Cryoglobulinaemic vasculitis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

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.

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.

Key points

Cryoglobulinaemic vasculitis is a clinical syndrome, not simply a positive cryoglobulin test: look for palpable purpura, arthralgia, weakness, neuropathy, glomerulonephritis and acral ischaemia.
Type I disease is usually monoclonal and predominantly occlusive; mixed type II and III disease is immune-complex vasculitis associated with hepatitis C, autoimmunity or another chronic immune stimulus.
A false-negative cryoglobulin result is common when blood cools before clotting and serum separation; contact the laboratory before collection and keep the whole specimen at 37 degrees Celsius during pre-analytical handling.
Low C4, rheumatoid-factor activity and a compatible syndrome support mixed cryoglobulinaemia, but neither confirms the causal driver nor replaces skin, kidney or nerve tissue when organ-threatening disease needs classification.
Test every patient for HCV antibody with reflex HCV RNA, hepatitis B and HIV, and investigate autoimmune and B-cell or plasma-cell causes according to phenotype and immunofixation.
For HCV-associated glomerulonephritis with stable kidney function and no nephrotic syndrome, KDIGO supports direct-acting antiviral therapy before immunosuppression.
A cryoglobulinaemic flare, rapidly progressive glomerulonephritis or other major organ threat requires antiviral therapy plus specialist immunosuppression; plasma exchange is added selectively when rapid cryoprotein removal is needed.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Hepatitis C driven mixed disease

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.

Autoimmune immune-complex disease

Sjogren disease, systemic lupus erythematosus and other connective-tissue disorders can sustain mixed cryoglobulin production even when hepatitis testing is negative.

Monoclonal clonal disease

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.

Other infection and unexplained disease

Hepatitis B, HIV, endocarditis and other chronic infections can generate cryoproteins; a minority remain essential after a structured infectious, autoimmune and haematological search.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Cold-dependent precipitation
Cryoglobulins precipitate below core temperature and redissolve on warming, so acral vessels are vulnerable and laboratory tubes must remain warm until serum separation.
2
Immune-complex complement activation
Mixed cryoglobulins deposit in post-capillary venules and glomeruli, activate classical complement and recruit neutrophils, commonly producing a disproportionately low C4 concentration.
3
Clonal immunoglobulin occlusion
Type I proteins increase viscosity, aggregate and obstruct small vessels, causing livedo, Raynaud symptoms, ulceration, infarction, neurological disturbance and retinal or mucosal hyperviscosity signs.
4
Membranoproliferative renal injury
Subendothelial immune-complex deposition drives endocapillary proliferation and a membranoproliferative pattern, presenting with haematuria, proteinuria, hypertension and variable loss of filtration.
5
Persistent B-cell autonomy
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.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Mixed vasculitic pattern

Dependent palpable purpura with arthralgia, fatigue, low C4, rheumatoid-factor activity, neuropathy or nephritic urine strongly suggests type II or III immune-complex disease.

Type I occlusive pattern

Raynaud symptoms, livedo, retiform purpura, ulcers, gangrene or hyperviscosity with a monoclonal immunoglobulin points toward a plasma-cell or B-cell clone.

Cryoglobulinaemic glomerulonephritisRed flag

Haematuria, proteinuria, hypertension, oedema and falling eGFR with complement consumption suggests an immune-complex membranoproliferative renal process.

Ischaemic neuropathyRed flag

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.

Hyperviscosity emergencyRed flag

Headache, confusion, visual blurring, retinal change, mucosal bleeding or cardiopulmonary compromise with a large cryoprotein burden requires urgent haematology and plasma-viscosity assessment.

