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Health condition · Clinically reviewed

Cryoglobulinaemia, the cold-precipitating antibody that inflames small vessels.

A rare vasculitis with three distinct Brouet types. Treat the underlying cause, add rituximab where needed, and involve a specialist vasculitis service early.

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Why trust this guide

  • 01

    Clinically reviewed

    Written by our editorial team and reviewed by a registered UK clinician before publication.

  • 02

    Sourced from guidance

    Checked against EULAR, KDIGO, BSR and peer-reviewed vasculitis sources you can see at the end.

  • 03

    Current for 2026

    Reflects modern UK practice including direct-acting antivirals for HCV and rituximab-first regimens for severe mixed disease.

Key facts

Cryoglobulinaemia at a glance.

The essentials, in plain English: what cryoglobulins are, the three Brouet types, and how UK specialists approach treatment today.

  • What it is

    A rare condition where abnormal immunoglobulins (cryoglobulins) precipitate below 37 degrees Celsius and redissolve on warming, driving small-vessel vasculitis and tissue damage.

  • Brouet classification

    Type 1 (monoclonal, 10 to 15 percent), Type 2 mixed (polyclonal IgG plus monoclonal IgM, 50 to 60 percent) and Type 3 mixed (polyclonal, 25 to 30 percent).

  • The big driver

    Historically Hepatitis C caused around 90 percent of Type 2 mixed cases. Direct-acting antivirals have transformed that picture.

  • Classic triad

    The Meltzer triad: palpable purpura on the lower limbs, arthralgia and weakness.

  • Organs at risk

    Skin, kidneys (membranoproliferative glomerulonephritis), peripheral nerves, joints, gut and, rarely, lungs.

  • Treatment backbone

    Treat the underlying cause first. Add rituximab, steroids and, for critical disease, plasma exchange.

Why this guide matters

Rare, but eminently treatable when the trigger is found.

Cryoglobulinaemia sits at the crossroads of infection, autoimmunity and haematological disease. The three points below shape everything else on this page.

  • Treat the underlying cause first

    HCV cure with direct-acting antivirals often resolves the vasculitis. Myeloma or lymphoma treatment does the same for Type 1.

  • Rituximab is first-line for severe MCV

    For skin, kidney or nerve involvement, rituximab combined with steroids has become the modern backbone of care.

  • MDT specialist input changes outcomes

    Rheumatology, nephrology, hepatology, haematology and neurology working together, ideally through a commissioned vasculitis centre.

How the diagnosis is made

From first purpura to a clear plan.

The steps a UK rheumatologist or nephrologist will normally follow, in order, so you know what to expect and why each investigation matters.

  1. 01

    Assessing

    Clinical pattern recognition

    Palpable purpura, Raynaud, arthralgia, neuropathy or unexplained renal disease should prompt a cryoglobulin work-up.

  2. 02

    Assessing

    Cryoglobulins done properly

    Blood drawn into a warmed tube at 37 degrees Celsius, transported warm, then refrigerated for up to 7 days with cryocrit measurement and immunofixation typing.

  3. 03

    Assessing

    Bloods and immunology

    FBC, U and Es, LFTs, inflammatory markers, complement (low C4 is characteristic of Type 2), rheumatoid factor, immunoglobulins, serum electrophoresis and free light chains.

  4. 04

    Confirming

    Viral and autoimmune screen

    HCV antibody, HCV RNA and genotype (critical), HBV and HIV serology, ANA, ENA, SSA/SSB, RF and ANCA to map the underlying trigger.

  5. 05

    Confirming

    Urine and organ assessment

    Urinalysis, urine protein-creatinine ratio, microscopy, nerve conduction studies and EMG when neuropathy is suspected.

  6. 06

    Preparing

    Tissue biopsy

    Skin biopsy shows leucocytoclastic vasculitis with intravascular cryoprecipitate. Kidney biopsy confirms MPGN and looks for crescents when renal disease is present.

  7. 07

    Preparing

    Malignancy screen

    CT or PET imaging and, in Type 1 or where there is a monoclonal spike, a bone-marrow biopsy to look for myeloma, Waldenstrom or lymphoma.

Typical timeline: a first specialist visit to a working diagnosis in a few weeks.

Symptoms

What cryoglobulinaemia actually looks like.

