The presence in the serum of one or more immunoglobulins that precipitate at temperatures below 37 °C and redissolve on rewarming is termed cryoglobulinemia (Figure 1) (1–6)(Zignego AL et al. J. Int. Medicine 2025, accepted for publication). The actual mechanism of this in vitro phenomenon, first described by Wintrobe and Buell in 1933 (7), remains quite obscure; the immunoglobulin (Ig) cryoprecipitation could be secondary to intrinsic characteristics of both monoclonal and polyclonal Ig and/or caused by the interaction among different components of the cryoprecipitate. The most accredited explanations of this phenomenon, not mutually exclusive, include the following pathogenetic mechanisms: structural modification of the variable portions of Ig heavy/light chains, reduced amounts of galactose in the Fc portion of the Ig, reduced concentration of sialic acid, and/or the presence of N-linked glycosylation sites in the CH3 domain secondary to somatic Ig mutations during autoimmune responses (1–7). The Ig self-aggregation might also be explained by both non-specific Fc–Fc interactions, or as for mixed IgG-IgM cryoglobulinemia (MC), by specific interactions among IgM rheumatoid factor (RF) and Fc portion of IgG, respectively the autoantibody and the autoantigen of cryoprecipitable immune-complexes (1–7).

According to Brouet and colleagues (4), cryoglobulinemia is traditionally classified into three immunological subtypes: type I, composed of a single monoclonal cryo-Ig (MoC), usually a paraprotein, types II and III mixed cryoglobulinemia (MC), characterised by polyclonal IgG and mono-oligo (type II) or polyclonal (type III) IgM RF, respectively. Type I, MoC is found mainly in the course of B-cell neoplasias (8, 9); while types II/III MC are frequently associated with different infectious, neoplastic, or immunological diseases (1–6, 10–13) (Figure 2).

With regards the types II/III MC that can be found in a variety of infectious diseases, we can hypothesize that they are the result of a chronic stimulation of the immune system by altered autologous IgG following the interaction with exogeneous factors, such as antigens of involved infectious agent(s). They may work as autoantigen able to elicit different cryo- and non-cryoprecipitable immune-complexes (IC), which in turn may be responsible for diffuse vasculitic lesions of mixed cryoglobulinemia syndrome (MCs) (1–6, 10–13).

The availability of shared nomenclature and definition systems is necessary to ensure unambiguous communication worldwide (nomenclature) and to establish specific features of a given disease and its boundaries (definition) towards other neighboring conditions, allowing uniform data collection and thus effective analysis. These latter are crucial either in the practical management of the disease and its clinical variants and for future research. Clinicians, researchers, and regulators can share information consistently within their own expertise as well across different medical disciplines. This is particularly relevant in the field of rare diseases, often characterized by high clinical-pathogenetic complexity and unpredictable outcomes, as for cryoglobulinemic syndromes.

Despite significant progress in recent decades regarding both disease etiopathogenesis and management (1–6, 10–13), the lack of a shared nomenclature and definition of cryoglobulinemia variants often leads to either patient selection and data collection quite inconsistent between different research centers, which may ultimately lead to poorly reliable results. Furthermore, a comprehensive nomenclature and definition of cryoglobulinemias may allow the definitive development of classification/diagnostic criteria for the main variants of cryoglobulinemia, i.e. MoC and MC. The vast literature available on the topic of ‘cryoglobulinemia’ (key word ‘cryoglobulinemia’ on PubMed: 5,261 results) offers a wide array of terms and definitions, most of which are correct per se, but potentially confusing, as noted above. These range from the generic term ‘cryoglobulinemia’, referring both to the simple in vitro phenomenon of cryoprecipitation and to the full-blown clinical syndrome, to ‘cryoglobulinemic disease’ instead of ‘cryoglobulinemia syndrome’, from ‘type I cryoglobulinemia’ as ‘monoclonal cryoglobulinemia’, from ‘essential’ or ‘idiopathic’ to ‘non-essential’ or ‘secondary’ cryoglobulinemia, to ‘cryoglobulinemic vasculitis’ synonymous with ‘mixed cryoglobulinemia syndrome’, and so on. Suitable and shared terminology and definitions are essential for developing classification/diagnostic criteria encompassing the numerous etiopathogenetic and clinical variants of cryoglobulinemia. Currently, classification criteria are available only for MCs; relating to this disorder, preliminary classification criteria were proposed by the Italian Group for the Study of Cryoglobulinaemias (GISC) back in 1989 (C Ferri et al. Proceedings of 10th Congress of the Italian Society of Immunology and Immunopathology, S. Margherita di Pula, Cagliari, 12 May, 1989), and subsequently revised and validated in multicenter GISC studies (14–16).

