Advanced Practice Rheum: Rheumatoid & Inflammation Testing Save

Other videos in the Advanced Practice Rheum Series:

• Antinuclear Antibodies (ANA)

• Evaluation of Rheumatic Complaints

TRANSCRIPT:
This is Advanced Practice Rheum. Hi, I'm Jack Cush with RheumNow.com. In this review, we'll be talking about labs, inflammation, and tests for rheumatoid arthritis.

When considering labs, you need to know a few important things. Labs should never be used as screening tests. Please don’t do that, you'll regret it. Labs should be (are) used to confirm a clinically suspected diagnosis; one ascertained from the history and the exam. Then, the application of labs such as serologies, ANA and rheumatoid factor, have higher predictive meaning. But if done indiscriminately on people regardless of symptoms they have far less very little predictive value. 

So be like a lawyer. Don't ask a question that you don't know the answer to. When a lawyer does that in court they’ll get in all kinds of trouble. When you do that in clinic, you're asking for trouble, when you were hoping for certainty. 

Let's consider inflammation tests. The two that we use the most are the sed rate (ESR: erythrocyte sedimentation rate or ‘sed rate’), and C reactive protein or CRP. What you need to know is that the sed rate will go up with age.

For the ESR, the formula for normal is, if you're a male, your age divided by two would be the upper limit of normal of your sed rate. So if you are a 40 year-old male, 40 divided by two, your upper limit should would be 20. If you are a female, it's different. It's your age + 10 divided by 2. So a 70-year-old female, it would be 70 + 10 = 80 divided 2. The upper limit of normal for a 70-y old woman is a sed rate of 40 mm/hr..

Sed rate varies by age. Sed rates will go up with inflammation, but also with age. CKD and proteinuria will always elevate the sed rate. Same for anemia, pregnancy, liver disease, cancer, infection, drugs and obesity. It's not so clear that all of these have the same effect on CRP. CRP is generally not affected by age, but can be increased by CKD and liver disease, cancer, infection, and maybe even drugs. 

CRP is probably more specific and sensitive than is sed rate, but you should order both as  they're very cheap and one may be elevated, the other might be normal. And you have to consider what that may mean. Usually I go with the higher one as being more indicative if I can't otherwise explain it by one of those other comorbidities that will falsely or actually, accurately but inappropriately, drive up the sed rate or CRP. 

There are other indications or other indicators of inflammation from lab tests, most notably from the CBC (the complete blood count). There are findings in the CBC and differential

that are telltale for inflammation. Of course you know about an elevated white blood cell count especially if there's a marked left shift, meaning a predominance of neutrophils. So a WBC count of greater than 12,000 should indicate many different causes, including inflammation. 

But I worry about inflammation, and especially infection, if the neutrophil percentage is above 85%. So that would apply to septic arthritis, to sepsis, to pneumonia etc. Other inflammation  indicators from the CBC would be thrombocytosis: a platelet count of greater than 400,000. And with hyper inflammation it's not uncommon to see 700,000 - 800,000, maybe even over a million. Other signs of  inflammation may include finding an anemia chronic disease or a low serum albumin.

Acute phase reactants (ESR, CRP) are increased with inflammation, and there are other acute phase reactants, like increased haptoglobin levels and increased complement levels.Two more that you might want to remember - the red cell distribution with on the CBC, RDW, it's a measure of variation in RBC size. It goes up with iron deficiency and macrocytic anemias, but it also goes up with inflammation. And lastly, the other one that you have to calculate (it doesn't come in any automated fashion on the CBC report) is the neutrophil to lymphocyte ratio, also known as the NLR. Again, it's a very good measure of high-end

inflammation that you see with very inflammatory conditions, like Still’s disease, especially if the ratio is over 4.0.

So what you need to know about laboratory tests cutoffs (normal values) are that rheumatoid factor and the ANA cutoffs are established such that less than or 5% of the normal population will have an abnormal test. 

If you apply those limits to an elderly or sick population, the ANA and the rheumatoid factor positivity goes up three-fold. Elder age, thyroid disease, and family history may yield a positive serology, as will CKD, chronic lung disease, chronic liver disease, hepatitis, pregnancy, cancer infection, and parasitic infections. 

80% of rheumatoids are rheumatoid factor and CCP or ACPA positive.  But rheumatoid factor (and CCP) alone are not diagnostic of RA. 

