Cryoglobulinaemic Vasculitis

A small vessel vasculitis caused by cryoglobulins, immunoglobulins that reversibly precipitate at temperatures below normal body temperature, depositing in small vessels and triggering complement mediated inflammation, with a classification based on the composition of the cryoglobulin that carries important aetiological and management implications.

Classification

Type one cryoglobulinaemia consists of a single monoclonal immunoglobulin, typically associated with an underlying lymphoproliferative disorder such as multiple myeloma or Waldenström macroglobulinaemia, and causes symptoms predominantly through hyperviscosity and vascular occlusion rather than immune complex mediated vasculitis.

Type two and type three, together termed mixed cryoglobulinaemia, comprise a combination of monoclonal (type two) or polyclonal (type three) rheumatoid factor activity bound to polyclonal IgG, and are the forms typically causing true immune complex mediated vasculitis, strongly associated with chronic hepatitis C infection, and less commonly with connective tissue disease (particularly Sjögren syndrome) or lymphoproliferative disorders.

Palpable purpura, typically affecting the lower limbs and often precipitated or worsened by cold exposure, is the characteristic cutaneous manifestation of mixed cryoglobulinaemic vasculitis.

Arthralgia, peripheral neuropathy (often painful and sensory predominant) and constitutional symptoms accompany the cutaneous features in classical disease.

Renal involvement, presenting as membranoproliferative glomerulonephritis with proteinuria, haematuria and hypertension, is a significant determinant of long term prognosis in mixed cryoglobulinaemic vasculitis.

Type one cryoglobulinaemia presents differently, with symptoms of hyperviscosity (headache, visual disturbance, mucosal bleeding) and vascular occlusion (Raynaud phenomenon, digital ischaemia, livedo reticularis) reflecting the physical precipitation of the monoclonal protein rather than a true inflammatory vasculitis.

Symptoms of the underlying driving condition (chronic liver disease from hepatitis C, sicca symptoms from Sjögren syndrome, or features of an underlying lymphoproliferative disorder) should be actively sought given their central role in both diagnosis and treatment.

Serum cryoglobulins are identified by collecting and transporting blood at body temperature (a critical preanalytical step, since specimens allowed to cool before separation will lose cryoglobulin into the clot and produce a false negative result), with subsequent immunofixation characterising the cryoglobulin type.

Hepatitis C serology and viral load should be checked in every patient with mixed cryoglobulinaemia given the strong association, alongside screening for underlying connective tissue disease (antinuclear antibody, anti Ro and anti La for Sjögren syndrome) and lymphoproliferative disorders where clinically indicated.

Complement levels, characteristically showing a markedly low C4 with relatively preserved C3, are a useful and relatively specific supportive finding in mixed cryoglobulinaemic vasculitis.

Rheumatoid factor is frequently strongly positive, reflecting the rheumatoid factor activity intrinsic to the mixed cryoglobulin complex itself rather than indicating coexisting rheumatoid arthritis.

Skin or renal biopsy, where performed, demonstrates leukocytoclastic vasculitis or membranoproliferative glomerulonephritis respectively, with characteristic intraluminal deposits in severe cutaneous or renal disease.

Treatment of the underlying driving condition is central to management and, where successful, often resolves the vasculitis without the need for additional immunosuppression: direct acting antiviral therapy for hepatitis C associated mixed cryoglobulinaemia has transformed outcomes for this group, achieving viral clearance and frequently resolving the associated vasculitis.

Immunosuppression, typically with corticosteroids and rituximab, is reserved for severe or organ threatening vasculitis (significant renal involvement, severe neuropathy, extensive skin ulceration) and is used alongside, rather than instead of, treatment of the underlying cause.

Plasma exchange is used for the most severe presentations, including hyperviscosity syndrome in type one disease or severe rapidly progressive vasculitis in mixed disease.

Cold avoidance is a simple and useful adjunctive measure given the temperature dependent nature of cryoglobulin precipitation.

Type one cryoglobulinaemia is managed primarily by treating the underlying lymphoproliferative disorder, with plasma exchange for acute hyperviscosity symptoms.

Long term monitoring for disease relapse, for progression of the underlying driving condition, and for renal function given the potential for chronic kidney disease, underpins ongoing management of this typically chronic, relapsing condition.