The present study, building on the currently used nomenclature, aims to propose a more orderly and comprehensive terminology and definition of the different cryoglobulinemia subtypes, with the primary goal of improving its applicability in routine clinical practice and facilitating the recruitment of homogeneous patient cohorts with distinct disease subtypes for clinical and etiopathogenetic research purposes.

As with any complex disorder, the development of nomenclature and definition of cyoglobulinemias is an ongoing process; it is necessarily based on the evolving knowledge of etiopathogenetic mechanisms with the indirect contribution of more recent clinical and therapeutic experiences. An updated nomenclature and definition of cryoglobulinemia subsettings is summarized in Table 1, which tray to rationalize all available terms, synonyms, and definitions often used but poorly suitable.

Their proper use may ensure the homogeneity of the cohorts studied and therefore the value of observed results; moreover, their refinement may contribute to the updating/development of classification/diagnostic criteria.

The first column reports the terminology of cryoglobulinemia subsettings as well their synonyms alongside (Table 1). In particular, the term ‘cryoglobulinemia’ should be reserved for the simple laboratory finding, i.e. the presence in the serum of one or more cryoprecipitable Igs (1–7). Similarly, either MoC or MC terms are specifically referred to only the presence of one monoclonal cryoprecipitable Ig or mixed Igs, more often IgG-IgM, respectively; in all cases regardless of the presence/absence of known causes and symptoms (Table 1, on the top). While the combination of serological (mono-/mixed cryoglobulins) and clinical features represents two distinct conditions, namely the MoC syndrome (MoCs) and the mixed cryoglobulinemia syndrome (MCs), which in turn may be termed ‘essential’ or ‘secondary’ according to the absence/presence of well-known causative factors or underlying disorders, respectively. The synonyms, type I and type II/III are referred to specific Ig composition of cryoprecipitates (1–7). Moreover, the term ‘cryoglobulinemic vasculitis’ is alternatively used to MCs; it focuses on the specific disease histopathological hallmark, i.e., leukocytoclastic vasculitis, for which the disease is traditionally classified among systemic vasculitis, in particular within the small vessel vasculitis subgroup (1–6, 17–19).

The definition of both MoCs and MCs is mainly based on different serological, clinical, and pathological features; they are commonly associated with various pre-malignant, malignant, infectious, or autoimmune conditions, which in turn represent the underlying cause for the cryoglobulin production (1–9). With regards to the disease domains involved in cryoglobulinemia variants (Figure 2, Table 1, column on the right), both MoCs and MCs may share the same hematological, rheumatic-autoimmune, and/or infectious disorders, with a marked prevalence of lymphoid neoplasms for MoC and infectious diseases, mainly HCV infection, for MC (1–6, 17, 18).

The serological hallmark of MoC is the presence of a single monoclonal cryoprecipitable Ig (mainly IgG or IgM; Table 2) produced by monoclonal expansion of B-cell clone as expression of different lymphoid neoplasms, namely indolent monoclonal gammopathy of unknown significance (MGUS), smoldering Waldenström’s macroglobulinemia, or overt malignant disorders such as multiple myeloma (MM), B-cell non-Hodgkin’s lymphoma (B-NHL), or chronic lymphocytic leukemia (CLL) (20). The two distinctive features best defining the MoC are the very frequent association with hematologic neoplasias (9) and the peculiar pathological alterations responsible for the clinical syndrome (1, 5, 17, 18) (Table 3). In a large series of 102 MoC patients (8), the presence of symptoms (MoCs) was observed in 87% of cases; the most common were cutaneous (total 63%, with purpura 42% and ulcers/gangrene 34%) and neurological manifestations (32% of cases), most frequently sensory neuropathy (24%), Raynaud’s phenomenon (25%), arthralgias (24%), and renal manifestations, mainly glomerulonephritis (14%). Of note, the large majority of MoC patients had an underlying lymphoproliferative disorder (92%), while essential MoC was present in only a small percentage of patients (8). The symptoms of MoCs are the consequence of intravascular cryoprecipitation and deposition of monoclonal cryo-immunoglobulin responsible for non-inflammatory vessel occlusion and ischemic tissue damage. In some individuals the large amount of cryoglobulins, not rarely presenting as cryogel in isolated serum samples, are responsible for in vivo marked increase of blood viscosity with overt hyperviscosity syndrome (8, 9, 18, 21). This harmful complication is characterized by neurological symptoms (headache, confusion, tinnitus, vertigo, confusion, ataxia, and coma), blurry vision or vision loss, retinal hemorrhages and venous “sausaging”, sudden deafness, epistaxis, necrotic lesions of acral districts (21–25). In anecdotal observations monoclonal cryoglobulins associated to MM or other lymphoid neoplasms, even at quite low concentrations may form various morphologies of cryoglobulin condensates from different patients, including crystals, amorphous aggregates, and gels (26, 27). The intravascular precipitation of MoC appears in vivo as hialin thrombi occluding small blood vessels, more often in endoneural microvessels (20) responsible for severe peripheral neuropathy as well in the renal glomeruli as massive intraluminal cryoprecipitation with rapidly progressive renal failure; the latter finding characterizes patients with so-called monoclonal gammopathy of renal significance (28).

