Cryoglobulinemia: The Triple Whammy

Triple whammy

Cryoglobulinemia: The Triple-Whammy!

Cryo has a way of hitting you from three different directions. Usually when we are flaring we only experience one or two of them. But in a big, bad flare it can really hit you hard with all three.

1) Hyperviscosity syndrome: Accumulating cryoglobulins can make your blood a lot thicker if the concentration is high. It can lead to some pretty nasty effects due to circulation being obstructed in the skin, muscles, and various organs, as circulation can rapidly become impaired in the smaller blood vessels. This can cause numerous problems. Hyperviscosity is a particularly onerous problem with type I cryo, but can also happen in types 2, 3, as well as mixed/combined types.

One problem that often occurs with hyperviscosity is damage to the eyes. In particular, the retina and optic nerve. We had a couple of people in this group experience a bad flare with effects on vision likely due to hyperviscosity syndrome last winter. You need to be alert to sudden changes in vision such as blurry vision, flashes of light in your side vision or a sudden increase in “floaters” in your eyes. This is a serious problem that could damage your vision permanently in hours if not treated right away, so be alert.

2) Autoimmune Vasculitis: Cryoglobulinemia is a vasculitis affecting small and medium blood vessels. Cryoglobulins are unusual molecules. They are large, heavy, and in the immune system they act as both antibodies and antigen. Once cryo starts, there is a tendency for it to not stop. The immune system processes the cryoglobulins and in the process a lot of inflammatory agents and autoimmune components are released which cause inflammation in small and medium blood vessels, and vasculitis results. Rashes, skin lesions, skin ulcers, and symptoms similar to rheumatoid arthritis are not uncommon. The process continues, usually until the cryoglobulins are gone or, more commonly, until the immune system is forced into remission and the inflammatory process is halted with medication.

3) Cryoprecipitation: Once the cryoglobulins have been processed by the immune system, the already large molecules tend to link up vis-a-vis a bond facilitated by immune system compliment molecules. Once this happens the cryoglobulins may rapidly begin to precipitate if the skin temperature drops below the core body temperature. This causes even more problems with outright plugging , and vasculitis in medium and small blood vessels. This will continue as long as cryoglobulins are available if the temperature is allowed to remain below the core body temperature. If cryoglobulins are present and you are not actively flaring, it is still possible to have cryoprecipitation.

Quantitative vs. Qualitative Cryoglobulinemia Testing and a Second Positive Cryo Test

Qualitative vs Quantitative testing for Cryoglobulins

The qualitative test for cryoglobulins is a test for the presence of cryoglobulins only. It gives no indication of the level or type of cryoglobulins found. The quantitative test for cryoglobulins returns the type and level of cryoglobulins present.

A single qualitative positive test for cryoglobulins qualifies as a diagnosis for cryoglobulinemia. Some doctors like to use the quantitative cryocrit test to measure the level of cryoglobulins as a diagnositic indicator.

The level of cryoglobulins in the blood are NOT good indicators for the severity or diagnosis of cryoglobulinemia.

It is well known that the cryoglobulin levels are highly variable from one patient to the next, and in any individual patient can fluctuate greatly, and may actually be absent altogether at times. Furthermore, while many labs make claims of accuracy, the accuracy of cryocrit measurements has never been well established, and a “standard” level for cryoglobulins as a diagnostic does not exist.

The bottom line is , one patient might have 3% cryoglobulins in their blood and be extremely ill with cryoglobulinemia, and yet another patient might have 11% cryoglobulins, and be completely asymptomatic. We don’t know why. . Every now and then one encounters a doctor who insists that cryoglobulin levels must be greater than 11% for a diagnosis of cryoglbulinemia. This is completely wrong, and arbitrary, and is simply not supported by the facts. Cryoglobulinemia is defined as the presence of cryoglobulins in the blood. Because of this clear and simple definition, the mere presence of cryoglobulins is taken as the diagnostic indicator for cryoglobulinemia. If you have cryoglobulins, regardless of the level, you have cryoglobulinemia, by definition.

