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Success with "treat-to-target" therapy for early-stage rheumatoid arthritis (RA) lasted up to 20 years, according to researchers who followed up with participants in two of the first clinical trials aimed at testing the strategy.

Most patients in the trials -- which aimed at drug-free remission in one, low disease activity in the other -- had maintained the benefits when examined again 7-10 years after the trials ended, which was 12-20 years after starting treatment, reported Sascha L. Heckert, MD, of Leiden University in the Netherlands, and colleagues.

In the follow-up exams, 91% of these patients had low disease activity (Disease Activity Score [DAS] <2.4), and 68% were in remission (DAS <1.6), the researchers .

Disease activity wasn't completely eradicated, however. Some degree of radiographic progression was common, but Heckert's group called it "relatively mild." Similarly, physical function was "relatively preserved," with some worsening evident. Heckert and colleagues added that the study represents the longest-term follow-up yet reported for treat-to-target strategies in RA.

"Our results imply the lasting benefit of early and prolonged treatment to target, but also show that there is still room for further improvement of treatment strategies to ensure better long-term outcomes in patients with RA/UA [undifferentiated arthritis]," the authors concluded.

The original trials whose participants were contacted for the new study were , which started treating patients in 2000-2002 and ran for 10 years, and , a 5-year trial in which treatment commenced in 2007-2010. Both were conducted in the Netherlands (and some investigators in the new study also helped lead them). During 2019-2022, Heckert's group reached out to as many of the original participants as they could locate, asking them to come into the clinic for physical exams, imaging, and interviews.

BeSt, with 508 patients, had four arms: sequential monotherapy beginning with methotrexate, a "step-up" regimen that also began with methotrexate with other nonbiologic agents added, initial combination therapy (methotrexate and sulfasalazine, and prednisone), or initial combination therapy with methotrexate plus infliximab (Remicade).

IMPROVED had 610 patients who first started on methotrexate and high-dose prednisone that was then tapered to a low dose; those achieving remission within 4 months remained on that treatment, while those not in remission were randomized to addition of either hydroxychloroquine or adalimumab (Humira). Treatments were tapered in patients achieving remission, since the goal was to allow patients to stop disease-modifying therapy altogether.

In both studies, after their conclusion, participants received ordinary care.

Heckert and colleagues found 153 former BeSt participants and 282 from IMPROVED who were willing to come in for the new exams, which represented 20 years of total follow-up from BeSt and 12 years from IMPROVED.

Among former BeSt participants, 17% said they were taking no anti-rheumatic medications; 28% were on a single conventional disease-modifying medication such as methotrexate; and most of the rest were using some type of targeted therapy, either alone or with conventional anti-rheumatic drugs.

More participants from IMPROVED were on no drugs for RA (26%) or only one conventional agent (31%). By the same token, fewer had resorted to biologic or targeted nonbiologic medications (30%).

Not everyone in the trials had reached the targets of low disease activity or remission at the last regular study visit. But among those who did, and returned for the new study's exams, rates of remaining at target were extremely high:

• Low disease activity in BeSt: 110/117 or 94%
• Remission in BeSt: 57/70 or 81%
• Low disease activity in IMPROVED: 228/245 or 93%
• Remission in IMPROVED: 131/170 or 77%

Not surprisingly, rates of these outcomes were lower among those who hadn't achieved the targets in the original trials. But they were not bad for a chronic and progressive disease, in the range of 50%-60% for remission and 70%-80% for low disease activity.

More than 90% of patients from both trials showed radiographic joint damage at the long-term follow-up. Mean Sharp-Van der Heijde scores were 25.0 and 12.7 for former BeSt and IMPROVED participants, though medians were much lower thanks to a few patients showing very high scores. Some 26% from BeSt and 9% from IMPROVED had scores above 30, the difference presumably being the 20 years since enrollment in BeSt versus 12 in IMPROVED, and perhaps less effective treatment in BeSt. Indeed, Heckert and colleagues observed that radiographic progression was less pronounced in BeSt patients assigned to infliximab compared with the other study arms; odds of being in clinical remission at the recent visit were also greater in the former infliximab arm.

Physical function was assessed with the 3-point Health Assessment Questionnaire. Mean scores rose slightly for participants in both studies since the trials' conclusion. Means at the last regular trial visits stood at 0.5 in BeSt and 0.54 in IMPROVED; at the new study's follow-up, scores averaged 0.8 and 0.6, respectively, reflecting some worsening in health status.

Limitations to the study included the nonparticipation of half of the original trials' patients who remained alive, and treatments received following the studies' conclusions weren't recorded. As well, Heckert and colleagues cautioned that the results can't be fully generalized to all treat-to-target approaches, since the ones used in BeSt and IMPROVED were "highly protocolized" and were restricted to drugs then available.

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