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The aim of the study is to explore whether the influence of gender, tobacco smoking and obesity on treatment response in tumor necrosis factor inhibitors (TNFIs) can be explained by high degree of inflammation, human leucocyte antigen (HLA) type, autoantibodies, TNF and TNFI concentration and presence of ADA.
Tumor necrosis factor inhibitors (TNFIs) have been uses with success since 1999 in Denmark in treatment of various inflammatory diseases, eg. rheumatoid arthritis (RA), Chrohn's disease, psoriasis, psoriatic arthritis (PsA) and ankylosing spondylitis (AS).
TNFIs block a central cytokine in the inflammatory process, tumor necrosis factor (TNF).
Because the drugs are large proteins, they are prone to trigger an immune response and elicit anti-drug antibodies(ADA).
Epidemiologic studies have revealed that groups of patients (women, tobacco smokers, obese patients) with inflammatory rheumatic diseases have a lower response to TNFIs. The reasons for this are not fully elucidated. The hypothesis is that immunogenicity and changed pharmacokinetic of TNFI are causes of the inferior response.
The investigators will carry out a prospective clinical studies of 120 arthritis patients (RA, PsA and AS) initiating treatment with adalimumab or infliximab. The patients will be followed for 12 months and will be registered in DANBIO as normal praxis. Blood samples will be collected at baseline, 2, 4 and 12 months or at termination of the treatment.
Genotypes, autoantibodies, inflammation markers, TNFI and ADA will be measured.
The aim of the study is to explore:
A: If differences between men and women with respect to different markers of inflammation, human leucocyte antigen (HLA), autoantibodies, TNFI concentration and presence of ADAs can explain the lower response and adherence to the treatment among women.
B: If differences between smokers and non-smokers with respect to different markers of inflammation, HLA, autoantibodies, TNFI concentration and presence of ADAs can explain the lower response and adherence to the treatment among patients with arthritis who smoke tobacco.
C: If differences between obese and normal weight patients with respect to different markers of inflammation, HLA, autoantibodies, TNFI concentration and presence of ADAs can explain the lower response and adherence to the treatment.
The study will contribute with new knowledge, which hopefully can make the treatment more personalized and efficient.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patient with arthritis starting infliximab or adalimumab | Patients with Rheumatoid Artritis, Psoriatic Arthritis, Anchylosing Spondylitis starting treament with infliximab or adalimumab |
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| Measure | Description | Time Frame |
|---|---|---|
| Treatment response | Changes in disease activity score according to the diagnose. A reduction in the disease activity score indicates a good treatment response.
| 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Immunogenesity | Antibodies directed against infliximab or adalimumab. Concentration of anti-drug-antibodies | 12 months |
| Drug koncentration | Plasma koncentration of infliximab or adalimumab |
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Inclusion Criteria:
Exclusion Criteria:
-
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Patients at department of Rheumatology in Aalborg Universityhospital, Denmark. Other sites in Jutland, Denmark may be inkluded later.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Karen B Lauridsen, MD | Contact | 0045 097665595 | kabula@rn.dk |
| Name | Affiliation | Role |
|---|---|---|
| Lene Dreyer, MD, Prof. | Department of Clinical Medicine, Aalborg University and Aalborg University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of rheumatology | Recruiting | Aalborg | 8000 | Denmark |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 18155297 | Background | Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008 Feb;117(2):244-79. doi: 10.1016/j.pharmthera.2007.10.001. Epub 2007 Oct 26. | |
| 7934491 | Background | Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet. 1994 Oct 22;344(8930):1105-10. doi: 10.1016/s0140-6736(94)90628-9. |
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| ID | Term |
|---|---|
| D001172 | Arthritis, Rheumatoid |
| D015535 | Arthritis, Psoriatic |
| D013167 | Spondylitis, Ankylosing |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
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EDTA Whole Blood EDTA-plasma, EDTA-buffy coat, serum.
