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COBRA therapy – Clinical trials and follow-up research

Boers M, Verhoeven AC, Markusse HM , van de Laar MA, Westhovens R, van Denderen JC, van Zeben D, Dijkmans BA, Peeters AJ, Jacobs P, van den Brink HR, Schouten HJ, van der Heijde DM, Boonen A, van der Linden S. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997;350:309-18.
In this very first article on COBRA therapy, the original randomized controlled trial is described in 155 early RA patients are randomized into two treatment groups: the COBRA group and the sulphasalazine group. Important conclusions are that treatment with COBRA therapy leads to faster suppression of disease activity and delay in the rate of radiological progression, compared to traditional monotherapy with sulphasalazine. Disease activity was almost immediately improved in patients using the COBRA therapy and  toxicity was low and equal between treatment groups.

Landewé RB, Boers M, Verhoeven AC, Westhovens R, van de Laar MA, Markusse HM, van Denderen JC, Westedt ML, Peeters AJ, Dijkmans BA, Jacobs P, Boonen A, van der Heide DM, van der Linden S. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum 2002;46:347-56.
In this article, five years follow up of the COBRA trial is described: damage control persists for up to 5 years after treatment, independent of subsequent DMARD use and disease activity.

van Tuyl LHD, Lems WF, Voskuyl AE, Kerstens PJSM, Garnero P, Dijkmans BAC, Boers M. Tight control and intensified COBRA combination therapy in rheumatoid arthritis: 90% remission in a pilot trial. Ann Rheum Dis 2008.
This article describes a pilot trial in which 90% of early RA patients achieves DAS28 remission, through tight control and intensified COBRA combination therapy.

COBRA therapy – cost-effectiveness

Verhoeven AC, Bibo JC, Boers M, Engel GL, van der Linden S. Cost-effectiveness and cost-utility of combination therapy in early rheumatoid arthritis: randomized comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone. COBRA Trial Group. Combinatietherapie Bij Reumatoide Artritis.
Br J Rheumatol 1998;37:1102-9

Direct costs are costs directly related to therapy and care. Cost-effectiveness and cost-utility of COBRA was better than SSZ due to similar or lower direct costs and better efficacy. Higher costs of the combination drugs was offset by lower use of NSAIDs and gastroprotection.

Korthals-de Bos I, Van Tulder M, Boers M, Verhoeven AC, Ader HJ, Bibo J, Boonen A, van der Linden S. Indirect and total costs of early rheumatoid arthritis: a randomized comparison of combined step-down prednisolone, methotrexate, and sulfasalazine with sulfasalazine alone.
J Rheumatol 2004;31:1709-16

Indirect costs concern societal costs related to loss of productive time caused by the disease or the associated health care; Totoal costs are the sum of direct costs and total costs. In this article it was confirmed that COBRA therapy adds additional disease control (improvements in disease activity, physical function, and rate of damage progression) at lower or equal cost compared to SSZ in early RA.

COBRA therapy – Implementation

van Tuyl LHD, Plass AMC, Lems WF, Voskuyl AE, Dijkmans BAC, Boers M. Why are rheumatologists reluctant to use the COBRA treatment strategy in early rheumatoid arthritis? Ann Rheum Dis 2007;66:974-976.
This article describes the results of a short questionnaire among all Dutch rheumatologists, in which their opinion and attitude towards COBRA therapy was investigated. It was seen that the average attitude towards the COBRA therapy was positive, and was mainly caused by high scores on the items effectiveness and safety. However, COBRA therapy was also perceived as somewhat complex to administer. In contrast to this positive attitude, most respondents did not intend to prescribe COBRA therapy in the near future.

van Tuyl LHD, Plass AMC, Lems WF, Voskuyl AE, Kerstens PJSM, Dijkmans BAC, Boers M. Discordant perspectives of rheumatologists and patients on COBRA combination therapy in rheumatoid arthritis. Rheumatology 2008.
This article describes the qualitative investigation of opinions of both rheumatologists and patients towards COBRA therapy: rheumatologists were positive concerning effectiveness of COBRA therapy, but highly concerned about their patients’ possible negative reaction to the large amount of pills to be prescribed. In addition, rheumatologists perceived lack of time explaining and prescribing COBRA therapy. Patients were positive about an aggressive combination therapy such as COBRA, and they had no qualms taking many pills if this could improve their prognosis. A decrease in the amount of pills after intensive treatment was highly appreciated.

COBRA therapy – Use of the trial dataset

Lassere M, Boers M, van der Heijde D, Boonen A, Edmonds J, Saudan A, Verhoeven AC. Smallest detectable difference in radiological progression. J Rheumatol 1999;26:731-9.