Some doctors like to have a second positive for cryogobulins to confirm the diagnosis. This approach is likely not workable most of the time unless you can find a facility that does the test themselves, does it correctly, does it reliably, and you don’t mind repeating the test *A LOT*. This is because the test for cryoglobulins is not done correctly by most labs, and a false negative is returned about 70-75% of the time, At the same time false positives are uncommon.

In very real terms, one positive in the face of symptoms for cryo is compelling, and this is where most doctors will make the call, and call it cryoglobulinemia. The hard part is finding what is causing the cryo…

NOTE:  putting heparin in the test tube is another way to get a false positive if the tech does not know how to tell fibrin deposits from cryoglobulins.

A second positive cryo test is something to try for, but is sometimes not possible or practical to obtain. I’ve had ONE positive qualitative test, and have been tested for quantitative cryoglobulins about 6 times. The trouble is that the only time I was tested for cryoglobulins when I was flaring, and I clearly observed that the specimen was collected and handled correctly, was the single qualitative positive. On one other occasion blood was drawn correctly and the sample was then placed in a thermos for mailing to an outside lab for a quantitative test… but at that time I was in remission and we were trying to make sure I was in remission before changing the meds…. of course it came back negative. Other attempts at getting a cryoglobulin test were clearly done incorrectly from the beginning with the blood simply being drawn, the test-tube placed in a rack and the sample shipped to an outside lab. The lab doing the test in most cases was LabCorp. My first positive was taken at Washington Adventist hospital, and it was drawn and handled carefully by a head nurse,, not just a phlebotomist. My most recent test was done at the University of Maryland Medical Center, and I had requested a test for cryogobulins while there. At no time was a blood specimen drawn and handled with regard to temperature. The hospital records reported a negative test result, but I’m not even sure the test was actually performed.

Animals, Cryo and So Much Unknown.

Did you know that dogs, cats, and horses also develop cryoglobulinemia?  And mice can naturally have cryo.

 

Cryo is likely as old as warm blooded mammals, is my guess. It’s evolution is utterly unknown. The ability to make cryoglobulins might be an old evolutionary trait, or a new one. It might be that having cryoglobulins is a good thing in some situation or another, and that might make it a positive evolutionary trait if it allows one to live long enough to increase the chances of having offspring. We just don’t know this stuff about cryo, it simply has not been studied in that way to my knowledge.
Obviously cryo requires an immune system to be present, and it seems that the immune system insists on making the cryoglobulins when confronted with a long-term inflammation. Obviously the immune system is trying to do *something*, but the vasculitis it causes is the effect we notice. There actually may be some other effect that is going unnoticed, such as the cryoglobulins attacking hep-c virus and embedding it in their molecular structure. Or are Hep-C infected B-cells placing the replicated virus into the cryoglobulin before it is released from the surface of the B cells ? We don’t know. Are the cryoglobulins trying to eradicate the Hep-C? We dont’ know. .
So this raises the question as to if the manufacturing of cryoglobulins abnormal? or is it a normal process of the immune system which has gone awry in some fashion that we don’t yet recognize? One can speculate endlessly, but the lack of credible information is the limiting factor. As far as I know only one effort was made for a cure and it seems to be falling into disfavor; The stem cell transplant. It is a rather dangerous and experimental procedure.

Scary Worst Case Body Stuff

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Picture by Dale Sears
Internal organ involvement is insidious. You might not feel any pain or discomfort until the affected organ is severely damaged. Fortunately, this does not happen most of the time.
The thing one has to remember is that cryo is a systemic vasculitis and can affect any organ and any system in the body. Some things are more likely than others, but pretty much anything can happen. This is why it is important to try to keep your core body temperature up , because if the cryoglobulins start precipitating deep inside your body, you are then setup for internal organ damage.
But sometimes you simply can’t tell that something bad is about to happen until it does happen. A sudden clotting cascade can be life threatening, and a necrotic lesion on the heart or in the brain can be so rapidly fatal that they are frequently found post mortem. A lesion in the brain or heart are simply catastrophic. In some cases people develop various problems from them, but is frequently instantly fatal. One simply falls over dead. Fortunately these are NOT very common. Several people in our support group have had clots in the heart, head, arteries and strokes associated with cryo, and survived (Eileen Propp has survived 2 blood clots – one in the transverse sinus and one in the internal jugular vein.)
  • Kidney involvement can be spotted with a simple urinalysis.
  • Lung involvement is easily checked with a CT scan once in a while.
  • A full metabolic panel is good for checking liver functionality.
Another thing that has not been discussed is the association of antiphospholipid syndrome with cryo. A small percentage of people who have cryo have a tendency to clot excessively. You can wind up with a pulmonary embolism and expire pretty fast. A really bad situation is when someone goes into a clotting cascade, and doctors might not have sufficient time to treat it. Usually it is treated successfully, but death can be rapid, otherwise. you will basically know you have a stroke when (and if) you have one.

