Cryoglobulinaemia — SAQ

Stem

A 45-year-old man has recurrent palpable purpura on both lower legs, small-joint arthralgia, fatigue and a painful stocking sensory neuropathy. C4 is markedly low, C3 is near normal, rheumatoid factor is strongly positive, and urinalysis shows protein and blood. He previously injected drugs.^[1]

Questions

a) What is the most likely diagnosis, and which findings support it? (2 marks) ^[1]

b) State the Brouet classification. Contrast the usual mechanism of Type I with mixed Types II and III, including the important exception to the usual Type I pattern. (2 marks) ^[1][6]

c) How will you confirm and classify the cryoglobulin, assess organ involvement and find the cause? Include the exact pre-analytical instruction. (3 marks) ^[1][5]

d) Give a cause- and severity-directed management plan. State when rituximab and therapeutic plasma exchange are considered. (3 marks) ^[3][4]

Model answer

a) Diagnosis and supporting features (2 marks) ^[1]

This is mixed cryoglobulinaemic vasculitis, probably Type II and potentially HCV-associated. Palpable purpura, arthralgia and weakness form Meltzer's triad; neuropathy, a disproportionately low C4, positive rheumatoid factor and an active urinary abnormality support systemic mixed disease. HCV must be tested, but the risk history alone does not establish the cause.^[1]

b) Brouet classification and mechanism (2 marks) ^[1]

• Type I: one monoclonal immunoglobulin, commonly IgM or IgG; cryoprotein precipitation and protein burden predominantly cause vascular occlusion or hyperviscosity.
• Type II: monoclonal IgM with rheumatoid-factor activity plus polyclonal IgG; immune-complex vasculitis.
• Type III: polyclonal IgM with rheumatoid-factor activity plus polyclonal IgG; immune-complex vasculitis.^[1]

Type I is predominantly occlusive, but purpura, renal involvement and complement consumption can occur. Therefore palpable purpura does not absolutely exclude Type I disease.^[6]

c) Investigations (3 marks) ^[1][5]

1. Confirm correctly: contact the laboratory, use a pre-warmed collection system, and maintain whole blood at 37°C through clotting, centrifugation and serum separation. Cool only the separated serum according to the validated laboratory protocol and confirm that any precipitate redissolves on warming. Premature cooling can cause a false-negative result.^[5]
2. Classify: immunofix the cryoprecipitate; perform serum protein electrophoresis, serum immunofixation and free light chains to identify a monoclonal process. Check C3, C4 and rheumatoid factor.^[1]
3. Find the cause and stage organs: HCV antibody with HCV RNA, HBV serology with HBV DNA when indicated, HIV testing, an autoimmune screen guided by symptoms, full blood count, renal/liver function, quantified urine protein, neurological assessment and skin or renal biopsy when it will confirm active vasculitis or define the renal lesion.^[1]

d) Cause- and severity-directed management (3 marks) ^[3][4]

• Treat active HCV with a current guideline-concordant direct-acting antiviral regimen. Explain that virological cure is highly likely but clinical or immunological vasculitis may persist or relapse; reassess organ activity after sustained virological response.^[2]
• For severe but not immediately life-threatening mixed disease, obtain specialist input. Rituximab is supported for active ulcers, neuropathy and glomerulonephritis; the regimen is selected by severity and protocol rather than assumed to be one universal dose.^[3]
• For life-threatening mixed disease, therapeutic plasma exchange is a first-line rapid-removal treatment; high-dose pulsed glucocorticoids may be used for acute inflammatory control, and rituximab is considered when life-threatening mixed disease persists after plasma exchange. Plasma exchange is also urgent for symptomatic Type I hyperviscosity, but definitive treatment there is clone-directed haematological therapy, not an automatic mixed-vasculitis bundle.^[4]

References6ShowHide

1. [1]Roccatello D, Saadoun D, Ramos-Casals M, et al. Cryoglobulinaemia Nat Rev Dis Primers, 2018.PMID 30072738
2. [2]Danishwar M, Jamil Z, Khan S, et al. Persistence of Cryoglobulinemic Vasculitis after DAA Induced HCV Cure J Clin Med, 2022.PMID 35207257
3. [3]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
4. [4]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
5. [5]Sargur R, White P, Egner W Cryoglobulin evaluation: best practice? Ann Clin Biochem, 2010.PMID 20040797
6. [6]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