Auto-inflammatory diseases – What can they tell us about ME/CFS?

[Woolie]

I promised to write something about this group of diseases, which I came across during my own diagnostic journey. They are not the same as MECFS, but they have some interesting similarities, and may provide some clues as to what's going wrong in many of us.

Background: The two main components of the immune system ​

The immune system consists of two major components: the adaptive (or acquired) immune system and the innate immune system.

The adaptive (or acquired) immune system learns from experience.

​

When we encounter a new infection, this system works to create specialised antibodies that target that infection specifically. This process takes a while (days to weeks). But it means that next time we encounter the same or a similar infection, these specialised antibodies can be mobilised quickly so that the infection is vanquished super efficiently.

Vaccinations target the adaptive immune system. The idea is to stimulate the creation of antibodies so that when we encounter the “real thing”, we’re ready to mount a full-scale, targetted attack.

The innate immune system is the “first response” unit.

​

It kicks in early, and its main job is to keep the infection under control until a full antibody-led attack can be mounted. It does generic things to make the body environment less habitable to the infection. e.g., raising body temperature. It mobilises certain types of white blood cells (e.g., NK cells, mast cells, neutrophils), that in turn produce inflammatory cytokines (e.g., IL-1 and TNF). This system is the main one responsible for making you feel sick. Its also responsible for many of the symptoms of common viral infections (e.g., sore throats, coughs, mucous, body aches).

Autoimmune vs. Auto-inflammatory disease​

Autoimmune disease occurs when the adaptive immune system goes awry.

​

This happens when something within the body is misidentified as harmful and specialised antibodies are created to attack it. The attack is usually localised to a particular type of tissue. e.g., the joints in RA. Often, symptoms are restricted to the tissue that’s affected (e.g., the joints). However, in some cases, the abnormal adaptive immune activity is also accompanied by innate immune activity, so the person may feel generally sick/tired as well.

Auto-inflammatory diseases occur when the innate immune system goes awry.

It overreacts, or fails to switch off when appropriate. The effect is that you feel sick all over. One of the key symptoms is recurrent fevers, but the inflammation can also set off gastrointestinal problems and cause severe headaches, rashes and a general flu-like feeling. People with these diseases generally feel much "sicker" than those with autoimmune diseases. This is because the key problem is with the system that causes "sick" feelings.

These diseases are harder to diagnose because autoantibody tests naturally come back negative. And there's often no obvious tissue damage. Doctors look for things like periodic fevers, especially if accompanied by rashes and stomach problems (it varies enormously with the specific disease). They also look for raised inflammatory markers in the blood during episodes – things like C-reactive protein. Onset of symptoms can be in childhood or early adulthood.

Auto-inflammatory diseases have only been recognised recently, and the forms that have been identified so far have a very extreme clinical profile that isn’t seen very often. However, there are likely to be yet more variants we don’t know of yet, and the inflammasome could turn out to be at the bottom of a much, much wider range of complaints.

There is a great summary of all this here.

 

[Gingergrrl]

@Woolie that was an excellent write up (for someone with my level of science background!) and in general.

If I understand it correctly, my illness would be "autoimmune" vs. "autoinflammatory" b/c I never feel "sick" (minus some post IVIG reactions) and I do test positive for multiple auto-antibodies. Would that be corrrct or could someone have both types of illnesses at the same time?

 

[Woolie]

If I understand it correctly, my illness would be "autoimmune" vs. "autoinflammatory" b/c I never feel "sick" (minus some post IVIG reactions) and I do test positive for multiple auto-antibodies. Would that be corrrct or could someone have both types of illnesses at the same time?

I'm no expert, but I think the idea is that you can have activation of the innate immune system with autoimmune diseases too (so yes, one can stimulate the other). But the inflammation part is much more severe in autoinflammatory diseases.

Edit: it doesn't seem that people often have an autoimmune AND an autoinflammatory disease at the same time. I haven't seen that anywhere. I think its generally either one or the other.

 

[Scarecrow]

@Woolie. If CRP and ESR are not elevated, then it can't be auto-inflammatory, is that right?

