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Since the first description of cryoglobulinemia in association with the clinical triad of skin purpura, joint pain, and weakness by Meltzer et al. in 1966, [4] [5] the percentage of cryoglobulinemic diseases described as essential cryoglobulinemia or idiopathic cryoglobulinemia (that is, cryoglobulinemic disease that is unassociated with an underlying disorder) has fallen.
Meltzer's triad describes the classical symptoms suggesting the diagnosis of cryoglobulinaemia of polyclonal CGs seen in essential-, viral-, or connective tissue disease-associated cryoglobulinaemia. [1] The triad consists of: palpable purpura; arthralgia (joint pain) weakness.
More severe symptoms involve renal, gastrointestinal, and neurological damage with cardiovascular and respiratory complications presenting more rarely in a population of 279 patients with cryoglobulins and hepatitis C infection. [4] Prevalence of these symptoms may vary depending on the underlying etiology contributing to the cryoglobulinemia. [7]
Cryofibrinogenemia is also often associated with the inflammatory vasculitis that accompanies mixed Cryoglobulinemia#Classification, i.e. cryoglobulinemic vasculitis, particularly but not exclusively in instances where hepatitis C virus is an underlining disease. [6]
Nonspecific systemic and musculoskeletal symptoms, such as cutaneous vasculitis and neuropathy, can also be seen in patients with mixed cryoglobulinemia. [28] Ninety-five percent of cases of immunoglobulin A vasculitis (IgAV) start with a skin rash. [29]
Rarely, cryoglobulinemia (i.e. essential cryoglobulinemia) occurs in patients without these or other identifiable conditions. Non-essential cryoglobulonemia is classified into three types. Type 1 cryoglobulinemia (10-25% of cases) involves a circulating myeloma protein, typically IgM or IgG but in rare case reports IgA.
Non-specific symptoms are common and include fever, headache, fatigue, myalgia, weight loss, and arthralgia. [5] [6] All forms of vasculitis, even large vessel vasculitides, may cause skin manifestations. The most common skin manifestations include purpura, nodules, livedo reticularis, skin ulcers, and purpuric urticaria. [7]
Mixed cryoglobulinemia, gait ataxia, late-onset polyneuropathy syndrome; Myelin-associated glycoprotein-associated gammopathy, polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome ; Other possible diagnoses are Bickerstaff brainstem encephalitis; Fisher syndrome; Guillain–Barré syndrome