The disease, first described by Meltzer et al. in 1966 (2), as ‘essential’ Mixed cryoglobulinemia syndrome (MCs), was classified as autonomous disorder when other well-known immunological, infectious, or neoplastic conditions had been ruled out. Besides the laboratory hallmark, i.e. serum mixed cryoglobulins, very often associated with low complement C4, other distinctive pathological features of MCs are the skin leukocytoclastic vasculitis with frequent multiple organ involvement (1–6, 10–12, 14–17, 29–31). Therefore, the disease is also termed ‘cryoglobulinemic vasculitis’, and classified among systemic small vessel vasculitides, which also includes cutaneous leucocytoclastic vasculitis and Schonlein-Henoch purpura (19).

MCs is clinically characterized be the triad—purpura, weakness, arthralgias— (Table 2) and by numerous organ involvement; namely, membranoproliferative glomerulonephritis, peripheral neuropathy, skin ulcers, diffuse vasculitis, and less frequently neoplastic complications, mainly lymphatic malignancies (2–6, 10–17, 29–31). The prevalence of MCs shows a great geographical heterogeneity; it is more common in Southern than in Northern Europe or North America. This is particularly true for MCs associated with hepatitis C virus (HCV) infection which is also much more diffuse in the same some geographical areas such as the Mediterranean basin countries (5, 6, 10, 32).

The term ‘‘essential’’ is referred to both MoCs and MCs as autonomous conditions when a number of well-known systemic autoimmune, infectious, or neoplastic disorders had been ruled out by careful patient evaluation (1–4, 6, 8, 10) (Table 2). However, in some individuals a definite diagnosis remains very difficult because of their clinical polymorphism. Clinically, both MoCs and MCs may share a number of symptoms with other autoimmune systemic diseases, particularly with primary Sjögren’s disease, rheumatoid arthritis (RA), and Systemic Lupus erythematosus (SLE) (1, 5, 10)(Table 2). Sicca syndrome may be recorded in about half of MCs patients, even if the current classification criteria for primary Sjögren’s disease are satisfied in very few cases (1, 5, 10, 47). Moreover, both primary Sjögren’s disease and MCs may share many symptoms, such as xerostomia and/or xerophthalmia, purpura, arthralgias, RF seropositivity, serum cryoglobulins, and less frequently B-cell lymphoma (1, 5, 10, 47). In these instances, a careful patient clinical assessment may be sufficient for a correct diagnosis on the basis of the following distinctive findings: primary Sjögren’s disease shows specific autoantibody patterns (anti-RoSSA/LaSSB) and histopathological alterations of salivary glands, which are rarely found in MCs; on the contrary, cutaneous leukocytoclastic vasculitis and visceral organ involvement, such as immune-complex-mediated membranoproloferative glomerulonephritis type I (MPGN type I) are typically found in MCs ( 2). In the few cases in which the differential diagnosis may result very difficult, it might be appropriate to classify this condition as overlapping MCs- primary Sjögren’s disease. This condition is often characterized by low rate of serum anti-RoSSA/LaSSB along with increased prevalence of hypocomplementemia, monoclonal/mixed cryoglobulinemia, other autoimmune-lymphoproliferative manifestations, mainly B-cell lymphomas, and overall more severe outcome (48), Hovewer, the risk of malignant lymphoma is significantly increased in cryoglobulinemic vasculitis patients compared to those with Sjögren’s disease, benign B-cell proliferation, and cutaneous hypergammaglobulinaemic vasculitis as reported by Quartuccio et al. (49) and more recently by Breillat et al. (50).

