Essential Cryo: Flare Remission Cycle

Essential Cryoglobulinemia: Flare/Remission Cycle:

One researcher stated that “Cryoglobulinemia is a disorder characterized by periods of remission followed by periods of flaring….“.

  • One of the interesting things about truly essential cryo is that it can sometimes be driven into full remission using medication, and if the meds are slowly withdrawn over a long period of time, the remission can remain , so you end up with a medication free remission.
  • Typically a medication free remission can last from weeks to months, and sometimes people remain in remission for a year or more. In a few cases the cryo never returns and after 10 years of medication free remission with no symptoms, the patient is deemed “cured”.
  • If one looks at the success rate of this approach, about 50% of patients with a medication free remission will flare within the first year.
    • Of the remaining patients still in remission about 10% will have a long term remission lasting longer than a year.
    • Also, the longer you are in remission, the better the chances seem to be for continued remission (I have no numbers for that but this is based on 8 years of anecdotal experience).
    • So lets assume that something like 3% of cryo patients have truly essential cryo (meaning there is no co-occuring cancerous, autoimmune or viral disease causing the cryo).
      • the odds of being “cured” in this manner come out to be about 1/10 of one percent if one is looking at all patients with cryo.
      • the odds of being “cured” and about two percent for patients with truly essential cryo.

My personal experience with flares and remission.

  • In general, if I am not in full remission, I flare anywhere from days to weeks of withdrawing medication. If I have been in full remission for a long time, I can go for weeks, to months. I have had one period of about a year of medication free remission. Genrally if I am going to flare big, it is in the fall months. But I have had flares in the summer too. It does not seem to be predictable, but it also seems as though things that stimulate my immune system make a flare more likely. On one occasion I caught a cold in the summer, anfter a couple of days of that I started to flare, the cold went away on a few days, but th flare persisted for a couple of weeks. It is like that old song “The weight”. a line in it says “I gotta go, but my friend can stick around…”
  • I’m lucky in that I seem to respond well to treatment. Even at that, I get surprised regularly and there are unforeseen medical events, and sudden flares.

NOTE: Cryo *always* requires vigilance. Being alert to your condition is the best way to reduce the risks of bad things happening.

Managing My Cryo: Imuran, Steroids and Balance

Starting on Imuran: 

  • I’ll be starting on Imuran this weekend. I was on a combination of cyclophosphamide, antibiotics, and prednisone for 3 months, to force remission and withdrew the cyclophosphamide two weeks ago to “wash out” a bit before starting the transition to Imuran.
  • Right now I am on 30 mg prednisone per day only and still seem to be in full remission. My tolerance of cold is basically “normal” right now….. if my life can be described as normal at all…..
  • Imuran is a very slow acting immunosuppressant.
    • It takes weeks for it to have any effect at all, and is typically a month or two before it is at full effect. (In the near term I expect to remain on antibiotics.)
  • Right now the plan is to start Imuran at 50 mg, twice a day, and in two weeks I’ll taper down the prednsone to 20mg/day and hold there until I get blood work done again in another month.
  • Once the Imuran is in full effect, and if I am not flaring, I’ll start tapering off of the prednisone completely and remain on imuran for remission maintennence….
    • This is the teter toter of transitioning off one medicine to another.. If down too fast on steroids I may flare. It is a balance that is difficult to maintain and is unpredictable.
  • Using steroids in conjunction with Imuran (or other immune suppressants) is a fairly standard protocol for establishing remission in essential cryoglobulinemia.

*NOTE:  It is really not what one would do in the case of cryo that is secondary to some other cause. In those cases the primary cause is usually treated first.

 

Disease Modifying Anti-Rheumatic Drugs (DMARD’s) and Monoclonal Antibody Therapy (MAB)

Disease Modifying Anti-Rheumatic Drugs (DMARD’s)

  •  If you are being treated for cryo, chances are that you are on one of the drugs that I have listed here or are considering them as options with your doctor.
  • DMARDs are a class of drugs commonly used to treat a variety of autoimmune disorders.
  • Some were developed primarily for the treatment of cancer, malaria, or for preventing organ rejection in transplant patients.
  • DMARDs are sometimes referred to as “steroid sparing” drugs because they often allow greater overall effectiveness at maintaining remission of autoimmune disorders when used in combination with low dose prednisone. In some cases more than one DMARD may be used in combination.
  • Each DMARD is a bit different from the others, effectiveness varies from one condition to the next and the side effect profiles are also highly variable.
  • Some DMARDs have a greater risk of potentially dangerous conditions and the patient must be monitored continuously for their safety.

