What is Cryoglobulinemic Vasculitis?
Cryoglobulinemic vasculitis, often referred to as CryoVas, involves inflammation of small and medium-sized blood vessels. This inflammation is caused by an immune response that activates components of the immune system known as complement.[1] The concept dates back to 1933, when scientists Wintrobe and Buell found a substance called “cryoprecipitate” in a patient’s blood who was battling multiple myeloma. In 1947, Lerner and Watson introduced the term “cryoglobulin”. This term is used for immune proteins that form clumps when the temperature dips below 37 C in both plasma and serum, a component of blood. But, they dissolve again when the temperature is increased.[2] CryoVas is often linked to Hepatitis C (Hep-C) and some blood disorders connected to B-cells.
What Causes Cryoglobulinemic Vasculitis?
Cryoglobulins, proteins found in the blood, can be detected in individuals dealing with various inflammation conditions. However, they don’t necessarily result in disease. The exact process of how these proteins precipitate, or become solid, in cold temperatures is complex and scientists haven’t fully worked it out yet. Often, this process is linked to the features of certain immune system components, called Immunoglobulins.
The condition known as cryoglobulinemic vasculitis, an inflammation of blood vessels, is rare and usually occurs as a consequence of other diseases. There are three main types of cryoglobulins, categorized based on the type of Immunoglobulins they consist of:
– Type 1 includes single type Immunoglobulins, mainly IgM, or less commonly IgG, IgA, or light chains. These are rare and are often found in certain blood disorders or diseases affecting the body’s immune cells.
– Type 2 contains single type IgM with an ability to bind to another Immunoglobulin (IgG), referred to as rheumatoid factor (RF) activity, along with multiple type IgG.
– Type 3 cryoglobulins involve multiple types of IgM with RF activity and multiple types of IgG.
There’s also a newly identified mixed type known as type II to III, which has a mixture of a few types of IgM and multiple types of IgG.
Types 2 and 3, known as mixed cryoglobulins, are usually found alongside infections, autoimmune diseases, and conditions involving an overgrowth of immune cells. Hepatitis C is the most common infection associated with them. Other related conditions can include other viral infections, certain autoimmune conditions including lupus and Sjogren syndrome, as well as blood cell disorders.
The presence of cryoglobulins suggests an overlap of diseases which can result in severe symptoms, such as non-healing ulcers coupled with tissue death.
Risk Factors and Frequency for Cryoglobulinemic Vasculitis
Cryoglobulinemic vasculitis is a rare disease, affecting about 1 in every 100,000 people and the rates can vary depending on the region. It’s most commonly seen in people aged 45 to 65 and it’s more frequently found in women, with a ratio of about 2-3 women for every man. The disease is more prevalent in southern Europe, which could be due to a high occurrence of hepatitis C in these areas. It’s worth noting that while 20-50% of patients with Hepatitis C may have cryoglobulins in their blood, only up to a third of these patients actually develop clinical symptoms of cryoglobulinemic syndrome.
Signs and Symptoms of Cryoglobulinemic Vasculitis
Cryoglobulinemic vasculitis is a condition that needs to be identified promptly because it can potentially be life-threatening and could result in the loss of limbs.
Type 1 Cryoglobulinemia usually shows up as skin symptoms such as Raynaud’s phenomenon, sores, gangrene, and in rare cases, may affect the kidneys.
In contrast, mixed cryoglobulinemia often impacts the skin, musculoskeletal system, and kidneys. There are reports of people experiencing joint pain, purple spots or patches on the skin (purpura), and weakness.
Some potential indicators of this condition include:
- Skin lesions like palpable purpura in depending parts, sores on fingers, gangrene
- Joint pain in hands and knees, without signs of arthritis
- Neurological symptoms such as numbness, tingling, or weakness in the hands and legs
- Kidney problems, which might suggest a worse prognosis, marked by blood in urine, protein in urine, deteriorating kidney function
However, there are some less common indications:
- CNS vasculitis, which can lead to paralysis on one side of the body, coma, brain disease, or seizures
- Gastrointestinal disorders like inflammation of the intestines or duodenum, or pancreatitis, which cause abdominal pain
- Bleeding in the lungs, indicated by coughing up blood, difficulty breathing, or respiratory failure as the initial signals
- Hypertrophic cardiomyopathy, exhibited by shortness of breath during exercise
- Inflammation of the heart’s outer lining, coronary vasculitis, and heart failure
- A condition where the blood becomes thick, known as hyperviscosity syndrome
- Dry eyes and dry mouth
- Swelling of the salivary gland, typically seen on both sides
Testing for Cryoglobulinemic Vasculitis
If you’re suspected to have a condition called cryoglobulinemic vasculitis, your doctor will run a few specific tests. They’ll start with a complete blood workup, check your kidney function, and also take a sample of your urine for testing. This will include measuring the protein levels in your urine, either via a simple ‘ratio’ method or by collecting your urine for a full 24 hours. The doctor may also recommend that you undergo specific tests that look for markers of inflammation in your body, such as erythrocyte sedimentation rate and C-reactive protein.
