Cryoglobulinemic vasculitis

Other Names: Familial mixed cryoglobulinemia; Mixed cryoglobulinemia; Essential cryoglobulinemia; Primary cryoglobulinemia; Essential mixed cryoglobulinemia; Meltzer syndrome

Cryoglobulinemic vasculitis occurs when the body makes a mix of abnormal immune system proteins called cryoglobulins. At temperatures less than 98.6 degrees Fahrenheit (normal body temperature), cryoglobulins become solid or gel-like and can block blood vessels. This causes a variety of health problems.

Epidemiology

The prevalence of cryoglobulinemic vasculitis is rare (1:100,000) with significant geographic variations. It is commonly seen in patients aged 45 to 65 years with a maximum incidence in women (sex ratio is 2-3:1). The disease is more common in southern Europe, which might be related to the endemic prevalence of hepatitis C. 20% to 50% of patients with hepatitis C can have serum cryoglobulins; however, only up to one-third of these develop clinical cryoglobulinemic syndrome.

Cause

The cause of cryoglobulinemic vasculitis is unknown. It occurs mainly in people with a chronic hepatitis C infection. Other viral, bacterial, and fungal infections have also been associated with cryoglobulinemic vasculitis.

Among infections, Hepatitis C is the most common. Other infections include Hepatitis B, Cytomegalovirus, Epstein B virus, Parvovirus B19, HIV, pyogenic bacterial infections, candidiasis, visceral leishmaniasis, and Coxiella burnetii.

Autoimmune conditions include systemic lupus erythematosus and Sjogren syndrome. Giuggioli et al. have found that 2.8% of systemic sclerosis (SSc) cases can have cryoglobulins, of which 1.6% can have manifestations, and they are linked to HCV. This overlap syndrome can cause severe vasculopathy symptoms like non-healing ulcers with gangrene.

Lymphoproliferative disorders like diffuse large B cell lymphoma and Non-Hodgkin lymphoma.

Signs and symptoms

The following list includes the most common signs and symptoms in people with cryoglobulinemic vasculitis. These features may be different from person to person. Some people may have more symptoms than others and symptoms can range from mild to severe. This list does not include every symptom or feature that has been described in this condition.

Signs and symptoms may include:

• Purple spots and patches on the skin (purpura)
• Nerve damage (peripheral neuropathy)
• Joint pain and swelling (arthralgia)
• Weakness
• Kidney problems
• Liver problems

Symptoms usually begin between ages 40 and 60. Although cryoglobulinemic vasculitis is a long-term disease, symptoms tend come and go. The severity of the symptoms can be difficult to predict, and may depend on underlying conditions. People who have organ involvement tend to have more severe disease.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Circulating immune complexes
• Cryoglobulinemia
• Cutis marmorata
• Fever
• Mediastinal lymphadenopathy(Swollen lymph nodes in center of chest)
• Muscle weakness(Muscular weakness)
• Petechiae
• Skin ulcer(Open skin sore)
• Vasculitis(Inflammation of blood vessel)

30%-79% of people have these symptoms

• Abdominal pain(Pain in stomach)
• Arthralgia(Joint pain)
• Arthritis(Joint inflammation)
• Gangrene(Death of body tissue due to lack of blood flow or infection)
• Gastrointestinal infarctions(Death of digestive organ tissue due to poor blood supply)
• Glomerulopathy
• Hematuria(Blood in urine)
• Hepatomegaly(Enlarged liver)
• Mononeuropathy(Single damaged nerve)
• Myalgia(Muscle ache)
• Proteinuria(High urine protein levels)
• Renal insufficiency(Renal failure)
• Sensorimotor neuropathy(Nerve damage causing decreased feeling and movement)
• Splenomegaly(Increased spleen size)
• Viral hepatitis

5%-29% of people have these symptoms

• Gastrointestinal hemorrhage(Gastrointestinal bleeding)
• Keratoconjunctivitis sicca(Dry eyes)

Diagnosis

Cryoglobulinemic vasculitis can be diagnosed based on a clinical history and exam, the symptoms, and testing to look for cryoglobulins in the blood.

Accurate detection of cryoglobulins can be difficult, and false-positive and false-negative values are not uncommon. The blood shall be drawn into preheated tubes at 37°C until coagulated followed by centrifugation after which, it should be stored at 4°C for 7 days. A white precipitate indicates the presence of cryoglobulins at the bottom of the tube, which dissolves when the tube is rewarmed to 37°C.