Below , I have listed some common DMARDs in order of their basic action on the body, this list is not complete and you will want to search the internet and find further information on your favorite DMARD with regard to risks, safety, drug interactions, and side effects.

  1. The following drugs include the antimalarial agents, are frequently slow to take effect and some have significant long-term side effects.
    1. gold (rarely used) Sometimes effective for rheumatoid arthritis). This treatment has been around since the Victorian era! It is not well understood and tends to cause increasingly severe side effects over time.
    2. hydrochloroquine (Plaquenil) An anti-malaral agent. Often used in combination with steroids, commonly used to treat Lupus.
    3. methotrexate commonly used for a variety of autoimmune disorders and may be used in cmbination with other DMARDs
    4. sulfasalazine Often used to treat Chron’s disease, may be used with other DMARDs.
    5. cyclosporine Developed to prevent organ rejection in transplant patients. This drug may have serious long term safety issues. It is sometimes used in cases where nothing else works.
  2. The following drugs are the immunosuppressants. They can be slow to take effect and carry a risk from infection due to suppression of the immune system. Side effects vary, some are not so bad, but others have *significant* risks and side effects and the patient must be closely monitored.
    1. cyclophosphamide (cytoxan) Commonly used in oral and IV form, frequently used in combination with prednisone to force remission. Has a relatively big risk and side effect profile. This is generally viewed as a serious “big gun” that suppresses the immune system deeply.
    2. Imuran (Azathioprine) Commonly used to maintain remission after remission is established. Commonly used with low dose prednisone.
      1. Less risk and fewer side effects than cytoxan. Slower to take effect than cytoxan. Does not suppress the immune system as deeply as cytoxan.
      2. Imuran carries a small, but real risk of causing the immune system to die off rather quickly, so your blood counts must be monitored carefully.  Low white blood cells and low producing neutophils are a risk.
    3. leflunomide Sometimes used alone, but may be used with another DMARD, or a biological agent.
    4. mycophenolate-mofetil (cellcept) Originally developed to prevent organ rejection in transplant patients. Often used in combination with other DMARD’s, and more recently used in combination with biological DMARDs.
  3. Biological Agents (so-called bDMARDs)
    1. Tumor Necrotic Factor (TNF) Inhibitors
    2. including etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab,
  4. Specific Biological Agents with specific targets (also called Monoclonal Antibody Therapy = MAB)
    1. These drugs are basically designer antibodies that have very specific targets.
    2. For example: rituximab (rituxin) targets B cells specifically.
    3. including anakinra, abatacept , rituximab, tocilizumab, and tofacitinib. These medications are often combined with methotrexate or other DMARDs to improve efficacy.

*Author NOTES:

  • Plaquenil is not a heavy hitter like the above immunosupressants are, but it is a lot safer and has fewer side effects, so if it works for you , it works…. and that is a good thing.
  • If you need to take the medication , you take it.
  • It is all about risk management. For a more serious situation a bigger risk may be warranted in order to gain more effectiveness. The doctor has to make this kind if decision… and so do you the patient. For example, using cyclophophamide with prednisone to force remission in a case of cryo is not unusual. Once remission is established, one can tansition to something like Imuran, methotrexate, or cellcept. Often a patient might not tolerate one of the medications very well, forcing a change to another.
  • Some get along with imuran very well, so it is a good choice, and has less risk than staying on cyclophosphamde.
  • Also, Imuran is a reasonably safe drug to stay on if you have to take it long-term. So it really boils down to risk management vs effecrtiveness and having a list of possible options.

Five Stages of Accepting: Learning to live with Cryo.

Five stages of accepting a Diagnosis of an incurable disorder or disease.

Receiving a diagnosis of Cryoglobulinemia is scary and it is hard for our families and friends too. It is actually a grief process that we go through, not unlike the loss of a loved one, and it takes a while for us to go through it.

  1. Denial
    1. Sometimes we ignore the facts and deny that it is real. Sometimes we can fall back on strong emottions… it sort of varies from one person to the next. We are all human, so this really should be viewed as good and necessary… and temporary.
  2. Anger
    1. We become angry because we feel like we have been treated unfairly… even cheated of having a normal life. Nobody is to blame for this, it is simply something that has happened. This will also pass after a while.
  3. Bargaining
    1. We try to make a deal with ourselves, or our condition to make it “better” somehow.
    2. We pretty soon discover that this approach does not work , and so we move on.
  4. Depression
    1. Once we fully realize the truth of the situation, we sometimes hit bottom for a while… feelings of being “lost” or of “no hope” are not unusual.
    2. Be patient with yourself, once you start to learn to cope with cryo, this will improve. (ganted, some days are better than others…)
  5. Acceptance
    1. We eventually learn to accept our condition for what it is and learn to cope with it as best we can.
    2. We learn that we *CAN* win some battles, and that others we can *NOT* win.
    3. Cryoglobulinemia is simply an illness, God is not punishing you, and cryo is not some evil entity out to get you.
    4. Cryoglobulinemia is simply what it is.. an autoimmune disorder, so to move on, we need to learn to work with what we have.