Detecting cryoglobulins (abnormal proteins) in the blood can be a bit tricky, and sometimes the test results can be misleading. If they test you for cryoglobulins, your blood will be taken and put into preheated tubes. The blood is then left to clot on its own, and afterwards it is centrifuged and kept in a cold environment for a week. If there’s a white precipitate at the bottom of the tube, that means you have cryoglobulins in your blood. However, it’s crucial to get this test done multiple times to increase reliability, because false-positive and false-negative results can often occur.
Your doctor might also ask for a couple more tests. These include tests to check the rheumatoid factor (another type of protein) in your blood and complement levels, as well as a series of autoantibody tests. These autoantibody tests can reveal if you have any underlying autoimmune diseases like systemic lupus erythematosus or Sjögren syndrome.
In addition to autoimmune diseases, viral infections like hepatitis can also be linked to cryoglobulinemic vasculitis. This is why your doctor will likely want you to undergo testing for hepatitis B and C. Depending on your personal situation, they might also want to rule out other infections.
Some types of cancers, like leukemia, lymphoma, and multiple myeloma, might be linked to cryoglobulinemic vasculitis. Therefore, your doctor might want to check your blood count, take a look at a sample of your blood under a microscope, and run some more specialized tests. If necessary, they might biopsy your bone marrow or a lymph node as well.
If your doctor is unsure or they think your skin or kidneys might be involved, they might take a biopsy from these areas. The skin biopsy, in particular, can help to identify immune complexes – evidence of a fight between your immune system and potential invaders.
Treatment Options for Cryoglobulinemic Vasculitis
Cryoglobulinemic vasculitis is a condition that requires combined expertise from various medical specialists like liver experts, rheumatologists, and blood specialists depending on the severity of the illness. The treatment is influenced by factors like the underlying cause, the disease’s severity, and the organ involved. The primary goal of this treatment is to limit B-cell growth, get rid of the hepatitis C viral infection (if it exists), and curtail damage caused by circulating immune complexes.
Immunosuppressive Therapy
For patients with severe symptoms like blood vessel inflammation in the small intestine, lung hemorrhage or rapidly progressing kidneys inflammation, a preliminary treatment procedure involves steroids and plasmapheresis (a blood purification procedure). This group of patients may also receive medications like rituximab or cyclophosphamide to reduce symptoms’ recurrence. Patients with hepatitis C usually don’t receive the antiviral therapy as the first line of treatment for severe cases as their immune response can function independently of the virus.
Patients experiencing milder symptoms like skin rash, kidney inflammation, or peripheral neuropathy benefit from corticosteroids and rituximab usually seeing improvement within six months. However, it’s important to note that these patients may need to take rituximab repeatedly to maintain their recovery.
Patients who have other autoimmune conditions like lupus or Sjogren syndrome often respond well to treatments with steroids. Some patients may also take immune-suppressing drugs, like cyclophosphamide for more severe symptoms or methotrexate for milder effects. Mycophenolate mofetil can be used in situations where other treatments have failed.
Antiviral Therapy:
In cases where cryoglobulinemic vasculitis is paired with Hepatitis C, a balance of immune-suppressing treatments (similar to those described above) with antiviral therapy (for the hepatitis C virus) can be effective. To this end, antiviral treatments using ribavirin with direct-acting agents such as sofosbuvir have shown to be successful.
Combining rituximab with the antiviral treatment has resulted in better clinical outcomes compared to antiviral therapy alone in some studies. However, it is essential to note that despite viral clearance, exceedingly rare cases exhibit persistent cryoglobulins (protein complexes in the blood that thicken in cold temperatures) and related symptoms. This condition is due to B cell stimulation, highlights the importance of long-term follow-up.
Other Therapeutic Considerations
Vasculitis stemmed from B-cell disorders can be treated with chemotherapy and possibly require immunosuppression. Medications cyclophosphamide, dexamethasone, and thalidomide can alleviate skin symptoms. Bortezomib is successful in treating vasculitis related to multiple myeloma, a cancer of plasma cells, and MGUS (monoclonal gammopathy of undetermined significance). For life-threatening complications of this vasculitis, plasmapheresis is undertaken.
For those who have cryoglobulinemic vasculitis and hepatitis B, starting antiviral treatment before or alongside immunosuppressive therapy is crucial, specifically when the latter involves rituximab. This prevents potential severe reactivation of hepatitis B.
