DAS28-CRP or DAS28-ESR: Are they Biosimilar? Save

The disease activity score (DAS28) has been developed as a dynamic assessment tool and a therapeutic response measure for use in clinical trials and practice. Although intended for use in patients with rheumatoid arthritis, its utility has been applied in the assessment of other inflammatory arthropathies.

The DAS has evolved from the DAS44 to the DAS28 by dropping the confusing Ritchie index and consolidating the joint exam to just 28 joints with a net improved ease of use. Similar to the ACR response criteria, the DAS is a mathematical activity measure drawn from the 7 core set variables: patient pain, MD and patient global assessments, a functional measure (HAQ), tender and swollen joint counts, and an acute phase reactant (APR). Unlike the ACR20, the DAS omits the HAQ, MD Global and patient Pain.  It is calculated from the patient global, TJC, SJC, and an APR. Depending on which APR is available (CRP or ESR), the DAS is calculated as either the DAS28-ESR or the DAS28-CRP.

But are they the same, interchangeable and as identical as a biosimilar?

One camp believes they are not, especially since the cut-offs for disease activity levels have only been reliably defined to the DAS28-ESR (remission < 2.6; LDAS 2.6-3.2; moderate activity 3.2-5.1; high activity >5.1). Yet many clinicians and trialists erroneously apply these cutoffs to DAS28-CRP, which is not quite as stringent a measure as the DAS28-ESR.

Others point to research done on RA cohorts showing the similar performance characteristics for both measures, suggesting interchangeability. This is not surprising as a) nearly half of all patients with RA will have normal ESR and CRP values – despite having active disease; and b) both measures are calculated using the core set 7 values found in the ACR20 response criteria. Similarly, the (more easily calculated) SDAI, CDAI, RAPID3, PAS and GAS score all utilize between 3 and 5 of the 7 core set variables and have very high correlation coefficients. But that’s because they are supposed to!

All rheumatologists and clinical trialists recognize the dynamic and pathogenic importance of including either the ESR or CRP in clinical decision-making or disease activity calculation. Moreover, there is a large volume of research indicating the value of high ESR or CRP in predicting radiographic progression and erosions. However, either or both may be normal in up to 60% of patients in practice or in RCTs.

Acute phase reactants appear to be critically important in ACR response and DAS 28 calculations. The more easily calculated SDAI and CDAI are based on the same variables used in the DAS28 and have a high correlation with the DAS28-ESR or –CRI. Yet the only difference between the SDAI and CDAI is the omission of the CRP from the latter. Studies have shown that the CRP only adds as little as 6% to the response equation. Hence, the CDAI and RAPID3, neither of which require the ESR or CRP, are the most popular outcome measures in clinical practice. At the 2014 ACR annual meeting, Dr. Curtis and I presented a survey of 500 US rheumatologists showing the RAPID3 and CDAI are being done by 43% of rheumatologists. I personally use the global arthritis score (GAS) that is a composite of patient pain, 28 tender joint count and the modified HAQ. The GAS, CDAI, SDAI and DAS28 have very high correlations (R > 0.85) underscoring the minimal effect of an acute phase reactant.

A number of research groups have studied the DAS28 issue. Their findings are chronicled in the capsule summaries listed below. Read through these studies to see if you agree with the following summary statements:

Summary

1. The DAS28-ESR and DAS28-CRP are not interchangeable.
2. The DAS28-CRP underestimates disease activity and overestimates clinical improvement.
3. Most studies show the ESR method to yield higher values than the CRP method. The DREAM registry estimates the DAS28-CRP scores to be 0.20 points lower than DAS28-ESR scores, with even greater bias in older women.

