Recognise immune-complex vasculitis caused by circulating cryoglobulins, preserve specimen integrity, identify hepatitis, autoimmune and clonal drivers, and match antiviral, B-cell and plasma-exchange treatment to organ severity.
Begin by deciding whether the syndrome is inflammatory, occlusive or both. Mixed cryoglobulinaemic vasculitis typically produces dependent palpable purpura, arthralgia, fatigue and sensory symptoms, then may involve glomeruli, peripheral nerves, skin ulcers or the gastrointestinal tract. Type I disease more often causes Raynaud symptoms, livedo, retiform purpura, painful acral ulcers, infarction and hyperviscosity. Ask about cold sensitivity, episodic colour change, hepatitis exposure or treatment, sicca symptoms, lupus features, weight loss, night sweats, adenopathy and previous monoclonal protein.
Cryoglobulin testing is unusually dependent on sample handling. The collection tube, transport and clotting phase must remain at approximately 37 degrees Celsius until serum has been separated; the laboratory then cools serum under controlled conditions and confirms reversibility on warming. Request cryocrit or concentration and immunotyping when available, but interpret them with the clinical picture. Concentration does not reliably grade tissue injury, and a correctly repeated negative test does not exclude another immune-complex vasculitis.
Chronic hepatitis C stimulates B-cell clones that produce rheumatoid-factor-active IgM bound to polyclonal IgG, creating type II or III circulating immune complexes.
Sjogren disease, systemic lupus erythematosus and other connective-tissue disorders can sustain mixed cryoglobulin production even when hepatitis testing is negative.
Type I cryoglobulin is usually a monoclonal immunoglobulin associated with plasma-cell or B-cell neoplasia and causes occlusion or hyperviscosity more than classic inflammation.
Hepatitis B, HIV, endocarditis and other chronic infections can generate cryoproteins; a minority remain essential after a structured infectious, autoimmune and haematological search.
Cryoglobulins precipitate below core temperature and redissolve on warming, so acral vessels are vulnerable and laboratory tubes must remain warm until serum separation.
Mixed cryoglobulins deposit in post-capillary venules and glomeruli, activate classical complement and recruit neutrophils, commonly producing a disproportionately low C4 concentration.
Type I proteins increase viscosity, aggregate and obstruct small vessels, causing livedo, Raynaud symptoms, ulceration, infarction, neurological disturbance and retinal or mucosal hyperviscosity signs.
Subendothelial immune-complex deposition drives endocapillary proliferation and a membranoproliferative pattern, presenting with haematuria, proteinuria, hypertension and variable loss of filtration.
Viral eradication removes a major stimulus but an established B-cell clone or deposited immune complexes can sustain vasculitis, nephritis or relapse after HCV RNA becomes undetectable.
Dependent palpable purpura with arthralgia, fatigue, low C4, rheumatoid-factor activity, neuropathy or nephritic urine strongly suggests type II or III immune-complex disease.
Raynaud symptoms, livedo, retiform purpura, ulcers, gangrene or hyperviscosity with a monoclonal immunoglobulin points toward a plasma-cell or B-cell clone.
Haematuria, proteinuria, hypertension, oedema and falling eGFR with complement consumption suggests an immune-complex membranoproliferative renal process.
Painful asymmetric sensory loss followed by weakness, foot drop or hand deficit reflects infarction of vasa nervorum and needs rapid treatment before axonal loss becomes fixed.
Headache, confusion, visual blurring, retinal change, mucosal bleeding or cardiopulmonary compromise with a large cryoprotein burden requires urgent haematology and plasma-viscosity assessment.
Pulmonary-renal disease and mononeuritis multiplex overlap, but pauci-immune biopsy, compatible ANCA and absence of immune-complex complement consumption redirect treatment.
Purpura with nephritis may reflect IgA-dominant or lupus immune deposits; direct immunofluorescence, ANA, dsDNA and the clinical phenotype separate these entities.
Livedo, blue toes, eosinophilia and kidney injury after vascular instrumentation can mimic cryoglobulinaemia while pulses remain present and biopsy shows cholesterol clefts.
Endocarditis can cause purpura, low complement, rheumatoid factor and glomerulonephritis; blood cultures and cardiac assessment precede escalation of immunosuppression when infection is plausible.
Haemolysis from cold-reactive erythrocyte antibodies and viscosity from non-cryoprecipitating paraproteins require haematological testing rather than assuming every cold-associated symptom is vasculitis.
