Diurnal variation of ESR, CRP, and PMR symptoms

"Remission" is commonly defined as "a diminution of the seriousness or intensity of disease or pain". Remission in PMR is described in many places as being evaluated as a combination of the reduction of symptoms and the results of a blood test, such as the measurement of CRP. The PMR-AS is one such example (also called "PMR response criteria". These parameters are, therefore, the criteria for remission as defined here. And you need to achieve this remission before you can reduce your dosage of pred. Tapering is not a criterion, it is the process that takes place when the criteria for remission have been reached. You cannot just start tapering out of the blue. You need some criteria.

What is difficult is to specify the criteria, especially when the symptoms - and possibly the blood markers as well - vary over the 24 hours. So, I am just trying to find out what criteria other PMR patients have been using to decide when to reduce their dosage, especially when their symptoms have a significant diurnal variation.

I read Dr. Kirwan's study about taking the pred at 2 am, and initially tried it out with 5 mg at 2 am and then 10 mg in the morning. It helped a lot with the night symptoms, but I found that splitting the dose 50/50 was even better. Even with this split I have some symptoms at night. I am wondering if taking the entire dose at 2 am would be better, but I haven't seen anybody do that.

Dr. Kirwan recommends the delayed release prednisolone (which is marketed as Lodotra/Rayos) because he believes that waking up to take the prednisolone at 2 am might disturb the circadian rhythm and thus the schedule of the cytokine release and the HPA axis. I have communicated with Dr. Kirwan on this issue and he doesn't have any data on what this disturbance may be. Many elderly people wake up frequently during the night anyway (I certainly do), so taking a pill at 2 am is not a big deal. The price of Lodotra/Rayos is prohibitive for most people.

 

I think there is a question of semantics here.  We long term sufferers tend to use the word "remission" to refer to the time when PMR is no longer active and causing the rise in painful inflammation.  This is different from using the word to describe the pred induced relief of symptoms, although I believe many doctors do, and it can lead to confusion.  Yes, you are right, we want to achieve the greatest relief of symptoms you can get before attempting to taper the dose to see if the lower dose will work as well.  It doesn't mean that PMR, the disease, is in remission, only that pred is doing its job. 

"You cannot just start tapering out of the blue. You need some criteria."

You are putting the cart before the horse: pred does nothing to the real disease process. All pred does is manage the symptoms to allow a reasonable quality of life while the underlying disease continues in the background until it chooses to burn out and go into remission. As long as it is active you need some pred - take the pred away and the symptoms will return. But you should be on the lowest possible dose to avoid long term problems.

In PMR (and GCA) patients are started on a dose that is expected to be adequate to achieve freedom from symptoms. Sometimes patients need a bit more - the activity of the disease and amount of inflammation created is also significant. Then the process of titration starts: you reduce the dose slowly to find the end point, the lowest dose that achieves the same result as that starting dose did.

This is based on the fact that every patient will respond differently to a given dose of pred, to some extent due to the pharmacodynamics criterion of bioavailabilty which varies from 50% to 90%. The patient who absorbs 90% of the drug will get 9mg-worth. The patient who absorbs 50% will only get 5mg-worth. So every patient needs to find their own ideal dose.

?I take my entire dose at 2am - I use Lodotra/Rayos. You take it at 10pm and it releases 4 hours later at 2am. I find it perfect and have no side effects at all. I assume you are in the USA where the price of Rayos IS prohibitive - but that is the system there. Here in mainland Europe it is not so expensive, 27 euros for 30 tablets, and is covered by our socialised medicine services. 

I also doubt whether the circadian rhythm is greatly disturbed or if it is it doesn't make much difference - as you say, most elderly people wake repeatedly during the night so what difference does it make waking to take a tablet? There are also a lot of people who use ordinary plain pred taken at night - and get the same relief. 

I think you are right on the semantics confusion. By now I have read quite a few scientific articles on PMR and they all use the term "remission" the way I have used it, namely to signify the amount of relief from symptoms and and the reduction of blood "markers" that is required to reduce the pred dose. What I have referred to as the "criteria". One example is the article "The Polymyalgia Rheumatica Activity Score in Daily Use: Proposal for a Definition of Remission" which can be found at http://onlinelibrary.wiley.com/doi/10.1002/art.22771/pdf. An overview of proposed criteria can be found in an article by Dejaco et al entitled "Definition of remission and relapse in polymyalgia rheumatica: data from a literature search compared with a Delphi-based expert consensus", found at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033531. Most importantly, I believe all physicians apply some sort of criteria to determine when the patient need to reduce the pred dose, whether they call this remission or not.