A Meltzer-triad of purpura, arthralgia and weakness, layered on top of organ-specific features and the features that mean urgent escalation.

  • Palpable purpura

    The hallmark rash: raised, non-blanching spots on the lower limbs that come in crops and often follow cold exposure.

  • Raynaud and acrocyanosis

    Cold-triggered colour change of the fingers and toes, sometimes with livedo reticularis or fixed dusky discolouration.

  • Skin ulcers and gangrene

    Sluggish, painful ulcers, particularly around the ankles, with rare digital gangrene in severe disease.

  • Kidney involvement

    Membranoproliferative glomerulonephritis with haematuria, proteinuria, nephritic features and, at worst, acute kidney injury or CKD.

  • Peripheral neuropathy

    Present in 30 to 50 percent, more often sensory than motor, with numbness, burning or a length-dependent pattern.

  • Joints and systemic features

    Arthralgia is far more common than true arthritis, alongside fever, weight loss and marked fatigue.

  • Gut and lung involvement

    Abdominal pain from mesenteric ischaemia, GI bleeding or hepatitis. Pulmonary haemorrhage and interstitial disease are rare but serious.

  • Red flag: hyperviscosity in Type 1

    Headache, blurred vision, retinal haemorrhage or confusion in Type 1 disease points to hyperviscosity and needs emergency care.

Treatment

How cryoglobulinaemia is treated in the UK.

Treat the underlying trigger first, add rituximab and steroids for severe mixed disease, and reserve plasma exchange for critical presentations.

  • Direct-acting antivirals for HCV

    Sofosbuvir/velpatasvir or glecaprevir/pibrentasvir cure over 95 percent of HCV cases and often resolve the cryoglobulinaemia. Specialist hepatology-led.

  • Rituximab (anti-CD20)

    First-line for severe mixed cryoglobulinaemic vasculitis, particularly with renal or neurological involvement. Delivered in a specialist infusion setting.

  • Corticosteroids

    Oral prednisolone or IV methylprednisolone to control acute inflammation, then tapered as rituximab or other agents take over.

  • Cyclophosphamide

    Reserved for the most severe or rapidly progressive disease, usually alongside steroids and always under specialist supervision.

  • Azathioprine, MMF, methotrexate

    Steroid-sparing options used for maintenance in mixed disease depending on organ involvement and tolerability.

  • Plasma exchange

    For hyperviscosity, rapidly progressive glomerulonephritis or severe neurological disease. Specialist nephrology or haematology-led.

  • Haemat-oncology for Type 1

    Treatment of the underlying myeloma, Waldenstrom or lymphoma with bortezomib, daratumumab, selected stem-cell transplant or CAR-T pathways.

  • Supportive and MDT care

    Analgesia, meticulous skin and ulcer care, cold avoidance, and joint working across rheumatology, nephrology, hepatology, haematology and neurology.

What this guide is based on

The sources behind every claim on this page.

UK and international guidance from vasculitis, nephrology and hepatology bodies, current at the time of last review.

Key references

Guidelines and standards we relied on.

A quiet reminder

This guide is for information, not medical advice.

Your rheumatology, nephrology or hepatology team knows your history and can tell you which parts apply to you. If in doubt, get seen.

  • EULAR recommendations for the management of ANCA-associated and cryoglobulinaemic vasculitis.

  • KDIGO Clinical Practice Guideline on Glomerular Diseases (cryoglobulinaemic glomerulonephritis section).

  • British Society for Rheumatology guidance on vasculitis management.

  • NHS England specialised commissioning: specialist vasculitis services.

  • BASL and EASL guidance on HCV treatment with direct-acting antivirals.

Red flags

When cryoglobulinaemia needs urgent attention.

Most flares are managed in scheduled specialist clinics. These are the situations that are not, and where an emergency assessment is needed.

  • Rapidly progressive glomerulonephritis

    Rising creatinine, active urinary sediment or nephritic syndrome needs emergency nephrology review and often plasma exchange.

  • Symptomatic hyperviscosity

    Headache, visual change, mucosal bleeding or confusion in Type 1 disease is a haematology emergency requiring urgent plasmapheresis.

  • Digital gangrene or spreading ulcers

    Threatened tissue loss needs same-day vascular and rheumatology input alongside aggressive immunosuppression.

