Rheumatoid Factor: The Most Remarkable Autoantibody in Rheumatoid Arthritis

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Rheumatoid Factor: The Most Remarkable Autoantibody in Rheumatoid Arthritis

12 October 2019

Rheumatoid Factor: The Most Remarkable Autoantibody in Rheumatoid Arthritis

The European League Against Rheumatism (EULAR) launched the ‘Don’t Delay, Connect Today’ campaign in 2017, continuing into 2019 for World Arthritis Day. The day is a global awareness day focusing on promoting the symptoms associated with rheumatic and musculoskeletal diseases (RMDs). Moreover, the world awareness day focuses on the importance of early diagnosis and access to care 1. Randox Reagents fully supports the importance of early diagnosis which aids in the early implementation of effective treatment plans, aiding in improved health outcomes. On this World Arthritis Day, Randox Reagents will delve deeper into rheumatoid factor (RF), the most remarkable autoantibody in rheumatoid arthritis.

Pathobiology of Rheumatoid Arthritis (RA)

Rheumatoid arthritis (RA), “the most common systemic inflammatory autoimmune disease” affecting 1% of the global population, is characterised by fatigue, synovial joint pain, stiffness, swelling and destruction, with severe symptoms resulting in disability. Whilst the exact cause of RA is unknown, it is believed that genetic and environmental factors play a role in triggering the disease 2, 3.  Differences in the human leukocyte antigen (HLA)-DRB1 alleles (proteins with a critical role in the immune system) have been identified as a genetic variant for RA, observed in >80% of patients, particularly in those testing positive for RF. Moreover, those with variations in the HLA-DRB1 who smoke, increase their risk of RA. As RA is more common in women (2-fold increased risk in women compared to men), hormonal influences are an area of active research, however, an inverse correlation with breastfeeding has been identified. Women who breastfeed for >13 months aids in reducing the risk of RA compared to women who have never breastfed 3, 4.

The pathophysiology of RA involves various signalling pathways and immune modulators (effector cells and cytokines) as indicated in figure 1. Joint destruction is caused by the intricate interactions of immune modulators, beginning at the synovial membrane and encompassing most IA structures, with synovitis caused by both or individually, the local activation or influx of mononuclear cells, including: B cells, T cells, dendritic cells, plasma cells, mast cells and macrophages. Consequently, “the synovial lining becomes hyperplastic, and the synovial membrane expands and forms villi”. The neutrophils, chondrocytes and synoviocytes secrete enzymes that degrades the cartilage in the joint whereas the osteoclast-rich area of the synovial membrane destroys the bone 4.

Figure 1: Schematic view of (a) a normal joint and (b) a joint affected by RA 4 

Clinical Significance of Rheumatoid Factor (RF)

Interestingly, elevated levels of RF have been observed in other autoimmune conditions such as Sjögren syndrome and systemic lupus erythematosus (SLE) as well as non-autoimmune conditions including old age and chronic infections. Despite this, RF in RA patients can be distinguished from RF in healthy individuals. RF in RA patients displays affinity maturation whereas RF in healthy individuals has low affinity and are polyreactive 2.

RF is a class of immunoglobulin (Ig) autoantibodies that are directed against the fragment crystallizable region (Fc region), the tail region of the IgG antibody. In RA, RF are produced by the B cells present in lymphoid follicles and the germinal center(GC)-like structures that mature in inflamed synovium. Most RF are IgM antibodies, but may also be IgG or IgA isoforms. IgM RF are detected in 60% to 80% of RA patients. “RF testing in RA patients has a sensitivity of 60% to 90% and a specificity of 85%” (5). RF is a highly valuable biomarker in RA 5, 2.

Key Features of the Randox Rheumatoid Factor Assay

The Randox automated latex enhanced immunoturbidimetric rheumatoid factor assay provides an accurate assessment of RF titre as the Randox rheumatoid factor calibrator is standardised against the primary WHO material, 1st British Standard 64/2. With a wide measuring range of 6.72 – 104lU/ml for the comfortable detection of clinically important results, the Randox RF assay is available in a liquid ready-to-use format for the comfortable detection of clinically important results. The Randox rheumatoid factor assay does not suffer from interference from C1q complement and is stable until expiry date. With dedicated calibrator and controls for a complete testing package, Randox offer applications, detailing instrument-specific settings for the convenient use of the Randox rheumatoid factor assay on a wide range of clinical chemistry analysers.

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Rheumatoid Arthritis and Women’s Health

Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterised by pain, swelling and stiffness in joints which commonly affects the hands, wrists and feet.  Whilst both men and women can suffer from rheumatoid arthritis, it is more commonly seen in women than men.

Rheumatoid arthritis is the most common autoimmune disease with a higher prevalence rate compared to lupus, multiple sclerosis, type 1 diabetes, Crohn’s disease and psoriasis.

(Simmons, 2013)

The incidence rates of rheumatoid arthritis differ between men and women.  The onset of RA occurs much earlier for women, for most, during their 30’s and 40’s.  In an American study, it was noted that the incidence rates peak for women around the ages of 55 to 64, compared to 75 to 84 years of age for men.

(Simmons, 2013)

As most women are diagnosed with rheumatoid arthritis in their 30’s and 40’s, a study found that the diagnosis negatively impacts both the body and mind of women, as indicated in their pain, disease activity, and quality of life scores.  This is due to women being diagnosed at a time when their burdens are the heaviest as this is the time when women are most likely to have children or are raising children combined with work and socialising.

