An intensive initial treatment strategy in rheumatoid arthritis (RA) that had a treatment goal of remission — a Disease Activity Score in 28 joints (DAS28) <1.6 — was not associated with higher rates of remission after withdrawal of disease-modifying antirheumatic drugs (DMARDs) compared with a routine care strategy that aimed for low disease activity or a DAS28 <2.4, Dutch researchers reported.
Patients who initiated the intensified treatment with methotrexate plus high-dose prednisone and reached remission did not have significantly greater rates of DMARD-free remission compared with patients starting methotrexate whose treatment target was low disease activity (35% vs 29%), according to Leonie E. Burgers, MD, and colleagues from Leiden University Medical Center in Leiden, the Netherlands.
Accordingly, the hazard ratio for achieving DMARD-free remission with intensive initial treatment was a nonsignificant 1.4 (95% CI 0.9-2.2), the researchers reported in Arthritis Research & Therapy .
With marked advances in therapy, evidence has been growing suggesting that some patients with RA are able to achieve DMARD-free remission, but treatment guidelines have expressed caution about tapering and withdrawing medications in RA because of the risk of subsequent flares.
An unanswered question has been whether intensifying early treatment in RA could influence the likelihood of patients having DMARD-free remission after medication tapering, so Burgers and colleagues compared outcomes of 155 patients in an earlier clinical trial known as IMPROVED that evaluated intensive treatment with outcomes in 124 patients enrolled at their center from 2007 to 2010 who received routine care.
Patients in IMPROVED had no previous exposure to DMARDs and initiated treatment with methotrexate starting at 7.5 mg/week and titrated to 25 mg/week. They also started prednisone in dosages of 60 mg/day, tapered over 7 weeks to 7.5 mg/day. If they had not achieved a DAS28 <1.6 by month 4, they were further randomized to additional sulfasalazine and hydroxychloroquine or adalimumab (Humira). Once the DAS28 goal was achieved, treatment could be tapered or stopped.
The routine care group started treatment with methotrexate with or without prednisone in a median dosage of 10 mg/day. Biologics were permitted only after the failure of at least two conventional DMARDs. Treatment taper could begin when the DAS28 fell below 2.4.
DMARD-free remission was defined as the absence of clinical synovitis for at least a year after stopping DMARDs, while sustained DMARD-free remission was defined as that outcome for the entirety of follow-up.
Patients in the intensified treatment group were younger (53 vs 61, P <0.001) and more often were positive for anti-citrullinated protein antibody (ACPA) (59% vs 40%, P =0.003) or rheumatoid factor (65% vs 48%, P =0.005). Median duration of follow-up for both groups was 7.8 years.
A previous study of DAS28 target-driven therapy found that patients who were ACPA positive more often had sustained remission. Therefore, because of the difference in ACPA positivity between the groups, the investigators also analyzed rates of remission according to seropositivity, and found that those who were ACPA positive were significantly more likely to achieve DMARD-free remission (25% vs 6%, HR 4.9, 95% CI 1.4-16.9). For ACPA-negative patients, the remission rates were similar, at 49% for the intensified group and 44% for the routine care group.
However, late flares were observed more often in patients in the intensified treatment group than in the routine care group (20% vs 8%, HR 2.3, 95% CI 0.6-8.3), and also among those who were ACPA positive (HR 1.23, 95% CI 1.02-1.50).
Sustained DMARD-free remission was seen in similar numbers in the intensified treatment and routine care groups (28% and 27%). Among ACPA-positive patients, sustained DMARD-free remission was seen in 17% of the intensified group and 6% of the routine care group, and although numerically different, the difference was not statistically significant. Among ACPA-negative patients, similar numbers of patients had sustained DMARD-free remission (43% and 42%).
Therefore, intensified treatment did not lead to greater proportions of sustained DMARD-free remission. Moreover, stratification according to ACPA positivity showed that seropositive patients receiving intensive treatment more often achieved DMARD-free remission, but they also more often experienced late flares.
"Our current results do not provide evidence for long-term benefits of an intensive DAS-steered treatment regimen with regard to achieving DMARD-free sustained remission," the investigators concluded.
And despite the lack of statistically significant differences for ACPA-positive patients in this analysis, longer follow-up might reveal differences, so future studies should include follow-up of 10 years or more, they noted.
A limitation of the study was the possibility of unmeasured confounding.
The study was supported by the Netherlands Organization for Scientific Research and the European Research Council. The first year of follow-up in IMPROVED was funded by AbbVie.
Burgers and co-authors disclosed no relevant relationships with industry.
last updated 05.08.2019
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