Cryoglobulinemia, Monoclonal and Mixed Cryoglobulinemia Syndromes, Cryoglobulinemic Vasculitis: a proposal for comprehensive nomenclature and definition

Abstract

Background. Cryoglobulinemia indicates the reversible, cold-dependent precipitation of immunoglobulins (Ig), which may be monoclonal (MoC) or mixed IgG–IgM (MC). Although this in vitro phenomenon is relatively frequent, only a minority of cases develop clinically relevant manifestations, often falling within lymphoproliferative, autoimmune, or infectious disease domains. This complexity highlights the need for clearer nomenclature and definition systems. Need for Standardized Nomenclature and Definitions. The term "cryoglobulinemia" is often used interchangeably to describe either simple laboratory finding, asymptomatic cryo-Ig precipitation (MoC or MC) or corresponding clinical syndromes (MoCs or MCs). This overlap creates ambiguity, hinders expert communication, and complicates the comparison of clinical studies. A standardized nomenclature is therefore essential to define disease subsets, establish boundaries with related conditions, and enable reliable data collection and multicenter analyses. Assessment of Cryoglobulinemia. When cryoglobulins are detected, the cryoprecipitate must be isolated and defined as MoC or MC, followed by a systematic clinical and laboratory assessment to identify potential underlying disorders. Immunoserological, microbiological, and pathological investigations are required to classify both MoC and MC as asymptomatic or symptomatic, and as essential or secondary. Asymptomatic individuals must be monitored over time for potential progression to overt clinical syndromes; similarly, those with essential forms require surveillance for the emergence of systemic diseases. Possible overlap with autoimmune conditions, particularly Sjögren's disease, should always be considered. Two Distinct Disorders. Despite some shared features, MoCs and MCs represent distinct clinical entities. Accurate diagnosis relies primarily on cryoprecipitate analysis. MoCs are usually associated with thrombotic, non-inflammatory microangiopathy and lymphoproliferative disorders, whereas MCs are characterized by immune-complex– mediated leukocytoclastic vasculitis, complement consumption, and frequent association with viral infections, especially HCV and HBV. The introduction of new-generation antivirals in the last decade has markedly reduced the prevalence of virus-related MCs in more developed countries. Conclusions. A harmonized nomenclature and standardized definitions for various cryoglobulinemia subsets, supported by careful clinical-immunological and pathological characterization, are essential to improve diagnostic accuracy, ensure interobserver consistency, and enable the development of evidence-based, mechanism-driven therapies for major cryoglobulinemic syndromes.