From a practical point of view, the overlapping MCs-primary Sjögren’s disease might be better managed as vasculitic disorder considering its therapeutic and prognostic implications (10).

In MCs patients we can observe the presence of symmetrical, erosive, rheumatoid-like polyarthritis resulting in an overlapping MCs/RA syndrome. In these cases, the detection of serum anti-cyclic citrullinated peptide antibodies, markers of classical seropositive RA, may be a useful tool for differential diagnosis (5, 10). A similar condition can be observed in patients with concomitance of MoCs or MCs and SLE; some MCs characteristics, such as purpuric lesions of the lower limbs with classical leukocytoclastic vasculitis, MPGN type I, and isolated low C4, from one side, and typical histologic pattern of SLE glomerulonephritis, with low levels of both C3 and C4, anti-dsDNA, ANA and anti-ENA seropositivity from the other side, are generally sufficient to differentiate these conditions (5, 10).

Finally, very high levels of cryocrit responsible for clinically overt hyperviscosity syndrome may complicate MoCs; this severe complication is very rare in the course of MCs as well other autoimmune systemic disorders (1, 10, 20, 21, 23–28, 51).

Cryoglobulinemia is a frequent laboratory finding, very often without any clinical relevance. Low serum levels of MoC or MC are detectable in a wide number of acute or chronic infections, as well in autoimmune or lymphoproliferative/neoplastic diseases (1–6).

For a correct evaluation of a patient with cryoglobulinemia the first steps can be crucial (Figure 1, 3). In a subject with either occasional cryoglobulin detection or clinical manifestations suggesting a cryoglobulinemic syndrome, it is necessary to firstly evaluate the immunological composition of the cryoprecipitate, i.e., mono-/mixed (type II/III) cryoglobulinemia (1, 5, 37). At the same time, a careful recording of typical cryoglobulinemia signs and symptoms should be performed in order to classify the serum MoC or MC as asymptomatic or symptomatic (Figure 3, points 1 & 2; Figure 1, Figure 3). As regards cryoglobulin detection, some simple precautions are necessary to avoid false negative/positive results. In particular, the first procedures, i.e. blood sampling, clotting, and serum separation by centrifugation, should invariably be performed at 37 °C, while the cryocrit determination and cryoglobulin characterization should always done at 4 °C, after seven days from the serum isolation (1, 5, 37) (Figure 1). Finally, the cryocrit determination should be done on blood samples without anticoagulation in order to exclude false positive results caused by cryofibrinogenemia (52). Since Ig cold precipitation may be an intermittent phenomenon, it is not rare to observe individuals with typical manifestations of cryoglobulinemia syndrome but without serum cryoglobulins at the first determination; therefore, in these cases periodic re-evaluations are appropriate (1, 5, 37). This particular condition is possibly due to an early Ig precipitation immediately after blood sampling at room temperature, considering that the temperature range (between 4° and 37 °C) and the rapidity of cryoprecipitation are very wide. Alternatively, it may be the expression of the wide variability in the percentage of cryoprecipitable immune-complexes observable either among patients and in single cases during the course of the disease (1, 5, 33, 37, 53).

After isolating and washing the cryoprecipitate, the identification of cryoglobulin components can be carried out by immuno-electrophoresis or immunofixation; these analyses must be performed always at 37 °C to avoid cryoglobulin precipitation/loss during the procedures (1, 5, 37).

Serum cryoglobulin levels, namely cryocrit percent, usually do not correlate with the severity and prognosis of the disease (1, 5). Particularly low cryocrit values may be observed also in severe MCs; while, high serum cryoglobulin concentrations may characterise a paucisymptomatic disease course, with the exception of individuals developing a classical hyperviscosity syndrome, in some cases with a cryogel phenomenon, responsible for severe rheological manifestations This harmful condition may be found in patients with MoCs but very rarely in MCs (1, 5, 37).

In patients with symptomatic cryoglobulinemia (Figure 3, point 3), the definition of MoCs or MCs should be based on some peculiar findings that characterize these distinct disorders. In particular, MoCs may show non-inflammatory thrombotic skin lesions and/or overt hyperviscosity syndrome, while other symptoms such as weakness, purpura, and especially peripheral neuropathy are frequently recorded in both disorders (1, 5, 18, 37). On the other hand, MCs is characterized by purpuric skin lesions secondary to typical leukocytoclastic vasculitis and frequent visceral organ involvement, with tissue deposits of IgG-M immune-complexes and complement at direct IF, as typically found in the cryoglobulienemic membrano-prolipherative glomerulonephritis type I (1, 5, 18, 33, 37).

