Hello. I'm Dr. Jonathan Kay, Professor of Medicine and Director of Clinical Research in the Division of Rheumatology at UMass Memorial Medical Center and the University of Massachusetts Medical School, both in Worcester, Massachusetts.
Today I would like to share with you an observation that we made and published in the February 2014 issue of Arthritis Research and Therapy about the correlation (or lack thereof) between acute-phase reactants and disease activity in rheumatoid arthritis. When trying to enroll patients in clinical trials of therapeutic agents for rheumatoid arthritis, I found that, often, patients who had active disease on the basis of clinical features failed to meet entry criteria that required elevation of an acute-phase reactant. Typical trials of novel agents to treat rheumatoid arthritis have required an erythrocyte sedimentation rate (ESR) of 28 mm/hr or a C-reactive protein (CRP) level of 15 mg/L or higher, or perhaps the upper limit of normal at most laboratories, which is 8 mg/L or higher.
When trying to enroll patients in clinical trials, the most common reason for failure to meet the entry criteria was the lack of an elevated acute-phase reactant despite the presence of the requisite number of swollen and tender joints, degree of morning stiffness, and patient and physician global assessment of disease activity. To quantitate the proportion of patients who do not meet these entry criteria, colleagues in the CORRONA database and I set out to assess what proportion of patients with active rheumatoid arthritis enrolled in the CORRONA database had an elevated ESR or CRP level.
We used cut-offs of 28 mm/hr for ESR and 8 mg/L for CRP. We looked at more than 9000 patients in the CORRONA database with a Clinical Disease Activity Index (CDAI) (which indicates low, moderate, or high disease activity) higher than 2.8. The CDAI does not require the use of an acute-phase reactant, so this avoids circular logic in the assessment.
We found, to our surprise, that 58% of the more than 9000 patients with active rheumatoid arthritis had both normal ESRs and CRP levels. In only 12% of patients were both acute-phase reactant levels elevated, and 13% of each group had elevated levels of one but not the other acute-phase reactant.
We also looked at more than 4000 patients in whom there was a visit 1 year later to see where these patients ended up. Did they show clinical improvement, or worsening?
We found that patients in whom both acute-phase reactant levels were elevated at baseline had the greatest improvement in the CDAI, the Health Assessment Questionnaire Disability Index, and individual components of the CDAI -- tender joint count, swollen joint count, patient global assessment, and physician global assessment. Patients in whom both acute-phase reactants were normal showed the least clinical improvement, and those in whom one acute-phase reactant was elevated and the other was normal were intermediate with respect to clinical improvement.
This suggests that the acute-phase reactant level is not elevated in most patients with active rheumatoid arthritis and that the number of acute-phase reactant levels elevated at baseline predicts the degree of improvement regardless of therapeutic intervention 1 year later. Finally, the use of the CDAI with a cut-off of 10 for high disease activity would be a more appropriate entry criterion for clinical trials of novel therapeutic agents.
Trials to date that have required an elevated acute-phase reactant are truly unrepresentative of the vast majority of patients who have active rheumatoid arthritis, in that more than one half have normal levels of ESR and CRP. I hope that this observation is useful in your clinical practice, and I welcome your comments and look forward to seeing you again on Medscape. Thanks.
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Cite this: Two Tests Not to Delay in RA - Medscape - May 02, 2014.