Seronegative rheumatoid arthritis
What is seronegative rheumatoid arthritis (RA)?
Seronegative RA is arthritis that is negative for antibodies in the blood. It tends to be associated with the HLA-DR1 more commonly than the HLA-DR4 gene (although other studies have found a similar rate of HLA-DR4 expression with seronegative and seropositive RA). It has also been suggested that seronegative patients can be recognised by a substitution of the amino acid arginine versus lysine at position 71 of the HLA-DRB1 gene.
In the past, the antibody measured was rheumatoid factor (RF), but there are many other associated antibodies (see below). Genetic markers for other associated autoimmune joint diseases, such as ankylosing spondylitis (HLA-B27), an inflammatory disease of the spine, and psoriasis (Cw6), a skin condition which may cause joint problems, have been found to be similar in both groups. It has also been suggested that seronegative RA may overlap with polymyalgia rheumatica, an inflammatory condition commoner in older people which causes neck and shoulder stiffness, and be part of the same disease spectrum.
Some studies have found that DR4 positivity could indicate a worse prognosis in seronegative RA. However, while smoking is a risk factor for seropositive RA, it does not appear to be for seronegative RA. Also, in seropositive RA, those without a university degree, patients who had received previous blood transfusions and those who drank large amounts of decaffeinated coffee had a greater risk of developing RA. However, these effects were less marked for seronegative RA than seropositive RA.
The two most common antibodies are rheumatoid factor (RF) and anti-cyclic citrullinated peptides (anti-CCP 1 and 2). Citrunillated peptides are proteins that have been converted from the amino acid arginine to citrulline. RF is good for predicting disease severity, whilst anti-CCP has 96% accuracy in diagnosing RA.
RF is also found in many other rheumatologic conditions including Sjogren’s syndrome, Systemic Sclerosis and Lupus. RF and anti-CCP are included in the 2010 EULAR/ACR criteria (European League Against Rheumatism / America College of Rheumatology) criteria for diagnosing RA.
Others include antikeratin (AKA), with a sensitivity of 37% for early RA, anti-MCV anti-RA33, anti-Sa (against citrullinated vimentin), antiperinuclear factor (APF), which is often associated with HLA-DR4, anti-nuclear antibody (associated with HLA-DR3), antifilaggrin antibody (AFA), calpastatin, and anti-p68. These are generally less effective in diagnosing but still present in many cases of the condition, and may be detected when RF or anti-CCP are not. They can also give an idea of disease severity: for instance, patients in a clinical trial with APF and RF had a worse prognosis than RF alone.
You may be one of the 20% of RA patients (ie one in five) who are seronegative. There are certain differences between seronegative and seropositive RA. For instance, patients with seronegative RA do not have subcutaneous nodules (under their skin) or vasculitis (inflammation of blood vessels). They are also less likely to have extra-articular (outside the joint) features such as rheumatoid lung disease or heart disease. However, you are more likely to have involvement of your larger joints in seronegative RA.
Rheumatoid nodules are only found in seropositive RA
You may find you change from seronegative to seropositive. This may be due to test errors, sub-threshold levels of RF or seroconversion, which occurs in around 5-10% of patients.
Other differences include the appearance of joints on your X-ray. In seronegative arthritis, there is less osteosclerosis (hardening of the bone which shows up as white) and erosions of bone (the difference is particularly noticeable in early onset RA before the age of 65), more fusion of the bones and the joints involved are more likely to be asymmetrical.
Seronegative RA tends to have a better prognosis, with fewer bony erosions than seropositive arthritis, although each individual is different. Other markers such as AKA or AFA tend to indicate worse outcomes and quicker disease progression. High C-reactive protein levels are also linked to reduced function and increased joint destruction. In terms of mortality, those with seronegative arthritis have a similar survival rate to the general population, while the death rates from seropositive arthritis can be up to 6 times greater.
People with seronegative and seropositive drugs respond in different ways. For instance, one study looked anti-CCP negative and anti-CCP positive patients with suspected RA who were treated with methotrexate. While the anti-CCP positive patients responded, the anti-CCP negative patients did not. It has also been suggested that gold therapy can cause kidney damage, particularly in seronegative RA.
Also, since seronegative arthritis tends to have a better prognosis, it is often treated more conservatively (ie less aggressive treatment) with disease-modifying anti-rheumatic drugs than biologic agents. However, early treatment is still recommended in both groups to improve long-term outcomes – see this YouTube video from Professor Weismann of the UCLA University:
1. Alarco G, et al. Seronegative rheumatoid arthritis. Arthritis & Rheumatism. 1982 May; 25(5):502-507.
2. Inanc M. Very early ‘Rheumatoid’ arthritis cohorts: limited by selection. Rheumatology 2007; 46(2): 185-187.
3. Machold K, et al. Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of disease. Rheumatology 2007; 46(2): 342-349.
4. Steiner G, et al. Autoantibodies in rheumatoid arthritis and their clinical significance. Arthritis Research & Therapy. 2002 Apr; 4(2).
5. Cordonnier C, et al. Diagnostic value of anti-RA33 antibody, antikeratin antibody, antiperinuclear factor and antinuclear antibody in early rheumatoid arthritis: comparison with rheumatoid factor.Br J Rheumatol 1996, 35:620-624.
6. Panay G, et al. Seronegative and seropositive rheumatoid arthritis: similar diseases. Rheumatology. 1987; 26 (3): 172-180.
Written by Dr Anne Parfitt-Rogers, Medical Writer, UK