| 12 months |
| Concentration of markers of inflammation | C-reactive protein (CRP), IL1, . | 12 months |
| Concentration of autoantibodies | ANA, ACPA, IgM-RF | Day 1 |
| HLA-type | Genomic determination of Human Leucocyte antigens | Day 1 |
| 27135483 | Background | Steenholdt C, Bendtzen K, Brynskov J, Ainsworth MA. Optimizing Treatment with TNF Inhibitors in Inflammatory Bowel Disease by Monitoring Drug Levels and Antidrug Antibodies. Inflamm Bowel Dis. 2016 Aug;22(8):1999-2015. doi: 10.1097/MIB.0000000000000772. |
| 25342759 | Background | van Schie KA, Hart MH, de Groot ER, Kruithof S, Aarden LA, Wolbink GJ, Rispens T. The antibody response against human and chimeric anti-TNF therapeutic antibodies primarily targets the TNF binding region. Ann Rheum Dis. 2015 Jan;74(1):311-4. doi: 10.1136/annrheumdis-2014-206237. Epub 2014 Oct 23. |
| 29158574 | Background | Kalden JR, Schulze-Koops H. Immunogenicity and loss of response to TNF inhibitors: implications for rheumatoid arthritis treatment. Nat Rev Rheumatol. 2017 Nov 21;13(12):707-718. doi: 10.1038/nrrheum.2017.187. |
| 25985765 | Background | Meroni PL, Valentini G, Ayala F, Cattaneo A, Valesini G. New strategies to address the pharmacodynamics and pharmacokinetics of tumor necrosis factor (TNF) inhibitors: A systematic analysis. Autoimmun Rev. 2015 Sep;14(9):812-29. doi: 10.1016/j.autrev.2015.05.001. Epub 2015 May 15. |
| 26367860 | Background | Mould DR. The Pharmacokinetics of Biologics: A Primer. Dig Dis. 2015;33 Suppl 1:61-69. doi: 10.1159/000437077. Epub 2015 Sep 14. |
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| 29893926 | Background | Hojgaard P, Ballegaard C, Cordtz R, Zobbe K, Clausen M, Glintborg B, Kristensen LE, Dreyer L. Gender differences in biologic treatment outcomes-a study of 1750 patients with psoriatic arthritis using Danish Health Care Registers. Rheumatology (Oxford). 2018 Sep 1;57(9):1651-1660. doi: 10.1093/rheumatology/key140. |
| 28762060 | Background | Chimenti MS, Triggianese P, Conigliaro P, Tonelli M, Gigliucci G, Novelli L, Teoli M, Perricone R. A 2-year observational study on treatment targets in psoriatic arthritis patients treated with TNF inhibitors. Clin Rheumatol. 2017 Oct;36(10):2253-2260. doi: 10.1007/s10067-017-3769-4. Epub 2017 Jul 31. |
| 30824404 | Background | Kennedy NA, Heap GA, Green HD, Hamilton B, Bewshea C, Walker GJ, Thomas A, Nice R, Perry MH, Bouri S, Chanchlani N, Heerasing NM, Hendy P, Lin S, Gaya DR, Cummings JRF, Selinger CP, Lees CW, Hart AL, Parkes M, Sebastian S, Mansfield JC, Irving PM, Lindsay J, Russell RK, McDonald TJ, McGovern D, Goodhand JR, Ahmad T; UK Inflammatory Bowel Disease Pharmacogenetics Study Group. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol. 2019 May;4(5):341-353. doi: 10.1016/S2468-1253(19)30012-3. Epub 2019 Feb 27. |
| 15708927 | Background | Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis. 2005 Mar;64 Suppl 2(Suppl 2):ii14-7. doi: 10.1136/ard.2004.032482. |
