Inflammatory Markers Question

I have been reading that often these are in the normal range on blood tests in people that have PsA.

Is this because there is no inflammation at the time of the test or because there is low level inflammation that isn’t detected ?

Great question Ktel. I’m guessing it’s not no inflammation at the time, but I’ll be really interested if anyone knows why the inflammation wouldn’t show up in the standard CRP ESR tests (I have this too).

That is a great question. I’ve always just accepted that it’s the case. I would imagine that there is likely to be inflammation that is ‘sub-clinical’ i.e. (I think) not circulating at high enough levels to be picked up by the tests but which may be present in affected joints etc.

I did have high inflammatory markers. I assume that means I should ideally have been treated earlier. Yep, great question, interested in what the definitive answer is, if there is one.

Good to know I’m not the only one with no or very low inflammatory markers. I too am interested in a real answer to this conundrum. Maybe @tntlamb will know? (Don’t you know everything? :grin:)

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I always assumed that the blood test simply didn’t work in some people?

A stunningly good question. I always assumed the test wasn’t sufficiently good enough to detect our type of inflammation. It seemed to me we all felt ‘inflammed’ and things were certainly getting damaged from our inflammation anyway so obviously the test simply wasn’t good enough to detect it.

This is a very good question… I too am one of those whose CRP and ESR are nearly always within “normal” range… I really don’t know how it all works, but I seem to remember reading somewhere something along the lines of that inflammation in the synovial membranes (whether in joints or tendons) often does not show in the blood as there is little to no blood flowing through those membranes… I may have that completely incorrect and be totally confused by it all though :laughing: I’m sure @tntlamb, or someone else) will have a better explanation :smile:

In searching the forum I came across a post by Seenie from a while ago- see below link.

From what I can determine these markers are a fairly small component in the diagnostic process but do act as a bench mark to monitor progression.

I still don’t fully understand however why these numbers wouldn’t be raised as it is an inflammatory condition.

n erythrocyte sedimentation rate (ESR) is a type of blood test that measures how quickly erythrocytes (red blood cells) settle at the bottom of a test tube that contains a blood sample. Normally, red blood cells settle relatively slowly. A faster-than-normal rate may indicate inflammation in the body. Inflammation is part of your immune response system. It can be a reaction to an infection or injury. Inflammation may also be a sign of a chronic disease, an immune disorder, or other medical condition. The sedimintation rate would increase IF there were an increase in several different white cells. Just about every medication we take including NSAIDs, DMARDs, and Biologics effects the binding of these white cells so the response is muted.

C-reactive protein (CRP) is a blood test marker for inflammation in the body. CRP is produced in the liver and its level is measured by testing the blood. In this case the protein is produced when the “blood is cleansed” in the liver. In PsA the inflammation occurs in joint areas where there is essentially no blodd flow so the reaction isn’t kicked off when the blood hits the liver.

Normal levels don’t necessarily apply to PsA patients BUT charting/graphing ESR and CRP levels CAN show trends. Not all Rheumies believe in this but those with Mayo Clinc experience almost always do. The chart both then pick one to track over time. Mayo did some pretty extensive research/studies in this area. The fella that lead these studies worked here as a locum a few years back. While he was a strong believer in the “trending” he admitted that it was a tough sell and that many Rheumies were resistent to embrace it as the last thing they wanted was any dependence on blood work. That doesn’t mean however that they don’t look, although they may not verbalize it. You will know if they are though, when at your routine appointments you report symptoms, they nodd maybe do some localized injections or add a course of predi etc but then at the end of the appointment make no changes in your routine meds saying “it looks like its working” OR they change the meds with little comment.

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Based on what you described there doesn’t appear to be a lot of value in these tests.

ESR is muted by the medications and CRP doesn’t detect inflammation in areas around the joints?

You mention that the values can be used to chart trends i.e. used as a baseline.

How would that work exactly if they are limited in what they can detect in the first place ?- does this mean that the inflammation would have to be high to show a response.

I’m just trying to understand the diagnostic process.

So far I have had blood tests and x rays.

I will be reviewing these tests with the rheum in 2 weeks time.

The blood tests show these markers in the normal range, however apparently that in of itself isn’t conclusive.

The x rays don’t show evidence of OA is the SI joints and mild osteoarthritic changes in my hands with no evidence of erosive anthropathy.
However if it is early in the disease then there wouldn’t be any significant damage there anyway.

But why does PsA, even when our bodies are on fire with inflammation, not send the CRP and ESR skyrocketing in half the patients? (Are you going to say “if I knew that, I’d be a wealthy man”?)

