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Recombinant Rheumatoid Factor: Elevating Autoimmune Diagnostics

May 28, 2025Recombinant Proteins, Recombinant Rheumatoid Factor

Recombinant Rheumatoid Factor: Elevating Autoimmune Diagnostics

Recombinant Rheumatoid Factor: A Reliable Alternative to Native Sera for Clinical Controls

Rheumatoid factor (RF) is a critical biomarker in the diagnosis and management of autoimmune diseases, particularly rheumatoid arthritis (RA). While human-derived sera have long served as the primary source for RF in clinical laboratories, challenges related to variability, supply, and biosafety have highlighted the need for standardized alternatives. Recombinant RF offers a consistent, scalable, and pathogen-free solution for assay development and clinical controls.

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune condition characterized by systemic inflammation that primarily affects the joints. Common symptoms include joint pain, stiffness, tenderness, warmth, and swelling, which may interfere with daily activities. If left untreated, RA can lead to irreversible joint damage, disability, and complications involving the cardiovascular, pulmonary, and nervous systems. Although the etiology of RA remains unclear, risk factors such as smoking, obesity, and air pollution have been identified. The disease is more prevalent in women and typically manifests with increasing age [1].
Rheumatoid Factor (RF) refers to a group of autoantibodies targeting the Fc region of activated IgG antibodies [2]. While RF is most commonly of the IgM isotype, IgA and IgG variants are also found in RA patients [3]. Elevated RF titres often precede clinical symptoms and are widely used as diagnostic and prognostic tools [4].
According to guidelines from the World Health Organization (WHO) and the American College of Rheumatology (ACR), RF testing forms a core component of autoimmune diagnostic panels [1,5]. Although RF is not disease-specific—it can also appear in conditions like Sjögren’s syndrome, hepatitis C, and in some healthy individuals—it remains an important early screening marker [6].

Limitations of Native RF-Positive Sera

Every clinical test that is performed around the world needs to be properly controlled and validated. RF used in the manufacture of these clinical controls and calibrators has traditionally been sourced from human donor materials. While this provides polyclonal antibodies that resemble the in vivo environment, it introduces several key challenges:

  • Donor variability: RF titres and isotype distribution differ among individuals.
  • Limited availability: High-titre RF samples are rare, and their availability is declining due to the widespread use of effective RA treatments such as methotrexate, rituximab, and abatacept, which reduce RF titres in donor materials [7–9].
  • Biosafety risks: Native sera may carry infectious agents and should be handled in Biosafety Level 2 (BSL-2) laboratories [10].
  • Multiplex complexity: When used in multianalyte reagents like clinical controls or linearity panels, each sample must be tested for all components, adding complexity and cost to the identification of useable donor materials.

These factors contribute to variability and inefficiency in the manufacture of diagnostic control and calibration reagents.

Recombinant RF: A Consistent and Scalable Alternative

To address the limitations of native sera, recombinant RF has been proposed as a robust alternative with several key advantages:

  • Defined isotype and affinity: Recombinant RF can be expressed as IgM, IgA, or IgG, with controlled binding characteristics.
  • Batch-to-batch consistency: Unlike polyclonal donor sera, recombinant RF production results in monoclonal antibodies with a predictable and repeatable response for consistent performance and production output.
  • Scalability: Recombinant systems allow for industrial-scale production, removing the reliance on rare donor material.
  • Pathogen-free: Recombinant production ensures biosafety, eliminating the risk of bloodborne pathogens and meeting regulatory guidelines [11].
  • Formulation flexibility: Buffer formulations and storage conditions can be optimized for improved shelf-life and compatibility with a variety of automated platforms and existing manufacturing workflows.

These benefits make recombinant RF ideal for clinical controls, calibrators, and validation standards in diagnostic testing.

Applications in Clinical Diagnostics

Recombinant RF can be applied across a range of immunoassay platforms:

  • Positive controls for ELISA, nephelometry, or turbidimetry
  • Calibrators in quantitative RF assays, e.g. in linearity panels
  • Reference standards during assay development or validation

The Clinical and Laboratory Standards Institute (CLSI) emphasizes the need for consistent and high-quality controls in diagnostic testing [12]. Regulatory bodies such as the WHO and the European Union’s In Vitro Diagnostic Regulation (IVDR) are also advocating for the use of reliable and traceable diagnostic components [13]

Recombinant Biomarkers to replace Native

To rise to the challenges outlined above, we have developed a recombinant RF product presented as a J-chain-stabilized IgM molecule with high titre and excellent cross-platform compatibility. It has demonstrated strong recovery across major clinical diagnostic systems, including Abbott Alinity, Roche cobas, and Beckman DxC.
As diagnostic innovation accelerates, replacing native materials with recombinant alternatives—starting with RF—will be critical in building a scalable and consistent future for clinical immunology.

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References

  1. World Health Organization. Rheumatoid arthritis fact sheet. WHO Website.
  2. Maibom-Thomsen SL, Trier NH, Holm BE, et al. Immunoglobulin G structure and rheumatoid factor epitopes. PLoS ONE. 2019;14(6):e0217624. https://doi.org/10.1371/journal.pone.0217624
  3. Annals of the Rheumatic Diseases. 2019;78:1667–1668.
  4. Aho K, Heliövaara M, Maatela J, et al. Rheumatoid factors antedating clinical rheumatoid arthritis. J Rheumatol. 1991;18(9):1282–1284.
  5. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid Arthritis Classification Criteria. Ann Rheum Dis. 2010;69(9):1580–1588.
  6. National Health Service (NHS) UK. Rheumatoid arthritis diagnosis. https://www.nhs.uk/conditions/rheumatoid-arthritis/diagnosis
  7. Spadaro A, Riccieri V, Sili Scavalli A, et al. One year treatment with low dose methotrexate in rheumatoid arthritis: Effect on class specific rheumatoid factors. Clin Rheumatol. 1993;12:357–360. https://doi.org/10.1007/BF02231579
  8. Borys O, Targonska-Stepniak B, Dryglewska M, et al. AB0413: The prospective assessment of rituximab and tocilizumab treatment effect on RF-IgM and ACPA titres in rheumatoid arthritis patients. RMD Open. 2018;4(1):e000564. https://doi.org/10.1136/rmdopen-2017-000564
  9. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005;353:1114–1123.
  10. CDC. Biosafety in Microbiological and Biomedical Laboratories (BMBL), 6th Edition.
  11. FDA. Guidance for Industry: In Vitro Diagnostic (IVD) Device Studies – Frequently Asked Questions.
  12. Clinical and Laboratory Standards Institute (CLSI). Quality Management System: A Model for Laboratory Services; Approved Guideline—QMS01-A4.
  13. European Commission. IVDR 2017/746 — Regulation on In Vitro Diagnostic Medical Devices.