrom V, Trollmo C, Lundberg IE. Increased BAFF Serum Levels in Patients with Myositis. Ann Rheum Dis 2007;66:A31(abstract No.078).

Krystufkova O, Wallerskog T, Helmers SB, Mann H, Malmstrom V, Trollmo C, Vencovsky J, Lundberg IE. Serum BAFF levels are increased in patients with myositis and anti-Jo-1 antibodies. Submitted to Congres of Europan League Against Rheumatism.

Lundberg I, Vencovsky J. Inflammatory diseases of muscle and other myopathies.

Van der Straaten R, et al. Exploratory analysis of four polymorphisms in human GGH and FPGS genes and their effect in methotrexate-treated rheumatoid arthritis patients. Pharmacogenomics . 2007 Feb;8(2):141-150.

The Response to TNF-alpha blockade In Rheumatoid Arthritis is in part dependent on TNF-alpha expression in the synovium. Wijbrands et al. ACR abstract 2006, L7/487

TCR{zeta}dim lymphocytes define populations of circulating effector cells that migrate to inflamed tissues. Zhangh Z, et al. Blood. 2007 Jan 25;

Feitsma AL et. al Risk of progression from undifferentiated arthritis to rheumatoid arthritis: the effect of the PTPN22 1858T-allele in anti-citrullinated peptide antibody positive patients. Rheumatology ( Oxford ). 2007 Mar 6; Epub ahead of print

Injections with iDC can lead to the expansion of a novel regulatory population with high immunomodulatory properties that are able to protect mice from CIA (Charbonnier, van Duivenvoorde et al. 2006) .

Charbonnier, L. M., L. M. van Duivenvoorde, et al. (2006). "Immature Dendritic Cells Suppress Collagen-Induced Arthritis by In Vivo Expansion of CD49b+ Regulatory T Cells." J Immunol 177 (6): 3806-13.

Feitsma, A. L., R. E. Toes, A. B. Begovich, A. P. Chokkalingam, R. R. de Vries, T. W. Huizinga, and van der Helm-van Mil AH. 2007. Risk of progression from undifferentiated arthritis to rheumatoid arthritis: the effect of the PTPN22 1858T-allele in anti-citrullinated peptide antibody positive patients. Rheumatology.(Oxford) 46:1092-1095.
Ref ID: 20

Recombinant AAV5 vectors containing a TNF-blocking agent were generated by Arthrogen and validated in animal models of arthritis in collaboration with partner 9 (Adriaansen et al. Ann Rheum. Dis . 2007, accepted for publication, Apparailly et al. submitted for publication

Thurlings RM, Wijbrandts CA, Mebius RE, Cantaert T, Dinant H, van der
Pouw-Kraan TCTM, Baeten D, Tak PP. Synovial Lymphoid Neogenesis Does
not Define A Specific Clinical Rheumatoid Arthritis Phenotype.
Arthritis Rheumatism (in press).

van der Pouw Kraan TC, van Baarsen LG, Wijbrandts CA, Voskuyl AE, Rustenburg F,Baggen JM, Dijkmans BA, Tak PP, Verweij CL. Expression of a pathogen-response program in peripheral blood cells defines a subgroup of Rheumatoid Arthritis patients. Genes Immun. 2007 Oct 11 [Epub ahead of print].

Thurlings RM, Vos K, Wijbrandts CA, Zwinderman A, Gerlag DM, Tak PP. Synovial tissue response to rituximab: mechanism of action and identification of biomarkers of response. Ann Rheum Dis. 2007 Oct 26; [Epub ahead of print].

Baeten D, Kruithof E, Breban M, Tak PP. Spondyloarthritis in the absence of B lymphocytes. Arthritis Rheum (in press).

Vandooren B, Cantaert T, Noordenbos T, Tak PP, Baeten D. The abundant synovial expression of the RANK-RANKL-OPG system in peripheral spondyloarthritis is partially disconnected from inflammation. Arthritis Rheum (in press).

Vergunst CE, Gerlag DM, Dinant H, Schulz L, Vinkenoog M, Smeets TJ, Sanders
ME, Reedquist KA, Tak PP. Blocking the receptor for C5a in patients with rheumatoid arthritis does not reduce synovial inflammation. Rheumatology (Oxford). 2007 Dec;46(12):1773-8. Epub 2007 Oct 27.

