Rheumatoid & Inflammation Testing Save
Transcription
This is Advanced Practice RheumNow. Hi, I'm Jack Cush with RheumNow.com. In this session, we'll be talking about labs, inflammation, gout, and tests for rheumatoid arthritis.
When considering labs, you need to know a few important things. Labs should never be used as a screening test. When you do that, you'll regret it. They are used to confirm a clinically suspected diagnosis — one ascertained from the history and the exam — then the application of labs such as serology, ANA, and rheumatoid factor have high meaning. But if they're done indiscriminately on people regardless of symptoms, they have 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 get in all kinds of trouble. When you do that in clinic, you're going to get in trouble.
Let's consider inflammation tests. The two that we use the most are the sed rate, ESR, erythrocyte sedimentation rate, and C-reactive protein or CRP. What you need to know is that the sed rate will go up with age. And the formula is that if you're a male, it's your age divided by two — that would be the upper limit of normal of your sed rate. So if you are a 40-year-old male divided by two, your upper limit should be 20. If you are a female, it's different. It's your age plus 10 divided by 2. So a 70-year-old female, it would be 70 plus 10, 80 divided by 2. The upper limit of normal for a 70-year-old woman is a sed rate of 40. Okay? So it varies by age. Sed rate will go up with inflammation but also with age. CKD and proteinuria will always elevate the sed rate. Anemia, pregnancy, liver disease, cancer, infection, drugs, and obesity.
Okay, 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 affected 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 of them because they're very cheap tests and one may be elevated while 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 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 white blood cell 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 indications from the CBC would be thrombocytosis — a platelet count of greater than 400,000 — and with high inflammation it's not uncommon to see 700,000, 800,000, maybe even over a million. And anemia of chronic disease. So thrombocytosis, leukocytosis, inhibiting erythrocyte formation in the marrow, and albumin are all driven by pro-inflammatory cytokines like IL-1. So another marker would be a low albumin as a sign of inflammation. Other tests that would be abnormal would be increased haptoglobin levels and increased complement levels.
Two more that you might want to remember: the red cell distribution width 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 do you need to know about tests and age? The rheumatoid factor and the ANA — their cutoffs are established at 5% of the normal population having 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. These are increased with age, thyroid disease, family history of a positive serology, CKD, chronic lung disease, chronic liver disease, hepatitis, pregnancy, cancer, infection, parasitic infections.
80% — up to 80% — of rheumatoid arthritis patients are rheumatoid factor positive. Up to 80% of rheumatoid arthritis patients are CCP or ACPA positive. But rheumatoid factor by itself is 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, one in 20 positive rheumatoid factors are going to be from RA. The rest are going to be from other causes or no cause at all. However, high titers are associated with a greater risk of RA.
As we said, the other causes for a positive rheumatoid factor is 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 20 or 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. Now you can have IgG, IgD, IgA, other forms of antibodies against the Fc portion of IgG, but again it is more sensitive, meaning it's found in more people with RA than is ACPA, but is less specific. So 70 to 80% of RA patients will be rheumatoid factor positive. Being rheumatoid factor positive is associated maybe with worse disease and extraarticular manifestations such as Sjögren's or rheumatoid nodules.
It is the titer that predicts the risk. So the highest titers — meaning greater — if you're doing it by an ELISA assay, readout as international units per mL, and normally the positive result is greater than 15 or 14. Levels up to 25 or 30 are relatively low, but levels that are 100 or more have up to a 25-fold higher risk of developing rheumatoid arthritis or having rheumatoid arthritis.
The better test — and it probably should be ordering both rheumatoid factor and CCP together — CCP is cyclic citrullinated peptide antibodies, or anti-citrullinated cyclic peptide antibodies. ACPA, CCP, and ACBA are the two terms this is used. These are antibodies against an arginine molecule. The sensitivity ranges from like 65% to 80% but the specificity is much higher than RA rheumatoid factor. Specificity by 80% specificity for ACPA/CCP is over 95% in all studies. You're identifying antibodies against citrulline-rich peptides and there are many different kinds — filaggrin, keratin, vimentin, α-enolase, plastin — doesn't really matter. But the most important thing is that it is very specific; it has 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 less than 1% in Caucasians and maybe up to 2% in Asians who do not have RA or a cause that we would identify with a positivity. You can sometimes see a positivity with increasing age, smokers, chronic lung disease, and those who have maybe more aggressive forms of psoriatic arthritis.
As we said, being positive increases the risk of X-ray damage. Being double positive for rheumatoid factor and CCP really increases your risk manyfold. 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 have a chance that they may develop RA in the future. ACPA positivity, CCP positivity in a pre-clinical RA person, meaning they don't have RA because they don't have synovitis, but they just have joint pain, has about a 30% chance of developing RA in the future. So that's important to note.
And just like with rheumatoid factor, 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.
It is not worth doing other tests for rheumatoid arthritis that are on the market. Carbamylated protein antibodies or 14-3-3η — I would not do that. The rules on CCP and rheumatoid factor: do not order those tests unless the patient has synovitis or unless they have chronic bilateral symmetric arthralgia in typical RA joints although they don't have synovitis. Don't repeat it if it was negative. You can repeat it 6 or 12 months later if symptoms change. Again, don't order carbamylated protein or 14-3-3η antibodies.
The biggest concern are people who have very high titers of either or both, and especially people 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 got to get serious about them.
