Cryoglobulinemia is usually classified into three subgroups according to Ig composition: type I cryoglobulinemia is composed of only one isotype or subclass of immunoglobulin. Both type II and type III mixed cryoglobulins are immune complexes composed of polyclonal IgGs, the autoantigens, and mono- or polyclonal IgMs, respectively; the IgMs are the corresponding autoantibodies with rheumatoid factor (RF) activity.
Classification and clinico-pathological characteristics of different cryoglobulinemias
| Cryoglobulins | Composition | Pathological findings | Clinical associations |
| Type I cryoglobulinemia | monoclonal Ig, mainly IgG, or IgM, or IgA self-aggregation through Fc fragment of Ig | tissue histological alterations of underlying disorder | -lymphoproliferative disorders: MM, WM, CLL, B-cell NHL |
| Type II mixed cryoglobulinemia |
monoclonal IgM (or IgG, or IgA) with RF activity (often cross-idiotype WA-mRF) and polyclonal Ig (mainly IgG) | -leukocytoclastic vasculitis -B-lymphocyte expansion with tissue infiltrates |
-infections (mainly HCV, HBV, HIV) -autoimmune/ lymphoproliferative disorders -rarely ‘essential’ |
| Type II–III mixed cryoglobulinemia |
oligoclonal IgM RF or mixture of poly/ monoclonal IgM (often cross-idiotype WA-mRF) |
-leukocytoclastic vasculitis -B-lymphocyte expansion with tissue infiltrates |
-infections (mainly HCV, HBV, HIV) -autoimmune/ lymphoproliferative disorders -rarely ‘essential’ |
| Type III mixed cryoglobulinemia |
polyclonal mixed Ig (all isotypes) with RF activity of one polyclonal component (usually IgM) | -leukocytoclastic vasculitis -B-lymphocyte expansion with tissue infiltrates |
-infections (mainly HCV) -more often autoimmune disorders -rarely ‘essential’ |
lymphoproliferative disorders: MM (multiple myeloma), WM (Waldenstrom’s macroglobulinemia), CLL (chronic lymphocytic leukemia), B-cell NHL (B-cell non-
Hodgkin’s lymphoma); Ig: immunoglobulin; RF: rheumatoid factor; HBV: hepatitis B virus; HCV: hepatitis C virus
Proposed criteria for the classification of mixed cryoglobulinemia (MC) patients
| Criteria | Major | Minor |
| Serological | Mixed cryoglobulins Low C4 |
Rheumatoid factor + HCV + HBV + |
| Pathological | Leucocytoclastic vasculitis | Clonal B cell infiltrates (liver and/or bone marrow) |
| Clinical | Purpura | Chronic hepatitis Membrano-proliferative glomerulonephritis Peripheral neuropathy Skin ulcers |
“Definite” mixed cryoglobulinaemia syndrome:
- Serum mixed cryoglobulins (±low C4) + purpura + leucocytoclastic vasculitis.
- Serum mixed cryoglobulins (±low C4) + 2 minor clinical symptoms + 2 minor serological/pathological findings.
“Incomplete” or “possible” mixed cryoglobulinaemia syndrome:
- Mixed cryoglobulins or low C4 + 1 minor clinical symptom + 1 minor serological ±pathological findings.
- Purpura and/or leucocytoclastic vasculitis + 1 minor clinical symptom + 1 minor serological ±pathological findings.
- Two minor clinical symptoms + 2 minor serological ± pathological findings.
“Essential” or “secondary” mixed cryoglobulinaemia:
Absence or presence of well known disorders (infectious, immunological, or neoplastic) at the time of the diagnosis.
References:
- Ferri C. Mixed cryoglobulinemia. Orphanet J Rare Dis. 2008 Sep 16;3:25. [Medlne]
- Terrier B, Cacoub P. Cryoglobulinemia vasculitis: an update. Curr Opin Rheumatol. 2013 Jan;25(1):10-8. [Medline]
Created Sep 12, 2013.