Lastly, certain treatments are contraindicated for cryoglobulinemic vasculitis. These include treatment with IV immunoglobulin, as it can cause immune complex precipitation leading to multiple organ failure, and TNF-alpha inhibitors, as they can lead to early relapses and occasional worsening of neuropathy and skin ulcers.
What else can Cryoglobulinemic Vasculitis be?
Systemic lupus erythematosus, often referred to as lupus, is a disease that can cause a range of symptoms including skin rashes, anemia, joint pain, positive RF (rheumatoid factor – a protein found in blood), and problems with kidneys. Also, it’s not uncommon to see patients with existing lupus developing a type of inflammation of the blood vessels known as cryoglobulinemic vasculitis. To distinguish between lupus and cryoglobulinemic vasculitis, doctors look at two components found in the blood known as complements C3 and C4. Lupus is often linked to low levels of both these components, not just C4 in isolation. In addition, testing for cryoglobulins in the blood and conducting a tissue examination can help in making the distinction between the two conditions.
Rheumatoid arthritis, another complex disease, is usually marked by joint pain and a positive RF. Occasionally, it can also cause a specific type of inflammation of small blood vessels called leukocytoclastic vasculitis. However, unlike cryoglobulinemic vasculitis, patients with rheumatoid arthritis usually experience inflammatory arthritis and swelling of the joints’ lining, a condition known as synovitis. Additionally, the presence of certain antibodies called anti-CCP, which are specific to rheumatoid arthritis, help doctors differentiate between the two conditions. Further, kidney involvement is rare in rheumatoid arthritis and blood complements levels usually remain normal.
Systemic sclerosis, another autoimmune condition, often causes skin issues, such as sores on the tips of the finger and gangrene. Many symptoms typical of systemic sclerosis, including thickening of the skin on the digits (sclerodactyly), an abundance of calcium deposits in tissues (calcinosis), lung disease, and problems with the functioning of the digestive system, are usually not found in those with cryoglobulinemic vasculitis. The impact on the kidneys due to systemic sclerosis is quite rare and different from that caused by cryoglobulinemic vasculitis. A biopsy of the kidney can help in differentiating the two conditions.
Henoch-Schönlein purpura, a type of vasculitis, creates visible rashes on the legs. However, it can be distinguished from cryoglobulinemic vasculitis by examining skin biopsy under a specific light called immunofluorescence. In Henoch-Schönlein purpura, this examination typically shows the deposition of a specific type of antibody called IgA, not the immune complexes usually seen in cryoglobulinemic vasculitis.
What to expect with Cryoglobulinemic Vasculitis
People with cryoglobulinemic vasculitis, a type of inflammation of the blood vessels, have a higher death rate compared to the general public. Most commonly, deaths are caused by kidney complications or widespread blood vessel inflammation, particularly when it affects the digestive system.
Using antiviral medicines can improve outcomes, but there are certain factors that can indicate a worse prognosis.
If this condition is associated with a Hepatitis C virus infection, poor outcomes may be associated with severe liver scarring present at diagnosis. If there is no liver scarring, a medical scoring system called five-factor score (FFS) can help predict outcomes. This system takes into account protein in urine, high serum creatinine (a waste product that indicates how well the kidneys are functioning), heart muscle disease, and involvement of the digestive and central nervous systems.
Having digestive system blood vessel inflammation can also imply a poor outcome.
In cases of mixed cryoglobulinemic vasculitis not caused by infection, the CryoVas score is used. This considers a person’s age over 65, lung and digestive system complications, and kidney failure.
In a type 1 cryoglobulinemia (a disorder in which abnormal proteins in the blood clot or “gel” in cold conditions), old age and kidney complications pose a poor prognosis. Additionally, signs of nerve damage at the start of the disease was also considered a poor indicator in one study.
Possible Complications When Diagnosed with Cryoglobulinemic Vasculitis
B-cell lymphomas, a type of cancer, are often seen in patients with a disease called mixed cryoglobulinemic vasculitis. The treatment for this condition usually aims to tackle the lymphoma.
People with Hepatitis C (Hep-C) who also have mixed cryoglobulinemic vasculitis are at a higher risk for death. However, in cases of other infections, how the disease progresses depends on the infection itself.
The most common causes of death in these cases include liver disease related to Hep-C and severe infections due to the use of medicines that weaken the immune system.
If many organs are involved in the disease, it’s usually a bad sign and it can indicate that the condition isn’t going to improve.
Preventing Cryoglobulinemic Vasculitis
Cryoglobulinemic vasculitis is a condition that can lead to severe symptoms, such as persistent pain due to nerve damage, and serious complications, like gangrene that necessitates amputations. Moreover, this condition has been linked with higher mortality rates and often relapses, or returns, throughout its progression. As a result, it’s crucial to start the right treatment as early as possible and continue with long-term follow-ups.