Steroid Side Effects

Common Steroid Side Effects  

→ Prednisone is commonly used to treat autoimmune disorders. The benefits of it are that it is fast-acting (takes effect within hours) and is frequently effective for bringing a flare to a speedy halt in many autoimmune disorders.  While the plus side is the good news, prednisone has an “evil” side to it!  It can cause unpleasant and damaging side effects to the body, and potentially dangerous. For this post I use prednisone as the drug but the info here is equally applicable to solumedrol, depomedrol and other brands of therapeutic steroids prescribed by a doctor.

Here I am going to list some of the more common side effects.

  1. Weight gain. You can plan on gaining weight while on prednisone. It also has the tendency to redistribute body fat such that a person ends up appearing “fatter” than they actually are. For many people this effect is less noticed at lower doses of prednisone.
  2. Sweating. Sudden, apparently random sweatng. It can be profuse. for me I have noticed a tendency to break ou tin a sweat a couple of hours after taking prednisone.
  3. Insomnia. For me, this is the most annoying side-effect, particularly at higher doses. It is hard to sleep. I wind up taking melatonin at night and it seems to help a bit.
  4. Neurological Effects. This tends to happen to me at higher doses (greater than 40 mg/day) In particular, sudden bouts of shaky hands. This can be severe, and you should talk to your doctor if you develop odd neurological effects from using prednisone.
  5. cataracts. Your chances of developing cataracts are greatly increased if you are on prednisone.
  6. osteoporosis Bone loss is a big problem with prednisone, especially at higher doses and long term use. This can be corrected for to an extent with medication.
  7. Immunosuppression After you have been on prednisone for a while, it will begin to suppress your immune system. You need to be more careful of opportunistic infections.

  • There are more, the list is long, but these are the more common side effects of prednisone use.
  • In general, side effects will be worse at higher doses and may get worse with chronic use over time.
  • Everybody is a little different, and some people will experience more or fewer side effects.
  • It is a good idea to go to the drug manufacturers web site for the fact sheet for prednisone and read it.
  • The essence of all of this is that prednisone can be a wonder drug in terms of getting fast relief from a flaring autoimmune disorder, but is not really a good drug to be on long term unless there is no other option.
  • It basically ages your body rapidly, and you become progressively weaker in time, and there is a looming toxicity that increases with long term use.
  • It is a good idea to not stay on it any longer than you must.

Author’s Personal Note:   I have a long-standing love-hate thing relationship with prednisone.  I love what prednisone does for me, but I hate what prednisone does to me.  As a “rescue” medication it is the bomb!  I’m glad to have it as a tool to use.

 

Triggers, Causes of Cryo and other Facts

What Triggers Cryo?

One researcher put it this way: “Cryoglobulinemia is the immune systems response to long-standing inflammation….”

  • There have been attempts at linking bacterial pneumonia and vaccines for it to connective tissue autoimmune disorders, but it has not been substantiated, and it really looks like it actually triggers an existing autoimmune disorder and not really cause it…. all of the facts are not yet in on this one. (Also, some have tried to link eipsteen-barr virus to cryo, but it is so sketchy that it is not credible.)

All of this stuff leads one to the idea of “triggers” for the flaring of an autoimmune disorder. This is a particularly hard thing to research and test, so there really are not known and confirmed triggers for a flare, but there are some things that are believed to be potential triggers for a flare.

  1. Injury; including surgery.
  2. Illness. Some have reported the onset of a flare after encountering a virus, for example.
  3. Stress.  Stress can stimulate your immune system and eventually cause it to fail.

The bottom line here is that things that stimulate the immune system may be a bad thing for people with autoimmune disorders.


Weird/Odd things that once in a while cause cryo; it’s possible but very unlikely for you to get or have most of these.

Here are a few odd things that have not been “officially” associated with cryoglobulinemia, but have caused cryo for a few people in the past.


