Cryoglobulinemia: what is it, causes, symptoms, treatment, prognosis

general information

Cryoglobulinemia Is a form of systemic vasculitis, characterized by the presence of immunocomplexes in the blood that fall out at certain temperatures. These immunocomplexes are known as cryoglobulins.

The impact of cryoglobulinemic vasculitis is manifold and can manifest itself in several areas of the body: skin, nervous system, kidneys, heart, brain, gastrointestinal tract, joints.

The diagnosis must be accurate, and also aimed at identifying the causes of cryoglobulinemia. In fact, this is the only way to plan the most appropriate therapy, which is exclusively medication.

A quick reminder of what immunoglobulins are

Antibodies, or immunoglobulins, Are globular proteins that play a fundamental role in the immune system: they allow you to fight foreign microorganisms (called antigens [bacteria, viruses]) that infect the body.

Immunoglobulins are secreted by B-lymphocytes, which are immune cells, and act as their surface “antennas”. In the presence of an antigen, antibodies located on the membrane of B-lymphocytes are activated, signaling the B-lymphocyte itself to produce other specific immunoglobulins against the detected antigen. From this point on, the protective barrier erected by the immune system becomes more powerful and effective. In fact, the production of large amounts of antibodies circulating in the blood allows the immune system to track antigens and destroy them.

It is not antibodies (acting as simple markers or labels) that are responsible for the destruction of the antigen, but other elements of the immune system: phagocytes and cytotoxic cells.
There are 5 types of immunoglobulins: IgM, IgA, IgE, IgG, IgD.

What is cryoglobulinemia?

Cryoglobulinemia - systemic vasculitis, in which small blood vessels are predominantly involved, characterized by the presence in the blood cryoglobulins.

Cryoglobulins - protein aggregates consisting of antibodies and antigens (antigen and antibody combined together form immune complexes), possessing special properties of precipitation at low temperatures. It is this last feature that distinguishes cryoglobulinemic vasculitis from other forms of vasculitis, always caused by immune complexes.

The consequences of cryoglobulinemia are numerous and can occur at various levels of the body: epidermis, joints, nerves, kidneys, cardiovascular system, brain, and gastrointestinal tract.

- What is vasculitis?

Vasculitis - inflammation of the walls of blood vessels, both arterial and venous. This inflammatory condition can occur for unknown reasons (primary vasculitis), as a result autoimmune reactions, as a result of a pathogenic infection or, finally, as a result of another more dangerous disease (secondary vasculitis).

Affected populations

Cryoglobulinemia is widespread in southern Europe and usually affects people between the ages of 40 and 60. Particular preference is given to the female sex, as the ratio of women to men is 3: 1.

As will be shown in the chapter on causes, cryoglobulinemia is associated with hepatitis C virus: in fact, more than 90% of affected patients have previously been infected with this virus, but it is necessary clarify that cryoglobulinemia develops in only 3% of patients with hepatitis C virus during their life.

Causes and risk factors

The pathogenic mechanism causing cryoglobulinemia is the formation of abnormal immune complexes within the blood vessels; the subsequent deposition of these immunocomplexes on the walls of blood vessels causes an inflammatory response responsible for vasculitis.

But what are the reasons that set this mechanism in motion?

The reasons may vary; they range from viral infections to autoimmune diseases and blood cancers.

In detail, we are talking about ..:

• Viral infections:
  • hepatitis C.
• Autoimmune diseases:
  • rheumatoid arthritis;
  • Sjogren's syndrome;
  • systemic lupus erythematosus.
• Blood cancer:
  • some types of lymphomas;
  • Waldenstrom's macroglobulinemia;
  • multiple myeloma.

Types of cryoglobulinemia

According to the so-called Bruet classificationThere are three types of cryoglobulinemia; below is a table describing their common characteristics and causes.

A type	Percentage of cases	Description
Type I or simple cryoglobulinemia	10-15%	Cryoglobulins are composed of a single monoclonal immunoglobulin, usually IgM, often IgG or IgA, without rheumatoid factor (RF) activity. The main causes are usually multiple myelomas and Waldenstrom's macroglobulinemia.
Type II	50-60%	Cryoglobulins consist of several classes of immunoglobulins, one of which is monoclonal (usually IgM with rheumatoid factor - RF activity). The main risk factor is the hepatitis C virus.
Type III	25-30%	Cryoglobulins are composed of one or more differently associated classes of polyclonal immunoglobulins. The most common association is IgM-IgG, with IgM having rheumatoid factor activity against IgG. Possible triggers: Hepatitis C virus, rheumatoid arthritis, and systemic lupus erythematosus.

Cryoglobulinemias II and III types belong to the class mixed cryoglobulinemiabecause cryoglobulins are composed of different types of antibodies.

Symptoms and Signs

The symptoms of cryoglobulinemia are very diverse and depend on its causes. In general, most patients complain of sensation weakness and fatigue, on the muscle and joint pain (arthralgia or arthritis).