Mottonen TT, Hannonen PJ, Boers M. Combination DMARD therapy including corticosteroids in early rheumatoid arthritis. Clin Exp Rheumatol 1999;17:S59-S65.

van Gestel AM, Anderson JJ, van Riel PL, Boers M, Haagsma CJ, Rich B, Wells G, Lange ML, Felson DT. ACR and EULAR improvement criteria have comparable validity in rheumatoid arthritis trials. American College of Rheumatology European League of Associations for Rheumatology. J Rheumatol 1999;26:705-11.

Verhoeven AC, Boers M, van der Linden S. Responsiveness of the core set, response criteria, and utilities in early rheumatoid arthritis. Ann Rheum Dis 2000;59:966-74.

Anderson JJ, Wells G, Verhoeven AC, Felson DT. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum 2000;43:22-9.

Verhoeven AC, Boers M, te Koppele JM, van der Laan WH, Markusse HM, Geusens P, van der Linden S. Bone turnover, joint damage and bone mineral density in early rheumatoid arthritis treated with combination therapy including high-dose prednisolone. Rheumatology (Oxford) 2001;40:1231-7.

Boers M, Kostense PJ, Verhoeven AC, van der Linden S; COBRA trial Group. Inflammation and damage in an individual joint predict further damage in that joint in patients with early rheumatoid arthritis. Arthritis Rheum 2001;44:2242-6.

Bruynesteyn K, van der HD, Boers M, Verhoeven A, Boonen A, van der Linden S; COBRA trial Group. Contribution of progression of erosive damage in previously eroded joints in early rheumatoid arthritis trials: COBRA trial as an example. Arthritis Rheum 2002;47:532-6.

Bruynesteyn K, van der Heijde D, Boers M, Daudan A, Peloso P, Paulus H, Houben H, Griffiths B, Edmonds J, Bresnihan B, Boonen A, van der Linden S. Detecting radiological changes in rheumatoid arthritis that are considered important by clinical experts: influence of reading with or without known sequence. J Rheumatol 2002;29:2306-12.

Garnero P, Landewe R, Boers M, Verhoeven A, van der Linden S, Christgau S, van der Heijde D, Boonen A, Geusens P. Association of baseline levels of markers of bone and cartilage degradation with long-term progression of joint damage in patients with early rheumatoid arthritis: the COBRA study. Arthritis Rheum 2002;46:2847-56.

Lard LR, Boers M, Verhoeven A, Vos K, Visser H, Hazes JM, Zwinderman AH, Schreuder GM, Breedveld FC, de Vries RR, van der Linden S, Zanelli E, Huizinga TW. Early and aggressive treatment of rheumatoid arthritis patients affects the association of HLA class II antigens with progression of joint damage. Arthritis Rheum 2002;46:899-905.

Boers M, Nurmohamed MT, Doelman CJ Lard LR, Verhoeven AC, Voskuyl AE, Huizinga TW, van de Stadt RJ, Dijkmans BA, van der Linden S. Influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis. Ann Rheum Dis 2003;62:842-5.

Bijlsma JW, Boers M, Saag KG, Furst DE. Glucocorticoids in the treatment of early and late RA. Ann Rheum Dis 2003;62:1033-7.

Bruynesteyn K, van der Heijde D, Boers M, van der LS, Lassere M, van der Vleuten C. The Sharp/van der Heijde method out-performed the Larsen/Scott method on the individual patient level in assessing radiographs in early rheumatoid arthritis. J Clin Epidemiol 2004;57:502-12.

Landewe R, Geusens P, Boers M, van der Heijde D, Lems W, te Koppele J, van der Linden S, Garnero P. Markers for type II collagen breakdown predict the effect of disease-modifying treatment on long-term radiographic progression in patients with rheumatoid arthritis. Arthritis Rheum 2004;50:1390-9.

Sharp JT, Wolfe F, Lassere M, Boers M, van der Heijde D, Larsen A, Paulus H, Rau R, Strand V. Variability of precision in scoring radiographic abnormalities in rheumatoid arthritis by experienced readers. J Rheumatol 2004;31:1062-72.

Welsing PM, Landewe RB, van Riel PL , Boers M, van Gestel AM, van der Linden S, Swinkels HL, van der Heijde DM. The relationship between disease activity and radiologic progression in patients with rheumatoid arthritis: a longitudinal analysis. Arthritis Rheum 2004;50:2082-93.

Landewe RB, Geusens P, van der Heijde DM, Boers M, van der Linden SJ, Garnero P. Arthritis instantaneously causes collagen type-I and type-II degradation in patients with early rheumatoid arthritis. A longitudinal analysis. Ann Rheum Dis 2005.

Landewe RB, van der Heijde DM, van der Linden S, Boers M. 28-joint counts invalidate the das28-remission definition due to the omission of the lower extremity joints: A comparison with the original das-remission. Ann Rheum Dis 2005.


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