Immunology and AllergyTier 1Disease (DEADMAN)

Cryoglobulinaemia

Description

Immunoglobulins that precipitate <37C and redissolve on warming
- Cryoglobulinaemia = the lab finding. Cryoglobulinaemic vasculitis = the disease

Brouet classification

	Composition	RF activity	Association	Mechanism
I (~10-15%)	Monoclonal Ig (IgM > IgG)	No	MGUS, Waldenstrom, myeloma, B-cell LPD	Occlusion / hyperviscosity
II (~50-60%)	Monoclonal IgM + polyclonal IgG	Yes	HCV, Sjogren, B-cell LPD	Immune complex vasculitis
III (~25-30%)	Polyclonal IgM + polyclonal IgG	Yes	HCV, SLE, Sjogren, chronic infection	Immune complex vasculitis

Two clinical phenotypes - drives everything

Type I -> vaso-occlusive: acrocyanosis, livedo, digital/acral ischaemia, retinal vein changes, ulceration
- Hyperviscosity syndrome is essentially confined to type I - reflects the underlying haematological neoplasm
Type II/III -> small-vessel leukocytoclastic vasculitis: palpable purpura, GN, peripheral neuropathy

Mixed cryoglobulinaemia: F>M ~2-3:1, peak 45-65
HCV underlies 70-90% of mixed disease
- Cryoglobulins detectable in 40-60% of chronic HCV; symptomatic vasculitis in only ~5%
Incidence falling in Australia - DAA-era HCV cure
Type I: epidemiology is that of the underlying paraprotein disorder

Mixed (II/III)

Chronic antigen drive (HCV E2 binds CD81 on B cells)
- -> clonal/oligoclonal B-cell expansion
- -> IgM with rheumatoid factor activity
IgM-RF binds IgG anti-HCV -> immune complexes
- Cold-insoluble -> deposit in small vessels (skin, glomerulus, vasa nervorum)
- -> classical complement activation
dec C4 markedly, C3 near-normal - the serological signature
Sustained clone can transform -> B-cell NHL (marginal zone)

Type I

Sampling - commonest cause of a false negative

Pre-warmed tube, transport and clot at 37C, then hold at 4C up to 7 days
- Sample cooling in transit -> cryoglobulin lost in the clot
Cryocrit quantifies; correlates poorly with disease severity

Clinical

Meltzer triad - purpura + arthralgia + weakness (complete in ~30%)
Palpable purpura: dependent, recurrent crops, resolves with haemosiderin staining
Fever, myalgia, non-erosive arthralgia (hands, knees, wrists) without overt synovitis
Neuropathy: distal sensory or mononeuritis multiplex
Renal: MPGN pattern

Classification - >=2 features from different domains

Domain	Features
Clinical	Purpura, necrotic cutaneous ulcers, GN, peripheral neuropathy, non-erosive arthritis, acral ischaemia, cold-induced acrocyanosis, Raynaud
Laboratory	Monoclonal IgM +/- hyperviscosity, unexplained low C4, high-titre RF, pseudothrombocytosis, rouleaux
Histopathology	Leukocytoclastic vasculitis, MPGN, hyaline intraluminal thrombi

Always look for the cause

Treat the cause; immunosuppress in proportion to organ threat.

HCV-associated - severity-stratified

Severity	Regimen
Mild-moderate (purpura, arthralgia, mild neuropathy, GN without renal failure)	DAA + corticosteroid
Severe (cutaneous ulcers, acral ischaemia, severe neuropathy, GN with renal failure or nephrotic syndrome, GI involvement)	Rituximab + corticosteroid; DAA added in maintenance
Life-threatening (RPGN, CNS, intestinal ischaemia, alveolar haemorrhage)	Plasma exchange + pulse methylprednisolone + rituximab or cyclophosphamide; DAA in maintenance

DAAs replace interferon entirely - 8-12 weeks, SVR >95%
- Antiviral cure alone resolves most mild disease; clinical response lags SVR by months
- Cryoglobulins may persist after SVR and relapse can occur - do not stop surveillance
Rituximab before DAA in severe disease - immunosuppression is not deferred while awaiting SVR

Type I

Treat the clone: myeloma or Waldenstrom-directed therapy
Plasma exchange for hyperviscosity or acral ischaemia - rapid, bridging only

Non-HCV mixed

Supportive

Renal - the main determinant of outcome

Involvement in ~20% at diagnosis, up to 30% over the disease course
Hypertension ~70%; raised creatinine 40-60% at diagnosis
~50% develop proteinuria, microscopic haematuria, red cell casts or renal impairment
Type I MPGN with hyaline thrombi on biopsy

Course

Relapsing-remitting; cold and infection trigger flares
5-year survival ~75%; renal involvement, age >60 and male sex are adverse
Death from renal failure, infection (often treatment-related), lymphoma, hepatic failure

Monitor for

Lymphoma transformation - persistent clone, new lymphadenopathy, rising IgM
Progressive CKD
Neuropathic pain and disability - often the least reversible feature
Rituximab: hypogammaglobulinaemia, HBV reactivation (screen HBsAg + anti-HBc before)

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