Steroid loading strategies in RA are more than snake oil! 4-year follow up results from the COBRA vs. COBRA-light trial.

All that is old is new again – the use of very high dose steroids in early RA (ERA) has been around since the Lancet article of the COBRA strategy (Boers, et al) published in 1997! 

Outside of The Netherlands, the COBRA strategy isn't used. There have been modifications with lower doses of steroids and altering the dose of MTX and/or excluding SSZ.

The 'COBRA-light' strategy uses two drugs (MTX and steroids) but lower doses of prednisone (starting at 30 mg/day, tapered to 7.5 mg/day in 9 weeks) and methotrexate (escalated to 25 mg/week in 9 weeks). COBRA-light was compared to COBRA therapy (prednisone 60 mg/day, tapered to 7.5 mg/day in 6 weeks, methotrexate 7.5 mg/week and sulfasalazine 2 g/day) (den Uyl D, Ann Rheum Dis 2014 Jun;73:1071-8). The protocol required an increase in MTX dose to 25 mg/week after 13 weeks if the DAS44 was >1.6 in COBRA and to consider MTX 25mg/wk sc for COBRA-light. 

By 6 months, the steroid difference cumulatively was approximately 300 mg less in COBRA-light (with both groups over 2 g by that time point). There were no significant differences in the endpoints at the end of the trial (numerically ESR and CRP were lower at 3 months in COBRA, but the same at 6 months. 

At 1 year of follow-up, the actual treatment instituted in these patients was often less intensive than required by the protocol: of the total population, 108 patients (67%) required etanercept (more in the COBRA-light group), but only 62% of those received it (40% overall). The two treatment strategies were not different and that protocolized addition of etanercept was often not instituted and patients receiving it appeared to have limited added benefit, probably because of low disease activity when etanercept was initiated (ter Wee, Ann Rheum Dis. 2015;74:1233-40).

So at this meeting, Konijin et al presented the 4-year results of COBRA-light trial (#OP0262).

Enrollment for this observational study was great: 142 of 162 agreed to have data collected for 4 years (92% of the original sample). At 4.5 years of disease duration of ERA, there were no differences between 3 of 4 key outcomes. Disease activity, HAQ, and X-rays were the same over time between the groups. However, Boolean remission was NOT similar only at the 4 years time point: 26% of COBRA were in remission vs. 12% with COBRA-light (p=0.04). 

So, either front end loading of more steroids or use of SSZ was associated with later remission or more subsequent changes in treatment (not presented:  differences of ongoing steroids, other DMARDs/biologics). Interestingly, vertebral and rib fractures were MORE common in the COBRA-light group (which receivedless prednisone!) This result could have been spurious. 

This makes me recall the BeST trial where faster response yielded better long-term outcomes. One could suggest the observed difference is due to more steroids in the COBRA group leading to higher rates of remission at 4 years, but one could also wonder if it was the initial treatment with MORE drugs (MTX, steroids and SSZ).

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