Signs of vasculitis on the skin usually include purple: it is usually characterized by purple round spots of various sizes, sometimes painful and itchy, but it is possible that the formation skin ulcers.

When nerves are damaged (infrequently, but possible) situations arise paresthesias (sensitivity disorders) and peripheral neuropathycharacterized by numbness, tingling in the hands, burning pain and weakness in the legs.

At the heart level, possible symptoms are: myocardial infarction (with chest pain, shortness of breath, heartburn etc.) and stagnant heart failure (with difficulty breathing and swelling of the lower limbs).

At the level of the brain, strokes, micro strokes and strong headaches.

Finally, mention should also be made of the possibility of a so-called secondary Raynaud's syndrome, abdominal pain variable intensity and some kidney disease, For example, membranoproliferative glomerulonephritis; the latter, in particular, are very dangerous, since they appear only at an advanced stage of the disease.

Specific symptoms of type I cryoglobulinemia acrocyanosis; retinal hemorrhage; Raynaud's phenomenon; arterial thrombosis (associated with heart disease, especially heart attack).

Specific Symptoms of Type II and III Cryoglobulinemia arthralgia (joint pain) and arthritis, especially in the knees and hips; membrane proliferative glomerulonephritis. purpura.

Cryoglobulinemia symptoms, from most common to least common:

• purpura and skin ulcers;
• joint diseases;
• kidney disease;
• Raynaud's syndrome;
• neurological disorders (paresthesia and peripheral neuropathy);
• abdominal pain;
• acrocyanosis;
• retinal hemorrhage;
• arterial thrombosis.

Complications

The occurrence of complications depends more on the pathologies causing the disease than on the disease itself. The situation is aggravated by the fact that blood cancer, autoimmune diseases or hepatitis C go into an advanced or chronic stage.

Diagnostics

The diagnosis of cryoglobulinemia is revealed when the patient has characteristic symptoms, the relationship of the syndrome with lymphoproliferative, infectious or systemic diseases, as well as in the determination of typical laboratory markers. The clinical criteria for cryoglobulinemia are the presence of 2 signs from the Meltzer triad, signs of kidney, liver or nervous system damage.

To confirm the diagnosis, the patient can be assigned immunological and biochemical blood tests, for identification of the type of immunoglobulins will require immunoelectrophoresis, as well as a general analysis and study of a biopsy skin and kidneys.

Treatment

The choice of the most appropriate therapy depends on the cause of the cryoglobulinemia.

Therefore, in addition to anti-inflammatory drugs (necessary to reduce inflammation), you can take specific antiviral drugsif the cause of the disease is viral hepatitis C, or immunosuppressive drugs if an autoimmune disease is observed.

Below are the drugs most commonly used for cryoglobulinemia, and a brief description of why they are taken.

• Antiviral therapy. As already mentioned, antiviral drugs are prescribed if viral hepatitis C is the basis of cryoglobulinemia. The drugs have proven to be effective against hepatitis viruses. Antiviral drugs are widely used by patients with cryoglobulinemia, since the hepatitis C virus is the cause of the disease in 90% of cases.
• Immunosuppressive therapy. Immunosuppressants reduce the inflammatory state of vasculitis by acting on the immune system, which is especially inadequate and causes serious harm to the body in autoimmune diseases, causing complications (arthritis, arthralgia, Raynaud's phenomenon, etc.). Cyclophosphamide, azathioprine, or methotrexate belong to this category of drugs. Immunosuppressive therapy puts the patient at an increased risk of infection.
• Corticosteroid therapy. Corticosteroids are powerful anti-inflammatory drugs taken to reduce the effects of vasculitis, kidney and neurological disorders, and purpura. These drugs can cause numerous side effects, which explains why they are prescribed at the lowest effective dose. For patients with cryoglobulinemia, the most commonly used corticosteroid is prednisone.
• Therapy based non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs, as the name suggests, reduce inflammation. Therefore, they represent an alternative to corticosteroids: compared to corticosteroids, NSAIDs, on the one hand, are less effective, and on the other hand, they have fewer side effects.
• Rituximab Therapy. Rituximab is a monoclonal antibody that reduces B lymphocytes, i.e. immune cells that secrete immunoglobulins.

The doctor also advises patients with cryoglobulinemia to avoid very cold conditions, at least until their condition improves.

Forecast

The prognosis, like the treatment, depends on the causes of cryoglobulinemia and how far the diseases that caused it have progressed. For example, if blood cancer or hepatitis C progresses, the prognosis will be less favorable, since all the most dangerous complications following them (kidney damage, heart attack, neuropathy, etc.) are difficult to respond to treatment.

Medication therapies also deserve special attention: some of them can cause various side effects, especially if used incorrectly. Therefore, it is necessary to carefully follow the doctor's recommendations regarding doses and any changes, and undergo periodic checks prepared to monitor the development of cryoglobulinemia.