  • Epstein-Barr Virus and Cryoglobulinemia  Eipstein-Barr virus (infectious mononucleosis) Has long been known to sometimes cause cryoglobulinemia, but the association with cryo remains uncertain. Here is a paper about this topic. The scary part of this is that if it is true, there is a huge number of people at risk for cryo.\http://www.ncbi.nlm.nih.gov/pubmed/2836115  (On a personal note:  I developed infectious mono at the age of 14. I was bedridden for a month and very weak for about 6 months. I sometimes wonder if it is the cause for my cryo. Technically EBV can lead to cryo if the virus is persistent but these things are poorly researched and impossible to prove.)

    Chickengunya virus. A somewhat rare tropical disease. It can be treated , and cured, but will generally spontaneously cure in a year or so and the cryo generally remits.

  • Lyme disease, sometime people with Lyme disease develop cryo.
  • Malaria A few cases of cryo in malaria patients have been reported.
  • Leporacy. Yup! the plague of the ages. It is known to cause cryoglobulinemia. Fortunately, Leporacy can be treated and cured.
  • Endocarditis. An infected heart valve can sometimes mimic cryo rather faithfully in terms of symptoms. -cryoglobulins are actually present in these cases… it is pretty rare.
  • HIV There have been reports of HIV patients developing cryo. Once they develope full-bown AIDS, the cryo goes away because the immune system is no longer functioning.
  • Silicosis. Poisoning with silicate minerals is known to sometimes cause cryo.This is a bad, bad, illness. to have.
  • Vinyl Chloride – Exposure. Vinyl chloride poisoning is known to cause cryoglobulinemia. But by that time, the cryo is likely the least of your worries as this is a seriously bad situation to get into.
  • parvovirus B19  The certainty of this association with cryo is unknown, but it is often listed as a possible cause for cryo.
  • Infectious monoucleosis.  This is caused by both Epstein Barr virus or cytomegalovirus, both have a somewhat uncertain association with cryoglobulinemia that continues to be reported.
  • Assorted Herpes viruses: These are among the most common viruses around. Roughly 90-95% of the population has one or more of these viruses. Most people are asymptomatic, some just get sick once and have no further problems, and a few are chronically afflicted.  Herpes viruses which have been named as associated with cryoglobulinemia at one time or another include the following:
    • chicken pox (Herpes varicella), and shingles (Herpes zoster). Chicken pox is a common childhood illness, and can cause outbreaks of shingles later in life when the virus suddenly reactivates.  There is no proven/confirmed association between cryoglobulinemia and chicken pox (herpes vericella) or shingles (herpes zoster) BUT
      • Here is a case report of cold agglutinins and anti-pr-3 antibodies associated with chicken pox!    http://www.ncbi.nlm.nih.gov/pubmed/8249368
      •  another report citing rubella (measles) as well !     http://www.ncbi.nlm.nih.gov/pubmed/9480085
      • yet another author lists herpes vericella as associated with cryoglobulinemia! Note: this is a very old citation that incorrectly lists syphilis as associated with cryoglobulinemia. Scroll down about a half page to see the chart.  https://books.google.com/books… (I sort of have dog in this fight because I was born with chicken pox and am at risk for shingles.)

  • Syphilis does NOT cause cryo!
    • But as an interesting side note this venereal disease was once thought that it was associated with cryo because patients with cryo kept testing positive for it.
    • It turned out that a problem with the test was causing a false positive.
    • The test the test for syphilis has since been improved to be a bit more specific. There are still a few doctors around who have not read the news on this one.

Cryo and Mortality

Cryoglobulinemia and Mortality

This is a topic which I have been avoiding to keep from alarming those who have been newly diagnosed without good reason to do so.

After researching this , and thinking about it for some time, I decided that I should talk about this in a post on the forum.

Based on work done by Claudio Ferri (2004) it appears that the mortality rate for persons with cryoglobulinemia are about 42 percent, possibly as high as 50 percent in the first 6 years after diagnosis. Rossa et-al (2008) included the work of Ferri and others to arrive at similar results.

Rieu et-al (2002) examined outcomes for various comorbid conditions with cryoglobulinemia and determined that a more positive outcome was likely in patients who did not have liver, kidney or lung involvement with cryoglobulinemia.

Later work by Bryce et-al (2006) revisited mortality and observed that for all patients in their study, overall the mean 50 percent survival time was about seven years, and that for patients over the age of 57.6 years, the 50 percent survival time was a little better than 5 years.

In all three of these studies, researchers point out that the outcome is likely to be significantly better if there is no involvement of the kidneys, liver, or lungs. Surprisingly, in spite of the seriousness of potential involvement of these organs, the leading single cause of death in cryoglobulemia appears to be vasculitis.

With a cure for hepatitis C now available and with patients getting treated successfully, I would expect to see the 5 year survivor rates improve over the next few years as the number of people having liver involvement with cryoglobulinemia ought to decline markedly. Unless a breakthrough in treatment is achieved, I would expect to see vasculitis continue to be the leading cause of death in persons with cryoglobulinemia.

