A treat-to-target protocol involving methotrexate plus hydroxychloroquine, along with an optional intramuscular triamcinolone acetonide injection, led to remission more quickly in patients with early rheumatoid arthritis than did initial methotrexate monotherapy in a registry study comparing two separate cohorts.

The study found that 71.9% (92/128) of patients in the Dutch Rheumatoid Arthritis Monitoring ( DREAM ) registry in a first multicenter cohort of methotrexate monotherapy that began in 2006 met remission criteria at 1 year of follow-up, based on a 28-joint Disease Activity Score (DAS28) less than 2.6, which was not statistically different from 77.3% (99/128) in a second multicenter cohort of disease-modifying antirheumatic drug (DMARD) combination therapy that began in 2012. However, at 6 months, a significantly higher percentage of the second cohort achieved a first remission, compared with the first cohort (63.3% vs. 48.4%). The median time to first remission also was significantly shorter among members of the second cohort (17 weeks vs. 27 weeks).

The first author of the study, Laura M.M. Steunebrink of Medisch Spectrum Twente hospital, Enschede, The Netherlands, and her colleagues noted that “in the United States, methotrexate plus hydroxychloroquine is by far the DMARD combination most commonly prescribed by rheumatologists. It has been shown to be more potent than methotrexate used alone. An explanation for this may be that hydroxychloroquine increases the bioavailability of methotrexate and/or reduces the clearance of the drug.”

The patients in both cohorts had RA symptoms for less than 1 year and a DAS28 greater than 2.6. The patients in the second cohort were matched with patients in the first cohort on gender, age, and baseline disease activity, although patients in the second cohort had 1 more tender joint (median of 4 vs. 3), higher DAS28 using erythrocyte sedimentation rate (mean of 4.8 vs. 4.5), and worse scores on the Health Assessment Questionnaire Disability Index, pain visual analog scale, and mental component of the 36-item Short Form Health Survey.

Remission rates in other treat-to-target studies in patients with recent-onset RA, using different criteria for remission and slightly different follow-up periods, have ranged from 10% to 78%. In accordance with the results from these previous randomized clinical trials, “the implementation of a [treat-to-target] protocol may in itself explain the high remission rates in both cohorts, [but] apparently even better results may be attained regarding the time needed to achieve first remission by implementing initial combination protocols in daily clinical practice,” the authors wrote ( Arthritis Res Ther. 2016;18:60. doi:10.1186/s13075-016-0962-9 ).

One of the main differences in protocols between the two cohorts was the starting and step-up doses of methotrexate. In the first cohort, methotrexate monotherapy started at 15 mg/week, with folic acid taken on the second day after methotrexate. When patients had DAS28 of 2.6 or greater at 2 months, methotrexate increased to 25 mg/week, and after 3 months, sulfasalazine 2,000 mg/day was added and then increased to 3,000 mg/day after 20 weeks. Anti–tumor necrosis factor-alpha (anti-TNF-alpha) treatment was prescribed at week 24 for patients whose DAS28 remained at 3.2 or higher, replacing sulfasalazine with subcutaneous adalimumab (Humira) 40 mg every 2 weeks with an escalation at week 36 to 40 mg/week for those with DAS28 of 2.6 or greater.

Patients who continued to have a DAS28 of 3.2 or higher at week 52 exchanged adalimumab for etanercept (Enbrel) 50 mg/week. The attending rheumatologist used discretion in permitting concomitant treatment with nonsteroidal anti-inflammatory drugs, prednisolone at 10 mg/day or less, and intra-articular corticosteroid injections.

Patients in the second cohort started on methotrexate 20 mg/week and hydroxychloroquine 200 mg twice daily, with an optional intramuscular triamcinolone injection to a maximum dosage of 120 mg as bridging therapy. Clinicians increased methotrexate to 25 mg/week after 1 month, regardless of disease activity. Folic acid was started on the second day after methotrexate. Methotrexate increased to 30 mg/week when there was a DAS28 of 2.6 or greater at 2 months, and an extra optional intramuscular triamcinolone injection could be administered. The attending rheumatologist added a TNF inhibitor (adalimumab, etanercept, or infliximab [Remicade]) at 4 months if DAS28 remained at 3.2 or higher. Patients in whom DAS28 remained between 2.6 and 3.2 at 4 months could receive either sulfasalazine 2,000-3,000 mg/day or an intramuscular triamcinolone injection.

In both cohorts, if at any time point the target of DAS28 less than 2.6 was met, medication was held constant. In case of sustained remission of 6 months or longer, medication was gradually reduced and eventually discontinued. Patients restarted their last effective medication or increased their dose if disease flared – defined as a DAS28 of 2.6 or greater. The attending rheumatologist was free to diverge from the medication schedule at any time based on clinical indication.

Most patients in both cohorts achieved the treatment target using only conventional synthetic DMARDs at 12 months (91% in first cohort and 81% in second), and a small number of the patients in both cohorts were using biologic DMARDs at 12 months (4% in first cohort and 9% in second). Slightly more than half (53%) of patients in the second cohort received an intramuscular injection with triamcinolone, compared with just 3% in the first cohort, and its use was associated with more than a doubling of the odds of achieving first remission within 6 months (odds ratio, 2.14; 95% confidence interval, 1.03-4.4; P = .04). However, it did not affect the odds of remission at 12 months.

“Although we did not conduct a randomized trial, we still think that the design and results of the study allow us to compare the two cohorts. The cohorts consist of very similar populations of all consecutive newly diagnosed patients with RA treated in the same hospitals by the same rheumatologists,” the authors wrote. “Because in our study we used real-life observational data, the results are generalizable to daily clinical practice.”

The authors declared that they have no competing interests.


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