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BREAKING RESEARCH DATA

Biomarker panel quantifies disease activity in patients with rheumatoid arthritis

In patients with rheumatoid arthritis (RA), ongoing disease activity assessment is recommended in international guidelines (ACR*, EULAR†) and in recent Treat-to-Target Guidelines.1,2 Tight control of RA disease activity, with regular assessments driving therapeutic decisions to reach a specific goal, such as remission, has been shown to improve long-term outcomes.3-5 Current disease activity monitoring focuses on symptom assessment; a more direct method for reliably monitoring disease activity in patients with RA may inform clinical decision-making.

Data presented at this year’s EULAR Congress (Rome, Italy; June 16-19, 2010) have demonstrated that a test measuring a combination of specific biomarkers correlates with RA disease activity in patients with RA.6-10 Data presented during the Congress also suggest that the test could help improve patient outcomes.11

Biomarkers representing multiple biologic pathways are associated with RA disease activity

In a comprehensive program, approximately 400 candidate protein biomarkers have been evaluated—including more than 100 that have been studied in clinical trials—and reduced in a stepwise fashion, over time, to those biomarkers that were found to provide the most information about disease activity.6-10

When the association between serum biomarker levels and disease activity was assessed in a series of studies involving more than 500 patients from 3 separate cohorts, 25 proteins were consistently correlated with disease activity across multiple studies.8 Individual biomarkers associated with disease activity have been shown to represent a range of biologic pathways.8,9

Patient characteristics did not affect the reliability of a biomarker panel

One of the studies presented during the EULAR Congress examined the correlation of these 25 biomarkers with RA disease activity in 679 patients who were diverse in terms of geographic location, ethnicity, age, disease duration, treatment, and degree of RA disease activity.10 The study provided data that allowed the definition of a robust assay for disease activity comprising 12 biomarkers and a mathematical algorithm to combine the biomarker concentrations into a single score for efficient use and interpretation. The study also found that patient characteristics, such as age, gender, and treatment, did not significantly affect the reliability of the biomarker panel in distinguishing patients with high levels of disease activity from those experiencing lower levels of disease activity, nor did these variables add significant benefit when included in the algorithm.

A separate study assessed the performance of this 12-biomarker algorithm in patients entered into the CAMERA‡ study, a Dutch study of tight control.9 In this set of patients, the algorithm also correlated strongly with disease activity, as defined by DAS28-CRP§, and effectively distinguished patients with moderate/high versus low disease activity. In addition, the 12-biomarker algorithm tracked a significant decrease in disease activity in study patients during the first 6 months of the study.

Biomarker panel accurately predicts radiographic progression

Two additional studies assessed the potential for biomarkers to predict radiographic progression. In one study, selected biomarkers were measured at baseline and at 1 year in serum obtained from 160 patients with early, aggressive RA who had been entered into the BeSt|| study.12 The concentrations of these biomarkers were then compared with changes in modified Sharp Scores at 2 years.

Certain combinations of biomarkers were found to be more accurate than DAS28, cyclic citrullinated peptide, CRP, and rheumatoid factor in predicting radiographic progression in this patient population.12 The biomarkers that demonstrated the strongest correlation with disease progression included the following:

  • Proteins associated with bone and cartilage destruction
  • Proinflammatory cytokines
  • Acute-phase proteins

In the second study, serum and urine biomarkers were measured at multiple time points in patients with early, aggressive RA treated with either methotrexate alone or methotrexate plus infliximab. Both serum and urine markers correlated with progression of joint damage. Predictive power was reported to be highest at 6 weeks after initiation of treatment, using a panel made up of serum biomarkers.11 This important finding suggests that the effects of therapy on patient outcomes could be evaluated early in the treatment course using a multi-biomarker test that captures objective information on a diverse set of biologic pathways.11

*ACR, American College of Rheumatology.
†EULAR, The European League Against Rheumatism.
‡CAMERA, Computed Assisted Management in Early Rheumatoid Arthritis.
§DAS28-CRP, Disease Activity Score in 28 joints, based on C-reactive protein.
||BeSt, Behandel Strategieen.

Mapping the future of RA

Delegates at the recent EULAR Congress received their first insights into the InFoRM study.13 Sponsored by Crescendo Bioscience, InFoRM is a longitudinal, observational study of patients with RA. InFoRM is a biorepository with a large volume of clinical data that could represent a valuable resource for biomarker discovery and research on a range of related clinical questions.