ADDENDUM: One thing that should be mentioned is that treatment of cryo has improved a lot in the last 2-3 decades. The expected survival of a person with severe cryoglobulinemia would be a matter of a few months, at most, without treatment.

I just added a citation for Rossa (2008). I had used his information but had not cited it.

If I Could Design Cryo Research

Cold Weather and the Cryo Patient’s Attempt to Control Temperature

I find it remarkable when doctors think that colder weather/climate is not a problem for people with cryoglobulinemia. Particularly when so .  . . so many people with cryo have a rather immediate response to cold. It is also known that individual responses to cold appear to be highly variable among people with cryoglobulinemia. There are also accounts of people moving to colder climates from warmer climates who suddenly display symptoms of cryoglobulinemia.

The debate over controls of precipitation temperature for cyoglobulins in the blood has neen a longstanding issue. In fact there is a lot more to it than just concentration and temperature, but the basic property of solubility is controlled by concentration and temperature as the saturation point will change with temperature. This is a fundamental physical property. The question does remain that the behavior of cryoglobulins in a petri dish is not guaranteed to be the same as in a living person, and the blood contains a lot more than just water and cryoglobulins, and the chemistry of it is rather dynamic… so technically it may well be correct to state that one can not clearly show that concentration and temperature are the big controls the precipitation of cryoglobulins.

At the same time common sense clearly suggests that given no other metric, one should seriously consider it from the standpoint of safety, especially since cryoglobulins DO precipitate/gel at temperatures below normal body temperature, and persons with cryogloblinemia DO experience adverse physical reactions to cold. Maybe some really bright grad student needs to get some funding and go after this rather fundamental question ?

Eating well and getting exercise is important and improving physical strength is helpful, always. It is particularly important when recovering from a long battle with a flare. It can take awhile to regain strength and wellness, so taking care of oneself is important.

As a normal emotional response  I do realize that it is easy to become fearful of cold when one has cryoglobulinemia, but realistically after a couple of bad experiences with cryo we have ample reasons to feel that way. It should not be surprising that some of us might be a little “over the top” with our cautions regarding cold. The reasons for that are quite sound. We don’t know for sure what the “safe” operational limits are.

Palpable Purpura

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Palpable Purpura survival.

This is a distillation of what I experience with palpable purpura. Others in Alliance for Cryo Support groups have had the same experience and so I thought you might find this useful.

Palpable Purpura is a kind of skin lesion common to small and medium vessel vasculitis.  Palpable Purpura is blood-filled lesions which are raised, and resemble blood-filled blisters, typically from tiny up to about a centimeter (about the size of a dime) in diameter. You can push on one with you finger and it will flatten out, and will not blanch (will not turn white) if the cause is vasculitis.  These lesion form rapidly (in a few minutes), and when active they can hurt much like a bee sting. Sometimes one only gets a few lesions, but at other times they can be numerous and the pain can become quite severe. The lesions can grow in size daily, and lesions which are close together may merge to form bigger lesions. The big risk here is that a large area of skin can die quickly , leading to ulcers, and infection and a host of other problems. This can be very bad.

The lesions are typically more active at night and it is not unusual to wake in the morning and find that your feet are covered with new lesions which formed while you slept. In the daytime, they may be less active and will be less full in appearance.  These lesions will continue to form until the vascultis remits. Once they begin to heal, it often takes about a week to ten days for the blisters to drain, and form scabs over the lesions which will gradually heal over a period of weeks, or months.

Here are some things you can do to make things a little more bearable:

  1. Reduce pressure on your skin in your feet, buttocks, thighs and legs. Get comfortable, and rest. Wear loose, comfortable clothing. Your skin is more prone to forming new lesions right now, and any pressure or abrasion to the skin can encourage new lesions to form. So, kick your shoes off , prop your feet up and take it easy.
  2. I found that taking Advil really helped reduce inflammation quite a lot. But at the same time, the process that was causing the lesions did not stop until my vascultis was treated well enough to force it to remit.
  3. For years, some doctors have advised taking an antihistamine ,particularly in the evening as a treatment for Palpable Purpura. The fact is that there is no medical basis for doing so, and there is no medical evidence that it ever worked for anyone. I know that it never worked for me….
  4. Watch out for signs of infection. If you are on immunosuppression therapy, the last thing you want to have happen is to pick up an opportunistic infection. Keep the lesions clean and dry, and take a good look at them daily to be sure they are healing. If you see signs of infection, see your doctor right away.