Citations
A retrospective study of Danish RA patients initiating biologic treatment analyzed the change in DAS28-ESR and DAS-CRP at baseline and following one year of treatment. The 75 eligible patients were classified as EULAR good, moderate, and nonresponders, and overall a high level of agreement (61/75; 81%) between DAS28-CRP and DAS28-ESR (κ = 0.75; 95% CI: 0.63 to 0.88) was found.  Nieulung L, et al. Validity and Agreement between the 28-Joint Disease Activity Score Based on C-Reactive Protein and Erythrocyte Sedimentation Rate in Patients with Rheumatoid Arthritis. Arthritis. 2015;2015:401690. Epub 2015 Jan 14

Data from 3073 RA patients in the large NinJa registry was used to calculate DAS28-ESR and DAS28-CRP and disease activity. The mean DAS28-CRP (3.59) was significantly smaller than that of mean DAS28-ESR (4.31) (p < 0.0001). The number of patients who were in remission was 297 (9.7%) in DAS28-ESR versus 705 (22.9%) in DAS28-CRP and the number of patients with high disease activity was 842 (27.4%) versus 357 (11.6%) for DAS28-ESR and DAS28-CRP (p < 0.0001). These findings suggest a relative “leniency” to the DAS28-CRP, as it underestimates disease activity and overestimates clinical improvement. Nevertheless the change in DAS28 showed a significant correlation between the DAS28-ESR and DAS28-CRP (p < 0.0001); however, the number of "good response" patients was significantly different (p < 0.03) between DAS28-ESR (97 patients, 6.5%) and DAS28-CRP (136 patients, 9.2%). Matsui T, et al. Disease Activity Score 28 (DAS28) using C-reactive protein underestimates disease activity and overestimates EULAR response criteria compared with DAS28 using erythrocyte sedimentation rate in a large observational cohort of rheumatoid arthritis patients in Japan. Ann Rheum Dis. 2007 Sep;66(9):1221-6.

In a prospective study from Korea, 540 patients with RA from two rheumatology clinics who had at least one DAS28 evaluation were examined. The mean DAS28-ESR was higher than the DAS28-CRP (3.65 vs. 3.44; P < 0.001). In the DAS28-ESR group, 126 patients (23.3%) satisfied the criteria for remission versus 134 (24.8%) in the DAS28-CRP group. High disease activity was determined in 80 (14.8%) patients in the DAS28-ESR group and in 43 (8.0%) in the DAS28-CRP group. A comparison of the two groups with respect to four DAS28 disease activity categories showed agreement in 344 patients (63.7%; κ = 0.45). In classifying patients as EULAR responders, agreement between the two methods was shown in 56 patients (71.8%; κ = 0.76). When disagreements between the two scores occurred, more patients had a better EULAR response based on the DAS28-ESR than on the DAS28-CRP (19.2% vs. 8.9%, respectively). The authors felt that discordance between the ESR-based and CRP-based DAS28 could affect clinical treatment decisions for patients with RA. Son KM, et al. Comparison of the disease activity score using the erythrocyte sedimentation rate and C-reactive protein levels in Koreans with rheumatoid arthritis. Int J Rheum Dis. 2015 Jul 22. [Epub ahead of print]

A single center study of DAS28 data of 112 Turkish RA patients analyzed the correlation between DAS28-CRP and DAS28-ESR. Although there was a strong correlation between DAS28-CRP and DAS28-ESR, the correlation between their unique components was fair. Although more than 95% of the point data fall between the upper and lower bounds of the limit of agreement, the percentage error (46%) was higher than the acceptable proportion of 30%. The κ coefficient of agreement between DAS28- ESR and DAS28-CRP with validated thresholds for DAS28-ESR was 0.42, which was close to the lower boundary for moderate agreement. This study demonstrated that there is discordance between DAS28-ESR and DAS28-CRP using the validated thresholds for DAS28-ESR. Using the DAS28-CRP with threshold values validated for DAS28-ESR may lead to errors in the determination of disease activity and therefore may lead to errors in the management of patients with rheumatoid arthritis. Sengul I, et al. Comparison of the DAS28-CRP and DAS28-ESR in patients with rheumatoid arthritis. Int J Rheum Dis. 2015 May 27. [Epub ahead of print]

