Cryoglobulinaemic Vasculitis

Notes

Rheumatology | Small-vessel Vasculitis | Vasculitides

Overview

Cryoglobulinaemic vasculitis is an immune complex–mediated small to medium vessel vasculitis caused by circulating cryoglobulins—immunoglobulins that precipitate below 37 °C and redissolve on warming. These immune complexes deposit in vessel walls, activate complement (typically with marked C4 consumption), and drive leukocytoclastic vasculitis. “Mixed” CV (types II and III) is most often linked to hepatitis C virus (HCV), autoimmune diseases, or B-cell clonal disorders, while type I CV is monoclonal and associated with plasma-cell dyscrasias or lymphoproliferative disorders. Adults are most commonly affected.

Definition

Cryoglobulins: Immunoglobulins that precipitate at <37 °C and dissolve on rewarming; quantified as cryocrit (%) and typed by immunofixation into Brouet types I–III.
Mixed cryoglobulinaemia: Type II (monoclonal IgM-RF + polyclonal IgG) or Type III (polyclonal IgM-RF + polyclonal IgG); RF activity drives immune complex formation.
Type I cryoglobulinaemia: Monoclonal immunoglobulin (IgM or IgG) from a haematologic clone; causes ischemia/hyperviscosity more than vasculitis.
Membranoproliferative glomerulonephritis (MPGN): Immune-complex GN typical of mixed CV renal disease.

Remember

Always keep blood samples at 37 °C until serum separation to avoid false-negative cryoglobulin results.

Aetiology & Risk Factors

Aetiology:

HCV infection (leading global cause of mixed CV)
Autoimmune diseases (e.g., Sjögren’s syndrome, SLE)
B-cell clonal disorders (Waldenström macroglobulinaemia, multiple myeloma, MGUS)
Less common: HBV, HIV, solid tumours

Risk Factors for Severe Disease:

High cryocrit level
Very low C4 and/or low C3
Active HCV viremia or persistent monoclonal B-cell clone
Renal or peripheral nerve involvement
Extensive skin ulcers/necrosis
Older age

Pathophysiology

Chronic antigenic stimulation (e.g., HCV) or B-cell clone produces IgM with RF activity + IgG.
Circulating immune complexes (cryoglobulins) form and precipitate in cooler environments.
Immune complexes deposit in vessel walls → activate classical/lectin complement pathways → marked C4 consumption.
Complement activation → neutrophil recruitment → leukocytoclastic vasculitis (skin/nerve) and immune-complex MPGN (kidney).
Type I CV: Monoclonal proteins → hyperviscosity and vascular occlusion → ischemia.

Remember

Low C4 + high RF in the right setting is a strong clue to mixed CV.

Clinical Manifestations

Skin: Palpable purpura (dependent areas), livedo, retiform purpura, ulcers/necrosis, acrocyanosis, Raynaud phenomenon.
Musculoskeletal: Arthralgia, non-erosive arthritis, myalgia
Mononeuritis multiplex.
Membranoproliferative Glomerulonephritis pattern, possible rapidly progressive GN
Type I CV may cause hyperviscosity (headache, visual changes, epistaxis) and digital ischemia.

Diagnosis

Serum cryoglobulin positivity
- Must include clinical features: Purpura, low C4, positive RF, renal involvement, peripheral neuropathy, leukocytoclastic vasculitis on biopsy.

Investigations

Cryoglobulin testing with proper handling (pre-warmed tubes, 37 °C transport until serum separation)
Complement levels (very low C4, ± low C3)
Rheumatoid factor (often high in mixed CV)
HCV Ab + RNA, HBV serology, ± HIV testing
Autoimmune serology (ANA, anti-SSA/SSB)
Monoclonal screen (SPEP/UPEP, serum free light chains)
Skin biopsy: leukocytoclastic vasculitis with IgM/IgG/C3 deposition
Renal biopsy: immune-complex MPGN
Nerve biopsy if diagnosis unclear

Differentials Diagnosis

ANCA-associated vasculitis
Infective endocarditis-related vasculitis
Antiphospholipid syndrome
Cholesterol embolism
Cold agglutinin disease

Classification (Brouet Types)

Type	Immunochemistry	Typical associations	Key complications
I	Monoclonal IgM/IgG	Waldenström, myeloma, MGUS	Hyperviscosity, ischemia
II	Monoclonal IgM-RF + polyclonal IgG	HCV, autoimmune disease, B-cell clone	Mixed CV – purpura, neuropathy, MPGN
III	Polyclonal IgM-RF + polyclonal IgG	Autoimmune disease, infections	Milder mixed CV, can evolve to type II

Treatment

Treat underlying cause, control immune complex production, protect organs, avoid cold exposure, wound care.

Type I CV:

Clone-directed therapy (e.g., BTK inhibitor, bortezomib-based regimen)
Plasma exchange for hyperviscosity, rapidly progressive GN, or severe ischemia

HCV-associated mixed CV:

First-line: DAAs (SVR >95%)
Add rituximab ± short glucocorticoid course for moderate–severe or organ-threatening disease
Avoid interferon-based therapy

Non-viral mixed CV:

Rituximab + short glucocorticoid course first-line
Cyclophosphamide for rituximab-refractory disease

Renal protection: RAAS blockade, BP <130/80 mmHg, avoid nephrotoxins.

Complications and Prognosis

Complications

Skin ulceration/necrosis ± infection
Peripheral neuropathy
MPGN → CKD/ESKD
Hyperviscosity syndrome (type I Cryoglobulinaemia)
Digital ischemia/gangrene (type I Cryoglobulinaemia)
Cardiovascular events

Prognosis

Improved outcomes for HCV-associated CV in the DAA era
Poor prognostic factors: renal involvement with creatinine rise, severe neuropathy, extensive ulcers/necrosis, cardiac involvement, older age, high cryocrit, very low C4, persistent HCV viremia or B-cell clone
Relapse risk if underlying cause remains untreated