Essential Cryo: My Medication Induced Remission

I’ve been diagnosed since late 2008. I’ve spent most of that time in treatment for it with pretty good results most of the time. My rheumy and I made a try for a medication free remission which lasted about a year. That remission failed in August of 2013, and until October of 2014 I was flaring pretty much constantly, even while being treated. In early 2014 it was discovered that I now have lung involvement, and we are trying to determine if it is gong to remit. In October of 2014 I stated on cyclophosphamide along with prednisone to force a remission (It seems to have worked!) and I have transitioned to an imuran and prednisone combination. This weekend I’ll try to reduce the prednisone a little and if all goes well I’ll slowly taper off the prednisone in stages and remain on imuran for remission maintenance while we try to figure out what i actually going on with my lungs. If the news is bad, it might not be survivable no matter what, but if the news is good, then it is all good 🙂

I’m no longer interested in trying for a medicine free remission until I get all the questionable stuff sorted out.  I have been considering rituxan. I want to gather more CT scans first.  I pretty much need to take the meds or start losing arms and legs to gangrene and likely expire. Plus I pretty much need to force remission to contain the lesions on my lungs. Yes, the cost of the medication is horrific. I basically switched to imuran to avoid the high price $900 / mo for cyclophosphamide, but I think the imuran is safer anyway, and I have had good results with it in the past, and it only costs about $60 per month. the prednisone is about $15 per month.
I have found that my flares are very much the same every time. In that sense, it is rather predictable. BUT, every now and then there is a nasty “surprise” event that is life threatening or severely damaging. I had an episode of foot drop and partial paralysis of my right foot (it has mostly resolved), I have had assorted blood clots, and at one point developed multiple pulmonary embolisms due to a rapid clotting cascade, now I have the issue with lung involvement.

Do I Have to Take Medication? Mild to the Serious Stuff.

Do I have to take medication to treat my cryo?  The answer is  “it depends.”  It depends on your health and rwhat you and your doctor decide.

The doctor will likely use the following info to help make a decision as to whether medication is necessary in your case.

  • The type of cryo you have
  • the severity of your cryo
  • is there internal organ involvment
  • the symptoms you experience
  • the length of time you have been sick
  • your quality of life.

The following is a range of answers for a few different scenarios.

  • More than one person has discovered they have cryo by moving from a warm climate to a colder one.  Moving back to a warmer climate has given them a medication free life.
  • Some patients do not need medication and can manage their cryo by temperature environment prevention.

Most people with severe cryo won’t survive very long without the medications. The history of the use of medications in treating cryo has largely been one of doctors trying something to help a patient because no fully researched treatments existed. Over time doctors found a few things that helped relieve cryo and the commonly used treatments which we now enjoy, evolved from there. In recent years this has been improved on to some extent, but the situation is little changed overall. One thing is known for sure; that a patient with severe cryo and no treatment likely won’t live very long, and the manner of death is typically not pleasant, or pretty. I recall meeting a woman whose husband died from cryoglobulinemic vasculitis a copule of decades ago. She said he died about 5 months after his first flare started in spite of efforts on the part of doctors.

If you go back and find some of the older literature you sill find that not all that long ago, untreated severe cryo was often fatal in anywhere from days to a few month after a flare starts, with estimates on survival on the order of 3-5 months, I’m pretty sure that, for the most part , the current medications used to treat most autoimmune disorders are NOT some conspiracy on the part of the drug companies, but represent a collection of medications developed for other purposes that have been found to be helpful , by means of trial and error over a period of the last several decades. Before that , if you had cryo, your chances were not so good as they are now with treatment. The thing that is lacking is research into the mechanisms and causes for cryo. We know that it is usually caused by some things, and the list is growing, we know that a very few people have gone into a remission long enough that they appear to have been effectively cured. We know that sometimes a patient with non-hep-c cryo can sometime have a long-term remission lasting months , or years, but we really don’t know why. We still have a noticeable number of people who simply have cryo for no apparent cause, and precious little research has been done in this area.