Wijbrandts CA, Vergunst CE, Haringman JJ, Gerlag DM, Smeets TJ, Tak PP. Absence of changes in the number of synovial sublining macrophages after ineffective treatment for rheumatoid arthritis: Implications for use of synovial sublining macrophages as a biomarker. Arthritis Rheum. 2007;56:3869-71.

van der Pouw Kraan TC, Wijbrandts CA, van Baarsen LG, Rustenburg F, Baggen JM,Verweij CL, Tak P. Responsiveness to anti-TNF{alpha} therapy is related to pre-treatment tissue inflammation levels in Rheumatoid Arthritis patients. Ann Rheum Dis. 2007 [Epub ahead of print].

Rainer H. Straub, Georg Pongratz, Maurizio Cutolo, Carla A. Wijbrandts, Dominique Baeten, Martin Fleck, Fabiola Atzeni, Mathias Grünke, Joachim R. Kalden, Jürgen Schölmerich, Hanns-Martin Lorenz, Paul P. Tak, Piercarlo Sarzi-Puttini, Baseline adrenal hormones predict improvement during anti-TNF therapy, A&R in press.

Adriaansen J, Khoury M, de Cortie CJ, Fallaux FJ, Bigey P, Scherman D, Gould
DJ, Chernajovsky Y, Apparailly F, Jorgensen C, Vervoordeldonk MJ, Tak PP. Reduction of arthritis following intra-articular administration of an adeno-associated virus serotype 5 expressing a disease-inducible TNF-blocking agent. Ann Rheum Dis. 2007 Sep;66(9):1143-50. Epub 2007 Mar 15.

Paul P. Tak, Novel approaches for the treatment of rheumatoid arthritis – Lessons from evaluation of synovial biomarkers in clinical trials. Best Pract Res Clin Rheumatol (In press).

Feitsma AL, Worthington J, van der Helm-van Mil AH, Plant D, Thomson W, Ursum
J, van Schaardenburg D, van der Horst-Bruinsma IE, van Rood JJ, Huizinga TW, Toes
RE, de Vries RR.
Protective effect of noninherited maternal HLA-DR antigens on rheumatoid
arthritis development.
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19966-70. Epub 2007 Dec 6.

Pincus, T., T. W. Huizinga, and Y. Yazici. 2007. N-of-1 trial of low-dose methotrexate and/or prednisolone in lieu of anti-CCP, MRI, or ultrasound, as first option in suspected rheumatoid arthritis? J.Rheumatol. 34:250-252.
Ref ID: 22

Remans, P. H., C. A. Wijbrandts, M. E. Sanders, R. E. Toes, F. C. Breedveld, P. P. Tak, J. M. van Laar, and K. A. Reedquist. 2006. CTLA-4IG suppresses reactive oxygen species by preventing synovial adherent cell-induced inactivation of Rap1, a Ras family GTPASE mediator of oxidative stress in rheumatoid arthritis T cells. Arthritis Rheum. 54:3135-3143.
Ref ID: 76

Sigurdsson, S., L. Padyukov, F. A. Kurreeman, U. Liljedahl, A. C. Wiman, L. Alfredsson, R. Toes, J. Ronnelid, L. Klareskog, T. W. Huizinga, G. Alm, A. C. Syvanen, and L. Ronnblom. 2007. Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis. Arthritis Rheum. 56:2202-2210.
Ref ID: 8

Steenvoorden, M. M., T. C. Tolboom, P. G. van der, C. Lowik, C. P. Visser, J. Degroot, A. C. Gittenberger-DeGroot, M. C. DeRuiter, B. J. Wisse, T. W. Huizinga, and R. E. Toes. 2006. Transition of healthy to diseased synovial tissue in rheumatoid arthritis is associated with gain of mesenchymal/fibrotic characteristics. Arthritis Res.Ther. 8:R165.
Ref ID: 37

. Steenvoorden, M. M., van der Helm-van Mil AH, G. Stoeken, R. A. Bank, R. R. Devries, T. W. Huizinga, J. Degroot, and R. E. Toes. 2006. The RAGE G82S polymorphism is not associated with rheumatoid arthritis independently of HLA-DRB1*0401. Rheumatology.(Oxford) 45:488-490.
Ref ID: 62