What I really wanted to discuss are the criteria, as I realize that none of the proposed criteria consider the diurnal variation of symptoms. In addition. I consider many of the proposed criteria, such as those defined by the PMR Activity Score (PMR-AS) difficult to assess with any degree of accuracy.

 

Actually I thought the diurnal nature was part of the way we approach treatment, as the variation in pain coincides with production of cytokines?  Or are you referring to something different?

I agree that much of the diurnal variation in symptoms is related to the production of cytokines. The problem is that none of the methods to determine whether remission or relapse has occurred address this variation. Remission in this context means a sufficient reduction of symptoms to warrant a reduction of the pred dose.

If you look at Table 2 in my second reference above you will find criteria for remission such as "Absence of pain on examination" and others like "No muscular tenderness" without any indication if it is on examination or throughout a 24 hour period. And I fear that many physicians apply their criteria to the patient's status at the time of examination. With the blood tests they certainly do. This could be the cause of many too early dose reductions and relapses.

As an example, if your blood tests are OK and you are mostly pain free during the day, but you have symptoms at night up to 40% of the pain you experienced before treatment, will this qualify as remission and for thus for reducing your dose? I probably would have this situation if I took the entire dose in the morning as recommended. With a split dose I can reduce the night symptoms to perhaps 15% of the pre-treatment pain. Does this qualify as remission?

The blood markers sometimes fail, so I believe the clinical symptoms are a better guide. But in order for the symptoms to be a guide in determining remission the diurnal variation needs to be addressed. And the use of split doses versus a single dose should probably be addressed as well. I had hoped to get comments from patients on successful as well as failed dose reductions when they had a significant diurnal variation in their clinical symptoms.

 

I have never had a diurnal variation in my symptoms. I had PMR for 5 years with no pred - I had pain almost all the time during the day when trying to do anything even sitting without support, EXCEPT the early part of the night when it faded enough for me to get to sleep because I was still and my whole body was supported, to be woken, usually about 4.30am, as the cytokines were shed in the body and the inflammation got going again in the hip joints and the stiffness stopped me turning in bed.

I repeat - pred does NOT have any effect on the actual disease process so it cannot induce remission of any sort. It manages the inflammation. That is all. The antiinflammatory effect of pred lasts from 12 to 36 hours. In the patient for whom it lasts towards the 36 hour end of the range they will take a dose at whatever time they choose and the effect will continue until the next dose. Those in the middle will get a bit of discomfort about 24 hours and the people at the 12 hour end will experience returning symptoms as the antiinflammatory effect wears off. Splitting the dose will stop that effect for most people. It is no different in that sense from using painkillers and taking the next dose before the effect wears off to maintain freedom from pain. In PMR pred is the painkiller.

 

I know many people do need to split their dose, which I think reflects your experience?  I usually feel pretty much the same around the clock.  Oddly enough when following the famous DSNS method I feel much the same on the day I take the new dose, but the next day, when taking the old, higher dose I feel worse.  I don't know why, but I suppose it has something to do with the rate at which my body metabolises pred.  I wonder if I metabolise it very slowly?  

If I were you and a doctor asked me about pain level (which oddly enough my GP doesn't) I would tell him/her what you told me - I'm fine during these hours after taking pred, but during these other hours I have significant pain, and give the specifics.  

I hope you no longer need the celebrex?  This medication is not without its own lovely suite of side effects and if you are taking enough pred you shouldn't need another painkiller for PMR.

Good diet really does help our general health.  

Thanks, Steve. I also feel that the night dose is the more important one. Does your GP consider your 24-hour pain levels when instructing you to lower the dose, or does he/she just follow a fixed schedule provided that the ESR and CRP "behave"? I have a feeling that most GPs do just that, and then see how it goes.

I assume that you are male, which leads me to speculate if men, on average, metabolize or excrete pred faster than women.

 

Split dosing certainly works for me.  I began on 17/7 at 8 am and 8 pm and, in almost 4 months, have tapered to 7/6.  I have no PMR symptoms whatsoever and exercise plenty. And yes, the evening dose does seem the more important, as you can see from my taper.

If I were to dose at 1 am and 6:30 am, I would expect bilateral shoulder pain by midnight.