If so, then it would rule out auto-inflammatory for most but by no means all of us.

When you refer to feeling "sick", do you mean in a generally "malaisey" way?

 

[Mij]

I've also read that autoinflammatory markers include high WBC. Mine have always been below normal or low/normal range.

 

[Woolie]

@Woolie. If CRP and ESR are not elevated, then it can't be auto-inflammatory, is that right?

CRP and ESR provide some sort of objective evidence of inflammation, but neither appear to be very good markers of how sick a person feels. They are probably not at the center of all the awfulness, but reflect some sort of side effect that occurs sometimes in some people.

If so, then it would rule out auto-inflammatory for most but by no means all of us.

What I was trying to say is that there are a whole host of newly discovered diseases that affect the innate immune system and although most people with MECFS don't fit the current diagnostic criteria for any of them, the innate immune system may turn out to be implicated in MECFS.

The thing about auto-inflammatory diseases that makes them look similar to MECFS is that the main problem of having them is not tissue damage, system failure, or early death - its just how awfully sick they make you feel. That just sounds a lot more like MECFS than do autoimmune diseases.

Depression is also a massive problem in auto-inflammatory diseases - much more so than in RA or lupus. Inflammation seriously messes with your mood.

When you refer to feeling "sick", do you mean in a generally "malaisey" way?

Yes. Not sick in the stomach. Sick in the sense of "sickness behaviour".

 

[Woolie]

I've also read that autoinflammatory markers include high WBC. Mine have always been below normal or low/normal range.

Yea, its maybe not a great fit for you.

In inflammatory disorders, you might expect to see high white blood cell counts. But those are a pretty blunt instrument, because there are so many different white blood cells. More specific markers are raised subsets. e.g lymphocytes overall or CD4+ or CD8+ Tcells specifically. Other markers of auto-inflammatory diseases include high neutrophil counts, high platelet counts, and high serum amyloid A (SAA).

 

[Daisybell]

It wouldn’t surprise me if there turn out to be both auto-immune and auto-inflammatory variants of ‘ME’...

 

[Woolie]

Oh, forgot to say: people with autoinflammatory disease report that the main triggers of their episodes appear to be:
- infection
- overexertion
- stress

Sounds a bit familiar, eh?

 

[chrisb]

One thing that struck me on looking-up some of these illnesses was the periodicity of the recurrence of symptoms. That certainly sounded familiar.

 

[arewenearlythereyet]

It does seem like some sort of immune response is involved to explain the inflammation type symptoms. The effect of histamine on other processes in the body seems to be key factor for some of the other symptoms (heat intolerance, some food intolerances etc).

Not sure how poor wound healing fits in? I'm prone to this being very slow (small cuts often get infected and take 8 weeks to heal). I've just had a severe cold and noticed that my normally sluggish wound healing was vastly improved. I didn't deliberately cut my thumb open with a bread knife during this time but this is a normal hazard of numb fingers. Well the cut was at least 4mm deep. That was on November the 5th and it's now completely healed! Still got the cold though.

 

[Mij]

More specific markers are raised subsets. e.g lymphocytes overall or CD4+ or CD8+ Tcells specifically. Other markers of auto-inflammatory diseases include high neutrophil counts, high platelet counts, and high serum amyloid A (SAA).

Those are all below normal for me too. A constant 'sickness behaviour' feeling fits how I feel 80-90% of the time. Then the off and on vertigo that sneaks in.

Thanks for you insights. Interesting.

 

[Gingergrrl]

Edit: it doesn't seem that people often have an autoimmune AND an autoinflammatory disease at the same time. I haven't seen that anywhere. I think its generally either one or the other.

Thanks @Woolie and I was just curious and trying to relate this to my own case which doesn't quite seem to fit in anywhere. My doctor said that I have a "B cell dependent autoimmune disease" and that my symptoms are auto-antibody driven but he has never used the word "auto-inflammatory" in my case.