The study enrolled more than 1200 patients with RA over 8 months at 10 academic sites and 15 community clinics. These patients contributed biologic samples and clinical data for use in the development of novel molecular tests designed to provide physicians with quantifiable information on a patient’s RA disease activity at any given point in time.

The InFoRM cohort is similar to other observational cohorts drawn from the North American RA population. The number of patients receiving treatment with a biologic agent, however, is higher in this study than in other reference populations.

Characteristics of the InFoRM Patient Cohort13
Caucasian 74.1%
Female 78.9%
Mean age (years) 58.1 ± 13.7
Mean disease duration (years) 14.6 ± 11.8
Average DAS28/ESR-4# score 3.95 ± 1.6
Treatments (range across sites)
     Nonbiologic DMARD** 62%–100%
     Biologic DMARD 16%–88%
     Steroid 10%–63%
Comorbidities
     Hypertension 39%
     Osteoarthritis 34%
     Osteoporotic bone fractures 24%
     Fibromyalgia 8%

InFoRM, Index For Rheumatoid Arthritis Measurement.
#DAS28/ESR-4, Disease Activity Score 28-joint assessment 4, based on erythrocyte sedimentation rate.
**DMARD, disease-modifying antirheumatic drug.

 

References

  1. Pincus T, Sokka T, Kavanaugh A. Relative versus absolute goals of therapies for RA: ACR 20 or ACR 50 responses versus target values for “near remission” of DAS or single measures. Clin Exp Rheumatol. 2004;22(5 suppl 35):S50-S56.
  2. Aletaha D, Landewe R, Karonitsch T, et al; EULAR; ACR. Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations. Arthritis Rheum. 2008;59(10):1371-1377.
  3. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364(9430):263-269.
  4. Verstappen SM, Jacobs JW, van der Veen MJ, et al; Utrecht Rheumatoid Arthritis Cohort study group. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis. 2007;66(11):1443-1449.
  5. Puolakka K, Kautiainen H, Möttönen T, et al; FIN-RACo Trial Group. Early suppression of disease activity is essential for maintenance of work capacity in patients with recent-onset rheumatoid arthritis: five-year experience from the FIN-RACo trial. Arthritis Rheum. 2005;52(1):36-41.
  6. Eastman S, Manning W, Qureshi F, et al. Assay development for precise measurement of disease activity serum biomarkers. Presented at: The European League Against Rheumatism Annual Congress; June 16-19, 2010; Rome, Italy. Poster: THU0065.
  7. Ramanujan S, Centola M, Cavet G, McInnes IB. Multi-protein biomarker panel integrates critical pathophysiologic mechanisms in measurement of RA disease activity. Presented at: The European League Against Rheumatism Annual Congress; June 16-19, 2010; Rome, Italy. Poster: FRI0034.
  8. Shen Y, Knowlton N, Turner M, et al. Stepwise discovery of disease activity biomarkers in rheumatoid arthritis. Presented at: The European League Against Rheumatism Annual Congress; June 16-19, 2010; Rome, Italy. Poster: THU0066.
  9. Bakker M, Bijlsma J, Jacobs J, et al. Performance of serum biomarkers and a pre-specified multivariate biomarker-based test to measure disease activity in early rheumatoid arthritis treated according to the CAMERA protocol. Presented at: The European League Against Rheumatism Annual Congress; June 16-19, 2010; Rome, Italy. Poster: FRI0106.
  10. Cavet G, Centola M, Shen Y, et al. Development of a multi-biomarker test for rheumatoid arthritis (RA) disease activity. Presented at: The European League Against Rheumatism Annual Congress; June 16-19, 2010; Rome, Italy. Oral Presentation: OP0278.
  11. Cavet G, Shen Y, Abraham S, et al. A comparison of serum and urine biomarkers for predicting radiographic progression in rheumatoid arthritis. Presented at: The European League Against Rheumatism Annual Congress; June 16-19, 2010; Rome, Italy. Poster: THU0485.
  12. Shen Y, Dirven L, Cavet G, et al. Serum biomarkers predict progressive structural damage in the BeSt study. Presented at: The European League Against Rheumatism Annual Congress; June 16-19, 2010; Rome, Italy. Poster: SAT0049.
  13. Fleischmann R, Curtis J, Hamburger M, et al. RA population characteristics in InFoRM, a longitudinal observational study. Presented at: The European League Against Rheumatism Annual Congress; June 16-19, 2010; Rome, Italy. Poster: SAT0518.