Red flags requiring action

Haemoptysis, falling haemoglobin, hypoxaemia or new bilateral alveolar shadowing suggests diffuse alveolar haemorrhage and requires immediate respiratory and vasculitis care.
Haematuria, proteinuria, oliguria, oedema, hypertension or a rapidly increasing creatinine indicates cryoglobulinaemic glomerulonephritis until a competing cause is established.
New foot drop, hand weakness, severe asymmetric neuropathic pain or rapidly extending sensory loss indicates ischaemic nerve injury and needs urgent specialist treatment.
Postprandial or severe abdominal pain, gastrointestinal bleeding, lactate elevation, digital infarction or skin necrosis suggests medium-vessel or severe small-vessel ischaemia.
Headache, visual change, mucosal bleeding, confusion or heart failure with a monoclonal protein may represent type I hyperviscosity and needs same-day haematology assessment.
Fever, rigors or an infected ulcer must trigger cultures and antimicrobial assessment because infection can drive immune complexes and can be worsened by glucocorticoid or rituximab.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Warm-handled cryoglobulin assay and immunotypingFirst step
Why
Demonstrate a reversible cryoprotein and classify monoclonal or mixed composition.
Interpretation and limitations
Pre-arrange collection; maintain the sample at 37 degrees Celsius until serum separation. Repeat a negative result when pre-analytical cooling or a compelling phenotype makes false negativity likely.
02
C3, C4, rheumatoid factor and quantitative immunoglobulins
Why
Support immune-complex activity and establish an immunological baseline.
Interpretation and limitations
Markedly low C4 with rheumatoid-factor activity is characteristic of mixed disease, while normal complement does not exclude type I occlusion or inactive disease.
03
HCV RNA, hepatitis B and HIV testing
Why
Identify treatable infection and make B-cell depletion safer.
Interpretation and limitations
HCV antibody alone cannot establish active infection; confirm RNA. Record HBsAg and anti-HBc before rituximab and arrange HBV prophylaxis or monitoring according to reactivation risk.
04
Electrophoresis, immunofixation and free light chains
Why
Detect and characterise an underlying plasma-cell or B-cell clone.
Interpretation and limitations
A monoclonal band, disproportionate light-chain ratio, cytopenia or organomegaly prompts haematology assessment, imaging and marrow or tissue sampling.
05
Renal profile, urine microscopy and protein quantification
Why
Detect glomerulonephritis and grade immediate renal threat.
Interpretation and limitations
Dysmorphic erythrocytes, casts, rising creatinine or increasing proteinuria require urgent nephrology review; quantify ACR or PCR rather than relying on dipstick alone.
06
Skin, kidney or nerve biopsy
Why
Confirm vessel injury, immune-deposit pattern and potentially reversible activity.
Interpretation and limitations
Leukocytoclastic vasculitis supports small-vessel injury; kidney immunofluorescence and electron microscopy define immune-complex GN, while vessel-wall inflammation with damage proves vasculitic neuropathy.
07
Blood cultures and cause-directed imaging
Why
Exclude infection and localise clonal or vascular complications before immunosuppression.
Interpretation and limitations
Obtain cultures before antibiotics when endocarditis is plausible; use echocardiography, marrow studies, CT or vascular imaging only when the phenotype supplies a focused question.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

ANCA-associated vasculitis

Pulmonary-renal disease and mononeuritis multiplex overlap, but pauci-immune biopsy, compatible ANCA and absence of immune-complex complement consumption redirect treatment.

IgA or lupus vasculitis

Purpura with nephritis may reflect IgA-dominant or lupus immune deposits; direct immunofluorescence, ANA, dsDNA and the clinical phenotype separate these entities.

Cholesterol embolisation

Livedo, blue toes, eosinophilia and kidney injury after vascular instrumentation can mimic cryoglobulinaemia while pulses remain present and biopsy shows cholesterol clefts.

Infection-related immune complexes

Endocarditis can cause purpura, low complement, rheumatoid factor and glomerulonephritis; blood cultures and cardiac assessment precede escalation of immunosuppression when infection is plausible.

Cold agglutinin and hyperviscosity syndromes

Haemolysis from cold-reactive erythrocyte antibodies and viscosity from non-cryoprecipitating paraproteins require haematological testing rather than assuming every cold-associated symptom is vasculitis.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01First diagnostic priorityPreserve the specimen and grade organsFirst stepPurpura, cold-related ischaemia, neuropathy or glomerular findings raise cryoglobulinaemic disease.

1Contact the laboratory before venepuncture, obtain a warm-handled cryoglobulin sample and simultaneously draw complement, infection, autoimmune and monoclonal-protein tests.
2Check urine, creatinine, pressure, oxygenation, haemoglobin, neurological power, perfusion and abdominal features to identify kidney, lung, nerve or bowel threat.
3Biopsy the safest active organ when classification will change treatment, but do not delay emergency organ rescue for a slow cryoglobulin result.

02Cause-directed first stepEradicate active hepatitis CHCV-associated disease is present with stable filtration and without nephrotic or rapidly progressive glomerulonephritis.

1Refer promptly to the regional hepatitis service and stage cirrhosis, kidney function, prior antiviral exposure, HBV status and medicine interactions.
2Start the selected pangenotypic direct-acting antiviral and monitor adherence, toxicity and HCV RNA according to the specialist eradication pathway.
3Track vasculitic organs after virological response because immune-complex or clonal disease can persist despite sustained viral clearance.

03Organ-threatening escalationSuppress B cells while treating the causeEscalationRapid renal decline, nephrotic syndrome, disabling neuropathy, ulceration, intestinal disease or another severe mixed-vasculitis manifestation develops.

1Admit and coordinate rheumatology, nephrology, hepatology, haematology and infection expertise; obtain tissue and cultures as rapidly as clinical stability permits.
2Use specialist rituximab plus glucocorticoid treatment alongside HCV antivirals or other cause-directed therapy, with HBV prophylaxis and opportunistic-infection measures.
3Add plasma exchange only for a defined rapid-removal indication such as hyperviscosity, life-threatening cryoglobulinaemic flare or selected rapidly progressive organ disease.

04Monoclonal routeTreat the pathogenic cloneType I cryoglobulin, hyperviscosity, monoclonal immunofixation or a marrow or tissue clone is identified.