What would be an example of a known disease that is auto-inflammatory but not autoimmune? I have Hashimoto's Disease which is clear-cut b/c I have the auto-antibodies and the abnormal blood tests (prior to taking thyroid medicine). But my other auto-antibodies do not quite match with a known disease (in my case). For example, I have the calcium autoantibody that goes with LEMS but I test negative for LEMS on EMG. I have the GAD65 autoantibody (that goes with diabetes and Stiff Person Syndrome), but I do not have either of these illnesses, just the auto-antibodies.

@Woolie. If CRP and ESR are not elevated, then it can't be auto-inflammatory, is that right?

My CRP and ESR have never been elevated. My last ESR was "6" and I don't remember my last CRP except that it was totally normal. I assume this rules me out of the auto-inflammatory category, especially b/c I literally never feel malaise or sick (with the exception of some post IVIG reactions).

 

[Woolie]

@Gingergrrl, there seems to be lots of evidence for autoimmune activity in your case, even if you have some symptoms that don't quite fit any specific disease category. But most of PwMEs are not like you - they don't show any evidence of autoantibodies, and they still have no clue what's going wrong with them. Its those people who might find this of interest.

There's been so much talk amongst us about autoimmunity and autoantibodies, but this other side of the immune system - the innate immune system - has received little attention. That was the point of my post, really. To talk about that other side and how relevant it might be to MECFS. Most of us here will not meet the diagnostic criteria for any currently known auto-inflammatory disease, and besides, they're pretty rare (but at the same time, probably hugely underdiagnosed). Nevertheless, the innate immune system could still be implicated in some other way we still don't yet understand.

Having said that, it looks very much like I might meet the criteria for one of these auto-inflammatory diseases (prefer not to say which one publicly), so maybe there are others out there like me. But I'm a bit weird - my symptoms are very episodic, and I get very severe flu-like episodes.

What would be an example of a known disease that is auto-inflammatory but not autoimmune?

Most are super rare things you will never have heard of. The most "common" is familial mediterranean fever or FMF. TRAPs (tumor necrosis factor associated periodic syndrome) is probably the one that's most ME-like. I'm not sure about multiple sclerosis, whether that counts as one too. Its not strictly autoimmune.

 

[Gingergrrl]

@Gingergrrl, there seems to be lots of evidence for autoimmune activity in your case, even if you have some symptoms that don't quite fit any specific disease category. But most of PwMEs are not like you - they don't show any evidence of autoantibodies, and they still have no clue what's going wrong with them. Its those people who might find this of interest.

I didn't know which category I was in and found your post really interesting. I never understood the difference between autoimmune or auto-inflammatory (except for inflammation markers like CRP or ESR).

But I'm a bit weird

No weirder than I am ...

Most are super rare things you will never have heard of. The most "common" is familial mediterranean fever or FMF. TRAPs (tumor necrosis factor associated periodic syndrome) is probably the one that's most ME-like. I'm not sure about multiple sclerosis, whether that counts as one too. Its not strictly autoimmune.

Thanks and you are right that I have never heard of those illnesses (except for MS of course).

 

[Samuel]

i stil don't get it if mcas or allergies don't fall into the second category.

 

[Woolie]

i stil don't get it if mcas or allergies don't fall into the second category.

I don't know for sure, @Samuel. They're usually classed separately from the autoimmune and autoinflammatory diseases, as part of a wider group of general hyperpsensitivity disorders. And they involve excessive antibody production, but of a different kind from autoimmune diseases (IgE is important). That's pretty much all I know.

Will check back in if I find out more.

 

[Josie]

Oh, forgot to say: people with autoinflammatory disease report that the main triggers of their episodes appear to be:
- infection
- overexertion
- stress

oh wow, I was really strucked my this!
I am struggling for years now finding out whats wrong with me. Auto-inflammatory disease....its the first time I read about this although I research a lot because I am a science girl at heart
@Woolie, thank you for posting it, I will certainly dig a bit deeper into this.

I was suspecting MCAD, but I dont fit into the typical pattern (although a german mast cell doctor told me I fit into a certain sub group, but I was never told which one).

I get flares nearly every second day from overexcertion. Which in my case means I cook a meal or I even stand up to use the loo. As I am conctantly exhausted i overexert myself constantly.