My GP was really angry with me when I assumed that my very rotten hip was PsA. She maintained that it was simple wear and tear, and she made sure that I knew that she thought I was playing the drama queen. It was all “It’s OA, you can have both OA and PsA you know …”

After my hip replacement, as Dr GP was picking out the staples, I casually mentioned that I had lost over 2 litres of blood during surgery. She made an offhand remark about that being strange for a part of the body that’s not very vascular. (There she goes, she thought, playing the drama queen again!) And then I told her that the surgeon had said that my hip joint had been inflamed so badly for so long that it had all vascularized. All while my inflammatory markers were well within the normal range. Dr. GP finished picking stitches silently.

What is it about the inflammation of PsA that it doesn’t trigger a response in CRP and ESR?

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That’s correct. The most current diagnostic criteria make no mention of blood tests. But if they had been positive (as they are in the other half of the PsA population) that might have been worth something.

X-rays won’t show inflammation, and in early disease, there won’t be visible damage. That’s good, and you want to keep it that way!

The most recent set of criteria is called CASPAR, and it is more accurate in reaching a diagnosis of PsA than the older, Moll and Wright criteria.

The thing is, it’s quite possible that a good deal of your pain comes from tendinitis and enthesitis (inflamed tendons and inflammation of the site where they attach to bone). I suffered that for years before being diagnosed, and it is awful. Before long you think the problem is really in your head.

When you go to your rheumatologist, make sure that you have done your homework, and that you perhaps even have the CASPAR criteria printed out.

Once you’ve been diagnosed and you begin treatment, though, the rheum will probably watch what happens to your inflammatory markers. If they go down, that could be an indication that the treatment is working. But at the diagnostic stage, normal markers mean absolutely nothing.

Let see if I can boil down at least a full semester of graduate level biochemistry into a few paragraphs LOL. Its never good if I get on a roll…

Inflammation from PsA is usually (but not always) caused by a cell signaling protein (cytokine) called Tumor Necrosis Factor. Usually (but not always) it is tumor necrosis factor alpha, (TNFα, cachexin, or cachectin). Commonly TNFα isTNF was thought to be produced primarily by macrophages (white blood cells) and it would trigger a huge rise in ESR. But it is produced also by a broad variety of cell types including lymphoid cells, mast cells, endothelial cells, cardiac myocytes, adipose tissue, fibroblasts, and neurons.and is released in response to lipopolysaccharide, other bacterial products, and Interleukin-1 (IL-1). In the skin, mast cells appear to be the predominant source of pre-formed TNF, which can be released upon inflammatory stimulus (ie psoriasis) but none of these process involve “blood” so it wouldn’t show up in an ESR.

Then in a completely different process it has a number of actions on various organ systems, generally together with IL-1 and Interleukin-6 (IL-6):

On the hypothalamus: Stimulation of the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH) suppressing appetite and causing fever

On the liver: stimulating the acute phase response, leading to an increase in C-reactive protein and a number of other mediators. It also induces insulin resistance by promoting serine-phosphorylation of insulin receptor substrate-1 (IRS-1), which impairs insulin signaling. In this case The CRP means something

It is also a potent chemoattractant for neutrophils, and promotes the expression of adhesion molecules on endothelial cells, helping neutrophils migrate. In this case a complete blood count would be helpful and is a routine test.

On macrophages: stimulates phagocytosis, and production of IL-1 oxidants and the inflammatory lipid Prostaglandin E2 (PGE2) (anyone have cholesterol issues???)

On other tissues: increasing insulin resistance. TNF phosphorylates insulin receptor serine residues, blocking signal transduction.

On metabolism and food intake: regulates bitter taste perception. (ever have a funny taste in your mouth has your doc ever asked? Mine does EVERY appointment)

So basically half the time it goes to the liver and blood and makes diagnoses easy, but the OTHER half of the time there is only a local increase in concentration of TNFα because it is produced by lymphoid cells, mast cells, endothelial cells, cardiac myocytes, adipose tissue, fibroblasts, and neurons. The cardinal signs of Inflammation such as heat, swelling, redness, pain and loss of function occur but only in a few specific spots.

With PsA patients its endothelial cells (skin), adipose tissue (fat which is why they scream about weight) and especially fibroblasts (the most common cells of connective tissue) (in my case I have all of those but the worst are the muscle cells (myocytes) that make up the cardiac muscle ie heart muscle).

