Rheumatoid factor is a type of antibody that was first detected in patients with rheumatoid arthritis in the 1940s. Despite the name, rheumatoid factor is an immune protein associated with many disease states and has also been measured in up to 5% of the healthy population. A proper understanding of RF test results enables precise diagnosis and the facilitation of appropriate health management. In preventive and integrative medicine, the importance of rheumatoid factor testing lies in its ability to serve as a biomarker for immune function. (9) 

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What Is Rheumatoid Factor (RF)?

Rheumatoid factor (RF) is an antibody present in the blood of many people with rheumatoid arthritis, as well as other autoimmune and inflammatory disorders. It's an autoantibody, meaning the immune system produces it. However, instead of targeting foreign substances, it mistakenly attacks healthy tissues in the body. Specifically, RF is an antibody that binds to the Fc portion of immunoglobulin G antibodies, forming complexes that deposit in tissues, leading to inflammation and tissue damage. (22) 

Let's break down these terms to understand this better:

Autoimmunity

Autoimmunity is a condition in which the body's immune system mistakenly identifies and attacks its own cells, tissues, and organs as if they were foreign invaders, leading to chronic inflammation, tissue damage, and disease states.

Immunoglobulin

Immunoglobulins, also known as antibodies, are large Y-shaped proteins produced by the immune system in response to the presence of foreign substances (antigens), such as viruses and bacteria. These molecules play a critical role in the immune response, defending the body against infections. There are five classes of immunoglobulins, each with specific purposes. (11) 

• Immunoglobulin G (IgG), the most abundant class, is found in body fluids and provides long-lasting protection by neutralizing toxins and enhancing phagocytosis, the process by which cells engulf and digest foreign particles. 
• Immunoglobulin M (IgM) is the first antibody produced during an initial infection, acting as an efficient first responder by activating complement, a group of proteins that enhance the immune response. 
• Immunoglobulin A (IgA) is the second most abundant immunoglobulin type found in the body found in mucosal secretions of the gastrointestinal, respiratory, and genitourinary tracts.
• Immunoglobulin D (IgD) is present on the surface of B cells and helps in the activation of these cells during the immune response. 
• Immunoglobulin E (IgE) is involved in allergic responses, triggering the release of histamine and other chemicals that lead to allergy symptoms. IgE has also been implicated in immune responses targeted against parasitic infections. 

Fc Portion of Immunoglobulins

The top part of the Y-shaped antibody, called the "Fab region," binds to the antigen, recognizing and neutralizing it. The bottom part of the Y, called the "Fc region," which stands for "fragment, crystallizable," doesn't bind to antigens directly. Instead, it plays a crucial role in the immune response in different ways. (7) 

Antibodies can mark pathogens for destruction by immune cells, a process called opsonization. The Fc region binds to immune cells, like macrophages, helping them recognize and engulf the targeted invader. (7) 

The Fc region can also activate the complement system, a group of proteins that enhance the immune response. This activation leads to the destruction of the target cell. (7) 

In a process called antibody-dependent cellular cytotoxicity (ADCC), immune cells called natural killer cells recognize the Fc portion of antibodies bound to infected or abnormal cells. The natural killer cells then release chemicals to destroy these marked cells. (7) 

The Rheumatoid Factor Test

In people with certain autoimmune conditions, the immune system manufactures higher levels of autoantibodies, such as RF, to attack healthy cells. Therefore, higher levels of RF in circulation can indicate autoimmune activity occurring in the body and can help diagnose autoimmune conditions. Symptoms that would warrant ordering the RF test include:

• Joint pain, stiffness, and swelling
• A loss of joint range of motion
• Nodules under the skin
• General fatigue
• Dry eyes and mouth
• Fever of unknown origin 
• Loss of appetite

RF can be measured with a blood test. The presence of RF in the blood is used along with clinical symptoms and other laboratory findings to help diagnose autoimmune disease. Examples of complementary tests to RF include anti-nuclear antibody (ANA), extractable nuclear antigen (ENA),  anti-cyclic citrullinated peptide (anti-CCP), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). 