Recurrent or untreated membranoproliferative glomerulonephritis can leave persistent proteinuria, hypertension, declining filtration, dialysis dependence and cardiovascular risk.
Axonal infarction may leave foot drop, hand weakness, sensory loss, neuropathic pain and falls even after immune activity is controlled.
Ischaemic purpura can progress to painful ulceration, secondary bacterial infection, osteomyelitis, extensive tissue necrosis, limb-threatening gangrene and amputation.
The underlying B-cell clone may evolve or declare lymphoma, so persistent monoclonality, adenopathy, splenomegaly or cytopenias require longitudinal haematology review.
Rituximab, glucocorticoid and cytotoxic exposure can reactivate hepatitis B, lower immunoglobulins and cause opportunistic or severe bacterial infection.
A technically ordinary blood draw can become a false-negative assay if the specimen cools before serum separation.
Classical complement consumption supports mixed immune complexes but infection, lupus and other processes can produce the same pattern.
Type I disease is chiefly occlusive and clone-driven; mixed disease is chiefly inflammatory, although severe patients can show both mechanisms.
Sustained HCV response removes antigenic drive but does not immediately erase an autonomous clone, deposited complexes or existing organ damage.
Stopping vessel injury may first stabilise weakness; axonal regrowth is slow, so lack of rapid power recovery does not alone prove treatment failure.
Sending a cryoglobulin sample through routine cool transport and accepting the resulting negative test as definitive.
Treating a laboratory cryoglobulin concentration rather than establishing that it explains the patient's organ syndrome.
Giving immunosuppression before checking for HCV, hepatitis B, endocarditis and an underlying B-cell or plasma-cell clone.
Using direct-acting antiviral monotherapy for rapidly progressive glomerulonephritis or another immediately organ-threatening cryoglobulinaemic flare.
Assuming plasma exchange is definitive when ongoing viral or clonal production has not been treated.
Repeating rituximab for pain or weakness caused by fixed axonal or structural damage without evidence of active vasculitis.
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A 54-year-old with chronic hepatitis C has palpable purpura, neuropathic foot pain, low C4 and haematuria. A previous cryoglobulin assay was negative after routine transport. What is the best next diagnostic step?
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Treatment has two simultaneous targets: stop pathogenic immunoglobulin production or its trigger, and protect injured organs. HCV-associated stable renal disease receives a pangenotypic direct-acting antiviral selected by the hepatitis team for cirrhosis, renal function, previous treatment and interactions. Severe mixed disease commonly receives rituximab with glucocorticoid; life-threatening hyperviscosity, pulmonary haemorrhage, rapidly progressive nephritis or extensive ischaemia may require plasma exchange as an adjunct. Type I disease requires urgent clone-specific haematology therapy.
Response is organ-specific. Purpura and arthralgia can improve quickly, while axonal recovery and proteinuria lag. Record creatinine, urine protein, sediment, pressure, neurological function, ulcer dimensions, C4, cryoglobulin result and the underlying viral or clonal marker. Treat infection and cardiovascular or renal risk, provide neuropathic-pain and rehabilitation care, and investigate apparent relapse before repeating immunosuppression because damage, infection and recurrent cryoprotein activity can look similar.
Do not use in severe hepatic impairment or decompensated liver disease. Check every medicine for transporter and CYP interactions, especially statins, anticonvulsants, rifampicin and HIV drugs; screen HBV and verify duration for genotype, cirrhosis and prior treatment. Use is not recommended in pregnancy because data are limited; decide whether to discontinue breastfeeding or treatment by weighing benefits.
Cryoglobulinaemic vasculitis is not a UK licensed rituximab indication. Screen HBsAg and anti-HBc and institute prophylaxis or monitoring, exclude active infection, check immunoglobulins and vaccines, premedicate and monitor infusion reactions. A high cryoglobulin burden can flare after infusion. Avoid pregnancy unless benefit outweighs risk and use effective contraception during treatment and for 12 months afterwards.
Obtain cultures and treat infection, screen diabetes, pressure, bone and gastrointestinal risk and provide steroid-card and infection advice. Repeated or prolonged exposure requires adrenal-safe tapering and pregnancy decisions should balance maternal organ threat against fetal and metabolic risk.
This is an adjunct, not definitive treatment. Coordinate vascular access, calcium, fibrinogen, coagulation, infection and haemodynamic monitoring; time rituximab and other removable medicines after exchange where possible and use blood-component governance.