To most medical students and patients uninitiated in the science of rheumatology, the diagnostic process whereby rheumatologists assess patients may seem bewildering. When considering any patient who presents with joint pain, there are over 100 types of arthritis to consider, lots of conditions which mimic arthritis, a huge array of blood tests to consider and any amount of expensive imaging tests at our disposal. Sounds complicated? It’s not as hard as it seems. When you take gout and joint infections out of the mix (usually easy to spot if you know what you’re doing), you are really trying to determine if your patient has one of two categories of joint problem; a problem relating to joint degeneration or one relating to inflammation.
Only two types of arthritis to consider. That shouldn’t be too hard to do now should it? Here’s some of blood tests that help us do it;
Inflammation blood tests (ESR, CRP)
The results from these two readily available and relatively inexpensive blood tests are probably the first tests any rheumatologist looks for on a patient are the ESR (‘sed rate’) and CRP. These two complementary blood tests help us differentiate between patients with active inflammatory arthritis (eg rheumatoid, psoriatic, reactive arthritis, undifferentiated inflammatory arthritis, ankylosing spondylitis) and those with degenerative joint problem or with other causes of their pain. Although they can be become elevated in conditions other than arthritis (infections and malignancies for example) I tend look on them as measuring the ‘temperature’ of any inflammatory process. The higher above the normal range they are, the more intense the inflammation present. In certain disease states (eg rheumatoid arthritis), very high levels can help us identify patients at higher risk of damage. The closer to the normal range they are, the less likely a patient it to have an inflammatory process. These tests are also used to help monitor the activity of inflammatory arthritis and its response to treatment (one of the ways we know treatment is working is that the CRP / ESR falls during treatment) These tests are not infallible by any means. For a list of pitfalls in their use see below under specific conditions.
Disease Markers (RF, CCP, ANF/ANA)
Once a doctor suspects a patient has inflammatory arthritis, these disease specific tests are used to determine which type of inflammatory arthritis (or other connective tissue disease) they have. Examples of these tests would be Rheumatoid Factor (RF), CCP antibody and Anti Nuclear antibodies (ANA/ANF).
The majority of rheumatoid arthritis will have a positive rheumatoid factor test (‘seropositive’) or a positive CCP antibody (CCP positive). Rheumatoid factors can also occur in some other conditions (eg SLE, Sjogren’s syndrome) but CCP antibodies are usually only present in patients with rheumatoid arthritis. The presence either of these antibodies can help identify patients who are at greater risk of more severe forms of rheumatoid.
There is also some evidence that these antibodies can be present for many years in people before they develop rheumatoid arthritis so be positive in patients without symptoms. The ANF* is usually positive in SLE but can be positive in patients with rheumatoid arthritis. Confused yet?
*Further discussion of the use of Antinuclear antibodies is beyond the scope of this piece
Osteoarthritis
This is the commonest form or arthritis and a condition where ALL of these blood tests listed above should be normal. That means normal ESR, CRP, RF and CCP antibodies unless there’s another condition present alongside the osteoarthritis.
Rheumatoid arthritis
The ESR or CRP may also be normal in patients newly presenting with rheumatoid arthritis. In a large study of RA patients from Finland and US, between 45-47% of patients had a normal ESR, 44-58% had normal CRP at presentation. BOTH were normal in 33% and 42% of patients**. When a rheumatoid factor test was included, 14-15% of patients had no abnormalities in all 3 tests.
Remember that only 70-80% of patients will have a positive rheumatoid factor or CCP antibody (and one can be positive whether the other is negative so we tend to do both) and even greater percentages of pts will have negative antibodies (‘seronegative arthritis’) early on. Having negative antibodies does not therefore exclude rheumatoid arthritis.
It is also well describedthat inflammation can be visible in the joints using MRI ultrasound scans in patients with known rheumatoid arthritis in the absence of inflammation clinically or on blood tests.
** the reason there’s two percentages mentioned is that they looked a patients in two different countries (Finland and USA)Psoriatic arthritis
Many patients with psoriatic arthritis (approximtely 50%) will have either normal or near normal ESR and or CRP levels. Patients with Psoriatic arthritis will usually have negative rheumatoid factors and CCP antibodies and Antinuclear factors.