Finally, for a comprehensive assessment of patients with MoCs or MCs it is important to define the etiopathological domains in which to frame these two disorders. The major disease domains underlying MoCs or MCs are: i. the B-cell lymphoproliferative diseases (Waldenström’s macroglobulinemia, multiple myeloma, B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, and monoclonal gammopathy), ii. some autoimmune systemic disorders, among which the primary Sjögren’s disease, rheumatoid arthritis, and systemic lupus erythematosus, and iii. infectious and toxic agents, more frequently the hepatitis C virus infection (1, 5, 18, 33, 37) (Figure 2). In the absence of underlying well-defined disorder, both MoCs or MCs should be defined as ‘essential’. A careful clinical and serological screening of cryoglobulienemic patients is necessary in all patients, at the referral and at periodic time intervals, especially in the case of rapid onset atypical clinical manifestations, especially given the important therapeutic implications (1, 5, 18, 33, 37).

The clinical syndromes associated to the presence of serum monoclonal or mixed cryoglobulinemia, i.e. MoCs and MCs, must be regarded as two distinct disorders, even if they may share a number of immune-lymphoproliferative and clinical similarities (1, 4, 5, 18) (Tables 2, 3). A part from the rare cases of ‘essential’ MoCs, the presence of underlying lymphoid malignancy is particularly common in MoCs and is instead a late event, much less frequent in MCs (1, 8, 9). The latter is often supported by a low-grade, indolent B-cell lymphoma (8, 9). Moreover, MoCs is less frequently associated with chronic infections or ASD (8, 9), while MCs may be triggered by numerous infectious agents, mainly HCV, in a significant proportion of individuals, and sometimes present in ASD, particularly the Sjögren’s disease (1, 5, 10) (Table 2).

Cryoglobulinemia refers to the mere presence of serum cryo-Ig. This phenomenon is a relatively frequent laboratory finding observable even in apparently healthy individuals, often transient and devoid of clinical significance. In many cases, it may remain asymptomatic; however, its clinical significance is highly context-dependent and should not be underestimated. Only in a limited number of cases does this peculiar in vitro phenomenon represent a true pathological condition, which may in turn conceal an underlying lymphoproliferative/neoplastic, autoimmune, and/or infectious disorder. In current usage, the term cryoglobulinemia is often employed interchangeably to denote both the innocent presence of serum cryoglobulin precipitation (MoC or MC) and the associated clinical syndromes (MoCs or MCs). Therefore, the term “cryoglobulinemia” alone is inadequate for the proper definition of cryoglobulinemic patients. For nosographic, diagnostic, and especially clinical reasons, a universally accepted nomenclature and definition are required. To achieve this, a series of straightforward evaluative steps should be followed. First, the detection of serum cryoglobulins, whether incidental or prompted by suggestive clinical manifestations, must always be followed by isolation and immunologic characterization of the cryoprecipitate as either MoC or MC, along with a comprehensive clinical assessment of the patient and a search for potential underlying or associated disorders, even in apparently asymptomatic cases. In particular, immune-serological, microbiological, and pathological investigations are essential to fully classify both MoC and MC, distinguishing between asymptomatic and symptomatic forms, and between essential and secondary forms when associated with one or more of the aforementioned disease domains.

Patients with asymptomatic serum MoC or MC require careful longitudinal monitoring, both for the potential progression to overt clinical syndromes (MoCs or MCs), as well as those with essential variants for the development of underlying disorder(s). The latter, when present, represent the primary therapeutic challenge, as in the case of B-cell malignancies, HCV or HBV infection, and/or systemic autoimmune diseases such as Sjögren’s disease.

The two main clinical entities, MoCs and MCs (also termed cryoglobulinemic vasculitis), share a wide spectrum of manifestations. Besides the Ig composition of cryoprecipitates, their definitive evaluation requires: i. histopathological assessment of microvascular skin lesions, typically non-inflammatory thrombotic lesions in MoCs and leukocytoclastic vasculitis in MCs, ii. detection of immunoserological abnormalities (e.g., complement consumption and circulating autoantibodies), and iii. evaluation of associated hematologic/lymphoproliferative disorders (predominant in MoCs), infectious, and/or systemic autoimmune diseases (more common in MCs).

Finally, a comprehensive multidisciplinary evaluation of the individual cryoglobulinemic patient is essential to determine the most appropriate therapeutic strategy, based on the distinctive etiopathogenetic mechanisms and prevalent clinical features of two major cryoglobulinemia sub-settings.