Animals, Cryo and So Much Unknown.

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.

Cryoglobulinemia: Labeled a disease in 1930’s.

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.

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.