Tune in for more videos and podcasts regarding advanced practice rheumatology. The next one in line is about ANAs and other serologies.
When considering labs, you need to know a few important things. Labs should never be used as a screening test. When you do that, you'll regret it. They are used to confirm a clinically suspected diagnosis — one ascertained from the history and the exam — then the application of labs such as serology, ANA, and rheumatoid factor have high meaning. But if they're done indiscriminately on people regardless of symptoms, they have 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 get in all kinds of trouble. When you do that in clinic, you're going to get in trouble.
Let's consider inflammation tests. The two that we use the most are the sed rate, ESR, erythrocyte sedimentation rate, and C-reactive protein or CRP. What you need to know is that the sed rate will go up with age. And the formula is that if you're a male, it's your age divided by two — that would be the upper limit of normal of your sed rate. So if you are a 40-year-old male divided by two, your upper limit should be 20. If you are a female, it's different. It's your age plus 10 divided by 2. So a 70-year-old female, it would be 70 plus 10, 80 divided by 2. The upper limit of normal for a 70-year-old woman is a sed rate of 40. Okay? So it varies by age. Sed rate will go up with inflammation but also with age. CKD and proteinuria will always elevate the sed rate. Anemia, pregnancy, liver disease, cancer, infection, drugs, and obesity.
Okay, 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 affected 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 of them because they're very cheap tests and one may be elevated while 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 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 white blood cell 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 indications from the CBC would be thrombocytosis — a platelet count of greater than 400,000 — and with high inflammation it's not uncommon to see 700,000, 800,000, maybe even over a million. And anemia of chronic disease. So thrombocytosis, leukocytosis, inhibiting erythrocyte formation in the marrow, and albumin are all driven by pro-inflammatory cytokines like IL-1. So another marker would be a low albumin as a sign of inflammation. Other tests that would be abnormal would be increased haptoglobin levels and increased complement levels.
Two more that you might want to remember: the red cell distribution width 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 do you need to know about tests and age? The rheumatoid factor and the ANA — their cutoffs are established at 5% of the normal population having 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. These are increased with age, thyroid disease, family history of a positive serology, CKD, chronic lung disease, chronic liver disease, hepatitis, pregnancy, cancer, infection, parasitic infections.
80% — up to 80% — of rheumatoid arthritis patients are rheumatoid factor positive. Up to 80% of rheumatoid arthritis patients are CCP or ACPA positive. But rheumatoid factor by itself is 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, one in 20 positive rheumatoid factors are going to be from RA. The rest are going to be from other causes or no cause at all. However, high titers are associated with a greater risk of RA.
As we said, the other causes for a positive rheumatoid factor is 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 20 or 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. Now you can have IgG, IgD, IgA, other forms of antibodies against the Fc portion of IgG, but again it is more sensitive, meaning it's found in more people with RA than is ACPA, but is less specific. So 70 to 80% of RA patients will be rheumatoid factor positive. Being rheumatoid factor positive is associated maybe with worse disease and extraarticular manifestations such as Sjögren's or rheumatoid nodules.
It is the titer that predicts the risk. So the highest titers — meaning greater — if you're doing it by an ELISA assay, readout as international units per mL, and normally the positive result is greater than 15 or 14. Levels up to 25 or 30 are relatively low, but levels that are 100 or more have up to a 25-fold higher risk of developing rheumatoid arthritis or having rheumatoid arthritis.
The better test — and it probably should be ordering both rheumatoid factor and CCP together — CCP is cyclic citrullinated peptide antibodies, or anti-citrullinated cyclic peptide antibodies. ACPA, CCP, and ACBA are the two terms this is used. These are antibodies against an arginine molecule. The sensitivity ranges from like 65% to 80% but the specificity is much higher than RA rheumatoid factor. Specificity by 80% specificity for ACPA/CCP is over 95% in all studies. You're identifying antibodies against citrulline-rich peptides and there are many different kinds — filaggrin, keratin, vimentin, α-enolase, plastin — doesn't really matter. But the most important thing is that it is very specific; it has 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 less than 1% in Caucasians and maybe up to 2% in Asians who do not have RA or a cause that we would identify with a positivity. You can sometimes see a positivity with increasing age, smokers, chronic lung disease, and those who have maybe more aggressive forms of psoriatic arthritis.
As we said, being positive increases the risk of X-ray damage. Being double positive for rheumatoid factor and CCP really increases your risk manyfold. 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 have a chance that they may develop RA in the future. ACPA positivity, CCP positivity in a pre-clinical RA person, meaning they don't have RA because they don't have synovitis, but they just have joint pain, has about a 30% chance of developing RA in the future. So that's important to note.
And just like with rheumatoid factor, 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.
It is not worth doing other tests for rheumatoid arthritis that are on the market. Carbamylated protein antibodies or 14-3-3η — I would not do that. The rules on CCP and rheumatoid factor: do not order those tests unless the patient has synovitis or unless they have chronic bilateral symmetric arthralgia in typical RA joints although they don't have synovitis. Don't repeat it if it was negative. You can repeat it 6 or 12 months later if symptoms change. Again, don't order carbamylated protein or 14-3-3η antibodies.
The biggest concern are people who have very high titers of either or both, and especially people 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 got to get serious about them.
Tune in for more videos and podcasts regarding advanced practice rheumatology. The next one in line is about ANAs and other serologies.
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