Negative Rheumatoid Factor

What is rheumatoid factor (RF)? RF refers to a group of autoantibodies, i.e. antibodies that attack your tissues. The presence of RF antibodies in the blood can help diagnose a range of autoimmune inflammatory conditions, most commonly rheumatoid arthritis (RA).  

What does it mean when the rheumatoid factor is negative?

RF is measured by taking a small amount of blood and either reacting it with latex beads covered in human antibodies that recognise RF (agglutination test) or a nephelometry test, where blood is mixed with antibodies that cause it to form clumps if RF is present. There is often a small amount of RF in the blood, but anything above 20 units/ml is considered a positive test and anything below 20 units/ml is considered a negative RF result.¹ The sensitivity of the RF test is 69%, sensitivity in this context means the proportion of those with RA that will have positive RF results.²

Can you have rheumatoid arthritis but test negative?

Yes, it’s possible. If a test for RF is negative, it doesn’t necessarily mean you don’t have RA (see below). About 30% of RA cases test negative for RF.³ However, RF is no longer the definitive test for RA; some subtypes of RA aren’t associated with a positive RF test.  

About seropositive and seronegative rheumatoid arthritis

It used to be thought that RA was a single condition with a corresponding “one size fits all” treatment regimen of high-dose aspirin and corticosteroids or disease-modifying drugs such as sulfasalazine or gold. However, according to the latest information from the Arthritis Foundation, RA may be a group of conditions distinguishable by different genetic markers, having different clinical courses and optimal treatment regimens.⁴

There are two main types of RA called seropositive and seronegative RA. Seropositive means that a blood test has revealed the presence of substances called anti-cyclic citrullinated peptides (anti-CCPs) - also called anti-citrullinated protein antibodies (ACPA’s). These are present in 60-80% of people with RA and can be present in the body before RA symptoms appear, by 5-10 years.⁴  

Seropositive RA used to mean the presence of RF in the blood, but since RF is a marker of other conditions, including infections, anti-CCPs are now used because they are much more specific for RA. Most seropositive patients are also positive for RF. Conversely, seronegative patients do not have anti-CCPs (and usually no RF) in their blood. You can still have RA if you are seronegative.

Aside from the presence of these key blood markers, seropositive and seronegative RA patients are different in that seropositive patients share a specific section of a protein called the shared epitope.⁵ This RA shared epitope or RA-SE is located in the HLA-DRβ protein encoded by the HLA-DRB1 gene. It may contribute to the production of anti-CCPs. Seronegative patients lack this in their HLA-DRB1 gene. There is no correlation between disease severity and seropositivity, and it is unlikely that seronegative patients will convert to seropositive.

What are the common first signs of rheumatoid arthritis?

RA occurs worldwide with a prevalence of 1-2% in the general population, meaning that, in the UK, there are approximately 680,000-1.36 million sufferers.⁶  However, the trevalence in people assigned female at birth (AFAB) over 55 is at nearly 5%.

The first sign of arthritis is commonly stiffness in one or more joints, often accompanied by pain when the joint or joints move. This happens over a period of weeks or months. It may start in one joint but almost always goes on to affect five or more. The joints most often involved are the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints of the hands and wrists, and small joints of the feet such as the metatarsophalangeal (MTP) joints.  https://commons.wikimedia.org/w/index.php?curid=3949051

The larger joints such as shoulders, elbows, and knees are also affected in many patients. The distal interphalangeal (DIP) joints are generally not affected, and the same is true of the spine, except for the cervical spine (neck).

Morning stiffness, persisting for more than an hour but possibly going on for several hours, is a feature of any inflammatory arthritis but is especially characteristic of rheumatoid arthritis. The duration of this stiffness is a useful gauge of how active the disease is. Advanced RA is typically characterised by symmetrical joint swelling (swelling on both sides of the joint), warmth, tenderness, and redness.

Weeks before pain and stiffness, patients commonly experience fatigue, malaise, and depression. These can be especially prominent during an RA “flare” or exacerbation. A low-grade fever sometimes accompanies these flares.

Can a blood test detect rheumatoid arthritis?