Interpreting Your Test Results

A negative (normal) RF result means you have little or no RF in your blood. A positive (abnormal) result means that higher levels of RF were measured in the blood. Normal reference ranges may vary slightly between different laboratories, but in general, a positive RF is reported in one of two ways:

• RF antibody value greater than 14 IU/mL
• RF titer greater than 1:80

The higher your RF test result, the more likely it is that you have a condition linked to rheumatoid factor. An RF antibody value greater than three times the upper limit of normal is considered a high positive (1). A 2012 study concluded that a person with an RF of 100 IU/mL or higher is up to 26 times more likely to develop rheumatoid arthritis than one with an RF level under 25 IU/mL. However, a positive RF alone cannot diagnose any condition. Factors affecting RF test results include viral and parasitic infections, preexisting chronic medical conditions, vaccinations, older age, and smoking. Therefore, precise interpretation of RF test results requires complete knowledge of the patient's medical history and health status. (10, 15, 18) 

Rheumatoid Factor and Rheumatoid Arthritis

As suggested by the name, a high level of circulating RF is often related to rheumatoid arthritis (RA). RA is the most common autoimmune inflammatory arthritis, affecting 1.5 million American adults. It causes painful swelling and bone erosion within joints, eventually resulting in joint deformity and disability. (2)

Clinicians use the 2010 American College of Rheumatology/European League Against Rheumatology classification criteria for RA as a guide to diagnosing RA. These criteria consider the number and size of joints affected, symptom duration, and biochemical markers of inflammation and autoimmunity to make a diagnosis. Making an RA diagnosis can be difficult because many patients with RA, especially in early disease, may not satisfy these criteria. (1) 

A positive RF is one of the diagnostic criteria that can help in making an RA diagnosis. Approximately 60-80% of people with RA have RF in their blood. However, it's important to note that RF results are positive in less than 40% of patients during early disease stages. (20) 

Seronegative RA is a form of RA in which patients do not have detectable levels of RF and anti-CCP antibodies in the blood. It is estimated that at least 15-25% of patients with RA are seronegative. In these cases, an RA diagnosis is clinical, based on symptoms, imaging, and patient response to medical intervention (1).  

Other Conditions Associated with Elevated RF

RF is not considered a specific biomarker for RA, meaning that it may also be present in other disease and non-disease conditions. RF may be present in other autoimmune and inflammatory connective tissue diseases, including lupus, sarcoidosis, and Sjögren's syndrome. RF is also observed in 1-5% of the general healthy population, especially older individuals (20). 

People with the following diseases and medical conditions may also have high levels of RF:

• Dermatomyositis
• Polymyositis
• Mixed cryoglobulinemia
• Mixed connective tissue disease
• Bacterial infections: endocarditis, tuberculosis
• Viral infections: AIDS, hepatitis, influenza, mononucleosis
• Kidney disease
• Chronic lung disease
• Chronic liver disease
• Cancers: leukemia, multiple myeloma

Next Steps After Receiving Your Results

Because diagnosing autoimmune disease can be complex, it is crucial to consult a rheumatologist or medical expert promptly after receiving a positive RF test. These specialists are experienced in autoimmune disorders and can conduct comprehensive evaluations, considering various factors such as medical history, physical examinations, and additional tests.

Based on rheumatoid factor results and definitive diagnosis, rheumatologists can recommend appropriate treatments and interventions. These may include disease-modifying antirheumatic drugs (DMARDs) to slow down the progression of the disease, nonsteroidal anti-inflammatory drugs (NSAIDs) to manage pain and inflammation, or, in more severe cases, biologic therapies to target specific parts of the immune system. An integrative approach to treating autoimmune diseases will also include therapeutic dietary modifications, natural supplements, and other complementary modalities, such as acupuncture. 

Regular monitoring and repeat testing is also an important aspect of effective treatment. RA is a progressive condition that causes irreversible joint damage and disability when not properly managed. Periodic assessments, including clinical examinations and blood tests, help doctors evaluate the disease's progression and response to therapy. Timely identification of autoimmunity flares and treatment adjustments can prevent further tissue damage and improve long-term patient outcomes.

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Summary

Understanding and interpreting RF test results is of paramount importance for proactive health management. It serves as a diagnostic tool, especially in autoimmune disorders like rheumatoid arthritis. Empowering health through understanding RF involves not only grasping the implications of these results but also encouraging individuals to engage in proactive health management. Regular consultations with healthcare professionals, particularly integrative rheumatologists, can provide personalized and appropriate interventional recommendations, enhancing the overall quality of life.