Steenvoorden, M. M., T. W. Huizinga, N. Verzijl, R. A. Bank, H. K. Ronday, H. A. Luning, F. P. Lafeber, R. E. Toes, and J. Degroot. 2006. Activation of receptor for advanced glycation end products in osteoarthritis leads to increased stimulation of chondrocytes and synoviocytes. Arthritis Rheum. 54:253-263.
Ref ID: 63

Steenvoorden, M. M., R. A. Bank, H. K. Ronday, R. E. Toes, T. W. Huizinga, and J. Degroot. 2007. Fibroblast-like synoviocyte-chondrocyte interaction in cartilage degradation. Clin.Exp.Rheumatol. 25:239-245.
Ref ID: 12

Steenvoorden MM, Toes RE, Ronday HK, Huizinga TW, Degroot J.
RAGE activation induces invasiveness of RA fibroblast-like synoviocytes in vitro.
Clin Exp Rheumatol. 2007 Sep-Oct;25(5):740-2.

Swen, J. J., T. W. Huizinga, H. Gelderblom, E. G. de Vries, W. J. Assendelft, J. Kirchheiner, and H. J. Guchelaar. 2007. Translating pharmacogenomics: challenges on the road to the clinic. PLoS.Med. 4:e209.
Ref ID: 5

Tchetverikov, I., M. C. Kraan, B. van El, R. Hanemaaijer, J. Degroot, and T. W. Huizinga. 2007. Leflunomide and methotrexate reduce levels of activated mmps in complexes with {alpha}2macroglobulin in serum of rheumatoid arthritis patients. Ann.Rheum.Dis.
Ref ID: 2

Teng YK, Levarht EW, Hashemi M, Bajema IM, Toes RE, Huizinga TW, van Laar JM.
Immunohistochemical analysis as a means to predict responsiveness to rituximab
treatment.
Arthritis Rheum. 2007 Dec;56(12):3909-18.

Thabet, M. M. and T. W. Huizinga. 2006. Drug evaluation: apratastat, a novel TACE/MMP inhibitor for rheumatoid arthritis. Curr.Opin.Investig.Drugs 7:1014-1019.
Ref ID: 36

Thabet, M. M., J. Wesoly, P. E. Slagboom, R. E. Toes, and T. W. Huizinga. 2007. FCRL3 promoter 169 CC homozygosity is associated with susceptibility to rheumatoid arthritis in Dutch Caucasians. Ann.Rheum.Dis. 66:803-806.
Ref ID: 29

Timmer, T. C., B. Baltus, M. Vondenhoff, T. W. Huizinga, P. P. Tak, C. L. Verweij, R. E. Mebius, and van der Pouw Kraan TC. 2007. Inflammation and ectopic lymphoid structures in rheumatoid arthritis synovial tissues dissected by genomics technology: identification of the interleukin-7 signaling pathway in tissues with lymphoid neogenesis. Arthritis Rheum. 56:2492-2502.
Ref ID: 6

Tolboom, T. C., Y. H. Zhang, N. V. Henriquez, R. G. Nelissen, R. E. Toes, M. H. Noteborn, and T. W. Huizinga. 2006. Fibroblast-like synoviocytes from patients with rheumatoid arthritis are more sensitive to apoptosis induced by the viral protein, apoptin, than fibroblast-like synoviocytes from trauma patients. Clin.Exp.Rheumatol. 24:142-147.
Ref ID: 51

van Aken, J., H. van Dongen, S. le Cessie, C. F. Allaart, F. C. Breedveld, and T. W. Huizinga. 2006. Comparison of long term outcome of patients with rheumatoid arthritis presenting with undifferentiated arthritis or with rheumatoid arthritis: an observational cohort study. Ann.Rheum.Dis. 65:20-25.

