Cryoglobulinemic Vasculitis and Rheumatology

Introduction:

Cryoglobulinemic vasculitis is a rare condition that causes blood vessel inflammation due to precipitation of cryoglobulins. This precipitation commonly occurs in small and medium-sized blood vessels throughout the body.

What Is Cryoglobulinemic Vasculitis?

The formation and accumulation of cryoglobulins within blood vessels in the body characterize cryoglobulinemic vasculitis. Cryoglobulins are a type of immunoglobulins that possess the capability to precipitate in cold temperatures. Upon rewarming, the precipitated immunoglobulins tend to dissolve.

There can be various factors that trigger the formation of cryoglobulins:

• Hepatitis C infection.

• Systemic lupus erythematosus.

• Rheumatoid arthritis.

• Sjogren syndrome.

• Lymphoma.

• Multiple myeloma.

• Hepatitis (chronic period).

• Chronic kidney disease.

• Inflammatory bowel disease.

• Genetic predisposition to form cryoglobulins.

• Exposure to extreme cold.

• High altitude.

What Is the Process of Cryoglobulin Formation?

When any of the above factors trigger the immune system, there is excessive production of antibodies against the triggering agent to neutralize them. When there is an abnormal immune response or surplus presence of antigens, the antibodies try to bind with the antigens to form immune complexes that contain foreign substances and immune proteins. When the body's temperature goes below (cooling temperature), such immune proteins can precipitate or become insoluble. These are called cryoglobulins.

Such cryoglobulins containing immune complexes have the potential to deposit in small and medium-sized blood vessels throughout the body. When they precipitate within the blood vessels, they can cause blockage or dysfunctional blood flow. Their mere presence within the blood vessels can trigger an inflammatory reaction, thus resulting in vasculitis. Ultimately, this can lead to tissue damage and death.

The exact mechanism underlying the precipitation of cryoglobulins at cold temperatures remains a complex one. It involves changes in the structure or conformation of antibodies and immune complexes, making them less soluble in colder environments.

Additionally, cryoglobulins can consist of different types of proteins, including immunoglobulins (antibodies), complement proteins, and other serum proteins. The composition of cryoglobulins can vary among individuals and may influence their clinical manifestations and severity of associated diseases.

What Are the Clinical Features of Cryoglobulinemic Vasculitis?

• Skin with purple spots.

• The mottled appearance of skin (livedo reticularis).

• Joint pain (especially in ankles and wrists).

• Urine with blood.

• Protein in the urine.

• Frequent urination.

• Numbness.

• Tingling sensation (specifically in peripheral areas of the body).

• Generalized weakness.

• Muscular atrophy with pain. This can lead to mononeuritis multiplex.

• Fever.

• Weight loss.

• Fatigue.

• Generalized malaise.

• Abdominal pain.

• Vomiting.

• Nauseous feeling.

• Diarrhea.

• Blood in feces (due to gastrointestinal bleeding).

• Inflammation in cardiac muscles.

• Improper heart rate.

• Irregular blood pressure.

• Breathlessness.

• Chest pain.

How to Diagnose Cryoglobulinemic Vasculitis?

• Clinical features of the patient will be well-evaluated to pinpoint the condition. Skin involvement and joint pain, along with renal and neurological manifestations, can help diagnose cryoglobulinemic vasculitis.

• The serum will be tested in the laboratory for the precipitation of cryoglobulins. The formation of cryoglobulins under cold incubation clearly indicates cryoglobulinemia.

• Patients with this condition also tend to have increased levels of rheumatoid factor (RF) and antinuclear antibodies (ANA). The presence of these factors indicates that there is an autoimmune response occurring within the body. This, combined with cryoglobulinemia, indicates an autoimmune condition.

• In cryoglobulinemic vasculitis, there is also a decrease in the levels of circulating complements like C3 and C4 due to consumption. Thus, decreased complement levels can act as an adjunct in diagnosing cryoglobulinemic vasculitis.

• Magnetic resonance imaging, ECHO, and electrocardiogram are performed to look for inflamed blood vessels. The main vessels involved will be the small and medium vessels.

• To find out the etiological agent behind the causation of cryoglobulinemic vasculitis, viral serological testing will be done. Given the strong association between hepatitis C virus (HCV) infection and cryoglobulinemic vasculitis, testing for HCV antibodies and the presence of viral RNA is recommended in all patients with suspected cryoglobulinemia. HCV infection should be ruled out or treated if present.

• To know the extent of damage caused to the renal system due to cryoglobulinemia, kidney function tests and urine analysis are performed. This will assess the levels of blood urea nitrogen, creatinine, and urea. It can also tell if there is presence of blood casts or protein in the urine. Imaging of the urinary system can explain the level of damage incurred to the kidney due to cryoglobulinemia.

• When any particular tissue of an organ is alone suspected to be affected by the condition, a tissue biopsy will be done. Biopsy of tissues like skin, kidney, or nerve will be performed to elicit the presence of inflamed cells (vasculitis), deposition of immune complexes, and any extensive damage to the tissue or organ.

How Is Cryoglobulinemic Vasculitis Managed?

• To manage cryoglobulinemic vasculitis, the underlying etiological agent should be treated. Direct-acting antiviral agents will be given to combat the viral (Hepatitis C) infection. Eradication of HCV can lead to resolution or improvement of cryoglobulinemic vasculitis in many patients.

• For patients with any kind of underlying autoimmune diseases (like systemic lupus erythematosus or rheumatoid arthritis), disease-modifying antirheumatic drugs (DMARDs) or immunosuppressive medications may be given. This is especially given to control autoimmune activity and reduce the production of cryoglobulins.

• To suppress the inflammatory process within the body, corticosteroids (usually Prednisolone) are prescribed. This will be followed by adjunctive use of non-steroidal anti-inflammatory drugs, if necessary. Immunosuppressants (Cyclophosphamide or Azathioprine) are also given to achieve the same objective.

• Plasma exchange may be considered in patients with severe cryoglobulinemic vasculitis, particularly for those individuals with rapidly progressive renal involvement or other life-threatening complications like neurological manifestations. The goal of plasma exchange is to remove circulating cryoglobulins and other inflammatory mediators from the bloodstream completely.

• Patients with skin lesions are provided with topical creams and are strictly advised not to expose themselves to cold temperatures.

• Specific kinds of medical or surgical interventions are highly essential to treat the complications arising due to cryoglobulinemic vasculitis. This involves renal replacement therapy for end-stage renal disease, immunosuppression for peripheral neuropathy, or anticoagulation for thrombotic events.

What Is the Role of Rheumatology in Cryoglobulinemic Vasculitis?

Rheumatologists are very important in comprehensively evaluating and managing all the conditions and complications caused by the precipitation of cryoglobulins. They are vital to treat all the underlying causes and manifestations of cryoglobulinemic vasculitis. Rheumatologists also collaborate with other specialists, such as nephrologists, dermatologists, and infectious disease experts, to develop adept treatment plans.

Conclusion:

With timely evaluation of clinical manifestations of cryoglobulinemic vasculitis and treatment of underlying causative agents, cryoglobulinemic vasculitis can be managed effectively. Research in this arena is still required to prevent the formation of cryoglobulins and treat the inflammatory and immune response. As a result of continued and coordinated efforts from rheumatologists and other healthcare professionals, individuals with cryoglobulinemic vasculitis can have a better life.