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Ann Rheum Dis. 2013 Mar;72(3):406-9. doi: 10.1136/annrheumdis-2012-202333. Epub 2012 Nov 15.

Meta-analysis suggests that intensive non-biological combination therapy with step-down prednisolone (COBRA strategy) may also 'disconnect' disease activity and damage in rheumatoid arthritis.

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Department of Epidemiology & Biostatistics, VU University Medical Center, 1007 MB Amsterdam, The Netherlands.



Treatment of rheumatoid arthritis (RA) with tumour necrosis factor (TNF) antagonists changes the relationship between disease activity and progression of radiological joint damage ('disconnect'): patients who have little or no response of disease activity still show reductions in damage progression. In early RA, the COBRA strategy (combination of methotrexate and sulfasalazine with step-down prednisolone) has been shown to be equivalent to high-dose methotrexate and infliximab in suppressing damage progression (BeSt trial). We investigated whether COBRA treatment can also 'disconnect' disease activity and damage.


A meta-analysis combined data from the COBRA trial (COBRA vs sulfasalazine monotherapy) with that of two arms of the BeSt trial (COBRA vs sequential monotherapy). Linear regression related 1-year progression of damage (Sharp van der Heijde score) as a dependent variable with disease activity (time-averaged Disease Activity Score in 44 joints (DAS44) or C-reactive protein (CRP)), treatment strategy (COBRA or control) and their interaction (indicator of a disconnect) as independent variables. The main outcome was the pooled interaction term.


Complete data from 60-100% of patients were available. Before pooling, disease activity was the only (strongly) significant independent factor related to damage progression. The pooled interaction term was (weakly) significant: time-averaged DAS44Ă—treatment interaction, one-sided p=0.027; time-averaged CRPĂ—treatment interaction, one-sided p=0.044.


Changes in the relationship between disease activity and damage progression may not be limited to anti-TNF treatment, but a property of early, rapid and deep suppression of joint inflammation, also induced by conventional strategies that include glucocorticoids.

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