As we said earlier, you have to have the symptoms of RA. You have to have symmetric polyarthritis, chronicity, synovitis, and meet criteria according to ACR and EULAR. The thing about the rheumatoid factor is it's not a good screening test because 20 million Americans have a positive rheumatoid factor. But there's only 1.3 million who have rheumatoid arthritis. Hence, only one in 20 positive rheumatoid factors (~5%) are going to be from RA. The rest are going to be from other causes or no cause at all. 

However, higher titers (of CCP or RF) do carry a greater risk of having RA. 

The other causes for a positive rheumatoid factor are chronic lung disease, chronic liver disease, bacterial endocarditis, hepatitis, chronic infections including TB and parasitic infections. And I think again the most important thing is that amongst people with rheumatoid arthritis, up to 30% are going to be seronegative for either rheumatoid factor or CCP antibodies.

Rheumatoid factor is an antibody, usually an IgM antibody against the Fc portion of IgG. You can also have IgD or IgA antibodies against the Fc portion of IgG.  So 70 to 80% of RA patients will be rheumatoid factor positive. Being rheumatoid factor positive may associate with worse disease and greater odds of having extraarticular manifestations such as Sjogren’s, rheumatoid vasculitis or rheumatoid nodules. 

The titer of RF or CCP that may predict the risk. Normally a positive result is RF of > 15 (done by ELISA, read out as international units per ml). Finding levels up to 25 or 30 are relatively low, but levels that are 100 or more have a a 25-fold higher risk of rheumatoid arthritis. 

It is normal to order both rheumatoid factor and CCP together, although CCP is the better test for RA. CCP stands for cyclic citrullinated peptide antibodies or anti-citronated cyclic peptide antibodies (ACPA). CCP and ACPA are the two terms that are used. These are antibodies against an arginine molecule. The sensitivity ranges from like 65% to 80%, but the specificity is much higher than RA. In RA, rheumatoid factor specificity is 80%, while ACPA/CCP specificity is over 95% in all studies. 

With CCP, you're identifying antibodies against citrulline rich peptides and there are many different kinds: filaggren, keratin, vimentin, sas caplastin, etc. The most important thing is that CCP is very specific; Unlike RF+, CCP+ comes with a much higher risk of very aggressive disease and X-ray progression, including erosive disease and X-ray damage. 

If you were to do an ACPA test on the general population, it would be found in less than 1% in Caucasians and maybe up to 2% in Asians who do not have RA. You can sometimes see ACPA positivity with increasing age, smokers, chronic lung disease, and those who have maybe more aggressive forms of psoriatic arthritis. As we said, being ACPA+ increases the risk of X-ray damage. 

Being double positive for rheumatoid factor and CCP really increases your risk many-fold. 

The important thing to know is that CCP and rheumatoid factor can be found months if not up to 10 years before the onset of disease. Such patients may or may not have symptoms, but if they have symptoms - arthralgia, no synovitis, and either rheumatoid factor or ACPA - they may develop RA in the future. 

Pre-clinical RA (also called clinically suspect arthralgia [CSA]) is defined as being ACPA/CCP or RF positive, with arthralgia but no evidence of synovitis. Such people have about a 30% chance of developing RA in the future. And just like with rheumatoid factor, high high titers of CCP are associated with worse disease. 

Lastly, being double positive - rheumatoid factor and CCP double positive - is also associated with worse disease. But I would not routinely do other marketed tests for rheumatoid arthritis, including carbamylated P antibodies or 14-3-3etat. 

The rules on ordering CCP and rheumatoid factor: 

1. Do not order unless the patient has synovitis (or unless they have chronic bilateral symmetric arthralgia in typical RA joints)
2. Don't repeat RF or CCP if negative. You can repeat it 6 or 12 months later if symptoms change.
3. Don't order Carbamylated P or 14-3-3 eta.
4. The biggest concern are people who have very high titers of either those who are double positive for RF and CCP. 

Lastly, being seronegative does not mean that you have mild disease. They have bad disease, too. You worry about them as much as you would worry about a seropositive individual. 

Tune in for more advanced practice rheumatology videos and podcasts. The next one in line is about ANAs and other serologies.

Editor’s note: This transcript has been prepared from the original recording and may include transcription inaccuracies. Please rely on the video for the most complete and accurate information.