April 12, 2022

Seronegative Rheumatoid Arthritis – What Does It Mean?

Written by: Marina Peric, M.D.

Have you recently been diagnosed with seronegative arthritis? If so, you’ve probably noticed how after trying to find more information online, rheumatoid arthritis keeps popping out.

Rheumatoid arthritis is a common systemic autoimmune disease that affects 0.5-1% of people worldwide. It primarily affects joints, usually of hands, feet, and knees, but many other organs such as the kidneys, blood vessels, or heart can also be affected. Common symptoms include joint pain, swelling, and stiffness - probably what brought you to see the doctor too. Actually, most of the information you find about rheumatoid arthritis fit your signs and symptoms.

Yet, after ordering several blood tests, you’ve been diagnosed with seronegative and not rheumatoid arthritis. So, what does ‘seronegative’ mean?

 

Seronegative vs. Seropositive: what’s the difference?

As mentioned, rheumatoid arthritis is an autoimmune disease. Simply put, autoimmune diseases occur when your immune system mistakes a component of your body for a component of a microorganism and attacks, causing inflammation. But unlike microorganisms, body components cannot be wiped out at some point. Hence, the inflammation persists, with intertwining processes of destruction and reparation – and this is why autoimmune diseases are chronic and incurable.

In the case of rheumatoid arthritis, the affected structures are the joints, and the inflammation is mediated by autoantibodies. The most characteristic is the rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), as also anti-carbamylated protein (anti-CarP) and anti-acetylated protein antibodies. It is these antibodies that the doctors search for in the blood of patients who present with the symptoms of rheumatoid arthritis. If they’re present, the patient is seropositive, and if not present or too low to detect, they’re seronegative. Interestingly, autoantibodies can sometimes be found in the blood of predisposed people years before the first symptoms appear.

 

So, is Seronegative Arthritis just a form of Rheumatoid Arthritis with No Autoantibodies in the Blood?

Yes, and no. Anyhow, it is how the nature of this disease was first understood. In general, the disease mechanisms, as well as genetic and environmental risk factors are disparate in seropositive and seronegative arthritis. The prognosis is different too: seronegative patients seem to have less aggressive disease and better outcomes.

Nowadays, with careful monitoring of the evolution of signs and symptoms and more advanced diagnostic methods and criteria, the originally set diagnosis of seronegative arthritis may be switched later on. For example, if autoantibodies become detectable, the diagnosis will be changed to seropositive rheumatoid arthritis. According to a study conducted by a group of Finnish scientists, this happens in about 3% of cases.

Spondyloarthritis is the diagnosis that most often comes into consideration. A recent study by Sokka and associates found that this happens in almost 50% of cases! Similar results were obtained in a 2002 study conducted in the Finnish city of Heinola by Jaanti, Kaarela, and Lehtinen. This study reported 23-year outcomes of 64 patients with seronegative arthritis - more than 50% of the patients (40/64) were reclassified with spondyloarthritis during follow-up.

Other types of seronegative arthritides such as IBD-related arthritis, psoriatic arthritis, ankylosing spondylitis, or reactive arthritis are rare differential diagnoses. Of course, the diagnosis will remain the same if the clinical presentation doesn’t develop to become characteristic of another entity.

 

Clinical presentation

The typical signs and symptoms of seronegative arthritis are the same as in rheumatoid arthritis and include:

  • Inflammation and pain in the joints, usually the small joints of hands and wrists, which is symmetrically present on both sides of the body in advanced disease and may only be present on one side in early disease
  • Morning stiffness that lasts over an hour
  • Swelling and thickening of affected joints
  • Fatigue, weight loss, and/or subtle fever can also be present with active disease.

Thirty-five years ago, signs of joint destruction seen on X-ray were also an important sign and a diagnostic criterion, but this is no longer the case as the aim is to detect and treat arthritis very early, long before these lesions can be detected.