Yes and no. There is no definitive blood test that can rule out or diagnose RA. However, according to the NHS, there is a panel of tests which are commonly performed.⁷ These include:

• Erythrocyte sedimentation rate (ESR) to assess the level of inflammation in the body.
• C-reactive protein CRP (another inflammatory biomarker).
• Full blood count (FBC), to assess your general health and to rule out other causes of your symptoms.  An FBC will be able to detect anaemia, a common feature in those with RA.

Blood tests for RF and anti-CCPs can detect seropositive RA. There is no definitive blood test for seronegative RA, which is mostly diagnosed symptomatically.

What diseases can be mistaken for rheumatoid arthritis?

In addition to RA, RF can also be positive for systemic lupus erythematosus (SLE), mixed connective tissue disorder (MCTD), Sjögren’s syndrome, systemic sclerosis and viral hepatitis B.¹  Seronegativity may result in misdiagnosis of patients with a disease symptomatically similar to RA; for example,  psoriatic arthritis, gout or osteoarthritis.

According to VeryWellHealth, other diseases that can mimic RA symptoms include:

• Viral Arthritis (VA). Viral infections such as parvovirus B19, rubella, HIV, and hepatitis B and C can cause pain and swelling in several joints (polyarthritis) in a similar way to RA.  VA often presents with a rash, unlike RA, and usually resolves after a few weeks.

• Lyme Disease. This is a tick-borne condition due to the bacteria Borrelia burgdorferi or Borrelia mayonii. It causes joint pain and swelling like RA, but non-RA like features include severe headaches and neck stiffness, loss of muscle tone, drooping on one or both sides of the face, and heart palpitations or irregular heartbeat.

• Fibromyalgia. Fibromyalgia is a widespread chronic pain condition often mistaken for RA. In fibromyalgia, the pain occurs at rest, not when moving, as in RA. In addition, RA is characterised by swelling of the joint linings (synovitis), while fibromyalgia is not. Unlike RA, fibromyalgia can cause depression, IBS, fatigue, anxiety, brain fog, and sleep problems, among other symptoms.

• Scleroderma. In RA, a lack of synovial fluid and bone erosion cause pain. In scleroderma, joint pain is caused by damaged connective tissue.⁹  Scleroderma may also give a seropositive result making diagnosis more difficult.  However, differences are apparent upon imaging the joints. Other symptoms of scleroderma that are uncommon in arthritis include Raynaud’s phenomenon, oesophageal dysfunction, and Sjögren’s syndrome.

• Reactive Arthritis. Reactive arthritis is a very painful form of inflammatory arthritis; caused by a bacterial infection of the genitals or bowels such as Chlamydia trachomatis, Campylobacter, Salmonella, Shigella, or Yersinia. Also called Reiter's syndrome, reactive arthritis is a seronegative condition.

• Bursitis. Bursitis is the inflammation of the small, fluid-filled sacs (bursae) that act as cushions between a bone and other moving parts in the joints, causing stiffness and pain. However, bursitis typically affects only one joint at a time.

• Sarcoidosis. This is an inflammatory condition that typically affects the lungs, skin, or lymph nodes, and can mimic RA. Sarcoidosis can cause synovitis in several joints and can be seropositive. Exactly like RA, sarcoidosis onset typically occurs between ages 30 and 50. However, unlike RA, sarcoidosis can be distinguished because it causes cough, shortness of breath, weight loss, night sweats and fatigue.

• Vasculitis. Is inflammation of blood vessels caused by an autoimmune condition. This can affect joints and mimic RA. Two forms of vasculitis, polymyalgia rheumatica (PMR) and giant cell arteritis (GCA,) can co-occur with polyarthritis. People with vasculitis are often seropositive for RF. However, vasculitis is usually characterised by headaches, unlike RA.

It’s also possible to have an RA mimicking disease in addition to RA (i.e., a dual diagnosis).  Common comorbidities of RA include:

• Cardiovascular disorders
• Gastrointestinal disease
• Renal diseases
• Pulmonary diseases
• Infections
• Osteoporosis
• Tumours
• Depression

Conclusion

Rheumatoid factor (RF) is a particular set of antibodies which are present in the blood when the immune system is attacking the body’s own tissue: an autoimmune disease like rheumatoid arthritis (RA) or lupus. However, the lack of RF does not mean that you don’t have RA since you might have a form called seronegative RA. The RF test is no longer considered a definitive diagnostic tool.