van der Helm-van Mil AH, T. W. Huizinga, R. R. de Vries, and R. E. Toes. 2007. Emerging patterns of risk factor make-up enable subclassification of rheumatoid arthritis. Arthritis Rheum. 56:1728-1735.
Ref ID: 13

van der Helm-van Mil AH, S. le Cessie, H. van Dongen, F. C. Breedveld, R. E. Toes, and T. W. Huizinga. 2007. A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: how to guide individual treatment decisions. Arthritis Rheum. 56:433-440.
Ref ID: 25

van der Helm-van Mil AH, K. N. Verpoort, S. le Cessie, T. W. Huizinga, R. R. de Vries, and R. E. Toes. 2007. The HLA-DRB1 shared epitope alleles differ in the interaction with smoking and predisposition to antibodies to cyclic citrullinated peptide. Arthritis Rheum. 56:425-432.
Ref ID: 26

van der Helm-van Mil AH, van der Kooij SM, Allaart CF, Toes RE, Huizinga TW.
A high body mass index is protective on the amount of joint destruction in small
joints in early rheumatoid arthritis.
Ann Rheum Dis. 2007 Oct 26; [Epub ahead of print]

van der, S. R., J. A. Wessels, J. K. Vries-Bouwstra, Y. P. Goekoop-Ruiterman, C. F. Allaart, J. Bogaartz, M. Tiller, T. W. Huizinga, and H. J. Guchelaar. 2007. Exploratory analysis of four polymorphisms in human GGH and FPGS genes and their effect in methotrexate-treated rheumatoid arthritis patients. Pharmacogenomics. 8:141-150.
Ref ID: 23

van Dongen, H., J. van Aken, L. R. Lard, K. Visser, H. K. Ronday, H. M. Hulsmans, I. Speyer, M. L. Westedt, A. J. Peeters, C. F. Allaart, R. E. Toes, F. C. Breedveld, and T. W. Huizinga. 2007. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 56:1424-1432.
Ref ID: 17

van der Woude D, Huizinga TW.
The battle between anti-cyclic citrullinated peptide and rheumatoid factor
tests--a winner at last? Nat Clin Pract Rheumatol. 2007 Dec;3(12):696-7. Epub 2007 Nov 6.

Vencovsky, J. and T. W. Huizinga. 2006. Rheumatoid arthritis: the goal rather than the health-care provider is key. Lancet 367:450-452.
Ref ID: 59

Verpoort, K. N., Jol-van der Zijde CM, Papendrecht-van der Voort EA, A. Ioan-Facsinay, J. W. Drijfhout, M. J. van Tol, F. C. Breedveld, T. W. Huizinga, and R. E. Toes. 2006. Isotype distribution of anti-cyclic citrullinated peptide antibodies in undifferentiated arthritis and rheumatoid arthritis reflects an ongoing immune response. Arthritis Rheum. 54:3799-3808.
Ref ID: 34

Verpoort, K. N., Papendrecht-van der Voort EA, van der Helm-van Mil AH, Jol-van der Zijde CM, M. J. van Tol, J. W. Drijfhout, F. C. Breedveld, R. R. de Vries, T. W. Huizinga, and R. E. Toes. 2007. Association of smoking with the constitution of the anti-cyclic citrullinated peptide response in the absence of HLA-DRB1 shared epitope alleles. Arthritis Rheum. 56:2913-2918.
Ref ID: 4

Verpoort KN, Cheung K, Ioan-Facsinay A, van der Helm-van Mil AH, de
Vries-Bouwstra JK, Allaart CF, Drijfhout JW, de Vries RR, Breedveld FC, Huizinga
TW, Pruijn GJ, Toes RE.
Fine specificity of the anti-citrullinated protein antibody response is
influenced by the shared epitope alleles.
Arthritis Rheum. 2007 Dec;56(12):3949-52.

Vries-Bouwstra, J. K., Y. P. Goekoop-Ruiterman, J. Wesoly, H. J. Hulsmans, A. J. de Craen, F. C. Breedveld, B. A. Dijkmans, C. F. Allaart, and T. W. Huizinga. 2007. Ex vivo interleukin 1 receptor antagonist production on lipopolysaccharide stimulation is associated with rheumatoid arthritis and with joint damage. Ann.Rheum.Dis. 66:1033-1037.
Ref ID: 28

Wesoly, J., X. Hu, M. M. Thabet, M. Chang, H. Uh, C. F. Allaart, R. E. Toes, J. J. Houwing-Duistermaat, A. B. Begovich, and T. W. Huizinga. 2007. The 620W allele is the PTPN22 genetic variant conferring susceptibility to RA in a Dutch population. Rheumatology.(Oxford) 46:617-621.
Ref ID: 33