1Protect the patient from cold, assess retina, brain, heart, kidneys and digits and measure viscosity when symptoms suggest clinically important hyperviscosity.
2Use urgent plasma exchange for symptomatic hyperviscosity or major occlusion while haematology defines the B-cell or plasma-cell disorder.
3DefinitiveBegin clone-specific systemic therapy and follow the monoclonal protein and organ response; immunosuppression alone is not definitive clonal treatment.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

A licensed pangenotypic direct-acting antiviral option that removes the HCV driver; it is not immediate rescue monotherapy for life-threatening cryoglobulinaemic vasculitis.

Glecaprevir 300 mg with pibrentasvir 120 mg

Give three 100 mg/40 mg tablets orally together once daily with food; treatment is commonly 8 weeks in treatment-naive adults without decompensated cirrhosis, but duration and suitability must be set by the hepatitis service.

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.

Depletes CD20-positive B cells producing pathogenic immunoglobulin and is favoured for severe nephritis, neuropathy, ulceration or persistent disease after causal treatment.

Rituximab intravenous infusion

For significant mixed cryoglobulinaemic vasculitis, a commonly studied specialist off-label regimen is 375 mg/m2 intravenously once weekly for 4 doses; an alternative protocol uses 1 g on days 1 and 15.

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.

Provides rapid anti-inflammatory control while antiviral or B-cell treatment takes effect; the cryoglobulinaemic indication and exact regimen are off-label and individualised.

Prednisolone for severe immune-complex inflammation

Use a specialist severity-based oral dose, commonly 0.5 mg/kg once daily for major but not immediately life-threatening disease, then taper promptly against organ response; pulse intravenous methylprednisolone may precede therapy in a critical presentation.

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.

Rapidly removes circulating cryoglobulin in hyperviscosity, extensive ischaemia, pulmonary haemorrhage or selected fulminant renal disease while production is suppressed.

Therapeutic plasma exchange

A specialist prescription commonly exchanges 1 to 1.5 plasma volumes per session daily or on alternate days, using albumin with plasma replacement when bleeding risk requires it; frequency and stopping point follow clinical and cryoprotein response.

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.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Chronic kidney disease

Recurrent or untreated membranoproliferative glomerulonephritis can leave persistent proteinuria, hypertension, declining filtration, dialysis dependence and cardiovascular risk.

Permanent nerve deficit

Axonal infarction may leave foot drop, hand weakness, sensory loss, neuropathic pain and falls even after immune activity is controlled.

Ulcer, infection and gangrene

Ischaemic purpura can progress to painful ulceration, secondary bacterial infection, osteomyelitis, extensive tissue necrosis, limb-threatening gangrene and amputation.

Lymphoproliferative transformation

The underlying B-cell clone may evolve or declare lymphoma, so persistent monoclonality, adenopathy, splenomegaly or cytopenias require longitudinal haematology review.

Treatment-related infection

Rituximab, glucocorticoid and cytotoxic exposure can reactivate hepatitis B, lower immunoglobulins and cause opportunistic or severe bacterial infection.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Record purpura distribution, ulcer dimensions, digital perfusion, pain, joint findings, named-nerve strength and functional gait or hand outcomes at each active-disease review.
Follow creatinine, eGFR, potassium, urine sediment, quantified ACR or PCR, albumin, oedema and blood pressure closely during glomerulonephritis, then at a risk-based interval in remission.
Track C4, cryoglobulin concentration or typing and rheumatoid factor as supportive trends, but never escalate treatment from a laboratory rise without clinical or organ evidence.
For HCV disease, document treatment completion and sustained virological response while continuing independent vasculitis surveillance after RNA clearance.
After rituximab monitor FBC, immunoglobulins, infection, HBV plan and vaccine timing; investigate recurrent infections or falling IgG before another course.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Temperature is part of the test

A technically ordinary blood draw can become a false-negative assay if the specimen cools before serum separation.

C4 is a clue, not a verdict

Classical complement consumption supports mixed immune complexes but infection, lupus and other processes can produce the same pattern.

Type determines mechanism

Type I disease is chiefly occlusive and clone-driven; mixed disease is chiefly inflammatory, although severe patients can show both mechanisms.

Viral cure and immune cure differ

Sustained HCV response removes antigenic drive but does not immediately erase an autonomous clone, deposited complexes or existing organ damage.

Neurology lags behind inflammation

Stopping vessel injury may first stabilise weakness; axonal regrowth is slow, so lack of rapid power recovery does not alone prove treatment failure.

11Common pitfallsFrequent interpretation and management errors.

01
Sending a cryoglobulin sample through routine cool transport and accepting the resulting negative test as definitive.
02
Treating a laboratory cryoglobulin concentration rather than establishing that it explains the patient's organ syndrome.
03
Giving immunosuppression before checking for HCV, hepatitis B, endocarditis and an underlying B-cell or plasma-cell clone.
04
Using direct-acting antiviral monotherapy for rapidly progressive glomerulonephritis or another immediately organ-threatening cryoglobulinaemic flare.
05
Assuming plasma exchange is definitive when ongoing viral or clonal production has not been treated.
06
Repeating rituximab for pain or weakness caused by fixed axonal or structural damage without evidence of active vasculitis.