Cryoglobulinaemia — Viva

Q1: Definition and classification (2 minutes)

What is cryoglobulinaemia? State the Brouet classification and give the safest one-line contrast between Type I and mixed disease.^[1][7]

Model answer: Cryoglobulinaemia is the presence of circulating immunoglobulins that precipitate below 37°C and redissolve on warming. Type I contains one monoclonal immunoglobulin. Type II contains monoclonal IgM rheumatoid factor plus polyclonal IgG; Type III contains polyclonal IgM rheumatoid factor plus polyclonal IgG.^[1][2]

The safe contrast is: Type I is predominantly occlusive or hyperviscosity-producing; mixed Types II and III are predominantly immune-complex vasculitic. Purpura, renal injury or low complement can occur in Type I, so none is an absolute exclusion.^[7]

Q2: Clinical pattern and complications (2 minutes)

A patient has palpable purpura, arthralgia and weakness. What is this triad, and which organs must you screen?^[1]

Model answer: This is Meltzer's triad of mixed cryoglobulinaemia. Screen the skin for ulcers or necrosis, the peripheral nerves for sensory loss or mononeuritis multiplex, and the kidneys with blood pressure, renal function and urinalysis. Ask about severe abdominal, pulmonary or rapidly progressive systemic features because these change urgency.^[1]

Type I more often presents with Raynaud phenomenon, livedo, digital ischaemia, ulcers or hyperviscosity symptoms such as visual change, neurological disturbance and mucosal bleeding.^[1]

Q3: The laboratory station (2 minutes)

How do you confirm cryoglobulinaemia? Give the pre-analytical instruction exactly.^[3]

Model answer: Contact the laboratory before collection. Use a pre-warmed system and keep the whole-blood sample at 37°C through clotting, centrifugation and serum separation. Then cool the separated serum according to the laboratory's validated protocol and confirm that the precipitate redissolves on warming. Cooling before serum separation can lose cryoprecipitate and cause a false-negative result.^[3]

Immunofix the cryoprecipitate to assign the Brouet type. Add C3/C4, rheumatoid factor, serum protein electrophoresis/immunofixation/free light chains, HCV antibody with HCV RNA, HBV and HIV testing, an indication-led autoimmune screen, renal assessment and skin or renal biopsy when needed.^[1][2]

Q4: Management (3 minutes)

How do you manage HCV-associated mixed cryoglobulinaemia? When are rituximab and therapeutic plasma exchange appropriate?^[4][5][6]

Model answer: Treat active HCV with a current regional guideline-concordant direct-acting antiviral regimen. Sustained virological response is achieved in more than 95% of treated patients, but complete clinical response is not guaranteed and relapse or persistent B-cell clones can occur. Reassess active vasculitis after virological cure rather than assuming immune cure.^[4]

Rituximab is supported for active ulcers, neuropathy and glomerulonephritis, and for disease that persists or recurs after cause-directed treatment. Several intravenous regimens have been studied, so selection is specialist- and protocol-dependent rather than one universal dose.^[5]

Therapeutic plasma exchange is first-line for life-threatening mixed cryoglobulinaemia and for symptomatic Type I hyperviscosity. It may also be considered in severe mixed disease that fails or cannot receive other treatment. The definitive partner differs: treat the Type I clone, whereas mixed disease may require short-term inflammatory control and B-cell-directed treatment while the cause is treated.^[6]

Q5: Examiner challenge — HCV cured, symptoms persist (1 minute)

HCV RNA remains undetectable, but purpura and neuropathic pain recur. Is the cryoglobulinaemia cured?^[4]

Model answer: No. Virological, clinical and immunological responses can dissociate. Confirm active organ disease, repeat correctly handled cryoglobulin and complement testing, and assess for a persistent pathogenic B-cell clone or another cause. Treat the remaining disease by severity rather than repeating antivirals without evidence of recurrent HCV.^[4]

References7ShowHide

1. [1]Roccatello D, Saadoun D, Ramos-Casals M, et al. Cryoglobulinaemia Nat Rev Dis Primers, 2018.PMID 30072738
2. [2]Ferri C, Zignego AL, Pileri SA Cryoglobulins J Clin Pathol, 2002.PMID 11825916
3. [3]Sargur R, White P, Egner W Cryoglobulin evaluation: best practice? Ann Clin Biochem, 2010.PMID 20040797
4. [4]Danishwar M, Jamil Z, Khan S, et al. Persistence of Cryoglobulinemic Vasculitis after DAA Induced HCV Cure J Clin Med, 2022.PMID 35207257
5. [5]Quartuccio L, Bortoluzzi A, Scirè CA, et al. Management of mixed cryoglobulinemia with rituximab: evidence and consensus-based recommendations from the Italian Study Group of Cryoglobulinemia (GISC) Clin Rheumatol, 2023.PMID 36169798
6. [6]Galli M, Monti G, Marson P, et al. Recommendations for managing the manifestations of severe and life-threatening mixed cryoglobulinemia syndrome Autoimmun Rev, 2019.PMID 31181326
7. [7]Petersen T, Riviere S, Malbos S, et al. Subclasses of Monoclonal (Type I) Immunoglobulin G Cryoglobulins: Report on Two Distinct Cases with Myeloma Clin Lab, 2018.PMID 29739081