Wessels, J. A., W. M. Kooloos, R. De Jonge, J. K. Vries-Bouwstra, C. F. Allaart, A. Linssen, G. Collee, P. De Sonnaville, J. Lindemans, T. W. Huizinga, and H. J. Guchelaar. 2006. Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 54:2830-2839.
Ref ID: 45

Wessels, J. A., S. M. van der Kooij, S. le Cessie, W. Kievit, P. Barerra, C. F. Allaart, T. W. Huizinga, and H. J. Guchelaar. 2007. A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Arthritis Rheum. 56:1765-1775.
Ref ID: 15

Wessels JA, Huizinga TW, Guchelaar HJ.
Recent insights in the pharmacological actions of methotrexate in the treatment
of rheumatoid arthritis.
Rheumatology (Oxford). 2008 Mar;47(3):249-55. Epub 2007 Nov 28.

2006

Spanakis E, Sidiropoulos P, Papadakis J, Ganotakis E, Katsikas G, Karvounaris
S, Bizaki A, Kritikos H, Boumpas DT. Modest but sustained increase of serum high density lipoprotein cholesterol levels in patients with inflammatory arthritides treated with infliximab. J Rheumatol. 2006 Dec;33(12):2440-6

Thabet et al, Ann Rheum Dis 2006: Dec 19. FCRL3 promoter 169CC homozygosity is associated with susceptibility to rheumatoid arthritis in Dutch Caucasians. (Partner 2)

Michou L et al , Proc Natl Acad Sc i 2007 Jan 30; 104(5):1649-54. Linkage proof for PTPN22, a rheumatoid arthritis susceptibility gene and a human autoimmunity gene. (Partner 18)

Wang, J. , A. Ioan-Facsinay, E. I. H. van der Voort, T. W. J. Huizinga and R. E. M. Toes. 2007. Transient expression of FOXP3 in human activated non-regulatory CD4+ T cells. Eur. J. Immunol . 37, 129-138.

Charbonnier, L. M., L. M. van Duivenvoorde, F. Apparailly, C. Cantos, W. G. Han, D. Noel, C. Duperray, T. W. Huizinga, R. E. Toes, C. Jorgensen, and P. Louis-Plence. 2006. Immature dendritic cells suppress collagen-induced arthritis by in vivo expansion of CD49b+ regulatory T cells. J.Immunol. 177:3806-3813.
Ref ID: 44

Linn-Rasker, S. P., van der Helm-van Mil AH, F. A. van Gaalen, M. Kloppenburg, R. R. de Vries, S. le Cessie, F. C. Breedveld, R. E. Toes, and T. W. Huizinga. 2006. Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann.Rheum.Dis. 65:366-371.
Ref ID: 70

Linn-Rasker, S. P., van der Helm-van Mil AH, F. C. Breedveld, and T. W. Huizinga. 2007. Arthritis of the large joints - in particular, the knee - at first presentation is predictive for a high level of radiological destruction of the small joints in rheumatoid arthritis. Ann.Rheum.Dis. 66:646-650.
Ref ID: 32

de Vries, R. R., T. W. Huizinga, and R. E. Toes. 2006. HLA and RA revisited: citrullinated food for the SE hypothesis, the DR6 effect, and NIMA. Hum.Immunol. 67:454-459.
Ref ID: 53

van der Helm-van Mil AH, F. C. Breedveld, and T. W. Huizinga. 2006. Aspects of early arthritis. Definition of disease states in early arthritis: remission versus minimal disease activity. Arthritis Res.Ther. 8:216.
Ref ID: 49

van der Helm-van Mil AH, M. Kern, P. K. Gregersen, and T. W. Huizinga. 2006. Variation in radiologic joint destruction in rheumatoid arthritis differs between monozygotic and dizygotic twins and pairs of unrelated patients. Arthritis Rheum. 54:2028-2030.
Ref ID: 52

van der Helm-van Mil AH, K. N. Verpoort, F. C. Breedveld, T. W. Huizinga, R. E. Toes, and R. R. de Vries. 2006. The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum. 54:1117-1121.
Ref ID: 54

van Duivenvoorde, L. M., G. J. van Mierlo, Z. F. Boonman, and R. E. Toes. 2006. Dendritic cells: vehicles for tolerance induction and prevention of autoimmune diseases. Immunobiology 211:627-632.
Ref ID: 78

van Duivenvoorde, L. M., W. G. Han, A. M. Bakker, P. Louis-Plence, L. M. Charbonnier, F. Apparailly, E. I. van der Voort, C. Jorgensen, T. W. Huizinga, and R. E. Toes. 2007. Immunomodulatory dendritic cells inhibit Th1 responses and arthritis via different mechanisms. J.Immunol. 179:1506-1515.
Ref ID: 7

