Methotrexate
The Dutch TREAT EARLIER (Treat Early Arthralgia to Reverse or Limit Impending Exacerbation to Rheumatoid Arthritis) trial is unique among the RA prevention trials for its inclusion of patients with clinically suspect arthralgia and subclinical inflammation on MRI in the hand or foot without any requirement for seropositivity. The trial’s 200 participants are randomized to methotrexate or placebo for 1 year. All subjects receive an initial 120-mg intramuscular injection of methylprednisolone. The primary outcome measured at 2 years is the frequency of clinically detectable arthritis fulfilling the 2010 European League Against Rheumatism/American College of Rheumatology criteria for RA or of unclassified arthritis with a swollen joint count of more than two joints, both persisting for at least 4 weeks. The trial, which is investigator initiated without industry sponsorship, has been enrolling patients for about 1.5 years and will need about that much more time to complete it.
Dr. Annette H.M. van der Helm-van Mil
“We do this because we don’t want to confine ourselves to autoantibody-positive patients; we also want to include the autoantibody-negative patients at risk for RA. That’s relevant because in the past, autoantibody-positive patients had more severe disease and more severe joint destruction, but clinically relevant joint destruction doesn’t develop anymore [because of effective treatment], and the problem is more that RA is still a chronic disease. Both ACPA-positive and -negative RA are chronic diseases.”
All the patients included in the trial are considered to be at risk for RA by rheumatologists because of their arthralgia. Because of the clinically relevant population, the results of TREAT EARLIER might be generalized more easily to daily practice, she said in an interview.
Abatacept
The APIPPRA (Arthritis Prevention in the Preclinical Phase of Rheumatoid Arthritis with Abatacept) trial hopes to find out whether RA or clinical synovitis can be prevented with abatacept (Orencia) 125 mg weekly by comparing it against placebo over a 12-month period in 206 British and Dutch patients with arthralgia who are rheumatoid factor (RF) and ACPA-positive. Subjects who are RF negative, but who carry high levels of serum ACPA defined as three times the upper limit of normal may be included. There will be a 1-year follow-up after the intervention period to monitor patients for arthritis.
The ARIAA (Abatacept Reversing Subclinical Inflammation as Measured by MRI in ACPA Positive Arthralgia) trial is randomizing 98 German patients with ACPA-positive arthralgia to 6 months of abatacept 125 mg weekly for 6 months vs. placebo, followed by a 12-month follow-up period. The primary outcome of the double-blind trial is the proportion of patients with an improvement of acute inflammation characterized as improvement of synovitis or osteitis in the MRI of the dominant hand after 6 months of treatment. The proportion of patients who develop RA based on ACR/EULAR 2010 criteria at 6-month intervals is one of a multitude of secondary outcomes that will be measured. Individuals in the study must test positive for ACPA (with or without RF); have joint pain in the hand, feet, knee, shoulder, or elbow for at least 6 weeks prior to inclusion or in past history; and synovitis or osteitis present on MRI of the dominant hand at baseline.
The two abatacept trials, both of which are expected to be completed in 2018, are sponsored by abatacept’s manufacturer, Bristol-Myers Squibb.
Rituximab
Results from the randomized, placebo-controlled PRAIRI (Prevention of RA by Rituximab) trial that were reported at the annual European Congress of Rheumatology in June showed that a single, intravenous infusion of 1,000 mg of rituximab (Rituxan) given to people with arthralgia and a high risk for developing rheumatoid arthritis did not prevent RA, but the treatment did appear to delay the development of RA. During follow-up, 16 of the 40 people in the placebo group (40%) developed RA after a median of 12 months, and 14 of the 41 in the treated arm (34%) developed RA after a median of 17 months. A Kaplan-Meier survival analysis found that the development of RA in 25% of people occurred at about 12 months in the placebo arm, whereas in the intervention arm it did not occur until 24 months.
At three Dutch centers, the PRAIRI trial investigators enrolled people with arthralgia who had never been diagnosed with arthritis, had never used a disease-modifying antirheumatic drug, and had at least one of these two risk factors: a serum level of IgM rheumatoid factor of more than 12.5 IU/mL and a serum level of anticitrullinated peptide antibodies of more than 25 IU/mL. Enrolled participants also needed to have at least one of the following: a serum level of C-reactive protein greater than 3 mg/L, an erythrocyte sedimentation rate of greater than 28 mm/hr, and evidence of subclinical synovitis identified by either ultrasound or MRI.