77 Prevention of rheumatoid arthritis every three months if DAS was >2.4. After 1 year, treatment was discontinued and patients were followed for 60 months. The primary outcomes were progression to RA, defined by the 1987 ACR criteria, and radiographic joint damage of the hand and feet joints [50]. After trial conclusion, a risk stratification score was applied to the results based on a validated prediction model, and patients were stratified based on their risk [51,52]. Only patients with a high risk of developing RA were considered in the analysis after stratification [52]. The PROMPT study found that methotrexate treatment delayed RA onset in ACPA-positive, but not in ACPA-negative patients. Without risk stratification, no difference was found in the number of patients who developed RA in the treatment arm compared to placebo [50]. Upon risk stratification and selection of the patients with highest risk of developing RA (11 patients in each arm), a 1-year course of methotrexate reduced the absolute risk of developing RA by 45%, with more frequent drug-free remission after 5 years compared to placebo [52]. However, there was no significant lasting effect of methotrexate at 5 years after treatment [49]. The TREAT Early Arthralgia to Reverse or Limit Impending Exacerbation to Rheumatoid arthritis (TREAT EARLIER) study recruited patients with CSA and arthralgia for less than 1 year coupled with subclinical inflammation of the small joints of either hands or feet, as identified by unilateral MRI findings. Patients were treated with a single intramuscular dose of 120 mg methylprednisolone followed by methotrexate in increasing dosages up to 25 mg/week for 1 year, versus placebo for both, in a double-blinded manner. In the last 4 weeks of treatment, methotrexate was gradually reduced before being stopped at week 53. Patient recruitment was independent of their serological status (i.e. both RF/ACPA positive and negative individuals were included as long as they were at risk) and they were followed for an additional year. The primary endpoint of the study was either development of clinical arthritis that lasted >2 weeks or RA by the American College of Rheumatology (ACR)/ EULAR 2010 RA classification criteria. The study’s co-primary endpoint was DMARD-free status for two years, and secondary endpoint was patient functioning, assessed by Health Assessment Questionnaire disability index (HAQ-DI) and Work Productivity And Impairment (WPAI), as well as symptoms (pain, fatigue, morning stiffness) at baseline and regular 4 month intervals after treatment initiation [53,54]. Joint inflammation was explored using MRI at baseline and 4, 12, 24 months after treatment initiation. A total of 236 participants (119 participants in the treatment group, 117 in the placebo group) were included in the study; three participants were lost to follow-up in the treatment group, while 5 participants were lost in the placebo group. Treatment with methotrexate did not prevent RA onset (20 % of RA onset in treatment group vs. 18% in placebo group), although decreased joint inflammation was detected by 4
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