Vries-Bouwstra, J., S. le Cessie, C. Allaart, F. Breedveld, and T. Huizinga. 2006. Using predicted disease outcome to provide differentiated treatment of early rheumatoid arthritis. J.Rheumatol. 33:1747-1753.
Ref ID: 50

Wesoly, J., J. A. Wessels, H. J. Guchelaar, and T. W. Huizinga. 2006. Genetic markers of treatment response in rheumatoid arthritis. Curr.Rheumatol.Rep. 8:369-377.
Ref ID: 42

Wessels, J. A., J. K. Vries-Bouwstra, B. T. Heijmans, P. E. Slagboom, Y. P. Goekoop-Ruiterman, C. F. Allaart, P. J. Kerstens, D. van Zeben, F. C. Breedveld, B. A. Dijkmans, T. W. Huizinga, and H. J. Guchelaar. 2006. Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum. 54:1087-1095.
Ref ID: 55

Klareskog L, Padyukov L, Lorentzen J, Alfredsson L

Rheumatoid arthritis (RA) is a complex disease in which environmental agents are thought to interact with genetic factors that influence susceptibility. This interaction triggers immunologic events that eventually result in the clinical signs of arthritis. Knowledge of the chain of etiological events that lead to the development of RA is incomplete. In this review, we describe the experimental approaches that are used to address the issue of gene-environment interactions in the etiology of RA, and discuss relevant examples of such interactions. We focus on how smoking, the best-known environmental risk factor for RA, interacts with HLA-DR shared epitope genes, the main genetic risk factors for RA, and result in a high risk of RA in individuals exposed to both of these risk factors. From these and other related findings, we can begin to define the distinct environmental risk factors (such as smoking) that in certain genetic contexts (for example, the presence of HLA-DR shared epitope alleles) can trigger immune reactions (such as autoantibodies to citrullinated peptides) many years before onset of RA, and consider how these immune reactions might contribute to clinical symptoms in a subset of affected patients. Increased knowledge about these and other events involved in the development of RA should enable the design of new tools for suppressing RA pathogenesis before the onset of disease. Nat Cli n Pract Rheumatol 2006;2:425-433. Article as pdf

L Michou , P Croiseau, E Petit-Teixeira, S Tezenas du Montcel,
I Lemaire, C Pierlot, J Osorio , W Frigui, S Lasbleiz, P Quillet, T Bardin, B Prum, F Clerget-Darpoux,
F Cornélis and the European Consortium on Rheumatoid Arthritis Families

Validation of the reshaped shared epitope HLA-DRB1 classification in rheumatoid arthritis

Abstract

Recently, we proposed a classification of HLA-DRB1 alleles that reshapes the shared epitope hypothesis in rheumatoid arthritis (RA); according to this model, RA is associated with the RAA shared epitope sequence (72–74 positions) and the association is modulated by the amino acids at positions 70 and 71, resulting in six genotypes with different RA risks. This was the first model to take into account the association between the HLA-DRB1 gene and RA, and linkage data for that gene. In the present study we tested this classification for validity in an independent sample. A new sample of the same size and population (100 RA French Caucasian families) was genotyped for the HLA-DRB1 gene. The alleles were grouped as proposed in the new classification: S 1 alleles for the sequences A-RAA or E-RAA; S 2 for Q or D-K-RAA; S 3D for D-R-RAA; S 3P for Q or R-R-RAA; and X alleles for no RAA sequence. Transmission of the alleles was investigated. Genotype odds ratio (OR) calculations were performed through conditional logistic regression, and we tested the homogeneity of these ORs with those of the 100 first trio families (one case and both parents) previously reported. As previously observed, the S 2 and S 3P alleles were significantly over-transmitted and the S 1 , S 3D and X alleles were under-transmitted. The latter were grouped as L alleles, resulting in the same three-allele classification. The risk hierarchy of the six derived genotypes was the same: (by decreasing OR and with L/L being the reference genotype) S 2 /S 3P , S 2 /S 2 , S 3P /S 3P , S 2 /L and S 3P /L. The homogeneity test between the ORs of the initial and the replication samples revealed no significant differences. The new classification was therefore considered validated, and both samples were pooled to provide improved estimates of RA risk genotypes from the highest (S 2 /S 3P [OR 22.2, 95% confidence interval 9.9–49.7]) to the lowest (S 3P /L [OR 4.4, 95% confidence interval 2.3–8.4]).