  • Severe or progressive neuropathy

    New motor weakness, foot drop or rapidly worsening sensory loss warrants urgent nerve conduction studies and treatment escalation.

  • Pulmonary haemorrhage

    Haemoptysis, hypoxia or new infiltrates on chest imaging is a life-threatening presentation needing critical-care-level support.

  • Mesenteric ischaemia

    Severe abdominal pain out of proportion to examination, GI bleeding or a rising lactate needs surgical and vasculitis MDT input.

  • Suspected underlying lymphoma or myeloma

    Monoclonal spike, cytopenias, weight loss or lymphadenopathy should trigger haemat-oncology referral before immunosuppression is escalated.

  • Untreated Hepatitis C

    Any HCV-positive patient with cryoglobulinaemia should be referred urgently for direct-acting antiviral therapy.

  • Pregnancy planning

    Rituximab, cyclophosphamide and methotrexate all need pre-pregnancy counselling and specialist review.

Living with it

A rare condition, but a well-mapped one.

Four things that make the biggest difference day to day: warmth, monitoring, infection vigilance and staying connected to a specialist team.

A quiet reminder

Small, steady habits beat heroic weeks.

Reliable clinic attendance, consistent medication and simple warmth strategies do more than any short burst of effort.

  1. 01 Warmth

    Keep the extremities warm

    Layered clothing, thermal gloves, heated insoles and avoiding sudden cold exposure reduce flare frequency and Raynaud attacks.

  2. 02 Monitoring

    Attend your specialist clinics

    Regular bloods, urinalysis and clinical review pick up renal or haematological change early, when it is most treatable.

  3. 03 Infection

    Vaccinate and act on infections

    On rituximab, cyclophosphamide or steroids, keep up with recommended vaccines and seek early advice for any fever or infection.

  4. 04 Support

    You are not alone with a rare disease

    Vasculitis UK and specialist commissioned vasculitis services offer information, peer support and expert MDT input.

Frequently asked

Everything we get asked about cryoglobulinaemia.

Quick answers on the Brouet types, HCV cure, blood-sample handling and modern treatment.

  • What is cryoglobulinaemia?

    Cryoglobulinaemia is a rare condition where abnormal immunoglobulins in the blood, called cryoglobulins, precipitate below 37 degrees Celsius and redissolve on warming. These deposits inflame small blood vessels, causing a form of vasculitis that can affect the skin, kidneys, nerves and other organs.

  • What are the three Brouet types?

    Type 1 (around 10 to 15 percent) is a monoclonal IgG or IgM linked to myeloma, Waldenstrom macroglobulinaemia, MGUS or lymphoma. Type 2 mixed (50 to 60 percent) combines polyclonal IgG with monoclonal IgM that has rheumatoid factor activity, and is strongly associated with Hepatitis C, HBV, HIV, Sjogren and lymphoma. Type 3 mixed (25 to 30 percent) is polyclonal and linked to autoimmune disease and chronic infection.

  • How is Hepatitis C linked to cryoglobulinaemia?

    Historically, around 90 percent of Type 2 mixed cases were driven by chronic HCV. Direct-acting antivirals such as sofosbuvir/velpatasvir or glecaprevir/pibrentasvir now cure over 95 percent of HCV cases and often resolve the cryoglobulinaemia, which is why HCV screening is a critical early step.

  • Why does the blood sample need to be kept warm?

    Cryoglobulins precipitate below body temperature. If the sample cools before it reaches the laboratory, the cryoglobulins fall out of solution in the tube rather than being measured, and the test can look falsely negative. A warmed tube kept at 37 degrees Celsius during transport is essential.

  • What does treatment look like for severe mixed disease?

    For severe mixed cryoglobulinaemic vasculitis, especially with renal or neurological involvement, rituximab has become first-line, typically alongside corticosteroids. Cyclophosphamide, azathioprine, methotrexate or mycophenolate are added for maintenance, and plasma exchange is used for hyperviscosity, rapidly progressive glomerulonephritis or severe neurological disease.

  • Which specialists should be involved?

    Care is multidisciplinary. Depending on organ involvement it involves rheumatology, nephrology, hepatology, haematology, dermatology and neurology, often through a specialist commissioned vasculitis service such as Addenbrookes in Cambridge, Birmingham, Newcastle or Barts in London.

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