056
Test #
Seronegative Rheumatoid Arthritis Profile (includes tests: Rheumatoid Factor (RF) IgM & IgA, Antibodies to Cyclic Citrullinated Peptide (CCP)- IgG, and Scavenger Receptor A (SR-A))
CPT Code(s) #
86200, 86431 x2, 83520
If Profile, Includes Tests:
N/A
Disease Name:
Rheumatoid Arthritis
Type of Study:
Serum Studies
Methodology:
Fluor enzyme immunoassay for RF and CCP: Enzyme Linked Immunosorbent assay (ELISA) for SR-A.
Substrate:
N/A
Reference Range:
CCP
<7 U/ml- Negative
7-10 U/ml-Equivocal
>10 U/ml -Positive
RF- IgA
<14 IU/ml- Negative
14-20 IU/ml-Equivocal
>20 IU/ml-Positive
RF-IgM
<3.5 IU/ml- Negative
3.5-5.0 IU/ml-Equivocal
>5.0 IU/ml-Positive
SR-A
Index value < 0.9: Negative
Index value 0.9 - < 1.0: Indeterminate
Index value ≥ 1.0: Positive
Units:
IU/ml; U/ml; Index Value
Schedule:
Assay performed once weekly on Wednesday. Report availability is within one week from the time of specimen receipt.
Specimen Requirements:
Collect 5-10 ml of blood in a red top or serum separator tube. Separate serum or plasma from cells ASAP or within 2 hours of collection. Transfer 1 mL serum or plasma to a Standard Transport Tube.
• Requested Specimen Volume: 2 mL
• Absolute Minimum Volume: 0.5 mL
• Cause for rejection: Specimens other than serum or CSF. Grossly hemolyzed, lipemic or icteric samples.
Sample Stability:
Sample is stable for 24 hours at room temperature. If sample is stored prior to shipment, it is stable refrigerated (2-8˚C) up to three days and up to three freeze thaw cycles.
Clinical Relevance:
Rheumatoid factor (RF) and Cyclic Citrullinated Peptide antibodies (ACPA) are serological biomarkers for diagnosis of Rheumatoid Arthritis (RA). Rheumatoid Factor (RF) is an autoantibody against the Fc portion of immunoglobulin (Ig). Rheumatoid factor IgM, the main isotype identified by RF assays, is found in 70–80% of patients with confirmed RA. The presence of all three RF isotypes (IgG, IgA, and IgM) at abnormal levels has high specificity for a diagnosis of RA. However, presence of RF isotypes in any combination may be found in other rheumatic conditions and in healthy individuals. The three RF isotypes (IgM, IgA, and IgG) are detected in 52% of RA patients but in fewer than 5% patients with other connective tissue diseases.
Anti-CCP positivity, particularly at elevated levels, at any time is associated with higher risk of more severe clinical outcomes, higher disease activity and worse radiographic progression. Anti-CCP can also be present in other disease states. The second generation CCP (CCP2) test has high sensitivity and specificity and is currently recognized as the gold standard of testing for anti-CCP antibodies (ACPA). The accumulated specificity and sensitivity from 164 studies performed from 2002 to 2010 showed a sensitivity in early RA to be 61.6% and 75.2% in established RA and specificity of 94.0%.
The routine biomarkers, i.e., rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (anti-CCP) used in the current classification criteria only show a modest discriminating power. The sensitivity and specificity are 67% and 94% for anti- CCP, and 69% and 85% for RF, respectively. The addition of scavenger
receptor -A (SR-A) adds the diagnostic value in RF and CCP seronegative RA patients.
Hu et al. (2020), have shown in a cohort of 179 anti-CCP-negative RA patients, 276 RF-negative RA patients, and 155 (anti-CCP and RF)-double negative RA patients that the positive rates of SR-A in anti-CCP-negative and RF-negative RA patients were 49.72% (89/179) and 39.13% (108/276), respectively. More importantly, in (anti-CCP and RF)-double negative RA patients, SR-A also demonstrated a 42.58% (66/155) prevalence. These results support the use of SR-A to facilitate the diagnosis in anti-CCP and/or RF-negative RA patients. The study also showed that in undifferentiated arthritis patients showed higher levels of SR-A and it increased during disease progression. These findings indicate the potential value of SR-A as a predictor of early RA.
Xie et al., 2022, showed that SR-A levels in patients with RA was significantly higher than that in healthy controls. Moreover, the patients with RA correlated positively with both erosion scores while none of the healthy controls showed elevation of SR-A or joint destruction.
Internal lab studies of 80 rheumatoid arthritis patients who fulfilled the 2010 ACR/EULAR diagnostic criteria, 378 autoimmune disease patients, 70 osteoarthritis and 148 infectious disease patients showed that SR-A sensitivity for RA was 56.3%. The specificity was 88.4%. Of the 24 seronegative patients (RA patients that are negative for RF and CCP) 37.5% were found positive for SR-A alone. Taken together, all these results suggest that SR-A when combined with traditional biomarkers RF and CCP will aid in a more robust serological diagnostic panel for RA. The panel will help in for an earlier and more accurate diagnosis particularly seronegative RA.
Selected Reference:
Aletaha, D., Neogi, T., Silman, A. J., Funovits, J., Felson, D. T., Bingham III, C. O., ... & Hawker, G. (2010). 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis & rheumatism, 62(9), 2569-2581.
Derksen, V. F. A. M., Huizinga, T. W. J., & Van Der Woude, D. (2017, June). The role of autoantibodies in the pathophysiology of rheumatoid arthritis. In Seminars in immunopathology (Vol. 39, pp. 437-446). Springer Berlin Heidelberg.
Paalanen, K., Rannio, K., Rannio, T., Asikainen, J., Hannonen, P., & Sokka, T. (2019). Does early seronegative arthritis develop into rheumatoid arthritis? A 10-year observational study. Clin Exp Rheumatol, 37(1), 37-43.
Sokolova, M. V., Schett, G., & Steffen, U. (2021). Autoantibodies in rheumatoid arthritis: historical background and novel findings. Clinical Reviews in Allergy & Immunology, 1-14.
Hu, F., Jiang, X., Guo, C., Li, Y., Chen, S., Zhang, W., ... & Li, Z. (2020). Scavenger receptor-A is a biomarker and effector of rheumatoid arthritis: A large-scale multicenter study. Nature communications, 11(1), 1911.
Xie, Y., Jiang, X., Wang, P., Zheng, X., Song, J., Bai, M., ... & Hu, F. (2022). SR-A neutralizing antibody: potential drug candidate for ameliorating osteoclastogenesis in rheumatoid arthritis. Clinical and Experimental Immunology, 207(3), 297-306.
