Abstract
ObjectiveThe change in number of CD68-positive sublining macrophages in serial synovial biopsies has been successfully used to discriminate on the group level between effective and ineffective treatment during early drug development in rheumatoid arthritis (RA) patients. Measurement of a soluble biomarker would clearly have practical advantages. Therefore, we investigated the sensitivity to change of myeloid related protein (MRP)8/14 in serum.Methods139 RA patients who received known effective biologics (infliximab, adalimumab and rituximab) and 28 RA patients who received placebo/ineffective therapies were included. MRP8/14 levels were analyzed in baseline and follow-up serum samples and the standardized response mean (SRM) was calculated to determine the sensitivity to change of MRP8/14 in comparison to C-reactive protein (CRP) levels and the disease activity score evaluated in 28 joints (DAS28).ResultsIn patients treated with effective treatment, the SRM for MRP8/14 was moderate (0.56), but in patients treated with placebo/ineffective treatment the SRM was 0.06, suggesting that this biomarker is perhaps not susceptible to placebo effects in proof-of-concept studies of relatively short duration. In contrast, the SRM for DAS28 was high for effective treatment (1.07), but also moderate for ineffective treatment (0.58), representing the placebo effect. The SRM for CRP was low in the effective (0.33) and ineffective (0.23) treatment groups.ConclusionThese data support the notion that quantification of changes in MRP8/14 serum levels could be used to predict potential efficacy of novel antirheumatic drugs in an early stage of drug development. A positive result would support the rationale for larger, conventional clinical trials to determine whether the effects are clinically relevant.
Highlights
Rheumatoid arthritis (RA) is a chronic systematic inflammatory disease affecting the synovial tissue in multiple joints
[1] We have previously identified and validated the expression of CD68+ cells in the synovial tissue of RA patients as a biomarker that is related to changes in clinical signs and symptoms independent of the primary mechanism of action. [2,3,4] We have recommended a rethinking of the decision to move ahead to large clinical trials when there is no trend towards clinical improvement, no specific effect related to the mechanism of action, and no change in CD68+ macrophage numbers in the synovium after treatment
This screening approach, where the change in the number of CD68-positive sublining macrophages in serial arthroscopic synovial biopsy specimens is used to discriminate on the group level between effective treatment and ineffective during early drug development, has been successfully used to test a wide variety of experimental medicines, [1,5] allowing early go/no go decisions related to further clinical development
Summary
139 RA patients who received known effective biologics (infliximab, adalimumab and rituximab) and 28 RA patients who received placebo/ineffective therapies were included. MRP8/14 levels were analyzed in baseline and follow-up serum samples and the standardized response mean (SRM) was calculated to determine the sensitivity to change of MRP8/ 14 in comparison to C-reactive protein (CRP) levels and the disease activity score evaluated in 28 joints (DAS28)
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