Cryoglobulinemia, Cryoglobulinemia Causes, Symptoms & Treatment

Cryoglobulinaemia

Overview

Cryoglobulinaemia refers to the presence of abnormal immunoglobulins in the blood that become insoluble at lower temperatures and dissolve again when warmed. These proteins can interfere with small-vessel blood flow and, in some patients, trigger an immune-complex-mediated vasculitis. The clinical presentation therefore ranges from an incidental laboratory finding to severe systemic disease affecting the skin, kidneys, nerves and other organs.

Causes

The underlying cause depends partly on the type of cryoglobulinaemia.

Type I cryoglobulinaemia is usually caused by a monoclonal immunoglobulin produced by an abnormal B-cell or plasma-cell population. Important associated conditions include:

• Multiple myeloma
• Waldenström macroglobulinaemia
• Other monoclonal gammopathies
• B-cell lymphoproliferative disorders

Mixed cryoglobulinaemia (Types II and III) is generally associated with immune-complex formation. Important causes and associations include:

• Hepatitis C virus infection, which is a major recognised cause
• Hepatitis B and HIV infection
• Systemic lupus erythematosus
• Rheumatoid arthritis
• Sjögren's syndrome
• Other autoimmune disorders
• B-cell lymphoproliferative diseases

In a patient with newly identified cryoglobulinaemia, investigation should therefore focus on identifying an underlying infection, autoimmune disorder or haematological malignancy. [1–3]

Clinical Manifestations

The clinical effects depend on the concentration and characteristics of the cryoglobulins, as well as the degree of vascular inflammation or obstruction.

Because cryoglobulins can precipitate in cooler peripheral tissues, patients may develop cold-sensitive vascular symptoms, including:

• Raynaud's phenomenon
• Acrocyanosis
• Livedo reticularis
• Digital ischaemia

Immune-complex deposition can produce a small-vessel vasculitis, particularly in mixed cryoglobulinaemia. Common manifestations include:

• Palpable purpura, particularly over the lower limbs
• Skin ulcers
• Arthralgia or arthritis
• Peripheral neuropathy
• Renal involvement, especially glomerulonephritis

Severe vascular involvement can result in tissue necrosis, digital gangrene or significant organ dysfunction.

A useful clinical combination to remember is purpura, arthralgia and weakness, although patients may present with only one or several of these features. [1–3]

Management

Treatment should be directed primarily at the underlying cause, while the severity and extent of organ involvement should guide the need for additional therapy.

Treatment of the underlying condition

For hepatitis C-associated cryoglobulinaemia, eradication of the viral infection with modern direct-acting antiviral therapy is central to management.

Where cryoglobulinaemia is related to a haematological malignancy or monoclonal gammopathy, treatment should target the underlying B-cell or plasma-cell disorder.

If an autoimmune disease is responsible, management should focus on controlling the underlying autoimmune process and any associated vasculitis. [2–4]

Immunosuppressive treatment

Patients with clinically significant or organ-threatening cryoglobulinaemic vasculitis may require immunosuppression.

Rituximab, often combined with corticosteroids, is an important treatment option for severe mixed cryoglobulinaemic vasculitis. The choice of treatment should be individualised according to the underlying disease, severity and organs involved. [3,4]

Plasma exchange

Plasma exchange is not required routinely for patients with uncomplicated cryoglobulinaemia.

It may be considered in selected patients with severe, rapidly progressive or life-threatening disease, particularly when there is significant tissue or organ injury. In such situations, plasma exchange is generally used as part of a broader treatment strategy rather than as definitive therapy on its own. [3,4]

Key Learning Points

• Cryoglobulinaemia is a syndrome, not a single disease.
• Type I disease is commonly associated with monoclonal haematological disorders.
• Mixed cryoglobulinaemia is strongly associated with hepatitis C and autoimmune disease.
• Think of purpura, Raynaud's phenomenon, arthralgia, neuropathy and renal disease as important clinical clues.
• Always investigate for an underlying infection, autoimmune disorder or haematological malignancy.
• Treatment should primarily address the underlying cause.
• Rituximab and corticosteroids may be required for significant cryoglobulinaemic vasculitis.
• Plasma exchange is reserved for selected severe or life-threatening presentations.

References

1. Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet. 2012;379(9813):348–360. doi:10.1016/S0140-6736(11)60242-0.
2. Ferri C. Mixed cryoglobulinemia. Orphanet Journal of Rare Diseases. 2008;3:25. doi:10.1186/1750-1172-3-25.
3. Cacoub P, Comarmond C, Domont F, Savey L, Saadoun D. Cryoglobulinemia vasculitis. American Journal of Medicine. 2015;128(9):950–955.
4. Terrier B, Karras A, Kahn JE, et al. The spectrum of type I cryoglobulinemia vasculitis: new insights based on the results of a multicenter study. Medicine (Baltimore). 2013;92(2):61–68.