| 28483767 | Background | Egeberg A, Kristensen LE, Thyssen JP, Gislason GH, Gottlieb AB, Coates LC, Jullien D, Gisondi P, Gladman DD, Skov L, Mallbris L. Incidence and prevalence of psoriatic arthritis in Denmark: a nationwide register linkage study. Ann Rheum Dis. 2017 Sep;76(9):1591-1597. doi: 10.1136/annrheumdis-2016-210963. Epub 2017 May 8. |
| 16855148 | Background | Kvien TK, Uhlig T, Odegard S, Heiberg MS. Epidemiological aspects of rheumatoid arthritis: the sex ratio. Ann N Y Acad Sci. 2006 Jun;1069:212-22. doi: 10.1196/annals.1351.019. |
| 28686639 | Background | Rifbjerg-Madsen S, Christensen AW, Christensen R, Hetland ML, Bliddal H, Kristensen LE, Danneskiold-Samsoe B, Amris K. Pain and pain mechanisms in patients with inflammatory arthritis: A Danish nationwide cross-sectional DANBIO registry survey. PLoS One. 2017 Jul 7;12(7):e0180014. doi: 10.1371/journal.pone.0180014. eCollection 2017. |
| 27651526 | Background | Hojgaard P, Glintborg B, Kristensen LE, Gudbjornsson B, Love TJ, Dreyer L. The influence of obesity on response to tumour necrosis factor-alpha inhibitors in psoriatic arthritis: results from the DANBIO and ICEBIO registries. Rheumatology (Oxford). 2016 Dec;55(12):2191-2199. doi: 10.1093/rheumatology/kew326. Epub 2016 Sep 19. |
| 24354889 | Background | Ternant D, Ducourau E, Perdriger A, Corondan A, Le Goff B, Devauchelle-Pensec V, Solau-Gervais E, Watier H, Goupille P, Paintaud G, Mulleman D. Relationship between inflammation and infliximab pharmacokinetics in rheumatoid arthritis. Br J Clin Pharmacol. 2014 Jul;78(1):118-28. doi: 10.1111/bcp.12313. |
| 28721154 | Background | Ellulu MS, Patimah I, Khaza'ai H, Rahmat A, Abed Y. Obesity and inflammation: the linking mechanism and the complications. Arch Med Sci. 2017 Jun;13(4):851-863. doi: 10.5114/aoms.2016.58928. Epub 2016 Mar 31. |
| 26772647 | Background | Perricone C, Versini M, Ben-Ami D, Gertel S, Watad A, Segel MJ, Ceccarelli F, Conti F, Cantarini L, Bogdanos DP, Antonelli A, Amital H, Valesini G, Shoenfeld Y. Smoke and autoimmunity: The fire behind the disease. Autoimmun Rev. 2016 Apr;15(4):354-74. doi: 10.1016/j.autrev.2016.01.001. Epub 2016 Jan 7. |
| 19447930 | Background | Mattey DL, Brownfield A, Dawes PT. Relationship between pack-year history of smoking and response to tumor necrosis factor antagonists in patients with rheumatoid arthritis. J Rheumatol. 2009 Jun;36(6):1180-7. doi: 10.3899/jrheum.081096. Epub 2009 May 15. |
| 26628579 | Background | Glintborg B, Hojgaard P, Lund Hetland M, Steen Krogh N, Kollerup G, Jensen J, Chrysidis S, Jensen Hansen IM, Holland-Fischer M, Hojland Hansen T, Nilsson C, Espesen J, Nordin H, Rasmussen Loft AG, Pelck R, Lorenzen T, Flejsborg Oeftiger S, Unger B, Jaeger F, Mosborg Petersen P, Rasmussen C, Dreyer L. Impact of tobacco smoking on response to tumour necrosis factor-alpha inhibitor treatment in patients with ankylosing spondylitis: results from the Danish nationwide DANBIO registry. Rheumatology (Oxford). 2016 Apr;55(4):659-68. doi: 10.1093/rheumatology/kev392. Epub 2015 Nov 30. |
