Cryoglobulinemic Vasculitis Classification Calculator (2022 ACR/EULAR)

Entry Requirement

Required before applying these criteria These criteria apply only to patients with an established diagnosis of vasculitis. They classify the type of vasculitis, not whether vasculitis is present. The diagnosis of vasculitis must be based on clinical, laboratory, imaging, or histopathologic evidence.

Diagnosis of vasculitis confirmed

Clinical, laboratory, imaging, or pathologic evidence of vasculitis established

Vasculitis diagnosis required before scoring

Scored Criteria - Accumulate Points (Threshold ≥6)

Clinical features Select all features present at any time during the current vasculitis episode.

Purpura or petechiae +2

Past or current palpable or non-palpable purpura or petechiae, predominantly in dependent areas (lower extremities, abdomen)

Peripheral neuropathy +1

Past or current peripheral neuropathy (sensory, motor, or mixed); confirmed clinically or electrophysiologically

Cryoglobulins detected in serum +3

Cryoglobulins (monoclonal or polyclonal immunoglobulins) detected in serum on at least one occasion with proper cold-chain handling

Low complement C4 +1

Serum C4 below the lower limit of normal; hypocomplementemia is common in Type II and III cryoglobulinemia

Positive rheumatoid factor +1

RF positive (any titer); reflects the IgM kappa component in mixed cryoglobulinemia with RF activity

Hepatitis C virus infection +2

Active or past HCV infection (HCV antibody positive or HCV RNA detectable); HCV is the most common cause of mixed cryoglobulinemia

Glomerulonephritis +2

Renal involvement: hematuria (dysmorphic RBCs or RBC casts), proteinuria, or biopsy-proven glomerulonephritis (characteristically membranoproliferative pattern)

Cryoglobulin deposits on biopsy +3

Cryoglobulin or immunoglobulin deposits on kidney, skin, or nerve biopsy (by immunofluorescence or electron microscopy)

Classification Score

Total Score (threshold ≥6)

0615

Entry Required

Confirm vasculitis diagnosis before scoring.

Criteria Breakdown

Purpura or petechiae+2

Peripheral neuropathy+1

Cryoglobulins detected+3

Low complement C4+1

Positive rheumatoid factor+1

Hepatitis C virus infection+2

Glomerulonephritis+2

Cryo deposits on biopsy+3

2022 ACR/EULAR classification criteria are for research classification, not clinical diagnosis. Requires prior diagnosis of vasculitis. Not a substitute for specialist evaluation.

Frequently Asked Questions

Cryoglobulinemic vasculitis (CV) is small-vessel vasculitis caused by cryoglobulins - immunoglobulins that precipitate in the cold and redissolve on rewarming. The vasculitis results from immune complex deposition in vessel walls. The classic triad is purpura, weakness, and arthralgias (Meltzer's triad). Most cases are associated with hepatitis C virus (HCV) infection, which triggers mixed (Type II or III) cryoglobulinemia. Other causes include other infections (HBV, HIV), autoimmune diseases (Sjogren's, SLE), and lymphoproliferative disorders. Type I cryoglobulinemia (monoclonal, no RF activity) is typically associated with B-cell malignancies.

Cryoglobulins are classified by Brouet criteria into three types. Type I consists of monoclonal immunoglobulins (usually IgM or IgG) and is associated with lymphoproliferative disorders (Waldenstrom macroglobulinemia, multiple myeloma). Type II is mixed: monoclonal IgM (usually with rheumatoid factor activity) plus polyclonal IgG; the IgM forms immune complexes with IgG. Type III is polyclonal IgM plus polyclonal IgG. Types II and III are called "mixed cryoglobulinemia" and are strongly associated with HCV infection. The 2022 criteria apply to cryoglobulinemic vasculitis from any cryoglobulin type, though clinical features may differ by type.

Proper cold-chain handling is essential - cryoglobulins will precipitate during transport at room temperature and may be missed. Blood must be collected in a pre-warmed syringe and transported at 37 degrees Celsius to the laboratory. Serum is then incubated at 4 degrees Celsius for at least 7 days and inspected for a precipitate (cryocrit). False negatives are common with improper collection. Testing should include immunofixation and immunoglobulin quantification of the precipitate. A cryocrit above 1-2% is typically considered clinically significant, though lower levels may still cause vasculitis.

HCV infects B lymphocytes directly via the CD81 receptor, leading to polyclonal and eventually oligoclonal or monoclonal B-cell expansion. This stimulates production of mixed cryoglobulins - typically monoclonal IgM with rheumatoid factor activity combined with polyclonal IgG. Up to 50% of HCV-infected patients have detectable cryoglobulins, though only about 5-10% develop symptomatic vasculitis. Successful HCV eradication with direct-acting antivirals (DAAs) leads to cryoglobulin disappearance and vasculitis remission in most patients, making it the primary treatment strategy.

Low C4 (with typically normal C3) in mixed cryoglobulinemia results from activation of the classical complement pathway by the cryoglobulin immune complexes. IgM-IgG immune complexes efficiently activate C1q, leading to consumption of C4 and sometimes C3. The pattern of low C4 with normal or mildly low C3 is characteristic of classical pathway activation. This hypocomplementemia is a useful diagnostic marker, as C4 levels often parallel disease activity and can be used to monitor treatment response. C4 deficiency from other causes (hereditary C4 deficiency, SLE) is a differential to exclude.

The characteristic pattern is membranoproliferative glomerulonephritis (MPGN) with intraluminal hyaline thrombi containing cryoglobulin deposits. Light microscopy shows mesangial and endocapillary proliferation, with PAS-positive intracapillary deposits. Immunofluorescence shows granular deposits of IgM, IgG, and C3 in the mesangium and capillary walls. Electron microscopy reveals organized, microtubular, or fibrillar structures within the deposits - distinctive for cryoglobulin. The thrombi are composed of precipitated cryoglobulins. Glomerulonephritis in CV can progress to renal failure and is an indication for more aggressive immunosuppressive therapy.

In the 2022 ACR/EULAR validation study, the cryoglobulinemic vasculitis criteria (score ≥6) demonstrated sensitivity of 90.9% and specificity of 93.0% against other vasculitides. These criteria were developed alongside criteria for eight other vasculitis types as part of a coordinated ACR/EULAR classification project. The high weight given to cryoglobulin detection (+3) and cryoglobulin deposits on biopsy (+3) reflects their high diagnostic specificity.