• Cryoglobulins are immunoglobulins that precipitate at low temperatures (4° C)
and that resolve with rewarming
• Cryoglobulins may be divided into three classes:
1. Type I—composed solely of monoclonal immunoglobulin (either kappa or
lambda) and usually associated with lymphoproliferative disorders (multiple
myeloma, Waldenstrom’s macroglobulinemia)
2. Type II (mixed) cryoglobulin—composed of monoclonal (usually IgM) immunoglobulin
3. Type III (polyclonal) cryoglobulin—composed of immunoglobulins IgG and IgM
• The last two subtypes (mixed cryoglobulins) function as immune complexes and
clinical manifestations are due, at least in part, to allergic vasculitis
• The eponym Meltzer’s triad has been applied to the combined features of purpura,
arthralgias, and weakness, which are often present.
• Cutaneous manifestations are common to all classes of cryoglobulinemia and are
often the presenting complaint.
• Type I cryoglobulinemia is usually characterized by purpuric lesions, including
inflammatory macules and papules on the extremities, accompanied by foci of ulceration.
• Mixed cryoglobulinemia is characterized by joint involvement (arthralgia and
arthritis), Raynaud’s phenomenon, fever, purpura, weakness, renal involvement,
hepatosplenomegaly, necrosis of extremities, and general vasculitis. Cutaneous
manifestations include palpable purpura, inflammatory macules and papules,
necrotizing vasculitis, and, occasionally, cold urticaria. Renal involvement may
be identified by proteinuria, hematuria, and red cell casts. Patients may also have
• Purpura (Fig. 3.87) is the most common initial sign.
• Additional features may include livedo reticularis, Raynaud’s phenomenon, scarring, ulceration, and infarction, which particularly affects the digits, ears, and
• Serum cryoglobulin level
• Skin biopsy
• Serum sickness
• Antiphospholipid antibody syndrome
• Waldenstrom’s hyperglobulinemia
• Septic vasculitis
• Polyarteritis nodosa
• Goodpasture syndrome
• Elimination of triggers by minimizing cold exposure
• Systemic corticosteroids
• Mycophenolate mofetil
• Cryoglobulins may be associated with hepatitis C, hepatitis B, SLE, lymphoreticular neoplasms, and infective processes (e.g., infective endocarditis).
• Prognosis is variable. Renal involvement, which occurs in 50% of cases, is associated with high morbidity and mortality