Cryoglobulinemic Vasculitis
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Cryoglobulinemic vasculitis is a form of
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
affecting the
blood vessel Blood vessels are the tubular structures of a circulatory system that transport blood throughout many Animal, animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the Tissue (biology), tissues of a Body (bi ...
s (
vasculitis Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both artery, arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily c ...
) caused by the deposition of abnormal
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s called cryoglobulins. These
immunoglobulin An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
proteins are
soluble In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubi ...
at normal body temperatures, but become insoluble below 37 °C (98.6 °F) and subsequently may aggregate within smaller blood vessels. Inflammation within these obstructed blood vessels is due to the deposition of
complement Complement may refer to: The arts * Complement (music), an interval that, when added to another, spans an octave ** Aggregate complementation, the separation of pitch-class collections into complementary sets * Complementary color, in the visu ...
proteins which activate inflammatory pathways. Cryoglobulinemic vasculitis most commonly affect the skin, causing a raised, pinpoint rash on the lower extremities known as
purpura Purpura () is a condition of red or purple discolored spots on the skin that do not blanch on applying pressure. The spots are caused by bleeding underneath the skin secondary to platelet disorders, vascular disorders, coagulation disorders, ...
. The
kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
s may additionally be affected by this form of vasculitis, resulting in membranoproliferative glomerulonephritis.
Fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...
s, painful
muscles Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...
and
joints A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw- ...
, and peripheral nerve damage are other common manifestations of cryoglobulinemic vasculitis.


Epidemiology

The incidence of cryoglobulinemic vasculitis is low and highly corresponds to the presence of
hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include ...
virus infection, with increased prevalence in Southern Europe. Only about 30% of individuals with cryoglobulinemia develop vasculitis and associated symptoms. In a review of 279 patients, the average age of patients with symptomatic disease associated with hepatitis C virus was 54 years old, with an equal distribution between men and women.


Pathophysiology

Cryoglobulinemia Cryoglobulinemia is a rare medical condition characterized by the presence of cryoglobulins in the blood. Cryoglobulins are abnormal proteins composed of immunoglobulins and sometimes complement components. Cryoglobulins specifically form g ...
is currently classified by the type of immunoglobulin, IgM or IgG, present in blood as well as whether the immunoglobulin is
monoclonal In biology, monoclonality refers to the state of a line of cells that have been derived from a single clonal origin. Thus, "monoclonal cells" can be said to form a single clone. The term ''monoclonal'' comes . The process of replication can occ ...
or
polyclonal Polyclonal B cell response is a natural mode of immune response exhibited by the adaptive immune system of mammals. It ensures that a single antigen is recognized and attacked through its overlapping parts, called epitopes, by multiple clones of ...
. Type II cryoglobulinemia, is defined as a mix of monoclonal IgM or polyclonal IgG, whereas type III cryoglobulinemia is classified as IgM and IgG that are both polyclonal only. The immunoglobulins in either cryoglobulinemia type have
rheumatoid factor Rheumatoid factor (RF) is the autoantibody that was first found in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG and different RFs can recognize different parts of the IgG-Fc. RF and IgG join to form immune co ...
activity, allowing binding of the Fc subunit of IgM to IgG which has the capacity to activate complement proteins and deposit in the endothelium of small and medium-sized blood vessels. In contrast, type I cryoglobulinemia causes damage solely due to
hyperviscosity syndrome Hyperviscosity syndrome is a group of symptoms triggered by an increase in the viscosity of the blood. Symptoms of high blood viscosity include spontaneous bleeding from mucous membranes, visual disturbances due to retinopathy, and neurologic symp ...
, which refers to the aggregation and resulting obstructing nature of cryoglobulins in blood vessels resulting in reduced perfusion of tissues and possibly necrosis if prolonged. Therefore, vasculitis generally occurs only in patients affected by mixed (type 2 and 3) cryoglobulinemia, as simple (type 1) cryoglobulinemia causes a hyperviscosity syndrome without complement activation. The large majority of cases of cryoglobulinemic vasculitis are associated with underlying medical conditions which contribute to or exacerbate the pathophysiology, the most common being hepatitis C virus infection. There are a number of other rheumatologic, oncologic, inflammatory, and infectious associations including Sjogren's syndrome, B-cell lymphoma, rheumatoid arthritis, systemic lupus erythematous, and other hepatitis viral infections. Type III cryoglobulinemia is most associated with autoimmune conditions.


Manifestations

At least 50% of patients with cryoglobulinemic vasculitis have only mild symptoms. More severe symptoms involve renal, gastrointestinal, and neurological damage with cardiovascular and respiratory complications presenting more rarely in a population of 279 patients with cryoglobulins and hepatitis C infection. Prevalence of these symptoms may vary depending on the underlying etiology contributing to the cryoglobulinemia. Only about 5–10% of patients with cryoglobulins found in the bloodstream due to Hepatitis C virus develop symptoms. Approximately 20-40% of individuals with symptomatic cryoglobulinemic vasculitis eventually develop renal damage, usually years following initial diagnosis. Relapse in vasculitis refers to the recurrence or reactivation of disease symptoms and inflammation after a period of improvement or remission.A systematic review was conducted to investigate the identifiable risk factors for relapse in non-infectious cryoglobulinemic vasculitis with an underlying immunopathological cause, specifically in relation to the type of immunoglobulin involved.


Diagnosis

The first step in quantitative assessment entails identification of the presence of cryoglobulins in the bloodstream, which can be a technically involved and inaccurate process with a high proportion of false-positives and false-negatives. Test tubes should be warmed to normal body temperature at 37 °C prior to collection of blood samples, which are centrifuged after the blood coagulates. This sample is then stored at reduced temperatures of 4 °C for a week. If present, cryoglobulins will form precipitate during this time and be visible as a white sedimented layer. If rewarmed from 4 °C to 37 °C, this precipitate will redissolve into the blood sample. Following centrifugation, the layer of cryoglobulins should be immunofixed and labeled to allow for classification of cryoglobulinemia type. Other nonspecific inflammatory markers are often elevated, including C-reactive protein and erythrocyte sedimentation rate, but are not required for diagnosis. Baseline laboratory markers, including metabolic panels, urinalysis, and urine protein, should be obtained to trend renal function through progression of the disease and monitor for glomerulonephritis. Complement levels and rheumatoid factor activity should additionally be assessed given the pathophysiology of cryoglobulinemia. Underlying inflammatory, infectious, and oncologic diseases should also be tested for as appropriate. Workup for viral RNA, autoantibodies, and malignant serological markers should be considered. Biopsy may be obtained to assess for immune complex deposition.


Treatment

The treatment of cryoglobulinemic vasculitis includes both immune modulator therapy and treatment of any underlying medical conditions.
Rituximab Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in children and ad ...
may also be used in conjunction with glucocorticoids to inhibit B-cell proliferation and therefore decrease cryoglobulin production, although risks include infection and anemia.


References

{{reflist Vascular-related cutaneous conditions