Quantification of cryoglobulins shall be determined by measuring the percentage of cryoglobulins. Cryoglobulins shall be then characterized by immunologic methods, including immunofixation and immunodiffusion, which help identify the type of immunoglobulin involved. As noted above, false-positive and false-negative test results are common and repeated testing increases accuracy.

Serologic Testing Rheumatoid factor testing shall be pursued in all patients with a suspicion of cryoglobulinemic vasculitis. Complement levels shall be tested as well and will usually indicate low serum C4 and normal C3. Serological workup including ANA, Anti-SSA, Anti-SSB, Anti-Ds-DNA, Anti-Smith, and other autoantibodies to detect underlying autoimmune diseases such as systemic lupus erythematosus or Sjogren syndrome shall be considered based on the patient's clinical presentation.

Infection Workup Viral hepatitis screening, including anti-hepatitis C viral antibody, hepatitis C viral RNA PCR, hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core antibody, shall be performed to detect underlying viral hepatitis. Workup for other potential infectious etiology can be considered on an individual basis.

Malignancy Workup Complete blood count with differential, peripheral smear, flow cytometry for evaluation of underlying leukemia or lymphoma should be considered. Serum protein electrophoresis and quantitative immunoglobulins shall be considered to rule out multiple myeloma or monoclonal gammopathy of unknown significance. Bone marrow or lymph node biopsy may be needed in some cases.

Pathological Workup Skin biopsy of cutaneous lesions can be done (and is recommended if initial presentation). Skin biopsy shall be sent for histopathology and for immunofluorescence to identify immune-complexes. In cases of suspicion of renal involvement, renal biopsy shall be considered.

Treatment

Treatment of cryoglobulinemic vasculitis can require combined inputs from different specialties like hepatologists, rheumatologists, and hematologists, depending on the underlying disease present and the severity of the illness. The treatment is dictated by the underlying associated etiology, disease severity, and organ involvement. Treatment should be aimed at suppressing B-cell proliferation, eradicating hepatitis C viral infection when present, and reducing circulating immune complex-mediated damage.

Immunosuppressive Therapy In patients with life-threatening or severe manifestations such as mesenteric vasculitis, pulmonary hemorrhage, and rapidly progressing glomerulonephritis, treatment with plasmapheresis and high dose corticosteroids is the first-line therapy. Immunosuppression with rituximab or cyclophosphamide in combination with plasmapheresis and high-dose corticosteroids reduces the risk of relapse.

Antiviral therapy: In patients with cryoglobulinemic vasculitis associated with hepatitis C infection who have milder manifestation, simultaneous treatment of immunosuppressive therapy, as documented above with antiviral therapy (for hepatitis C viral infection), has been shown to be effective and is the cornerstone of management.

Other Therapeutic Considerations Cryoglobulinemic vasculitis associated with B-cell dyscrasias and lymphoproliferative diseases can be treated with the disease-specific chemotherapy and occasionally requires immunosuppression. Cyclophosphamide, dexamethasone, and thalidomide can treat cutaneous symptoms (with no renal involvement). Bortezomib has been successfully used to treat cryoglobulinemic vasculitis related to multiple myeloma and MGUS.

In patients with cryoglobulinemic vasculitis and hepatitis B infection, treatment with rituximab alone without antiviral therapy can lead to severe reactivation of hepatitis B. It is recommended that antiviral therapy be started before or concomitantly with immunosuppressive therapy (especially rituximab) in these patients.

Other infections causing mixed CryoVas can be treated with specific antimicrobial therapy for sustained remission, immunosuppression is to be used only in refractory cases.

IV immunoglobulin treatment is contraindicated in CryoVas as it can cause immune complex precipitation leading to multi-organ failure.

TNF-alpha inhibitors are not to be used in CryoVas as they have shown to cause early relapses and occasional worsening of neuropathy and skin ulcers.

Prognosis

Mortality rates for cryoglobulinemic vasculitis are higher compared to the general population. Most deaths occur due to renal involvement or widespread vasculitis, especially gastrointestinal involvement. The use of antiviral treatment results in better outcomes; however, several poor prognostic factors have been documented.

NIH genetic and rare disease info

• NIH info on Cryoglobulinemic vasculitis

Cryoglobulinemic vasculitis is a rare disease.

Cryoglobulinemic vasculitis Resources
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