Occurs in 10 to 15% of patients with hepatitis C and has a spectrum of disease ranging from mild to life-threatening.
B-lymphocytes stimulation place a critical role in survival of B cells and it’s over expression in hepatitis C possibly contributes to the progression of lymphoproliferative change is seen in cryoglobulinemia related to hepatitis C.
Chronic stimulation of the viral antigen plays essential role in HCV related lymphoproliferation.
Cryoglobulinemia vasculitis is the most significant risk factor for B cell cancer in patients with chronic HCV infection conferring that a risk that is 35 times as high as patients in the general population.
HCV, induces biased immunoglobulin somatic hypermutation, resulting in hypergammaglobulin anemia, with production of cryoglobulinemia in a polyclonal manner.
If this viral stimulation persists and autonomous lymph disease with IgM molecules with rheumatoid factor activity are able to form immune complexes with IgG and complement, leading to tissue inflammation and injury.
The large majority of patients with mixed cryoglobulinemic vasculitis are HCV positive.
Among patients with HCV related mixed cryoglobulinemia, 25 to 30% of patients remain asymptomatic, 40 to 45% have predominantly mild cutaneous manifestations and 20 to 30% present with significant organ damage, 7 to 12% progress to B cell eoplasms, and 2 to 5% will have rapidly progressive and life-threatening vasculitis.
Patients with with type III cryoglobulinemia usually have milder clinical manifestations than those with type two disease.
With the introduction of direct acting antiviral agents, a sustained virologic response is expected in more than 95% of the patients and has dramatically improved the prognosis of HCV related mixed cryoglobulinemia.
In a large perspective, study of patients with HCV related cryoglobulinemia vasculitis only 2.8% died after a median follow up of 15.3 months.
With the declining global prevalence of HCV infection, the overall incidence of mixed cryoglobulinemia has decreased with a younger median age and a higher proportion of female patients being more prevalent.
As a result, autoimmune diseases, such as Sjogren syndrome and SLE accounted for more than 50% of cases and have emerged as the leading causes of mixed cryoglobulinemia.
In a study of patients with type I cryoglobulinemia an estimated survival without clinical relapse, treatment complications, or death was 26% at five years.
Treatment approaches have involved different combinations of agents, including cortical, steroids, conventional immuno suppressant, plasma, exchange, all of which yielded inconsistent outcomes, and poor prognosis.
Treatment includes eradication of viral triggers in cases with infectious causes.
With mild to moderate disease, direct acting antiviral therapy alone is usually sufficient to achieve a viroialogic response and remission of vasculitis.
With severe forms of disease-glomerulonephritis, motor deficits, multiple mononeuropathy, extensive skin necrosis, digestive, cardiac, pulmonary involvement, direct acting antiviral therapy should be combined with rituximab.
For life-threatening manifestations, plasma exchanges and glucocorticoid pulses can be added.
In patients who to not respond to direct acting antiviral agents, or have contraindications to the above agents, rituximab could be used alone as induction treatment.
Alpha interferon yields a clinical, biochemical and virologic response in 40 to 60% of cases , however relapse within six months after completion of therapy is usual.
The addition of low to intermediate dose steroids mitigates vasculitic flares and provides symptomatic relief, however long term use of glucocorticoids should be avoided because of questionable effectiveness and long-term side effects.
High, pulsed doses of glucocorticoids may help manage severe vasculitic findings, including renal and neurologic involvement, and may prevent permanent organ damage.
Type I cryoglobulinemia is characterized as a hemostatic disorder, accompanied by multiple thromboses of small and median sized vessels, and sometimes by signs of vascular inflammation.
Type I cryoglobulinemia typically arises from a single clone within pathologic blood cells, which can be indolent, smoldering, or malignant.
Conditions associated with monoclonal gammopathy and cryoglobulinemia include Waldenstrom’s disease 27%, non-Hodgkin’s lymphoma in 20%, multiple myeloma and 15% and chronic lymphocytic leukemia in 7%.
Types II and III mixed cryoglobulinemias are considered inflammatory small vessel vasculitis caused by complement mediated immune complex deposition.
Time I cryoglobulinemia involves IgG and IgM, whereas mixed cryoglobulinemia anemia comes mainly from HCV related vasculitis.
Skin involvement is present in most cases of mixed cryoglobulinemia and manifests primarily as vascular purpura that is sometimes necrotic.
In type I cryoglobulinemia, skin manifestations depend on ambient temperatures and cutaneous necrosis is much more marked than with mixed cryoglobulinemia.
Joint and muscle involvement is seen with most patients with mixed cryoglobulinemia with bilateral symmetric, non-destructive anrthralgia affecting large joints: frequently misdiagnosed as rheumatoid arthritis.
With type I arthralgias less frequently.
The most common neurologic impairment in mixed cryoglobulinemia is sensory-motor polyneuropathy.
Hyperviscosity symptoms can occur when the mono immunoglobin is present in large amounts and this typical type of type I cryoglobulinemia.
Approximately 1/3 of patients with mixed cryoglobulinemia have renal involvement, typically with membranoproliferative glomerulonephritis.
Treatment of mixed cryoglobulinemia involves the direct acting antiviral agents against HCV with or without rituximab and much less frequently involves the use of steroids.
For type I cryoglobulinemia treatment regimens may include steroids, plasma exchange, and immunosuppressants.
Plasmapheresis is a therapeutic option in the context of IgM disease as 80% of IgM antibodies remain in the circulation.
In cases associated with HCV, eradication of the virus is imperative:it reduces the activity of cryoglobulinemia vasculitis and restores the balance between a typical memory B cells and pathogenic T lymphocytes and decreases regulatory T cells to prevent lymphoproliferation.