Ankylosing Spondylitis / Undifferentiated spondyloarthritis
Ankylosing Spondylitis is a form of inflammatory arthritis (largely affecting the spine). Whereas abnormal CRP and ESR can be very helpful in making a diagnosis of AS in certain patients with back pain, these tests will only be abnormal in about 50% of patients. The rheumatoid factor, CCP antibodies and ANA should be negative in this group of patients.
Palindromic Rheumatism
Palindromic Rheumatism describes a syndrome where there are recurrent episodes of pain swelling warmth and stiffness of joints. The symptoms can have onset over hours and last days – weeks, before subsiding. However episodes of recurrence form a pattern, with symptom free periods between attacks lasting for weeks to months and some of these patients will go on to develop rheumatoid arthritis. It is not unusual for these patients to have normal inflammatory indices (especially between attacks, when they are well) and approximately 50%will have negative Rheumatoid factor and CCP antibodies.]
Conclusions
Making a diagnosis of inflammatory arthritis in patients is usually straightforward but there are some pitfalls to catch the unwary. Whereas the tests can be unreliable in some settings, with the right history and clinical examination in the hands of an experienced rheumatologist, it is possible to make a diagnosis of inflammatory arthritis and offer effective treatment even where the labs don’t quite fit the picture.
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According to the European League Against Rheumatism every patient presenting with joint pain should have RF/CCP done.
Despite having two sisters with two different autoimmune disease when I presented to my rheumatologist with joint pain in my hip and shoulder, these test were not done.
Unfortunately, there was a delay in my diagnosis and treatment and I suffer now from joint damage in my shoulder and neck and bone erosions.
I would encourage you to spend the word for these test to be done as a part of the primary workup of patients who present with joint pain.
By the way, my symptoms were joint pain in my hip and shoulder for over a month, raynards, dry eyes, fuzzy memory, skin rash, and difficult writing.
I was told I had no autoimmune disease, despite having a positive ANA, anemia, and increased lymphocytes.
Rheumatoid factor is easily available and the CCP antibody is available ‘almost’ everywhere these days and I agree they should be performed where rheumatoid arthritis is suspected. The earlier a diagnosis, the earlier treatment can be started and the better patients respond to treatment.
What a brilliant post. I have PA and normal blood tests so was diagnosed thanks to my history and ultrasound and MRI scans.However, it took a very long time to get anyone in primary care to take me seriously because I had normal bloods. Now on Humira and doing very well. As my consultant put it ‘if it looks like a duck, and sounds like a duck…’
So to test in the normal range for sed rate does not negate the positive result for Rheumatoid Factor? My doctor seems troubled by this.
Sorry for the delay in replying. You can have rheumatoid arthritis with a positive rheumatoid factor and a normal ESR / CRP. Of course not everyone with a positive rheumatoid factor has rheumatoid arthritis either! It can occur in otherwise healthy smokers and in a number of other conditions like lupus, sjogren’s syndrome, sarcoidosis to name a few.
I’d be interested in a follow-up post that expands on exceptions to those “usually” occurring results. Those of us who seem to be exceptions love that you’re spreading the word about this.
My positive ANA got me a referral to a rheumatologist, but repeated tests have been negative. My positive CCP got me treatment (despite negative RF), but repeated CCP tests have been negative. My sed rate typically runs 0-3, which puzzles my doctors.
I have also had normal results for ANA, ESR and rheumatoid factor. However, I suffered from Still’s disease as a child (I’m now in my early 30s) so despite the normal test results it now seems to be accepted that I have some form of arthritis though no-one seems too sure which kind I have! I can only imagine that people must find it very frustrating to have all the outward signs of arthritis but to be dismissed because their test results are within normal range.
I am HLA-B27+ neg RF neg CCP ..always normal ESR CRP ..yet I have enthesitis, tendonitis, bursitis (evidenced by Ultrasound) ..multiple joint pain including back neck shoulders fingers… have other autoimmune conditions including hashimotos, pernicious anemia…sicca syndrome.. my Doctors say there is no evidence of inflammation and have been reluctant to treat the symptoms…this now 6 years on…I can barely function… in constant pain my diagnosis is currently undifferentiated spondylarthropathies … there is also the issue that my diagnosis does not gain access to the expensive treatments as it is not listed as a condition that can be helped. NSAIDS are not helping…. why is it so hard to get treatment…. and what does this tell us about the disease…the fact that no inflammation markers are elevated yet disease is very present….? Is this still Immune dysfunction…or persistent infection? How can we progress the understanding of these diseases… currently patients like me are suffering without hope.