Arthritis Research & Therapy 2006, 8:R79 (doi:10.1186/ar1949)
Article as PDF

Mahr S, Burmester GR, Hilke D, Gobel U, Grutzkau A, Haupl T, Hauschild M, Koczan D, Krenn V, Neidel J, Perka C, Radbruch A, Thiesen HJ, Muller B.

Institute for Immunology, Medical Faculty, University of Rostock, Rostock, Germany.

Cis- and trans-acting gene regulation is associated with osteoarthritis

Osteoarthritis (OA) is a complex disease of the skeleton and is associated with aging. Both environmental and genetic factors contribute to its pathogenesis. We set out to identify novel genes associated with OA, concentrating on regulatory polymorphisms allowing for differential expression. Our strategy to identify differentially expressed genes included an initial transcriptome analysis of the peripheral blood mononuclear cells of six patients with OA and six age-matched healthy controls. These were screened for allelic expression imbalances and potentially regulatory single-nucleotide polymorphisms (SNPs) in the 5' regions of the genes. To establish disease association, disparate promoter SNP distributions correlating with the differential expression were tested on larger cohorts. Our approach yielded 26 candidate genes differentially expressed between patients and controls. Whereas BLP2 and CIAS1 seem to be trans-regulated, as the absence of allelic expression imbalances suggests, the presence of allelic imbalances confirms cis-regulatory mechanisms for RHOB and TXNDC3. Interestingly, on/off-switching suggests additional trans-regulation for TXNDC3. Moreover, we demonstrate for RHOB and TXNDC3 statistically significant associations between 5' SNPs and the disease that hint at regulatory functions. Investigating the respective genes functionally will not only shed light on the disease association but will also add to the understanding of the pathogenic processes involved in OA and may point out novel therapeutic approaches.
Am J Hum Genet. 2006 May;78(5):793-803

Makrygiannakis D, Af Klint E, Catrina SB, Botusan IR, Klareskog E, Klareskog L, Ulfgren AK, Catrina AI.

Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.

Intraarticular corticosteroids decrease synovial RANKL expression in inflammatory arthritis

OBJECTIVE: Intraarticular corticosteroids are frequently used as successful adjuvant therapy for inflammatory arthritides, but little is known about their effects on molecules that regulate bone biology. We undertook this study to investigate the effect of intraarticular corticosteroids on the synovial expression of RANKL and osteoprotegerin (OPG). METHODS: We evaluated RANKL, OPG, and surface marker expression by immunohistochemical methods in synovial knee biopsy samples obtained from 13 patients with inflammatory arthritis before and 2 weeks following intraarticular injection of triamcinolone hexacetonide. We further investigated the effect of dexamethasone (DEX) on RANKL expression by lymphocytes from rheumatoid arthritis synovial fluids (RA SF), using flow cytometric analysis. Finally, we evaluated the in vitro effect of DEX on RANKL and OPG expression in osteoblast-like cells, by Western blotting. RESULTS: Intraarticular corticosteroids induced a decrease in the number of synovial T cells without influencing the number of macrophages, evaluated as both CD68+ and CD163+ cells. This change was paralleled by a decrease of synovial RANKL expression with a concomitant reduction of the RANKL:OPG ratio. DEX down-regulated RANKL expression on lymphocytes derived from RA SF. Moreover, in vitro pretreatment of osteoblast-like cells with tumor necrosis factor favored an antiresorptive effect of DEX treatment through a similar down-regulation of RANKL expression. CONCLUSION: The decrease in inflammation attributed to intraarticular corticosteroids is accompanied by down-modulation of bone destruction markers. These findings offer a rationale for the beneficial effect of corticosteroids on joint erosion in arthritis.
Arthritis Rheum. 2006 May;54(5):1463-72.