Some of the signs and symptoms that could lead to a switch in diagnosis include:

  • Development of radiographic changes typical for a certain type of arthritis
  • Discovery of autoantibodies in the blood, not only those typical for rheumatoid arthritis but also different classes of antinuclear antibodies (ANCAs) and other
  • Positivity for HLA-B27 antigen in the blood
  • Dactylitis (global inflammation and swelling of fingers which become sausage-like)
  • Uveitis (a type of eye inflammation)
  • Enthesitis (inflammation of entheses)
  • Inflammatory back pain
  • Psoriatic changes of nails and skin: pitted, ridged, and crumbled nails, and inflamed, itchy, silvery dead-skin scales usually on the knees, elbows, and scalp
  • Newly discovered inflammatory bowel disease
  • Inflammation of several joints without developing permanent arthritis similar to rheumatoid
  • Renal failure.

Correct diagnosis – correct treatment?

Establishing the right diagnosis right away isn’t crucial for the treatment or outcomes. Seronegative arthritis is treated in the same way as seropositive and similarly to other arthritides that it may switch to, so, even if a switch in diagnosis happens, the administered therapy was almost surely adequate whatsoever. Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are the primary drugs used to diminish inflammation, but they do not have an impact on the course of the disease. For this purpose, disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, are added. Physical therapy and exercising have irreplaceable beneficial effects: they aim to strengthen muscles, stabilize joints, maintain their range of motion and mobility, mitigate the pain, and overall ease everyday activities. The final treatment option is joint replacement and reconstruction surgery.

What may come up as a problem regarding therapy is the dosage: due to an imprecise diagnosis, a patient may be prescribed drugs in doses that are unnecessarily high over a period of time. If drugs mask the developing symptoms, the correct diagnosis may never be made – this doesn’t have a practical but rather scientific importance.

 Finally, as the presence of autoantibodies in the blood is an important diagnostic criterion for rheumatoid arthritis, to establish the diagnosis of seronegative arthritis the symptoms at onset must be more pronounced – and the disease more advanced. Several studies confirmed that the clinical presentation of seronegative patients is much more severe at the time of making the diagnosis as compared to seropositive patients. Because of this, the treatment of seronegative patients begins rather late, while it is known that early treatment correlates with better outcomes. Modern imaging methods have already fastened the correct diagnosis establishment process, but this is something to be further improved, most likely through the discovery of new relevant biomarkers.

 

References

  1. Derksen VFAM, Huizinga TWJ, van der Woude D. The role of autoantibodies in the pathophysiology of rheumatoid arthritis. SeminImmunopathol. 2017;39(4):437-446.
  2. Aletaha D, Blüml S. Therapeutic implications of autoantibodies in rheumatoid arthritis. RMD Open. 2016;2(1):e000009.
  3. Paalanen K, Puolakka K, et al. Is seronegative rheumatoid arthritis true rheumatoid arthritis? A nationwide cohort study. Rheumatology (Oxford). 2021;60(5):2493-2494.
  4. Paalanen K, Rannio K, et al. Does early seronegative arthritis develop into rheumatoid arthritis? A 10-year observational study. 2019;37(1):37-43.
  5. Reed E, Hedström AK, et al. Presence of autoantibodies in "seronegative" rheumatoid arthritis associates with classical risk factors and high disease activity. Arthritis Res Ther. 2020;22(1):170.
  6. RantapääDahlqvist S, Andrade F. Individuals at risk of seropositive rheumatoid arthritis: the evolving story. J Intern Med. 2019;286(6):627-643.
Article written by Marina Peric, M.D.
Marina is a medical doctor from Belgrade, Serbia. She graduated with high honors in 2020 and is aspiring to become a pathologist. During her studies, she took part in several scientific researches, mostly in the pharmacology niche. She was also an assisting teacher at the Department of Histology and Embryology for 5 years (2015-2020). Marina has years of experience as a writer on health-related topics. Apart from English, she fluently speaks several languages, including Spanish, Russian, and Czech.

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