You can live a long time with cryo. If it is severe, you probably won’t last long untreated. Obviously treating it improves the long term outcome by a lot. The mortality figures have improved a lot with the treatments since the 70’s  I know that Eileen has been in treatment for cryo a long time. These treatments did not always exist you know, and I know that a lot of people endure for years before getting a proper diagnosis. Also, it is possible to have “mild” cryoglobulinemia, which could potentially go untreated for a long time.

Cryoglobulinemia: Labeled a disease in 1930’s.

In the Victorian era cryo was simply “vasculitis”. Cryoglobulins were discovered in the late 1930’s. A couple of decades later cryoglobulinemia was named as a form of vasculitis. By the 1950’s people were getting diagnosed with cryo. For a while it was not considered an autoimmune disorder but eventually the industry stuck the label “immune system mediated” on it, and now it is considered an autoimmune disorder. Once it was getting diagnosed in the 1950’s doctors started having a go at treating it. You have to realize that prednisone and immunosuppressants did not come along until the late 1950’s. By the late 60’s and early 70’s patients were getting treated for cryo with increasing success, but from what I’ve seen in the literature, things really started getting a lot better in terms of successful treatment in the early 80’s.

The bottom line is that very little is still known about cryo. What we have now is a suite of treatments that were arrived at by trial and error over a long time. We still don’t know very much abot how cryo works., but if we did , the doctors might actually have better treatments and maybe even a cure. For now, treatment consists largely of tools from cancer chemotherapy and organ transplant procedures to simply hammer the immune system into submission. Truly effective treatment will only be developed when the mechanisms by which cryo works are understood, and that work is yet to be done.

Remission in Essential Cryo: A simplified explanation.

This is a  *vastly* simplified breakdown of how remission probably works in essential cryo.

The cryoglobulin is both an antigen AND an antibody. Cryoglobulins are produced on the surface of B cells that apparently have matured past the usual age at which they are programmed to die. In essence, the immune system wakes up due to an inflammatory process, and promptly attacks itself. This process never ends because the T cells remember to tell the immune system to make the cryoglobulins as a response to the activity. Using immunosuppressants tend to kill off fast growing cells such as B cells and T cells. The B cells are the cryo factory, and the T cells are the memory of what to attack. The thinking is, that if you suppress the immune system deeply, for a long enough period to eliminate the cryoglobulins, the T cells sometimes eventually “forget” about cryoglobulins altogether, and you have a “true” remission that can often be maintained for long periods after the immunosuppressant is withdrawn (typically withdrawn slowly, over the period of a year or more). In a very, very few cases, the cryo never comes back.

Short term remission is a bit different. The cryo is gone because the immunosuppression has killed off the B cells. As soon as the body generates a new batch of B cells , a flare is likely. This can be anywhere from a few days to a few weeks after withdrawing the immunosuppresant.

Cryo and Pain Medications

Pain is the body’s way of alerting – please talk to your doctor about any pain so that the cause can be diagnosed.

Here are some medications some of us in the support group have tried.  Check with your doctor and report your pain to them.

  • For neuropathic pain ,
    • neurontin works for some people, and
    • Lyrica is very good (but a lot more expensive).
    • Tegretol – an anti seizure medicine that can help nerve pain.
  • If you are having joint pain from rheumatoid arthritis or from arthritis like symptoms caused by the cryo
    • NSAID such as motrin or advil, but these have a potential for interacting with certain medications so do talk to your doctor before starting on an NSAID.
    • Asprin can sometimes help a little.
  • Aspercreme is sometimes helpful for joint and muscle pain.
  • Topical creams of lidocaine or patches of lidoderm can help some nerve pain.
  • Voltarin gel is helpful for inflammation and swelling in the joints.
  • Be advised that Voltaren is an NSAID and should not be taken along with other NSAIDs.
  • You might wish to read the posting about using ADVIL for more information.