The important thing is when TNFα is produce anywhere EXCEPT white blood cells and the liver it doesn’t show up in most blood work although there can be clues. BTW IF TNFα is produced by macrophages or the liver, you have a much better response to Biologics which are generally TNF inhibitors although some of the newer ones are now targeting IL-6 which should be helpful for a lot of folks (most of the Psoriasis Biologics you are seeing on TV are IL-6 inhibitors but aren’t all that great for the arthritis.

I’m sure that,s as clear as mud, BUT the blood tests are helpful and are not worthless and there is a good reason you can be full of inflammation and have “normal” blood work.

Just to throw another clinker in things BTW there is no such thing as “normal” in bloodwork. The correct term is “Norm” Docs get lazy in explaining it. Norm means that you have the same numbers as 67% of the population and nothing more (or less)…


Thank you for such a detail answer to this… I’ll NOT begin to make out I understand any of it really, but it does help to clear up the question a little for me… I did figure that perhaps the ESR and CRP tests were limited to the inflammation “type” or “type of tissue that was effected” and had wondered about the value of TNF or IL-6 tests as well as cholesterol/lipid tests as a more accurate guide… I guess though that many things can affect cholesterol levels, which would make it only a possible guide, and that TNF or IL-6 tests are probably expensive (or perhaps not all that reliable), I think you have kinda explained all that now… again not that I pretend to really understand most of it :laughing:

Thank you once again for sharing your in-depth knowledge of these things… most appreciated!!!

I have to admit, you sort of lost me after the first sentence, but still it IS interesting. I just can’t process stuff like that. You obviously are a genius. It must be fun to be that smart!!!
Anyway, all this mention of CRP and I thought, I wonder if my doctor ever checks that? So, I searched CRP on my chart online and sure enough, I was tested in the past, from 2009 to 2011. My internal medicine doctor checked me at first, and then my former rheumy. It was low around .053 the first times and then went up to .244 and then back down again. I suppose she checked it a couple times after it went to .244 because it was quite a jump from .05. After that it was checked twice and never checked since.
Does anybody else get their CPK checked? The normal for that one is 0 - 200. Mine has been checked about twice a year since 2011. It’s always been above normal, from 350 to 694 - 694 being right before I went on Enbrel. My rheumy, in fact, when he mentioned he’d send me for tests at the MAO Clinic, said that my elevated CPK could be a factor in determining if I had a metabolic myopathy. He tried to explain it to me in simple terms. I also read a little about it online because it is very interesting how, with something like that, what you eat could make a difference in how your muscles work. I mean, yes, we all know we should eat healthy to be healthy. But, when you have a metabolic myopathy, the cells don’t process energy the way they’re supposed to and that’s why the muscles get weak…with a little rest, they perk up, but it’s a vicious cycle…just keeps happening.
I should have switched this to a different discussion.
I’m just wondering if anyone else has an elevated CPK.

I do follow what you wrote and know I’ve learned it before haha I cant reproduce it though…

I just wonder how much of that doctor’s actually think about when they are advising which drug to try next…

That was more than helpful, just awesome. It’s the first time I’ve seen a clear explanation that I can follow even at least a bit!

I guess the good news for me (I think) is that my PsA isn’t doing too much to my liver since I don’t have a significantly raised CRP :blush:

Meanwhile, I wonder if malfunctioning mast cells is the reason MGUS has a higher incidence in inflammatory autoimmune diseases… hmmm

I’ll have to re-read it a few times to try to get my head around that info as is… I probably shouldn’t jump to too many more “what ifs” :joy:

I’ve just realised that virtually my entire being is affected by inflammation even though my levels are now nearly zero. Dire cholesterol levels, changed taste buds, the lot.

Actually, I knew that PsA affects pretty much everything already - not in a scientific way, just from living with it. I’d just prefer it if docs gave at least a nod to that reality too. And of course, much more than an understanding nod is required for those who need to advance their treatment.

Thank you so much for this, even without understanding the science the gist affirms how things are for us.

Thank you @tntlamb. Your excellent succinct explanation was very helpful. It answered the question of why I don’t “look” like I have an inflammation issue when I seem to always have some sort of connective tissue pain. And also possibly why I have bouts of phantom tastes. (Thought I was starting to hallucinate…) Your mention of the docs at Mayo being on board with charting ESR and CRP is encouraging. I have my first appt with Wang (rheumy #3) at Mayo Monday. I’m hoping to sort out what is just OA, what is PsA, are they connected, am I JPN or losing my mind. (If anyone sees it wandering around please let me know and send it home :crazy_face:)

Thanks again!

This bit is really interesting to me anyhow. Often have it but have been asked about it.