The lower my cortisol levels drop, the more intense the reaction is.

It begins mostly in the evening and lasts for 24 hours. Symptoms are:

- severe flu like limb pain (never get a fever)
- being restless and agitated, cortisol and catecholamines shooting up (feels like some inflammatory agents stimulate a stress response), horrible insomnia
- also feels like too much histamine in the system, but on a system level
- feeling of whole body inflammation and like poisoned

But: i got some markers tested some hours after a flare started and all came back normal (attached in the files).

Cortisone helps to some extrend as does ibuprofen, so there must some inflammation going on.

When I have really high stress hormones I dont get this! Lets say I had a dispute with my hubby and I feel my stress response coming up, that saves me from getting this horrible reaction. But when I am very tired and exhausted I always get it, it starts in the evening when cortisol levels naturally decline.

i am really desperated, no doctor knows what is wrong with me, the only doctor that knows about mastcells dropped me, he never answered again (despite the fact he has offered his help before).

Any advice is helpful. I am in a constant spiral of low cortisol triggering this response and then after 24 h of feeling sick to death with elevated stress hormones i crash again. This cycle is going on for 3 years now and I get worse and worse.

Thanks @ all

 

[Woolie]

Hi @Josie. Sorry, I only just saw your message.

When I have really high stress hormones I dont get this! Lets say I had a dispute with my hubby and I feel my stress response coming up, that saves me from getting this horrible reaction. But when I am very tired and exhausted I always get it, it starts in the evening when cortisol levels naturally decline.

I was struck by this. A few of us here on the forum have described a similar thing, a sort of paradoxical stress response. You get a little symptomatic relief during the stress, and when that passes, then the symptoms come back to bite you in the bum.

I had a look at your test results. The IL-beta one is perhaps worth asking someone about. IL-B is elevated in people with autoinflammatory diseases.

Its unlikely that you'd fit the criteria for any of the known autoinflammatory diseases. They almost all involve fevers (high temperatures). But some of the same mechanisms might be involved.

When you say cortisone helps, do you mean drugs like prednisone? If so, how much of a dose gives you relief and for how long?

 

[Jonathan Edwards]

I had not noticed this thread.

In general I agree with what has been said. However, it is a bit more complicated because 'auto inflammatory' tends to be used for diseases that at least sometimes feature inflammation but which are not known to be associated with a specific auto reactive antibody or T cell response. That casts the net a bit wider than it might seem.

One lot of these diseases are genuinely based on innate immune abnormalities alone as far as we can see. These include the hereditary fevers - Familial Mediterranean Fever, Hibernian Fever, and other rare syndromes. Typical inflammatory markers are present like CRP and high white cell count.

But there is another group of illnesses that come under auto inflammatory that in fact involve adaptive immune cells but where there is no particular evidence for these adaptive cells being auto reactive. This is quite hard to explain but it is relevant to the suggestion from Mark Davis that there might be T cell clonal expansion. We all have T cells recognising foreign antigens as they are supposed to but it might be that if some of these get too enthusiastic we get ill just because of the faff going on from T cells that ought to be doing a useful job.

There is a specific group of diseases that follow this story - psoriasis, Reiter's syndrome and especially ankylosing spondylitis. Nobody has ever found auto reactive T cells in these conditions but genetic linkage to MHC Class I and to certain T cell cytokine receptors and response to IL-17 blockade makes it pretty likely that they are due to overenthusiastic T cells.

There is also a disease that seems to show a bit of everything - Crohn's disease. It has a genetic association with innate immune proteins. It seems to link to the above group of overenthusiastic T cells diseases (overlaps with AS and Reiter's) but can also have autoantibodies (to a carbohydrate found on baker's yeast but also on lymphocyte surfaces).

So maybe the take home message is that there is no very general rule to auto inflammatory diseases. Nevertheless, I very much agree that they are of interest in the context of ME for the reasons given. They are often a bit covert, without obvious markers. They make people feel terrible in a way that might be called fatigue or malaise. On so on.