| 25063827 | Background | Hojgaard P, Glintborg B, Hetland ML, Hansen TH, Lage-Hansen PR, Petersen MH, Holland-Fischer M, Nilsson C, Loft AG, Andersen BN, Adelsten T, Jensen J, Omerovic E, Christensen R, Tarp U, Ostgard R, Dreyer L. Association between tobacco smoking and response to tumour necrosis factor alpha inhibitor treatment in psoriatic arthritis: results from the DANBIO registry. Ann Rheum Dis. 2015 Dec;74(12):2130-6. doi: 10.1136/annrheumdis-2014-205389. Epub 2014 Jul 25. |
| 26424837 | Background | Kiely PD. Biologic efficacy optimization--a step towards personalized medicine. Rheumatology (Oxford). 2016 May;55(5):780-8. doi: 10.1093/rheumatology/kev356. Epub 2015 Sep 30. |
| 24326008 | Background | Pouw MF, Krieckaert CL, Nurmohamed MT, van der Kleij D, Aarden L, Rispens T, Wolbink G. Key findings towards optimising adalimumab treatment: the concentration-effect curve. Ann Rheum Dis. 2015 Mar;74(3):513-8. doi: 10.1136/annrheumdis-2013-204172. Epub 2013 Dec 10. |
| 19939280 | Background | Mulleman D, Meric JC, Paintaud G, Ducourau E, Magdelaine-Beuzelin C, Valat JP, Goupille P; Centre National de la Recherche Scientifique UMR 6239 GICC. Infliximab concentration monitoring improves the control of disease activity in rheumatoid arthritis. Arthritis Res Ther. 2009;11(6):R178. doi: 10.1186/ar2867. Epub 2009 Nov 25. |
| 27822121 | Background | Ibfelt EH, Jensen DV, Hetland ML. The Danish nationwide clinical register for patients with rheumatoid arthritis: DANBIO. Clin Epidemiol. 2016 Oct 25;8:737-742. doi: 10.2147/CLEP.S99490. eCollection 2016. |
| 28612180 | Background | Strand V, Balsa A, Al-Saleh J, Barile-Fabris L, Horiuchi T, Takeuchi T, Lula S, Hawes C, Kola B, Marshall L. Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review. BioDrugs. 2017 Aug;31(4):299-316. doi: 10.1007/s40259-017-0231-8. |
| 30420245 | Background | Quistrebert J, Hassler S, Bachelet D, Mbogning C, Musters A, Tak PP, Wijbrandts CA, Herenius M, Bergstra SA, Akdemir G, Johannesson M, Combe B, Fautrel B, Chollet-Martin S, Gleizes A, Donnellan N, Deisenhammer F, Davidson J, Hincelin-Mery A, Donnes P, Fogdell-Hahn A, De Vries N, Huizinga T, Abugessaisa I, Saevarsdottir S, Hacein-Bey-Abina S, Pallardy M, Broet P, Mariette X; ABIRISK Consortium. Incidence and risk factors for adalimumab and infliximab anti-drug antibodies in rheumatoid arthritis: A European retrospective multicohort analysis. Semin Arthritis Rheum. 2019 Jun;48(6):967-975. doi: 10.1016/j.semarthrit.2018.10.006. Epub 2018 Oct 12. |
| 29701536 | Background | Siljehult F, Arlestig L, Eriksson C, Rantapaa-Dahlqvist S. Concentrations of infliximab and anti-drug antibodies in relation to clinical response in patients with rheumatoid arthritis. Scand J Rheumatol. 2018 Sep;47(5):345-350. doi: 10.1080/03009742.2018.1433232. Epub 2018 Apr 27. |
| D003240 |
| Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D025242 | Spondylarthropathies |
| D025241 | Spondylarthritis |
| D013166 | Spondylitis |
| D013122 | Spinal Diseases |
| D001847 | Bone Diseases |
| D011565 | Psoriasis |
| D017444 | Skin Diseases, Papulosquamous |
| D012871 | Skin Diseases |
| D000089183 | Axial Spondyloarthritis |
| D000844 | Ankylosis |