An analysis of US African-Americans from the Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) registry, compared variants of the DAS28 scores: ESR-based and CRP-based DAS28 scores (DAS28-ESR3 and DAS28-CRP3) and the DAS28-ESR4 and DAS28-CRP4. Among the 233 participants, the mean DAS28-ESR3 was significantly higher than DAS28-CRP3 (4.8 vs 3.9; p < 0.001); and the mean DAS28-ESR4 was significantly higher than DAS28-CRP4 (4.7 vs 3.9; p < 0.001). Overall agreement was not high between DAS28-ESR3 and DAS28-CRP3 (50%) or between DAS28-ESR4 and DAS28-CRP4 (59%). DAS28-CRP3 underestimated disease activity in 47% of the participants relative to DAS28-ESR3 and DAS28-CRP4 in 40% of the participants relative to DAS28-ESR4. These authors also found significant discordance between the ESR-based and CRP-based DAS28 that could affect clinical treatment decisions for African Americans with RA. Tamhane A, et al. Comparison of the disease activity score using erythrocyte sedimentation rate and C-reactive protein in African Americans with rheumatoid arthritis. J Rheumatol. 2013 Nov;40(11):1812-22.

The DAS28, SDAI and CDAI were studied in a cross-sectional analysis of 111 patients.  DAS28 (ESR) was significantly higher than DAS28 (CRP) (4.0 vs. 3.5; p<0.001) even with stratification for age, gender, disease duration, rheumatoid factor and HAQ. Correlations among indexes (SDAI or CDAI and DAS) ranged from 0.84 to 0.99, with better correlation between SDAI and CDAI. Agreements among activity strata ranged from 46.8% to 95.8%. DAS28 (CRP) with cut-off point for the remission of 2.3 underestimated disease activity by 45.8% compared with DAS28 (ESR). SDAI and CDAI showed agreement of 95.8%. The four indexes were associated with disease duration and HAQ. Medeiros MM, et al. Correlation of Rheumatoid Arthritis activity indexes (Disease Activity Score 28 measured with ESR and CRP, Simplified Disease Activity Index and Clinical Disease Activity Index) and agreement of disease activity states with various cut-off points in a Northeastern Brazilian population. Rev Bras Reumatol. 2015 Feb 7. [Epub ahead of print]

The interchangeability of the DAS28-ESR and DAS28-CRP was studied in 682 RA patients from the DREAM registry. Despite a strong linear correlation between the DAS28 scores and a high intraclass correlation coefficient of 0.931, a considerable lack of agreement was seen with Bland-Altman 95% limits of agreement ranging between -0.85 and +1.25 points. On average, DAS28-CRP scores were 0.20 points lower than DAS28-ESR scores, and this bias was most severe in older women. The overall classification agreement across DAS28 categories was 76.69%, with the lowest agreement (35.37%) in the low disease activity group. Patients were more easily classified as being in remission when using the DAS28-CRP measure. DAS28-ESR and DAS28-CRP scores are not interchangeable within individuals, and their interchangeability could result in substantial classification differences.  Siemons L, et al. Interchangeability of 28-joint disease activity scores using the erythrocyte sedimentation rate or the C-reactive protein as inflammatory marker. Clin Rheumatol. 2014 Jun;33(6):783-9.

The authors recognized that the values for remission and low disease activity (LDAS) for DAS28-CRP have not been validated and that ACR/EULAR guidelines suggest remission should be calculated by Simplified Disease Activity Index (SDAI) rather than DAS28-ESR. They sought to establish cutoffs for remission and LDAS of DAS28-CRP that correspond to established limits for the same using the DAS28-ESR and SDAI. Using data from 5 clinical trials, rates of remission and LDAS by DAS28-ESR was greater for DAS28-CRP. Discordance between CRP and ESR cut-offs ranged from 4%-26% and 8%-23% for remission and LDAS, respectively, and 19%-40% and 6%-11% for DAS28-CRP versus SDAI, respectively. The comparative ranges for remission and LDAS are shown below:

Fleischmann R, et al. How much does Disease Activity Score in 28 joints ESR and CRP calculations underestimate disease activity compared with the Simplified Disease Activity Index? Ann Rheum Dis. 2015 Jun;74(6):1132-7