Changes in hormone levels also impacts women.  It has been noted that before a menstrual period, women find the symptoms of rheumatoid arthritis to be more severe, but settles during their cycle.  Also, due to the changes in hormone levels during pregnancy, 50 – 60% of women with rheumatoid arthritis noticed that their symptoms improved.

The key to managing rheumatoid arthritis is to start the treatment as early as possible as it can halt or slow the disease, preventing joint damage and complications, including: osteoporosis and cardiovascular disease.  Rheumatoid arthritis increases the risk of heart attack by 60%.  To start treatment as early as possible, it is important that it is diagnosed as early as possible.

Randox offer a number of key assays for the diagnosis of rheumatoid arthritis.

Rheumatoid factor is the most routinely run test to diagnose rheumatoid arthritis as 80% of rheumatoid arthritis patients test positive for rheumatoid factor.  The Randox Rheumatoid Factor reagent offers the following benefits:

  • Wide measuring range of 6.72 – 104lU/ml for the accurate measurement of clinically important results
  • Accurate assessment of rheumatoid factor titre (calibrant standardised against primary WHO material; 1st British Standard 64/2)
  • No interference from complement C1q
  • Automated immunoturbidimetric assay
  • Applications available for a wide range of biochemistry analysers, detailing instrument-specific settings

It has been found that complement C4 and CRP upregulation indicates the middle to late stages of rheumatoid arthritis.

The Randox Complement C4 reagent offers the following benefits:

  • Wide measuring of 3.41 – 152mg/dl for the accurate measurement of clinically significant results
  • Limited interferences from Bilirubin, Haemoglobin, Intralipids, and Triglycerides, producing more accurate results
  • Automated immunoturbidimetric assay
  • Applications available for a wide range of biochemistry analysers, detailing instrument-specific settings

The Randox High-Sensitivity CRP reagent offers the following benefits:

  • Wide measuring of 0.477 – 10mg/l fir the accurate measurement of clinically significant results
  • Liquid ready-to-use reagents for convenience and ease of use
  • Applications available for a wide range of biochemistry analysers, detailing instrument-specific settings

Complement C4 – Biomarker for Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematosus (SLE) is an autoimmune disorder associated with a deficiency in complement C4.  Complement C4 is one of nine components of the complement system which is an integral part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from the host, promote inflammation, and attack the cell membrane of pathogens.

 

Complement C4 is a vital component of two immunology pathways: Classical pathway and Mannrose Binding Lectin (MBL) pathway.

The classical pathway is triggered by antibody-antigen complexes which induces a conformational change in the C1 complex.  The activated C1 complex cleaves the C4 component, resulting in a reactive C4b which covalently binds to proteins or polysaccharides at the surface in close proximity of the C1 component.  The bound C4b complexes binds to the C2 component rendering C2 for proteolysis by C1.

The MBL pathway is activated through the binding of MBL to mannose residues on the pathogen surface.  This in turn activates the MBL-associated serine proteases, MASP-1 and MASP-2, which activates the C4 and C2 components, to form the C3 convertase, C4b2a.  The C4b2a complex splits C3 into two fragments which causes the release of vasoactive mediators such as histamine.

Complement C4 deficiency is commonly associated with systemic lupus erythematosus (SLE).

According to lupus.org, 16,000 new cases of lupus are reported each year.  Approximately 1 in 250 people may end up developing SLE at some point with 90% of SLE patients being female aged between 15-44 years.  The causes of SLE are unknown, but are believed to be linked to environmental, genetic, and hormonal factors.  1.5 million Americans are living with diagnosed lupus.

There are four forms of lupus:

  • Systemic – accounts for approximately 70% of all lupus cases. In half of these cases, a major organ or tissue in the body, such as the heart, lungs, kidneys, or brain will be affected.
  • Cutaneous lupus – accounts for approximately 10% of all lupus cases and only affects the skin.
  • Drug-induced lupus accounts for approximately 10% of all lupus cases and is caused by high doses of certain medications.
  • Neonatal lupus is a rare condition in which the mother’s antibodies affect the fetus. At birth, the baby may have a skin rash, liver problems, or low blood cell counts, but these symptoms typically disappear completely after six months with no lasting effects.

The Randox Complement C4 assay

The Randox Complement C4 assay is used for the quantitative in vitro determination of complement C4 concentration in serum.  The Randox Complement C4 assay can be used as a biomarker in the diagnosis and monitoring of SLE.  It is the cell-bound levels of processed complement activation products, especially E-C4d (erythrocyte-bound C4) that makes the complement C4 assay a biomarker for SLE.

Key Features of the Randox Complement C4 assay

Liquid ready-to-use reagents – The Randox reagent comes in a convenient liquid format requiring minimal preparation thus reducing the risk of errors.

Exceptional correlation with standard methods – The Randox methodology was compared against other commercially available methods and the Randox Complement C4 assay showed a correlation coefficient of r=0.98.

Wide measuring range – The healthy range for Complement C4 is 7 -49 mg/dl. The Randox Complement C4 assay can comfortably detect levels outside of the healthy range measuring between 2.90 – 152 mg/dl.

Excellent stability – Stable until expiry date when stored at +2 to +8°C.

For health professionals

If you are a clinician or laboratory who are interested in running specific protein assays, Randox offer a wide range of high-quality routine and niche assays including:  Cystatin C, Complement C3, CRP, Lipoprotein (a), Apolipoprotein C-II, Apolipoprotein C-III and Apolipoprotein E. These can be run on most automated biochemistry analysers.

Instrument Specific Application (ISA’s) are available for a wide range of biochemistry analysers.  Contact us to enquire about your specific analyser.

For more information, download our Specific Proteins Brochure email reagents@randox.com

 

 


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